Fourth ventricle outlet obstruction

Fourth ventricle outlet obstruction

The fourth ventricle outlet obstruction (FVOO) is a rare but well-established cause of obstructive tetra-ventricular hydrocephalus, characterizing with dilatation or large cerebrospinal fluid collection of the foramen of Magendie and foramen of Luschka.

Hydrocephalus is classified as noncommunicating and communicating based on whether all ventricular and subarachnoid spaces are communicating. Although the diagnosis between the two different states is crucial, it is difficult in certain conditions. In particular, communicating hydrocephalus and noncommunicating hydrocephalus owing to fourth ventricle outlet obstruction are highly misdiagnosed.

In FVOO, cerebrospinal fluid (CSF) is blocked at the fourth ventricle outlets by a membranous structure in the absence of any additional obstructive organic pathologies. Various terms for referring to FVOO have been used in previous reports, such as fourth ventricle/ventricular outlet obstruction 1) 2) 3) 4), fourth ventricular outflow obstruction 5), membranous obstruction of the fourth ventricle outlet 6) , obstruction of Magendie’s and Luschka’s foramina 7) , obstruction of fourth ventricular exit8) and primary obstruction of the fourth ventricle outlets 9). Far distal obstructive hydrocephalus is a term that includes Dandy Walker or Arnold Chiari malformation, membranous obstruction or fourth ventricle and intercisternal external obstruction of the CSF 10).


The etiology and pathogenesis of FVOO are unclear, although some cases present with a history of meningitis or intraventricular hemorrhage.

In children, it is usually the consequence of posterior cerebral fossa malformations; while in adult, the occlusion is rather acquired than congenital, mostly linked to an inflammatory process, intraventricular hemorrhagehead traumabrain tumors or Arnold-Chiari malformation. However, idiopathic FVOO is extremely rare, and only 6 such cases have been reported in the English literature.

Bai et al., described an extraordinarily rare case of idiopathic FVOO in a 15-year-old patient successfully treated with direct microsurgical excision of the obstruction membrane. Furthermore, the clinical characteristics and treatment for this rare disease were investigated and reviewed 11).


CT ventriculography in infants, and CT cisternography in elder children, may assist to differentiate between FVOO and communicating hydrocephalus. The importance of these tests is for children with MRI suggestive of FVOO related hydrocephalus, but with no clear demonstration of the obstruction site. The implication of this differentiation may be for deciding between treatment of hydrocephalus with a ventriculoperitoneal shunt or with an endoscopic third ventriculostomy 12).


Third ventricle-fourth ventriculostomy is by far the most frequently used technique for cannulation of the aqueduct in a trapped fourth ventricle. In reported cases of , they have introduced a silicone tube stent from below after accessing the fourth ventricle through a small suboccipital craniectomy, ascending it on the aqueduct in order to reach the third ventricle. Management of this infrequently isolated fourth ventricle, but communicated with the rest of ventricular system, remains a challenge for neurosurgeons. Lack of knowledge of the pathophysiology makes it difficult to treat a problem that we do not understand 13).

ETV is a viable option for treatment of patients with FVOO. The high failure rate in infants younger than 6 months of age suggests that ventriculoperitoneal shunting is a favorable option in this age group, rather than ETV. Isolated fourth ventricle is uncommon after ETV in hydrocephalus attributable to FVOO 14).

Suehiro et al., reported the use of neuroendoscopic third ventriculostomy to treat successfully both hydrocephalus and syringomyelia associated with fourth ventricle outlet obstruction. A 27-year-old woman presented with dizziness, headache, and nausea. Magnetic resonance (MR) imaging demonstrated dilation of all ventricles, downward displacement of the third ventricular floor, obliteration of the retrocerebellar cerebrospinal fluid (CSF) space, funnellike enlargement of the entrance of the central canal in the fourth ventricle, and syringomyelia involving mainly the cervical spinal cord. Cine-MR imaging indicated patency of the aqueduct and an absent CSF flow signal in the area of the cistema magna, which indicated obstruction of the outlets of the fourth ventricle. Although results of radioisotope cisternography indicated failure of CSF absorption, neuroendoscopic third ventriculostomy completely resolved all symptoms as well as the ventricular and spinal cord abnormalities evident on MR images. Neuroendoscopic third ventriculostomy is an important option for treating hydrocephalus in patients with fourth ventricle outlet obstruction15).

Case series

Three patients who were 21, 53, and 68 years of age presented with either headaches (isolated or associated with raised intracranial pressure) or vertigo, or a combination of gait disorders, sphincter disorders, and disorders of higher functions. In each case, magnetic resonance (MR) imaging demonstrated hydrocephalus involving the four ventricles (mean transverse diameter of third ventricle 14.15 mm; mean sagittal diameter of fourth ventricle 23.13 mm; and mean ventricular volume 123.92 ml) with no signs of a Chiari Type I malformation (normal posterior fossa dimensions, no herniation of cerebellar tonsils). The diagnosis of obstruction was confirmed using ventriculography (in two patients) and/or MR flow images (in two patients). All patients presented with marked dilation of the foramen of Luschka that herniated into the cisterna pontis. All patients were treated using ETV. No complications were observed. All three patients became asymptomatic during the weeks following the surgical procedure and remained stable at a mean follow-up interval of 36 months. Postoperative MR images demonstrated regression of the hydrocephalus (mean transverse diameter of third ventricle 7.01 mm; mean sagittal diameter of fourth ventricle 16.6 mm; and mean ventricular volume 79.95 ml), resolution of dilation of the foramen of Luschka, and good patency of the ventriculostomy (flow sequences). These results confirm the existence of hydrocephalus caused by idiopathic fourth ventricle outflow obstruction without an associated Chiari Type I malformation, and the efficacy of ETV for this rare indication 16).

Case reports

Duran D, Hadzipasic M, Kahle KT. Mystery Case: Acute hydrocephalus caused by radiographically occult fourth ventricular outlet obstruction. Neurology. 2017 Jan 31;88(5):e36-e37. doi: 10.1212/WNL.0000000000003555. PubMed PMID: 28138085 17).

A 66-year-old woman with gait disturbance and incontinence caused by hydrocephalus underwent ventriculoperitoneal shunt surgery. After 9 months, her fourth ventricle became enlarged and could not be controlled by lowering the shunt pressure. Magnetic resonance imaging (MRI) demonstrated obstruction at the foramen of Magendie, foramina of Luschka, and the cerebral aqueduct. Endoscopic surgery for aqueduct plasty with third ventriculostomy was planned. Because the aqueduct was observed to open spontaneously, only the standard third ventriculostomy was performed. When MRI findings were reviewed retrospectively, an unnatural space was observed between the lower cranial nerves and cerebellar hemisphere that grew along with the fourth ventricular enlargement. This space was determined by MRI cisternography to be the cystic membrane ballooning out from the foramen of Luschka. The primary hydrocephalus likely resulted from fourth ventricle outlet obstruction.

Enlargement of the whole ventricular system with an expanded space between the lower cranial nerves and cerebellar hemisphere can be caused by fourth ventricle outlet obstruction. In such cases, preoperative evaluation of anatomic architecture and cerebrospinal fluid obstruction using MRI cisternography is essential and leads to a successful endoscopic strategy 18).

A 3-year old boy without any remarkable medical history presented with a headache and vomiting. Computed tomography (CT) images, which had incidentally been taken 2 years previously due to a minor head injury, showed no abnormality. Magnetic resonance imaging on admission showed tetra-ventricular hydrocephalus associated with the dilatation of the fourth ventricle outlets, without any obstructive lesions. However, CT ventriculography, involving contrast medium injection through a ventricular catheter, suggested mechanical obstruction of the cerebrospinal fluid (CSF) at the fourth ventricle outlets. Thus, the patient was diagnosed with FVOO and ETV was performed; the hydrocephalus was subsequently resolved. Although hydrocephalus recurred 1 year postoperatively, re-ETV for the highly stenosed fenestration successfully resolved this condition.

ETV should be considered for FVOO treatment, particularly in idiopathic cases without CSF malabsorption 19).

A 15-year-old girl with amenorrhea and a several-week history of headache. After the diagnosis of membranous obstruction of the foramen of Magendie suggested by MRI, suboccipital craniotomy for removal of the membrane was carried out. The patient made an excellent postoperative recovery, and postoperative phase-contrast MRI demonstrated patent cerebrospinal fluid (CSF) pathways at the level of the foramina of Magendie and Luschka. We believe that this case is of interest because of the unequivocal evidence on MRI studies of the occlusion of the foramen of Magendie preoperatively, and because of the dramatic postoperative MRI findings demonstrating the effectiveness of the surgical procedure both in terms of ventricular size and CSF flow characterization 20).


1) , 13)

Ferrer E, de Notaris M. Third ventriculostomy and fourth ventricle outlets obstruction. World Neurosurg. 2013 Feb;79(2 Suppl):S20.e9-13. doi: 10.1016/j.wneu.2012.02.017. Epub 2012 Feb 10. Review. PubMed PMID: 22381846.
2) , 14)

Mohanty A, Biswas A, Satish S, Vollmer DG. Efficacy of endoscopic third ventriculostomy in fourth ventricular outlet obstruction. Neurosurgery. 2008 Nov;63(5):905-13; discussion 913-4. doi: 10.1227/01.NEU.0000333262.38548.E1. PubMed PMID: 19005381.
3) , 12)

Roth J, Ben-Sira L, Udayakumaran S, Constantini S. Contrast ventriculo-cisternography: an auxiliary test for suspected fourth ventricular outlet obstruction. Childs Nerv Syst. 2012 Mar;28(3):453-9. doi: 10.1007/s00381-011-1639-y. Epub 2011 Nov 29. PubMed PMID: 22124573.
4) , 15)

Suehiro T, Inamura T, Natori Y, Sasaki M, Fukui M. Successful neuroendoscopic third ventriculostomy for hydrocephalus and syringomyelia associated with fourth ventricle outlet obstruction. Case report. J Neurosurg. 2000 Aug;93(2):326-9. PubMed PMID: 10930021.
5) , 16)

Karachi C, Le Guérinel C, Brugières P, Melon E, Decq P. Hydrocephalus due to idiopathic stenosis of the foramina of Magendie and Luschka. Report of three cases. J Neurosurg. 2003 Apr;98(4):897-902. PubMed PMID: 12691419.
6) , 20)

Huang YC, Chang CN, Chuang HL, Scott RM. Membranous obstruction of the fourth ventricle outlet. A case report. Pediatr Neurosurg. 2001 Jul;35(1):43-7. Review. PubMed PMID: 11490191.

Carpentier A, Brunelle F, Philippon J, Clemenceau S. Obstruction of Magendie’s and Luschka’s foramina. Cine-MRI, aetiology and pathogenesis. Acta Neurochir (Wien). 2001;143(5):517-21; discussion 521-2. PubMed PMID: 11482704.

Choi JU, Kim DS, Kim SH. Endoscopic surgery for obstructive hydrocephalus. Yonsei Med J. 1999 Dec;40(6):600-7. PubMed PMID: 10661039.

Longatti P, Fiorindi A, Martinuzzi A, Feletti A. Primary obstruction of the fourth ventricle outlets: neuroendoscopic approach and anatomic description. Neurosurgery. 2009 Dec;65(6):1078-85; discussion 1085-6. doi: 10.1227/01.NEU.0000360133.29217.44. PubMed PMID: 19934967.

Oertel JM, Mondorf Y, Schroeder HW, Gaab MR. Endoscopic diagnosis and treatment of far distal obstructive hydrocephalus. Acta Neurochir (Wien). 2010 Feb;152(2):229-40. doi: 10.1007/s00701-009-0494-z. Epub 2009 Aug 26. PubMed PMID: 19707715.

Bai J, Yu Q, Sun X, Xiao H, Wang K, Sun F, Sui Q. Hydrocephalus Due to Idiopathic Fourth Ventricle Outflow Obstruction. J Craniofac Surg. 2019 Mar 6. doi: 10.1097/SCS.0000000000005314. [Epub ahead of print] PubMed PMID: 30865115.

Duran D, Hadzipasic M, Kahle KT. Mystery Case: Acute hydrocephalus caused by radiographically occult fourth ventricular outlet obstruction. Neurology. 2017 Jan 31;88(5):e36-e37. doi: 10.1212/WNL.0000000000003555. PubMed PMID: 28138085.

Shimoda Y, Murakami K, Narita N, Tominaga T. Fourth Ventricle Outlet Obstruction with Expanding Space on the Surface of Cerebellum. World Neurosurg. 2017 Apr;100:711.e1-711.e5. doi: 10.1016/j.wneu.2017.01.088. Epub 2017 Jan 31. PubMed PMID: 28153613.

Ishi Y, Asaoka K, Kobayashi H, Motegi H, Sugiyama T, Yokoyama Y, Echizenya S, Itamoto K. Idiopathic fourth ventricle outlet obstruction successfully treated by endoscopic third ventriculostomy: a case report. Springerplus. 2015 Sep 30;4:565. doi: 10.1186/s40064-015-1368-x. eCollection 2015. PubMed PMID: 26543700; PubMed Central PMCID: PMC4627988.

Dentatorubrothalamic tract

Dentatorubrothalamic tract

The dentatothalamic tract (or dentatorubrothalamic tract) is a tract which connects the dentate nucleusand the thalamus while sending collaterals to the red nucleus.

The term “dentatorubrothalamocortical” is sometimes used to emphasize termination in the cerebral cortex.

The dentatothalamic tract or dentatorubrothalamic tract (DRTT) originates from the dentate nucleus in the cerebellum and terminates in the contralateral ventral lateral nucleus (VL) of the thalamus after decussating to the contralateral red nucleus. Identification of the DRTT is difficult due to the fact that it is a long, multisynaptic, neural tract crossing to the opposite hemisphere.

The dentato-rubro-thalamic tract (DRTT) regulates motor control, connecting the cerebellum to the thalamus. This tract is modulated by deep brain stimulation in the surgical treatment of medically refractory tremor, especially in essential tremor, where high-frequency stimulation of the thalamus can improve symptoms. The DRTT is classically described as a decussating pathway, ascending to the contralateral thalamus. However, the existence of a nondecussating (i.e. ipsilateral) DRTT in humans was recently demonstrated, and these tracts are arranged in distinct regions of the superior cerebellar peduncle.

Petersen et al., hypothesized that the ipsilateral DRTT is connected to specific thalamic nuclei and therefore may have unique functional relevance. The goals of this study were to confirm the presence of the decussating and nondecussating DRTT pathways, identify thalamic termination zones of each tract, and compare whether structural connectivity findings agree with functional connectivity. Diffusion-weighted imaging was used to perform probabilistic tractography of the decussating and nondecussating DRTT in young healthy subjects from the Human Connectome Project(n = 91) scanned using multi-shell diffusion-weighted imaging (270 directions; TR/TE = 5500/89 ms; spatial resolution = 1.25 mm isotropic). To define thalamic anatomical landmarks, a segmentation procedure based on the Morel stereotactic atlas of the human thalamus was employed, and DRTT targeting was quantified based on the proportion of streamlines arriving at each nucleus. In parallel, functional connectivity analysis was performed using resting-state functional MRI (TR/TE = 720/33 ms; spatial resolution = 2 mm isotropic). It was found that the decussating and nondecussating DRTTs have significantly different thalamic endpoints, with the former preferentially targeting relatively anterior and lateral thalamic nuclei, and the latter connected to more posterior and medial nuclei (p < 0.001). Functional and structural connectivity measures were found to be significantly correlated (r = 0.45, p = 0.031). These findings provide new insight into pathways through which unilateral cerebellum can exert bilateral influence on movement and raise questions about the functional implications of ipsilateral cerebellar efferents 1).

Pineda-Pardo et al., published a cohort of 24 essential tremor patients before and 3 months after unilateral transcranial magnetic resonance guided focused ultrasound targeting at the posteroventral part of the VIM. Microstructural changes along the dentatorubrothalamic tract (DRTT) were quantified by means of probabilistic tractography, and later related to the clinical improvement of the patients at 3-months and at 1-year after the intervention. In addition the changes along two neighboring tracts, that is, the corticospinal tract and the medial lemniscus, were assessed, as well as the relation between these changes and the presence of side effects. Thalamic lesions produced local and distant alterations along the trajectory of the DRTT, and each correlated with clinical improvement. Regarding side effects, gait imbalance after thalamotomy was associated with greater impact on the DRTT, whereas the presence of paresthesias was significantly related to a higher overlap between the lesion and the medial lemniscus. This work represents the largest series describing the microstructural changes following transcranial MR-guided focused ultrasound thalamotomy in essential tremor. These results suggest that clinical benefits are specific for the impact on the cerebello-thalamo-cortical pathway, thus reaffirming the potential of tractography to aid thalamotomy targeting 2).

Diffusion tensor imaging was performed at 1.5-T using a synergy-L sensitivity encoding head coil. DRTTs were obtained by selection of fibers passing through three regions of interest (the dentate nucleus, the superior cerebellar peduncle, and the contralateral red nucleus) from 41 healthy volunteers. Probabilistic mapping was obtained from the highest probabilistic location at 2.3 mm above the anterior commissure-posterior commissure level.

DRTTs of all subjects, which originated from the dentate nucleus, ascended through the junction of the superior cerebellar peduncle and the contralateral red nucleus and then terminated at the VL nucleus of the thalamus. The highest probabilistic location for the DRTT at the thalamus was compatible with the location of the VL nucleus.

Kwon et al identified the DRTT in the human brain using probabilistic tractography. Our results could be useful in research on movement control 3)

The dentatorubrothalamic tract (DRTT) is the major efferent cerebellar pathway arising from the dentate nucleus (DN) and decussating to the contralateral red nucleus (RN) and thalamus. Surprisingly, hemispheric cerebellar output influences bilateral limb movements. In animals, uncrossed projections from the DN to the ipsilateral RN and thalamus may explain this phenomenon. The aim of a study was to clarify the anatomy of the dentatorubrothalamic connections in humans.

Meola et al applied advanced deterministic fiber tractography to a template of 488 subjects from the Human Connectome Project (Q1-Q3 release, WU-Minn HCP consortium) and validated the results with microsurgical dissection of cadaveric brains prepared according to Klingler’s method.

The authors identified the “classic” decussating DRTT and a corresponding nondecussating path (the nondecussating DRTT, nd-DRTT). Within each of these 2 tracts some fibers stop at the level of the RN, forming the dentatorubro tract and the nondecussating dentatorubro tract. The left nd-DRTT encompasses 21.7% of the tracts and 24.9% of the volume of the left superior cerebellar peduncle, and the right nd-DRTT encompasses 20.2% of the tracts and 28.4% of the volume of the right superior cerebellar peduncle.

The connections of the DN with the RN and thalamus are bilateral, not ipsilateral only. This affords a potential anatomical substrate for bilateral limb motor effects originating in a single cerebellar hemisphere under physiological conditions, and for bilateral limb motor impairment in hemispheric cerebellar lesions such as ischemic stroke and hemorrhage, and after resection of hemispheric tumors and arteriovenous malformations. Furthermore, when a lesion is located on the course of the dentatorubrothalamic system, a careful preoperative tractographic analysis of the relationship of the DRTT, nd-DRTT, and the lesion should be performed in order to tailor the surgical approach properly and spare all bundles 4).



Petersen KJ, Reid JA, Chakravorti S, Juttukonda MR, Franco G, Trujillo P, Stark AJ, Dawant BM, Donahue MJ, Claassen DO. Structural and functional connectivity of the nondecussating dentato-rubro-thalamic tract. Neuroimage. 2018 Aug 1;176:364-371. doi: 10.1016/j.neuroimage.2018.04.074. Epub 2018 May 4. PubMed PMID: 29733955; PubMed Central PMCID: PMC6002752.

Pineda-Pardo JA, Martínez-Fernández R, Rodríguez-Rojas R, Del-Alamo M, Hernández F, Foffani G, Dileone M, Máñez-Miró JU, De Luis-Pastor E, Vela L, Obeso JA. Microstructural changes of the dentato-rubro-thalamic tract after transcranial MR guided focused ultrasound ablation of the posteroventral VIM in essential tremor. Hum Brain Mapp. 2019 Mar 13. doi: 10.1002/hbm.24569. [Epub ahead of print] PubMed PMID: 30865338.

Kwon HG, Hong JH, Hong CP, Lee DH, Ahn SH, Jang SH. Dentatorubrothalamic tract in human brain: diffusion tensor tractography study. Neuroradiology. 2011 Oct;53(10):787-91. doi: 10.1007/s00234-011-0878-7. Epub 2011 May 3. PubMed PMID: 21547376.

Meola A, Comert A, Yeh FC, Sivakanthan S, Fernandez-Miranda JC. The nondecussating pathway of the dentatorubrothalamic tract in humans: human connectome-based tractographic study and microdissection validation. J Neurosurg. 2015 Oct 9:1-7. [Epub ahead of print] PubMed PMID: 26452117.



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).



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.

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.

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.

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.

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.
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