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Kenneth C. Liu, Robert M. Starke, Christopher R. Durst, Tony R. Wang, Dale Ding, R. Webster Crowley and Steven A. Newman

OBJECTIVE

Idiopathic intracranial hypertension (IIH) may cause blindness due to elevated intracranial pressure (ICP). Venous sinus stenosis has been identified in select patients, leading to stenting as a potential treatment, but its effects on global ICP have not been completely defined. The purpose of this pilot study was to assess the effects of venous sinus stenting on ICP in a small group of patients with IIH.

METHODS

Ten patients for whom medical therapy had failed were prospectively followed. Ophthalmological examinations were assessed, and patients with venous sinus stenosis on MR angiography proceeded to catheter angiography, venography with assessment of pressure gradient, and ICP monitoring. Patients with elevated ICP measurements and an elevated pressure gradient across the stenosis were treated with stent placement.

RESULTS

All patients had elevated venous pressure (mean 39.5 ± 14.9 mm Hg), an elevated gradient across the venous sinus stenosis (30.0 ± 13.2 mm Hg), and elevated ICP (42.2 ± 15.9 mm Hg). Following stent placement, all patients had resolution of the stenosis and gradient (1 ± 1 mm Hg). The ICP values showed an immediate decrease (to a mean of 17.0 ± 8.3 mm Hg), and further decreased overnight (to a mean of 8 ± 4.2 mm Hg). All patients had subjective and objective improvement, and all but one improved during follow-up (median 23.4 months; range 15.7–31.6 months). Two patients developed stent-adjacent stenosis; retreatment abolished the stenosis and gradient in both cases. Patients presenting with papilledema had resolution on follow-up funduscopic imaging and optical coherence tomography (OCT) and improvement on visual field testing. Patients presenting with optic atrophy had optic nerve thinning on follow-up OCT, but improved visual fields.

CONCLUSIONS

For selected patients with IIH and venous sinus stenosis with an elevated pressure gradient and elevated ICP, venous sinus stenting results in resolution of the venous pressure gradient, reduction in ICP, and functional, neurological, and ophthalmological improvement. As patients are at risk for stent-adjacent stenosis, further follow-up is necessary to determine long-term outcomes and gain an understanding of venous sinus stenosis as a primary or secondary pathological process behind elevated ICP.

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Dale Ding, Robert M. Starke, Christopher R. Durst, R. Webster Crowley and Kenneth C. Liu

Increasing evidence supports dural venous sinus stenosis as the patho-etiology of pseudotumor cerebri (PTC) in a subset of affected patients. In this video, we demonstrate our technique for 1) diagnostic venous manometry to identify a flow-limiting stenosis of the transverse sinus in a PTC patient; and 2) successful treatment of the patient with venous stenting across the structural and physiological stricture in the dural sinus. The pressure gradient decreased from 20 mmHg pre-stent to 3 mmHg post-stent. In order to further quantify the effect of our intervention, concurrent intracranial pressure monitoring was performed.

The video can be found here: http://youtu.be/auxRg17F8yI.

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Robert M. Starke, Dale Ding, Christopher R. Durst, R. Webster Crowley and Kenneth C. Liu

Dissecting vertebral artery (VA) aneurysms are difficult to obliterate when the parent artery cannot be safely occluded. In this video, we demonstrate a combined microsurgical and endovascular treatment technique for a ruptured, dissecting VA aneurysm incorporating the origin of the posterior inferior cerebellar artery (PICA). We first performed a PICA-PICA side-to-side bypass to preserve flow through the right PICA. An endovascular approach was then utilized to embolize the proximal portion of the aneurysm from the right VA and the distal portion of the aneurysm from the left VA.

The video can be found here: http://youtu.be/dkkKsX2BiJI.

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Dongmei Yang, Yuxia Han, Jianfeng Zhang, Christopher Ding, John Anagli and Donald M. Seyfried

Object

This study investigates a potential novel application of a selective cathepsin B and L inhibitor in experimental intracerebral hemorrhage (ICH) in rats.

Methods

Forty adult male Wistar rats received an ICH by stereotactic injection of 100 μl of autologous blood or sham via needle insertion into the right striatum. The rats were treated with a selective cathepsin B and L inhibitor (CP-1) or 1% dimethyl sulfoxide sterile saline intravenously at 2 and 4 hours after injury. Modified neurological severity scores were obtained and corner turn tests were performed at 1, 4, 7, and 14 days after ICH. The rats were sacrificed at 3 and 14 days after ICH for immunohistological analysis of tissue loss, neurogenesis, angiogenesis, and apoptosis.

Results

The animals treated with CP-1 demonstrated significantly reduced apoptosis as well as tissue loss compared with controls (p < 0.05 for each). Neurological function as assessed by modified neurological severity score and corner turn tests showed improvement after CP-1 treatment at 7 and 14 days (p < 0.05). Angiogenesis and neurogenesis parameters demonstrated improvement after CP-1 treatment compared with controls (p < 0.05) at 14 days.

Conclusions

This study is the first report of treatment of ICH with a selective cathepsin B and L inhibitor. Cathepsin B and L inhibition has been shown to be beneficial after cerebral ischemia, likely because of its upstream regulation of the other prominent cysteine proteases, calpains, and caspases. While ICH may not induce a major component of ischemia, the cellular stress in the border zone may activate these proteolytic pathways. The observation that cathepsin B and L blockade is efficacious in this model is provocative for further investigation.

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Dongmei Yang, Robert A. Knight, Yuxia Han, Kishor Karki, Jianfeng Zhang, Christopher Ding, Michael Chopp and Donald M. Seyfried

Object

Longitudinal multiparametric MR imaging and histological studies were performed on simvastatin- or atorvastatin-treated rats to evaluate vascular repair mechanisms after experimental intracerebral hemorrhage (ICH).

Methods

. Primary ICH was induced in adult Wistar rats by direct infusion of 100 μl of autologous blood into the striatal region adjacent to the subventricular zone. Atorvastatin (2 mg/kg), simvastatin (2 mg/kg), or phosphate-buffered saline was given orally at 24 hours post-ICH and continued daily for 7 days. The temporal evolution of ICH in each group was assessed by MR imaging measurements of T2, T1sat, and cerebral blood flow in brain areas corresponding to the bulk of the hemorrhage (core) and edematous border (rim). Rats were killed after the final MR imaging examination at 28 days, and histological studies were performed. A small group of sham-operated animals was also studied. Neurobehavioral testing was performed in all animals. Analysis of variance methods were used to compare results from the treatment and control groups, with significance inferred at p ≤ 0.05.

Results

. Using histological indices, animals treated with simvastatin and atorvastatin had significantly increased angiogenesis and synaptogenesis in the hematoma rim compared with the control group (p ≤ 0.05). The statin-treated animals exhibited significantly increased cerebral blood flow in the hematoma rim at 4 weeks, while blood-brain barrier permeability (T1sat) and edema (T2) in the corresponding regions were reduced. Both statin-treated groups showed significant neurological improvement from 2 weeks post-ICH onward.

Conclusions

The results of the present study demonstrate that simvastatin and atorvastatin significantly improve the recovery of rats from ICH, possibly via angiogenesis and synaptic plasticity. In addition, in vivo multiparametric MR imaging measurements over time can be effectively applied to the experimental ICH model for longitudinal assessment of the therapeutic intervention.

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Nasser Mohammed, Dale Ding, Yi-Chieh Hung, Zhiyuan Xu, Cheng-Chia Lee, Hideyuki Kano, Roberto Martínez-Álvarez, Nuria Martínez-Moreno, David Mathieu, Mikulas Kosak, Christopher P. Cifarelli, Gennadiy A. Katsevman, L. Dade Lunsford, Mary Lee Vance and Jason P. Sheehan

OBJECTIVE

The role of primary stereotactic radiosurgery (SRS) in patients with medically refractory acromegaly who are not operative candidates or who refuse resection is poorly understood. The aim of this multicenter, matched cohort study was to compare the outcomes of primary versus postoperative SRS for acromegaly.

METHODS

The authors reviewed an International Radiosurgery Research Foundation database of 398 patients with acromegaly who underwent SRS and categorized them into primary or postoperative cohorts. Patients in the primary SRS cohort were matched, in a 1:2 ratio, to those in the postoperative SRS cohort, and the outcomes of the 2 matched cohorts were compared.

RESULTS

The study cohort comprised 78 patients (median follow-up 66.4 months), including 26 and 52 in the matched primary and postoperative SRS cohorts, respectively. In the primary SRS cohort, the actuarial endocrine remission rates at 2 and 5 years were 20% and 42%, respectively. The Cox proportional hazards model showed that a lower pre-SRS insulin-like growth factor–1 level was predictive of initial endocrine remission (p = 0.03), whereas a lower SRS margin dose was predictive of biochemical recurrence after initial remission (p = 0.01). There were no differences in the rates of radiological tumor control (p = 0.34), initial endocrine remission (p = 0.23), biochemical recurrence after initial remission (p = 0.33), recurrence-free survival (p = 0.32), or hypopituitarism (p = 0.67) between the 2 matched cohorts.

CONCLUSIONS

Primary SRS has a reasonable benefit-to-risk profile for patients with acromegaly in whom resection is not possible, and it has similar outcomes to endocrinologically comparable patients who undergo postoperative SRS. SRS with medical therapy in the latent period can be used as an alternative to surgery in selected patients who cannot or do not wish to undergo resection.

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Diogo Cordeiro, Zhiyuan Xu, Gautam U. Mehta, Dale Ding, Mary Lee Vance, Hideyuki Kano, Nathaniel Sisterson, Huai-che Yang, Douglas Kondziolka, L. Dade Lunsford, David Mathieu, Gene H. Barnett, Veronica Chiang, John Lee, Penny Sneed, Yan-Hua Su, Cheng-chia Lee, Michal Krsek, Roman Liscak, Ahmed M. Nabeel, Amr El-Shehaby, Khaled Abdel Karim, Wael A. Reda, Nuria Martinez-Moreno, Roberto Martinez-Alvarez, Kevin Blas, Inga Grills, Kuei C. Lee, Mikulas Kosak, Christopher P. Cifarelli, Gennadiy A. Katsevman and Jason P. Sheehan

OBJECTIVE

Recurrent or residual adenomas are frequently treated with Gamma Knife radiosurgery (GKRS). The most common complication after GKRS for pituitary adenomas is hypopituitarism. In the current study, the authors detail the timing and types of hypopituitarism in a multicenter, international cohort of pituitary adenoma patients treated with GKRS.

METHODS

Seventeen institutions pooled clinical data obtained from pituitary adenoma patients who were treated with GKRS from 1988 to 2016. Patients who had undergone prior radiotherapy were excluded. A total of 1023 patients met the study inclusion criteria. The treated lesions included 410 nonfunctioning pituitary adenomas (NFPAs), 262 cases of Cushing’s disease (CD), and 251 cases of acromegaly. The median follow-up was 51 months (range 6–246 months). Statistical analysis was performed using a Cox proportional hazards model to evaluate factors associated with the development of new-onset hypopituitarism.

RESULTS

At last follow-up, 248 patients had developed new pituitary hormone deficiency (86 with NFPA, 66 with CD, and 96 with acromegaly). Among these patients, 150 (60.5%) had single and 98 (39.5%) had multiple hormone deficiencies. New hormonal changes included 82 cortisol (21.6%), 135 thyrotropin (35.6%), 92 gonadotropin (24.3%), 59 growth hormone (15.6%), and 11 vasopressin (2.9%) deficiencies. The actuarial 1-year, 3-year, 5-year, 7-year, and 10-year rates of hypopituitarism were 7.8%, 16.2%, 22.4%, 27.5%, and 31.3%, respectively. The median time to hypopituitarism onset was 39 months.

In univariate analyses, an increased rate of new-onset hypopituitarism was significantly associated with a lower isodose line (p = 0.006, HR = 8.695), whole sellar targeting (p = 0.033, HR = 1.452), and treatment of a functional pituitary adenoma as compared with an NFPA (p = 0.008, HR = 1.510). In multivariate analyses, only a lower isodose line was found to be an independent predictor of new-onset hypopituitarism (p = 0.001, HR = 1.38).

CONCLUSIONS

Hypopituitarism remains the most common unintended effect of GKRS for a pituitary adenoma. Treating the target volume at an isodose line of 50% or greater and avoiding whole-sellar radiosurgery, unless necessary, will likely mitigate the risk of post-GKRS hypopituitarism. Follow-up of these patients is required to detect and treat latent endocrinopathies.