A Comprehensive Review of Risk Factor, Mechanism, and Management of Left Ventricular Assist Device-Associated Stroke.

The use of left ventricular assist devices (LVADs) has been increasing in the last decade, along with the number of patients with advanced heart failure refractory to medical therapy. Ischemic stroke and intracranial hemorrhage remain the leading causes of morbidity and mortality in LVAD patients. Despite the common occurrence and the significant outcome impact, underlying mechanisms and management strategies of stroke in LVAD patients are controversial. In this article, we review our current knowledge on pathophysiology and risk factors of LVAD-associated stroke, outline the diagnostic approach, and discuss treatment strategies.

Adapting Clinical Practice of Thrombolysis for Acute Ischemic Stroke Beyond 4.5 Hours: A Review of the Literature.

Several clinical trials have demonstrated that advanced neuroimaging can select patients for recanalization therapy in an extended time window. The favorable functional outcomes and safety profile of these studies have led to the incorporation of neuroimaging in endovascular treatment guidelines, and most recently, also extended to decision making on thrombolysis. Two randomized clinical trials have demonstrated that patients who are not amenable to endovascular thrombectomy within 4.5 hours from symptoms discovery or beyond 4.5 hours from the last-known-well time may also be safely treated with intravenous thrombolysis and have a clinical benefit above the risk of safety concerns. With the growing aging population, increased stroke incidence in the young, and the impact of evolving medical practice, healthcare and stroke systems of care need to adapt continuously to provide evidence-based care efficiently. Therefore, understanding and incorporating appropriate screening strategies is critical for the prompt recognition of potentially eligible patients for extended-window intravenous thrombolysis. Here we review the clinical trial evidence for thrombolysis for acute ischemic stroke in the extended time window and provide a review of new enrolling clinical trials that include thrombolysis intervention beyond the 4.5 hour window.

The impact of COVID-19 on acute ischemic stroke admissions: Analysis from a community-based tertiary care center.

BACKGROUND/OBJECTIVE: To evaluate the impact of the COVID-19 pandemic on hospital admissions and outcomes in patients admitted with acute ischemic stroke. METHODS: Single-center retrospective analysis of patients admitted to the hospital with acute ischemic stroke, between December 1st, 2019 and June 30th, 2020. Outcomes were classified as none-to-minimal disability, moderate-to-severe disability, and death based on discharge disposition, and compared between two time periods: pre-COVID-19 era (December 1st, 2019 to March 11th, 2020) and COVID-19 era (March 12th to June 30th, 2020). We also performed a comparative trend analysis for the equivalent period between 2019 and 2020. RESULTS: Five hundred and seventy-five patients with a mean age (years±SD) of 68±16 were admitted from December 1st, 2019 to June 30th, 2020, with a clinical diagnosis of acute ischemic stroke. Of these, 255 (44.3%) patients were admitted during the COVID-19 era. We observed a 22.1% and 39.5% decline in admission for acute ischemic stroke in April and May 2020, respectively. A significantly higher percentage of patients with acute ischemic stroke received intravenous thrombolysis during the COVID-19 era (p = 0.020). In patients with confirmed COVID-19, we found a higher percentage of older men with preexisting comorbidities such as hyperlipidemia, coronary artery disease, and diabetes mellitus but a lower rate of atrial fibrillation. In addition, we found a treatment delay in both intravenous thrombolysis (median 94.5 min versus 38 min) and mechanical thrombectomy (median 244 min versus 86 min) in patients with confirmed COVID-19 infection. There were no differences in patients' disposition including home, short-term, and long-term facility (p = 0.60). CONCLUSIONS: We observed a reduction of hospital admissions in acute ischemic strokes and some delay in reperfusion therapy during the COVID-19 pandemic. Prospective studies and a larger dataset analysis are warranted.

Influence of Intracerebral Hemorrhage Location on Outcomes in Patients With Severe Intraventricular Hemorrhage.

Background and Purpose- We investigated the prognostic significance of spontaneous intracerebral hemorrhage location in presence of severe intraventricular hemorrhage. Methods- We analyzed diagnostic computed tomography scans from 467/500 (excluding primary intraventricular hemorrhage) subjects from the CLEAR (Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage) III trial. We measured intracerebral hemorrhage engagement with specific anatomic regions, and estimated association of each region with blinded assessment of dichotomized poor stroke outcomes: mortality, modified Rankin Scale score of 4 to 6, National Institutes of Health Stroke Scale score of >4, stroke impact scale score of <60, Barthel Index <86, and EuroQol visual analogue scale score of <50 and <70 at days 30 and 180, respectively, using logistic regression models. Results- Frequency of anatomic region involvement consisted of thalamus (332 lesions, 71.1% of subjects), caudate (219, 46.9%), posterior limb internal capsule (188, 40.3%), globus pallidus/putamen (127, 27.2%), anterior limb internal capsule (108, 23.1%), and lobar (29, 6.2%). Thalamic location was independently associated with mortality (days 30 and 180) and with poor outcomes on most stroke scales at day 180 on adjusted analysis. Posterior limb internal capsule and globus pallidus/putamen involvement was associated with increased odds of worse disability at days 30 and 180. Anterior limb internal capsule and caudate locations were associated with decreased mortality on days 30 and 180. Anterior limb internal capsule lesions were associated with decreased long-term morbidity. Conclusions- Acute intracerebral hemorrhage lesion topography provides important insights into anatomic correlates of mortality and functional outcomes even in severe intraventricular hemorrhage causing obstructive hydrocephalus. Models accounting for intracerebral hemorrhage location in addition to volumes may improve outcome prediction and permit stratification of benefit from aggressive acute interventions. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT00784134.

Heart-Brain Axis: Effects of Neurologic Injury on Cardiovascular Function.

A complex interaction exists between the nervous and cardiovascular systems. A large network of cortical and subcortical brain regions control cardiovascular function via the sympathetic and parasympathetic outflow. A dysfunction in one system may lead to changes in the function of the other. The effects of cardiovascular disease on the nervous system have been widely studied; however, our understanding of the effects of neurological disorders on the cardiovascular system has only expanded in the past 2 decades. Various pathologies of the nervous system can lead to a wide range of alterations in function and structure of the cardiovascular system ranging from transient and benign electrographic changes to myocardial injury, cardiomyopathy, and even cardiac death. In this article, we first review the anatomy and physiology of the central and autonomic nervous systems in regard to control of the cardiovascular function. The effects of neurological injury on cardiac function and structure will be summarized, and finally, we review neurological disorders commonly associated with cardiovascular manifestations.

Third Ventricle Obstruction by Thalamic Intracerebral Hemorrhage Predicts Poor Functional Outcome Among Patients Treated with Alteplase in the CLEAR III Trial.

INTRODUCTION: The Clot Lysis: Evaluating Accelerated Resolution of IVH trial examined whether irrigating the ventricular system with alteplase improved functional outcomes in patients with small intracerebral hemorrhage (ICH) and large intraventricular hemorrhage (IVH). Thalamic ICH location was common and was associated with poor outcome. One possible explanation is thalamic ICH-associated mass effect obstructing the third ventricle. We hypothesized that patients with thalamic ICH obstructing the third ventricle would have worse functional outcomes compared to patients without obstructing lesions. METHODS: ICH obstruction of third ventricle was defined as third ventricle compression on 1 or more axial computed tomography slices visually impeding cerebral spinal fluid flow. If the third ventricle was casted with IVH, it was scored as such. Multivariable logistic regression analyses were used to determine whether obstruction of the third ventricle predicts poor functional outcomes defined as modified Rankin score (mRS) 4-6, higher mRS, and mortality at 180 days. Models were adjusted for thalamic ICH location, ICH volume, IVH volume, age, hydrocephalus, baseline Glasgow coma scale, and percentage of low cerebral perfusion pressures during treatment. RESULTS: Among saline-treated patients, obstruction of the third ventricle by IVH was a significant predictor of higher mRS at 180 days (OR 1.87, CI 1.01-3.47) and mortality at 180 days (OR 2.73, CI 1.27-5.87) while obstruction by ICH was not. In contrast, among alteplase-treated patients, obstruction by ICH was a significant predictor of mRS 4-6 (OR 3.20, CI 1.30-7.88) and higher mRS at 180 days (OR 2.33, CI 1.24-4.35), while obstruction by IVH was not. CONCLUSIONS: Poor outcomes were associated with mass-related obstruction of the third ventricle from thalamic ICH in alteplase-treated patients and from IVH in saline-treated patients. Once the ventricular system is cleared with alteplase, obstruction of cerebral spinal fluid flow from thalamic ICH might become important in functional recovery.

Intraosseous Administration of 23.4% NaCl for Treatment of Intracranial Hypertension.

BACKGROUND/OBJECTIVE: Prompt treatment of acute intracranial hypertension is vital to preserving neurological function and frequently includes administration of 23.4% NaCl. However, 23.4% NaCl administration requires central venous catheterization that can delay treatment. Intraosseous catheterization is an alternative route of venous access that may result in more rapid administration of 23.4% NaCl. METHODS: Single-center retrospective analysis of 76 consecutive patients, between January 2015 and January 2018, with clinical signs of intracranial hypertension received 23.4% NaCl through either central venous catheter or intraosseous access. RESULTS: Intraosseous cannulation was successful on the first attempt in 97% of patients. No immediate untoward effects were seen with intraosseous cannulation. Time to treatment with 23.4% NaCl was significantly shorter in patients with intraosseous access compared to central venous catheter (p < 0.0001). CONCLUSIONS: Intraosseous cannulation resulted in more rapid administration of 23.4% NaCl with no immediate serious complications. Further investigations to identify the clinical benefits and safety of hypertonic medication administration via intraosseous cannulation are warranted.

Antiepileptic drugs in critically ill patients.

BACKGROUND: The incidence of seizures in intensive care units ranges from 3.3% to 34%. It is therefore often necessary to initiate or continue anticonvulsant drugs in this setting. When a new anticonvulsant is initiated, drug factors, such as onset of action and side effects, and patient factors, such as age, renal, and hepatic function, should be taken into account. It is important to note that the altered physiology of critically ill patients as well as pharmacological and nonpharmacological interventions such as renal replacement therapy, extracorporeal membrane oxygenation, and target temperature management may lead to therapeutic failure or toxicity. This may be even more challenging with the availability of newer antiepileptics where the evidence for their use in critically ill patients is limited. MAIN BODY: This article reviews the pharmacokinetics and pharmacodynamics of antiepileptics as well as application of these principles when dosing antiepileptics and monitoring serum levels in critically ill patients. The selection of the most appropriate anticonvulsant to treat seizure and status epileptics as well as the prophylactic use of these agents in this setting are also discussed. Drug-drug interactions and the effect of nonpharmacological interventions such as renal replacement therapy, plasma exchange, and extracorporeal membrane oxygenation on anticonvulsant removal are also included. CONCLUSION: Optimal management of antiepileptic drugs in the intensive care unit is challenging given altered physiology, polypharmacy, and nonpharmacological interventions, and requires a multidisciplinary approach where appropriate and timely assessment, diagnosis, treatment, and monitoring plans are in place.

Cerebrovascular Events After Continuous-Flow Left Ventricular Assist Devices.

BACKGROUND: Cerebrovascular events (CVE) are among the most common and serious complications after implantation of continuous-flow left ventricular assist devices (CF-LVAD). We studied the incidence, subtypes, anatomical distribution, and pre- and post-implantation risk factors of CVEs as well as the effect of CVEs on outcomes after CF-LVAD implantation at our institution. METHODS: Retrospective analysis of clinical and neuroimaging data of 372 patients with CF-LVAD between May 2005 and December 2013 using standard statistical methods. RESULTS: CVEs occurred in 71 patients (19%), consisting of 35 ischemic (49%), 26 hemorrhagic (37%), and 10 ischemic+hemorrhagic (14%) events. History of coronary artery disease and female gender was associated with higher odds of ischemic CVE (OR 2.84 and 2.5, respectively), and diabetes mellitus was associated with higher odds of hemorrhagic CVE (OR 3.12). While we found a higher rate of ischemic CVEs in patients not taking any antithrombotic medications, no difference was found between patients with ischemic and hemorrhagic CVEs. Occurrence of CVEs was associated with increased mortality (HR 1.62). Heart transplantation was associated with improved survival (HR 0.02). In patients without heart transplantation, occurrence of CVE was associated with decreased survival. CONCLUSIONS: LVADs are associated with high rates of CVE, increased mortality, and lower rates of heart transplantation. Further investigations to identify the optimal primary and secondary stroke prevention measures in post-LVAD patients are warranted.

Modafinil attenuates reinstatement of cocaine seeking: role for cystine-glutamate exchange and metabotropic glutamate receptors.

Modafinil may be useful for treating stimulant abuse, but the mechanisms by which it acts to do so are unknown. Indeed, a primary effect of modafinil is to inhibit dopamine transport, which typically promotes rather than inhibits motivated behavior. Therefore, we examined the role of nucleus accumbens extracellular glutamate and the group II metabotropic glutamate receptor (mGluR2/3) in modafinil effects. One group of rats was trained to self-administer cocaine for 10 days and extinguished, then given priming injections of cocaine to elicit reinstatement. Modafinil (300 mg/kg, intraperitoneal) inhibited reinstated cocaine seeking (but did not alter extinction responding by itself), and this effect was prevented by pre-treatment with bilateral microinjections of the mGluR2/3 antagonist LY-341495 (LY) into nucleus accumbens core. No reversal of modafinil effects was seen after unilateral accumbens core LY, or bilateral LY in the rostral pole of accumbens. Next, we sought to explore effects of modafinil on extracellular glutamate levels in accumbens after chronic cocaine. Separate rats were administered non-contingent cocaine, and after 3 weeks of withdrawal underwent accumbens microdialysis. Modafinil increased extracellular accumbens glutamate in chronic cocaine, but not chronic saline-pre-treated animals. This increase was prevented by reverse dialysis of cystine-glutamate exchange or voltage-dependent calcium channel antagonists. Voltage-dependent sodium channel blockade partly attenuated the increase in glutamate, but mGluR1 blockade did not. We conclude that modafinil increases extracellular glutamate in nucleus accumbens from glial and neuronal sources in cocaine-exposed rats, which may be important for its mGluR2/3-mediated antirelapse properties.

End to end stroke triage using cerebrovascular morphology and machine learning.

Background: Rapid and accurate triage of acute ischemic stroke (AIS) is essential for early revascularization and improved patient outcomes. Response to acute reperfusion therapies varies significantly based on patient-specific cerebrovascular anatomy that governs cerebral blood flow. We present an end-to-end machine learning approach for automatic stroke triage. Methods: Employing a validated convolutional neural network (CNN) segmentation model for image processing, we extract each patient's cerebrovasculature and its morphological features from baseline non-invasive angiography scans. These features are used to detect occlusion's presence and the site automatically, and for the first time, to estimate collateral circulation without manual intervention. We then use the extracted cerebrovascular features along with commonly used clinical and imaging parameters to predict the 90 days functional outcome for each patient. Results: The CNN model achieved a segmentation accuracy of 94% based on the Dice similarity coefficient (DSC). The automatic stroke detection algorithm had a sensitivity and specificity of 92% and 94%, respectively. The models for occlusion site detection and automatic collateral grading reached 96% and 87.2% accuracy, respectively. Incorporating the automatically extracted cerebrovascular features significantly improved the 90 days outcome prediction accuracy from 0.63 to 0.83. Conclusion: The fast, automatic, and comprehensive model presented here can improve stroke diagnosis, aid collateral assessment, and enhance prognostication for treatment decisions, using cerebrovascular morphology.

Analgosedation in Critically Ill Adults Receiving Extracorporeal Membrane Oxygenation Support.

Extracorporeal membrane oxygenation (ECMO) is an increasingly utilized intervention for cardiopulmonary failure. Analgosedation during ECMO support is essential to ensure adequate pain and agitation control and ventilator synchrony, optimize ECMO support, facilitate patient assessment, and minimize adverse events. Although the principles of analgosedation are likely similar for all critically ill patients, ECMO circuitry alters medication pharmacodynamics and pharmacokinetics. The lack of clinical guidelines for analgosedation during ECMO, especially at times of medication shortage, can affect patient management. Here, we review pharmacological considerations, protocols, and special considerations for analgosedation in critically ill adults receiving ECMO support.

Hypothermia and brain inflammation after cardiac arrest.

The cessation (ischemia) and restoration (reperfusion) of cerebral blood flow after cardiac arrest (CA) induce inflammatory processes that can result in additional brain injury. Therapeutic hypothermia (TH) has been proven as a brain protective strategy after CA. In this article, the underlying pathophysiology of ischemia-reperfusion brain injury with emphasis on the role of inflammatory mechanisms is reviewed. Potential targets for immunomodulatory treatments and relevant effects of TH are also discussed. Further studies are needed to delineate the complex pathophysiology and interactions among different components of immune response after CA and identify appropriate targets for clinical investigations.

Melatonin enhances the anticonvulsant and proconvulsant effects of morphine in mice: role for nitric oxide signaling pathway.

Melatonin has different interactions with opioids including enhancing their analgesic effect and reversal of opioid tolerance and dependence. Opioids are known to exert dose-dependent anti- and proconvulsant effects in different experimental seizure paradigms. This study investigated the effect of melatonin on biphasic modulation of seizure susceptibility by morphine, in mouse model of pentylenetetrazole (PTZ)-induced clonic seizures. We further investigated the involvement of the nitric oxidergic pathway in this interaction, using a nitric oxide synthase inhibitor, NG-nitro-L-arginine-methyl-ester (L-NAME). Melatonin exerted anticonvulsant effect with doses as high as 40-80 mg/kg, but with a dose far bellow that amount (10 mg/kg), it potentiated both the anticonvulsant and proconvulsant effects of morphine on the PTZ-induced clonic seizures. Possible pharmacokinetic interaction of melatonin and morphine cannot be ruled out in the enhancement of two opposing effects of morphine on seizure threshold. L-NAME (1 mg/kg) reversed the anticonvulsant property of the combination of melatonin (10 mg/kg) plus morphine (0.5 mg/kg). Moreover, L-NAME (5 mg/kg) blocked the enhancing effect of melatonin (10 mg/kg) on proconvulsant activity of morphine (60 mg/kg). Our results indicate that co-administration of melatonin enhances both anti- and proconvulsant effects of morphine via a mechanism that may involve the nitric oxidergic pathway.

Agmatine potentiates morphine-induced conditioned place preference in mice: modulation by alpha2-adrenoceptors.

The effects of agmatine, an endogenous polyamine metabolite formed by decarboxylation of L-arginine, and its combination with morphine on conditioned place preference (CPP) has been investigated in male mice. Our data show that subcutaneous administration of morphine (1-7.5 mg/kg) significantly increases the time spent in the drug-paired compartment in a dose-dependent manner. Intraperitoneal administration of agmatine (1-40 mg/kg) alone does not induce either CPP or conditioned place aversion, while combination of agmatine and subeffective doses of morphine leads to potent rewarding effects. Lower doses of morphine (0.1, 0.05, and 0.01 mg/kg) are able to induce CPP in mice pretreated with agmatine 1, 5, and 10 mg/kg, respectively. Concomitant intraperitoneal administration of UK 14 304 (0.5 mg/kg), a highly selective alpha2-agonist, with per se noneffective dose of morphine (0.5 mg/kg) and also its combination with noneffective doses of agmatine (1 mg/kg) plus morphine (0.05 mg/kg) produces significant CPP. UK 14 304 (0.05, 0.5 mg/kg) alone, or in combination with agmatine (1, 5 mg/kg) have had no effect. We have further investigated the possible involvement of the alpha2-adrenoceptors in the potentiating effect of agmatine on morphine-induced place preference. Selective alpha2-antagonists, yohimbine (0.005 mg/kg) and RX821002 (0.1, 0.5 mg/kg), block the CPP induced by concomitant administration of agmatine (5 mg/kg) and morphine (0.05 mg/kg). Yohimbine (0.001-0.05 mg/kg) or RX821002 (0.05-0.5 mg/kg) alone or in combination with morphine (0.05 mg/kg) or agmatine (5 mg/kg) fail to show any significant place preference or aversion. Our results indicate that pretreatment of animals with agmatine enhances the rewarding properties of morphine via a mechanism which may involve alpha2-adrenergic receptors.

Rewarding properties of sildenafil citrate in mice: role of the nitric oxide-cyclic GMP pathway.

RATIONALE: Sildenafil citrate is widely prescribed for erectile dysfunction and acts by inhibiting phosphodiesterase type-5, resulting in accumulation of cyclic-guanosine monophosphate (cGMP) via activation of nitric oxide synthase (NOS). The nitric oxide (NO) system is relevant to the rewarding effects of various drugs of abuse. Several epidemiologic studies indicate that sildenafil is abused in a recreational fashion. OBJECTIVES: In the present study, the rewarding properties of sildenafil and probable involvement of the NO-cGMP pathway were investigated in adult male NMRI mice. METHODS: The ability of sildenafil citrate (1-40 mg/kg) to produce conditioned place preference (CPP) was studied in an unbiased CPP paradigm. The effects of NO precursor L-arginine, nonselective NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME), and the inhibitor of guanylyl cyclase methylene blue (MB) on sildenafil-induced CPP were assessed. RESULTS: Mice that received sildenafil (20 and 40 mg/kg) in one environment during conditioning phase displayed a preference for this environment. Both L-NAME (5 mg/kg) and MB (1 mg/kg) in combination with sildenafil (20 mg/kg) suppressed the acquisition of sildenafil-induced place preference. Lower and per se noneffective dose of sildenafil (10 mg/kg) and L-arginine (60 mg/kg), when coadministered, exerted a significant place conditioning. CONCLUSIONS: Sildenafil shows rewarding properties that may involve the NO-cGMP pathway.

Involvement of nitric oxide system in enhancement of morphine-induced conditioned place preference by agmatine in male mice.

Agmatine recently has been suggested as a neurotransmitter, is able to interact with various effects of morphine like analgesia and dependence. In this study, the effects of agmatine on rewarding properties of morphine, and the possible involvement of nitric oxide (NO) system has been evaluated in an unbiased conditioned place preference (CPP) paradigm. Agmatine (1, 5 and 10mg/kg, i.p.) alone induced neither CPP nor conditioned place aversion (CPA). Morphine (0.01, 0.05, 0.1 and 0.5mg/kg, s.c.), while unable to show CPP or CPA, induced CPP in mice pretreated with agmatine. L-arginine (200mg/kg, i.p.), a NO precursor, significantly enhanced the effect of agmatine (5mg/kg) on morphine (0.5mg/kg)-induced place preference. NG-nitro-L-arginine methyl ester (L-NAME; 2.5mg/kg, i.p.), a non specific nitric oxide synthase (NOS) inhibitor, and aminoguanidine (50 and 100mg/kg, i.p.), a specific inducible NOS inhibitor, significantly reduced the effect of agmatine (5mg/kg) on morphine (0.5mg/kg)-induced place preference. These results suggest the possible involvement of inducible nitric oxide system in potentiating effects of agmatine on morphine-induced place preference.

Involvement of nitric oxide pathway in the acute anticonvulsant effect of melatonin in mice.

Melatonin, the major hormone produced by the pineal gland, is shown to have anticonvulsant effects. Nitric oxide (NO) is a known mediator in seizure susceptibility modulation. In the present study, the involvement of NO pathway in the anticonvulsant effect of melatonin in pentylenetetrazole (PTZ)-induced clonic seizures was investigated in mice. Acute intraperitoneal administration of melatonin (40 and 80 mg/kg) significantly increased the clonic seizure threshold induced by intravenous administration of PTZ. This effect was observed as soon as 1 min after injection and lasted for 30 min with a peak effect at 3 min after melatonin administration. Combination of per se non-effective doses of melatonin (10 and 20 mg/kg) and nitric oxide synthase (NOS) substrate L-arginine (30, 60 mg/kg) showed a significant anticonvulsant activity. This effect was reversed by NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 30 mg/kg), implying an NO-dependent mechanism for melatonin effect. Pretreatment with L-NAME (30 mg/kg) and N(G)-nitro-L-arginine (L-NNA, 10 mg/kg) inhibited the anticonvulsant property of melatonin (40 and 80 mg/kg) and melatonin 40 mg/kg, respectively. Specific inducible NOS (iNOS) inhibitor aminoguanidine (100 and 300 mg/kg) did not affect the anticonvulsant effect of melatonin, excluding the role of iNOS in this phenomenon, while pretreatment of with 7-NI (50 mg/kg), a preferential neuronal NOS inhibitor, reversed this effect. The present data show an anticonvulsant effect for melatonin in i.v. PTZ seizure paradigm, which may be mediated via NO/L-arginine pathway by constitutively expressed NOS.

Radiosurgery for glomus jugulare tumors: experience treating 16 patients in Iran.

OBJECT: Glomus jugulare tumors (GJT) have traditionally been treated by surgery or fractionated external-beam radiotherapy. The aim of this retrospective study was to determine the tumor control rate, clinical outcome, and short-term complications of stereotactic radiosurgery in subsets of patients who are poor candidates for these procedures, based on age, medical problems, tumor size, or prior treatment failure. METHODS: The Leksell Gamma Knife was used to treat 16 patients harboring symptomatic, residual, recurrent, or unresectable GJTs. The age of the patients ranged from 12 to 77 years (median 46.5 years). Gamma Knife surgery (GKS) was performed as primary treatment in five patients (31.3%). Microsurgery preceded radiosurgery in 10 patients (62.5%) and fractionated radiotherapy in three patients (18.8%). The median tumor volume was 9.8 cm3 (range 1.7-20.6 cm3). The median marginal dose applied to a mean isodose volume of 50% (range 37-70%) was 18 Gy (range 14-20 Gy). Neurological follow-up examinations revealed improved clinical status in 10 patients (62.5%), a stable neurological status in six (37.5%), and no complications. After radiosurgery, follow-up imaging was conducted in 14 patients; the median interval from GKS to the last follow up was 18.5 months (range 4-28 months). Tumor size had decreased in six patients (42.9%), and the volume remained unchanged in the remaining eight (57.1%). None of the tumors increased in volume during the observation period. CONCLUSIONS: According to the authors' experience, GKS represents a useful therapeutic option to control symptoms and may be safely conducted in patients with primary or recurrent GJTs with no death and no acute morbidity. Because of the tumor's naturally slow growth rate, however, long-term follow-up data are needed to establish a cure rate after radiosurgery.