Protective effects of histone deacetylase 6 specific inhibitor tubastatin A on subarachnoid hemorrhage in rats and the underlying mechanisms / 中南大学学报(医学版)

OBJECTIVES@#Subarachnoid hemorrhage (SAH) is a serious cerebrovascular disease. Early brain injury (EBI) and cerebral vasospasm are the main reasons for poor prognosis of SAH patients. The specific inhibitor of histone deacetylase 6 (HDAC6), tubastatin A (TubA), has been proved to have a definite neuroprotective effect on a variety of animal models of acute and chronic central nervous system diseases. However, the neuroprotective effect of TubA on SAH remains unclear. This study aims to investigate the expression and localization of HDAC6 in the early stage of SAH, and to evaluate the protective effects of TubA on EBI and cerebral vasospasm after SAH and the underlying mechanisms.@*METHODS@#Adult male SD rats were treated with modified internal carotid artery puncture to establish SAH model. In the first part of the experiment, rats were randomly divided into 6 groups: a sham group, a SAH-3 h group, a SAH-6 h group, a SAH-12 h group, a SAH-24 h group, and a SAH-48 h group. At 3, 6, 12, and 24 h after SAH modeling, the injured cerebral cortex of rats in each group was taken for Western blotting to detect the expression of HDAC6. In addition, the distribution of HDAC6 in the cerebral cortex of the injured side was measured by immunofluorescence double staining in SAH-24 h group rats. In the second part, rats were randomly divided into 4 groups: a sham group, a SAH group, a SAH+TubAL group (giving 25 mg/kg TubA), and a SAH+TubAH group (giving 40 mg/kg TubA). At 24 h after modeling, the injured cerebral cortex tissue was taken for Western blotting to detect the expression levels of HDAC6, endothelial nitric oxide synthase (eNOS), and inducible nitric oxide synthase (iNOS), terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining to detect apoptosis, and hematoxylin and eosin (HE) staining to detect the diameter of middle cerebral artery.@*RESULTS@#The protein expression of HDAC6 began to increase at 6 h after SAH (P<0.05), peaked at 24 h (P<0.001), and decreased at 48 h, but there was still a difference compared with the sham group (P<0.05). HDAC6 is mainly expressed in the cytoplasm of the neurons. Compared with the sham group, the neurological score was decreased significantly and brain water content was increased significantly in the SAH group (both P<0.01). Compared with the SAH group, the neurological score was increased significantly and brain water content was decreased significantly in the SAH+TubAH group (both P<0.05), while the improvement of the above indexes was not significant in the SAH+TubAL group (both P>0.05). Compared with the sham group, the expression of eNOS was significantly decreased (P<0.01) and the expressions of iNOS and HDAC6 were significantly increased (P<0.05 and P<0.01, respectively) in the SAH group. Compared with the SAH group, the expression of eNOS was significantly increased, and iNOS and HDAC6 were significantly decreased in the SAH+TubA group (all P<0.05). Compared with the SAH group, the number of TUNEL positive cells was significantly decreased and the diameter of middle cerebral artery was significantly increased in the SAH+TubA group (both P<0.05) .@*CONCLUSIONS@#HDAC6 is mainly expressed in neurons and is up-regulated in the cerebral cortex at the early stage of SAH. TubA has protective effects on EBI and cerebral vasospasm in SAH rats by reducing brain edema and cell apoptosis in the early stage of SAH. In addition, its effect of reducing cerebral vasospasm may be related to regulating the expression of eNOS and iNOS.

Chemical Angioplasty with Nitroglycerin for Vasospasm after Subarachnoid Hemorrhage: Case Series and Review

Introduction Vasospasm is a common and potentially devastating complication in patients with subarachnoid hemorrhage, causing high morbidity and mortality. There is no effective and consistent way to prevent or treat cerebral vasospasm capable of altering the morbidity and mortality of this complication. Animal and human studies have attempted to show improvement in aneurysmal vasospasm. Some sought their prevention; others, the treatment of already installed vasospasm. Some achieved only angiographic improvement without clinical correlation, others achieved both, but with ephemeral duration or at the expense of very harmful associated effects. Endovascular techniques allow immediate and aggressive treatment of cerebral vasospasm and include methods such as mechanical and chemical angioplasty. These methods have risks and benefits. Objectives To analyze the results of chemical angioplasty using nitroglycerin (GTN). In addition, to performa comprehensive review and analysis of aneurysmal vasospasm. Methods We describe our series of 77 patients treated for 8 years with angioplasty for vasospasm, either mechanical (with balloon), chemical (with GTN) or both. Results Eleven patients received only balloon; 37 received only GTN; 29 received both. Forty-four patients (70.1%) evolved with delayed cerebral ischemia and 19 died (mortality of 24.7%). Two deaths were causally related to the rupture of the vessel by the balloon. The only predictors of poor outcome were the need for external ventricular drainage in the first hours of admission, and isolated mechanical angioplasty. Conclusions Balloon angioplasty has excellent results, but it is restricted to proximal vessels and is not without complications. Chemical angioplasty using nitroglycerin has reasonable but short-lived results and further research is needed about it. It is restricted to vasospasm angioplasties only in hospitals, like ours, where better and more potent vasodilator agents are not available.

Vasoespasmo cerebral relacionado a hiperglicemia en paciente con hemorragia subaracnoidea aneurismatica: caso clínico y revisión de la literatura / Cerebral vasospasm related to hyperglycemia in patient with subaracoid aneurysmatic haemorrhage: clinical case and review of literature

La hemorragia subaracnoidea aneurismática es un fenómeno muy grave asociado a altas tasas de morbimortalidad, esta depende de la severidad inicial. El control de la glucosa es uno de los cuidados que se debe tener en cuenta ya que está estrechamente relacionada con el desarrollo de las complicaciones secundarias. Se presenta el caso clínico de un paciente con antecedente de diabetes tipo 2 tratada irregularmente, que presentó una hemorragía subaracnoidea aneurismática, complicada con vasoespasmo cerebral, infarto, hidrocefalia secundaria e infecciones pulmonares en relación a hiperglicemia durante el post operatorio de difícil y refractario tratamiento. Exponemos los mecanismos fisiopatológicos que ocasionan alteraciones de los fenómenos de autorregulación vascular cerebral y en consecuencia trastornos de la perfusión cerebral que decaen sobre el estado neurológico del paciente, sobresaltando que el control de la glucemia en el transcurso de una hemorragia subaracnoidea puede ayudar a un mejor desenlace de los pacientes.

Aneurysmal subarachnoid hemorrhage is a very serious phenomenon associated with high rates of morbidity and mortality, this depends on the initial severity. The control of glucose is one of the care that must be taken into account since it is closely related to the development of secondary complications. We present the clinical case of a patient with a history of type 2 diabetes treated irregularly, who presented an aneurysmal subarachnoid hemorrhage, complicated by cerebral vasospasm, infarction, secondary hydrocephalus and pulmonary infections in relation to hyperglycemia during the post-operative period of difficult and refractory treatment. We expose the pathophysiological mechanisms that cause alterations in the cerebral vascular self-regulation phenomena and consequently cerebral perfusion disorders that decrease the neurological state of the patient, highlighting that the control of glycemia in the course of a subarachnoid hemorrhage can help a better outcome of the patients.

Eficácia e segurança da milrinona no tratamento do vasoespasmo cerebral após hemorragia subaracnóidea: uma revisão sistemática / Efficacy and safety of milrinone in the treatment of cerebral vasospasm after subarachnoid hemorrhage: a systematic review

RESUMO Objetivo: Revisar sistematicamente a evidência atual da eficácia de milrinona no tratamento do vasoespasmo cerebral após hemorragia subaracnóidea. Métodos: Triaram-se as bases de dados Pubmed®, Cochrane e Embase quanto a artigos publicados entre abril de 2001 e fevereiro de 2019. Dois revisores independentes realizaram uma triagem metodológica da qualidade e a extração dos dados dos estudos. Resultados: Encontraram-se 22 estudos considerados relevantes, sendo que apenas um deles era um ensaio randomizado controlado. Os estudos demonstraram acentuada heterogeneidade e debilidade de seus critérios metodológicos. A maioria dos pacientes apresentava vasoespasmo moderado a grave. O principal método para diagnóstico do vasoespasmo foi a angiografia. Em três estudos, realizou-se administração de milrinona por via intra-arterial; em nove estudos, a administração foi endovenosa, e, em seis estudos, utilizaram-se ambas as vias de administração. A via intratecal foi utilizada em dois estudos, em um estudo, a administração foi realizada via cisterna e, em um estudo, a via de administração foi a endovascular. Os efeitos colaterais de milrinona foram descritos em seis estudos. Vinte e um estudos indicaram a resolução do vasoespasmo. Conclusão: A evidência atual indica que o uso de milrinona teve um papel no tratamento do vasoespasmo após hemorragia subaracnóidea aneurismática. Contudo, só foi realizado um ensaio randomizado controlado, com baixo nível de qualidade. Nossos achados indicam a necessidade de futuros estudos randomizados controlados com desfechos centrados no paciente, com o fim de proporcionar recomendações definitivas.

ABSTRACT Objective: To systematically review the current evidence on the efficacy of milrinone in the treatment of cerebral vasospasm after subarachnoid hemorrhage. Methods: The Pubmed®, Cochrane and Embase databases were screened for articles published from April 2001 to February 2019. Two independent reviewers performed the methodological quality screening and data extraction of the studies. Results: Twenty-two studies were found to be relevant, and only one of these was a randomized control trial. Studies showed marked heterogeneity and weaknesses in key methodological criteria. Most patients presented with moderate to severe vasospasm. Angiography was the main method of diagnosing vasospasm. Intra-arterial administration of milrinone was performed in three studies, intravenous administration was performed in nine studies, and both routes of administration in six studies; the intrathecal route was used in two studies, the cisternal route in one study and endovascular administration in one study. The side effects of milrinone were described in six studies. Twenty-one studies indicated resolution of vasospasm. Conclusion: The current evidence indicates that milrinone may have a role in treatment of vasospasm after aneurysmal subarachnoid hemorrhage. However, only one randomized control trial was performed, with a low quality level. Our findings indicate the need for future randomized control trials with patient-centered outcomes to provide definitive recommendations.

Effect of magnesium sulphate and milrinone on cerebral vasospasm after aneurysmal subarachnoid hemorrhage: a randomized study / Efeitos do sulfato de magnésio e da milrinona sobre o vasoespasmo cerebral após hemorragia subaracnoidea por aneurisma: estudo randômico

Abstract Background: Aneurysmal subarachnoid hemorrhage is an important cause of premature death and disability worldwide. Magnesium sulphate is shown to have a neuroprotective effect and it reverses cerebral vasospasm. Milrinone is also used in the treatment of cerebral vasospasm. The aim of the present study was to compare the effect of prophylactic magnesium sulphate and milrinone on the incidence of cerebral vasospasm after subarachnoid hemorrhage. Methods: The study included 90 patients with aneurysmal subarachnoid hemorrhage classified randomly (by simple randomization) into two groups: magnesium sulphate was given as an infusion of 500 mg.day-1 without loading dose for 21 days. Group B: milrinone was given as an infusion of 0.5 µg.kg-1.min-1 without loading dose for 21 days. The cerebral vasospasm was diagnosed by mean cerebral blood flow velocity in the involved cerebral artery (mean flow velocity ≥ 120 cm.s-1), neurological deterioration by Glasgow coma scale, or angiography (the decrease in diameter of the involved cerebral artery >25%). Results: The mean cerebral blood flow velocity decreased significantly in the magnesium group compared to milrinone group through Day 7, Day 14 and Day 21 (p < 0.001). The incidence of cerebral vasospasm decreased significantly with magnesium compared to milrinone (p = 0.007). The Glasgow coma scale significantly improved in the magnesium group compared to milrinone group through Day 7, Day 14 and Day 21 (p = 0.036, p = 0.012, p = 0.016, respectively). The incidence of hypotension was higher with milrinone than magnesium (p = 0.012). Conclusions: The incidence of cerebral vasospasm after aneurysmal subarachnoid hemorrhage was significantly lower and Glasgow coma scale significantly better with magnesium when compared to milrinone. Milrinone was associated with a higher incidence of hypotension and requirement for dopamine and norepinephrine when compared to magnesium.

Resumo Justificativa: A hemorragia subaracnoidea por aneurisma é uma importante causa de morte prematura e de incapacidade em todo o mundo. O sulfato de magnésio mostra um efeito neuroprotetor e reverte o vasoespasmo cerebral. A milrinona também é usada no tratamento de vasoespasmo cerebral. O objetivo do presente estudo foi comparar o efeito profilático do sulfato de magnésio e da milrinona sobre a incidência de vasoespasmo cerebral após hemorragia subaracnoidea. Métodos: O estudo incluiu 90 pacientes com hemorragia subaracnoidea por aneurisma randomicamente distribuídos (randomização simples) em dois grupos: sulfato de magnésio foi administrado em infusão de 500 mg.dia-1 sem dose de ataque durante 21 dias. O Grupo B recebeu milrinona em infusão de 0,5 µg.kg-1·min-1 sem dose de ataque durante 21 dias. O vasoespasmo cerebral foi diagnosticado pela velocidade média do fluxo sanguíneo cerebral na artéria cerebral envolvida (velocidade média do fluxo ≥ 120 cm.s-1), a deterioração neurológica por escala de coma de Glasgow ou angiografia (diminuição do diâmetro da artéria cerebral envolvida > 25%). Resultados: A velocidade média do fluxo sanguíneo cerebral diminuiu significativamente no grupo magnésio em comparação com o grupo milrinona nos dias 7, 14 e 21 (p < 0,001). A incidência de vasoespasmo cerebral diminuiu significativamente com o magnésio em comparação com milrinona (p = 0,007). A escala de coma de Glasgow melhorou significativamente no grupo magnésio em comparação com o grupo milrinona nos dias 7, 14 e 21 (p = 0,036, p = 0,012, p = 0,016, respectivamente). A incidência de hipotensão foi maior com milrinona do que com magnésio (p = 0,012). Conclusões: A incidência de vasoespasmo cerebral após hemorragia subaracnoidea por aneurisma foi significativamente menor e a escala de coma de Glasgow significativamente melhor com magnésio em comparação com milrinona. A milrinona foi associada a uma maior incidência de hipotensão e necessidade de dopamina e norepinefrina em comparação com o magnésio.

Fluoxetine is Neuroprotective in Early Brain Injury via its Anti-inflammatory and Anti-apoptotic Effects in a Rat Experimental Subarachnoid Hemorrhage Model / 神经科学通报·英文版

Fluoxetine, an anti-depressant drug, has recently been shown to provide neuroprotection in central nervous system injury, but its roles in subarachnoid hemorrhage (SAH) remain unclear. In this study, we aimed to evaluate whether fluoxetine attenuates early brain injury (EBI) after SAH. We demonstrated that intraperitoneal injection of fluoxetine (10 mg/kg per day) significantly attenuated brain edema and blood-brain barrier (BBB) disruption, microglial activation, and neuronal apoptosis in EBI after experimental SAH, as evidenced by the reduction of brain water content and Evans blue dye extravasation, prevention of disruption of the tight junction proteins zonula occludens-1, claudin-5, and occludin, a decrease of cells staining positive for Iba-1, ED-1, and TUNEL and a decline in IL-1β, IL-6, TNF-α, MDA, 3-nitrotyrosine, and 8-OHDG levels. Moreover, fluoxetine significantly improved the neurological deficits of EBI and long-term sensorimotor behavioral deficits following SAH in a rat model. These results indicated that fluoxetine has a neuroprotective effect after experimental SAH.

Evaluation of the Accuracy in Maximum Intensity Projection Images of Cerebral Computed Tomographic Angiography for the Diagnosis of Cerebral Vasospasm Following Subarachnoid Hemorrhage, in Comparison to Digital Subtraction Angiography

OBJECTIVE: The purpose of this retrospective study is to determine the accuracy of maximum intensity projection (MIP) images of computed tomographic angiography (CTA) for diagnosis of cerebral vasospasm (CV) following subarachnoid hemorrhage (SAH) compared with that of digital subtraction angiography (DSA). MATERIALS AND METHODS: For patients admitted to our hospital for SAH, MIP images of CTA and DSA were checked at admission, and images were taken again 1 week later. This protocol was used in 39 cases. MIP images of CTA and DSA examinations were reviewed by two independent readers. RESULTS: Accuracy of MIP images of CTA in various arterial segments, using DSA as the gold standard: the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy for different segments varied from 84 to 97, 33–100, 84–100%, 25–85, and 79–97%, respectively, for readers. Accuracy of CTA in various vasospasm severity, using DSA as the gold standard: the sensitivity, specificity, PPV, NPV, and accuracy for different vasospasm severity varied from 44 to 100, 69–100, 36–100%, 61–100, and 88–100%, respectively, for readers. Accuracy of CTA in central segments versus peripheral segments, using DSA as the gold standard: the sensitivity, specificity, PPV, NPV, and accuracy for central segments and peripheral segments varied from 90 to 94, 68–83, 93–97%, 56–69, and 87–93%, respectively, for readers. CONCLUSION: MIP imaging of CTA is a useful modality when diagnosing CV after SAH.

Bilateral Infarction of the Recurrent Arteries of Heubner Following Clipping of an Anterior Communicating Artery Aneurysm

A 50-year-old woman reported to the emergency department with thunderclap headache and vomiting. Non-enhanced brain computed tomography (CT) showed a subarachnoid hemorrhage of Hunt-Hess Grade II and Fisher Grade III. Brain angiography CT and transfemoral cerebral angiography (TFCA) revealed an aneurysm of the anterior communicating artery. A direct neck clipping was performed using the pterional approach. The post-operation CT was uneventful. Six days postoperatively, the patient became lethargic. The mean velocity (cm/s) of the middle cerebral artery peaked at 173 cm/s on the right side and 167 cm/s on the left. A TFCA revealed decreased perfusion in both recurrent arteries of Heubner (RAH), but no occlusion in either. Intra-arterial nimodipine injection was administered. On the 7th postoperative day, CT demonstrated a newly developed low-density lesion in the RAH territory bilaterally. The cause of the infarction was attributed to decreased perfusion caused by cerebral vasospasm. The patient was discharged with no definite neurologic deficit except for mild cognitive disorder.

Síndrome de vasoconstricción cerebral reversible: Presentación como hemorragia subaracnoidea de la convexidad / Reversible Cerebral Vasoconstriction: Subarachnoid Convexity Hemorrhage

Objetivo: El propósito de este estudio es describir las características clínicas, epidemiológicas e imaginológicas de 5 pacientes con diagnóstico de síndrome de vasoconstricción reversible. Métodos: Se hizo una evaluación retrospectiva de las historias clínicas de cinco pacientes con clínica e imágenes compatibles con síndrome de vasoconstricción cerebral reversible en un hospital de alta complejidad de la ciudad de Medellín. Resultados: Los cinco casos correspondían a mujeres con una edad promedio de 50 años. En un caso se identificó como posible agente causal el consumo de bebidas energizantes con alto contenido de taurina. Todos los pacientes se presentaron con hemorragia subaracnoidea en la convexidad y evolucionaron de forma favorable. Conclusión: El síndrome de vasoconstricción cerebral reversible debe ser uno de los diagnósticos diferenciales etiológicos de hemorragia subaracnoidea de la convexidad; se presenta predominantemente en mujeres entre la cuarta y sexta década de la vida y usualmente tiene un curso benigno.

Objective: The purpose of this study is to describe the clinical, epidemiological and imaging characteristics of 5 patients with a diagnosis of reversible vasoconstriction syndrome. Methods: A retrospective evaluation of the clinical records of 5 patients with clinical and imaging diagnosis of reversible cerebral vasoconstriction syndrome was carried out in a high complexity hospital in the city of Medellín. Results: The five cases were women with an average age of 50 years. In one case, the consumption of energy drinks with a high taurine content was identified as a possible causative agent. All cases presented with brain convexity subarachnoid haemorrhage. The clinical outcome was favorable. Conclusion: The reversible cerebral vasoconstriction syndrome should be included in the differential diagnosis of convexity subarachnoid haemorrhage. It occurs predominantly in women between the fourth and sixth decade of life and usually has a benign course.

Factores de riesgo para vasoespasmo cerebral en pacientes con hemorragia subaracnoidea espontánea / Risk Factors for Cerebral Vasospasm in Patients with Spontaneous Subarachnoid Hemorrhage

Objetivos: Establecer la asociación de vasoespasmo cerebral detectado por Doppler transcraneal y la condición clínica, de acuerdo con la escala de la Federación Mundial de Sociedades de Neurocirugía, y con otros factores de riesgo en pacientes con hemorragia subaracnoidea espontánea. Materiales y métodos: Estudio observacional retrospectivo de casos y controles, con 141 pacientes diagnosticados con hemorragia subaracnoidea espontánea a quienes se les realizó Doppler transcraneal de seguimiento entre el 8 de marzo de 2011 y el 15 de marzo de 2015. Del total de pacientes se escogieron 47 con vasoespasmo detectado por Doppler transcraneal y 2 controles, sin vasoespasmo, por cada caso (94 pacientes). En las historias clínicas y las imágenes de los pacientes se estableció la asociación entre la detección de vasoespasmo por Doppler transcraneal con la condición clínica neurológica en el momento del examen, y otros factores de riesgo. Para el análisis de las variables cualitativas se utilizaron frecuencias absolutas y relativas. Para variables cuantitativas se utilizó la prueba de Shapiro Wilk. Los datos con distribución normal se presentan con medias y desviaciones estándar y aquellos sin distribución normal con medianas y rangos intercuartiles. Se evaluó la homogeneidad entre los dos grupos a través de la prueba de Chi cuadrado y el test de homogeneidad de varianzas (Levene) de acuerdo con el tipo de variable. Se consideró estadísticamente significativa una p ≤ 0,05. Resultados: El análisis bivariado no demostró resultados estadísticamente significativos en la relación entre la condición clínica neurológica y el vasoespasmo, pero sí encontró que pacientes menores de 50 años de edad presentaron más vasoespasmo (OR de 3,55 [95 % IC; 1,52-7,39]), y p: 0,003 que los de mayor edad. Conclusiones: Los pacientes menores de 50 años de edad tienen más riesgo de desarrollar vasoespasmo y no existe asociación entre la condición clínica y los resultados del Doppler transcraneal.

Objectives: Establish the association between cerebral vasospasm, detected by transcranial doppler, with the clinical condition according to the scale of the World Federation of Neurosurgical Societies (WFNS) and other risk factors in patients with spontaneous subarachnoid hemorrhage. Materials and methods: This is an observational retrospective case-control study, including 141 patients with a diagnosis of spontaneous subarachnoid hemorrhage who underwent transcranial doppler monitoring in the radiology department of the University Hospital San Vicente Foundation (HUSVF) from 8 March 2011 to 15 March 2015. Of the total number of patients with subarachnoid hemorrhage, 47 cases with vasospasm, detected by transcranial Doppler, and two controls without vasospasm (94 patients) were consecutively chosen. Subsequently, we review the medical records and images stored in the hospital´s radiology department and established the association between vasospasm detection by trasncranial Doppler with clinical neurological status at the time of the study and other risk factors. For the analysis of the qualitative variables, absolute and relative frequencies were used. Quantitative variables were tested for normal distribution with a Shapiro Wilk test. Data with normal distribution were presented with means and standard deviations and those without normal distribution with medians and interquartile ranges. Homogeneity between the two groups were evaluated by Chi-square test and test for homogeneity of variances, Levene's test, according to the type of variable (qualitative and quantitative respectively). Results were considered statistically significant if p ≤ 0.05. Results: Data from 141 patients (47 cases and 94 controls) were analyzed. The bivariate analysis didn´t show statistically significant results in the relationship between vasospasm and clinical neurological condition but found that patients younger than 50 years had more vasospasm. In the adjusted model for patients with this age, the OR was 3.55 (95 % CI, 1.52-7.39) and p: 0.003 when compared with older patients. Conclusions: This study found that patients under 50 have a higher risk of developing vasospasm compared with older patients and that there is no association between clinical condition and the results of transcranial Doppler.

Intracranial aneurysms clipping in Rwanda, can it be done? What are the challenges?

Background: Intracranial aneurysms are vascular abnormalities that cause outpouching of the arterial wall [1]. Although they are not uncommon, there is scanty information regarding intracranial aneurysms in Africa [2]. Intracranial aneurysms are often asymptomatic until they cause symptoms and signs resulting from mass compression and/ or spillage of blood products into the arachnoid space. Currently available diagnostic tools are computed tomography (CT) angiography, magnetic resonance angiography (MRA) and intra-arterial digital subtraction angiography (IADSA) [1]. In our setting we continue to diagnose and achieve clipping of intracranial aneurysms amongst the currently available choices of managing intracranial aneurysms.Objectives: To establish the feasibility and reflect on the challenges of clipping intracranial aneurysms in our settings. To raise awareness among health professionals and the general population.Methods: This is a retrospective case series of 5 patients diagnosed with intracranial aneurysms at King Faisal Hospital and Kigali University Teaching Hospital from October 2014 to October 2015. Available diagnostic methods used are the computed tomography (CT) angiography and/ or magnetic resonance angiography (MRA). We have excluded cases that were diagnosed with intracranial aneurysm at autopsy.Results: Five patients met inclusion criteria for our study. We describe case by case, the choices of therapeutic measures, the challenges encountered during their management and their outcome.Conclusion: Despite the challenges, intracranial aneurysms are treatable in Rwanda with good outcome. However, there is still lack of awareness about this pathology

Treatment of Cerebral Vasospasm in an Infant Using a Modified Dotter Technique

An 8-month old female presented with spontaneous subarachnoid hemorrhage and was treated successfully with endovascular coil embolization of the ruptured aneurysm. Transcranial Doppler ultrasound performed four days later demonstrated middle cerebral artery (MCA) velocities greater than 350 cm/sec on the right and greater than 200 cm/sec on the left, despite medical management. The patient demonstrated no focal neurological deficits, though examination was limited by our patient's sedation and intubation. Angiography revealed severe vasospasm of the supraclinoid internal carotid and MCA territories, bilaterally. The vasospasm was refractory to the administration of intra-arterial verapamil. Balloon angioplasty was attempted, but the device could not be advanced safely due to the small size of the patient's vessels and the stiffness of the device. A microcatheter (0.0165" diameter) was advanced over a J-shaped soft microwire (0.014" diameter) to perform mechanical angioplasty in the internal carotid artery and MCA vessels bilaterally. Dramatic improvement was seen angiographically and on transcranial Doppler, and no complications were seen.

Feasibility and Safety of Mild Therapeutic Hypothermia in Poor-Grade Subarachnoid Hemorrhage: Prospective Pilot Study

Therapeutic hypothermia (TH) improves the neurological outcome in patients after cardiac arrest and neonatal hypoxic brain injury. We studied the safety and feasibility of mild TH in patients with poor-grade subarachnoid hemorrhage (SAH) after successful treatment. Patients were allocated randomly to either the TH group (34.5°C) or control group after successful clipping or coil embolization. Eleven patients received TH for 48 hours followed by 48 hours of slow rewarming. Vasospasm, delayed cerebral ischemia (DCI), functional outcome, mortality, and safety profiles were compared between groups. We enrolled 22 patients with poor-grade SAH (Hunt & Hess Scale 4, 5 and modified Fisher Scale 3, 4). In the TH group, 10 of 11 (90.9%) patients had a core body temperature of 95% of the 48-hour treatment period. Fewer patients in the TH than control group (n = 11, each) had symptomatic vasospasms (18.1% vs. 36.4%, respectively) and DCI (36.3% vs. 45.6%, respectively), but these differences were not statistically significant. At 3 months, 54.5% of the TH group had a good-to-moderate functional outcome (0–3 on the modified Rankin Scale [mRS]) compared with 9.0% in the control group (P = 0.089). Mortality at 1 month was 36.3% in the control group compared with 0.0% in the TH group (P = 0.090). Mild TH is feasible and can be safely used in patients with poor-grade SAH. Additionally, it may reduce the risk of vasospasm and DCI, improving the functional outcomes and reducing mortality. A larger randomized controlled trial is warranted.

Traumatic Intracerebral and Subarachnoid Hemorrhage Due to a Ruptured Pseudoaneurysm of Middle Meningeal Artery Accompanied by a Medial Sphenoid Wing Dural Arteriovenous Fistula / 대한신경손상학회지

Traumatic pseudoaneurysms of middle meningeal artery (MMA) and medial sphenoid wing dural arteriovenous fistula (dAVF) are rare. These lesions usually result from traumatic brain injury, and associated with skull fracture. In this paper, the authors report a case of a patient with a ruptured traumatic pseudoaneurysm of MMA and medial sphenoid wing dAVF presented with an intracerebral hemorrhage in the left temporal region and subarachnoid hemorrhage. These lesions were completely obliterated by endovascular treatment, and the patient was recovered without any neurologic deficit. However, 18-day after the procedure, delayed neurologic deficits were developed due to cerebral vasospasm.

Endovascular Treatment of Symptomatic Vasospasm after Aneurysmal Subarachnoid Hemorrhage: A Three-year Experience

OBJECTIVE: The cause of severe clinical vasospasm after aneurysmal subarachnoid hemorrhage remains unknown, despite extensive research over the past 30 years. However, the intra-arterial administration of vasodilating agents and balloon angioplasty have been successfully used in severe refractory cerebral vasospasm. MATERIALS AND METHODS: We retrospectively analyzed the data of 233 patients admitted to our institute with aneurysmal subarachnoid hemorrhage (SAH) over the past 3 years. RESULTS: Of these, 27 (10.6%) developed severe symptomatic vasospasm, requiring endovascular therapy. Vasospasm occurred at an average of 5.3 days after SAH. A total of 46 endovascular procedures were performed in 27 patients. Endovascular therapy was performed once in 18 (66.7%) patients, 2 times in 4 (14.8%) patients, 3 or more times in 5 (18.5%) patients. Intra-arterial vasodilating agents were used in 44 procedures (27 with nimodipine infusion, 17 with nicardipine infusion). Balloon angioplasty was performed in only 2 (7.4%) patients. The Average nimodipine infusion volume was 2.47 mg, and nicardipine was 3.78 mg. Most patients recovered after the initial emergency room visit. Two patients (7.4%) worsened, but there were no deaths. CONCLUSION: With advances in endovascular techniques, administration of vasodilating agents and balloon angioplasty reduces the morbidity and mortality of vasospasm after aneurysmal SAH.

Vasoespasmo cerebral y déficit isquémico tardío en la hemorragia subaracnoídea aneurismática: guías para su manejo clínico / Cerebral vasospasm and delayed ischemic deficit in the aneurysmal subarachnoid hemorrhage: guidelines to its clinical management

La presente revisión del tema Vasoespasmo y Déficit Isquémico Cerebral tardío (DIT) en la Hemorragia subaracnoidea aneurismática tiene como objetivo actualizar su manejo, basado en las hipótesis mas aceptadas que se han logrado para explicar su patogénesis. Se efectúa una introducción con conceptos generales, se revisan las bases patogénicas del Vasoespasmo y se plantea su manejo, tomando en cuenta su diagnóstico, monitorización, profilaxis y manejo avanzado de acuerdo a las últimas Guías de Manejo Clínico y según medicina basada en las evidencias.

The objective of the present review on cerebral vasospasm and cerebral delayed isquemic deficit due to subarachnoid haemorrhage secondary to ruptured cerebral aneurysm, is to update their management, based on the most accepted pathophysiological hypotesis explaining their pathogenetic mechanisms. An introduction is performed presenting general concepts, review of the most recent research works explaining their pathogenesis, and the management is stated touching diagnosis, monitoring, prophylaxis, and advanced management according with the last clinical guidelines for his management using medicine based on evidences.

Ergotismo del sistema nervioso central: Reporte de dos muertes maternas asociadas a vasoespasmo cerebral por medicamentos derivados del ergot en Antioquia, Colombia, y revisión de la literatura / Ergotism of the central nervous system: Report of two maternal deaths associated with cerebral vasospasm due to ergot-derived drugs in Antioquia, Colombia, and review of the literature

Objetivo: presentar dos casos de muerte materna asociados al uso de medicamentos derivados del ergot (ergotismo agudo severo), y realizar una revisión de la literatura de la presentación de eventos adversos en el sistema nervioso central en puérperas expuestas a estos medicamentos. Materiales y métodos: se presentan dos casos de muerte materna posparto, el primero se asoció al uso de bromocriptina para supresión de lactancia y el segundo al uso metilergometrina para controlar hemorragia poscesárea. Las pacientes fueron atendidas en instituciones de tercer nivel de complejidad en la ciudad de Medellín, Colombia. Se realizó revisión de la literatura, registrada en la base de datos Medline vía PubMed. Los términos empleados para la búsqueda fueron: derivados del ergot, bromocriptina, angeítis cerebral posparto, ergotismo, enfermedad vascular cerebral posparto. Se buscaron, sin límite de tiempo, reportes de caso, reportes de series de caso y revisiones de tema. Se buscaron informes o alertas de seguridad de agencias reguladoras tales como: la Federal Drugs Administration (FDA), la European Medicines Agency (EMA) y del Instituto Nacional de Vigilancia de Medicamentos y Alimentos (Invima). Se consultaron artículos en inglés, francés y español. Resultados: se incluyeron 16 publicaciones que cumplieron con los criterios de búsqueda. Se lograron identificar 33 casos. Dos fueron fatales, uno asociado al uso de metilergonovina venosa para el alumbramiento y el otro a ergometrina oral usado como abortivo en la semana 20 de gestación. En las neuroimágenes predominan los hallazgos isquémicos (sugestivos de vasoespasmo cerebral). En tres casos se reportó hemorragia intracerebral, uno de estos fue un caso fatal. Los síntomas más frecuentes de presentación fueron la cefalea intensa, seguida de la convulsión. Solo en nueve casos se logró identificar el antecedente de hipertensión o preeclampsia, y en cuatro migraña. La indicación para el uso de bromocriptina en todos los casos fue suprimir la lactancia. En los tres casos reportados en que se usó metilergonovina fue para realizar alumbramiento. En el sistema de farmacovigilancia colombiano no se encontraron reportes de eventos adversos serios asociados a estos medicamentos. Conclusión: se debe reconocer el ergotismo del sistema nervioso central en el puerperio por el uso de medicamentos tales como la bromocriptina y la metilergonovina, como una entidad potencialmente fatal. Es importante crear una cultura de reporte de eventos adversos serios de estos medicamentos en nuestro país.

Objective: To report two cases of maternal death associated with ergot-derived drugs (acute sever ergotism), and to conduct and review of the literature on central nervous system adverse events during the postpartum period in women exposed to these medications. Materials and methods: Two cases of maternal death during the postpartum period. The first was associated with the use of bromocriptine for breast milk suppression, and the second was associated with the use of methylergometrine for the control of bleeding after Cesarean section. The patients received care at Level III institutions in the city of Medellín, Colombia. A review of the literature was conducted in the Medline database through Pubmed. The terms used for the search were: ergot derivatives, bromocriptine, postpartum cerebralangiitis, ergotism, postpartum cerebral vascular disease. The search was conducted without a time limitation and included, case reports, case series reports, and reviews. The search also included safety reports or alerts from regulatory agencies such as the FDA, the European Medicines Agency (EMA), and Invima. Articles in English, French and Spanish were reviewed. Results: Overall, 16 publications that met the search criteria were included, and 33 cases were identified. Two of the cases were fatal, one associated with the use of intravenous methylergonovine for delivery and the second one was associated with the use of oral ergometrine to induce abortion at 20 weeks of gestation. Neuroimaging studies show, predominantly, ischemic findings (suggestive of cerebral vasospasm). In three cases, intracranial haemorrhage was reported, and one of the three cases was fatal. The most frequent presenting symptoms were intense headache, followed by seizures. It was possible to identify a history of hypertension and/or preeclampsia only in nine cases, and a history of migraine in four. The vast majority of patients were otherwise healthy. In all the cases, the indication for using bromocriptine was breast milk suppression. In the three reported cases in which methylergonovine was used, the indication was to assist delivery. No reports of serious adverse events associated with these drugs were found in the Colombian pharmacovigilance system. Conclusion: Ergotism of the central nervous system due to the use of drugs such as bromocriptine and methylergonovine must be recognised during the postpartum period because it is life-threatening. It is important to create a culture of reporting of serious adverse events associated with these medications in our country.

Hemorragia subaracnóidea espontânea não aneurismática: perimesencefálica versus não perimesencefálica / Non-aneurysmal spontaneous subarachnoid hemorrhage: perimesencephalic versus non-perimesencephalic

RESUMO Objetivo: Comparar a evolução clínica da hemorragia subaracnóidea perimesencefálica com a da hemorragia subaracnóidea não perimesencefálica. Métodos: Estudo retrospectivo, que incluiu pacientes portadores de hemorragia subaracnóidea sem causa conhecida em um hospital terciário localizado na região norte de Portugal. Os dados epidemiológicos, clínicos e de imagem foram analisados estatisticamente, levando em conta a divisão dos pacientes em duas categorias: hemorragia subaracnóidea perimesencefálica e hemorragia subaracnóidea não perimesencefálica. Resultados: Cumpriram os critérios de inclusão 62 pacientes, 46,8% deles com hemorragia subaracnóidea perimesencefálica e 53,2% com hemorragia subaracnóidea não perimesencefálica. As caraterísticas demográficas, assim como os antecedentes clínicos, foram similares entre os grupos. As complicações foram observadas mais comumente no grupo com hemorragia subaracnóidea não perimesencefálica, sendo que 84,8% desses pacientes tiveram, no mínimo, uma complicação, comparados a 48,3% dos pacientes com hemorragia subaracnóidea perimesencefálica. Vasoespasmo, infecções e hidrocefalia foram as complicações mais comuns - todas observadas mais frequentemente nos pacientes com hemorragia subaracnóidea não perimesencefálica. Dois pacientes vieram a falecer, ambos com hemorragia subaracnóidea não perimesencefálica. A mediana do tempo de permanência no hospital foi maior nos pacientes com hemorragia subaracnóidea não perimesencefálica (21 dias, em comparação aos 14 dias observados nos pacientes com hemorragia subaracnóidea perimesencefálica). Não se observaram recidivas de sangramento durante o acompanhamento (tempo médio de 15 ± 10,3 meses). Conclusão: As hemorragias subaracnóideas perimesencefálica e não perimesencefálica tiveram formas diferentes de evolução clínica, principalmente no que se referiu à taxa de complicações e ao tempo mediano de permanência no hospital. Assim, a abordagem dessas duas formas de hemorragia subaracnóidea deve ser distinta, tanto em busca de melhorar o tratamento dos pacientes quanto para obter um melhor aproveitamento dos recursos de saúde.

ABSTRACT Objective: To compare the clinical evolution of perimesencephalic subarachnoid hemorrhage and non-perimesencephalic subarachnoid hemorrhage. Methods: The study was conducted retrospectively in a tertiary hospital center in the north region of Portugal. Included patients had no identifiable cause for subarachnoid hemorrhage. Several epidemiologic, clinical and imaging aspects were statistically analyzed, taking into account the differences in perimesencephalic subarachnoid hemorrhage and non-perimesencephalic subarachnoid hemorrhage. Results: Sixty-two patients met the inclusion criteria (46.8% - perimesencephalic subarachnoid hemorrhage; 53.2% - non-perimesencephalic subarachnoid hemorrhage). Demographic and clinical background characteristics were similar in both groups. Complications were more frequent in patients with non-perimesencephalic subarachnoid hemorrhage - 84.8% of the patients had at least one complication versus 48.3% in perimesencephalic subarachnoid hemorrhage. Vasospasm, infection and hydrocephaly were the most common complications (each was detected more frequently in the non-perimesencephalic subarachnoid hemorrhage group than in perimesencephalic subarachnoid hemorrhage group). Two patients died, both had a non-perimesencephalic subarachnoid hemorrhage. The median inpatient time was longer in the non-perimesencephalic subarachnoid hemorrhage group (21 versus 14 days). No incidents of rebleeding were reported during the follow-up period (mean time of 15 ± 10.3 months). Conclusion: Perimesencephalic subarachnoid hemorrhage and non-perimesencephalic subarachnoid hemorrhage are two different entities that have different clinical outcomes, namely in terms of complication rate and median inpatient time. The management of these patients should respect this difference to improve treatment and optimize health care resources.

Severe Cerebral Vasospasm in Patients with Hyperthyroidism

Cerebral vasospasm associated with hyperthyroidism has not been reported to cause cerebral infarction. The case reported here is therefore the first of cerebral infarction co-existing with severe vasospasm and hyperthyroidism. A 30-year-old woman was transferred to our hospital in a stuporous state with right hemiparesis. At first, she complained of headache and dizziness. However, she had no neurological deficits or radiological abnormalities. She was diagnosed with hyperthyroidism 2 months ago, but she had discontinued the antithyroid medication herself three days ago. Magnetic resonance imaging and angiography showed cerebral infarction with severe vasospasm. Thus, chemical angioplasty using verapamil was performed two times, and antithyroid medication was administered. Follow-up angiography performed at 6 weeks demonstrated complete recovery of the vasospasm. At the 2-year clinical follow-up, she was alert with mild weakness and cortical blindness. Hyperthyroidism may influence cerebral vascular hemodynamics. Therefore, a sudden increase in the thyroid hormone levels in the clinical setting should be avoided to prevent cerebrovascular accidents. When neurological deterioration is noticed without primary cerebral parenchyma lesions, evaluation of thyroid function may be required before the symptoms occur.

Delayed Vasospasm after Aneurysmal Subarachnoid Hemorrhage in Behcet Syndrome

A man visited the emergency room with a headache. Brain computed tomography showed aneurysmal subarachnoid hemorrhage (SAH) and multiple aneurysms. After aneurysm clipping surgery, the patient was discharged. After 5 days, he was admitted to the hospital with skin ulceration and was diagnosed with Behcet syndrome. An angiogram taken 7 weeks after aneurysmal SAH showed intracranial vasospasm. Because inflammation in Behcet syndrome may aggravate intracranial vasospasm, intracranial vasospasm after aneurysmal SAH in Behcet syndrome should be monitored for longer compared to general aneurysmal SAH.