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1.
Indian J Surg Oncol ; 15(Suppl 1): 22-28, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38545582

RESUMO

Chondroblastoma is a rare benign cartilaginous bone tumor typically seen at the epiphysis of long axial bones. In this regard, there are rare findings about spinal chondroblastomas. We report a 29-year-old man with T1 vertebral chondroblastoma misdiagnosed with a traumatic fracture following an accident. The patient was admitted to our clinic with a chief complaint of axial back pain and kyphosis following posterior spinal fixation. We report his clinical and imaging data before his past operation and at this admission. Our patient underwent a two-stage operation. In the first stage, posterior spinal reconstruction and kyphosis correction was performed. In the second stage, mass resection was performed anteriorly in the T1 vertebral body as much as possible. The results confirmed the chondroblastoma diagnosis histologically. Our patient remained symptom-free with no growth in tumor remnant during 6 months follow-up. Although vertebral chondroblastoma is a sporadic tumor, it should be considered in the differential diagnosis when facing a vertebral infiltrative osteolytic mass, even when mimicking a traumatic fracture after the accident. In addition, histological confirmation is necessary under such conditions. We also reviewed the literature's clinical presentations, imaging findings, and treatments of 34 case reports with vertebral chondroblastoma.

2.
Biomed Opt Express ; 14(11): 5795-5816, 2023 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-38021132

RESUMO

Here, the discrimination of two types of lethal brain cancers, i.e., glioblastoma multiforme (GBM) and oligodendroglioma (OG) are investigated under the laser-induced breakdown spectroscopy (LIBS) and the electrical spark-assisted laser-induced breakdown spectroscopy (SA-LIBS) in order to discriminate the human brain glioma lesions against the infiltrated tissues. It is shown there are notable differences between the plasma emissions over the brain gliomas against those of infiltrated tissues. In fact, a notable enhancement appears in the characteristic emissions in favor of SA-LIBS against those of conventional LIB spectra. Moreover, the plasma properties such as temperature, electron density, and degree of ionization are probed through the data processing of the plasma emissions. The corresponding parameters, taken from SA-LIBS data, attest to be lucidly larger than those of LIBS up to one order of magnitude. In addition, the ionic species such as Mg II characteristic line at 279 nm and caII emission at 393 nm are notably enhanced in favor of SA-LIBS. In general, the experimental evidence verifies that SA-LIBS is beneficial in the discrimination and grading of GBM/OG neoplasia against healthy (infiltrate) tissues in the early stages.

3.
Int J Mol Cell Med ; 12(2): 135-143, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38313377

RESUMO

Glioblastoma multiforme (GBM) is incurable with routine treatments. Ascorbic acid (Asc) has antioxidant and anti-cancer properties. However, its specific anti-cancer mechanisms are only partially understood. In this study, the effect of Asc on the c-Myc, HIF-1α, and lnc-SNHG16 genes in GBM cells and their exosomes was investigated. Cells isolated from the tissue were characterized by the immunocytochemistry method (GFAP+). The cell-doubling time was determined, and FBS-free medium supplemented with Asc (5 mM) was added to the cells. The extracted exosomes in the cell culture medium were scanned by electron microscopy, Zetasizer, and BCA assay. The expression of lnc-SNHG16 in the exosomes and c-Myc and HIF-1α in the treated and control cells was evaluated by real-time PCR. The interactions between Asc and the c-Myc and HIF-1α proteins were studied using the molecular docking method. The cells showed 90-100% GFAP+ in passage 4, with a cell-doubling time of 4.8 days. Exosomal vesicles measuring 98.25-105.9 were observed. Zetasizer results showed a sharp pick at 90 nm. Protein quantitation showed 3.812 µg/ml protein in the exosomes. Lnc-SNHG16 expression was reduced (P = 0.041), and c-Myc was upregulated (P = 0.002). The expression of HIF-1α was not significant in the treated cells. Also, Asc was able to interact and affect c-Myc and HIF-1α. Asc exerts its effect by reducing lnc-SNHG16 expression in exosomes, upregulating c-Myc in GBM cells, and interacting with HIF-1α and c-Myc. Further research is necessary to achieve a full understanding of these findings.

4.
Iran J Child Neurol ; 16(3): 205-212, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36204427

RESUMO

One rare and low-grade soft tissue tumor with intermediate malignant potential is angiomatoid fibrous histiocytoma (AFH)و which occurs mainly in children and adolescents. The tumor naturally tends to local recurrence and recurrent hemorrhage but rarely to remote metastasis. AFH has been reported in different organs; however, there are rare reports of primary intracranial AFH. The diagnosis of AFH may be difficult due to its occurrence at multiple unusual anatomic sites and its spectrum of morphologic patterns; thus, it is especially important to diagnose it correctly because of the small risk of metastasis and death. The lesion is simply confused with a hematoma, soft tissue hemangioma, or malignant fibrous histiocytoma from clinical and radiographical aspects. We report a case of intracranial AFH in a 5-year-old boy. The tumor is a heterogeneous intra-axial with a size of 78*73mm at the right front temporal. There was also an extra-axial mass measured 8*12mm at the left superior frontal lobe in favor of metastasis. The diagnosis was confirmed using radiographical, immunohistochemical, and molecular tests. AFH is a rare tumor with a high probability of misdiagnosis. Surgeons must be aware of the presence of AFH and conduct a careful follow-up.

5.
J Clin Lab Anal ; 36(1): e24150, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34837714

RESUMO

BACKGROUND: Chordoma is a locally aggressive bone tumor with a high capability of recurrence. Because chordoma often occurs at critical locations next to neurovascular structures, there is an urgent need to introduce validated biomarkers. T-box transcription factor T (TBXT; OMIM: 601397) plays an important role in the pathogenesis and survival of chordoma cells. METHODS: Herein, we aimed to show whether rs2305089 polymorphism is correlated with chordoma in the Iranian population. In order to detect rs2305089, tetra-primer amplification refractory mutation system-polymerase chain reaction (T-ARMS-PCR) was used. In total, 19 chordoma patients and 108 normal healthy individuals were recruited and screened using T-ARMS-PCR. The results were subsequently validated by Sanger sequencing. RESULTS: The genotype distributions and allele frequencies were significantly different among the patient and healthy groups (p-value <0.05). The A allele of rs2305089 showed a significant positive association with chordoma risk (p-value <0.05). DNA sequencing verified the T-ARMS-PCR results as well. This study demonstrated the association between TBXT rs2305089 and chordoma in an Iranian population using a simple, accurate, and cost-effective T-ARMS-PCR assay. CONCLUSIONS: Our results were in line with those of previous studies showing that TBXT rs2305089 is associated with chordoma development. We also developed an efficient T-ARMS-PCR assay to determine the genotype of rs2305089.


Assuntos
Cordoma , Proteínas Fetais/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas com Domínio T/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Neoplasias Ósseas/epidemiologia , Neoplasias Ósseas/genética , Estudos de Casos e Controles , Cordoma/epidemiologia , Cordoma/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Adulto Jovem
6.
Prague Med Rep ; 122(1): 14-24, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33646938

RESUMO

There are reports that in patients with aSAH (aneurysmal subarachnoid hemorrhage), LTF (lamina terminalis fenestration) reduces the rate of shunt-needed hydrocephalus via facilitation of CSF (cerebrospinal fluid) dynamic, diminished leptomeningeal inflammation, and decreased subarachnoid fibrosis. Regarding the conflicting results, this study was conducted to evaluate the effects of LTF on decreased shunt-needed hydrocephalus in patients with aSAH. A cross-sectional retrospective study was carried out to survey all patients with confirmed aSAH operated from March 2011 to September 2016 in an academic vascular center (Rasool Akram Hospital in Tehran, Iran). Of a total of 151 patients, 72 patients were male and 79 were female. The mean age of the participants was 51 years. A transiently CSF diversion (EVD - external ventricular drainage) was performed (the acute hydrocephalus rate) on 21 patients (13.9%). In 36 patients (23.8%), aneurysm occlusion with LTF and in 115 patients (76.2%) only aneurysm occlusion surgery was performed. In hydrocephalus follow-up after surgery, 13 (12%) patients needed shunt insertion (the rate of shunt-needed hydrocephalus). The statistical analysis demonstrated no significant relation between LTF and shunt-needed hydrocephalus. Confirmation of the hypothesis that LTF may decrease the rate of shunt-needed hydrocephalus can significantly decrease morbidity, mortality, and treatment costs of shunting (that is a simple, but a potentially dangerous procedure). So, it is advised to plan and perform an RCT (randomized controlled trial) that can remove the confounding factors, match the groups, and illustrate the exact effect of LTF on shunt-needed hydrocephalus.


Assuntos
Hidrocefalia , Hemorragia Subaracnóidea , Ventriculostomia , Estudos Transversais , Feminino , Humanos , Hidrocefalia/etiologia , Hidrocefalia/cirurgia , Hipotálamo/cirurgia , Irã (Geográfico) , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Hemorragia Subaracnóidea/complicações , Hemorragia Subaracnóidea/cirurgia
7.
Cureus ; 13(12): e20772, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35111457

RESUMO

OBJECTIVE: The most common indications for spinal surgery are low back pain and associated disabilities caused by disc herniation. Given the high prevalence of low back pain, the critical nature of pain assessment in these patients, and knowledge about the influencing and predisposing factors, we sought to evaluate the clinical and radiologic findings associated with pain relief and postoperative recovery in patients who underwent bilateral lumbar discectomy. METHODS: From March 2016 to October 2020, a prospective cohort study was conducted. This study included adult patients with symptomatic disc herniation in the L4-L5 and L5-S1 segments who were candidates for bilateral discectomy. Before and after surgery, patients were evaluated for lumbar and radicular pain and the Oswestry Disability Index (ODI) score and at the four, 12, and 24-week follow-up. Meanwhile, a variety of demographic, clinical, and radiologic factors was collected and statistically analyzed. RESULTS: This study enrolled 30 patients. The average age of the patients was 41.2 years, with 22 males and eight females. Twelve of these patients had disc involvement in the L4-L5 region, while 18 had disc involvement in the L5-S1 region. Statistical analysis revealed that radicular pain and disability associated with low back pain significantly decreased following surgery (P=0.001). However, there was no significant reduction in back pain (P>0.05). Patients with a higher body mass index (BMI) and neurological claudication had a lower reduction in radicular pain (P<0.05). Moreover, a higher BMI and the presence of instability pain are associated with an increased likelihood of postoperative lumbar pain relief (P<0.01). Among the radiological variables, increased disc height was associated with a more rapid recovery from low back disability (P=0.003). Furthermore, a larger diameter of paraspinal muscles at the level of the herniated disc was associated with a more rapid improvement of lower back pain (P=0.021). CONCLUSION: The use of discectomy in patients with lumbar disc herniation significantly alleviates postoperative and follow-up radicular pain. Age, BMI, neurological claudication, instability pain, and paraspinal muscle diameter played a role in postoperative pain relief. Increased disc height was associated with a more rapid decline in the ODI score. Future studies with larger sample sizes are recommended.

8.
Prague Med Rep ; 121(1): 49-54, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32191620

RESUMO

Tethered cord syndrome (TCS) may rarely remain asymptomatic until degenerative or nondegenerative lumbar diseases superimpose in adulthood and expose the hidden anomaly. In such cases, different treatment options can be selected and simultaneous detethering might be considered too. We are reporting an undiscovered TCS in a young lady who underwent lumbar diskectomy due to symptomatic disk extrusion and suffered complete cauda equina syndrome (CES), postoperatively.


Assuntos
Síndrome da Cauda Equina , Deslocamento do Disco Intervertebral , Polirradiculopatia , Adulto , Humanos , Vértebras Lombares , Medula Espinal
9.
Iran J Med Sci ; 45(1): 67-72, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32038061

RESUMO

Hemangioblastoma (HB) in the supratentorial region of the brain is rare and only a few cases are reported on intraventricular HB. HB of the lateral ventricles is even rarer. We present a case of a 30-year-old man with generalized tonic clonic seizures. The brain computed tomography showed a 5.5 cm heterogeneous mass extending into both lateral ventricles with partial enhancement. Based on the size and imaging features, we present the fourth documented case of a large solitary intraventricular HB. Our approach to this unique case and some treatment complexities are also described. Considering the rarity of the case and the patient's imaging features, the present study provides a better understanding of HB and recommends HB to be considered in the differential diagnosis of masses in the lateral ventricles. In addition, some preventable pitfalls in the treatment of such complex cases are described.

10.
Clin Neurol Neurosurg ; 190: 105652, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31896490

RESUMO

OBJECTIVE: Glioblastoma (GBM) is the most common primary malignant neoplasm of the central nervous system (CNS). Despite the progress in therapeutic strategies such as surgical techniques, radiotherapy, chemotherapy, and targeted therapy, prognosis and therapeutically convenient monitoring tools in patients with GBM has not improved significantly up to now.Therefore, exosomal miRNAs as novel non-invasive biomarkers having high sensitivity and specificity are required to improve diagnosis and to develop new targeted therapy strategies for GBM patients. The aim of the present study was to investigate a novel miRNA signature as a predictive biomarker for diagnosis and measurement of response to therapeutic interventions in plasma of GBM patients versus traumatic brain injury and diffuse low-grade astrocytoma (LGA) patients. PATIENTS AND METHODS: Plasma exosomal-microRNAs were isolated from GBM (n = 25), LGA (n = 25), and head trauma patients (n = 15) as non-glioma control from March 2017 to June 2018 in Department of Neurosurgery at Rasoul-e-Akram Hospital. Through a bioinformatics analysis, we used Miranda, TargetScan, mirBase, DIANA-microT-CDS, and KEGG database as well as microarray data analysis from GEO for microRNA candidates. Finally, miR-210, miR-185, miR-5194, and miR-449 were selected among those miRNAs because they were recorded to target the maximum number of genes in EGFR and c-MET signaling pathways. Then, exosomal microRNAs were extracted from plasma of patients and quantitated by locked nucleic acid real-time PCR in GBM, LGA, and trauma patients. RESULTS: This result is the first report on the role of circulating miR-185, miR-449, and miR-5194 in GBM compared to LGA and trauma. The plasma expression of miR-210 as an oncogenic miR was upregulated in GBM and LGA groups (P < 0.0001). Otherwise, miR-185, miR-5194, and miR-449 were significantly downregulated (P ≤ 0.05) in GBM and LGA compared to trauma patients. There was no significant downregulation in the expression of miR-185 between GBM and LGA, while the expression of miR-5194 (P ≤ 0.05) and miR-449 (P ≤ 0.05) was significantly decreased in GBM patients compared with LGA. CONCLUSIONS: These results indicate that the levels of miR-210, miR-449, and miR-5194 are a promising diagnostic and prognostic biomarker positively correlated with histopathological grade and invasiveness of GBM. These findings imply that circulating microRNA can be potentially used as novel biomarkers for glioma that might be beneficial in clinical management of glioma patients.


Assuntos
Astrocitoma/genética , Neoplasias Encefálicas/genética , Glioblastoma/genética , MicroRNAs/genética , Adulto , Astrocitoma/diagnóstico , Astrocitoma/patologia , Astrocitoma/terapia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Lesões Encefálicas Traumáticas/metabolismo , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Estudos de Casos e Controles , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Glioblastoma/diagnóstico , Glioblastoma/patologia , Glioblastoma/terapia , Humanos , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , Regulação para Cima
11.
Asian J Neurosurg ; 15(4): 1096-1101, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33708697

RESUMO

Although the occurrence of cerebral aneurysms in pediatric age group describes as rare, giant ones are more commonly be found than in adults. Insufficient epidemiological information, their association with other medical comorbidities, diagnostic pitfalls, complex surgical anatomy, and issues should be considered during surgery to make them difficult to diagnose and manage. We report a 6-year-old boy with presenting complaint of acute-onset headache without any other symptoms and a small area of intracerebral hemorrhage detected on initial computed tomography (CT) scan. Primary evaluations failed to result in a definite diagnosis, and delayed vascular studies suggested vascular malformation or an aneurysm as the causative factor of hemorrhage. Surgical exploration led to the diagnosis of a giant partially thrombosed aneurysm at the A2 segment of the left anterior cerebral artery and successful clipping. One of our findings on preoperative CT angiography, "fountain sign," may be useful for the diagnosis of partially thrombosed aneurysms when active bleeding from the aneurysm has been ruled out. Fountain sign can be a useful finding in the diagnosis of partially thrombosed aneurysms. Vascular lesions should always be considered as the primary cause of intracranial hemorrhage in pediatrics despite negative initial studies. Therefore, close follow-up and using delayed and multimodality vascular evaluations are crucial for successful management.

12.
Basic Clin Neurosci ; 11(5): 631-638, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33643556

RESUMO

INTRODUCTION: The primary and definitive diagnosis of meningioma is based on histological assessment; however, employing imaging methods, like Magnetic Resonance Imaging (MRI) is very helpful to describe lesion's characteristics. Accordingly, we decided to study the effect of imaging factors, like MRI data on the volume of hemorrhage (estimated blood loss) during meningioma surgery. METHODS: This was a cross-sectional, retrospective, and analytical study. The eligible patients were those with meningioma who were candidates for surgery. A total of 40 patients with meningioma were selected and assessed. The preoperative imaging findings were recorded, then estimated blood loss during the surgery was determined. RESULTS: A reverse association was revealed between the degree of proximity to the nearest sinus and the rate of bleeding. Furthermore, the size of the mass was positively associated with the rate of bleeding; however, there was no significant correlation between the volume of bleeding and other parameters, including the degree of edema, the volume of mass, the site of the tumor in the brain, and the histological subtype of the tumor. The mean time of operation was strongly correlated with blood loss. The rate of bleeding was more expected in hypertensive versus normotensive patients. CONCLUSION: Bleeding in various volumes could be a frequent finding in intracranial meningioma surgery. Overall, tumor size, the duration of surgery, a history of hypertension, and distance to the nearest sinuses were the main determinants for the severity of hemorrhage in patients undergoing meningioma surgery.

13.
Iran J Med Sci ; 44(3): 265-269, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31182895

RESUMO

Meningioma is the second most common brain tumor. The extent of peritumoral brain edema (PTBE) is one of the important prognostic factors in patients with meningioma. A 55-year-old female patient suffering from a progressive severe headache and mild left hemiparesis was referred to the Department of Neurosurgery, Rasool Akram Hospital (Tehran, Iran). The preoperative imaging revealed a 2×2 cm solid extra-axial mass with bright enhancement at the outer third of the right sphenoid wing. In addition, there was a disproportionately extensive peritumoral brain edema in the right cerebral hemisphere that even involved the right internal capsule. The patient was operated through the right pterional approach and the mass was totally resected. Twenty-one days after surgery, the brain CT scan surprisingly showed only mild frontal edema and the patient was asymptomatic 1 year after the surgical treatment. According to the literature, the size and extension of the PTBE are correlated with the prognosis of meningioma. A larger edema is associated with a larger tumor, higher grade, and a more invasive meningioma with a higher recurrence rate. Our patient had a very large hemispheric PTBE which was disproportionate to the small size of the meningioma and the tumor had not directly invaded the adjacent brain tissue. We believe that the visible compression of the tumor on major veins of the Sylvian fissure was the reason for the PTBE in our patient. The presence of a large PTBE concomitant with a meningioma does not necessarily indicate a poor prognosis. Hence, we recommend a preoperative venogram to be performed in such patients.

14.
Surg Neurol Int ; 10: 235, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31893136

RESUMO

BACKGROUND: Pilomyxoid astrocytoma (PMA) is a variant of pilocytic astrocytomas but exhibits more aggressive behavior. Further, it is more prevalent in the hypothalamic/chiasmatic regions and is only rarely encountered in the thoracic spine. CASE DESCRIPTION: A 9-year-old male presented with severe spastic paraparesis (motor/sensory) attributed to a thoracic cord PMA and scoliosis. The magnetic resonance (MR) showed an intraaxial ill-defined expansile lesion with heterogeneous enhancement extending from the cervicothoracic junction to conus medullaris. A multilevel decompressive laminectomy was performed with restricted tumor debulking; an expansile duraplasty was also effected. Two years later, the patient has moderately improved and has not shown any symptom progression. CONCLUSION: We recommend the early performance of a thoracic MR in children with idiopathic scoliosis presenting with the onset of a significant spastic paraparesis.

15.
J Neurochem ; 148(2): 188-203, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30347482

RESUMO

Astrocytic gliomas are the most common and lethal form of intracranial tumors. These tumors are characterized by a significant heterogeneity in terms of cytopathological, transcriptional, and (epi)genomic features. This heterogeneity has made these cancers one of the most challenging types of cancers to study and treat. To uncover these complexities and to have better understanding of the disease initiation and progression, identification, and characterization of underlying cellular and molecular pathways related to (epi)genetics of astrocytic gliomas is crucial. Here, we discuss and summarize molecular and (epi)genetic mechanisms that provide clues as to the pathogenesis of astrocytic gliomas.


Assuntos
Astrocitoma/genética , Astrocitoma/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Epigênese Genética , Animais , Humanos
16.
Surg Neurol Int ; 9: 227, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30533274

RESUMO

BACKGROUND: Gliosarcoma (GS) is a primary rare malignant brain tumor that accounts 4% of all high-grade glial tumor of the brain. CASE DESCRIPTION: We present a 45-year-old female admitted to our center with progressive headache since 1 month ago concomitant with nausea and emesis and generalized weakness. Imaging revealed a large solid mass with well-defined margin and some cystic portions that enhanced brightly with contrast. We decided to operate the patient via right parietal craniotomy and we totally resected all visible portions of the mass, as en bloc resection. The histopathological report of the mass was GS. We are following the patient up to now, for about 50 months, and she is good without any compliant or neurologic deficit. All follow-up magnetic resonance imaging (MRI) did not show any tumor recurrence. CONCLUSION: Aiming to achieve longer progression-free survival in cases of GS, we recommend resecting all portions of the mass as much as possible, so named en bloc resection, and then refer the patients for appropriate and timely chemoradiotherapy.

18.
Surg Neurol Int ; 8: 54, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28540120

RESUMO

BACKGROUND: Remote cerebellar hemorrhage (RCH) is a rare complication after supratentorial craniotomies, which usually presents as linear hemorrhages on the surface of the cerebellum; the exact mechanism of it is not established yet. CASE DESCRIPTION: In case one, a 57-year-old patient demonstrated hemorrhage in the cerebellar sulci in favor of RCH 2 days after craniotomy for sphenoidal wing meningioma resection. He was asymptomatic and showed good prognosis after conservative treatment. However, in the second case, a 21-year-old man presented with symptomatic RCH just after the surgery for resection of huge intraaxial parietooccipital lesion. He had a poor prognosis despite the treatment and died ultimately. CONCLUSION: Although some studies reported the good prognosis for this type of hemorrhage, it can cause neurological and clinical deterioration and result to patient death.

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