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BACKGROUND: The transpetrosal approach is a complex skull base procedure with a high risk of complications, particularly caused by injury of the venous system. It is in part related to variability of blood outflow pathways and their distinctive patterns in each individual patient. OBJECTIVE: To evaluate outcomes and complications after skull base surgery with use of the petrosal approach modifications, which selection was based on the detailed preoperative assessment of venous drainage patterns. METHODS: Overall, 74 patients, who underwent surgery via the transpetrosal approach at our institution between 2000 and 2017, were included in this study. In all cases, the venous drainage pattern was assessed preoperatively and categorized according to the predominant blood outflow pathway into four types as previously suggested by Hacker: (1) sphenoparietal sinus (SpPrt), (2) sphenobasal vein (SpB), (3) sphenopetrosal sinus (SpPS), and (4) cortical. The blood outflow through the bridging petrosal vein and the vein of Labbé was also taken into consideration. In patients with SpPrt- and a cortical-type venous drainage, the transpetrosal approach was used in a standard way. In patients with SpB-type venous drainage, limited extradural anterior petrosectomy was combined with intradural anterior petrosectomy after dural opening, superior petrosal sinus transection, tentorial cutting, Meckel's cave opening, and trigeminal nerve mobilization. In patients with SpPS-type venous drainage, after standard petrosectomy, dural opening, and tentorial cutting, SpPS ligation was done followed by 2-week interval before staged definitive tumor resection. RESULTS: Gross total, near-total, and subtotal resection of the lesion (meningioma, 48 cases; retrochiasmatic craniopharyngioma, 11 cases; brain stem cavernoma, 7 cases; other tumors, 8 cases) was achieved in 30 (40.5%), 24 (32.4%), and 20 (27.0%) patients, respectively. Postoperative complications that were possibly related to venous compromise were noted in 18 patients (24.3%), but neither one was major. Of these 18 patients, 9 were symptomatic, but all symptoms-aphasia (4 cases), seizures (2 cases), and confusion (3 cases)-fully resolved after conservative treatment. Overall, 13 patients, including 4 symptomatic, had signal changes on T2-weighted brain MRI, which were permanent only in 3 cases (all asymptomatic). CONCLUSION: Our suggested surgical strategy can be applied to any type of the venous drainage pattern. Preoperative evaluation and intraoperative preservation of the blood outflow pathways are crucial means for safe and effective application of the transpetrosal approach.
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Neoplasias Meníngeas , Meningioma , Humanos , Base do Crânio/diagnóstico por imagem , Base do Crânio/cirurgia , Meningioma/irrigação sanguínea , Meningioma/cirurgia , Procedimentos Neurocirúrgicos/efeitos adversos , Procedimentos Neurocirúrgicos/métodos , Craniotomia/métodos , Neoplasias Meníngeas/cirurgiaRESUMO
Surgical treatment is an effective option for medically intractable epilepsy. Amygdalohippocampectomy for mesial temporal lobe epilepsy is a surgically remediable epileptic syndrome. It is a well-established surgery and various approaches to the mesial temporal lobe have been reported. To reduce the complication rate, surgeons should have sufficient knowledge of anatomy in the mesial temporal region. Here, we summarize the surgical treatments for mesial temporal lobe epilepsy, focusing on anatomical understanding. We described in detail the surgical anatomy of amygdalohippocampectomy and various approaches to the mesial temporal region. In addition, we describe hippocampal transection aimed at preserving memory function, which is an alternative surgery in patients without hippocampal sclerosis. An anatomical understanding of the mesial temporal region helps surgeons not only in the field of epilepsy surgery, but also in other fields of neurosurgery, such as brain tumor and vascular surgery.
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Epilepsia Resistente a Medicamentos , Epilepsia do Lobo Temporal , Epilepsia , Humanos , Epilepsia do Lobo Temporal/cirurgia , Epilepsia do Lobo Temporal/patologia , Hipocampo/cirurgia , Hipocampo/patologia , Procedimentos Neurocirúrgicos , Epilepsia/cirurgia , Epilepsia Resistente a Medicamentos/cirurgia , Resultado do TratamentoRESUMO
A 253 J with 26â ns at 0.2â Hz laser performance was demonstrated using a LD pumped cryogenically cooled Yb:YAG ceramics laser amplifier. A high energy storage of 344 J was achieved with a stored energy density of 0.58 J/cm3 using a 1 kJ output multidirectional-pumping system. High energy-extraction efficiency of 56.5% was achieved with high energy fluence of 4.63 J /cm2. To the best of our knowledge, this is the highest output energy obtained with a repetitive nanosecond pulse by LD pumped solid-state laser. This paper presented a design of 1 kJ amplifier based on experimentally proven numerical data.
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Optic canal invasion by tuberculum sellae meningiomas (TSMs) has been reported, but the characteristics of invasion remain unclear. This study was performed to clarify the incidence and characteristics of optic canal invasion by TSM and to determine whether optic canal invasion could be predicted preoperatively by magnetic resonance imaging (MRI). Between February 2002 and August 2014, 31 patients with TSM underwent tumor resection in our institute. In all cases, the optic canal was explored to identify any tumor invasion. We classified the characteristics of optic canal invasion from intraoperative findings. Invasion was classified into four types: type 1: no invasion; type 2: secondary invasion; type 3: partial wall invasion (two subtypes); and type 4: invasion into the supero-medial-inferior walls of the optic canal. Thirty of 31 cases showed optic canal invasion. Of these 30 cases, 9 (30 %) showed bilateral optic canal invasion. The most common finding was type 1 (23 sides). Among cases with optic canal invasion (39 sides), type 4 was the most common pattern (17 sides), followed by type 3-infero-medial (13 sides), type 2 (5 sides), and type 3-supero-medial (4 sides). Blinded prediction of tumor invasion was accurate in 61 % of cases, but characteristics of tumor invasion were undeterminable from preoperative MRI. In conclusion, optic canal invasion was frequently seen in our consecutive series of TSM, characteristics of which were unpredictable preoperatively. Neurosurgeons should be aware of the high incidence and variety of optic canal invasion in planning strategies for TSM treatment.
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Neoplasias Meníngeas/cirurgia , Meningioma/cirurgia , Procedimentos Neurocirúrgicos , Sela Túrcica/cirurgia , Neoplasias Cranianas/cirurgia , Neoplasias Supratentoriais/cirurgia , Adulto , Idoso , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Neoplasias Meníngeas/diagnóstico , Meningioma/diagnóstico , Pessoa de Meia-Idade , Procedimentos Neurocirúrgicos/métodos , Nervo Óptico/cirurgia , Neoplasias Cranianas/diagnóstico , Osso Esfenoide/cirurgia , Adulto JovemRESUMO
Experimental amplification of 10-ns pulses to energy of 1 J at repetition rate of 10-100 Hz in cryogenic multipass total-reflection active-mirror (TRAM) amplifier is reported for the first time. By using a monolithic multi-TRAM, which is a YAG ceramic composite with three thin Yb:YAG active layers, efficient energy extraction was achieved without parasitic lasing. A detailed measurement of output characteristics of the laser amplifier is presented; results are discussed and compared with numerical calculations.
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Minimally invasive surgery is gaining increasing interest in epilepsy surgery. In this video, the authors present the endoscopic transorbital approach for an epileptogenic lesion located at the temporal tip. The patient was a man in his 40s who has had intractable focal impaired awareness seizures and focal to bilateral tonic-clonic seizures since he was 31 years of age. According to the preoperative examination, including stereotactic electroencephalography, a cavernous angioma located at the tip of the right temporal lobe was diagnosed as an epileptogenic lesion. Lesionectomy for this lesion was performed using the endoscopic transorbital approach as minimally invasive surgery and a favorable outcome was achieved. The video can be found here: https://stream.cadmore.media/r10.3171/2024.4.FOCVID2414.
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Two main surgical techniques are available for corpus callosotomy (CC): conventional microscopic CC and endoscopic CC.1 Microscopic CC is more familiar to neurosurgeons and allows three-dimensional visualization, but it requires a larger craniotomy and has a narrower visual angle in the deep part. Endoscopic CC has only recently been introduced to epilepsy surgery, but it is gaining increasing interest among epilepsy surgeons. The endoscope provides two-dimensional visualization and requires a camera as an additional instrument inserted into the surgical corridor. The merits of endoscopic CC include the smaller craniotomy and smaller skin incision, potentially reducing invasiveness.2 Bridging veins to the superior sagittal sinus are also less problematic because of the reduced need for brain retraction. The lack of need of arachnoid dissection is another advantage. Generally, an anterior approach is applied for CC, but this approach makes interhemispheric fissure dissection mandatory, especially at the cingulate gyri. In some cases, this procedure can take a long time. On the other hand, a posterior approach requires less interhemispheric arachnoid dissection, or sometimes none at all, due to the anatomy of the falx cerebri. These reasons have driven the development of a posterior approach for an endoscopic-alone technique.3 Here, we present a 5-year-old girl with medically intractable epileptic spasms that were diagnosed as infantile epileptic spasms syndrome, who underwent endoscopic total CC via a posterior approach to control her seizures (Video 1).
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Corpo Caloso , Neuroendoscopia , Humanos , Feminino , Neuroendoscopia/métodos , Corpo Caloso/cirurgia , Pré-Escolar , Epilepsia Resistente a Medicamentos/cirurgiaRESUMO
BACKGROUND: Seizure onset pattern (SOP) represents an alteration of electroencephalography (EEG) morphology at the beginning of seizure activity in epilepsy. With stereotactic electroencephalography (SEEG), a method for intracranial EEG evaluation, many morphological SOP classifications have been reported without established consensus. These inconsistent classifications with ambiguous terminology present difficulties to communication among epileptologists. METHODS: We reviewed SOP in SEEG by searching the PubMed database. Reported morphological classifications and the ambiguous terminology used were collected. After thoroughly reviewing all reports, we reconsidered the definitions of these terms and explored a more consistent and simpler morphological SOP classification. RESULTS: Of the 536 studies initially found, 14 studies were finally included after screening and excluding irrelevant studies. We reconsidered the definitions of EEG onset, period for determining type of SOP, core electrode and other terms in SEEG. We proposed a more consistent and simpler morphological SOP classification comprising five major types with two special subtypes. CONCLUSIONS: A scoping review of SOP in SEEG was performed. Our classification may be suitable for describing SOP morphology.
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Eletroencefalografia , Convulsões , Técnicas Estereotáxicas , Humanos , Convulsões/classificação , Convulsões/fisiopatologia , Convulsões/diagnóstico , Convulsões/patologia , Eletroencefalografia/métodos , Eletrocorticografia/métodosRESUMO
A 12.5 J second-harmonic generation with 71.5% conversion efficiency at 0.6 Hz repetition rate from a diode-pumped Nd:glass laser system has been demonstrated by using a CsLiB(6)O(10) (CLBO) nonlinear optical crystal as a frequency doubler. The CLBO has aperture of 40 mm x 40 mm and thickness of 14 mm with Type-II phase matching. The CLBO is mounted into a housing which flows dry nitrogen gas on the CLBO's face. There is no significant reduction of conversion efficiency by exposing of over 600,000 shots for intermissive experiment during 3 years. In our knowledge, these experimental results of output energy and conversion efficiency are highest performance as second-harmonic generation of a diode-pumped solid state laser by using one CLBO nonlinear crystal. In this paper, potential of the CLBO as a frequency converter for repetitive kJ class laser is discussed.
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Lasers de Estado Sólido , Cristalização , Desenho de Equipamento , Análise de Falha de Equipamento , Vidro/química , Dinâmica não LinearRESUMO
Anti-cyclic citrullinated peptide (anti-CCP) antibodies are well-established serological markers that show high sensitivity and specificity in early rheumatoid arthritis (RA) and are associated with bone erosions of RA. However, some patients subsequently progress to RA even if there is no presence of anti-CCP antibodies in an early stage. The aim of this study is to evaluate the diagnostic utility of matrix metalloproteinase-3 (MMP-3), high-sensitivity C-reactive protein (hsCRP) and IgM rheumatoid factor for predicting RA in anti-CCP-negative patients with recent-onset undifferentiated arthritis (UA). Baseline levels of those markers were measured at the entry of the study. A total of 99 patients with UA were included, among them 44 patients (44.4 %) had been classified as having RA by a skilled rheumatologist at some point during 1-year follow-up. Of these 99 patients, 34 patients (34.3 %) had anti-CCP antibodies and 65 patients (65.7 %) had no anti-CCP antibodies. Eleven patients who were anti-CCP-negative developed RA. We compared sensitivity, specificity, positive predictive value and negative predictive value of serum markers of these anti-CCP-negative RA patients. The combined usage of MMP-3 with hsCRP is relatively superior to other markers as predictors of RA.
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Artrite Reumatoide/diagnóstico , Autoanticorpos/sangue , Proteína C-Reativa/análise , Metaloproteinase 3 da Matriz/sangue , Peptídeos Cíclicos/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/sangue , Artrite Reumatoide/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Electrodes for stereotactic electroencephalography (SEEG) are typically fixed to the skull with anchor bolts. When anchor bolts are unavailable, electrodes have to be fixed using other methods, carrying the possibility of electrode shift. This study, therefore, evaluated the characteristics of electrode tip shift during SEEG monitoring in patients with electrodes fixed using the suture technique. METHODS: We retrospectively included patients who underwent SEEG implantation with suture fixation and evaluated the tip shift distance (TSD) of electrodes. Possible influences evaluated included: 1) implantation period, 2) lobe of entry, 3) unilateral or bilateral implantation, 4) electrode length, 5) skull thickness, and 6) scalp thickness difference. RESULTS: A total of 50 electrodes in 7 patients were evaluated. TSD was 1.4 ± 2.0 mm (mean ± standard deviation). Implantation period was 8.1 ± 2.2 days. Entry lobe was frontal for 28 electrodes and temporal for 22 electrodes. Implantation was bilateral for 25 electrodes and unilateral for 25 electrodes. Electrode length was 45.4 ± 14.3 mm. Skull thickness was 6.0 ± 3.7 mm. Scalp thickness difference was -1.5 ± 2.1 mm, which was found greater in temporal lobe entry compared with frontal lobe entry. According to univariate analyses, neither implantation period nor electrode length correlated with TSD. Multivariate regression analysis showed that only greater scalp thickness difference correlated significantly with greater TSD (P = 0.0018). CONCLUSIONS: Greater scalp thickness difference correlated with greater TSD. Surgeons need to consider the degree of scalp thickness difference and electrode shift when using suture fixation, especially with temporal lobe entry.
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Eletroencefalografia , Técnicas Estereotáxicas , Humanos , Estudos Retrospectivos , Eletrodos Implantados , Eletroencefalografia/métodos , SuturasRESUMO
BACKGROUND AND OBJECTIVES: Corpus callosotomy (CC) is an epilepsy surgery that disconnects the commissural fibers at the corpus callosum, a structure that often plays a key role in propagating seizure activity. CC is particularly beneficial in patients with drop attacks. Less invasive endoscopic surgeries have recently been introduced to some fields of neurosurgery but have not yet become common in epilepsy surgery. Endoscopic surgeries offer better visualization and require a smaller corridor than conventional microscopic surgeries. Here, we presented a case series comparing endoscopic CC with microscopic CC. METHODS: This 2-center retrospective study involved patients who underwent all types of CC (anterior, total, or posterior CC [pCC]) between January 2014 and May 2022. We excluded patients who underwent additional craniotomy for electrocorticography rather than CC, prior craniotomy, or CC without craniotomy. The primary outcomes were comparing size of craniotomy, operative time, and surgical complications between endoscopic CC and microscopic CC. RESULTS: We included 14 CCs in 11 patients in the endoscopic group and 58 CCs in 55 patients in the microscopic group. No significant difference in age was seen between groups. Craniotomies were significantly smaller in the endoscopic group for anterior (13.36 ± 1.31 cm 2 vs 27.55 ± 3.78 cm 2 ; P = .001), total (14.07 ± 2.54 cm 2 vs 26.63 ± 6.97 cm 2 ; P = .001), and pCC (9.44 ± 1.18 cm 2 vs 30.23 ± 10.76 cm 2 ; P = .002). Moreover, no significant differences in operative time (anterior CC [261 ± 53.11 min vs 298.73 ± 81.08 min, P = .226], total CC [339.5 ± 48.2 min vs 321.39 ± 65.98 min, P = .452], pCC [198 ± 24.73 min vs 242.5 ± 59.12 min, P = .240]), or complication rate were seen. CONCLUSION: Endoscopic CC is a promising technique requiring a smaller craniotomy than microscopic CC, without significantly increasing operative time or complication rate compared with microscopic CC.
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Epilepsia , Humanos , Estudos Retrospectivos , Duração da Cirurgia , Resultado do Tratamento , Epilepsia/cirurgia , Craniotomia/métodos , EndoscópiosRESUMO
The complication rate of stereotactic electroencephalography (SEEG) is generally low, but various types of postoperative hemorrhage have been reported. We presented an unusual hemorrhagic complication after SEEG placement. A 20-year-old man presented with suspected frontal lobe epilepsy. We implanted 11 SEEG electrodes in the bilateral frontal lobes and the left insula. Computed tomography after implantation showed intraparenchymal hemorrhage in the left temporal lobe and insula and subarachnoid hemorrhage in the left Sylvian cistern. Later, the point of vessel injury was revealed from the identification of a pseudoaneurysm, but this location was not along the planned or actual electrode trajectory. The cause of hemorrhage was suggested to be indirect injury from stretching of the arachnoid trabeculae by the puncture needle.
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Polyploidization of megakaryocytes (MKs), the platelet precursors, occurs by endomitosis, a mitotic process that fails at late stages of cytokinesis. Expression and function of Aurora B kinase during endomitosis remain controversial. Here, we report that Aurora B is normally expressed during the human MK endomitotic process. Aurora B localized normally in the midzone or midbody during anaphase and telophase in low ploidy megakaryocytes and in up to 16N rare endomitotic MKs was observed. Aurora B was also functional during cytokinesis as attested by phosphorylation of both its activation site and MgcRacGAP, its main substrate. However, despite its activation, Aurora B did not prevent furrow regression. Inhibition of Aurora B by AZD1152-HQPA decreased cell cycle entry both in 2N to 4N and polyploid MKs and induced apoptosis mainly in 2N to 4N cells. In both MK classes, AZD1152-HQPA induced p53 activation and retinoblastoma hypophosphorylation. Resistance of polyploid MKs to apoptosis correlated to a high BclxL level. Aurora B inhibition did not impair MK polyploidization but profoundly modified the endomitotic process by inducing a mis-segregation of chromosomes and a mitotic failure in anaphase. This indicates that Aurora B is dispensable for MK polyploidization but is necessary to achieve a normal endomitotic process.
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Megacariócitos/citologia , Megacariócitos/enzimologia , Mitose/genética , Mitose/fisiologia , Poliploidia , Proteínas Serina-Treonina Quinases/fisiologia , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Aurora Quinase B , Aurora Quinases , Segregação de Cromossomos/efeitos dos fármacos , Segregação de Cromossomos/fisiologia , Fase G1/efeitos dos fármacos , Fase G1/fisiologia , Humanos , Técnicas In Vitro , Proteínas Inibidoras de Apoptose , Megacariócitos/efeitos dos fármacos , Proteínas Associadas aos Microtúbulos/metabolismo , Mitose/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Fase S/efeitos dos fármacos , Fase S/fisiologia , Fuso Acromático/enzimologia , SurvivinaRESUMO
We report on a passively mode-locked ytterbium-doped fiber oscillator pumped by polarization-combined diodes emitting at a wavelength of 915 nm instead of 976 nm. Stable mode-locked operation based on nonlinear polarization evolution generated a broad spectrum of 140 nm, spanning from 950 to 1090 nm. The output power was 16.3 mW at a repetition rate of 93.1 MHz. External compression using a pair of transmission gratings resulted in pulse durations as short as 21.6 fs, which is equivalent to 6.6 cycle optical pulses at a wavelength of around 1000 nm.
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BACKGROUND: We aimed to evaluate the resected area of endonasal endoscopic approach (EEA) and transcranial approach (TCA) for skull base meningiomas (SBMs) using voxel-based-lesion mapping and visualized the appropriate tumor location in each approach. METHODS: We retrospectively examined 182 patients with SBMs who underwent tumor resection in our hospital between 2014 and 2019. Pre- and post-operative SBMs were manually delineated on MRI to create the voxels-of-interest (VOIpre and VOIpost) and were registered onto the normalized brain (normalized VOIpre and normalized VOIpost). The resected map was created by subtracting normalized VOIpost from the normalized VOIpre divided by the number of cases. The resected maps of TCA and EEA were compared by subtracting them. RESULTS: Twenty patients underwent EEA and 135 patients underwent TCA. The tumor resected map demonstrated that the resected area of EEA frequently accumulated on the central skull base, while that of TCA accumulated near the central skull base. The border of both approaches matched the circle that connects neural foramens at the skull base. CONCLUSIONS: The resected area of SBMs by EEA and TCA was well visualized by voxel-based-lesion mapping. The circle connecting the neural foramens was the border of EEA and TCA.
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The use of robot-assisted frameless stereotactic electroencephalography (SEEG) is becoming more common. Among available robotic arms, Stealth Autoguide (SA) (Medtronic, Minneapolis, MN, USA) functions as an optional instrument of the neuronavigation system. The aims of this study were to present our primary experiences with SEEG using SA and to compare the accuracy of implantation between SA and navigation-guided manual adjustment (MA). Seventeen electrodes from two patients who underwent SEEG with SA and 18 electrodes from four patients with MA were retrospectively reviewed. We measured the distance between the planned location and the actual location at entry (De) and the target (Dt) in each electrode. The length of the trajectory did not show a strong correlation with Dt in SA (Pearson's correlation coefficient [r] = 0.099, p = 0.706) or MA (r = 0.233, p = 0.351). De and Dt in SA were shorter than those in MA (1.99 ± 0.90 vs 4.29 ± 1.92 mm, p = 0.0002; 3.59 ± 2.22 vs 5.12 ± 1.40 mm, p = 0.0065, respectively). SA offered higher accuracy than MA both at entry and target. Surgical times per electrode were 38.9 and 32 min in the two patients with SA and ranged from 51.6 to 88.5 min in the four patients with MA. During the implantation period of 10.3 ± 3.6 days, no patients experienced any complications.
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Neuronavegação , Robótica , Eletrodos Implantados , Eletroencefalografia , Humanos , Estudos Retrospectivos , Técnicas EstereotáxicasRESUMO
Dysembryoplastic neuroepithelial tumors (DNTs) are benign brain tumors classified as grade 1 in the 2021 World Health Organization (WHO) classification of central nervous system tumors. DNTs rarely undergo malignant transformation and cause symptomatic intracranial hemorrhage. We report a case of malignant transformation of DNT presenting with intraventricular hemorrhage and review the literature on malignant transformation of DNTs. An 18-year-old woman with a history of epilepsy presented with a sudden headache and vomiting. Radiological examination revealed a mass lesion in the left parietal lobe and intraventricular hemorrhage. The patient underwent an emergency craniotomy for brain tumor resection. The lesion was pathologically diagnosed as a malignant transformation of DNT. She had been followed up without tumor recurrence for 2 years after surgery.
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Thrombolytic therapy in the treatment of cardiogenic acute cerebral embolism caused by coagulated blood carries the risk of hemorrhagic complications, and there is a need to develop safer and more reliable treatment methods. Laser thrombolysis therapy, which utilizes the difference in energy absorption between the thrombus and the arterial wall, has shown promise as a new treatment method because it can selectively act only on the thrombus. It has not been applied clinically, however, and one of the main reasons for this is that its underlying mechanism has not been elucidated. We developed a pulse laser thrombolysis system for treating cerebral blood vessels that consists of a diode-pumped solid-state neodymium-yttrium aluminum garnet laser, which has excellent stability and maintainability and is suitable for clinical applications coupled to a small-diameter optical fiber. Moreover, we analyzed the mechanisms that occur during pulsed laser irradiation of transparent glass tubes and gelatin phantoms. We found that bubbles form as a thermal effect in addition to ablation of the pulsed laser irradiation. Furthermore, we detected no shock waves or water jets associated with the bubbles. We analyzed the bubbles' dynamics and growth rate, and their effect on a rabbit blood clot phantom. We concluded that the bubbles generated by the laser irradiation physically cut the thrombus and thereby had a thrombectomy effect. We believe that this study will clarify the mechanism of laser thrombolysis therapy and contribute greatly to the realization of its clinical application.