Large germline deletions and duplication in isolated cerebral cavernous malformation patients

Cerebral cavernous malformations (CCM) are vascular lesions that predispose to headaches, seizures, and hemorrhagic stroke. Hereditary CCMs are usually associated with the occurrence of multiple CCMs and occur with a frequency of 1:2,000 to 1:10,000. In this study, eight isolated cases with multiple CCMs but no CCM1-3 point mutation were analyzed using the multiplex ligation-dependent probe amplification assay. Four genomic rearrangements were identified including a previously unreported large duplication within the CCM1 gene and a novel deletion involving the entire coding region of the CCM2 gene. Consequently, systematic screening for CCM deletions/duplications is recommended.     

神经导航下手术切除幕上脑内海绵状血管畸形

目的探讨神经导航在幕上脑内海绵状血管畸形手术中的应用价值。方法回顾性分析手术切除26例幕上脑内海绵状血管畸形患者的临床资料,术前应用StealthStation神经导航系统制定手术计划。术中导航探针指引显微镜下切除病变。结果导航显示病灶的定位误差均在2 mm以内。26例海绵状血管畸形均获全切除,术后所有患者恢复良好,均未出现新的神经功能障碍。结论应用神经导航系统辅助手术可对病变准确定位,手术侵袭性小,可减少手术并发症。     

散发性颅内海绵状血管畸形CCM1基因新突变位点

BACKGROUND： A cerebral cavernous malformation-1 （CCM1） gene mutation might result in functional loss of KREV interaction trapped-1 （KRIT1）, which is related to onset of cavernous malformations （CM）. However, data addressing sporadic CM in Chinese patients remains limited to date. OBJECTIVE： To analyze CCM1 mutation of Chinese patients with sporadic intracranial CM. DESIGN, TIME AND SETTING： Genetics experiment was performed in the Department of Neurosurgery, Huashan Hospital Affiliated to Fudan University between January 2004 and December 2005. PARTICIPANTS： Ninety patients with sporadic CM served as the CM group, and 30 healthy subjects were considered to be the control group. METHODS： Peripheral blood was collected from patients with CM and from control group subjects Genomic DNA was extracted, and exons 8, 9, 11, 12, 13, 15, 16, 17, and 18, as well as the related introns, were amplified using polymerase chain reaction. DNA sequences were compared with GeneBank. MAIN OUTCOME MEASURES： Abnormal mutable site of CCM1 gene in the two groups. RESULTS： Four exclusive mutations of CCM1 were detected in the CM group, with a sporadic CM mutational rate of 32% （6/19）. Of the four exclusive mutations, there was one missense mutation [exon 12, 1172C→T （S391 F）], one insertion mutation [exon 8, 704insT （K246stop）], one intervening sequence mutation （IVS12-4C→T）, and one synonymous mutation （exon 17, 1875C→T）. With the exception of 1875C→T, all mutations detected in the CM group led to functional changes of the KRIT1 protein, which was encoded by the CCM1 gene. Gene mutations were not detected in the control group. CONCLUSION： Four exclusive mutations of the CCM1 gene were determined in Chinese patients with sporadic CM, which led to functional changes or loss of the encoding KRIT1 protein. KRIT1 protein is considered to be the genetic basis of CM occurrence.     

Thrombus and encapsulated hematoma in cerebral cavernous malformations

Thrombi, encapsulated hematomas, and granulation tissue are frequently seen in cerebral cavernous malformations (CCMs). We investigated the role that these histological changes play in repeated hemorrhages in CCMs as well as lesion growth, examining specimens of CCMs surgically harvested from 20 patients. The immunohistochemical study included thrombomodulin (TM) and endothelial cell protein C receptor (EPCR), which are important regulators of blood coagulation. Thick capsules, which contained blood degradation product, were seen in cases with encapsulated hematomas. Clusters of sinusoidal vessels were found outside of these thick capsules. Granulation tissue with inflammatory infiltrates and capillaries was seen in 4 cases with non-capsulated hematomas. Organizing thrombi were seen in sinusoidal vessels in 15 out of 20 cases. Factor VIII-related antigen staining demonstrated numerous capillaries in and around organizing thrombi and within the thickened vessel walls as well as in both the inner and outer sides of the hematoma capsule. TM and EPCR were positive in the endothelial cells of these capillaries, whereas they were negative in those of capillaries in the brain surrounding the lesions. Our study suggests that thrombosed sinusoidal blood vessels could gradually expand by repeated bleeding from numerous capillaries inside the wall and become encapsulated hematomas, and capillaries outside the thickened vessel wall could become sinusoidal blood vessels. Thrombosis within cerebral venules could be one of the causal factors of CCMs.     

Cerebral infarction in the caudate nucleus associated with acute epidural hematoma and diffuse brain injury in a child after severe head injury

Case report A 6-year-old boy was admitted to our hospital 20 min after receiving a direct impact to his head in an automobile accident. He was semi-comatose on admission and computed tomography showed acute epidural hematoma in the right supratentorial region. Three hours later, his consciousness deteriorated due to the enlargement of the hematoma. Surgical removal of hematoma relieved his consciousness disturbance. Post-operative magnetic resonance imaging revealed spotty high-intensity lesions in the corpus callosum on T2-weighted images, and a solitary high-intensity lesion in the left caudate nucleus extending to the medial globus pallidum on T2-weighted and diffusion-weighted images. Magnetic resonance angiography showed no abnormality in the main arteries. These results suggested cerebral infarction in the vascular territory supplied by the recurrent artery of Heubner in association with diffuse brain injury. Post-operative course was uneventful and he was discharged without neurological deficit.Conclusions Post-traumatic cerebral infarction in the caudate nucleus is extremely rare, and its association with diffuse brain injury and epidural hematoma is apparently unique.     

Intramedullary spinal arteriovenous malformation in a boy of familial cerebral cavernous hemangioma

Object The coexistence of spinal arteriovenous malformation (AVM) and a familial cerebral cavernous hemangioma (CCH) is extremely rare. Methods A 9-year-old boy suddenly developed severe paraplegia and urinary dysfunction. Spinal magnetic resonance imaging (MRI) scan revealed a cervical and upper thoracic intramedullary lesion. Due to acute neurological dysfunction, the patient underwent emergency surgical exploration. An intramedullary vascular lesion was found and excised. Pathologically, AVM was noted. After the surgery, the boy was ambulatory with left lower limb stiffness. MRI scan of the brain revealed multiple cerebral cavernous hemangioma. Symptomatic multiple CCH in his mother and grandmother were also noted. Conclusions We concluded that the presence of spinal AVM should be suspected if the patient with familial CCH develops the signs of space-occupying lesion of the spinal cord, facilitating early diagnosis of the spinal AVM.     

Glioblastoma with the appearance of arteriovenous malformation: Pitfalls in diagnosis

Objectives

Very few cases of arteriovenous malformations (AVMs) associated with gliomas were reported so far in the literature.

Methods

Here, we report a rare case of a glioblastoma with an AVM-like lesion and review the existing literature.

Results

We report an unusual case of a 72-year old woman, who presented with a progressive history of aphasia, memory deficit, and headache. Initial MRI imaging was suggestive of a high-grade glioma for which a pterional craniotomy was performed. Intraoperatively, the lesion resembled a vascular malformation. Total extirpation of the lesion was verified by intraoperative MR imaging. Initial histopathological analysis revealed an AVM. Due to the discrepancy between the radiologic and histopathologic findings, the patient was monitored at close intervals. Two month later, multiple lesions were visible on MRI imaging, thus, supporting the diagnosis of malignant glioma. Therefore, after reinvestigating the histopathological sections and cutting the paraffin block in additional serial sections, in only 5% of the section a glioblastoma was discerned which was surrounded by an AVM-like lesion.

Conclusion

Gliomas are rarely found in association with AVMs and require accurate diagnostic evaluation and interpretation for adequate therapeutic interventions.     

Ultrastructural analysis of vascular features in cerebral cavernous malformations

Objective

Investigation of the structure of vascular malformations highlights the pathogenic mechanisms underlying their clinical behavior. One of the vascular malformations is called cerebral cavernous malformation (CCM). However, the ultrastructural features of the vascular malformations are not defined in detail.

Methods

We aimed to investigate the ultrastructural features of CCMs using transmission (TEM), scanning (SEM) electron microscopy, and also immunohistochemistry methods with antibodies against CCM proteins such as CCM2 and CCM3. CCM tissues (n = 6) microsurgically excised from patients for conventional indications.

Results

CCM2 and CCM3 were strongly detected in the vascular endothelium. However, there was a very weak immunostaining in stroma. SEM observations revealed that there were ruptures and damages in the luminal endothelium, possibly due to the damage of intercellular junctions. TEM observations also showed a few ruptures and detachments between the endothelium and basal lamina as observed with partially damages and disconnections. The architecture of pericytes showed protrusions and shrinkages. Our results suggest that the thin vessel walls of CCMs were lacking of subendothelial support and intact basal lamina underlying the endothelial cells.

Conclusion

This study is so far the first study attempting to show human CCM lesions with SEM. We believe that an understanding of the ultrastructural features of these lesions by light and electron microscopy techniques would help to understand the pathology of these diseases.     

中枢神经系统海绵状血管畸形的新分类

目的 基于术前MRI影像和术中病理形态特征,提出中枢神经系统海绵状血管畸形的新分类.方法 回顾性分析经显微手术切除的97例海绵状血管畸形的临床资料.根据术前MRI表现和术中病理形态特征,将病变分为团块型、假包膜型、混合型和巨大型,并统计分析.结果 团块型47例(48.5%),假包膜型33例(34.0%),混合型14例(14.4%),巨大型3例(3.1%).不同类型海绵状血管畸形病人的就诊年龄、首发症状构成比有显著性差异(均P<0.05),但分布部位、病程无差别(均P >0.05).巨大型病人平均就诊年龄最小,为.17.7岁.假包膜型的首发症状以神经功能障碍(48.5%)和头痛(27.3%)居多,团块型以癜癎(46.8%)和神经功能障碍(25.5%)居多,混合型以癜癎(42.9%)和头痛(35.7%)居多.除巨大型,其他类型病灶大小有显著性差异(P<0.05),混合型最大,团块型最小.结论 不同类型的海绵状血管畸形各有临床特点,区分不同类型病变有助于精细手术.     

女性抑郁症患者尾状核和杏仁体磁共振研究

目的:探讨女性抑郁症患者的尾状核和杏仁体的体积变化.方法:采用3.0磁共振,分别测量抑郁症患者(30例,抑郁组)及对照组(30名)的尾状核和杏仁体的体积. 结果:抑郁症组尾状核体积左右侧分别为( 4349±517.5 )mm3,( 4208±394.3 )mm3;对照组组尾状核体积左右侧为( 5086±449.3)mm...     

The role of the nucleus raphe pontis and the caudate nucleus in alfentanil rigidity in the rat

Attempts to eliminate or reduce the rigidity with high-dose narcotic anesthesia in the operating room have been only partially successful. Previous investigations of opioid receptor sites mediating this rigidity have implicated two central regions: the nucleus raphe pontis (NRP) within the reticular formation and the caudate nucleus (CN) within the basal ganglia. The present study used systematically administered alfentanil (ALF), a potent, short-acting fentanyl analog, and intracerebrally infused methylnaloxonium (MN), a quaternary derivative of naloxone, to elucidate further the functional role of the NRP and CN in rigidity. ALF (0.5 mg/kg s.c.) produced a reliable model of rigidity, as documented by gastrocnemius electromyography. The onset of this rigidity was within 60 s of ALF administration, with a total duration of approximately 40–50 min. Intracerebroventricular (i.c.v.) injections of 2.0 or 4.0 μg of MN 15 min prior to ALF treatment prevented rigidity, while 0.125 or 0.5 μg had no significant effect on rigidity. MN injected directly into the NRP at doses as low as 0.125 μg significantly antagonized ALF-induced rigidity, while injections of MN into the caudate nucleus at doses as high as 4.0 μg failed to antagonize ALF-induced rigidity. These observations demonstrate that injection of MN into the NRP is at least 16-fold more effective in blocking ALF-induced rigidity than MN injected into the ventricle and, more importantly, at least 32-fold more effective than MN injected into the CN. The results suggest that the NRP may be an important site for the neural control of muscular rigidity associated with high-dose narcotic administration.     

Morphometric study of synaptic patterns in the rat caudate nucleus and hippocampus under haloperidol treatment

A morphometric study of the synapses on dendritic shafts and spines was performed in the rat caudate nucleus and the CAI area of the hippocampus under chronic haloperidol treatment. In the nucleus caudatus, the synaptic density on dendritic shafts increased by 83% and those on spines by 53%. Most of the parameters measured in axospinous synapses were significantly increased: the area of presynaptic axon terminals (20%), the number of mitochondria per axon terminal (51%), the length of active zone (11%), the area of postsynaptic density (23%), and the perimeter of postsynaptic density (12.5%). The area of postsynaptic spines showed no changes. In the synapses on dendritic shafts, the area of presynaptic terminals decreased (31%), the area of mitochondria per terminal decreased (40%), the length of active zone increased (14%), and other parameters were unchanged. There were no significant differences in the same parameters measured in the hippocampus. The data are discussed as morphological correlates of behavioral supersensitivity and dopamine D2 receptor up-regulation.     

Encoding of social state information by neuronal activities in the macaque caudate nucleus

Social animals adjust their behavior according to social relationships and momentary circumstances. Dominant–submissive relationships modulate, but do not completely determine, their competitive behaviors. For example, a submissive monkey's decision to retrieve food depends not only on the presence of dominant partners but also on their observed behavior. Thus, behavioral expression requires a dynamic evaluation of reward outcome and momentary social states. The neural mechanisms underlying this evaluation remain elusive. The caudate nucleus (CN) plays a pivotal role in representing reward expectation and translating it into action selection. To investigate whether their activities encode social state information, we recorded from CN neurons in monkeys while they performed a competitive food-grab task against a dominant competitor. We found two groups of CN neurons: one primarily responded to reward outcome, while the other primarily tracked the monkey's social state. These social state-dependent neurons showed greater activity when the monkeys freely retrieved food without active challenges from the competitor and reduced activity when the monkeys were in a submissive state due to the competitor's active behavior. These results indicate that different neuronal activities in the CN encode social state information and reward-related information, which may contribute to adjusting competitive behavior in dynamic social contexts.     

Functional outcome after initial and multiple intracerebral hemorrhages in children with cerebral cavernous malformations

Background and purpose

We aimed to assess the course and predictors of functional outcome after single and multiple intracerebral hemorrhage (ICH) in pediatric patients with cerebral cavernous malformations (CCMs) and to conduct a risk assessment of a third bleed during the first follow-up year after second ICH.

Methods

We included patients aged ≤18 years with complete baseline characteristics, a magnetic resonance imaging dataset, ≥1 CCM-related ICH and ≥1 follow-up examination, who were treated between 2003 and 2021. Neurological functional status was obtained using modified Rankin Scale scores at diagnosis, before and after each ICH, and at last follow-up. Kaplan–Meier analysis was performed to determine the cumulative 1-year risk of third ICH.

Results

A total of 55 pediatric patients (median [interquartile range] age 12 [11] years) were analyzed. Univariate analysis identified brainstem cavernous malformation (BSCM; p = 0.019) as a statistically significant predictor for unfavorable outcome after second ICH. Outcome after second ICH was significantly worse in 12 patients (42.9%; p = 0.030) than after first ICH and in five patients (55.6%; p = 0.038) after a third ICH compared to a second ICH. Cumulative 12-month risk of rebleeding during the first year after a second ICH was 10.7% (95% confidence interval 2.8%–29.37%).

Conclusions

Pediatric patients with a BSCM have a higher risk of worse outcome after second ICH. Functional outcome improves over time after an ICH but worsens following each ICH compared to baseline or previous ICH. Second bleed was associated with neurological deterioration compared to initial ICH, and this deteriorated further after a third ICH.     

De novo development of a cerebral arteriovenous malformation following radiation therapy: Case report and an update to classical arteriovenous malformation nomenclature

Cerebral arteriovenous malformations (AVM) are traditionally considered primary congenital lesions that result from embryological aberrations in vasculogenesis. Recent insights, however, suggest that these lesions may be secondary to a vascular insult such as ischemia or trauma. Herein, the authors present a rare case of a secondary cerebral AVM, occurring in a young girl who received prior cranial radiation therapy. At age 3 years, she underwent surgical resection, chemotherapy, and photon radiation therapy for treatment of a fourth ventricular ependymoma. At age 19 years, she developed new onset seizures and was found to have a left medial temporal lobe AVM. Her seizures were managed successfully with anti-epileptic medications and the AVM was treated with proton radiation therapy. This case highlights a rare but possible vascular sequela of radiation therapy and adds to the growing body of evidence that cerebral AVM may arise as secondary lesions.     

建立家猪脑动静脉畸形模型的方法与体会

目的以家猪为实验对象,通过显微外科手术血管吻合的方法建立一种新型、经济、简单的脑动静脉畸形(AVM)模型及对其相关方面进行研究。方法选用健康家猪8头,3~4个月,30~45 kg,雌雄不限。行显微手术建立AVM模型。手术前3d随机将2例行颈总动脉造影为对照组。分别于手术后3d、1w及1m时行手术对侧颈总动脉血管造影。观察模型建立是否成功。结果(1)8头家猪手术后全部成活,无切口感染现象。无肢体偏瘫现象。(2)对照组行双侧颈总动脉造影,均仅能看到造影侧单侧颅底微血管网。实验组在手术后3d、1w及1w时行手术对侧颈总动脉造影,均可见血流经手术对侧咽升动脉到双侧颅底微血管网,并引流入手术侧咽升动脉和(或)颌内动脉。结论(1)应用家猪通过显微外科手术端-端吻合同侧颈总动脉及颈内静脉的方法建立AVM模型是一种经济易得、操作简单、重复性强的实验方法。(2)此模型可用于栓塞材料栓塞效能的实验研究、模拟AVM形态学及血流动力学方面的研究和介入神经放射学医生的培训。     

以癫痫为首发症状的颞叶海绵状血管畸形的手术治疗方式

目的探讨以癫痫为首发症状的颞叶及颞叶内侧海绵状血管畸形的手术治疗方式。方法回顾性分析广东三九脑科医院2009~2013年手术治疗的49例以癫痫为首发症状的颞叶及颞叶内侧海绵状血管畸形患者,其中全面性强直-阵挛性发作26例,复杂部分性发作23例,20例行单纯病灶切除(A组),29例根据术中脑电监测结果,病灶及颞叶及/或内侧结构癫痫灶扩大切除术(B组)。结果采用Engel效果分级,A组中Ⅰ级为70%,Ⅱ级为20%,Ⅲ级10%;病理检查均为海绵状血管畸形。B组中Ⅰ级89.66%,Ⅱ级6.9%,Ⅲ级3.44%;病理检查为海绵状血管畸形,其中25例包括海马硬化,3例皮质发育不良。术中及术后均无明显并发症及死亡患者。结论对以癫痫为首发症状的颞叶海绵状血管畸形患者,通过积极的手术治疗可有效控制癫痫发作。结合术前及术中脑电结果,采用选择性扩大切除癫痫灶,对控制癫痫更为有效。颞叶及颞叶内侧海绵状血管畸形患者可能存在双重病理改变。