Shear stress and pathophysiological PI3K involvement in vascular malformations.

Molecular characterization of vascular anomalies has revealed that affected endothelial cells (ECs) harbor gain-of-function (GOF) mutations in the gene encoding the catalytic α subunit of PI3Kα (PIK3CA). These PIK3CA mutations are known to cause solid cancers when occurring in other tissues. PIK3CA-related vascular anomalies, or "PIKopathies," range from simple, i.e., restricted to a particular form of malformation, to complex, i.e., presenting with a range of hyperplasia phenotypes, including the PIK3CA-related overgrowth spectrum. Interestingly, development of PIKopathies is affected by fluid shear stress (FSS), a physiological stimulus caused by blood or lymph flow. These findings implicate PI3K in mediating physiological EC responses to FSS conditions characteristic of lymphatic and capillary vessel beds. Consistent with this hypothesis, increased PI3K signaling also contributes to cerebral cavernous malformations, a vascular disorder that affects low-perfused brain venous capillaries. Because the GOF activity of PI3K and its signaling partners are excellent drug targets, understanding PIK3CA's role in the development of vascular anomalies may inform therapeutic strategies to normalize EC responses in the diseased state. This Review focuses on PIK3CA's role in mediating EC responses to FSS and discusses current understanding of PIK3CA dysregulation in a range of vascular anomalies that particularly affect low-perfused regions of the vasculature. We also discuss recent surprising findings linking increased PI3K signaling to fast-flow arteriovenous malformations in hereditary hemorrhagic telangiectasias.

CCM3 Loss-Induced Lymphatic Defect Is Mediated by the Augmented VEGFR3-ERK1/2 Signaling.

OBJECTIVE: Cerebral cavernous malformations (CCMs) can happen anywhere in the body, although they most commonly produce symptoms in the brain. The role of CCM genes in other vascular beds outside the brain and retina is not well-examined, although the 3 CCM-associated genes (CCM1, CCM2, and CCM3) are ubiquitously expressed in all tissues. We aimed to determine the role of CCM gene in lymphatics. Approach and Results: Mice with an inducible pan-endothelial cell (EC) or lymphatic EC deletion of Ccm3 (Pdcd10ECKO or Pdcd10LECKO) exhibit dilated lymphatic capillaries and collecting vessels with abnormal valve structure. Morphological alterations were correlated with lymphatic dysfunction in Pdcd10LECKO mice as determined by Evans blue dye and fluorescein isothiocyanate(FITC)-dextran transport assays. Pdcd10LECKO lymphatics had increased VEGFR3 (vascular endothelial growth factor receptor-3)-ERK1/2 (extracellular signal-regulated kinase 1/2) signaling with lymphatic hyperplasia. Mechanistic studies suggested that VEGFR3 is primarily regulated at a transcriptional level in Ccm3-deficient lymphatic ECs, in an NF-κB (nuclear factor κB)-dependent manner. CCM3 binds to importin alpha 2/KPNA2 (karyopherin subunit alpha 2), and a CCM3 deletion releases KPNA2 to activate NF-κB P65 by facilitating its nuclear translocation and P65-dependent VEGFR3 transcription. Moreover, increased VEGFR3 in lymphatic EC preferentially activates ERK1/2 signaling, which is critical for lymphatic EC proliferation. Importantly, inhibition of VEGFR3 or ERK1/2 rescued the lymphatic defects in structure and function. CONCLUSIONS: Our data demonstrate that CCM3 deletion augments the VEGFR3-ERK1/2 signaling in lymphatic EC that drives lymphatic hyperplasia and malformation and warrant further investigation on the potential clinical relevance of lymphatic dysfunction in patients with CCM.

Mortality in Patients with Brainstem Cavernous Malformations.

OBJECTIVE: Brainstem cavernous malformations (BSCM)-associated mortality has been reported up to 20% in patients managed conservatively, whereas postoperative mortality rates range from 0 to 1.9%. Our aim was to analyze the actual risk and causes of BSCM-associated mortality in patients managed conservatively and surgically based on our own patient cohort and a systematic literature review. METHODS: Observational, retrospective single-center study encompassing all patients with BSCM that presented to our institution between 2006 and 2018. In addition, a systematic review was performed on all studies encompassing patients with BSCM managed conservatively and surgically. RESULTS: Of 118 patients, 54 were treated conservatively (961.0 person years follow-up in total). No BSCM-associated mortality was observed in our conservatively as well as surgically managed patient cohort. Our systematic literature review and analysis revealed an overall BSCM-associated mortality rate of 2.3% (95% CI: 1.6-3.3) in 22 studies comprising 1,251 patients managed conservatively and of 1.3% (95% CI: 0.9-1.7) in 99 studies comprising 3,275 patients with BSCM treated surgically. CONCLUSION: The BSCM-associated mortality rate in patients managed conservatively is almost as low as in patients treated surgically and much lower than in frequently cited reports, most probably due to the good selection nowadays in regard to surgery.

Astrocytes propel neurovascular dysfunction during cerebral cavernous malformation lesion formation.

Cerebral cavernous malformations (CCMs) are common neurovascular lesions caused by loss-of-function mutations in 1 of 3 genes, including KRIT1 (CCM1), CCM2, and PDCD10 (CCM3), and generally regarded as an endothelial cell-autonomous disease. Here we reported that proliferative astrocytes played a critical role in CCM pathogenesis by serving as a major source of VEGF during CCM lesion formation. An increase in astrocyte VEGF synthesis is driven by endothelial nitric oxide (NO) generated as a consequence of KLF2- and KLF4-dependent elevation of eNOS in CCM endothelium. The increased brain endothelial production of NO stabilized HIF-1α in astrocytes, resulting in increased VEGF production and expression of a "hypoxic" program under normoxic conditions. We showed that the upregulation of cyclooxygenase-2 (COX-2), a direct HIF-1α target gene and a known component of the hypoxic program, contributed to the development of CCM lesions because the administration of a COX-2 inhibitor significantly prevented the progression of CCM lesions. Thus, non-cell-autonomous crosstalk between CCM endothelium and astrocytes propels vascular lesion development, and components of the hypoxic program represent potential therapeutic targets for CCMs.

Abortive intussusceptive angiogenesis causes multi-cavernous vascular malformations.

Mosaic inactivation of CCM2 in humans causes cerebral cavernous malformations (CCMs) containing adjacent dilated blood-filled multi-cavernous lesions. We used CRISPR-Cas9 mutagenesis to induce mosaic inactivation of zebrafish ccm2 resulting in a novel lethal multi-cavernous lesion in the embryonic caudal venous plexus (CVP) caused by obstruction of blood flow by intraluminal pillars. These pillars mimic those that mediate intussusceptive angiogenesis; however, in contrast to the normal process, the pillars failed to fuse to split the pre-existing vessel in two. Abortive intussusceptive angiogenesis stemmed from mosaic inactivation of ccm2 leading to patchy klf2a overexpression and resultant aberrant flow signaling. Surviving adult fish manifested histologically typical hemorrhagic CCM. Formation of mammalian CCM requires the flow-regulated transcription factor KLF2; fish CCM and the embryonic CVP lesion failed to form in klf2a null fish indicating a common pathogenesis with the mammalian lesion. These studies describe a zebrafish CCM model and establish a mechanism that can explain the formation of characteristic multi-cavernous lesions.

Mapping endothelial-cell diversity in cerebral cavernous malformations at single-cell resolution.

Cerebral cavernous malformation (CCM) is a rare neurovascular disease that is characterized by enlarged and irregular blood vessels that often lead to cerebral hemorrhage. Loss-of-function mutations to any of three genes results in CCM lesion formation; namely, KRIT1, CCM2, and PDCD10 (CCM3). Here, we report for the first time in-depth single-cell RNA sequencing, combined with spatial transcriptomics and immunohistochemistry, to comprehensively characterize subclasses of brain endothelial cells (ECs) under both normal conditions and after deletion of Pdcd10 (Ccm3) in a mouse model of CCM. Integrated single-cell analysis identifies arterial ECs as refractory to CCM transformation. Conversely, a subset of angiogenic venous capillary ECs and respective resident endothelial progenitors appear to be at the origin of CCM lesions. These data are relevant for the understanding of the plasticity of the brain vascular system and provide novel insights into the molecular basis of CCM disease at the single cell level.

Evolution of Developmental Venous Anomalies in the Setting of a Torcular Dural Arteriovenous Fistula and Cerebrofacial Venous Metameric Syndrome.

BACKGROUND: We describe evolution of a developmental venous anomaly (DVA) over time in a patient with a complex intracranial vascular malformation. CASE DESCRIPTION: A 26-year-old male patient initially presented with a scalp vascular malformation and was later diagnosed to have a torcular dural arteriovenous fistula resembling a dural sinus malformation. The dural fistula increased in size over 4 years. The dural fistula also was associated with multiple complex developmental venous anomalies draining the bilateral cerebral hemispheres and cerebellum. The DVA was only faintly demonstrated on the baseline magnetic resonance imaging but appeared to increase in size and extent over time as the dural arteriovenous fistula developed more aggressive angioarchitecture features. In addition to the evolution manifestation of the DVAs, the patient developed multiple de novo cavernous malformations in the venous radicles of the DVA. Increased venous hypertension in the superficial venous system from the dural fistula likely resulted in growth of the DVAs, as they served as the primary means of venous drainage for the bilateral cerebral hemispheres. The patient also had reopening of the persistent falcine sinus, which was not present at baseline. CONCLUSIONS: This would be the first reported case of growth or evolution of a DVA in association with a dural arteriovenous fistula in an adult patient and highlights the dynamic nature of both the medullary venous and dural venous sinuses of the cerebral venous system, even into adulthood.

Focal epilepsy caused by single cerebral cavernous malformation (CCM) is associated with regional and global resting state functional connectivity (FC) disruption.

Epilepsy, including the type with focal onset, is increasingly viewed as a disorder of the brain network. Here we employed the functional connectivity (FC) metrics estimated from the resting state functional MRI (rsfMRI) to investigate the changes of brain network associated with focal epilepsy caused by single cerebral cavernous malformation (CCM). Eight CCM subjects and 21 age and gender matched controls were enrolled in the study. Seven of 8 CCM subjects underwent surgical resection of the CCM and became seizure free and 4 of the surgical subjects underwent a repeat rsfMRI study. We showed that there was both regional and global disruption of the FC values among the CCM subjects including decreased in homotopic FC (HFC) and global FC (GFC) in the regions of interest (ROIs) where the CCMs were located. There was also the disruption of the default mode network (DMN) especially the FC between the middle prefrontal cortex (MPFC) and the right lateral parietal cortex (LPR) among these individuals. We observed the trend of alleviation of these disruptions after the individual has become seizure free from the surgical resection of the CCM. Using a voxel-based approach, we found the disruption of the HFC and GFC in the brain tissue immediately adjacent to the CCM and the severity of the disruption appeared inversely proportional to the distance of the brain tissue to the lesion. Our findings confirm the disruption of normal brain networks from focal epilepsy, a process that may be reversible with successful surgical treatments rendering patients seizure free. Some voxel-based metrics may help identify the epileptogenic zone and guide the surgical resection.

Blood Flow Suppresses Vascular Anomalies in a Zebrafish Model of Cerebral Cavernous Malformations.

RATIONALE: Pathological biomechanical signaling induces vascular anomalies including cerebral cavernous malformations (CCM), which are caused by a clonal loss of CCM1/KRIT1 (Krev interaction trapped protein 1), CCM2/MGC4607, or CCM3/PDCD10. Why patients typically experience lesions only in lowly perfused venous capillaries of the cerebrovasculature is completely unknown. OBJECTIVE: In contrast, animal models with a complete loss of CCM proteins lack a functional heart and blood flow and exhibit vascular anomalies within major blood vessels as well. This finding raises the possibility that hemodynamics may play a role in the context of this vascular pathology. METHODS AND RESULTS: Here, we used a genetic approach to restore cardiac function and blood flow in a zebrafish model of CCM1. We find that blood flow prevents cardiovascular anomalies including a hyperplastic expansion within a large Ccm1-deficient vascular bed, the lateral dorsal aorta. CONCLUSIONS: This study identifies blood flow as an important physiological factor that is protective in the cause of this devastating vascular pathology.

Microsurgical Management of Midbrain Cavernous Malformations: Predictors of Outcome and Lesion Classification in 72 Patients.

BACKGROUND: Due to the complex segmental organization of the brainstem, it is preferable to study midbrain cavernous malformations (MCMs) separately from pontine and medullary lesions. OBJECTIVE: To evaluate clinical results after microsurgical removal of MCMs, assess predictors for outcome and introduce a topographical classification of MCMs. METHODS: A retrospective study was conducted on consecutive patients who underwent MCM resection. Clinical parameters before and after surgery, morphological CM features, surgical approaches and outcomes were analyzed. MCMs were classified according to their exact location within the midbrain and their axial and sagittal extension. RESULTS: The authors reviewed 72 patients (35 male). Lesions varied in size between 4 and 55 mm. The vast majority of patients benefited from surgery. The mean modified Rankin Scale (mRS) decreased significantly from 1.6 at admission to 1.3 at discharge and to 0.7 at follow-up (6-247 mo postoperatively). Five patients (6.9%) suffered from delayed hypertrophic olivary degeneration as visualized on magnetic resonance imaging. One male suffered from early postoperative re-bleeding that required surgical hematoma evacuation. There were no severe long tract impairment or other disabling complications, no delayed re-bleedings, and no surgical mortality. CONCLUSION: We present a new topographic classification of MCMs that may be useful for predicting the occurrence of postoperative eye movement disorders. Other predictors of persistent oculomotor disturbances are time interval between onset of symptoms and surgery, and patient's age over 40 yr. Early surgery is recommendable in patients with oculomotor disturbances. MCM size over 18 mm, patient age over 40 yr, and poor mRS at admission are important predictors for the long-term outcome.

Intraoperative facial motor evoked potential monitoring for pontine cavernous malformation resection.

OBJECTIVE: The aim of this study was to predict postoperative facial nerve function during pontine cavernous malformation surgery by monitoring facial motor evoked potentials (FMEPs). METHODS: From 2008 to 2017, 10 patients with pontine cavernous malformations underwent total resection via the trans-fourth ventricle floor approach with FMEP monitoring. House-Brackmann grades and Karnofsky Performance Scale (KPS) scores were obtained pre- and postoperatively. The surgeries were performed using one of 2 safe entry zones into the brainstem: the suprafacial triangle and infrafacial triangle approaches. Six patients underwent the suprafacial triangle approach, and 4 patients underwent the infrafacial triangle approach. A cranial peg screw electrode was used to deliver electrical stimulation for FMEP by a train of 4 or 5 pulse anodal constant current stimulation. FMEP was recorded from needle electrodes on the ipsilateral facial muscles and monitored throughout surgery by using a threshold-level stimulation method. RESULTS: FMEPs were recorded and analyzed in 8 patients; they were not recorded in 2 patients who had severe preoperative facial palsy and underwent an infrafacial triangle approach. Warning signs appeared in all patients who underwent the suprafacial triangle approach. However, after temporarily stopping the procedures, FMEP findings during surgery showed recovery of the thresholds. FMEPs in patients who underwent the infrafacial triangle approach were stable during the surgery. House-Brackmann grades were unchanged postoperatively in all patients. Postoperative KPS scores improved in 3 patients, decreased in 1, and remained the same in 6 patients. CONCLUSIONS: FMEPs can be used to monitor facial nerve function during surgery for pontine cavernous malformations, especially when the suprafacial triangle approach is performed.

Emerging Pharmacologic Targets in Cerebral Cavernous Malformation and Potential Strategies to Alter the Natural History of a Difficult Disease: A Review.

Importance: Cerebral cavernous malformations (CCMs) are vascular lesions of the brain that may lead to hemorrhage, seizures, and neurologic deficits. Most are linked to loss-of-function mutations in 1 of 3 genes, namely CCM1 (originally called KRIT1), CCM2 (MGC4607), or CCM3 (PDCD10), that can either occur as sporadic events or are inherited in an autosomal dominant pattern with incomplete penetrance. Familial forms originate from germline mutations, often have multiple intracranial lesions that grow in size and number over time, and cause an earlier and more severe presentation. Despite active preclinical research on a few pharmacologic agents, clinical translation has been slow. Open surgery and, in some cases, stereotactic radiosurgery remain the only effective treatments, but these options are limited by lesion accessibility and are associated with nonnegligible rates of morbidity and mortality. Observations: We discuss the limits of CCM management and introduce findings from in vitro and in vivo studies that provide insight into CCM pathogenesis and indicate molecular mechanisms as potential therapeutic targets. These studies report dysregulated cellular pathways shared between CCM, cardiovascular diseases, and cancer. They also suggest the potential effectiveness of proper drug repurposing in association with, or as an alternative to, targeted interventions. Conclusions and Relevance: We propose methods to exploit specific molecular pathways to design patient-tailored therapeutic approaches in CCM, with the aim to alter its natural progression. In this scenario, the lack of effective pharmacologic options remains a critical barrier that poses an unfulfilled and urgent medical need.

Cerebral cavernous malformations form an anticoagulant vascular domain in humans and mice.

Cerebral cavernous malformations (CCMs) are common brain vascular dysplasias that are prone to acute and chronic hemorrhage with significant clinical sequelae. The pathogenesis of recurrent bleeding in CCM is incompletely understood. Here, we show that central nervous system hemorrhage in CCMs is associated with locally elevated expression of the anticoagulant endothelial receptors thrombomodulin (TM) and endothelial protein C receptor (EPCR). TM levels are increased in human CCM lesions, as well as in the plasma of patients with CCMs. In mice, endothelial-specific genetic inactivation of Krit1 (Krit1 ECKO ) or Pdcd10 (Pdcd10 ECKO ), which cause CCM formation, results in increased levels of vascular TM and EPCR, as well as in enhanced generation of activated protein C (APC) on endothelial cells. Increased TM expression is due to upregulation of transcription factors KLF2 and KLF4 consequent to the loss of KRIT1 or PDCD10. Increased TM expression contributes to CCM hemorrhage, because genetic inactivation of 1 or 2 copies of the Thbd gene decreases brain hemorrhage in Pdcd10 ECKO mice. Moreover, administration of blocking antibodies against TM and EPCR significantly reduced CCM hemorrhage in Pdcd10 ECKO mice. Thus, a local increase in the endothelial cofactors that generate anticoagulant APC can contribute to bleeding in CCMs, and plasma soluble TM may represent a biomarker for hemorrhagic risk in CCMs.

Developmental venous anomalies and brainstem cavernous malformations: a proposed physiological mechanism for haemorrhage.

The incidental diagnosis of both developmental venous anomalies (DVAs) and cavernous malformations (CMs) in the central nervous system is increasing with improved imaging techniques. While classically silent diseases, these cerebrovascular pathologies can follow an aggressive course, particularly when present in the brainstem. In the last decade, substantial research has focussed on KRIT1-mediated tight junction gene expression and their role in CM development. However, our understanding of the physiologic conditions precipitating symptomatic CM development or CM haemorrhage with and without concomitant DVAs, remains lacking. The only established risk factor for CM haemorrhage is a previous history of haemorrhage, and literature currently reports trauma as the only precipitant for symptomatic events. While plausible, this occurs in a minority, with many patients experiencing occult events. This manuscript presents a hypothesis for symptomatic CM events by first discussing the anatomical pathways for intracranial venous outflow via the internal jugular veins (IJV) and vertebral venous plexus (VVP), then exploring the role of venous flow diversion away from the IJVs under physiologic stress during dynamic postural shift. The resultant increase in intracranial venous pressure can exacerbate normal and pre-existing structural DVA pathologies, with repeated exposure causing symptomatic or CM-inducing events. This pathophysiological model is considered in the context of the role of the autonomic nervous system (ANS) in postural intracranial venous outflow diversion, and how this may increase the risk of DVA or CM events. It is hoped that this hypothesis invokes further investigation into precipitants for DVA or CM events and their sequela and, also, furthers the current knowledge on pathophysiological development of DVAs and CMs.

Systematic pharmacological screens uncover novel pathways involved in cerebral cavernous malformations.

Cerebral cavernous malformations (CCMs) are vascular lesions in the central nervous system causing strokes and seizures which currently can only be treated through neurosurgery. The disease arises through changes in the regulatory networks of endothelial cells that must be comprehensively understood to develop alternative, non-invasive pharmacological therapies. Here, we present the results of several unbiased small-molecule suppression screens in which we applied a total of 5,268 unique substances to CCM mutant worm, zebrafish, mouse, or human endothelial cells. We used a systems biology-based target prediction tool to integrate the results with the whole-transcriptome profile of zebrafish CCM2 mutants, revealing signaling pathways relevant to the disease and potential targets for small-molecule-based therapies. We found indirubin-3-monoxime to alleviate the lesion burden in murine preclinical models of CCM2 and CCM3 and suppress the loss-of-CCM phenotypes in human endothelial cells. Our multi-organism-based approach reveals new components of the CCM regulatory network and foreshadows novel small-molecule-based therapeutic applications for suppressing this devastating disease in patients.

Cerebral Venous Malformations in a Chinese Population: Clinical Manifestations, Radiological Characteristics, and Long-Term Prognosis.

OBJECTIVE: We elucidated the clinical and radiological characteristics and analyzed the risk factors for hemorrhage and poor outcomes of cerebral venous malformations (CVMs) in a northern Chinese population. METHODS: We included 60 consecutive patients with CVM patients in Beijing Tiantan Hospital from January 2011 to February 2018. The clinical manifestations, radiological characteristics, management, and outcomes were elucidated and analyzed. The patients were followed up for 5-64 months (median, 26). Poor outcomes included repeat bleeding, secondary infarction, severe disability (modified Rankin scale score ≥3), and death. RESULTS: Infratentorial CVMs were more prone to intracranial hemorrhage (75% vs. 28.6%; P < 0.001), dizziness (37.5% vs. 10.7%; P = 0.017), and focal neurological deficits (65.6% vs. 25%; P = 0.002) than were supratentorial CVMs. Supratentorial CVMs were more prone to seizure (32.1% vs. 0%; P = 0.001) than were infratentorial CVMs. Multivariate logistic regression revealed that the major risk factors for intracranial hemorrhage in CVMs were infratentorial lesions (P = 0.003) and complicated cavernous angiomas (P = 0.016). Compared with conservative treatment, resection of hematoma or cavernous angiomas with CVM preservation did not increase the risk of poor outcomes (P = 0.646). However, CVM resection significantly increased that risk (odds ratio, 44.0; P = 0.003). CONCLUSIONS: Our results have shown that conservative treatment of CVMs results in a relatively good prognosis. For those complicated by hemorrhage or cavernous angiomas requiring surgical interventions, the integrity of the CVM should be preserved, irrespective of the treatment. In exceptional cases, before CVM resection, the CVM drainage should be comprehensively evaluated.

Craniotomy for a Large and Aggressive De Novo Cavernous Malformation Resection in the Basal Ganglia Region.

BACKGROUND: Cerebral cavernous malformations (CCMs) are present in up to 0.5% of the general population. Although CCMs have been considered congenital lesions, numerous reports have observed de novo formations in patients with the familial form of CCM and in patients after cranial radiotherapy. Outside of these circumstances, there is scant evidence as to the potential etiologies of CCM. CASE DESCRIPTION: We present a 48-year-old woman with a medical history of endometrial hyperplasia concomitant endometrial polyps demonstrating a large de novo CCM, which grew to a large size in a period of 20 months. A previous magnetic resonance imaging scan showed no abnormalities. This CCM exhibited aggressive biological behavior characterized by recurrent overt bleeding and seizure. Histopathologic analysis confirmed the diagnosis of CCM. Here, we discuss the growth mechanisms of these lesions. CONCLUSIONS: Given the patient's medical history and imaging findings, we propose that de novo CCMs can arise directly from angiogenic proliferation, secondary to BCL-2 overexpression from underlying causes. We hypothesize that inappropriate secretion of estrogen could have set off a genetic cascade with attendant endothelial proliferation. Thus, female hormones may play an important role in influencing the biological behavior of CCMs. The relationship between estrogen and CCM needs further investigation.

Computer-aided diagnosis of cavernous malformations in brain MR images.

Cavernous malformation or cavernoma is one of the most common epileptogenic lesions. It is a type of brain vessel abnormality that can cause serious symptoms such as seizures, intracerebral hemorrhage, and various neurological disorders. Manual detection of cavernomas by physicians in a large set of brain MRI slices is a time-consuming and labor-intensive task and often delays diagnosis. In this paper, we propose a computer-aided diagnosis (CAD) system for cavernomas based on T2-weighted axial plane MRI image analysis. The proposed technique first extracts the brain area based on atlas registration and active contour model, and then performs template matching to obtain candidate cavernoma regions. Texture, the histogram of oriented gradients and local binary pattern features of each candidate region are calculated, and principal component analysis is applied to reduce the feature dimensionality. Support vector machines (SVMs) are finally used to classify each region into cavernoma or non-cavernoma so that most of the false positives (obtained by template matching) are eliminated. The performance of the proposed CAD system is evaluated and experimental results show that it provides superior performance in cavernoma detection compared to existing techniques.

Surgical outcome of motor deficits and neurological status in brainstem cavernous malformations based on preoperative diffusion tensor imaging: a prospective randomized clinical trial.

OBJECTIVE: Surgical management of brainstem lesions is challenging due to the highly compact, eloquent anatomy of the brainstem. This study aimed to evaluate the safety and efficacy of preoperative diffusion tensor imaging (DTI) and diffusion tensor tractography (DTT) in brainstem cavernous malformations (CMs). METHODS: A prospective randomized controlled clinical trial was performed by using stratified blocked randomization. The primary eligibility criterion of the study was being a surgical candidate for brainstem CMs (with informed consent). The study enrolled 23 patients who underwent preoperative DTI/DTT and 24 patients who did not (the control group). The pre- and postoperative muscle strength of both limbs and modified Rankin Scale (mRS) scores were evaluated. Muscle strength of any limb at 12 months after surgery at the clinic visit was the primary outcome; worsened muscle strength was considered to be a poor outcome. Outcome assessors were blinded to patient management. This study reports the preliminary results of the interim analysis. RESULTS: The cohort included 47 patients (22 women) with a mean age of 35.7 years. The clinical baselines between these 2 groups were not significantly different. In the DTI/DTT group, the corticospinal tract was affected in 17 patients (73.9%): it was displaced, deformed/partially interrupted, or completely interrupted in 6, 7, and 4 patients, respectively. The surgical approach and brainstem entry point were adjusted in 3 patients (13.0%) based on DTI/DTT data. The surgical morbidity of the DTI/DTT group (7/23, 30.4%) was significantly lower than that of the control group (19/24, 79.2%, p = 0.001). At 12 months, the mean mRS score (1.1, p = 0.034) and percentage of patients with worsened motor deficits (4.3%, p = 0.006) were significantly lower in the DTI/DTT group than in the control group (1.7% and 37.5%). Multivariate logistic regression identified the absence of preoperative DTI/DTT (OR 0.06, 95% CI 0.01-0.73, p = 0.028) and use of the 2-point method (OR 4.15, 95% CI 1.38-12.49, p = 0.011) as independent adverse factors for a worsened motor deficit. The multivariate model found a significant correlation between poor mRS score and both an increased preoperative mRS score (t = 3.559, p = 0.001) and absence of preoperative DTI/DTT (t = -2.747, p = 0.009). CONCLUSIONS: DTI/DTT noninvasively allowed for visualization of the anatomical relationship between vital tracts and pathologies as well as facilitated the brainstem surgical approach and entry-point decision making. The technique was valuable for complex neurosurgical planning to reduce morbidity. Nonetheless, DTI/DTT data should be interpreted cautiously.■ CLASSIFICATION OF EVIDENCE Type of question: therapeutic; study design: randomized controlled trial; evidence: class I. Clinical trial registration no.: NCT01758211 (ClinicalTrials.gov).