Differential angiogenesis function of CCM2 and CCM3 in cerebral cavernous malformations 

Neurosurgical FOCUS, Volume 29, Issue 3, Page E1, September 2010.

Yuan Zhu, Ph.D., Qun Wu, M.D., Jin-Fang Xu, M.D., Dorothea Miller, M.D., I. Erol Sandalcioglu, M.D., Jian-Min Zhang, M.D., and Ulrich Sure, M.D.

Object

Loss-of-function mutations in CCM genes are frequently detected in familial cerebral cavernous malformations (CCMs). However, the current functional studies of the CCM genes in vitro have been performed mostly in commercially purchased normal cell lines and the results appeared discrepant. The fact that the cerebral vascular defects are rarely observed in CCM gene-deficient animals suggests the requirement of additional pathological background for the formation of vascular lesions. Consistent with these data, the authors assumed that silencing CCM genes in the endothelium derived from CCMs (CCM-ECs) serves as a unique and valuable model for investigating the function of the CCM genes in the pathogenesis of CCMs. To this end, the authors investigated the role and signaling of CCM2 and CCM3 in the key steps of angiogenesis using CCM-ECs.

Methods

Endothelial cells (ECs) derived from CCMs were isolated, purified, and cultured from the fresh operative specimens of sporadic CCMs (31 cases). The CCM2 and CCM3 genes were silenced by the specific short interfering RNAs in CCM-ECs and in control cultures (human brain microvascular ECs and human umbilical vein ECs). The efficiency of gene silencing was proven by real-time reverse transcriptase polymerase chain reaction. Cell proliferation and apoptosis, migration, tube formation, and the expression of phosphor-p38, phosphor-Akt, and phosphor-extracellular signal-regulated kinase

The pathogenetic features of cerebral cavernous malformations: a comprehensive review with therapeutic implications 

Neurosurgical FOCUS, Volume 29, Issue 3, Page E2, September 2010.

Khaled M. Krisht, M.D., Kevin J. Whitehead, M.D., Toba Niazi, M.D., and William T. Couldwell, M.D., Ph.D. Cerebral cavernous malformations (CCMs) are common vascular lesions of the CNS that may lead to seizures, focal neurological deficits, and fatal hemorrhagic stroke. Human genetic studies have identified 3 genes associated with CCM, and biochemical and molecular studies in mice have elucidated signaling pathways with important therapeutic implications. In this review, the authors shed light on the 3 discovered CCM genes as well as their protein products, with particular emphasis on their signal transduction pathways and their interaction with one another. Close focus is directed at mice model studies involving the Ccm2 gene product signaling pathway, revealing an important role for the use of simvastatin or other RhoA inhibitors as a therapeutic modality in the treatment of CCM. The remaining challenges to creating a more faithful CCM animal model as well as future clinical and research implications are reviewed.

Upregulation of transmembrane endothelial junction proteins in human cerebral cavernous malformations 

Neurosurgical FOCUS, Volume 29, Issue 3, Page E3, September 2010.

Jan-Karl Burkhardt, M.D., Dörthe Schmidt, M.D., Ph.D., Roman Schoenauer, Ph.D., Chad Brokopp, M.S., Irina Agarkova, Ph.D., Oliver Bozinov, M.D., Helmut Bertalanffy, M.D., and Simon P. Hoerstrup, M.D., Ph.D.

Object

Cerebral cavernous malformations (CCMs) are among the most prevalent cerebrovascular malformations, and endothelial cells seem to play a major role in the disease. However, the underlying mechanisms, including endothelial intercellular communication, have not yet been fully elucidated. In this article, the authors focus on the endothelial junction proteins CD31, VE-cadherin, and occludin as important factors for functional cell-cell contacts known as vascular adhesion molecules and adherence and tight junctions.

Methods

Thirteen human CCM specimens and 6 control tissue specimens were cryopreserved and examined for the presence of VE-cadherin, occludin, and CD31 by immunofluorescence staining. Protein quantification was performed by triplicate measurements using western blot analysis.

Results

Immunofluorescent analyses of the CCM sections revealed a discontinuous pattern of dilated microvessels and capillaries as well as increased expression of occludin, VE-cadherin, and CD31 in the intima and in the enclosed parenchymal tissue compared with controls. Protein quantification confirmed these findings by showing upregulation of the levels of these proteins up to 2

Cerebral cavernous malformations as a disease of vascular permeability: from bench to bedside with caution 

Neurosurgical FOCUS, Volume 29, Issue 3, Page E4, September 2010.

Sanjay Yadla, M.D., Pascal M. Jabbour, M.D., Robert Shenkar, Ph.D., Changbin Shi, M.D., Ph.D., Peter G. Campbell, M.D., and Issam A. Awad, M.D. Tremendous insight into the molecular and genetic pathogenesis of cerebral cavernous malformations (CCMs) has been gained over the past 2 decades. This includes the identification of 3 distinct genes involved in familial CCMs. Still, a number of unanswered questions regarding the process from gene mutation to vascular malformation remain. It is becoming more evident that the disruption of interendothelial junctions and ensuing vascular hyperpermeability play a principal role. The purpose of this review is to summarize the current understanding of CCM genes, associated proteins, and functional pathways. Promising molecular and genetic therapies targeted at identified molecular aberrations are discussed as well.

Susceptibility weighted magnetic resonance imaging of cerebral cavernous malformations: prospects, drawbacks, and first experience at ultra 

Neurosurgical FOCUS, Volume 29, Issue 3, Page E5, September 2010.

Philipp Dammann, M.D., Markus Barth, Ph.D., Yuan Zhu, Ph.D., Stefan Maderwald, Ph.D., Marc Schlamann, M.D., Mark E. Ladd, Ph.D., and Ulrich Sure, M.D. High-resolution susceptibility weighted MR imaging at high field strength provides excellent depiction of venous structures, blood products, and iron deposits, making it a promising complementary imaging modality for cerebral cavernous malformations (CCMs). Although already introduced in 1997 and being constantly improved, susceptibility weighted imaging is not yet routine in clinical neuroimaging protocols for CCMs. In this article, the authors review the recent literature dealing with clinical and scientific susceptibility weighted imaging of CCMs to summarize its prospects and drawbacks and provide their first experience with its use in ultra

Emerging clinical imaging techniques for cerebral cavernous malformations: a systematic review 

Neurosurgical FOCUS, Volume 29, Issue 3, Page E6, September 2010.

Peter G. Campbell, M.D., Pascal Jabbour, M.D., Sanjay Yadla, M.D., and Issam A. Awad, M.D. Cerebral cavernous malformations (CCMs) are divided into sporadic and familial forms. For clinical imaging, T2-weighted gradient-echo sequences have been shown to be more sensitive than conventional sequences. Recently more advanced imaging techniques such as high-field and susceptibility-weighted MR imaging have been employed for the evaluation of CCMs. Furthermore, diffusion tensor imaging and functional MR imaging have been applied to the preoperative and intraoperative management of these lesions. In this paper, the authors attempt to provide a concise review of the emerging imaging methods used in the clinical diagnosis and treatment of CCMs.

Update on the natural history of cavernous malformations and factors predicting aggressive clinical presentation 

Neurosurgical FOCUS, Volume 29, Issue 3, Page E7, September 2010.

Chad W. Washington, M.D., Kathleen E. McCoy, B.S., and Gregory J. Zipfel, M.D. Cavernous malformations (CMs) are angiographically occult, low-pressure neurovascular lesions with distinct imaging and clinical characteristics. They present with seizure, neurological compromise due to lesion hemorrhage or expansion, or as incidental findings on neuroimaging studies. Treatment options include conservative therapy, medical management of seizures, surgical intervention for lesion resection, and in select cases stereotactic radiosurgery. Optimal management requires a thorough understanding of the natural history of CMs including consideration of issues such as mode of presentation, lesion location, and genetics that may impact the associated neurological risk. Over the past 2 decades, multiple studies have been published, shedding valuable light on the clinical characteristics and natural history of these malformations. The purpose of this review is to provide the reader with a concise consolidation of this published material such that they may better understand the risks associated with CMs and their implications on patient treatment.

Surgical approaches to brainstem cavernous malformations 

Neurosurgical FOCUS, Volume 29, Issue 3, Page E8, September 2010.

Adib A. Abla, M.D., Jay D. Turner, M.D., Ph.D., Alim P. Mitha, M.D., M.Sc., Gregory Lekovic, M.D., Ph.D., J.D., and Robert F. Spetzler, M.D. Brainstem cavernous malformations (CMs) are low-flow vascular lesions in eloquent locations. Their presentation is often marked with symptomatic hemorrhages that appear to occur more frequently than hemorrhage from supratentorial cavernomas. Brainstem CMs can be removed using 1 of the 5 standard skull-base approaches: retrosigmoid, suboccipital (with or without telovelar approach), supracerebellar infratentorial, orbitozygomatic, and far lateral. Patients being referred to a tertiary institution often have lesions that are aggressive with respect to bleeding rates. Nonetheless, the indications for surgery, in the authors' opinion, are the same for all lesions: those that are symptomatic, those that cause mass effect, or those that abut a pial surface. Patients often have relapsing and remitting courses of symptoms, with each hemorrhage causing a progressive and stepwise decline. Many patients experience new postoperative deficits, most of which are transient and resolve fully. Despite the risks associated with operating in this highly eloquent tissue, most patients have had favorable outcomes in the authors' experience. Surgical treatment of brainstem CMs protects patients from the potentially devastating effects of rehemorrhage, and the authors believe that the benefits of intervention outweigh the risks in patients with the appropriate indications.

Brainstem cavernous malformations: anatomical, clinical, and surgical considerations 

Neurosurgical FOCUS, Volume 29, Issue 3, Page E9, September 2010.

Giuliano Giliberto, M.D., Desiree J. Lanzino, Ph.D., Felix E. Diehn, M.D., David Factor, M.S., Kelly D. Flemming, M.D., and Giuseppe Lanzino, M.D. Symptomatic brainstem cavernous malformations carry a high risk of permanent neurological deficit related to recurrent hemorrhage, which justifies aggressive management. Detailed knowledge of the microscopic and surface anatomy is important for understanding the clinical presentation, predicting possible surgical complications, and formulating an adequate surgical plan. In this article the authors review and illustrate the surgical and microscopic anatomy of the brainstem, provide anatomoclinical correlations, and illustrate a few clinical cases of cavernous malformations in the most common brainstem areas.

Operative management of brainstem cavernous malformations 

Neurosurgical FOCUS, Volume 29, Issue 3, Page E10, September 2010.

Wael F. Asaad, M.D., Ph.D., Brian P. Walcott, M.D., Brian V. Nahed, M.D., and Christopher S. Ogilvy, M.D. Brainstem cavernous malformations (CMs) are complex lesions associated with hemorrhage and neurological deficit. In this review, the authors describe the anatomical nuances relating to the operative techniques for these challenging lesions. The resection of brainstem CMs in properly selected patients has been demonstrated to reduce the risk of rehemorrhage and can be achieved relatively safely in experienced hands.

Stereotactic radiosurgery for the treatment of symptomatic brainstem cavernous malformations 

Neurosurgical FOCUS, Volume 29, Issue 3, Page E11, September 2010.

Edward A. Monaco III, M.D., Ph.D., Aftab A. Khan, M.D., Ajay Niranjan, M.Ch., M.B.A., Hideyuki Kano, M.D., Ph.D., Ramesh Grandhi, M.D., Douglas Kondziolka, M.D., F.R.C.S., John C. Flickinger, M.D., and L. Dade Lunsford, M.D.

Object

The authors performed a retrospective review of prospectively collected data to evaluate the safety and efficacy of stereotactic radiosurgery (SRS) for the treatment of patients harboring symptomatic solitary cavernous malformations (CMs) of the brainstem that bleed repeatedly and are high risk for resection.

Methods

Between 1988 and 2005, 68 patients (34 males and 34 females) with solitary, symptomatic CMs of the brainstem underwent Gamma Knife surgery. The mean patient age was 41.2 years, and all patients had suffered at least 2 symptomatic hemorrhages (range 2

Clinical presentation and surgical management of intramedullary spinal cord cavernous malformations 

Neurosurgical FOCUS, Volume 29, Issue 3, Page E12, September 2010.

Daniel C. Lu, M.D., Ph.D., and Michael T. Lawton, M.D.

Object

Intramedullary cavernous malformation (CM) is a rare entity, accounting for 5% of all intraspinal lesions. The objective in this study was to define the clinical characteristics of this disease, detail the surgical approach and technique, and present the clinical outcome.

Methods

Retrospective chart review was performed in 22 patients with histologically confirmed CMs. The authors used a laminectomy approach for midline dorsal lesions, with unilateral radical facetectomy and dentate ligament resection for laterally or ventrally located lesions. Patient profiles, operative indications, surgical approaches, operative findings, complications, and long-term follow-up were reviewed.

Results

The average age of patients in the cohort was 43 ± 14 years, the average duration of symptoms was 7 ± 7 months, and the average follow-up was 6 ± 4 years. The average size of the lesion was 1 ± 0.4 cm, the average surgical time was 4 ± 0.96 hours, and the average estimated blood loss was 350 ± 131 ml. The rate of complication was 5% (1 patient; due to a wound infection). According to the McCormick classification, the score for the cohort was 1.8 ± 1.2 preoperatively, 2.1 ± 1.2 postoperatively, and 1.3 ± 0.65 at late follow-up. (All preceding values are given as the mean ± SD.) There was a significant neurological improvement at follow-up compared with the preoperative state (p < 0.05). The majority of patients (50%) had a stable outcome compared with their preoperative state, with a large proportion (41%) having an improved outcome. A minority of patients (9%) had a worsened outcome due to dysesthetic pain. Patients with dysesthesia had a longer duration of clinical symptoms prior to surgery compared with patients without dysesthesia (p < 0.05).

Conclusions

The authors demonstrated the safety, efficacy, and durability of their surgical approach for resection of spinal intramedullary CM. Proper examination, preoperative imaging, and prompt surgical intervention were necessary for a satisfactory outcome.

Prognostic factors for the outcome of surgical and conservative treatment of symptomatic spinal cord cavernous malformations: a review of a series of 20 patients 

Neurosurgical FOCUS, Volume 29, Issue 3, Page E13, September 2010.

Hans-Jakob Steiger, M.D., Bernd Turowski, M.D., and Daniel Hänggi, M.D.

Object

In this study, the authors present a review of a series of 20 intramedullary spinal cord cavernous malformations (SCCMs) with particular focus on MR imaging and prognostic factors.

Methods

Between 1994 and 2009, 20 patients with SCCM were treated under the care of the senior author. The diagnosis was made in all patients after the onset of clinical symptoms. The age of the 9 men and 11 women ranged between 26 and 71 years (median 38.5 years). The duration of symptoms prior to referral ranged from 1 week to 9 years (median 6.5 months). At the time of referral, 4 patients had no significant neurological deficits, 10 patients suffered significant functional restrictions, and 6 patients presented with severe paraparesis and loss of functional strength. None of the patients had complete paraplegia. Seventeen patients underwent microsurgical removal, while 3 patients opted for conservative therapy. For the present analysis, the medical records and MR images and/or reports were reviewed. Classification of length of history, pretreatment status, MR imaging pattern, and treatment modality was done and correlated with outcome.

Results

The cavernoma was located at the cervical level in 8 patients and between T-1 and L-1 in 12 patients. The cavernoma appeared as mainly T2 hyperintense on MR images in 7 patients, mainly T2 hypointense in 2 patients, and mixed in the remaining 10 patients. The craniocaudal extension of the core varied between 5 and 45 mm. In 2 patients with cervical cavernomas, a distinct T2 signal of the spinal cord cranial and distal to the cavernoma was seen, and in a patient with a large thoracic cavernoma, T2 extinction cranial and caudal to the cavernoma was seen as a sign of hemosiderosis. Neurological deficits improved postoperatively in 12 of the surgically treated patients, remained stable in 2, and deteriorated in 3. The 3 patients who were conservatively treated remained stable over a follow-up of 3

Intramedullary spinal cord cavernous malformations 

Neurosurgical FOCUS, Volume 29, Issue 3, Page E14, September 2010.

Bradley A. Gross, M.D., Rose Du, M.D., Ph.D., A. John Popp, M.D., and Arthur L. Day, M.D. Although originally the subject of rare case reports, intramedullary spinal cord cavernous malformations (CMs) have recently surfaced in an increasing number of case series and natural history reports in the literature. The authors reviewed 27 publications with 352 patients to consolidate modern epidemiological, natural history, and clinical and surgical data to facilitate decision making when managing these challenging vascular malformations. The mean age at presentation was 42 years without a sex predilection. Thirty-eight percent of the cases were cervical, 57% thoracic, 4% lumbar, and 1% unspecified location. Nine percent of the patients had a family history of CNS CMs. Twenty-seven percent of the patients had an associated cranial CM. On presentation 63% of the patients had motor deficits, 65% had sensory deficits, 27% had pain, and 11% had bowel or bladder dysfunction. Presentation was acute in 30%, recurrent in 16%, and progressive in 54% of cases. An overall annual hemorrhage rate was calculated as 2.5% for 92 patients followed up for a total of 2571 patient-years. Across 24 reviewed surgical series, a 91% complete resection rate was found. Transient morbidity was seen in 36% of cases. Sixty-one percent of patients improved, 27% were unchanged, and 12% were worse at the long-term follow-up. Using this information, the authors review surgical nuances in treating these lesions and propose a management algorithm.

Pain outcomes after surgery in patients with intramedullary spinal cord cavernous malformations 

Neurosurgical FOCUS, Volume 29, Issue 3, Page E15, September 2010.

Harel Deutsch, M.D.

Object

The objective of the study was to quantify the improvement in pain levels for patients who have undergone surgery for intramedullary spinal cord cavernous malformations (SCCMs).

Methods

The author reviewed medical records of patients who underwent surgery for an intramedullary SCCM between 2003 and 2010. Numerical pain scores (range 0

Patient-assessed satisfaction and outcome after microsurgical resection of cavernomas causing epilepsy 

Neurosurgical FOCUS, Volume 29, Issue 3, Page E16, September 2010.

Jamie J. Van Gompel, M.D., W. Richard Marsh, M.D., Fredric B. Meyer, M.D., and Gregory A. Worrell, M.D., Ph.D.

Object

Microsurgical resection of supratentorial cavernomas associated with intractable epilepsy is performed frequently. Despite its common occurrence, little is known about patient perceptions of microsurgical resection for cavernomas. This survey study was performed to investigate patient perceived outcome after surgery for cavernomas associated with intractable epilepsy.

Methods

The authors' surgical database was searched for cavernoma resection performed between 1971 and July of 2006. Of the initial 173 patients identified, 102 met criteria for medically intractable seizures. These 102 patients were then mailed a survey to determine follow-up and patient satisfaction. Thirty-nine surveys were returned as undeliverable, and 30 (48%) of the remaining 63 patients responded.

Results

The average age at surgery for patients responding to this survey was 40 ± 16 years compared with 35 ± 15 years for all 102 patients. At prolonged follow-up, 87% of patients reported being seizure-free. Of those with seizures, 2 (7%) reported being nearly seizure-free (rare disabling seizures), 2 (7%) believed they had a worthwhile improvement in seizure frequency, and no patient (0%) in this series believed they did not have a worthwhile improvement in seizure frequency. Ninety percent of responders stated they definitely, and 10% probably, would have surgery again. No patient responded that they probably or definitely would not have epilepsy surgery. Mean clinical follow-up was 36 ± 8 months and survey follow-up was 97 ± 13 months for these 30 patients. Use of the mail-in survey increased follow-up length 2.7 times longer compared with clinical follow-up.

Conclusions

It is clear from this select group of survey responders that patients undergoing surgery for cavernomas associated with medically intractable epilepsy are happy they underwent surgery (100%) and had excellent surgical outcomes (87% seizure-free) at prolonged follow-up of 97 ± 13 months. These survey results support that microsurgical resection for cavernomas is highly effective and significantly improves these patients' quality of life.

Cavernous malformations of the optic pathway and hypothalamus: analysis of 65 cases in the literature 

Neurosurgical FOCUS, Volume 29, Issue 3, Page E17, September 2010.

James K. Liu, M.D., Yuan Lu, B.S., Ahmed M. Raslan, M.D., S. Humayun Gultekin, M.D., and Johnny B. Delashaw Jr., M.D.

Object

Cavernous malformations (CMs) of the optic pathway and hypothalamus (OPH) are extremely rare. Patients with these lesions typically present with chiasmal apoplexy, characterized by sudden visual loss, acute headaches, retroorbital pain, and nausea. Surgical removal is the recommended treatment to restore or preserve vision and to eliminate the risk of future hemorrhage. However, the anatomical location and eloquence of nearby neural structures can make these lesions difficult to access and remove. In this study, the authors review the literature for reported cases of OPH CMs to analyze clinical and radiographic presentations as well as surgical approaches and neurological outcomes.

Methods

A MEDLINE/PubMed search was performed, revealing 64 cases of OPH CMs. The authors report an additional case in the study, making a total of 65 cases. Each case was analyzed for clinical presentation, lesion location, radiographic features, treatment method, and visual outcome.

Results

In 65 patients with OPH CMs, the optic chiasm was affected in 54 cases, the optic nerve(s) in 35, the optic tract in 13, and the hypothalamus in 5. Loss of visual field and acuity was the most common presenting symptom (98%), followed by headache (60%). The onset of symptoms was acute in 58% of patients, subacute in 15%, and chronic progressive in 26%. Computed tomography scans revealed hyperdense suprasellar lesions, with calcification visible in 56% of cases. Magnetic resonance imaging typically demonstrated a heterogeneous lesion with mixed signal intensities suggestive of blood of different ages. The lesion was often surrounded by a peripheral rim of hypointensity on T2-weighted images in 60% of cases. Minimal or no enhancement occurred after the administration of gadolinium. Hemorrhage was reported in 82% of cases. Most patients were surgically treated (97%) using gross-total resection (60%), subtotal resection (6%), biopsy procedure alone (6%), biopsy procedure with decompression (23%), and biopsy procedure followed by radiation (2%). Those patients who underwent gross-total resection had the highest rate of visual improvement (85%). Two patients were treated conservatively, resulting in complete blindness in 1 patient and spontaneous recovery of vision in the other patient.

Conclusions

Cavernous malformations of the OPH are rare and challenging lesions. Gross-total resection of these lesions is associated with favorable visual outcomes. Emergent surgery is warranted in patients presenting with chiasmal apoplexy to prevent permanent damage to the visual pathway.

Giant posterior fossa cavernous malformations in 2 infants with familial cerebral cavernomatosis: the case for early screening 

Neurosurgical FOCUS, Volume 29, Issue 3, Page E18, September 2010.

Sean M. Lew, M.D. The author reports the details in 2 cases of infants with familial cerebral cavernomatosis who presented in dire condition from hemorrhagic posterior fossa cavernous malformations. In Case 1, a 4-month-old boy presented with opisthotonos, gaze palsy, and lethargy. Magnetic resonance imaging revealed a multilobulated cavernous malformation in the fourth ventricle with evidence of bleeding and obstructive hydrocephalus. In Case 2, a 7-month-old girl presented with lethargy, followed by rapid neurological decline. Imaging demonstrated a large lesion involving both the brainstem and cerebellum, with obstructive hydrocephalus. Both patients required immediate surgical intervention, and external ventricular drainage and posterior fossa craniotomies were performed. Both patients made excellent recoveries. These cases suggest that infants in families with suspected or confirmed familial cerebral cavernomatosis should be screened at an early age.