Hugo Andrade-Barazarte

Somatic Activating KRAS Mutations in Arteriovenous Malformations of the Brain

BACKGROUND Sporadic arteriovenous malformations of the brain, which are morphologically abnormal connections between arteries and veins in the brain vasculature, are a leading cause of hemorrhagic stroke in young adults and children. The genetic cause of this rare focal disorder is unknown. METHODS We analyzed tissue and blood samples from patients with arteriovenous malformations of the brain to detect somatic mutations. We performed exome DNA sequencing of tissue samples of arteriovenous malformations of the brain from 26 patients in the main study group and of paired blood samples from 17 of those patients. To confirm our findings, we performed droplet digital polymerase‐chain‐reaction (PCR) analysis of tissue samples from 39 patients in the main study group (21 with matching blood samples) and from 33 patients in an independent validation group. We interrogated the downstream signaling pathways, changes in gene expression, and cellular phenotype that were induced by activating KRAS mutations, which we had discovered in tissue samples. RESULTS We detected somatic activating KRAS mutations in tissue samples from 45 of the 72 patients and in none of the 21 paired blood samples. In endothelial cell–enriched cultures derived from arteriovenous malformations of the brain, we detected KRAS mutations and observed that expression of mutant KRAS (KRASG12V) in endothelial cells in vitro induced increased ERK (extracellular signal‐regulated kinase) activity, increased expression of genes related to angiogenesis and Notch signaling, and enhanced migratory behavior. These processes were reversed by inhibition of MAPK (mitogen‐activated protein kinase)–ERK signaling. CONCLUSIONS We identified activating KRAS mutations in the majority of tissue samples of arteriovenous malformations of the brain that we analyzed. We propose that these malformations develop as a result of KRAS‐induced activation of the MAPK–ERK signaling pathway in brain endothelial cells. (Funded by the Swiss Cancer League and others.)

Transient Cardiac Arrest Induced by Adenosine: A Tool for Contralateral Clipping of Internal Carotid Artery-Ophthalmic Segment Aneurysms.

BACKGROUND The disadvantages of a contralateral approach (CA) include deep and narrow surgical corridors and inconsistent ability to achieve proximal control of the supraclinoid internal carotid artery (ICA). However, a CA remains as a microsurgical option for selected ICA-ophthalmic (opht) segment aneurysms. OBJECTIVE To describe transient cardiac arrest induced by adenosine as an alternative tool to obtain proximal vascular control and soften the aneurysm sac in selected patients while performing a CA. METHODS From January 1998 to December 2013, we retrospectively identified 30 patients with ICA-opht segment aneurysms treated through a CA. Of those, 8 patients received an intravenous bolus of adenosine to induce transient cardiac arrest for softening of the aneurysm sac. We reviewed preoperative clinical status, characteristics of the contralateral aneurysm, adenosine doses, asystole time, recovery of normal circulation, outcome, and complications. RESULTS No preoperative cardiac or pulmonary pathologies were found in the study population. All contralateral ICA-opht segment aneurysms were unruptured, small, and saccular in shape. Transient cardiac arrest was induced because it was impossible to apply a temporary clip on the parent contralateral supraclinoid ICA. The median dose of adenosine was 22.5 mg (range, 5-50 mg) and the asystole time ranged from 20 to 40 seconds. All patients (n = 8) had good postoperative outcomes. No brain infarction or cardiac complications appeared postoperatively. CONCLUSIONS In selected patients, transient cardiac arrest induced by adenosine during a contralateral approach allows a brief flow arrest and softening of the aneurysm for safer exposure and clipping.

Contralateral Approach to Internal Carotid Artery Ophthalmic Segment Aneurysms: Angiographic Analysis and Surgical Results for 30 Patients.

BACKGROUND Contralateral aneurysm clipping can be applied to bilateral intracranial aneurysms of the anterior circulation and to selected aneurysms on the medial wall of the internal carotid artery (ICA). OBJECTIVE To identify anatomic and radiological parameters that would favor a contralateral microsurgical approach to ICA-ophthalmic segment (ICA-opht) aneurysms. METHODS For the period January 1957 to December 2012, we retrospectively analyzed 268 patients with ICA-opht aneurysms treated in our institution. Of these patients, 30 underwent a contralateral approach; 15 patients (50%) had multiple intracranial aneurysms, and 15 patients had a single aneurysm on the contralateral side of the craniotomy. RESULTS Thirty saccular aneurysms located on the contralateral ICA were treated. Six aneurysms (20%) were present in patients with a subarachnoid hemorrhage due to associated aneurysms, whereas 24 aneurysms (80%) had no history of bleeding. Contralateral aneurysms were smaller than 14 mm and showed no wall irregularities, calcifications, or secondary pouches. Projections of the aneurysms were superomedial (n = 23, 77%), medial (n = 4, 13%), and superior (n = 3, 10%). The median prechiasmatic distance was 5.7 mm (range, 3.4-8.7 mm), the median interoptic distance was 10.5 mm (range, 7.6-15.9 mm), and the median distance between both ICAs was 14.7 mm (range, 10.4-21.4 mm). CONCLUSION The contralateral approach for ICA-opht aneurysms remains a treatment option for intracranial aneurysms. Its feasibility depends on specific anatomic parameters related to the aneurysm itself and to the prechiasmatic distance, interoptic distance, and relationship of the ICA with the anterior clinoid process.

Contralateral Approach to Bilateral Middle Cerebral Artery Aneurysms: Comparative Study, Angiographic Analysis, and Surgical Results.

BACKGROUND Bilateral aneurysms located between the 2 middle cerebral artery (MCA) bifurcations may be approachable through a single unilateral approach. OBJECTIVE To identify anatomic parameters based on imaging that would favor a contralateral approach. METHODS From January 1998 to December 2013, we retrospectively identified 173 patients with bilateral intracranial aneurysms. Fifty-one patients had bilateral MCA aneurysms. A total of 38 patients underwent a single craniotomy with a contralateral microsurgical approach (group 1 or contralateral group) and 13 patients underwent bilateral craniotomies (group 2 or bilateral group). For both groups, we analyzed aneurysm characteristics, morphology, size, projections, and distance to the contralateral corridor, as well as surgical time, outcome, and postoperative complications. RESULTS All aneurysms approached contralaterally were unruptured and without wall calcifications. Of the contralaterally approached aneurysms, 97% were smaller than 14 mm. The median length of the contralateral A1 was 13.2 mm (range: 6-19.8 mm) and the median length of the contralateral M1 was 14.2 mm (range: 4.6-21 mm). The contralateral group had a good postoperative outcome (modified Rankin Scale 0-3) in 80% of ruptured cases and 86% of unruptured cases. The median surgical time was 120 minutes (range: 75-255 minutes), 43% shorter than the bilateral group. CONCLUSION The contralateral approach for bilateral MCA aneurysms in selected patients is feasible in experienced hands, with acceptable morbidity and mortality. The contralateral approach requires a meticulous preoperative analysis of the characteristics of the aneurysms to be clipped and of the anatomic constraints of the microsurgical operative corridor. ABBREVIATIONS A1, anterior cerebral artery proximal segmentbMCA, bilateral middle cerebral arteryCTA, computed tomographic angiographyHH, Hunt-Hess scaleIA, intracranial aneurysmsICA, internal carotid arteryICAbif, internal carotid artery bifurcationMCA, middle cerebral arteryM1, middle cerebral artery proximal segmentmRS, modified Rankin ScaleSAH, subarachnoid hemorrhage.

Retrograde Suction Decompression for Clip Occlusion of Internal Carotid Artery Communicating Segment Aneurysms

BACKGROUND Retrograde suction decompression (RSD) can achieve proximal parent vessel control, improve aneurysm neck visualization, and allow parent vessel reconstruction for direct clipping of internal carotid artery (ICA) aneurysms. The aim of the present study was to describe the technique and surgical results of RSD for direct clipping of ICA communicating segment (C1) aneurysms. METHODS The clinical data and treatment summaries of 20 patients who underwent RSD-assisted clipping of ICA C1 aneurysms were retrospectively reviewed. Pre- and postoperative three- or four-dimensional computed tomography angiograms, postoperative magnetic resonance images, surgical notes, operative complications, and outcomes were assessed. RESULTS All patients except one harbored unruptured C1 aneurysms. Extracranial-intracranial graft bypass using the radial artery was performed in five patients. Fifteen patients required temporary clipping of the posterior communicating artery for further reduction of blood back-flow into the aneurysm. All aneurysms were successfully clipped and postoperative three- or four-dimensional computed tomography angiography revealed no major branch occlusion or residual aneurysm. At the 6-month follow-up examination, 19 patients had a good outcome and 1 patient had poor outcome associated with anterior choroidal artery ischemia. No death had occurred at 6-month follow-up examination. CONCLUSIONS The RSD technique is a useful procedure to achieve proximal vascular control, to soften and shrinkage the aneurysm sac, and to provide a wide and clean operative field allowing safe clip placement. The RSD technique requires special attention to the relationship between the perforators and the aneurysm, and close cooperation between the surgeon and the assistant.

Lateral supraorbital approach to ipsilateral PCA-P1 and ICA-PCoA aneurysms.

Background: Aneurysms of the posterior cerebral artery (PCA) are rare and often associated with anterior circulation aneurysms. The lateral supraorbital approach allows for a very fast and safe approach to the ipsilateral lesions Circle of Willis. A technical note on the successful clip occlusion of two aneurysms in the anterior and posterior Circle of Willis via this less invasive approach has not been published before. The objective of this technical note is to describe the simultaneous microsurgical clip occlusion of an ipsilateral PCA-P1 and an internal carotid artery - posterior communicating artery (ICA-PCoA) aneurysm via the lateral supraorbital approach. Case Description: The authors present a technical report of successful clip occlusions of ipsilateral located PCA-P1 and ICA-PCoA aneurysms. A 59-year-old female patient was diagnosed with a PCA-P1 and an ipsilateral ICA-PCoA aneurysm by computed tomography angiography (CTA) after an ischemic stroke secondary to a contralateral ICA dissection. The patient underwent microsurgical clipping after a lateral supraorbital craniotomy. The intraoperative indocyanine green (ICG) videoangiography and the postoperative CTA showed a complete occlusion of both aneurysms; the parent vessels (ICA and PCA) were patent. The patient presents postoperative no new neurologic deficit. Conclusion: The lateral supraorbital approach is suitable for the simultaneous microsurgical treatment of proximal anterior circulation and ipsilateral proximal PCA aneurysms. Compared to endovascular treatment, direct visual control of brainstem perforators is possible.

Anatomic Features of Paraclinoid Aneurysms: Computed Tomography Angiography Study of 144 Aneurysms in 136 Consecutive Patients

BACKGROUND Paraclinoid aneurysms are among the most challenging aneurysms to treat. Computed tomography (CT) angiography helps in evaluating the radiological characteristics of these aneurysms next to bony structures. OBJECTIVE To present the CT angiography characteristics of paraclinoid aneurysms in order to better understand such pathology. METHODS The study examined CT angiography-based anatomical characteristics obtained retrospectively from 136 patients with 144 paraclinoid aneurysms selected from single-defined catchment populations in Finland. We examined the diameters of the parent artery (internal carotid artery), the location of the aneurysm, its dimensions (width, height, neck), and aneurysm wall irregularity. RESULTS We analyzed 144 paraclinoid aneurysms in 136 patients admitted to the hospital during 2000-2014. Multivariable analysis reveals that rupture aneurysms have the following radiological features: aneurysm larger than 5 mm in diameter (P = .006), irregular wall (P = .046), superior location, larger aspect ratio (P = .039), and neck wider than parent artery (P < .001). CONCLUSION Smaller diameter of the internal carotid artery and superior location, as well as a large and irregular aneurysm wall, are radiological characteristics of ruptured paraclinoid aneurysms, which CT angiography can measure easily.

Long-Term Causes of Death and Excess Mortality After Carotid Artery Ligation.

OBJECTIVE Carotid artery ligation (CAL) is used to treat large and complex intracranial aneurysms. However, little is known about long-term survival and causes of death in patients who undergo the procedure. This study was intended to evaluate if patients who have undergone CAL have long-term excess mortality and what the causes of death are. METHODS All patients were treated at Helsinki University Hospital between 1937 and 2009. Patients who had undergone CAL and survived ≥1 year after the procedure were included in the cohort. Follow-up was until death or 2015 (2711 patient-years). Causes of death were reviewed and relative survival ratios calculated using the Ederer II method and a matched population. RESULTS There was 12% excess mortality in all patients 20 years after CAL and 22% after 30 years. A higher proportion of the patients who had subarachnoid hemorrhage (SAH) died during follow-up compared with unruptured patients undergoing CAL. Cardiovascular disease and cerebrovascular accident were the leading causes of death. CONCLUSIONS Patients with unruptured aneurysms did not experience as much excess mortality as those who had an SAH. The higher proportion of deaths observed in ruptured patients may be partly because of long-term excess mortality conferred by the SAH itself or SAH risk factors. Although the entire population did display excess mortality compared with the general population, this may be because of shared risk factors for aneurysm development and rupture and the cause of death.

Superficial Temporal Artery: Distal Posterior Cerebral Artery Bypass through the Subtemporal Approach: Technical Note and Pilot Surgical Cases

BACKGROUND Posterior cerebral artery (PCA) aneurysms are rare and the majority are fusiform in shape. Proximal occlusion of PCA represents a treatment option for these lesions. However, this procedure carries a high risk of ischemic complications. OBJECTIVE To describe the technique of trapping a fusiform PCA aneurysm and revascularization of the distal PCA using a superficial temporal artery (STA) graft through the same microsurgical approach. METHODS From September 2012 to October 2014, we retrospectively identified 3 patients harboring a fusiform PCA aneurysm (P2 segment aneurysm) who underwent trapping of the aneurysm and reconstruction of the distal PCA through the same subtemporal approach. We analyzed immediate morbidity, surgical complications, and the patency of the bypass to determine the feasibility of this procedure. RESULTS All 3 patients underwent successful trapping of the fusiform PCA aneurysm and revascularization of the distal PCA. The origin of P3 segment or posterior temporal artery (PTA) served as recipient arteries. In all 3 cases, adequate blood flow was evident after performing the STA-P3/PTA bypass. None of the patients experienced a new permanent neurological deficit. At 1-year follow-up, the STA-PTA/PCA bypasses remained patent. CONCLUSION The STA-P3/PTA bypass through the subtemporal approach is a feasible option to maintain blood flow in cases of PCA fusiform aneurysms requiring trapping of the P2 segment.

Intracranial Vertebral Artery Aneurysms: Clinical Features and Outcome of 190 Patients

BACKGROUND Vertebral artery (VA) aneurysms comprise approximately one-third of posterior circulation aneurysms. They are morphologically variable, and located critically close to the cranial nerves and the brainstem. We aim to represent the characteristics of these aneurysms and their treatment, and to analyze the outcome. METHODS We reviewed retrospectively 9709 patients with intracranial aneurysms. Of these, we included 190 with aneurysms at the VA or VA-posterior inferior cerebellar artery junction. These patients were treated in the Department of Neurosurgery, Helsinki, Finland, between 1934 and 2011. RESULTS The 190 patients had 193 VA aneurysms, among which 131 (68%) were ruptured. The VA aneurysm caused a mass effect in 7 and ischemia in 2 patients. Compared to 4387 patients with a ruptured aneurysm in other locations, those with a VA aneurysm were older, their aneurysms were more often fusiform, and more often caused intraventricular hemorrhages. Among surgically treated aneurysms, clipping was the treatment in 91 (88%) saccular and 11 (50%) fusiform aneurysms. Treatment was endovascular in 13 (9%), and multimodal in 6 (4%) aneurysms. Within a year after aneurysm diagnosis, 53 (28%) patients died. Among the survivors, 104 (93%) returned to an independent or to their previous state of life; only 2 (2%) were unable to return home. CONCLUSIONS Microsurgery is a feasible treatment for VA aneurysms, although cranial nerve deficits are more common than in endovascular surgery. Despite the challenge of an often severe hemorrhage, of challenging morphology, and risk for laryngeal palsy, most patients surviving the initial stage return to normalcy.