Cerebrofacial vascular metameric syndrome is caused by somatic pathogenic variants in PIK3CA

Disorganized morphogenesis of arteries, veins, capillaries, and lymphatic vessels results in vascular malformations. Most individuals with isolated vascular malformations have postzygotic (mosaic), activating pathogenic variants in a handful of oncogenes within the PI3K–RAS–MAPK pathway (Padia et al., Laryngoscope Investig Otolaryngol 4: 170–173 [2019]). Activating pathogenic variants in the gene PIK3CA, which encodes for the catalytic subunit of phosphatidylinositol 3-kinase, are present in both lymphatic and venous malformations as well as arteriovenous malformations in other complex disorders such as CLOVES syndrome (congenital, lipomatous, overgrowth, vascular malformations, epidermal anevi, scoliosis) (Luks et al., Pediatr Dev Pathol 16: 51 [2013]; Luks et al., J Pediatr 166: 1048–1054.e1–5 [2015]; Al-Olabi et al., J Clin Invest 128: 1496–1508 [2018]). These vascular malformations are part of the PIK3CA-related overgrowth spectrum, a spectrum of entities that have regionalized disordered growth due to the presence of tissue-restricted postzygotic PIK3CA pathogenic variants (Keppler-Noreuil et al., Am J Med Genet A 167A: 287–295 [2015]). Cerebrofacial vascular metameric syndrome (CVMS; also described as cerebrofacial arteriovenous metameric syndrome, Bonnet–Dechaume–Blanc syndrome, and Wyburn–Mason syndrome) is the association of retinal, facial, and cerebral vascular malformations (Bhattacharya et al., Interv Neuroradiol 7: 5–17 [2001]; Krings et al., Neuroimaging Clin N Am 17: 245–258 [2007]). The segmental distribution, the presence of tissue overgrowth, and the absence of familial recurrence are all consistent with CVMS being caused by a postzygotic mutation, which has been hypothesized by previous authors (Brinjiki et al., Am J Neuroradiol 39: 2103–2107 [2018]). However, the genetic cause of CVMS has not yet been described. Here, we present three individuals with CVMS and mosaic activating pathogenic variants within the gene PIK3CA. We propose that CVMS be recognized as part of the PIK3CA-related overgrowth spectrum, providing justification for future trials using pharmacologic PIK3CA inhibitors (e.g., alpelisib) for these difficult-to-treat patients.

Diagnostic Accuracy of SWAN in the Diagnosis of Low-Flow Brain Vascular Malformations in Childhood

Purpose The main objective of this study is to demonstrate the diagnostic accuracy of susceptibility-weighted angiography (SWAN) in the diagnosis of slow-flow cerebral vascular malformations, especially developmental venous anomaly (DVA). We also aimed to determine the prevalence of DVAs identified by SWAN at 1.5 T. Methods We retrospectively evaluated 1,760 axial SWAN images for the diagnosis of low-flow vascular anomaly. Among them were 305 patients who underwent contrast-enhanced examination due to different indications. Postcontrast images were analyzed by different radiologists who were blinded to patients. The presence of DVA and other features such as location, length, depth, and direction of drainage vein was evaluated. Results Twenty-six patients with DVA had both SWAN and postcontrast images. There were four false-negative patients with SWAN. The sensitivity of the SWAN sequence was 84.6%. In addition, totally 77 DVA (4.36%), 2 capillary telangiectasia (0.11%), and 2 cavernous malformations (0.11%) were detected in 1,760 patients. Conclusion SWAN is an effective method for the diagnosis of developmental venous anomalies and other low-flow cerebral vascular malformations. Especially in the pediatric age, susceptibility-weighted imaging sequences are useful to limit contrast use.

Unexpected Binding of Tozuleristide “Tumor Paint” to Cerebral Vascular Malformations: A Potentially Novel Application of Fluorescence-Guided Surgery

BACKGROUND Fluorescence-guided surgery (FGS) is under investigation as a means to improve the extent of resection for primary central nervous system (CNS) tumors. Tozuleristide, known also as “Tumor Paint,” is an investigational tumor-targeting agent covalently conjugated to a derivative of the fluorescent dye indocyanine green. OBJECTIVE To report the finding of avid intraoperative fluorescence of tozuleristide on cerebral vascular malformations. METHODS Our institution is participating in a phase 2/3 study of intraoperative near-infrared fluorescence detection of pediatric primary CNS tumors in patients receiving intravenous tozuleristide and imaged with the Canvas system. Our site enrolled 2 patients with intracranial lesions, suspected preoperatively of possibly being gliomas that proved to be cavernous vascular malformations after resection. RESULTS Each lesion had a dark blue mulberry appearance and each fluoresced avidly with tozuleristide. Each was completely resected, and the patients recovered without deficit. Pathological assessment showed cavernous angioma for both cases. Tozuleristide fluorescence is postulated to result from binding to matrix metalloproteinase-2 and annexin A2, and literature review demonstrates expression of both these ligands on multiple cerebrovascular lesions, including cavernous malformations. CONCLUSION This finding deserves further investigation to determine if tozuleristide “Tumor Paint” may have a wider role in the identification of non-neoplastic intracranial pathologies.

Developmental Venous Anomaly with Adjacent Parenchymal Abnormality Masquerading as Glioma-A Unique Case Report

Developmental venous anomaly (DVA)/ Cerebral Venous Angioma is the most common type of cerebral vascular malformations, mostly an incidental benign finding. But there are documented associated complications like parenchymal signal abnormalities, thrombosis, cavernous malformations and parenchymal atrophy. In this report, we present a unique case of cerebral DVA with cortical changes mimicking the Glioma. Altered haemodynamics in DVA is the underlying pathophysiology for these changes. Correct MRI interpretation, by an expert neuroradiologist, can establish the diagnosis of DVA and its related changes. Therefore, it can reduce the morbidity and mortality by preventing the unnecessary invasive procedures like biopsy for diagnosis.

Neurosurgical Issues in Pregnancy

Although rare, intracranial hemorrhage due to rupture of cerebral vascular malformations or intracranial aneurysms during pregnancy is a potentially devastating and life-threatening disorder, posing a diagnostic and therapeutic challenge to a multidisciplinary team of neurosurgeons, neurologists, obstetricians, and anesthesiologists. Despite the significant risk of morbidity and mortality affecting both the mother and the unborn child, knowledge of the natural history, epidemiology, and appropriate management of cerebral vascular malformations and intracranial aneurysms in pregnant women is limited. Although emergent neurosurgical concerns usually outweigh obstetric considerations, and treatment of these disorders is generally similar in pregnant and nonpregnant women, any necessary and feasible modifications to protect the unborn child should be made. This article reviews the management of ruptured intracranial aneurysms and cerebral vascular malformations, including arteriovenous malformations, cavernous malformations, and moyamoya disease, in women during pregnancy, partus, and puerperium.