Faculty Bibliography

OBJECTIVE:The objective of this study was to assess long-term outcomes of facial pain and numbness after radiosurgery for multiple sclerosis (MS)-related trigeminal neuralgia (MS-TN). METHODS:The authors conducted a retrospective review of their Gamma Knife radiosurgeries (GKRSs) to identify all patients treated for MS-TN (1998-2014) with at least 3 years of follow-up. Treatment and clinical data were obtained via chart review and mailed or telephone surveys. Pain control was defined as a facial pain score of I-IIIb on the Barrow Neurological Institute (BNI) Facial Pain Intensity Scale. Kaplan-Meier analysis was performed to determine the rates of pain control after index and first salvage GKRS procedures. Patients could have had more than 1 salvage procedure. Pain control rates were based on the number of patients at risk during follow-up. RESULTS:Of the 50 living patients who underwent GKRS, 42 responded to surveys (31 women [74%], median age 59 years, range 32-76 years). During the initial GKRS, the trigeminal nerve root entry zone was targeted with a single isocenter, using a 4-mm collimator with the 90% isodose line completely covering the trigeminal nerve and the 50% isodose line abutting the surface of the brainstem. The median maximum radiation dose was 85 Gy (range 50-85 Gy). The median follow-up period was 78 months (range 36-226 months). The rate of pain control after the index GKRS (n = 42) was 62%, 29%, 22%, and 13% at 1, 3, 5, and 7 years, respectively. Twenty-eight patients (67%) underwent salvage treatment, including 25 (60%) whose first salvage treatment was GKRS. The rate of pain control after the first salvage GKRS (n = 25) was 84%, 50%, 44%, and 17% at 1, 3, 5, and 7 years, respectively. The rate of pain control after the index GKRS with or without 1 salvage GKRS (n = 33) was 92%, 72%, 52%, 46%, and 17% at 1, 3, 5, 7, and 10 years, respectively. At last follow-up, 9 (21%) of the 42 patients had BNI grade I facial pain, 35 (83%) had achieved pain control, and 4 (10%) had BNI grade IV facial numbness (very bothersome in daily life). CONCLUSIONS:Index GKRS offers good short-term pain control for MS-TN, but long-term pain control is uncommon. If the index GKRS fails, salvage GKRS appears to offer beneficial pain control with low rates of bothersome facial numbness.

OBJECTIVE:Preoperative embolization may facilitate skull base meningioma resection, but its safety and efficacy in the Onyx era have not been investigated. In this retrospective cohort study, we evaluated the outcomes of preoperative embolization of skull base meningiomas using Onyx as the primary embolysate. METHODS:We queried an endovascular database for patients with skull base meningiomas who underwent preoperative embolization at our institution in 2007-2017. Patient, tumor, procedure, and outcome data were analyzed. RESULTS:. There were 1, 2, or 3 arterial pedicles embolized in 21 cases (75%), 6 cases (21%), and 1 case (4%), respectively. The embolized pedicles included branches of the middle meningeal artery in 19 cases (68%), the internal maxillary artery in 8 cases (29%), the ascending pharyngeal artery in 2 cases (7%), and the posterior auricular, ophthalmic, occipital, and anterior cerebral arteries in 1 case each (4%). The embolysates used were Onyx alone in 20 cases (71%), n-butyl cyanoacrylate alone in 3 cases (11%), coils/particles and Onyx/n-butyl cyanoacrylate in 2 cases each (7%), and Onyx and coils in 1 case (4%). The median degree of tumor devascularization was 60%. Significant neurologic morbidity occurred in 1 patient (4%) who developed symptomatic peritumoral edema after Onyx embolization. CONCLUSIONS:For appropriately selected skull base meningiomas supplied by dura mater-based arterial pedicles without distal cranial nerve supply, preoperative embolization with current embolysate technology affords substantial tumor devascularization with a low complication rate.

This corrects the article DOI: 10.1038/ncomms14433.

Primary cardiomyopathy is one of the most common inherited cardiac diseases and harbors significant phenotypic and genetic heterogeneity. Because of this, genetic testing has become standard in treatment of this disease group. Indeed, in recent years, next-generation DNA sequencing has found broad applications in medicine, both as a routine diagnostic tool for genetic disorders and as a high-throughput discovery tool for identifying novel disease-causing genes. We describe a male infant with primary dilated cardiomyopathy who was diagnosed using intrauterine echocardiography and found to progress to hypertrophic cardiomyopathy after birth. This proband was born to a nonconsanguineous family with a past history of a male fetus that died because of cardiac abnormalities at 30 wk of gestation. Using whole-exome sequencing, a novel homozygous frameshift mutation (c.2018delC; p.Gln675SerfsX30) in ALPK3 was identified and confirmed with Sanger sequencing. Heterozygous family members were normal with echocardiographic examination. To date, only two studies have reported homozygous pathogenic variants of ALPK3, with a total of seven affected individuals with cardiomyopathy from four unrelated consanguineous families. We include a discussion of the patient's phenotypic features and a review of relevant literature findings.

Occlusion of the basilar artery can be treated with endovascular thrombectomy, although the results have not been well studied. Persistent fetal cerebrovascular anatomy can lead to unusual presentation of carotid atherosclerotic disease and can be a barrier to successful mechanical thrombectomy if not recognized. This case presents a rare persistent carotico-basilar anastomosis which resulted in basilar occlusion via the persistent hypoglossal artery and coincident absence of contralateral vertebral arterial access due to a left vertebral artery terminating in the left posterior inferior cerebellar artery. Preoperative recognition of this anatomy afforded by review of cross-sectional imaging was critical to success during this emergent procedure.

Meningiomas are mostly benign brain tumours, with a potential for becoming atypical or malignant. On the basis of comprehensive genomic, transcriptomic and epigenomic analyses, we compared benign meningiomas to atypical ones. Here, we show that the majority of primary (de novo) atypical meningiomas display loss of NF2, which co-occurs either with genomic instability or recurrent SMARCB1 mutations. These tumours harbour increased H3K27me3 signal and a hypermethylated phenotype, mainly occupying the polycomb repressive complex 2 (PRC2) binding sites in human embryonic stem cells, thereby phenocopying a more primitive cellular state. Consistent with this observation, atypical meningiomas exhibit upregulation of EZH2, the catalytic subunit of the PRC2 complex, as well as the E2F2 and FOXM1 transcriptional networks. Importantly, these primary atypical meningiomas do not harbour TERT promoter mutations, which have been reported in atypical tumours that progressed from benign ones. Our results establish the genomic landscape of primary atypical meningiomas and potential therapeutic targets.

Occlusion of the basilar artery can be treated with endovascular thrombectomy, although the results have not been well studied. Persistent fetal cerebrovascular anatomy can lead to unusual presentation of carotid atherosclerotic disease and can be a barrier to successful mechanical thrombectomy if not recognized. This case presents a rare persistent carotico-basilar anastomosis which resulted in basilar occlusion via the persistent hypoglossal artery and coincident absence of contralateral vertebral arterial access due to a left vertebral artery terminating in the left posterior inferior cerebellar artery. Preoperative recognition of this anatomy afforded by review of cross-sectional imaging was critical to success during this emergent procedure.

RNA polymerase II mediates the transcription of all protein-coding genes in eukaryotic cells, a process that is fundamental to life. Genomic mutations altering this enzyme have not previously been linked to any pathology in humans, which is a testament to its indispensable role in cell biology. On the basis of a combination of next-generation genomic analyses of 775 meningiomas, we report that recurrent somatic p.Gln403Lys or p.Leu438_His439del mutations in POLR2A, which encodes the catalytic subunit of RNA polymerase II (ref. 1), hijack this essential enzyme and drive neoplasia. POLR2A mutant tumors show dysregulation of key meningeal identity genes, including WNT6 and ZIC1/ZIC4. In addition to mutations in POLR2A, NF2, SMARCB1, TRAF7, KLF4, AKT1, PIK3CA, and SMO, we also report somatic mutations in AKT3, PIK3R1, PRKAR1A, and SUFU in meningiomas. Our results identify a role for essential transcriptional machinery in driving tumorigenesis and define mutually exclusive meningioma subgroups with distinct clinical and pathological features.

The fat mass and obesity associated (FTO) gene has previously been associated with a variety of diseases and conditions, notably obesity, acute coronary syndrome and metabolic syndrome. Reports describing mutations in FTO as well as in FTO animal models have further demonstrated a role for FTO in the development of the brain and other organs. Here, we describe a patient born of consanguineous union who presented with microcephaly, developmental delay, behavioral abnormalities, dysmorphic facial features, hypotonia and other various phenotypic abnormalities. Whole-exome sequencing revealed a novel homozygous missense mutation in FTO and a nonsense mutation in the cholesteryl ester transfer protein (CETP). Exome copy number variation analysis revealed no disease-causing large duplications or deletions within coding regions. Patient's, her parents' and non-related control' fibroblasts were analyzed for morphologic defects, abnormal proliferation, apoptosis and transcriptome profile. We have shown that FTO is located in the nucleus of cells from each tested sample. Western blot analysis demonstrated no changes in patient FTO. Quantitative (qPCR) analysis revealed slightly decreased levels of FTO expression in patient cells compared with controls. No morphological or proliferation differences between the patient and control fibroblasts were observed. There is still much to be learned about the molecular mechanisms by which mutations in FTO contribute to such severe phenotypes.