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Michael Karsy, Jian Guan, and L. Eric Huang

OBJECTIVE

Gliomas are one of the most common types of primary brain tumors. Recent studies have supported the importance of key genetic alterations, including isocitrate dehydrogenase (IDH) mutations and 1p19q codeletion, in glioma prognosis. Mutant IDH produces 2-hydroxyglutarate from α-ketoglutarate, a key metabolite of the Krebs cycle. The mitochondrial pyruvate carrier (MPC) is composed of MPC1 and MPC2 subunits and is functionally essential for the Krebs cycle. The authors sought to explore the impact of MPC1 and MPC2 expression on patient prognosis.

METHODS

Genomic and clinical data in patients with lower-grade glioma (WHO grades II and III) from The Cancer Genome Atlas (TCGA) were evaluated using Kaplan-Meier analysis and hazards modeling. Validation was conducted with additional data sets, including glioblastoma.

RESULTS

A total of 286 patients with lower-grade glioma (mean age 42.7 ± 13.5 years, 55.6% males) included 54 cases of IDH–wild type (18.9%); 140 cases of IDH-mutant, 1p19q-intact (49.0%); and 85 cases of IDH-mutant, 1p19q-codeleted (29.7%) tumors. Kaplan-Meier analysis showed that an MPC1 z-score > 0 distinguished better survival, particularly in IDH-mutant (p < 0.01) but not IDH–wild type tumors. Conversely, an MPC2 z-score > 0 identified worsened survival, particularly in IDH-mutant (p < 0.01) but not IDH–wild type tumors. Consistently, neither MPC1 nor MPC2 was predictive in a glioblastoma data set containing 5% IDH-mutant cases. Within the IDH-stratified lower-grade glioma data set, MPC1 status distinguished improved survival in 1p19q-codeleted tumors (p < 0.05), whereas MPC2 expression delineated worsened survival in 1p19q-intact tumors (p < 0.01). A hazards model identified IDH and 1p19q status, age (p = 0.01, HR = 1.03), Karnofsky Performance Scale (KPS) score (p = 0.03, HR = 0.97), and MPC1 (p = 0.003, HR = 0.52) but not MPC2 (p = 0.38) as key variables affecting overall survival. Further validation confirmed MPC1 as an independent predictor of lower-grade glioma. A clinical risk score using IDH and 1p19q status, age, KPS score, and MPC1 and MPC2 z-scores defined 4 risk categories for lower-grade glioma; this score was validated using a secondary glioma data set.

CONCLUSIONS

These results support the importance of MPC, especially MPC1, in improving prognostication of IDH-mutant tumors. The generation of a risk score system directly translates this finding to clinical application; however, further research to improve the molecular understanding of the role of MPC in the metabologenomic regulation of gliomas is warranted.

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Michael T. Bounajem, Michael Karsy, and Randy L. Jensen

OBJECTIVE

Primary brain tumors are the most common cause of cancer-related deaths in children and pose difficult questions for the treating physician regarding issues such as the risk/benefit of performing a biopsy, the accuracy of monitoring methods, and the availability of prognostic indicators. It has been recently shown that tumor-specific DNA and proteins can be successfully isolated in liquid biopsies, and it may be possible to exploit this potential as a particularly useful tool for the clinician in addressing these issues.

METHODS

A review of the current literature was conducted by searching PubMed and Scopus. MeSH terms for the search included “liquid biopsy,” “brain,” “tumor,” and “pediatrics” in all fields. Articles were reviewed to identify the type of brain tumor involved, the method of tumor DNA/protein analysis, and the potential clinical utility. All articles involving primary studies of pediatric brain tumors were included, but reviews were excluded.

RESULTS

The successful isolation of circulating tumor DNA (ctDNA), extracellular vesicles, and tumor-specific proteins from liquid biopsies has been consistently demonstrated. This most commonly occurs through CSF analysis, but it has also been successfully demonstrated using plasma and urine samples. Tumor-related gene mutations and alterations in protein expression are identifiable and, in some cases, have been correlated to specific neoplasms. The quantity of ctDNA isolated also appears to have a direct relationship with tumor progression and response to treatment.

CONCLUSIONS

The use of liquid biopsies for the diagnosis and monitoring of primary pediatric brain tumors is a foreseeable possibility, as the requisite developmental steps have largely been demonstrated. Increasingly advanced molecular methods are being developed to improve the identification of tumor subtypes and tumor grades, and they may offer a method for monitoring treatment response. These minimally invasive markers will likely be used in the clinical treatment of pediatric brain tumors in the future.

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Spencer Twitchell, Michael Karsy, Jian Guan, William T. Couldwell, and Philipp Taussky

The term “radiation vasculopathy” defines a heterogeneous and poorly defined complex of vessel injury due to radiation. Radiation vasculopathy remains underrecognized and poorly treated with respect to head and neck radiotherapy. Distinct injury patterns to small (≤ 100-μm), medium (> 100-μm), and large (> 500-μm) vessels can occur, resulting in carotid stenosis, intracranial stenosis, and vascular anomalies (e.g., cavernous malformations, aneurysms). Because of the lack of clinical evidence and guidelines, treatment plans involve medical management, carotid endarterectomy, and carotid artery stenting and are developed on a patient-by-patient basis. In this review, the authors discuss the current pathophysiology, imaging, clinical impact, and potential treatment strategies of radiation vasculopathy with clinical pertinence to practicing neurosurgeons and neurologists. A review of 4 patients with prior head and neck tumors in whom delayed radiation vasculopathy developed after radiotherapy demonstrates the application of various treatment options in a case-by-case manner. Earlier recognition of radiation vasculopathy disease patterns may enable earlier initiation of treatment and monitoring for complications. Standardized terminology and treatments may assist with improving clinical outcomes.

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Al-Wala Awad, Craig Kilburg, Michael Karsy, William T. Couldwell, and Philipp Taussky

OBJECTIVE

The Pipeline embolization device (PED) is a self-expanding mesh stent that diverts blood flow away from an aneurysm; it has been successfully used to treat aneurysms of the proximal internal carotid artery (ICA). PEDs have a remarkable ability to alter regional blood flow along the tortuous segments of the ICA and were incidentally found to alter the angle of the anterior genu after treatment. The authors quantified these changes and explored their implications as they relate to treatment effect.

METHODS

The authors retrospectively reviewed cases of aneurysms treated with a PED between the ophthalmic and posterior communicating arteries from 2012 through 2015. The angles of the anterior genu were measured on the lateral projections of cerebral angiograms obtained before and after treatment with a PED. The angles of the anterior genu of patients without aneurysms were used as normal controls.

RESULTS

Thirty-eight patients were identified who had been treated with a PED; 34 (89.5%) had complete obliteration and 4 (10.5%) had persistence of their aneurysm at last follow-up (mean 11.3 months). After treatment, 32 patients had an increase, 3 had a decrease, and 3 had no change in the angle of the anterior genu. The average measured angle of the anterior genu was 36.7° before treatment and 44.3° after treatment (p < 0.0001). The average angle of the anterior genu of control patients was 43.32° (vs 36.7° for the preoperative angle in the patients with aneurysms, p < 0.057). The average change in the angle of patients with postoperative Raymond scores of 1 was 9.10°, as compared with 1.25° in patients with postoperative Raymond scores > 1 (p < 0.001).

CONCLUSIONS

Treatment with a PED significantly changes the angle of the anterior genu. An average change of 9.1° was associated with complete obliteration of treated aneurysms. These findings have important implications for the treatment and management of cerebral aneurysm.

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Michael Karsy, Daxa M. Patel, Kyle Halvorson, Vance Mortimer, and Robert J. Bollo

Anterior two-thirds corpus callosotomy is a common palliative surgical intervention most commonly employed in patients with atonic or drop seizures. Recently, stereotactic laser ablation of the corpus callosum without a craniotomy has shown promise in achieving similar outcomes with fewer side effects and shorter hospitalizations. The authors demonstrate ablation of the anterior two-thirds corpus callosum in a patient with Lennox-Gastaut syndrome and drug-resistant drop seizures. Technical nuances of laser ablation with 3 laser fibers are described. Postoperatively, the patient showed a significant reduction in seizure frequency and severity over a 9-month follow-up period.

The video can be found here: https://youtu.be/3-mMq5-PLiM.

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Michael Karsy, Daxa M. Patel, and Robert J. Bollo

Magnetic resonance imaging–guided stereotactic laser ablation of intracranial targets, including brain tumors, has expanded dramatically over the past decade, but there have been few reports of complications, especially those occurring in a delayed fashion. Laser ablation of subependymal giant cell astrocytomas (SEGAs) is an attractive alternative to maintenance immunotherapy in some children with tuberous sclerosis complex (TSC); however, the effect of treatment on disease progression and the nature and frequency of potential complications remains largely unknown. The authors report the case of a 5-year-old boy with TSC who underwent stereotactic laser ablation of a SEGA at the right foramen of Monro on 2 separate occasions. After the second ablation, immediate posttreatment MRI revealed gadolinium extravasation from the tumor into the lateral ventricle. Nine months later, the patient presented with papilledema and delayed obstructive hydrocephalus secondary to intraventricular adhesions causing a trapped right lateral ventricle. This was successfully treated with endoscopic septostomy. The authors discuss the potential cause and clinical management of a delayed complication not previously reported after a relatively novel surgical therapy.

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Hussam Abou-Al-Shaar, Michael Karsy, Vijay Ravindra, Evan Joyce, and Mark A. Mahan

Particularly challenging after complete brachial plexus avulsion is reestablishing effective hand function, due to limited neurological donors to reanimate the arm. Acute repair of avulsion injuries may enable reinnervation strategies for achieving hand function. This patient presented with pan–brachial plexus injury. Given its irreparable nature, the authors recommended multistage reconstruction, including contralateral C-7 transfer for hand function, multiple intercostal nerves for shoulder/triceps function, shoulder fusion, and spinal accessory nerve–to–musculocutaneous nerve transfer for elbow flexion. The video demonstrates distal contraction from electrical stimulation of the avulsed roots. Single neurorrhaphy of the contralateral C-7 transfer was performed along with a retrosternocleidomastoid approach.

The video can be found here: https://youtu.be/GMPfno8sK0U.

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Michael Karsy, Hussam Abou-Al-Shaar, Christian A. Bowers, and Richard H. Schmidt

OBJECTIVE

Idiopathic intracranial hypertension (IIH), or pseudotumor cerebri, is a complex and difficult-to-manage condition that can lead to permanent vision loss and refractory headaches if untreated. Traditional treatment options, such as unilateral ventriculoperitoneal (VP) or lumboperitoneal (LP) shunt placement, have high complication and failure rates and often require multiple revisions. The use of bilateral proximal catheters has been hypothesized as a method to improve shunt survival. The use of stereotactic technology has improved the accuracy of catheter placement and may improve treatment of IIH, with fewer complications and greater shunt patency time.

METHODS

The authors performed a retrospective chart review for all patients with IIH who underwent stereotactic placement of biventriculoperitoneal (BVP) shunt catheters from 2008 to 2016 at their institution. Bilateral proximal catheters were Y-connected to a Strata valve with a single distal catheter. We evaluated clinical, surgical, and ophthalmological variables and outcomes.

RESULTS

Most patients in this series of 34 patients (mean age 34.4 ± 8.2 years, mean body mass index 38.7 ± 8.3 kg/m2; 91.2% were women) undergoing 41 shunt procedures presented with headache (94.1%) and visual deficits (85.3%). The mean opening pressure was 39.6 ± 9.0 cm H2O. In addition, 50.0% had undergone previous unilateral shunt placement, and 20.6% had undergone prior optic nerve sheath fenestration. After BVP shunt placement, there were no cases of proximal catheter obstruction and only a single case of valve obstruction at 41.9 months, with a mean follow-up of 24.8 ± 20.0 months. Most patients showed improvement in their headache (82.4%), subjective vision (70.6%), and papilledema (61.5% preoperatively vs 20.0% postoperatively, p = 0.02) at follow-up. Additional primary complications included 4 patients with migration of their distal catheters out of the peritoneum (twice in 1 patient), and an infection of the distal catheter after catheter dislodgment. The proximal obstructive shunt complication rate in this series (2.9%) was lower than that with LP (53.5%) or unilateral VP (37.8%) shunts seen in the literature.

CONCLUSIONS

This small series suggests that stereotactic placement of BVP shunt catheters appears to improve shunt survival rates and presenting symptoms in patients with IIH. Compared with unilateral VP or LP shunts, the use of BVP shunts may be a more effective and more functionally sustained method for the treatment of IIH.