Laser scanning confocal endomicroscopy (LSCE) is an emerging technology for examining brain neoplasms in vivo. While great advances have been made in macroscopic fluorescence in recent years, the ability to perform confocal microscopy in vivo expands the potential of fluorescent tumor labeling, can improve intraoperative tissue diagnosis, and provides real-time guidance for tumor resection intraoperatively. In this review, the authors highlight the technical aspects of confocal endomicroscopy and fluorophores relevant to the neurosurgeon, provide a comprehensive summary of LSCE in animal and human neurosurgical studies to date, and discuss the future directions and potential for LSCE in neurosurgery.
Michael A. Mooney, Aqib H. Zehri, Joseph F. Georges and Peter Nakaji
Alan F. Utria, Joseph Lopez, Regina S. Cho, Gerhard S. Mundinger, George I. Jallo, Edward S. Ahn, Craig Vander Kolk and Amir H. Dorafshar
Due to the changing properties of the infant skull, there is still no clear consensus on the ideal time to surgically intervene in cases of nonsyndromic craniosynostosis (NSC). This study aims to shed light on how patient age at the time of surgery may affect surgical outcomes and the subsequent need for reoperation.
A retrospective cohort review was conducted for patients with NSC who underwent primary cranial vault remodeling between 1990 and 2013. Patients' demographic and clinical characteristics and surgical interventions were recorded. Postoperative outcomes were assessed by assigning each procedure to a Whitaker category. Multivariate logistic regression analysis was performed to determine the relationship between age at surgery and need for minor (Whitaker I or II) versus major (Whitaker III or IV) reoperation. Odds ratios (ORs) for Whitaker category by age at surgery were assigned.
A total of 413 unique patients underwent cranial vault remodeling procedures for NSC during the study period. Multivariate logistic regression demonstrated increased odds of requiring major surgical revisions (Whitaker III or IV) in patients younger than 6 months of age (OR 2.49, 95% CI 1.05–5.93), and increased odds of requiring minimal surgical revisions (Whitaker I or II) in patients older than 6 months of age (OR 2.72, 95% CI 1.16–6.41).
Timing, as a proxy for the changing properties of the infant skull, is an important factor to consider when planning vault reconstruction in NSC. The data presented in this study demonstrate that patients operated on before 6 months of age had increased odds of requiring major surgical revisions.
Ali M. Elhadi, Joseph M. Zabramski, Kaith K. Almefty, George A. C. Mendes, Peter Nakaji, Cameron G. McDougall, Felipe C. Albuquerque, Mark C. Preul and Robert F. Spetzler
Hemorrhagic origin is unidentifiable in 10%–20% of patients presenting with spontaneous subarachnoid hemorrhage (SAH). While the patients in such cases do well clinically, there is a lack of long-term angiographic followup. The authors of the present study evaluated the long-term clinical and angiographic follow-up of a patient cohort with SAH of unknown origin that had been enrolled in the Barrow Ruptured Aneurysm Trial (BRAT).
The BRAT database was searched for patients with SAH of unknown origin despite having undergone two or more angiographic studies as well as MRI of the brain and cervical spine. Follow-up was available at 6 months and 1 and 3 years after treatment. Analysis included demographic details, clinical outcome (Glasgow Outcome Scale, modified Rankin Scale [mRS]), and repeat vascular imaging.
Subarachnoid hemorrhage of unknown etiology was identified in 57 (11.9%) of the 472 patients enrolled in the BRAT study between March 2003 and January 2007. The mean age for this group was 51 years, and 40 members (70%) of the group were female. Sixteen of 56 patients (28.6%) required placement of an external ventricular drain for hydrocephalus, and 4 of these subsequently required a ventriculoperitoneal shunt. Delayed cerebral ischemia occurred in 4 patients (7%), leading to stroke in one of them. There were no rebleeding events. Eleven patients were lost to followup, and one patient died of unrelated causes. At the 3-year follow-up, 4 (9.1%) of 44 patients had a poor outcome (mRS > 2), and neurovascular imaging, which was available in 33 patients, was negative.
Hydrocephalus and delayed cerebral ischemia, while infrequent, do occur in SAH of unknown origin. Long-term neurological outcomes are generally good. A thorough evaluation to rule out an etiology of hemorrhage is necessary; however, imaging beyond 6 weeks from ictus has little utility, and rebleeding is unexpected.
Nikolay L. Martirosyan, Joseph Georges, Jennifer M. Eschbacher, Daniel D. Cavalcanti, Ali M. Elhadi, Mohammed G. Abdelwahab, Adrienne C. Scheck, Peter Nakaji, Robert F. Spetzler and Mark C. Preul
The authors sought to assess the feasibility of a handheld visible-wavelength confocal endomicroscope imaging system (Optiscan 5.1, Optiscan Pty., Ltd.) using a variety of rapid-acting fluorophores to provide histological information on gliomas, tumor margins, and normal brain in animal models.
Mice (n = 25) implanted with GL261 cells were used to image fluorescein sodium (FNa), 5-aminolevulinic acid (5-ALA), acridine orange (AO), acriflavine (AF), and cresyl violet (CV). A U251 glioma xenograft model in rats (n = 5) was used to image sulforhodamine 101 (SR101). A swine (n = 3) model with AO was used to identify confocal features of normal brain. Images of normal brain, obvious tumor, and peritumoral zones were collected using the handheld confocal endomicroscope. Histological samples were acquired through biopsies from matched imaging areas. Samples were visualized with a benchtop confocal microscope. Histopathological features in corresponding confocal images and photomicrographs of H & E–stained tissues were reviewed.
Fluorescence induced by FNa, 5-ALA, AO, AF, CV, and SR101 and detected with the confocal endomicroscope allowed interpretation of histological features. Confocal endomicroscopy revealed satellite tumor cells within peritumoral tissue, a definitive tumor border, and striking fluorescent cellular and subcellular structures. Fluorescence in various tumor regions correlated with standard histology and known tissue architecture. Characteristic features of different areas of normal brain were identified as well.
Confocal endomicroscopy provided rapid histological information precisely related to the site of microscopic imaging with imaging characteristics of cells related to the unique labeling features of the fluorophores. Although experimental with further clinical trial validation required, these data suggest that intraoperative confocal imaging can help to distinguish normal brain from tumor and tumor margin and may have application in improving intraoperative decisions during resection of brain tumors.
Hun Joo Kim, Joseph E. Levasseur, John L. Patterson Jr., George F. Jackson, Gordon E. Madge, John T. Povlishock and Hermes A. Kontos
✓ The effect of indomethacin administration on the mortality rate of brain-injured rats was studied in four groups of animals subjected to a level of injury with a fluid-percussion apparatus predetermined to cause 50% mortality (50% lethal dose, or LD50). There were 24 animals in each of the following groups: 1) a control group, on which the LD50 was evaluated; 2) an ethanol-treated group with a mean blood serum level of 0.32 ± 0.03 gm% (± standard error of the mean); 3) an indomethacin-treated group at a dose level of 3 mg/kg body weight administered intraperitoneally 10 to 15 minutes before injury; and 4) an indomethacin/ethanoltreated group. Significant differences in mortality rates were found in these experimental groups; namely, 50%, 58%, 8.3% (p < 0.005), and 25% (p < 0.05), respectively. The predetermined LD50 level of a 2.5- to 2.6-atm peak pressure pulse produced immediate apnea in all animals, which was either sustained (Type III), followed by temporary respiratory recovery (Type II), or followed by permanent resumption of breathing (Type I). The most important effect of indomethacin on respiratory function was manifested by a much higher percentage of Type I respiratory responses and a much lower percentage of Type II and III responses (hence a lower mortality rate). There was also a more rapid return to normal breathing in the postapneic period of recovery. Suppression of prostaglandin synthesis and of superoxide anion production at the onset of trauma may explain, at least in part, these favorable effects of indomethacin.
David S. Hersh, Nir Shimony, Mari L. Groves, Gerald F. Tuite, George I. Jallo, Ann Liu, Tomas Garzon-Muvdi, Thierry A. G. M. Huisman, Ryan J. Felling, Joseph A. Kufera and Edward S. Ahn
Pediatric cerebral venous sinus thrombosis has been previously described in the setting of blunt head trauma; however, the population demographics, risk factors for thrombosis, and the risks and benefits of detection and treatment in this patient population are poorly defined. Furthermore, few reports differentiate between different forms of sinus pathology. A series of pediatric patients with skull fractures who underwent venous imaging and were diagnosed with intrinsic cerebral venous sinus thrombosis or extrinsic sinus compression is presented.
The medical records of patients at 2 pediatric trauma centers were retrospectively reviewed. Patients who were evaluated for blunt head trauma from January 2003 to December 2013, diagnosed with a skull fracture, and underwent venous imaging were included.
Of 2224 pediatric patients with skull fractures following blunt trauma, 41 patients (2%) underwent venous imaging. Of these, 8 patients (20%) had intrinsic sinus thrombosis and 14 patients (34%) displayed extrinsic compression of a venous sinus. Three patients with intrinsic sinus thrombosis developed venous infarcts, and 2 of these patients were treated with anticoagulation. One patient with extrinsic sinus compression by a depressed skull fracture underwent surgical elevation of the fracture. All patients with sinus pathology were discharged to home or inpatient rehabilitation. Among patients who underwent follow-up imaging, the sinus pathology had resolved by 6 months postinjury in 80% of patients with intrinsic thrombosis as well as 80% of patients with extrinsic compression. All patients with intrinsic thrombosis or extrinsic compression had a Glasgow Outcome Scale score of 4 or 5 at their last follow-up.
In this series of pediatric trauma patients who underwent venous imaging for suspected thrombosis, the yield of detecting intrinsic thrombosis and/or extrinsic compression of a venous sinus was high. However, few patients developed venous hypertension or infarction and were subsequently treated with anticoagulation or surgical decompression of the sinus. Most had spontaneous resolution and good neurological outcomes without treatment. Therefore, in the setting of pediatric skull fractures after blunt injury, venous imaging is recommended when venous hypertension or infarction is suspected and anticoagulation is being considered. However, there is little indication for pervasive venous imaging after pediatric skull fractures, especially in light of the potential risks of CT venography or MR venography in the pediatric population and the unclear benefits of anticoagulation.