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Spontaneous subarachnoid hemorrhage of unknown origin: hospital course and long-term clinical and angiographic follow-up

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

OBJECT

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).

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.

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Fluorescence-guided stereotactic biopsy: a proof-of-concept study

Robert Lynagh, Mark Ishak, Joseph Georges, Danielle Lopez, Hany Osman, Michael Kakareka, Brandon Boyer, H. Warren Goldman, Jennifer Eschbacher, Mark C. Preul, Peter Nakaji, Alan Turtz, Steven Yocom, and Denah Appelt

OBJECTIVE

Accurate histopathological diagnoses are often necessary for treating neuro-oncology patients. However, stereotactic biopsy (STB), a common method for obtaining suspicious tissue from deep or eloquent brain regions, fails to yield diagnostic tissue in some cases. Failure to obtain diagnostic tissue can delay initiation of treatment and may result in further invasive procedures for patients. In this study, the authors sought to determine if the coupling of in vivo optical imaging with an STB system is an effective method for identification of diagnostic tissue at the time of biopsy.

METHODS

A minimally invasive fiber optic imaging system was developed by coupling a 0.65-mm-diameter coherent fiber optic fluorescence microendoscope to an STB system. Human U251 glioma cells were transduced for stable expression of blue fluorescent protein (BFP) to produce U251-BFP cells that were utilized for in vitro and in vivo experiments. In vitro, blue fluorescence was confirmed, and tumor cell delineation by fluorescein sodium (FNa) was quantified with fluorescence microscopy. In vivo, transgenic athymic rats implanted with U251-BFP cells (n = 4) were utilized for experiments. Five weeks postimplantation, the rats received 5–10 mg/kg intravenous FNa and underwent craniotomies overlying the tumor implantation site and contralateral normal brain. A clinical STB needle containing our 0.65-mm imaging fiber was passed through each craniotomy and images were collected. Fluorescence images from regions of interest ipsilateral and contralateral to tumor implantation were obtained and quantified.

RESULTS

Live-cell fluorescence imaging confirmed blue fluorescence from transduced tumor cells and revealed a strong correlation between tumor cells quantified by blue fluorescence and FNa contrast (R2 = 0.91, p < 0.001). Normalized to background, in vivo FNa-mediated fluorescence intensity was significantly greater from tumor regions, verified by blue fluorescence, compared to contralateral brain in all animals (301.7 ± 34.18 relative fluorescence units, p < 0.001). Fluorescence intensity measured from the tumor margin was not significantly greater than that from normal brain (p = 0.89). Biopsies obtained from regions of strong fluorescein contrast were histologically consistent with tumor.

CONCLUSIONS

The authors found that in vivo fluorescence imaging with an STB needle containing a submillimeter-diameter fiber optic fluorescence microendoscope provided direct visualization of neoplastic tissue in an animal brain tumor model prior to biopsy. These results were confirmed in vivo with positive control cells and by post hoc histological assessment. In vivo fluorescence guidance may improve the diagnostic yield of stereotactic biopsies.

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Fluorescence-guided stereotactic biopsy: a proof-of-concept study

Robert Lynagh, Mark Ishak, Joseph Georges, Danielle Lopez, Hany Osman, Michael Kakareka, Brandon Boyer, H. Warren Goldman, Jennifer Eschbacher, Mark C. Preul, Peter Nakaji, Alan Turtz, Steven Yocom, and Denah Appelt

OBJECTIVE

Accurate histopathological diagnoses are often necessary for treating neuro-oncology patients. However, stereotactic biopsy (STB), a common method for obtaining suspicious tissue from deep or eloquent brain regions, fails to yield diagnostic tissue in some cases. Failure to obtain diagnostic tissue can delay initiation of treatment and may result in further invasive procedures for patients. In this study, the authors sought to determine if the coupling of in vivo optical imaging with an STB system is an effective method for identification of diagnostic tissue at the time of biopsy.

METHODS

A minimally invasive fiber optic imaging system was developed by coupling a 0.65-mm-diameter coherent fiber optic fluorescence microendoscope to an STB system. Human U251 glioma cells were transduced for stable expression of blue fluorescent protein (BFP) to produce U251-BFP cells that were utilized for in vitro and in vivo experiments. In vitro, blue fluorescence was confirmed, and tumor cell delineation by fluorescein sodium (FNa) was quantified with fluorescence microscopy. In vivo, transgenic athymic rats implanted with U251-BFP cells (n = 4) were utilized for experiments. Five weeks postimplantation, the rats received 5–10 mg/kg intravenous FNa and underwent craniotomies overlying the tumor implantation site and contralateral normal brain. A clinical STB needle containing our 0.65-mm imaging fiber was passed through each craniotomy and images were collected. Fluorescence images from regions of interest ipsilateral and contralateral to tumor implantation were obtained and quantified.

RESULTS

Live-cell fluorescence imaging confirmed blue fluorescence from transduced tumor cells and revealed a strong correlation between tumor cells quantified by blue fluorescence and FNa contrast (R2 = 0.91, p < 0.001). Normalized to background, in vivo FNa-mediated fluorescence intensity was significantly greater from tumor regions, verified by blue fluorescence, compared to contralateral brain in all animals (301.7 ± 34.18 relative fluorescence units, p < 0.001). Fluorescence intensity measured from the tumor margin was not significantly greater than that from normal brain (p = 0.89). Biopsies obtained from regions of strong fluorescein contrast were histologically consistent with tumor.

CONCLUSIONS

The authors found that in vivo fluorescence imaging with an STB needle containing a submillimeter-diameter fiber optic fluorescence microendoscope provided direct visualization of neoplastic tissue in an animal brain tumor model prior to biopsy. These results were confirmed in vivo with positive control cells and by post hoc histological assessment. In vivo fluorescence guidance may improve the diagnostic yield of stereotactic biopsies.

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Quantitative anatomical comparison of the ipsilateral and contralateral interhemispheric transcallosal approaches to the lateral ventricle

Evgenii Belykh, Kaan Yağmurlu, Ting Lei, Sam Safavi-Abbasi, Mark E. Oppenlander, Nikolay L. Martirosyan, Vadim A. Byvaltsev, Robert F. Spetzler, Peter Nakaji, and Mark C. Preul

OBJECTIVE

The best approach to deep-seated lateral and third ventricle lesions is a function of lesion characteristics, location, and relationship to the ventricles. The authors sought to examine and compare angles of attack and surgical freedom of anterior ipsilateral and contralateral interhemispheric transcallosal approaches to the frontal horn of the lateral ventricle using human cadaveric head dissections. Illustrative clinical experiences with a contralateral interhemispheric transcallosal approach and an anterior interhemispheric transcallosal transchoroidal approach are also related.

METHODS

Five formalin-fixed human cadaveric heads (10 sides) were examined microsurgically. CT and MRI scans obtained before dissection were uploaded and fused into the navigation system. The authors performed contralateral and ipsilateral transcallosal approaches to the lateral ventricle. Using the navigation system, they measured areas of exposure, surgical freedom, angles of attack, and angle of view to the surgical surface. Two clinical cases are described.

RESULTS

The exposed areas of the ipsilateral (mean [± SD] 313.8 ± 85.0 mm2) and contralateral (344 ± 87.73 mm2) interhemispheric approaches were not significantly different (p = 0.12). Surgical freedom and vertical angles of attack were significantly larger for the contralateral approach to the most midsuperior reachable point (p = 0.02 and p = 0.01, respectively) and to the posterosuperior (p = 0.02 and p = 0.04) and central (p = 0.04 and p = 0.02) regions of the lateral wall of the lateral ventricle. Surgical freedom and vertical angles of attack to central and anterior points on the floor of the lateral ventricle did not differ significantly with approach. The angle to the surface of the caudate head region was less steep for the contralateral (135.6° ± 15.6°) than for the ipsilateral (152.0° ± 13.6°) approach (p = 0.02).

CONCLUSIONS

The anterior contralateral interhemispheric transcallosal approach provided a more expansive exposure to the lower two-thirds of the lateral ventricle and striothalamocapsular region. In normal-sized ventricles, the foramen of Monro and the choroidal fissure were better visualized through the lateral ventricle ipsilateral to the craniotomy than through the contralateral approach.

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Endoscopic endonasal atlantoaxial transarticular screw fixation technique: an anatomical feasibility and biomechanical study

George A. C. Mendes, Curtis A. Dickman, Nestor G. Rodriguez-Martinez, Samuel Kalb, Neil R. Crawford, Volker K. H. Sonntag, Mark C. Preul, and Andrew S. Little

OBJECT

The primary disadvantage of the posterior cervical approach for atlantoaxial stabilization after odontoidectomy is that it is conducted as a second-stage procedure. The goal of the current study is to assess the surgical feasibility and biomechanical performance of an endoscopic endonasal surgical technique for C1–2 fixation that may eliminate the need for posterior fixation after odontoidectomy.

METHODS

The first step of the study was to perform endoscopic endonasal anatomical dissections of the craniovertebral junction in 10 silicone-injected fixed cadaveric heads to identify relevant anatomical landmarks. The second step was to perform a quantitative analysis using customized software in 10 reconstructed adult cervical spine CT scans to identify the optimal screw entry point and trajectory. The third step was biomechanical flexibility testing of the construct and comparison with the posterior C1–2 transarticular fixation in 14 human cadaveric specimens.

RESULTS

Adequate surgical exposure and identification of the key anatomical landmarks, such as C1–2 lateral masses, the C-1 anterior arch, and the odontoid process, were provided by the endonasal endoscopic approach in all specimens. Radiological analysis of anatomical detail suggested that the optimal screw entry point was on the anterior aspect of the C-1 lateral mass near the midpoint, and the screw trajectory was inferiorly and slightly laterally directed. The custommade angled instrumentation was crucial for screw placement. Biomechanical analysis suggested that anterior C1–2 fixation compared favorably to posterior fixation by limiting flexion-extension, axial rotation, and lateral bending (p > 0.3).

CONCLUSIONS

This is the first study that demonstrates the feasibility of an endoscopic endonasal technique for C1–2 fusion. This novel technique may have clinical utility by eliminating the need for a second-stage posterior fixation operation in certain patients undergoing odontoidectomy.

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Real-time intraoperative surgical telepathology using confocal laser endomicroscopy

Irakliy Abramov, Marian T. Park, Timothy C. Gooldy, Yuan Xu, Michael T. Lawton, Andrew S. Little, Randall W. Porter, Kris A. Smith, Jennifer M. Eschbacher, and Mark C. Preul

OBJECTIVE

Communication between neurosurgeons and pathologists is mandatory for intraoperative decision-making and optimization of resection, especially for invasive masses. Handheld confocal laser endomicroscopy (CLE) technology provides in vivo intraoperative visualization of tissue histoarchitecture at cellular resolution. The authors evaluated the feasibility of using an innovative surgical telepathology software platform (TSP) to establish real-time, on-the-fly remote communication between the neurosurgeon using CLE and the pathologist.

METHODS

CLE and a TSP were integrated into the surgical workflow for 11 patients with brain masses (6 patients with gliomas, 3 with other primary tumors, 1 with metastasis, and 1 with reactive brain tissue). Neurosurgeons used CLE to generate video-flow images of the operative field that were displayed on monitors in the operating room. The pathologist simultaneously viewed video-flow CLE imaging using a digital tablet and communicated with the surgeon while physically located outside the operating room (1 pathologist was in another state, 4 were at home, and 6 were elsewhere in the hospital). Interpretations of the still CLE images and video-flow CLE imaging were compared with the findings on the corresponding frozen and permanent H&E histology sections.

RESULTS

Overall, 24 optical biopsies were acquired with mean ± SD 2 ± 1 optical biopsies per case. The mean duration of CLE system use was 1 ± 0.3 minutes/case and 0.25 ± 0.23 seconds/optical biopsy. The first image with identifiable histopathological features was acquired within 6 ± 0.1 seconds. Frozen sections were processed within 23 ± 2.8 minutes, which was significantly longer than CLE usage (p < 0.001). Video-flow CLE was used to correctly interpret tissue histoarchitecture in 96% of optical biopsies, which was substantially higher than the accuracy of using still CLE images (63%) (p = 0.005).

CONCLUSIONS

When CLE is employed in tandem with a TSP, neurosurgeons and pathologists can view and interpret CLE images remotely and in real time without the need to biopsy tissue. A TSP allowed neurosurgeons to receive real-time feedback on the optically interrogated tissue microstructure, thereby improving cross-functional communication and intraoperative decision-making and resulting in significant workflow advantages over the use of frozen section analysis.

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Potential application of a handheld confocal endomicroscope imaging system using a variety of fluorophores in experimental gliomas and normal brain

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

Object

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.

Methods

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.

Results

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.

Conclusions

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.

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Moving toward the petroclival region: a model for quantitative and anatomical analysis of tumor shift

Sam Safavi-Abbasi, Joseph M. Zabramski, Pushpa Deshmukh, Cassius V. Reis, Nicholas C. Bambakidis, Nicholas Theodore, Neil R. Crawford, Robert F. Spetzler, and Mark C. Preul

Object

The authors quantitatively assessed the effects of balloon inflation as a model of tumor compression on the brainstem, cranial nerves, and clivus by measuring the working area, angle of attack, and brain shift associated with the retrosigmoid approach.

Methods

Six silicone-injected cadaveric heads were dissected bilaterally via the retrosigmoid approach. Quantitative data were generated, including key anatomical points on the skull base and brainstem. All parameters were measured before and after inflation of a balloon catheter (inflation volume 4.8 ml, diameter 20 mm) intended to mimic tumor compression.

Results

Balloon inflation significantly shifted (p < 0.001) the brainstem and cranial nerve foramina (mean [± standard deviation] displacement of upper brainstem, 10.2 ± 3.7 mm; trigeminal nerve exit, 6.99 ± 2.38 mm; facial nerve exit, 9.52 ± 4.13 mm; and lower brainstem, 13.63 ± 8.45 mm). The area of exposure at the petroclivus was significantly greater with balloon inflation than without (change, 316.26 ± 166.75 mm2; p < 0.0001). Before and after balloon inflation, there was no significant difference in the angles of attack at the origin of the trigeminal nerve (p > 0.5).

Conclusions

This study adds an experimental component to the emerging field of quantitative neurosurgical anatomy. Balloon inflation can be used to model the effects of a mass lesion. The tumor simulation created “natural” retraction and an opening toward the upper clivus. The findings may be helpful in selecting a surgical approach to increase the working space for resection of certain extraaxial tumors.

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Use of in vivo near-infrared laser confocal endomicroscopy with indocyanine green to detect the boundary of infiltrative tumor

Laboratory investigation

Nikolay L. Martirosyan, Daniel D. Cavalcanti, Jennifer M. Eschbacher, Peter M. Delaney, Adrienne C. Scheck, Mohammed G. Abdelwahab, Peter Nakaji, Robert F. Spetzler, and Mark C. Preul

Object

Infiltrative tumor resection is based on regional (macroscopic) imaging identification of tumorous tissue and the attempt to delineate invasive tumor margins in macroscopically normal-appearing tissue, while preserving normal brain tissue. The authors tested miniaturized confocal fiberoptic endomicroscopy by using a near-infrared (NIR) imaging system with indocyanine green (ICG) as an in vivo tool to identify infiltrating glioblastoma cells and tumor margins.

Methods

Thirty mice underwent craniectomy and imaging in vivo 14 days after implantation with GL261-luc cells. A 0.4 mg/kg injection of ICG was administered intravenously. The NIR images of normal brain, obvious tumor, and peritumoral zones were collected using the handheld confocal endomicroscope probe. Histological samples were acquired from matching imaged areas for correlation of tissue images.

Results

In vivo NIR wavelength confocal endomicroscopy with ICG detects fluorescence of tumor cells. The NIR and ICG macroscopic imaging performed using a surgical microscope correlated generally to tumor and peritumor regions, but NIR confocal endomicroscopy performed using ICG revealed individual tumor cells and satellites within peritumoral tissue; a definitive tumor border; and striking fluorescent microvascular, cellular, and subcellular structures (for example, mitoses, nuclei) in various tumor regions correlating with standard clinical histological features and known tissue architecture.

Conclusions

Macroscopic fluorescence was effective for gross tumor detection, but NIR confocal endomicroscopy performed using ICG enhanced sensitivity of tumor detection, providing real-time true microscopic histological information precisely related to the site of imaging. This first-time use of such NIR technology to detect cancer suggests that combined macroscopic and microscopic in vivo ICG imaging could allow interactive identification of microscopic tumor cell infiltration into the brain, substantially improving intraoperative decisions.

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Activated autologous macrophage implantation in a large-animal model of spinal cord injury

Laboratory investigation

Rachid Assina, Tejas Sankar, Nicholas Theodore, Sam P. Javedan, Alan R. Gibson, Kris M. Horn, Michael Berens, Volker K. H. Sonntag, and Mark C. Preul

Object

Axonal regeneration may be hindered following spinal cord injury (SCI) by a limited immune response and insufficient macrophage recruitment. This limitation has been partially surmounted in small-mammal models of SCI by implanting activated autologous macrophages (AAMs). The authors sought to replicate these results in a canine model of partial SCI.

Methods

Six dogs underwent left T-13 spinal cord hemisection. The AAMs were implanted at both ends of the lesion in 4 dogs, and 2 other dogs received sham implantations of cell media. Cortical motor evoked potentials (MEPs) were used to assess electrophysiological recovery. Functional motor recovery was assessed with a modified Tarlov Scale. After 9 months, animals were injected with wheat germ agglutinin–horseradish peroxidase at L-2 and killed for histological assessment.

Results

Three of the 4 dogs that received AAM implants and 1 of the 2 negative control dogs showed clear recovery of MEP response. Behavioral assessment showed no difference in motor function between the AAM-treated and control groups. Histological investigation with an axonal retrograde tracer showed neither local fiber crossing nor significant uptake in the contralateral red nucleus in both implanted and negative control groups.

Conclusions

In a large-animal model of partial SCI treated with implanted AAMs, the authors saw no morphological or histological evidence of axonal regeneration. Although they observed partial electrophysiological and functional motor recovery in all dogs, this recovery was not enhanced in animals treated with implanted AAMs. Furthermore, there was no morphological or histological evidence of axonal regeneration in animals with implants that accounted for the observed recovery. The explanation for this finding is probably multifactorial, but the authors believe that the AAM implantation does not produce axonal regeneration, and therefore is a technology that requires further investigation before it can be clinically relied on to ameliorate SCI.