Short-segment percutaneous pedicle screw fixation with cement augmentation for tumor-induced spinal instability.

BACKGROUND CONTEXT: Pathologic vertebral compression fractures (VCFs) represent a major source of morbidity and diminished quality of life in the spinal oncology population. Procedures with low morbidity that effectively treat patients with pathologic fractures are especially important in the cancer population where life expectancy is limited. Vertebroplasty and kyphoplasty are often not effective for mechanically unstable pathologic fractures extending into the pedicle and facet joints. Combination of cement augmentation and percutaneous instrumented stabilization represents a minimally invasive treatment option that does not delay radiation and systemic therapy. PURPOSE: The objective of the study was to evaluate the safety and efficacy of cement-augmented short-segment percutaneous posterolateral instrumentation for tumor-associated VCF with pedicle and joint involvement. METHODS: Forty-four consecutive patients underwent cement-augmented percutaneous spinal fixation for unstable tumors between 2011 and 2014. Retrospective analysis of prospectively collected data, including visual analog pain scale (VAS) response score and procedural complications, was performed. RESULTS: Patients with a median composite Spinal Instability Neoplastic Scale score of 10 (range=8-15) were treated with constructs spanning one to four disk spaces (median of two spaces, constituting 84% of all cases). The proportion of patients with severe pain decreased from 86% preoperatively to 0%; 65% of patients reported no referable instability pain postoperatively. There was one adjacent-level fracture responsive to kyphoplasty, and one case of asymptomatic screw pullout. Two patients subsequently required decompression in the setting of disease progression despite radiation; there was no perioperative morbidity. CONCLUSIONS: Percutaneous cement-augmented posterolateral spinal fixation is a safe and effective option for palliation of appropriately selected mechanically unstable VCF that extends into pedicle and/or joint.

Intra-arterial delivery of AAV vectors to the mouse brain after mannitol mediated blood brain barrier disruption.

The delivery of therapeutics to neural tissue is greatly hindered by the blood brain barrier (BBB). Direct local delivery via diffusive release from degradable implants or direct intra-cerebral injection can bypass the BBB and obtain high concentrations of the therapeutic in the targeted tissue, however the total volume of tissue that can be treated using these techniques is limited. One treatment modality that can potentially access large volumes of neural tissue in a single treatment is intra-arterial (IA) injection after osmotic blood brain barrier disruption. In this technique, the therapeutic of interest is injected directly into the arteries that feed the target tissue after the blood brain barrier has been disrupted by exposure to a hyperosmolar mannitol solution, permitting the transluminal transport of the therapy. In this work we used contrast enhanced magnetic resonance imaging (MRI) studies of IA injections in mice to establish parameters that allow for extensive and reproducible BBB disruption. We found that the volume but not the flow rate of the mannitol injection has a significant effect on the degree of disruption. To determine whether the degree of disruption that we observed with this method was sufficient for delivery of nanoscale therapeutics, we performed IA injections of an adeno-associated viral vector containing the CLN2 gene (AAVrh.10CLN2), which is mutated in the lysosomal storage disorder Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL). We demonstrated that IA injection of AAVrh.10CLN2 after BBB disruption can achieve widespread transgene production in the mouse brain after a single administration. Further, we showed that there exists a minimum threshold of BBB disruption necessary to permit the AAV.rh10 vector to pass into the brain parenchyma from the vascular system. These results suggest that IA administration may be used to obtain widespread delivery of nanoscale therapeutics throughout the murine brain after a single administration.

Comparative efficacy and safety of multiple routes of direct CNS administration of adeno-associated virus gene transfer vector serotype rh.10 expressing the human arylsulfatase A cDNA to nonhuman primates.

Metachromatic leukodystrophy (MLD), a fatal disorder caused by deficiency of the lysosomal enzyme arylsulfatase A (ARSA), is associated with an accumulation of sulfatides, causing widespread demyelination in both central and peripheral nervous systems. On the basis of prior studies demonstrating that adeno-associated virus AAVrh.10 can mediate widespread distribution in the CNS of a secreted lysosomal transgene, and as a prelude to human trials, we comparatively assessed the optimal CNS delivery route of an AAVrh.10 vector encoding human ARSA in a large animal model for broadest distribution of ARSA enzyme. Five routes were tested (each total dose, 1.5 × 10(12) genome copies of AAVrh.10hARSA-FLAG): (1) delivery to white matter centrum ovale; (2) deep gray matter delivery (putamen, thalamus, and caudate) plus overlying white matter; (3) convection-enhanced delivery to same deep gray matter locations; (4) lateral cerebral ventricle; and (5) intraarterial delivery with hyperosmotic mannitol to the middle cerebral artery. After 13 weeks, the distribution of ARSA activity subsequent to each of the three direct intraparenchymal administration routes was significantly higher than in phosphate-buffered saline-administered controls, but administration by the intraventricular and intraarterial routes failed to demonstrate measurable levels above controls. Immunohistochemical staining in the cortex, white matter, deep gray matter of the striatum, thalamus, choroid plexus, and spinal cord dorsal root ganglions confirmed these results. Of the five routes studied, administration to the white matter generated the broadest distribution of ARSA, with 80% of the brain displaying more than a therapeutic (10%) increase in ARSA activity above PBS controls. No significant toxicity was observed with any delivery route as measured by safety parameters, although some inflammatory changes were seen by histopathology. We conclude that AAVrh.10-mediated delivery of ARSA via CNS administration into the white matter is likely to be safe and yields the widest distribution of ARSA, making it the most suitable route of vector delivery.

Multi-institutional neurosurgical training initiative at a tertiary referral center in Mwanza, Tanzania: where we are after 2 years.

BACKGROUND: The paucity of neurosurgical care in East Africa remains largely unaddressed. A sustained investment in local health infrastructures and staff training is needed to create an independent surgical capacity. The Madaktari organization has addressed this issue by starting initiatives to train local general surgeons and assistant medical officers in basic neurosurgical procedures. We report illustrative cases since beginning of the program in Mwanza in 2009 and focus on the most recent training period. METHODS: A multi-institutional neurosurgical training program and a surgical database was created at a tertiary referral center in Mwanza, Tanzania. We collected clinical data on consecutive patients who underwent a neurosurgical procedure between September 9th and December 1st, 2011. All procedures were performed by a local surgeon under the supervision of a visiting neurosurgeon. Since the inception of the training initiative, comprehensive multidisciplinary training courses in Tanzania and an annual visiting fellowship for East African surgeons to travel to a major U.S. medical center have been established. RESULTS: At initial visits infrastructure and feasibility of complex case scenarios was assessed. Surgeries for brain tumors and complex spinal cases were performed. During the 3-month training period, 62 patients underwent surgery. Pediatric hydrocephalus comprised 52% of patients, 11% suffered from meningomyelocelia, and 6% presented with an encephalocele. A total of 24% of patients were treated for trauma-related conditions, representing 75% of the adult patients. A total of 10% of patients had surgery because of traumatic spine injury, and 15% of operations were on patients with severe head injury. A total of 6% of patients presented with degenerative spine disease. One patient sustained a fatal perioperative complication. At the end of the training period, the local general surgeon was able to perform all basic neurosurgical cases independently. CONCLUSIONS: Neurosurgical care in Tanzania needs to address a diverse, unique disease burden. We found that local surgeons could be enabled to safely perform basic cranial and spinal neurosurgical procedures through immersive, 1-on-1 on-site collaborations, multidisciplinary courses, and educational visiting fellowships.

Cannulation of the internal carotid artery in mice: a novel technique for intra-arterial delivery of therapeutics.

We have developed a novel minimally invasive technique for the intra-arterial delivery of therapeutics to the mouse brain. CD-1 mice were anesthetized and placed in a lateral decubitus position. A 10mm midline longitudinal incision was made over the thyroid bone. The omohyoid and sternomastoid muscles were retracted to expose the common carotid artery and external carotid artery (ECA). To maximize delivery of administered agents, the superior thyroid artery was ligated or coagulated, and the occipital artery and the pterygopalatine artery (PPA) were temporarily occluded with 6-0 prolene suture. The ECA was carefully dissected and a permanent ligature was placed on its distal segment while a temporary 6-0 prolene ligature was placed on the proximal segment in order to obtain a flow-free segment of vessel. A sterilized 169 µm outer diameter polyimide microcatheter was introduced into the ECA and advanced in retrograde fashion toward the carotid bifurcation. The catheter was then secured and manually rotated so that the microcatheter tip was oriented cephalad in the internal carotid artery (ICA). We were able to achieve reproducible results for selective ipsilateral hemispheric carotid injections of mannitol mediated therapeutics and/or gadolinium-based MRI contrast agent. Survival rates were dependent on the administered agent and ranged from 78 to 90%. This technique allows for reproducible delivery of agents to the ipsilateral cerebral hemisphere by utilizing anterograde catheter placement and temporary ligation of the PPA. This method is cost-effective and associated with a low rate of morbimortality.

The NOMS framework: approach to the treatment of spinal metastatic tumors.

BACKGROUND: Spinal metastases frequently arise in patients with cancer. Modern oncology provides numerous treatment options that include effective systemic, radiation, and surgical options. We delineate and provide the evidence for the neurologic, oncologic, mechanical, and systemic (NOMS) decision framework, which is used at Memorial Sloan-Kettering Cancer Center to determine the optimal therapy for patients with spine metastases. METHODS: We provide a literature review of the integral publications that serve as the basis for the NOMS framework and report the results of systematic implementation of the NOMS-guided treatment. RESULTS: The NOMS decision framework consists of the neurologic, oncologic, mechanical, and systemic considerations and incorporates the use of conventional external beam radiation, spinal stereotactic radiosurgery, and minimally invasive and open surgical interventions. Review of radiation oncology and surgical literature that examine the outcomes of treatment of spinal metastatic tumors provides support for the NOMS decision framework. Application of the NOMS paradigm integrates multimodality therapy to optimize local tumor control, pain relief, and restoration or preservation of neurologic function and minimizes morbidity in this often systemically ill patient population. CONCLUSION: NOMS paradigm provides a decision framework that incorporates sentinel decision points in the treatment of spinal metastases. Consideration of the tumor sensitivity to radiation in conjunction with the extent of epidural extension allows determination of the optimal radiation treatment and the need for surgical decompression. Mechanical stability of the spine and the systemic disease considerations further help determine the need and the feasibility of surgical intervention.

Fusion of intraoperative three-dimensional rotational angiography and flat-panel detector computed tomography for cerebrovascular neuronavigation.

OBJECTIVE: We introduce a technique that uses intraoperative flat-panel detector computed tomography (FD-CT) and three-dimensional rotational angiography (3D-RA) acquired in the hybrid operative suite to provide full neuronavigation capabilities during cerebrovascular surgery without the use of preoperative imaging studies. METHODS: An Artis Zeego FD system (Siemens AG, Forchheim, Germany), mounted on a robotic C-arm was used during the clipping of an aneurysm to acquire intraoperative FD-CT and 3D-RA images. These images were then fused via the use of BrainLab iPlan 3.0 software and sent to a Vector Vision Sky neuronavigation system (NNS; BrainLAB, Heimstetten, Germany) to provide intraoperative image guidance. RESULTS: The use of intraoperative FD-CT and 3D-RA with a NNS allowed for accurate visualization of the vascular anatomy and localization of pathology. In a case of a patient harboring two aneurysms, one that was surgically clipped and a second that was treated endovascularly, the 3D-RA clearly showed neck remnants at both aneurysms. Use of the NNS assisted in further clip placement for obliteration of these neck remnants. CONCLUSIONS: Hybrid operating suites equipped with FD-CT, 3D-RA, and NNS capabilities can be used to provide intraoperative 3D image guidance during cerebrovascular surgery with excellent accuracy and without the need for preoperative angiography. Furthermore, this technique required less than 15 minutes for image acquisition and utilizes digitally subtracted angiographic images that are superior to conventional CT or MRI for the imaging of cerebrovascular pathology.

Transsphenoidal resection of sellar tumors using high-field intraoperative magnetic resonance imaging.

There has been increasing experience in the utilization of intraoperative magnetic resonance imaging (iMRI) for intracranial surgery. Despite this trend, only a few U.S centers have examined the use of this technology for transsphenoidal resection of tumors of the sella. We present the largest series in North America examining the role of iMRI for pituitary adenoma resection. We retrospectively reviewed our institutional experience of 59-patients who underwent transsphenoidal procedures for sellar and suprasellar tumors with iMRI guidance. Of these, 52 patients had a histological diagnosis of pituitary adenoma. The technical results of this subgroup were examined. A 1.5-T iMRI was integrated with the BrainLAB (Feldkirchen, Germany) neuronavigation system. The majority (94%) of tumors in our series were macroadenomas. Seventeen percent of tumors were confined to the sella, 49% had suprasellar extensions without involvement of the cavernous sinus, 34% had frank cavernous sinus invasion. All patients underwent at least one iMRI, and 19% required one or more additional sets of intraoperative imaging. In 58% of patients, iMRI led to the surgeon attempting more resection. A gross total resection was obtained in 67% of the patients with planned total resections. There was one case of permanent postoperative diabetes insipidus and no other instances of new hormone replacement. In summary, iMRI was most useful for tumors of the sella with and without suprasellar extension where the information from the iMRI extended the complete resection rate from 40 to 72% and 55 to 88%, respectively. As one would expect, it did not substantially increase the rate of resection of tumors with cavernous sinus invasion. Overall, iMRI was particularly useful in guiding resection safely, aiding in clinical decision making, and allowing identification and preservation of the pituitary stalk and normal pituitary gland. Limitations of the iMRI include a need for additional personnel and training as well as additional operative time, which diminishes over time as personnel learn to optimize workflow efficiency. Additional costs are mitigated in part by using the iMRI as an immediate postoperative scan. Other data emerging from our experience suggest that preservation of normal gland and thus avoidance of hypopituitarism may be improved by iMRI use, but longer follow-up periods are required to test this conclusion. iMRI can detect unsuspected complications sooner than routine postoperative imaging, potentially leading to improved outcomes. However, larger studies are needed.

Impaired axonal transport and altered axolemmal permeability occur in distinct populations of damaged axons following traumatic brain injury.

Traumatic axonal injury (TAI) evolves within minutes to hours following traumatic brain injury (TBI). Previous studies have identified axolemmal disruption and impaired axonal transport (AxT) as key mechanisms in the evolution of TAI. While initially hypothesized that axolemmal disruption culminates in impaired AxT, previous studies employed single-label methodologies that did not allow for a full determination of the spatial-temporal relationships of these two events. To explore directly the relationship between impaired AxT and altered axolemmal permeability, the current investigation employed 40, 10, and 3 kDa fluorescently conjugated dextrans as markers of axolemmal integrity, with antibodies targeting the anterogradely transported amyloid precursor protein (APP) utilized as a marker of impaired AxT. Rats underwent impact acceleration TBI and were intrathecally administered 40 kDa, 40 + 10 kDa or 40 + 3 kDa fluorescently tagged dextrans, with brains subsequently prepared for APP immunofluorescence. Brainstem corticospinal tracts (CSpT), medial lemnisci (ML), and medial longitudinal fasciculi were examined for evidence of TAI. APP and all dextrans consistently localized to distinct classes of TAI. Dextrans were noted as early as 5 min following injury within axonal segments demonstrating an irregular/tortuous appearance, and were seen within thin and elongate/vacuolated axons by 30 min-6 h following injury. APP, first noted within swollen axons at 30 min following injury, was found within progressively swollen axons that showed no dextran colocalization within 3 h of injury. However, by 6 h, dextrans colocalized in disconnected axonal bulbs. At this time-point, dextrans also persisted within single-labeled, highly vacuolated/thin, and elongate axons. These studies confirm that axolemmal disruption and impaired AxT occur as distinct non-related events early in the pathogenesis of TAI. Further, these studies provide evidence that the process of impaired axonal transport and subsequent axonal disconnection leads to delayed axolemmal instability, rather than proceeding as a consequence of initial axolemmal failure. This finding underscores the need of multiple approaches to fully assess the axonal response to TBI.

Illuminating protein interactions in tissue using confocal and two-photon excitation fluorescent resonance energy transfer microscopy.

Traumatic brain injury (TBI) remains the most common cause of death in persons under age 45 in the Western world. One of the principal determinants of morbidity and mortality following TBI is traumatic axonal injury (TAI). Current hypotheses on the pathogenesis of TAI involve activation of apoptotic cascades secondary to TBI. While a number of studies have demonstrated direct evidence for the activation of apoptotic cascades in TAI, the precise pathway by which these cascades are initiated remains a subject of intense investigation. As axolemmal disruption with the subsequent intra-axonal influx of large molecular weight species has been demonstrated to occur in relation to local axonal breakdown, attention has focused on cascades that may occur as a result of loss of ionic homeostasis. One proposed pathway by which this has been hypothesized to occur is the Ca(2+)-mediated activation of calmodulin and subsequent activation of the phosphatase calcineurin with dephosphorylation of a protein known as BAD, leading to a proapoptotic interaction between BAD and the mitochondrial protein Bcl-xL. While this pathway is an intriguing route for traumatic axonal pathogenesis, neither conventional immunocytochemical/histochemical nor ultrastructural approaches have had the capacity to shed insight on whether BAD and Bcl-xL interact in TAI in vivo. We describe the implementation of confocal and two-photon excitation fluorescence resonance energy transfer (FRET) microscopy techniques through which we demonstrate interaction between the proapoptotic protein BAD and the prosurvival protein Bcl-xL within TAI following TBI. Further, we report on a method to reliably detect protein interactions within aldehyde fixed tissue sections through conventional immunohistochemical approaches.

Dose-response of cyclosporin A in attenuating traumatic axonal injury in rat.

Cyclosporin A has emerged as a promising therapeutic agent in traumatic brain injury (TBI), although its precise neuroprotective mechanism is unclear. Cyclosporin A, given as a single-dose intrathecal bolus, has previously been shown to attenuate mitochondrial damage and reduce axonal injury in experimental TBI. We assessed the effect of a range of intravenous cyclosporin A doses upon axonal injury attenuation to determine the ideal dose. Rats were subjected to experimental TBI and given one of five intravenous doses of cyclosporin A. At 3 h post-injury, brains were processed for brain tissue cyclosporin A concentration. In a second set of animals, at 24 h postinjury, brains were processed for amyloid precursor protein immunoreactivity, a widely used marker of axonal injury. Intravenous administration produced therapeutic levels of cyclosporin A in brain parenchyma. Higher concentrations were achieved with equivalent doses given intrathecally; this is consistent with the reported poor blood-brain barrier permeability of cyclosporin A. Cyclosporin A 10 mg/kg i.v. produced the greatest degree of neuroprotection against diffuse axonal injury; cyclosporin A 50 mg/kg i.v. was toxic. Intravenous cyclosporin A administration achieves therapeutic levels in brain parenchyma and 10 mg/kg is the most effective dose in attenuating axonal damage after traumatic brain injury.