Diffusion Tensor Imaging in Pediatric Brain Tumor Patients

In this dissertation, we outline our efforts to introduce an advanced MRI imaging technique called Diffusion Tensor Imaging (DTI) to the pediatric brain tumor population. We discuss the theory and application of DTI as it was performed in a series of translational investigations at St. Jude Children’s Research Hospital. We present evidence of how the introduction of this technique impacted diagnosis, and treatment. And finally, we demonstrate how DTI was used to investigate cognitive morbidities associated with cancer treatment and how this research provided insight into the underlying pathophysiology involved in the development of these treatment sequela. This research has generated important insights into the fundamental causes of neuroanatomical and cognitive deficits associated with cancer and cancer therapy. The use of DTI has permitted us to identify potential targets for improved radiological and surgical techniques as well as targets for pharmacological and behavioral interventions that might improve cognitive function in cancer survivors. The discoveries here afford us an opportunity to reduce the negative effects of cancer therapy on patients treated in the future while maintaining successful survival rates

Spinal vascular lesions: anatomy, imaging techniques and treatment

Vascular lesions of the spinal cord are rare but potentially devastating conditions whose accurate recognition critically determines the clinical outcome. Several conditions lead to myelopathy due to either arterial ischemia, venous congestion or bleeding within the cord. The clinical presentation varies, according with the different aetiology and mechanism of damage

Assessment of a novel computer aided learning tool in neuroanatomy education

Impaired understanding of intricate neuroanatomical concepts and structural inter-relationships has been associated with a fear of managing neurology patients, called neurophobia, among medical trainees. As technology advances, the role of e-learning pedagogies becomes more important to supplement the traditional dissection / prosection and lecture-based pedagogies for teaching neuroanatomy to undergraduate students. However, despite the availability of a myriad of e-learning resources, the neuro (-anatomy-) phobia – neurophobia nexus prevails. The focus of the PhD was to investigate the difficulties associated with learning neuroanatomy and to develop and assess the efficacy of a novel e-learning tool for teaching neuroanatomy, in the context of the strengths and pitfalls of the currently available e-learning resources. Firstly, we sought to provide direct evidence of the medical and health science students’ perception regarding specific challenges associated with learning neuroanatomy. The initial results showed that neuroanatomy is perceived as a more difficult subject compared to other anatomy topics, with spinal pathways being the most challenging to learn. Participants believed that computer assisted learning and online resources could enhance neuroanatomy understanding and decrease their neurophobia. Next, in the context of the significance of e-learning for supplementing traditional pedagogies, we identified features of neuroanatomy web-resources that were valued by students and educators with regards to learning neuroanatomy of the spinal pathways. Participants identified strengths and weaknesses of existing neuroanatomy web-resources and ranked one resource above the others in terms of information delivery and integration of clinical, physiological and medical imaging correlates. This provides a novel user perspective on the influence of specific elements of neuroanatomy web-resources to improve instructional design and enhance learner performance. Finally, considering the data acquired from students and educators, a novel, interactive, neuroanatomy learning e-resource was developed to support teaching of the neuroanatomy of the spinal pathways. The instructional design included a discussion of the clinical interpretation of basic neuroanatomical facts to aid in neurological localization. The e-learning tool was assessed and evaluated by undergraduate medical and neuroscience students using neuroanatomy knowledge quizzes and Likert-scale perception questionnaires and compared to the previously identified best-ranked neuroanatomy e-resource. Participants’ opinion regarding the usefulness of various components of the tools was also gauged. The results showed that usage of the UCC e-resource led to a significant increase in participants’ knowledge of the neuroanatomy of the spinal pathways compared to students’ who did not use e-resources. Moreover, the participants reported a greater interest in learning neuroanatomy with the novel tool, showing a greater appreciation for it while learning clinical neurological correlates compared to those using the best available e-resource identified earlier. In summary, the prevailing problem of neurophobia could be addressed by enhancing student-interest. Technological e-learning pedagogies, with intelligently designed interactive user-interface and clinical correlation of basic neuroanatomical facts can play a pivotal role in helping students learn neuroanatomy and breaking the nexus between neuro (-anatomy-) phobia and neurophobia

Clinical translation of a regeneration strategy for spinal cord injury

The complex and vulnerable tissue of the spinal cord does not heal after injury, leaving patients with lifelong disability after spinal cord injury (SCI). Many milestones have been reached during the last century through specialized centers for SCI, greatly increasing life expectancy and quality of life by battling common medical problems such as urinary tract infections, pressure ulcers, spasticity, neurogenic pain, and sexual function as well as providing means of rehabilitation to a meaningful and productive life after SCI. Despite the advances in preclinical knowledge of mechanisms in SCI and several clinical trials completed, to date no pivotal treatment exists for acute spinal cord injury or for the regeneration of lost function in the chronic state. The first reports of experimental regeneration of central axons through peripheral nerve grafts are more than a century old. In the last decades, regeneration of function after SCI has been reported by several research groups in different species using peripheral nerve grafts and FGF1. The regeneration strategy was furthered refined in our group by the use of a biodegradable scaffold for exact positioning of the nerve grafts. This thesis describes the translational process to reach a clinical trial of glial scar resection and implantation of peripheral nerve grafts and FGF1 using a biodegradable guiding scaffold. In paper I, we show that both the cranial and caudal demarcation of a thoracic spinal cord injury can be defined with electromyography of intercostal muscles in chronic SCI patients. We also present an MRI protocol with acceptable image contrast despite the presence of spinal instrumentation and showed that the injury length found with electromyography correlates well with length of injury on MRI. In paper II, we use a novel conversion table between spinal cord neuronal segments and vertebral segments and combine data on human spinal cord cross-sectional diameters from different published sources to yield continuous estimates on human spinal cord size and variability. In paper III, we describe the design of a set of spinal cord injury guiding devices based on the data from paper II, covering the normal variability found in human thoracic spinal cord segments T2–T12 with an acceptable error-of-fit for the elliptical shape as well as guiding channels proposed. In paper IV, we detail the adverse events reported during the first 60 days postoperatively in the ongoing clinical trial “Safety and Efficacy of SC0806 (Fibroblast Growth Factor 1 and a Device) in Traumatic Spinal Cord Injury Subjects.” Early results from the first six complete (AIS-A) thoracic spinal cord injury subjects operated on in the ongoing trial show that with precise preoperative and intraoperative neurophysiology, surgery and implantation can be performed without negative effects on neurological level, and safety and tolerability are acceptable to merit the continuation of the trial. In paper V, we describe the construction of a cost-effective light-sheet microscope by modification of an outdated microarray-scanner. The microscope was applied to an experimental model of hypoglossal nerve avulsion injury, and proliferation of Iba1+ cells could be quantified automatically demonstrating a possible application of the microscope. In conclusion, reaching clinical trial in a translational process is a significant and collaborative undertaking requiring co-operation of multiple institutions and professions as well as rigorous external control of data quality and adverse events to ensure safety of study subjects. The papers in this thesis detail some relevant steps necessary for the clinical translation of regeneration strategies in chronic SCI

Evidence gaps in endovascular treatment of acute ischemic stroke

In this PhD thesis, current evidence gaps in endovascular treatment of acute ischemic stroke are discussed. Followed by an introduction in chapter 1, we first discuss the clinical course of acute ischemic stroke due to medium vessel occlusion in chapter 2, which is not as benign as commonly assumed. In chapters 3 and 4, we assess the combined effect of baseline variables on post-stroke outcome, namely the combined effect of age and Alberta Stroke Program Early CT Score (ASPECTS) in chapter 3, and the combined effect of age and National Institutes of Health Stroke Scale (NIHSS) in chapter 4. We found no evidence of interaction between age and ASPECTS, or age and NIHSS. We further assessed the impact of different infarct patterns and tissue specific infarct volumes on 24-hour follow-up imaging after endovascular treatment in chapter 5, and found that certain infarct patterns, such as a territorial infarct pattern, are independent strong predictors of poor outcome, even when adjusting for total infarct volume. In chapter 6, we analyzed features that distinguish patients with and without fast infarct progression, and showed that cerebral vascular anatomy seems to be the most important predictor of fast infarct progression. Chapter 8 summarizes a consensus statement on antiplatelet management for carotid stenting in the setting of endovascular treatment, and chapter 9 investigates starting points for improving in-hospital acute stroke workflow efficiency. Chapter 10 provides a summary and an outlook on future directions in acute ischemic stroke research and management

Diffusion imaging and tractography in the paediatric neurosurgical population

Diffusion MRI uses magnetic field gradients to sensitise a MR sequence to in vivo water diffusion. Application of these gradients in specific directions (20 in this work) enables a 3D representation of diffusion on a voxel basis. Quantitative diffusion measures are derived; using the voxel maximal diffusion direction and linking neighbouring voxels iteratively based on this creates a visual construct of the white matter: tractography. It is not possible, currently, to non-invasively determine the histological nature of an intracranial tumour. We recruited paediatric patients with radiological evidence of such lesions from April 2006 to January 2008 and retrospectively to August 2003. We used diffusion MR metrics to discriminate paediatric central nervous system tumours based on existing histological diagnoses. Using apparent diffusion coefficient histograms, common posterior fossa childhood tumours were differentiated with 93% success; Primitive neuroectodermal tumours (PNET) and supratentorial atypical teratoid rhabdoid tumours (ATRT) were separated in 100% of cases. Development of these methods with a larger population may facilitate the obviation of surgical biopsy and its attendant risks. Diffusion data was used to reconstruct the cerebellar white matter anatomy using tractography. Initially a population of normal subjects were investigated using single region of interest (ROI) analysis. DTI metrics were implemented, demonstrating the existence of white matter asymmetry where lateralisation corresponded to handedness in 17 right-handed subjects. To asses functional significance of changes in DTI metrics; clinical cerebellar dysfunction was correlated with changes in cerebellar white matter DTI metrics in a patient population with posterior fossa tumours and with the normal population. Fractional anisotropy of the tracts was reduced in patients with tumours d clinical cerebellar signs as compared to healthy individuals. This work demonstrates that diffusion MRI and tractography metrics may enable discrimination of paediatric CNS tumour type and are related to the functional integrity of cerebellar white matter tracts