Alexander E. Ropper

Primary Vertebral Tumors: A Review of Epidemiologic, Histological, and Imaging Findings, Part I: Benign Tumors

Primary vertebral tumors, although less common than metastases to the spine, make up a heterogeneous group of neoplasms that can pose diagnostic and treatment challenges. They affect both the adult and the pediatric population and may be benign, locally aggressive, or malignant. An understanding of typical imaging findings will aid in accurate diagnosis and help neurosurgeons appreciate anatomic subtleties that may increase their effective resection. An understanding of the histological similarities and differences between these tumors is imperative for all members of the clinical team caring for these patients. In this first review of 2 parts, we discuss the epidemiological, histological, and imaging features of the most common benign primary vertebral tumors—aneurysmal bone cyst, chondroma and enchondroma, hemangioma, osteoid osteoma, and osteoblastoma—and lesions related to eosinophilic granuloma and fibrous dysplasia. In addition, we discuss the basic management paradigms for each of these diagnoses. In combination with part II of the review, which focuses on locally aggressive and malignant tumors, this article provides a comprehensive review of primary vertebral tumors.

Alleviation of chronic pain following rat spinal cord compression injury with multimodal actions of huperzine A

Significance Neuropathic pain, one of the most debilitating sequelae of neurotrauma, is an unmet clinical need for at least 40% of patients with spinal cord injury (SCI). We demonstrate that [-]-huperzine A (HUP-A), a naturally occurring Lycopodium alkaloid isolated from the Chinese club moss, Huperzia serrata, with potent reversible inhibitory action on acetylcholinesterase and N-methyl-D-aspartate glutamate receptors, offers an exceptional prospect for multimodal treatment of SCI-induced neuropathic pain in rats. HUP-A restores homeostasis of central sensory neurocircuitry without invoking drug tolerance and dependence or respiratory suppression. We therefore conclude that multimodal actions provide a fresh translational approach to reduce chronic pain. Diverse mechanisms including activation of NMDA receptors, microglial activation, reactive astrogliosis, loss of descending inhibition, and spasticity are responsible for ∼40% of cases of intractable neuropathic pain after spinal cord injury (SCI). Because conventional treatments blocking individual mechanisms elicit only short-term effectiveness, a multimodal approach with simultaneous actions against major pain-related pathways may have value for clinical management of chronic pain. We hypothesize that [-]-huperzine A (HUP-A), an alkaloid isolated from the club moss Huperzia serrata, that is a potent reversible inhibitor of acetylcholinesterase and NMDA receptors, could mitigate pain without invoking drug tolerance or dependence by stimulating cholinergic interneurons to impede pain signaling, inhibiting inflammation via microglial cholinergic activation, and blocking NMDA-mediated central hypersensitization. We tested our hypothesis by administering HUP-A i.p. or intrathecally to female Sprague–Dawley rats (200–235 g body weight) after moderate static compression (35 g for 5 min) of T10 spinal cord. Compared with controls, HUP-A treatment demonstrates significant analgesic effects in both regimens. SCI rats manifested no drug tolerance following repeated bolus i.p. or chronic intrathecal HUP-A dosing. The pain-ameliorating effect of HUP-A is cholinergic dependent. Relative to vehicle treatment, HUP-A administration also reduced neural inflammation, retained higher numbers of calcium-impermeable GluR2-containing AMPA receptors, and prevented Homer1a up-regulation in dorsal horn sensory neurons. Therefore, HUP-A may provide safe and effective management for chronic postneurotrauma pain by reestablishing homeostasis of sensory circuits.

Functional Multipotency of Stem Cells: A Conceptual Review of Neurotrophic Factor-Based Evidence and Its Role in Translational Research

We here propose an updated concept of stem cells (SCs), with an emphasis on neural stem cells (NSCs). The conventional view, which has touched principally on the essential property of lineage multipotency (e.g., the ability of NSCs to differentiate into all neural cells), should be broadened to include the emerging recognition of biofunctional multipotency of SCs to mediate systemic homeostasis, evidenced in NSCs in particular by the secretion of neurotrophic factors. Under this new conceptual context and taking the NSC as a leading example, one may begin to appreciate and seek the “logic” behind the wide range of molecular tactics the NSC appears to serve at successive developmental stages as it integrates into and prepares, modifies, and guides the surrounding CNS micro- and macro-environment towards the formation and self-maintenance of a functioning adult nervous system. We suggest that embracing this view of the “multipotency” of the SCs is pivotal for correctly, efficiently, and optimally exploiting stem cell biology for therapeutic applications, including reconstitution of a dysfunctional CNS.

Primary vertebral tumors: a review of epidemiologic, histological and imaging findings, part II: locally aggressive and malignant tumors.

This second part of a comprehensive review of primary vertebral tumors focuses on locally aggressive and malignant tumors. As discussed in the earlier part of the review, both benign and malignant types of these tumors affect the adult and the pediatric population, and an understanding of their subtleties may increase their effective resection. In this review, we discuss the epidemiologic, histological, and imaging features of the most common locally aggressive primary vertebral tumors (chordoma and giant-cell tumor) and malignant tumors (chondrosarcoma, Ewing sarcoma, multiple myeloma or plasmacytoma, and osteosarcoma). The figures used for illustration are from operative patients of the senior authors (Z.L.G. and J.H.C.). Taken together, parts 1 and 2 of this article provide a thorough and illustrative review of primary vertebral tumors.

Vascular complications of stereotactic radiosurgery for arteriovenous malformations

OBJECTIVE Although vasculopathy and de novo aneurysm formation are known complications of traditional radiation therapy, their occurrence following AVM SRS is rare and thus infrequently addressed in the literature. We sought to evaluate these phenomena through a review of our institutional experience. METHODS Our review afforded 32 patients treated with LINAC-based SRS over an eight year period. We noted obliteration rates, complication rates and long-term outcomes, with particular attention paid to follow-up angiographic studies. RESULTS After a mean follow-up of 4.3 years, the overall obliteration rate was 50%, increasing to 87% for AVMs less than 3cm. Eight patients had nine hemorrhages following SRS (25%). One occurred in the context of a de novo arterial pseudoaneurysm and another in the context of a new venous varix. Two patients with post-SRS hemorrhage had intranidal aneurysms that were not as apparent on initial angiography. Two patients that did not suffer from latency period hemorrhage developed dysplastic changes of feeding arteries, and one patient suffered from early venous thrombosis with resultant permanent hemiparesis from infarction. After a mean follow-up of 4.3 years, 8 patients were clinically improved (25%), 19 were the same (59%), and 5 were worse (16%), including 2 that died as a result of latency period hemorrhage. CONCLUSION While radiosurgery of AVMs is safe and successful in the vast majority of cases, vasculopathic complications including de novo aneurysm and varix development, early venous occlusion and stenotic vasculopathy, while infrequent, can occur. Closer long-term angiographic surveillance of these patients may thus be warranted.

Defining recovery neurobiology of injured spinal cord by synthetic matrix-assisted hMSC implantation.

Significance We developed a platform technology to determine therapeutic mechanisms of human mesenchymal stromal stem cells (hMSCs) in a dorsal root ganglion coculture system and an intraspinal cord implantation model. The unique poly(lactic-co-glycolic) acid scaffolding augments hMSC stemness, engraftment, and function without neural transdifferentiation or mesenchymal lineage development, resulting in robust motosensory improvement, pain and tissue damage mitigation, and myelin preservation in adult rat spinal cord after injury. The scaffolded hMSC-derived neurotrophism, neurogenesis, angiogenesis, antiautoimmunity, and antiinflammation support the propriospinal network, neuromuscular junctions, and serotonergic reticulospinal reinnervation to activate the central pattern generator for restoring hindlimb locomotion. Our findings illuminate “recovery neurobiology”—i.e., the injured spinal cord may deploy polysynaptic neural circuits different from normal adulthood pathways for postinjury improvement. Mesenchymal stromal stem cells (MSCs) isolated from adult tissues offer tangible potential for regenerative medicine, given their feasibility for autologous transplantation. MSC research shows encouraging results in experimental stroke, amyotrophic lateral sclerosis, and neurotrauma models. However, further translational progress has been hampered by poor MSC graft survival, jeopardizing cellular and molecular bases for neural repair in vivo. We have devised an adult human bone marrow MSC (hMSC) delivery formula by investigating molecular events involving hMSCs incorporated in a uniquely designed poly(lactic-co-glycolic) acid scaffold, a clinically safe polymer, following inflammatory exposures in a dorsal root ganglion organotypic coculture system. Also, in rat T9–T10 hemisection spinal cord injury (SCI), we demonstrated that the tailored scaffolding maintained hMSC stemness, engraftment, and led to robust motosensory improvement, neuropathic pain and tissue damage mitigation, and myelin preservation. The scaffolded nontransdifferentiated hMSCs exerted multimodal effects of neurotrophism, angiogenesis, neurogenesis, antiautoimmunity, and antiinflammation. Hindlimb locomotion was restored by reestablished integrity of submidbrain circuits of serotonergic reticulospinal innervation at lumbar levels, the propriospinal projection network, neuromuscular junction, and central pattern generator, providing a platform for investigating molecular events underlying the repair impact of nondifferentiated hMSCs. Our approach enabled investigation of recovery neurobiology components for injured adult mammalian spinal cord that are different from those involved in normal neural function. The uncovered neural circuits and their molecular and cellular targets offer a biological underpinning for development of clinical rehabilitation therapies to treat disabilities and complications of SCI.

Stemness enhancement of human neural stem cells following bone marrow MSC coculture.

Rapid loss of stemness capacity in purified prototype neural stem cells (NSCs) remains a serious challenge to basic and clinical studies aiming to repair the central nervous system. Based on the essential role of mesodermal guidance in the process of neurulation, we hypothesized that coculture of human NSCs (hNSCs) with human bone marrow-derived mesenchymal stromal stem cells (hMSCs) could enhance the stemness of hNSCs through Notch-1 signaling. We have now tested the hypothesis by assessing behaviors of hNSCs and hMSCs under systematically designed coculture conditions relative to monocultures, with or without Notch-1 manipulation in vitro. Our data demonstrate that expression levels of Notch-1 and Hes-1 as determined by immunocytochemistry are significantly higher in hNSCs cocultured with hMSCs than those of controls. Furthermore, coculturing significantly increases immunoreactivity of CD15, a neural stemness marker, but decreases CD24, a marker of neural/neuronal commitment in hNSCs. The effect is independent from the physical status of cell growth since coculture and notch signaling actually promotes hNSC adhesion. Importantly, coculture with hMSCs markedly augments hNSC proliferation rate (e.g., higher yield in G2/M phase subpopulation in a notch-dependent manner detected by flow cytometry) without diminishing their lineage differentiation capabilities. The results suggest that coculture of hNSCs with hMSCs enhances stemness biology of hNSCs partially via activation of Notch-1 signal transduction. Our finding sheds new light on mesoderm-ectoderm cell fate determination via contact-based hMSC-hNSC interactions and provides mechanistic leads for devising effective regimens to sustain and augment stemness of in vitro established hNSC and hMSC lines for basic science, translational and clinical applications.

An efficient device to experimentally model compression injury of mammalian spinal cord

We report an efficient and effective device to reproducibly model clinically relevant spinal cord injury (SCI) via controlled mechanical compression. In the present study, following skin incision, dorsal laminectomy was performed to expose T10 spinal cord of adult female Sprague-Dawley rats (230-250 g). The vertebral column was suspended and stabilized by Allis clamps at T8 and 12 spinous processes. A metal impounder was then gently loaded onto T10 dura (20, 35 or 50 g × 5 min; n=7/group), resulting in acute mild, moderate, or severe standing weight compression, respectively. Neurobehavioral outcomes were evaluated using the BBB locomotor scale and inclined plane test for coordinated hindlimb function, and a battery of spinal reflex tests for sensorimotor functions, at 1 day following SCI and weekly thereafter for 7 weeks. Quantitative histopathology was used to assess injury-triggered loss of white matter, gray matter and ventral horn motor neurons. Immunocytochemical levels of glial fibrillary acidic protein (GFAP) and β-amyloid precursor protein (APP) at the cervical and lumbar regions were measured to determine the distal segment impact of T10 compression. The data demonstrates that the standardized protocol generates weight-dependent hindlimb motosensory deficits and neurodegeneration primarily at and near the lesion epicenter. Importantly, there are significantly increased GFAP and APP expressions in spinal cord segments involved in eliciting post-SCI allodynia. Therefore, the described system reliably produces compression trauma in manners partially emulating clinical quasi-static insults to the spinal cord, providing a pragmatic model to investigate pathophysiological events and potential therapeutics for compression SCI.

Targeted Treatment of Experimental Spinal Cord Glioma With Dual Gene-Engineered Human Neural Stem Cells.

BACKGROUND There are currently no satisfactory treatments or experimental models showing autonomic dysfunction for intramedullary spinal cord gliomas (ISCG). OBJECTIVE To develop a rat model of ISCG and investigate whether genetically engineered human neural stem cells (F3.hNSCs) could be developed into effective therapies for ISCG. METHODS Immunodeficient/Rowett Nude rats received C6 implantation of G55 human glioblastoma cells (10K/each). F3.hNSCs engineered to express either cytosine deaminase gene only (i.e., F3.CD) or dual genes of CD and thymidine kinase (i.e., F3.CD-TK) converted benign 5-fluorocytosine and ganciclovir into oncolytic 5-fluorouracil and ganciclovir-triphosphate, respectively. ISCG rats received injection of F3.CD-TK, F3.CD, or F3.CD-TK debris near the tumor epicenter 7 days after G55 seeding, followed with 5-FC (500 mg/kg/5 mL) and ganciclovir administrations (25 mg/kg/1 mL/day × 5/each repeat, intraperitoneal injection). Per humane standards for animals, loss of weight-bearing stepping in the hindlimb was used to determine post-tumor survival. Also evaluated were autonomic functions and tumor growth rate in vivo. RESULTS ISCG rats with F3.CD-TK treatment survived significantly longer (37.5 ± 4.78 days) than those receiving F3.CD (21.5 ± 1.75 days) or F3.CD-TK debris (19.3 ± 0.85 days; n = 4/group; P < .05, median rank test), with significantly improved autonomic function and reduced tumor growth rate. F3.DC-TK cells migrated diffusively into ISCG clusters to mediate oncolytic effect. CONCLUSION Dual gene-engineered human neural stem cell regimen markedly prolonged survival in a rat model that emulates somatomotor and autonomic dysfunctions of human cervical ISCG. F3.CD-TK may provide a novel approach to treating clinical ISCG. ABBREVIATIONS 5FC, 5-fluorocytosineBBB, Basso, Beattie, and BresnahanCD, cytosine deaminaseDP, diastolic blood pressureGCV, ganciclovir; hNSCs, human neural stem cellsISCG, intramedullary spinal cord gliomasMAP, mean arterial blood pressureNSCs, neural stem cellsSP, systolic blood pressureTK, thymidine kinase.

Association between kinase insert domain-containing receptor gene polymorphisms and silent brain infarction: A Korean study

BACKGROUND Kinase insert domain-containing receptor (KDR), vascular endothelial growth factor receptor-2, play a pivotal role in endothelial dysfunction, which may lead to silent brain infarction (SBI). We evaluated whether single nucleotide polymorphisms (SNPs) of KDR genes are associated with increased risk of SBI in a Korean population. METHODS A total of 383 patients with SBI and 387 controls were genotyped for the KDR -604T>C, 1192G>A, and 1719A>T SNPs. We separately analyzed this association according to the age (age≥65 and age<65) and the gender. We also compared haplotype frequencies between SBI patients and controls. RESULTS Genotype frequencies for three SNPs did not differ significantly between SBI patients and controls. In addition, haplotype analysis for three SNPs did not show a difference between patients and controls. However, the frequency of genotype of KDR -604T>C was significantly associated with an increased risk of SBI in the age<65 years old group (AOR=1.515, 95% CI, 1.003 to 2.289, p=0.048) and in male group (AOR=1.596, 95% CI, 1.018 to 2.503, p=0.042). CONCLUSIONS KDR -604T>C SNP may serve as genetic markers for the increased risk of SBI among the younger (<65 years) or male only Korean subpopulations.