Delayed-onset neurological deficit following correction of severe thoracic kyphotic deformity.

There are many potential risks associated with spinal deformity correction procedures including transient and/or permanent neurological deficits. Typically, neurological deficits caused by the surgical correction of spinal kyphosis occur acutely during surgery or immediately after surgery. Delayed postoperative neurological deficits are extremely rare. The authors report a case of delayed neurological deficit that occurred 48 hours after surgical correction of thoracic hyperkyphosis. An 18-year-old man with myotonic dystrophy presented with a 110 degrees T7-L1 kyphosis. The patient underwent an uneventful two-stage correction procedure of the hyperkyphotic deformity. First, anterior discectomies and fusion were performed from T-7 to L-1 using rib autograft, and all segmental vessels were preserved. Subsequently, on the same day, the patient underwent posterior Smith-Petersen osteotomies and T7-L2 pedicle screw fixation. Intact somatosensory and motor evoked potentials were maintained throughout both operations. Postoperatively, he remained neurologically intact without sequelae for nearly 48 hours. On postoperative Day 2, the patient developed delayed monoplegia of the left leg and sensory level loss below T-10. Medical management enabled complete reversal of the patient's monoplegia and sensory loss. At 2-year follow-up, the patient had no adverse neurological sequelae. In this case, a delayed postoperative neurological deficit occurred following spinal hyperkyphosis correction. The authors discuss the possible etiological mechanisms behind this complication and suggest strategies for its management.

The effects of diffuseness and deep perforating artery supply on outcomes after microsurgical resection of brain arteriovenous malformations.

OBJECTIVE: Diffuse arteriovenous malformations (AVM) have non-compact niduses, irregular margins, and intervening brain parenchyma. Deep perforating arteries often contribute to the ragged border of these diffuse AVMs. We hypothesized that diffuseness and deep perforator supply increase the difficulties and risks associated with microsurgical AVM resection. METHODS: Diffuseness was quantified using computer-generated outlines of AVMs on angiograms, contour plots with varying image intensities, and calculations of nidus area-intensity profiles. Diffuse AVMs had nonlinear area-intensity profiles with high transition intensities ([I*] greater than 0.5). A consecutive series of 304 patients who were treated with microsurgical AVM resection over a period of 7.8 years was analyzed, along with quantification of diffuseness in a subset of 103 consecutive patients. Neurological outcomes were assessed by using the Modified Rankin Scale, and logistic regression analysis was used to identify predictors of deterioration and poor outcome at late follow-up evaluation. RESULTS: Diffuse niduses were observed in 25% of patients, and 18% of patients had deep perforating artery supply. Patients with compact AVMs were more likely to have good outcomes or overall improvement (88 and 87%, respectively) than patients with diffuse AVMs (65 and 54%, respectively) (P = 0.008 and P < 0.001, respectively). Similarly, absence of deep perforator supply was associated with good outcomes or improvement in 85 and 78% of patients, respectively, compared with 63 and 64% of patients, respectively, in patients with deep perforator supply (P < 0.001 and P = 0.028, respectively). By logistic regression analysis, diffuseness and deep perforator supply were both associated with significant increases in surgical risk. CONCLUSION: Diffuseness and deep perforating artery supply are subtle features of an AVM that predict worse outcomes after microsurgical resection. Diffuseness makes surgical planes more difficult to determine and follow, whereas deep perforators are friable, poorly visualized, and located in eloquent white matter tracts. The Spetzler-Martin grading scale does not directly account for these two features; however, they should be considered carefully when making treatment recommendations to patients with AVMs.

Glial progenitor-based repair of demyelinating neurological diseases.

Demyelinating diseases of the brain and spinal cord affect more than one-quarter million of Americans, with numbers reaching more than two million across the world. These patients experience not only the vascular, traumatic, and inflammatory demyelinations of adulthood but the congenital and childhood dysmyelinating syndromes of the pediatric leukodystrophies. Several disease-modifying strategies have been developed that slow disease progression, especially in the inflammatory demyelinations and in multiple sclerosis in particular. Yet, currently available disease modifiers typically influence the immune system and are neither intended to nor competent to reverse the structural neurologic damage attending acquired demyelination. Fortunately, however, the disorders of myelin lend themselves well to attempts at structural repair, because central oligodendrocytes are the primary, and often sole, victims of the underlying disease process. Given the relative availability and homogeneity of human oligodendrocyte progenitor cells, the disorders of myelin formation and maintenance may be especially compelling targets for cell-based neurologic therapy.

Neurocytoma is a tumor of adult neuronal progenitor cells.

Central neurocytoma (CN) is a rare periventricular tumor, whose derivation, lineage potential, and molecular regulation have been mostly unexplored. We noted that CN cells exhibited an antigenic profile typical of neuronal progenitor cells in vivo, yet in vitro generated neurospheres, divided in response to bFGF (basic fibroblast growth factor), activated the neuroepithelial enhancer of the nestin gene, and gave rise to both neuron-like cells and astrocytes. When CN gene expression was compared with that of both normal adult VZ (ventricular zone) and E/nestin:GFP (green fluorescent protein)-sorted native neuronal progenitors, significant overlap was noted. Marker analysis suggested that the gene expression pattern of CN was that of a proneuronal population; glial markers were conspicuously absent, suggesting that the emergence of astroglia from CN occurred only with passage. The expression pattern of CN was distinguished from that of native progenitor cells by a cohort of differentially expressed genes potentially involved in both the oncogenesis and phenotypic restriction of neurocytoma. These included both IGF2 and several components of its signaling pathway, whose sharp overexpression implicated dysregulated autocrine IGF2 signaling in CN oncogenesis. Both receptors and effectors of canonical wnt signaling, as well as GDF8 (growth differentiation factor 8), PDGF-D, and neuregulin, were differentially overexpressed by CN, suggesting that CN is characterized by the concurrent overactivation of these pathways, which may serve to drive neurocytoma expansion while restricting tumor progenitor phenotype. This strategy of comparing the gene expression of tumor cells to that of the purified native progenitors from which they derive may provide a focused approach to identifying transcripts important to stem and progenitor cell oncogenesis.

Telomerase immortalization of neuronally restricted progenitor cells derived from the human fetal spinal cord.

Lineage-restricted progenitors of the central nervous system (CNS) are not readily expandable because their mitotic competence is limited. Here we used retroviral overexpression of human telomerase reverse transcriptase (hTERT) to immortalize progenitors from human fetal spinal cord. The hTERT-immortalized cells divided in basic fibroblast growth factor (bFGF) expressed high telomerase activity, and gave rise to phenotypically restricted subpopulations of either glia or neurons. The latter included a prototypic line, hSC11V-TERT, that gave rise only to neurons. These included both chx10(+) interneurons and Islet1(+)/Hb9(+)/ChAT(+) motor neurons; the latter were recognized by green fluorescent protein (GFP) driven by the Hb9 enhancer. The neurons were postmitotic and achieved electrophysiologic competence. Upon xenograft to both fetal rat brain and injured adult spinal cord, they matured as neurons and survived for 6 months, with no evident tumorigenesis. The cells have survived >168 doublings in vitro, with karyotypic normalcy and without replicative senescence. hTERT overexpression thus permits the generation of progenitor lines able to give rise to phenotypically restricted neurons.

Identification and isolation of multipotential neural progenitor cells from the subcortical white matter of the adult human brain.

The subcortical white matter of the adult human brain harbors a pool of glial progenitor cells. These cells can be isolated by fluorescence-activated cell sorting (FACS) after either transfection with green fluorescent protein (GFP) under the control of the CNP2 promoter, or A2B5-targeted immunotagging. Although these cells give rise largely to oligodendrocytes, in low-density culture we observed that some also generated neurons. We thus asked whether these nominally glial progenitors might include multipotential progenitor cells capable of neurogenesis. We found that adult human white-matter progenitor cells (WMPCs) could be passaged as neurospheres in vitro and that these cells generated functionally competent neurons and glia both in vitro and after xenograft to the fetal rat brain. WMPCs were able to produce neurons after their initial isolation and did not require in vitro expansion or reprogramming to do so. These experiments indicate that an abundant pool of mitotically competent neurogenic progenitor cells resides in the adult human white matter.