The Impact of Targetable Mutations on Clinical Outcomes of Metastatic Epidural Spinal Cord Compression in Patients With Non-Small-Cell Lung Cancer Treated With Hybrid Therapy (Surgery Followed by Stereotactic Body Radiation Therapy).

BACKGROUND: In treatment of metastatic epidural spinal cord compression (MESCC), hybrid therapy, consisting of separation surgery, followed by stereotactic body radiation therapy, has become the mainstay of treatment for radioresistant pathologies, such as non-small-cell lung cancer (NSCLC). OBJECTIVE: To evaluate clinical outcomes of MESCC secondary to NSCLC treated with hybrid therapy and to identify clinical and molecular prognostic predictors. METHODS: This is a single-center, retrospective study. Adult patients (≥18 years old) with pathologically confirmed NSCLC and spinal metastasis who were treated with hybrid therapy for high-grade MESCC or nerve root compression from 2012 to 2019 are included. Outcome variables evaluated included overall survival (OS) and progression-free survival, local tumor control in the competing risks setting, surgical and radiation complications, and clinical-genomic correlations. RESULTS: One hundred and three patients met inclusion criteria. The median OS for this cohort was 6.5 months, with progression of disease noted in 5 (5%) patients at the index tumor level requiring reoperation and/or reirradiation at a mean of 802 days after postoperative stereotactic body radiation therapy. The 2-year local control rate was 94.6% (95% CI: 89.8-99.3). Epidermal growth factor receptor (EGFR) treatment-naïve patients who initiated EGFR-targeted therapy after hybrid therapy had significantly longer OS (hazard ratio 0.47, 95% CI 0.23-0.95, P = .04) even after adjusting for smoking status. The presence of EGFR exon 21 mutation was predictive of improved progression-free survival. CONCLUSION: Hybrid therapy in NSCLC resulted in 95% local control at 2 years after surgery. EGFR treatment-naïve patients initiating therapy after hybrid therapy had significantly improved survival advantage. EGFR-targeted therapy initiated before hybrid therapy did not confer survival benefit.

Effects of Axial Compression and Distraction on Vascular Bud and VEGFA Expression in the Vertebral Endplate of an Ex Vivo Rabbit Spinal Motion Segment Culture Model.

STUDY DESIGN: An ex vivo study of the rabbit's vertebral endplate. OBJECTIVE: The aim of this study was to assess the effect of axial compression and distraction on vascular buds and vascular endothelial growth factor (VEGFA) expression of the vertebral endplate (VEP). SUMMARY OF BACKGROUND DATA: The abnormal load can lead to intervertebral disc degeneration (IDD), whereas axial distraction can delay this process. The effects of different mechanical loads on the intervertebral disc (IVD) have been hypothesized to be related to changes in the vascular buds of the VEP; moreover, the process that might involve the vascular endothelial growth factor (VEGF) within the VEP. METHODS: Rabbit spinal segments (n = 40) were harvested and randomly classified into four groups: Control group, no stress was applied; Group A, a constant compressive load applied; Group B, compression load removed for a fixed time daily on a continuous basis, and substituted with a distraction load for 30 minutes; and Group C, compression removed for 30 minutes for a fixed period daily on a continuous basis. Tissue specimens were collected before the culture (day 0) and on day 14 post-culture of each group for analysis of IVDs' morphology, and protein and mRNA expression of Aggrecan, COL2al, VEGFA, and vascular endothelial growth factor receptor 2 of the VEPs. RESULTS: Application of axial distraction and dynamic load compression significantly delayed time- and constant compression-mediated VEP changes and IDD. Moreover, the degree of degeneration was associated with loss of vascular buds, as well as the downregulation of VEGFA and its receptor. CONCLUSION: The regulation of vascular buds and VEGF expression in the VEP represents one of the mechanisms of axial distraction and dynamic loading.Level of Evidence: N/A.

Integrated Bioinformatics Analysis of Hub Genes and Pathways Associated with a Compression Model of Spinal Cord Injury in Rats.

BACKGROUND Spinal cord injury (SCI) is a serious nervous system condition that can cause lifelong disability. The aim of this study was to identify potential molecular mechanisms and therapeutic targets for SCI. MATERIAL AND METHODS We constructed a weighted gene coexpression network and predicted which hub genes are involved in SCI. A compression model of SCI was established in 45 Sprague-Dawley rats, which were divided into 5 groups (n=9 per group): a sham operation group, and 1, 3, 5, and 7 days post-SCI groups. The spinal cord tissue on the injured site was harvested on 1, 3, 5, and 7 days after SCI and 3 days after surgery in the sham operation group. High-throughput sequencing was applied to investigate the expression profile of the mRNA in all samples. Differentially expressed genes were screened and included in weighted gene coexpression network analysis (WGCNA). Co-expressed modules and hub genes were identified by WGCNA. The biological functions of each module were investigated using the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases. RESULTS According to the RNA-seq data, a total of 1965 differentially expressed genes were screened, and WGCNA identified 10 coexpression modules and 5 hub genes. Module function analysis revealed that SCI was associated with immune response, cell division, neuron projection development, and collagen fibril organization. CONCLUSIONS Our study revealed dynamic changes in a variety of biological processes following SCI and identified 5 hub genes via WGCNA. These results provide insights into the molecular mechanisms and therapeutic targets of SCI.

Bone-derived mesenchymal stem cells alleviate compression-induced apoptosis of nucleus pulposus cells by N6 methyladenosine of autophagy.

N6 methyladenosine (m6A) is one of the most prevalent epitranscriptomic modifications of mRNAs, and plays a critical role in various bioprocesses. Bone-derived mesenchymal stem cells (BMSCs) can attenuate apoptosis of nucleus pulposus cells (NPCs) under compression; however, the underlying mechanisms are poorly understood. This study showed that the level of m6A mRNA modifications was decreased, and the autophagic flux was increased in NPCs under compression when they were cocultured with BMSCs. We report that under coculture conditions, RNA demethylase ALKBH5-mediated FIP200 mRNA demethylation enhanced autophagic flux and attenuated the apoptosis of NPCs under compression. Specific silencing of ALKBH5 results in impaired autophagic flux and a higher proportion of apoptotic NPCs under compression, even when cocultured with BMSCs. Mechanistically, we further identify that the m6A "reader" YTHDF2 is likely to be involved in the regulation of autophagy, and lower m6A levels in the coding region of FIP200 lead to a reduction in YTHDF2-mediated mRNA degradation of FIP200, a core molecular component of the ULK1 complex that participates in the initiating process of autophagy. Taken together, our study reveals the roles of ALKBH5-mediated FIP200 mRNA demethylation in enhancing autophagy and reducing apoptosis in NPCs when cocultured with BMSCs.

A case of Erdheim-Chester disease with spinal cord compression and sphenoid sinus involvement.

Erdheim-Chester disease is a rare form of non-Langerhans cell histiocytosis. It is an inflammatory disorder associated with BRAF V600E mutation in 50% of cases. This multisystem disease is rarely associated with spinal involvement. Neurological involvement is an independent predictive factor of poor prognosis. The diagnosis is histopathological based on CD68-positive and CD1A-negative histiocytes. Treatment with interferon-alpha is an independent predictor of survival in Erdheim-Chester disease and vemurafenib has also been shown to be effective for BRAF V600E mutation. We report a clinical case of a 51-year-old patient with multiple and rare locations of Erdheim-Chester disease, particularly at the sphenoid sinus.

The retrograde delivery of adenovirus vector carrying the gene for brain-derived neurotrophic factor protects neurons and oligodendrocytes from apoptosis in the chronically compressed spinal cord of twy/twy mice.

STUDY DESIGN: The twy/twy mouse undergoes spontaneous chronic mechanical compression of the spinal cord; this in vivo model system was used to examine the effects of retrograde adenovirus (adenoviral vector [AdV])-mediated brain-derived neurotrophic factor (BDNF) gene delivery to spinal neural cells. OBJECTIVE: To investigate the targeting and potential neuroprotective effect of retrograde AdV-mediated BDNF gene transfection in the chronically compressed spinal cord in terms of prevention of apoptosis of neurons and oligodendrocytes. SUMMARY OF BACKGROUND DATA: Several studies have investigated the neuroprotective effects of neurotrophins, including BDNF, in spinal cord injury. However, no report has described the effects of retrograde neurotrophic factor gene delivery in compressed spinal cords, including gene targeting and the potential to prevent neural cell apoptosis. METHODS: AdV-BDNF or AdV-LacZ (as a control gene) was injected into the bilateral sternomastoid muscles of 18-week old twy/twy mice for retrograde gene delivery via the spinal accessory motor neurons. Heterozygous Institute of Cancer Research mice (+/twy), which do not undergo spontaneous spinal compression, were used as a control for the effects of such compression on gene delivery. The localization and cell specificity of ß-galactosidase expression (produced by LacZ gene transfection) and BDNF expression in the spinal cord were examined by coimmunofluorescence staining for neural cell markers (NeuN, neurons; reactive immunology protein, oligodendrocytes; glial fibrillary acidic protein, astrocytes; OX-42, microglia) 4 weeks after gene injection. The possible neuroprotection afforded by retrograde AdV-BDNF gene delivery versus AdV-LacZ-transfected control mice was assessed by scoring the prevalence of apoptotic cells (terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling-positive cells) and immunoreactivity to active caspases -3, -8, and -9, p75, neurofilament 200 kD (NF), and for the oligodendroglial progenitor marker, NG2. RESULTS.: Four weeks after injection, the retrograde delivery of the LacZ marker gene was identified in cervical spinal neurons and some glial cells, including oligodendrocytes in the white matter of the spinal cord, in both the twy/twy mouse and the heterozygous Institute of Cancer Research mouse (+/twy). In the compressed spinal cord of twy/twy mouse, AdV-BDNF gene transfection resulted in a significant decrease in the number of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling-positive cells present in the spinal cord and a downregulation in the caspase apoptotic pathway compared with AdV-LacZ (control) gene transfection. There was a marked and significant increase in the areas of the spinal cord of AdV-BDNF-injected mice that were NF- and NG2-immunopositive compared with AdV-LacZ-injected mice, indicating the increased presence of neurons and oligodendrocytes in response to BDNF transfection. CONCLUSION: Our results demonstrate that targeted retrograde BDNF gene delivery suppresses apoptosis in neurons and oligodendrocytes in the chronically compressed spinal cord of twy/twy mouse. Further work is required to establish whether this method of gene delivery may provide neuroprotective effects in other situations of compressive spinal cord injury.

Effects of retrograde gene transfer of brain-derived neurotrophic factor in the rostral spinal cord of a compression model in rat.

Recovery after spinal cord injury (SCI) is rare in humans and experimental animals. Following SCI in adults, changes in gene expression and the regulation of these genes are associated with the pathological development of the injury. High levels of brain-derived neurotrophic factor (BDNF) in the injury area during the post-injury period contribute to enhanced neuroprotection and axonal regeneration. Intervention at the level of gene regulation has the potential to promote SCI repair. In this study, the injection of adenovirus-mediated BDNF in the lesion area (rostral spinal cord) up-regulated the expression of BDNF in the injury zone of a compression model in rat, thereby protecting neurons and enhancing behavioral function.

Apoptosis of neurons and oligodendrocytes in the spinal cord of spinal hyperostotic mouse (twy/twy): possible pathomechanism of human cervical compressive myelopathy.

INTRODUCTION: Cervical compressive myelopathy is the most serious complication of cervical spondylosis or ossification of the posterior longitudinal ligament (OPLL) and the most frequent cause of spinal cord dysfunction. There is little information on the exact pathophysiological mechanism responsible for the progressive loss of neural tissue in the spinal cord of such patients. In this study, we used the spinal hyperostotic mouse (twy/twy) as a suitable model of human spondylosis, and OPLL to investigate the cellular and molecular changes in the spinal cord. Mutant twy/twy mouse developed ossification of the ligamentum flavum at C2-C3 and exhibited progressive paralysis. MATERIALS AND METHODS: The mutant twy/twy mice, aged 16 and 24 weeks, were used in the present study. The cervical spinal cord was analyzed histologically and immunohistochemically. RESULTS: We observed that a significant correlation between the proportion of apoptotic oligodendrocytes in the compressed area of the spinal cord and the magnitude of cord compression. Immunohistochemical analysis indicated overexpression of TNFR1, CD95, and p75NTR in the twy/twy mice, which was localized by the immunofluorescence in the neurons and oligodendrocytes. CONCLUSION: The expression of such factors seems to play at least some role in the apoptotic process, which probably contributes to axonal degeneration and demyelination in the twy/twy mice spinal cords with severe compression.

A novel association between RASA1 mutations and spinal arteriovenous anomalies.

BACKGROUND AND PURPOSE: CM-AVM is a recently recognized autosomal dominant disorder associated with mutations in RASA1. Arteriovenous lesions have been reported in the brain, limbs, and the face in 18.5% of patients. We report a novel association between RASA1 mutations and spinal arteriovenous anomalies. MATERIALS AND METHODS: In a collaborative study, 5 index patients (2 females, 3 males) with spinal AVMs or AVFs and cutaneous multifocal capillary lesions were investigated for the RASA1 gene mutation. RESULTS: All 5 patients were found to have RASA1 mutation (2 de novo, 3 familial), and all had multifocal capillary malformations at birth. Neurologic deficits developed at ages ranging from infancy to early adulthood. All spinal anomalies (2 AVMs at the conus, 1 AVM at the lumbosacral junction, and 1 cervical and 1 cervicothoracic AVF) were complex, extensive, and fast-flow lesions. All patients required treatment based on the clinical and/or radiologic appearance of the lesions. CONCLUSIONS: To our knowledge, an association of RASA1 mutation and spinal AVM/AVF has not been described. MR imaging screening of patients with characteristic CMs and neurologic symptoms presenting at a young age may be useful in detecting the presence of fast-flow intracranial or intraspinal arteriovenous anomalies before potentially significant neurologic insult has occurred.

Adenovirus-mediated retrograde transfer of neurotrophin-3 gene enhances survival of anterior horn neurons of twy/twy mice with chronic mechanical compression of the spinal cord.

Chronic mechanical compression of the spinal cord causes neural tissue damage, including loss of anterior horn cells around the level of injury. Exogenous delivery of neurotrophins to neuronal cells could provide neuroprotection to a spinal cord subjected to mechanical injury. We investigated the efficacy of retrograde gene delivery of adenoviral vector (AdV) carrying neurotrophin-3 (NT-3) gene into twy (twy/twy) mouse spinal cord anterior horn neurons with chronic and progressive mechanical compression at C1-C2 level. AdV-NT-3 was used for retrograde delivery via the sternomastoid muscle to the cervical spinal accessory motoneurons in 16-week-old adult twy mice with relatively mild spinal cord compression. Four weeks after the AdV-NT-3 or AdV-beta-galactosidase cDNA (LacZ) as a marker gene injection, the compressed cervical spinal cord was examined histologically, immunohistologically, and by immunoblot analysis. Immunoreactivity to NT-3 was significantly enhanced in the AdV-NT-3-injected twy mice compared with the AdV-LacZ-injected mice. The numbers of anterior horn neurons of Nissl-, choline acetyltransferase (ChAT)-, and trkC-stained and wheat germ agglutinin-horseradish peroxidase (WGA-HRP)-labeled neurons at the spinal cord level with maximum compression were significantly higher in AdV-NT-3-transfected than in AdV-LacZ-transfected twy mice. Retrograde NT-3 gene transfer to twy mouse anterior horn neurons increased neurite axonal length and arborization of WGA-HRP-labeled neurons. Our results suggest that targeted retrograde NT-3 gene delivery is feasible in the intact animal and that it enhances neuronal survival even under chronic mechanical compression of the spinal cord.

Intravenous infusion of dihydroginsenoside Rb1 prevents compressive spinal cord injury and ischemic brain damage through upregulation of VEGF and Bcl-XL.

Red ginseng root (Panax Ginseng CA Meyer) has been used clinically by many Asian people for thousands of years without any detrimental effects. One of the major components of Red ginseng root is ginsenoside Rb(1) (gRb1). Previously, we showed that intravenous infusion of gRb1 ameliorated ischemic brain damage through upregulation of an anti-apoptotic factor, Bcl-x(L) and that topical application of gRb1 to burn wound lesion facilitated wound healing through upregulation of vascular endothelial growth factor (VEGF). In the present study, we produced dihydroginsenoside Rb1 (dgRb1), a stable chemical derivative of gRb1, and showed that intravenous infusion of dgRb1 improved spinal cord injury (SCI) as well as ischemic brain damage. As we expected, the effective dose of dgRb1 was ten times lower than that of gRb1. Intravenous infusion of dgRb1 at this effective dose did not affect brain temperature, blood pressure or cerebral blood flow, suggesting that dgRb1 rescued damaged neurons without affecting systemic parameters. In subsequent in vitro studies that focused on dgRb1-induced expression of gene products responsible for neuronal death or survival, we showed that dgRb1 could upregulate the expression of not only Bcl-x(L), but also a potent angiogenic and neurotrophic factor, VEGF. We also showed that dgRb1-induced expression of bcl-x(L) and VEGF mRNA was HRE (hypoxia response element) and STRE (signal transducers and activators of transcription 5 (Stat5) response element) dependent, respectively.

Identical twins with cervical myelopathy: a case for hereditary cervical spondylosis? Report of two cases and review of the literature.

Although degenerative cervical spondylosis is a common neurosurgical problem, not much has been published about the hereditary factors responsible for it. The authors report on a set of identical twins who presented to their service at a relatively young age with myelopathy due to degenerative cervical disc prolapse and who needed surgery. The early age of presentation and the fact that the patients were identical twins suggest a genetic element. The authors also review the available literature on the genetic factors in the causation of degenerative cervical spondylosis. To the best of their knowledge this is the first reported instance of identical twins with cervical myelopathy at a young age needing curative surgery.

Familial Chiari type I malformation with syringomyelia in two siblings: case report and review of the literature.

OBJECTIVE: Familial cases of Chiari malformation with syringomyelia are rare. The majority of the reported series and case reports detail sporadic cases. The authors report two siblings who presented with Chiari type I malformation and syringomyelia (CMI+S). CLINICAL PRESENTATION: We report two sisters who each presented with scoliosis on routine school physicals. Their clinical examination was unremarkable; however, imaging studies demonstrated a Chiari malformation with syringomyelia. Both underwent cervicomedullary decompression, and follow-up imaging studies revealed resolution of the syringomyelia. CONCLUSION: A review of the literature reveals fewer than ten previous reports of familial CMI+S in the past 30 years. Although rare, the existence of familial cases of CMI+S suggests a genetic component to the pathogenesis of this condition in at least a proportion of patients. Neurosurgeons should be aware of the familial aggregation of CMI+S.

Nicotine attenuates oxidative stress, activation of redox-regulated transcription factors and induction of proinflammatory genes in compressive spinal cord trauma.

Pathophysiology of neurodegeneration following spinal cord injury (SCI) involves alterations of cellular redox status, activation of transcription factors and induction of proinflammatory genes. In addition, recent evidence indicates that nicotine can induce potent neuroprotective effects. To study the influence of nicotine on the redox signaling pathways in relationship to SCI, moderate contusions of spinal cords at the level of T-10 were induced in rats treated or untreated with nicotine. Cellular oxidative stress, DNA binding activity of redox-responsive transcription factors (AP-1, NF-kappaB and CREB) as well as mRNA levels of inflammatory genes (MCP-1 and TNF-alpha) were determined in the thoracic and lumbar regions of the spinal cords. Nicotine was administrated 2 h after the SCI in a single i.p. injection at the dose of 0.35, 3.5 or 7 mg/kg, and rats were sacrificed 3 h following such an injection. Spinal cord trauma was associated with a significant increase in oxidative stress, and activation of NF-kappaB, AP-1 and CREB, as well as overexpression of MCP-1 and TNF-alpha in both the thoracic and lumbar regions. Nicotine administration following the SCI markedly attenuated, especially in the lumbar region, these oxidative and proinflammatory responses. These protective effects of nicotine were fully reversed by inhibition of neuronal nicotinic receptors by mecamylamine. The present results indicate that nicotine administration can attenuate the oxidative injury to spinal cords and suggest that neuronal nicotinic receptors can be attractive targets for neuroprotective therapy.

Conus medulla-cauda compression from nerve root hypertrophy in a child with Dejerine-Sottas syndrome: improvement with laminectomy and duraplasty. Case report.

This 7-year-old boy with Dejerine-Sottas syndrome caused by a mutation in the myelin protein zero gene began to suffer rapid deterioration with increasing leg weakness, loss of the ability to ambulate, and bowel and bladder incontinence. Magnetic resonance imaging of the spine revealed nerve root hypertrophy resulting in compression of the conus medullaris and cauda equina. Decompressive surgery was successful in reversing some of his deficits.

Cervical spinal cord compression attributable to a calcified intervertebral disc in a patient with X-linked hypophosphatemic rickets: case report and review of the literature.

OBJECTIVE AND IMPORTANCE: X-linked hypophosphatemic rickets is a common inherited phosphate-wasting disorder, but it is a rare cause of spinal cord compression. We present the first reported case of a calcified intervertebral disc causing spinal canal stenosis in X-linked hypophosphatemic rickets. CLINICAL PRESENTATION: A 44-year-old woman presented with paresthesia of her left arm and a loss of grip in both hands. Magnetic resonance imaging revealed a calcified intervertebral disc, as well as a posterior osteophytic bar causing marked cervical cord compression at C6/C7. INTERVENTION: An anterior cervical discectomy at C6/C7 and fusion with autologous bone graft were performed. The patient then exhibited significant improvement. CONCLUSION: A review of the 16 published cases demonstrates that thickening of the vertebral laminae, facet joint hypertrophy, and ossification of the intervertebral discs, posterior longitudinal ligament, and/or ligamentum flavum contribute to spinal canal stenosis in X-linked hypophosphatemic rickets. Those changes are caused by the disease itself and are unlikely to be related to long-term vitamin D treatment. Eleven of 16 patients were reported to have experienced favorable outcomes after surgery.

Atlantoaxial instability in Dyggve-Melchior-Clausen syndrome. Case report and review of the literature.

Dyggve-Melchior-Clausen (DMC) syndrome is a very rare disease. Only 58 cases have been reported in the literature. The syndrome is probably an autosomal recessive inherited disorder, one that is characterized by mental retardation, the short-spine type of dwarfism, and skeletal abnormalities, especially of the spine, hands, and pelvis. Atlantoaxial instability-induced spinal cord compression is a serious and preventable complication. The purpose of this report is to describe the first case of DMC syndrome in which anterior transarticular atlantoaxial screw fixation was used to treat atlantoaxial instability. The authors report on a 17-year-old man with DMC syndrome and concomitant severe atlantoaxial instability. Computerized tomography scanning and magnetic resonance angiography demonstrated an irregular course of the vertebral artery (VA) at C-2, which made a posterior fixation procedure impossible. Additionally, transoral fusion was impossible because the patient was unable to open his mouth sufficiently. Therefore, the patient underwent anterior transarticular screw fixation. Follow-up examination 36 weeks after surgery showed solid fusion without implant failure. In conclusion, treatment of atlantoaxial instability in DMC syndrome must be considered. Specific care must be taken to determine the course of the VA. If posterior and transoral fusion are impossible, anterior transarticular atlantoaxial screw fixation might be the only alternative.

Osteological features in pure-bred dogs predisposing to cervical spinal cord compression.

Relative to body size, midsagittal and interpedicular diameters of the cranial and caudal aspects of cervical vertebral foramina (C3-C7) were found to be significantly (P < 0.05) larger in small breeds than in large breeds and Dachshunds, and also larger in Dachshunds (P < 0.05) than in large breeds. This condition increases the risk for spinal cord compression resulting from relative stenosis of the cervical vertebral foramina, especially in large dogs, and this is also exacerbated by the typical shape of the vertebral foramina (i.e. dorsoventrally flattened cranially and bilaterally narrowed caudally). Within large dogs those breeds highly predisposed to cervical spinal cord compression were Great Danes (the breed with the smallest midsagittal vertebral foramen diameters from cranial C6 to cranial T1) and Doberman Pinschers, because of the most strikingly cranially dorsoventrally narrowed cone-shaped vertebral foramina at C6 and C7. The existence of a small midsagittal diameter in the cranial cervical spine was a high risk factor predisposing to spinal cord compression in small breeds and Dachshunds. Remarkable consistency was noted between the spinal level of the maximum enlargement of the spinal cord which previously was reported to be at C6, and the site of maximum enlargement of the vertebral canal currently stated in Dachshunds and small breeds. In large breeds the maximum enlargement of the vertebral canal tended to be located more caudally at the caudal limit of C7. The average age at which large dogs were most susceptible to noxious factors causing abnormal growth of the pedicles was determined to be 16 wk.

Chiari malformation, cervical spine anomalies, and neurologic deficits in velocardiofacial syndrome.

The purpose of this investigation was to evaluate the prevalence of Chiari malformation, cervical spine anomalies, and neurologic deficits in patients with velocardio-facial syndrome. This study was a prospective evaluation of 41 consecutive patients with velocardiofacial syndrome, documented by fluorescence in situ hybridization, between March of 1994 and September of 1998. The 23 girls and 18 boys ranged in age from 0.5 to 15.2 years, with a mean age of 6.7 years. Nineteen patients were assessed with magnetic resonance imaging, 39 underwent lateral cephalometric radiography, and all patients were examined for neurologic deficits. Eight of 19 patients (42 percent) had anomalies of the craniovertebral junction, including Chiari type I malformations (n = 4), occipitalization of the atlas (n = 3), and narrowing of the foramen magnum (n = 1). One patient with Chiari malformation required suboccipital craniectomy with laminectomy and decompression. Fourteen of 41 patients (34 percent) had demonstrated neurologic deficits; 10 patients (24 percent) had velar paresis (6 unilateral and 4 bilateral). Chiari malformations, cervical spine anomalies, and neurologic deficits are common in velocardiofacial syndrome. Because these findings may influence the outcome of surgical intervention, routine assessment of patients with velocardiofacial syndrome should include careful orofacial examination, lateral cephalometric radiography, and magnetic resonance imaging of the craniovertebral junction.