Michael L. Levy

Pathogenesis and pharmacological strategies for mitigating secondary damage in acute spinal cord injury.

OBJECTIVE Experimental models and clinical observations of acute spinal cord injury (SCI) support the concepts of primary and secondary injury, in which the initial mechanical insult is succeeded by a series of deleterious events that promote progressive tissue damage and ischemia. Whereas the primary injury is fated by the circumstances of the trauma, the outcome of the secondary injury may be amenable to therapeutic modulation. This article reviews the pathogenetic determinants of these two phases of injury and summarizes the pharmacological manipulations that may restore neurological function after SCI. METHODS Experimental models of SCI and their inherent limitations in simulating human SCI are surveyed. The pathogenesis of primary and secondary injury, as well as the theoretical bases of neurological recovery, are examined in detail. The effects of glucocorticoids, lazeroids, gangliosides, opiate antagonists, calcium channel blockers, glutamate receptor antagonists, antioxidants, free radical scavengers, and other pharmacological agents in both animal models and human trials are summarized. Practical limitations to inducing neural regeneration are also addressed. RESULTS The molecular events that mediate the pathogenesis of SCI are logical targets for pharmacological manipulation and include glutamate accumulation, aberrant calcium fluxes, free radical formation, lipid peroxidation, and generation of arachidonic acid metabolites. Enhancement of neural regeneration and plasticity comprise other possible strategies. CONCLUSION Pharmacological agents must be given within a narrow window of opportunity to be effective. Although many therapeutic agents show potential promise in animal models, only methylprednisolone has been shown in large, randomized, double-blinded human studies to enhance the functional recovery of neural elements after acute SCI. Future therapy is likely to involve various combinations of these agents.

Temporary occlusion of the middle cerebral artery in intracranial aneurysm surgery: time limitation and advantage of brain protection

The risk of focal infarction secondary to the induced reversible arrest of local arterial flow during microsurgical dissection of middle cerebral artery (MCA) aneurysms was evaluated further to define the optimal approach to temporary arterial occlusion. To compare the effectiveness of brain-protection anesthetics, a group of patients treated with the intravenous agents, propofol, etomidate, and pentobarbital, administered individually or in combination, was compared to a group treated with the inhalational agent isoflurane. Forty-nine consecutive MCA aneurysm surgeries involving the temporary clipping of the parent vessel were retrospectively reviewed. Thirty-eight patients received intravenous brain-protection (IVBP) anesthesia. Groups of patients with and without infarctions, and receiving and not receiving IVBP, were compared based on the duration and nature of temporary arterial occlusion. Postoperative radiographic evidence of new infarction was used as the threshold for failure of occlusion tolerance. The overall infarction rate was 22.4% (11 of 49 patients), including 15.8% (six of 38 patients) in the IVBP group versus 45.5% (five of 11 patients) in the isoflurane (ISO) group. In the ISO group, the mean duration of temporary occlusion was 3.9 +/- 2.2 minutes for patients without infarction versus 12.2 +/- 4.3 minutes for patients with focal infarction (p < 0.01). In contrast, the mean duration was 13.6 +/- 10.6 minutes for patients without infarction and 18.5 +/- 9.9 minutes for patients with infarction in the IVBP group. All patients in the ISO group who underwent occlusion lasting 10 minutes or longer suffered an infarction versus five of 23 patients in the IVBP group. Patients with multiple aneurysms were found to be at increased risk of developing focal infarction, whereas those treated with intermittent temporary clip application were at a decreased risk. It is concluded that patients in whom focal iatrogenic ischemia is induced during MCA aneurysm clip ligation have a significant advantage compared with those receiving ISO when they are given pentobarbital as the primary neuroprotective agent or when they receive propofol or etomidate titrated to achieve electroencephalographic burst suppression, particularly if more than 10 minutes of occlusion time is required. It is also concluded that 10 minutes is a general guideline for safe, temporary occlusion of the MCA. The use of intermittent temporary arterial occlusion and patients with multiple aneurysms need further evaluation before specific recommendations can be made.

An institutional experience with cervical vagus nerve trunk stimulation for medically refractory epilepsy: rationale, technique, and outcome.

OBJECTIVE Intermittent stimulation of the left cervical vagus nerve trunk is emerging as a novel adjunct in the treatment of medically refractory seizures. We sought to evaluate theoretical and practical issues attendant to this concept. We review the anatomic and physiological background arguing for clinical application of vagus nerve stimulation, discuss salient aspects of patient selection and the nuances of surgical technique, and present our observations of and results from application of the method. METHODS Each of 18 patients with medically refractory epilepsy and at least six complex partial or secondarily generalized seizures per month underwent placement of a NeuroCybernetic Prosthesis pulse generator (Cyberonics, Webster, TX) in the chest, connected to helical platinum leads applied to the left cervical vagus nerve trunk. The patients were then randomized in a double-blinded fashion to receive either high (presumably therapeutic) or low (presumably less therapeutic) levels of vagus nerve stimulation. Reduction in seizure frequency, global assessments of quality of life, physiological measurements, and adverse events were recorded during a 3-month period. Patients in the low group were then crossed over to high-stimulation paradigms during a 15-month extension trial. RESULTS All operations were successful, uneventful, and without adverse postoperative sequelae. One patient was excluded from analysis because of inadequate seizure calendars. Of the seven patients initially assigned to high stimulation, the mean reduction in seizure frequency was 71% at 3 months and 81% at 18 months. Five (72%) of these patients had a greater than 75% reduction in seizure frequency, and one (14%) remained seizure-free after more than 1.5 years of follow-up. The mean reduction in seizure frequency among the low-stimulation group was only 6% at 3 months. No serious complications, device failures, or physiological perturbations occurred. CONCLUSION In our experience, vagus nerve stimulation has proven to be a safe, feasible, and potentially effective method of reducing seizures in select patient populations. However, the elements of strict definition for the application of the method require further study.

Toward a Simpler Surgical Management of Chiari I Malformation in a Pediatric Population

A wide variety of surgical adjuvants to the standard bony decompression have been advocated in the treatment of the Chiari I malformation, especially when the tonsillar herniation is associated with hydrosyringomyelia. These include various shunting procedures, duroplasty, obex plugging, and resection of the cerebellar tonsils. Our practice has been to avoid these adjuvants and to perform a simple limited occipital craniectomy, C1 laminectomy, and dural opening. The dura mater is left open and overlain with oxidized cellulose. To evaluate the efficacy of this more limited procedure, a retrospective review was performed of the medical records of 31 consecutive patients treated over a 6-year period. Twenty-six (84%) of these patients had an associated spinal cord syrinx; all underwent the same procedure. The follow-up period ranged from 15 to 93 months, with all patients having at least one postoperative magnetic resonance imaging at 6 months. Twenty-three of the 26 patients (88%) who presented with a syrinx had significant resolution of the syrinx on follow-up scans with concomitant improvement of presenting signs and symptoms. Of the remaining 3 patients, 1 had progressive hydrocephalus and received a ventriculoperitoneal shunt, with symptom resolution. In the other 2 patients the syrinx did not diminish; both received syringopleural shunts. Postoperative morbidity includes a 26% incidence of headaches, of which half resolved within 5 days, and only 1 persisted beyond 2 weeks. Nausea and vomiting occurred in 16%. Neither of these figures significantly exceeds those of other large surgical series in which the dura mater was closed with a patch graft. Three patients (10%) did have a postoperative cerebrospinal fluid leak; all responded to bedside suturing without further sequelae. This study indicates that a simple bone removal and open dural decompression of the cervicomedullary junction is a safe, effective operative treatment for Chiari I malformation in children. Shunts, duroplasty, obex plugging, and tonsillar resection offer no benefit regarding the outcome when our series is compared to others in which such adjuvants were used.

Management of intraoperative rupture of aneurysm without hypotension.

A retrospective analysis was performed on all aneurysms operated on by one of us (SLG) from July 1980 to October 1988 to determine the factors that govern outcome from the intraoperative rupture of aneurysms. A total of 276 consecutive surgical procedures for 317 intracranial aneurysms produced 41 perioperative or intraoperative ruptures for analysis. Five cases were pre-exposure ruptures, 3 of which occurred during anesthetic induction. Four of these patients died, and 1 made a good recovery. Of the remaining 36 cases, outcome was analyzed in terms of the adjuncts used to deal with the intraoperative rupture. There was no statistically significant difference in outcome between those cases in which tamponade was used to control hemorrhage versus temporary clipping; however, those cases in which hypotension was used did less well than those in which it was not used. From October 1986 to October 1988, 108 operations for 132 aneurysms were performed without the use of induced hypotension. There were 16 intraoperative ruptures (14.8%). All 16 of these patients made a good recovery. In the group before 1986, of which there were 20 intraoperative ruptures (of 168 operations, 11.9%), 11 of those 20 patients suffered a permanent deficit or died. We conclude that hypotension may not be a necessary adjunct to the management of intraoperative rupture of aneurysms.

An environment-dependent transcriptional network specifies human microglia identity

Of mice and mens microglia Microglia are immune system cells that function in protecting and maintaining the brain. Gosselin et al. examined the epigenetics and RNA transcripts from single microglial cells and observed consistent profiles among samples despite differences in age, sex, and diagnosis. Mouse and human microglia demonstrated similar microglia-specific gene expression profiles, as well as a shared environmental response among microglia collected either immediately after surgery (ex vivo) or after culturing (in vitro). Interestingly, those genes exhibiting differences in expression between humans and mice or after culturing were often implicated in neurodegenerative diseases. Science, this issue p. eaal3222 Single-cell sequencing of brain microglia reveals ex vivo and in vitro differences in transcription. INTRODUCTION Microglia play essential roles in central nervous system homeostasis and influence diverse aspects of neuronal function, including refinement of synaptic networks and elaboration of neuromodulatory factors for memory and motor learning. Many lines of evidence indicate that dysregulation of microglial functions contributes to the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. Emerging evidence from mouse and human studies also suggests that microglia influence neurodevelopmental and psychiatric disorders such as schizophrenia and depression. Most disease risk alleles associated with neurodegenerative diseases reside in noncoding regions of the genome, requiring the delineation of functional genomic elements in the relevant human cell types to establish mechanisms of causation. The recent observation that mouse brain environment strongly influences microglia-specific gene expression has implications for understanding pathogenic responses of microglia in diseases and disorders and modeling their phenotypes in vitro. RATIONALE Although dysregulation of microglial activity is genetically linked to neurodegenerative diseases and psychiatric disorders, no systematic evaluations of human microglia gene expression or regulatory landscapes are currently available. In addition, the extent to which mice provide suitable models for human microglia is unclear. The major goals of this study were to define the transcriptomes and DNA regulatory elements of human microglia ex vivo and in vitro in comparison to the mouse and to systematically relate these features to expression of genes associated with genome-wide association study (GWAS) risk alleles or exhibiting altered expression in neurodegenerative diseases and psychiatric disorders. RESULTS We used RNA sequencing, chromatin immunoprecipitation sequencing, and assay for transposase-accessible chromatin sequencing to characterize the transcriptomes and epigenetic landscapes of human microglia isolated from surgically resected brain tissue in excess of that needed for diagnosis. Although some effects of underlying disease cannot be excluded, the overall pattern of gene expression was markedly consistent. Microglia-enriched genes were found to overlap significantly with genes exhibiting altered expression in neurodegenerative diseases and psychiatric disorders and with genes associated with a wide spectrum of disease-specific risk alleles. Human microglia gene expression was well correlated with mouse microglia gene expression, but numerous species-specific differences were also observed that included genes linked to human disease. More than half of the genes associated with noncoding GWAS risk alleles for Alzheimer’s disease are preferentially expressed in microglia. DNA recognition motifs enriched at active enhancers and expression of the corresponding lineage-determining transcription factors were very similar for human and mouse microglia. Transition of human and mouse microglia from the brain to tissue culture revealed remodeling of their respective enhancer landscapes and extensive down-regulation of genes that are induced in primitive mouse macrophages following migration into the fetal brain. Treatment of microglia in vitro with transforming growth factor β1 (TGF-β1) had relatively modest effects in maintaining the ex vivo pattern of gene expression. A significant subset of the genes up- or down-regulated in vitro exhibited altered expression in neurodegenerative diseases and psychiatric disorders. CONCLUSION These studies identify core features of human microglial transcriptomes and epigenetic landscapes. Intersection of the microglia-specific gene signature with GWAS and transcriptomic data supports roles of microglia as both responders and contributors to disease phenotypes. The identification of an environment-sensitive program of gene expression and corresponding regulatory elements enables inference of a conserved and dynamic transcription factor network that maintains microglia identity and function. The combinations of signaling factors in the brain necessary to maintain microglia phenotypes remain largely unknown. In concert, these findings will inform efforts to generate microglia-like cells in simple and complex culture systems and understand gene-environment interactions that influence homeostatic and pathogenic functions of microglia in the human brain. Brain environment specifies gene expression in microglia. Human microglia transcriptomes and enhancer landscapes were defined ex vivo following purification from surgically resected brain tissue and in vitro after transfer to a tissue culture environment. Dynamic changes in these features enabled delineation of transcription factors controlling an environment-dependent program of gene expression that overlaps with genes that are dysregulated in brain pathologies. Microglia play essential roles in central nervous system (CNS) homeostasis and influence diverse aspects of neuronal function. However, the transcriptional mechanisms that specify human microglia phenotypes are largely unknown. We examined the transcriptomes and epigenetic landscapes of human microglia isolated from surgically resected brain tissue ex vivo and after transition to an in vitro environment. Transfer to a tissue culture environment resulted in rapid and extensive down-regulation of microglia-specific genes that were induced in primitive mouse macrophages after migration into the fetal brain. Substantial subsets of these genes exhibited altered expression in neurodegenerative and behavioral diseases and were associated with noncoding risk variants. These findings reveal an environment-dependent transcriptional network specifying microglia-specific programs of gene expression and facilitate efforts to understand the roles of microglia in human brain diseases.

Radiosurgical management of benign cavernous sinus tumors: dose profiles and acute complications.

OBJECTIVE Radiosurgery has emerged as an alternative treatment modality for cranial base tumors in patients deemed not suited for primary surgical extirpation, patients with recurrent or residual tumor after open surgery, or patients who refuse surgical treatment. We review our short-term experience with radiosurgical management of cavernous sinus region tumors with the Leksell gamma knife. METHODS From August 1994 to February 1999, 69 patients with cavernous sinus lesions were treated in 72 separate treatment sessions. The tumor type distribution was 29 pituitary adenomas, 35 meningiomas, 4 schwannomas, and 1 paraganglioma. The median follow-up was 122 weeks. Lesions were stratified according to a five-level surgical grade. The grade distribution of the tumors was as follows: Grade I, 13; Grade II, 21; Grade III, 19; Grade IV, 12; Grade V, 4. Median tumor volume was 4.7 cm3. The median radiation dose was 15 Gy to the 50% isodose line. Median maximal radiation dose was 30 Gy. RESULTS Analysis of tumor characteristics and radiation dose to optic nerve and pontine structures revealed a significant correlation between distance and dose. Much lower correlation coefficients were found between tumor volume and dose. One lesion in this series had evidence of transient progression and later regression on follow-up radiographic studies. No other lesions in this series were demonstrated to have exhibited progression. Complications after radiosurgical treatment were uncommon. Two patients had cranial nerve deficits after treatment. One patient with a surgical Grade III pituitary adenoma had VIth cranial nerve palsy 25 months after radiosurgical treatment that spontaneously resolved 10 months later. A patient with a bilateral pituitary adenoma experienced bilateral VIth cranial nerve palsy 3 months after treatment that had not resolved at 35 months after treatment. Six patients with preoperative cranial nerve deficits experienced resolution or improvement of their deficits after treatment. One patient with a prolactin-secreting adenoma experienced normalization of endocrine function with return of menses. CONCLUSION Radiosurgical treatment represents an important advance in the management of cavernous sinus tumors, with low risk of neurological deficit in comparison with open surgical treatment, even in patients with high surgical grades.

Use of Methylprednisolone as an Adjunct in the Management of Patients with Penetrating Spinal Cord Injury: Outcome Analysis

OBJECTIVE Since the results of the Second National Acute Spinal Cord Injury Study were published in 1990, methylprednisolone has become a mainstay in the treatment of nonpenetrating spinal cord injury. Although potential significant relationships between the prompt administration of high-dose methylprednisolone after blunt spinal cord injury and outcome have recently been addressed, the relationship between the prompt administration of high-dose methylprednisolone after penetrating spinal cord injury and outcome remain unanswered. METHODS To explore this relationship, we performed a retrospective nonrandomized study on a series of 252 patients with penetrating missile injuries to the spine who presented to our institution from March 1980 to July 1993. One hundred eighty-one patients (71%) were treated conventionally without adjunctive steroid therapy before 1990. Sixteen patients followed up during the 13-year study period received steroid protocols that were not consistent with the Second National Acute Spinal Cord Injury Study protocol and were excluded from the study. Since 1990, 55 patients (21%) were treated with intravenous methylprednisolone according to the Second National Acute Spinal Cord Injury Study protocol. All patients were subsequently transferred for rehabilitative care, and prospective evaluations of their neurological status were performed at admission and discharge. RESULTS The study included 236 men and 16 women (mean age, 25.6 yr). The mean duration of stay for initial hospitalization was 94.6 days, and the mean duration of stay in rehabilitation was 78.6 days. Frankel scores were used to assess outcome (P < 0.05) and were assessed at admission and at the time of definitive discharge from the Spinal Cord Injury Care System. The hypothesis that methylprednisolone therapy significantly improves functional outcomes in patients with gunshot wound injuries to the spine was rejected. Only the total number of days in rehabilitation and the degree of neurological injury at admission contributed significantly to explaining outcome at discharge. CONCLUSION The administration of methylprednisolone did not significantly improve functional outcomes in patients with gunshot wound injuries to the spine or increase the number of complications experienced by patients during their hospitalizations.

Magnetic Resonance Imaging and Pathological Correlates of Meningiomas

We examined the relationships between specific magnetic resonance imaging features and certain gross and microscopic characteristics of meningiomas, including vascularity, gross texture (consistency), and venous sinus involvement. Magnetic resonance imaging scans, surgery reports, and the histopathological findings of tumors were examined retrospectively in 54 patients. Sinus involvement was accurately predicted on T1-weighted images in 9 of 10 cases (P = 0.001) and tumors with cystic changes in 3 of 3 cases. T1-weighted images were not useful for predicting vascularity unless actual flow voids could be visualized (five of six cases). There was no correlation between T1 signal intensity, tumor consistency, or histological findings. In tumors without detectable vascularity on T1-weighted images, hyperintensity relative to gray matter on T2-weighted images was correlated with increased vascularity (P = 0.004). Tumors with soft consistency (P = 0.007), cellular atypia, invasion, angioblastic, or melanocytic components were also hyperintense, compared with gray matter on T2-weighted images (P = 0.0266). Aggressive meningiomas were found to be more vascular (P = 0.045). No correlation was found between the degree of surrounding edema or contrast enhancement with histopathological findings, vascularity, or consistency.

Correction of Large (>25 cm2) Cranial Defects with “Reinforced” Hydroxyapatite Cement: Technique and Complications

INTRODUCTIONHydroxyapatite cement is both biocompatible and osteoconductive, and it lacks significant toxic or immunogenic properties, making it an ideal substrate for the repair of cranial defects. However, with its putty-like composition, the repair of large cranial defects can be difficult because significant settling occurs as the cement hardens. We describe a technique in which we use hydroxyapatite cement, reinforced with tantalum mesh and titanium miniplates, for the repair of large (>25 cm2) cranial defects. METHODSAfter the margins of the cranioplasty are delineated, tantalum mesh is placed under the edges of the defect. Titanium miniplate single-hole bars are used to criss-cross the defect and are then secured to the surrounding bone with screws. The mesh is secured to the bars with 28-gauge stainless steel wire. Hydroxyapatite cement is applied in the defect and contoured appropriately. RESULTSWe performed nine cranioplasties in eight patients ranging in age from 1.5 to 35 years (mean, 12.2 ± 10.1 yr). The reasons for cranioplasty included cranial defect from prior trauma (n = 4), fibrous dysplasia (n = 2), infected bone flaps (n = 2), and tumor (n = 1). The cranioplasties ranged in size from 40 to 196 cm2 (mean, 128.3 ± 56.9 cm2). Follow-up ranged from 2 to 33 months (mean, 11.4 ± 12.8 mo). Two cranioplasty constructs were removed at 1 and 3 months postoperatively owing to infection. CONCLUSIONThe use of hydroxyapatite cement with mesh and miniplates provides internal structural support and increased stability of the construct. Although this technique provides an excellent cosmetic result and no evidence to date of bony resorption, the rate of infection is alarmingly high in these large constructs.