Papaverine has been associated with transient cranial nerve dysfunction after topical application during craniotomy. The authors report similar dysfunction after the use of papaverine affected brainstem structures. Two patients undergoing craniotomy for clipping of an aneurysm experienced bilateral depression of cortical somatosensory evoked potentials to both median and tibial nerve stimulation after administration of papaverine. Arterial blood gas analysis, hemodynamic parameters, and anesthetic levels remained constant throughout these somatosensory evoked potential changes. In addition, intraoperative angiography and immediate postoperative CT imaging showed intact blood flow with complete exclusion of the aneurysm. Both patients recovered within 1–2 hours and had normal neurological examination findings after extubation. Topical papaverine use may be associated with direct effects on brainstem structures. The transient nature of those changes suggests that aggressive intervention may not be needed. Maneuvers to limit the spread of papaverine to basal cisterns should be considered.
Colleen M. Moran, Michael E. Mahla, Brett Reichwage, Stephen Lewis, Keith Peters and Christoph N. Seubert
Stephen B. Lewis, Dongwoo John Chang, David A. Peace, Pamela J. Lafrentz and Arthur L. Day
Object. Aneurysms located on the distal portion of the posterior inferior cerebellar artery (PICA) are uncommon, and their underlying pathology, natural history, and clinical management are poorly understood. To clarify these lesions more fully, the authors undertook a retrospective analysis of the clinical features and management results of 22 distal PICA aneurysms in 20 consecutive patients treated at one institution by the same surgeon during the past decade.
Methods. The series included 10 men and 10 women (mean age at presentation 51 years). Nine patients presented with only subarachnoid and/or intraventricular hemorrhage (median Hunt and Hess Grade II). In seven patients intracerebellar hemorrhage was also found; two patients presented with pressure effects and two hemorrhages were incidentally discovered. Prominent comorbidities included cigarette smoking (50%) and hypertension (50%). The 13 saccular and nine fusiform distal PICA aneurysms were distributed on the following segments of the PICA: lateral medullary (seven lesions), tonsillomedullary (five lesions), telovelotonsillar (five lesions), and cortical (five lesions). Six cases were associated with cerebellar arteriovenous malformations. Skull-base and far-lateral transcondylar surgical approaches were used to secure the aneurysms in 86% of cases, either by direct clipping (13 lesions), vessel sacrifice (four lesions), or vessel sacrifice plus bypass (two lesions). Two aneurysms were treated using endovascular PICA ablation. Overall outcome at hospital discharge was excellent or good in 70% of cases. At long-term follow up (100% of patients, mean 123 days), an excellent or good outcome had been achieved in 85% of cases.
Conclusions. Depending on the PICA segment that was affected, variations in clipping strategies and surgical exposures aimed at the PICA branch and main trunk preservation were major contributors to good long-term results.
Jobyna Whiting, John Reavey-Cantwell, Gregory Velat, Gregory Fautheree, Christopher Firment, Stephen Lewis and Brian Hoh
Angiogram-negative subarachnoid hemorrhage (SAH) accounts for 15% of nontraumatic SAH and has been reported with low morbidity and mortality rates. We report on a large series of patients with angiogram-negative SAH who experienced an atypical nonbenign clinical course.
Between December 2001 and November 2006, 95 patients with spontaneous nonaneurysmal SAH and negative initial angiographic evaluation were treated at the University of Florida. The authors retrospectively reviewed the patients' medical records and radiological images to determine associated morbidity and mortality.
Aneurysms were found in 6 of the 95 patients on follow-up imaging after an initial negative angiogram (6.3% false negative rate); these patients were excluded leaving 89 patients as the study group. Hydrocephalus necessitating temporary CSF diversion developed in 22 of these patients (25%); 12 (13%) ultimately required permanent CSF diversion. Clinically significant vasospasm developed in 4 patients (4%), and 2 (2%) had cerebral infarctions. Three patients (3%) died.
The authors' experience with a large series of angiogram-negative SAH patients who had an atypical nonbenign clinical course associated with hydrocephalus, vasospasm, stroke, and mortality differs significantly from previously published case series of angiogram-negative SAH.
Report of two cases
Lewis C. Hou, Anand Veeravagu, Andrew R. Hsu, Gregory M. Enns and Stephen L. Huhn
✓Glutaric acidemia type I (GA-I) is a rare, autosomal recessive metabolic disorder that leads to severe dystonia, basal ganglia degeneration, and bilaterally enlarged anterior middle cranial fossae. The current management of this disease includes early diagnosis with newborn screening, prevention of catabolism, carnitine supplementation, and a strict dietary protein restriction. Neurosurgical evaluation and intervention may be necessary in patients with structural lesions associated with this disease. In this report, the authors present two pediatric patients with GA-I and discuss the neurosurgical aspects of this rare medical disorder.
William G. B. Singleton, Alison S. Bienemann, Max Woolley, David Johnson, Owen Lewis, Marcella J. Wyatt, Stephen J. P. Damment, Lisa J. Boulter, Clare L. Killick-Cole, Daniel J. Asby and Steven S. Gill
The pan–histone deacetylase inhibitor panobinostat has preclinical efficacy against diffuse intrinsic pontine glioma (DIPG), and the oral formulation has entered a Phase I clinical trial. However, panobinostat does not cross the blood-brain barrier in humans. Convection-enhanced delivery (CED) is a novel neurosurgical drug delivery technique that bypasses the blood-brain barrier and is of considerable clinical interest in the treatment of DIPG.
The authors investigated the toxicity, distribution, and clearance of a water-soluble formulation of panobinostat (MTX110) in a small- and large-animal model of CED. Juvenile male Wistar rats (n = 24) received panobinostat administered to the pons by CED at increasing concentrations and findings were compared to those in animals that received vehicle alone (n = 12). Clinical observation continued for 2 weeks. Animals were sacrificed at 72 hours or 2 weeks following treatment, and the brains were subjected to neuropathological analysis. A further 8 animals received panobinostat by CED to the striatum and were sacrificed 0, 2, 6, or 24 hours after infusion, and their brains explanted and snap-frozen. Tissue-drug concentration was determined by liquid chromatography tandem mass spectrometry (LC-MS/MS). Large-animal toxicity was investigated using a clinically relevant MRI-guided translational porcine model of CED in which a drug delivery system designed for humans was used. Panobinostat was administered at 30 μM to the ventral pons of 2 juvenile Large White–Landrace cross pigs. The animals were subjected to clinical and neuropathological analysis, and findings were compared to those obtained in controls after either 1 or 2 weeks. Drug distribution was determined by LC-MS/MS in porcine white and gray matter immediately after CED.
There were no clinical or neuropathological signs of toxicity up to an infused concentration of 30 μM in both small- and large-animal models. The half-life of panobinostat in rat brain after CED was 2.9 hours, and the drug was observed to be distributed in porcine white and gray matter with a volume infusion/distribution ratio of 2 and 3, respectively.
CED of water-soluble panobinostat, up to a concentration of 30 μM, was not toxic and was distributed effectively in normal brain. CED of panobinostat warrants clinical investigation in patients with DIPG.
Michael P. Kelly, Lawrence G. Lenke, Jakub Godzik, Ferran Pellise, Christopher I. Shaffrey, Justin S. Smith, Stephen J. Lewis, Christopher P. Ames, Leah Y. Carreon, Michael G. Fehlings, Frank Schwab and Adam L. Shimer
The authors conducted a study to compare neurological deficit rates associated with complex adult spinal deformity (ASD) surgery when recorded in retrospective and prospective studies. Retrospective studies may underreport neurological deficits due to selection, detection, and recall biases. Prospective studies are expensive and more difficult to perform, but they likely provide more accurate estimates of new neurological deficit rates.
New neurological deficits were recorded in a prospective study of complex ASD surgeries (pSR1) with a defined outcomes measure (decrement in American Spinal Injury Association lower-extremity motor score) for neurological deficits. Using identical inclusion criteria and a subset of participating surgeons, a retrospective study was created (rSR1) and neurological deficit rates were collected. Continuous variables were compared with the Student t-test, with correction for multiple comparisons. Neurological deficit rates were compared using the Mantel-Haenszel method for standardized risks. Statistical significance for the primary outcome measure was p < 0.05.
Overall, 272 patients were enrolled in pSR1 and 207 patients were enrolled in rSR1. Inclusion criteria, defining complex spinal deformities, and exclusion criteria were identical. Sagittal Cobb measurements were higher in pSR1, although sagittal alignment was similar. Preoperative neurological deficit rates were similar in the groups. Three-column osteotomies were more common in pSR1, particularly vertebral column resection. New neurological deficits were more common in pSR1 (pSR1 17.3% [95% CI 12.6–22.2] and rSR1 9.0% [95% CI 5.0–13.0]; p = 0.01). The majority of deficits in both studies were at the nerve root level, and the distribution of level of injury was similar.
New neurological deficit rates were nearly twice as high in the prospective study than the retrospective study with identical inclusion criteria. These findings validate concerns regarding retrospective cohort studies and confirm the need for and value of carefully designed prospective, observational cohort studies in ASD.
Use of osteogenic protein-1 in patients at high risk for spinal pseudarthrosis: a prospective cohort study assessing safety, health-related quality of life, and radiographic fusion
Invited submission from the Joint Section on Disorders of the Spine and Peripheral Nerves, March 2007
Julio C. Furlan, Richard G. Perrin, Preneshlin V. Govender, Yuriy Petrenko, Eric M. Massicotte, Yoga R. Rampersaud, Stephen Lewis and Michael G. Fehlings
The capability of osteogenic protein (OP)–1 to induce bone formation has led to an increasing interest in its use in fusion surgery. This prospective study examines the safety and efficacy of OP-1 use in patients considered to be at a high risk for developing pseudarthrosis following reconstructive spinal surgery.
Outcome measures included documentation of adverse events, radiographic evaluation of fusion by an independent musculoskeletal radiologist blinded to treatment, the Oswestry Disability Index (ODI), and the 36-Item Short Form Health Survey (SF-36). The health-related quality of life (HRQOL) assessments (ODI and SF-36) were given at baseline and at 3, 6, 12, 18, and 24 months after the surgical OP-1 implant.
The study consisted of 17 male and 13 female patients, with a mean age of 53 years (range 20–77 years). Fourteen patients underwent operations for cervical disease, and 16 for lumbar disease, with a median postoperative follow-up of 24 months (range 13–46 months). There were significant improvements in the physical health (from 28.7 ± 1.5 to 34.2 ± 3; p = 0.025) and mental health (from 43.7 ± 2 to 47.5 ± 3.1; p = 0.015) summary scores on the SF-36. The mean postoperative ODI score at 6, 9, 12, and 18 months was significantly lower than the baseline ODI score, after taking into consideration a 10-point measurement error (p = 0.0003, p = 0.003, p = 0.004, and p = 0.032, respectively). At 24 months, however, the differences in ODI scores were no longer significant. Of the 30 patients, 24 (80%) were deemed to have a solid fusion. There were no allergic reactions to OP-1 and no symptomatic postoperative hematomas.
Our results suggest that the use of OP-1 is safe and may contribute to high fusion rates, as demonstrated by radiographs, reduced levels of disability, and improved HRQOL in patients considered to be at a high risk for developing a nonunion after spinal reconstructive surgery.
Stephen B. Lewis, Gregory J. Velat, Lynn Miralia, Linda Papa, Jada M. Aikman, Regina A. Wolper, Chris S. Firment, Ming Chen Liu, Jose A. Pineda, Kevin K. W. Wang and Ronald L. Hayes
Aneurysmal subarachnoid hemorrhage (ASAH) is a serious event with grave consequences. Delayed ischemic neurological deficits caused by cerebral arterial vasospasm contribute significantly to death and disability. Biomarkers may reflect brain injury and provide an early warning of impending neurological decline and stroke from ASAH-induced vasospasm. Alpha-II spectrin is a cytoskeletal protein whose breakdown products are candidate surrogate markers of injury magnitude, treatment efficacy, and outcome. In addition, αII spectrin breakdown products (SBDPs) can provide information on the proteolytic mechanisms of injury.
Twenty patients who received a diagnosis of Fisher Grade 3 ASAH were enrolled in this study to examine the clinical utility of SBDPs in the detection of cerebral vasospasm in patients with ASAH. All patients underwent placement of a ventriculostomy for continual cerebrospinal fluid drainage within 72 hours of ASAH onset. Cerebrospinal fluid samples were collected every 6 hours and analyzed using Western Blotting for SBDPs. Onset of vasospasm was defined as an acute onset of a focal neurological deficit or a change in Glasgow Coma Scale score of two or more points. All suspected cases of vasospasm were confirmed on imaging studies.
Both calpain- and caspase-mediated SBDP levels are significantly increased in patients suffering ASAH. The concentration of SBDPs was found to increase significantly over baseline level up to 12 hours before the onset of cerebral arterial vasospasm.
Differential expression of SBDPs suggests oncotic necrotic proteolysis may be predominant in acute brain injury after ASAH and cerebral arterial vasospasm.