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Stephen L. Fedder

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Stephen R. Marano, Peter C. Johnson and Robert F. Spetzler

✓ A case of recurrent Lhermitte-Duclos disease (dysplastic gangliocytoma of the cerebellum) in a child is described with a summary of the clinical presentation and associated malformations, and a review of other cases reported in the literature. The histological examination and electron microscopic findings, with special reference to the cytological changes found during evaluation of the recurrence, are presented. Theories regarding the pathogenesis of Lhermitte-Duclos disease are reviewed.

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Brian J. Karlovits, Matthew R. Quigley, Stephen M. Karlovits, Lindsay Miller, Mark Johnson, Olivier Gayou and Russell Fuhrer

Object

Whole-brain radiation therapy (WBRT) has been the traditional approach to minimize the risk of intracranial recurrence following resection of brain metastases, despite its potential for late neurotoxicity. In 2007, the authors demonstrated an equivalent local recurrence rate to WBRT by using stereotactic radiosurgery (SRS) to the operative bed, sparing 72% of their patients WBRT. They now update their initial experience with additional patients and more mature follow-up.

Methods

The authors performed a retrospective review of all cases involving patients with limited intracranial metastatic disease (≤ 4 lesions) treated at their institution with SRS to the operative bed following resection. No patient had prior cranial radiation and WBRT was used only for salvage.

Results

From November 2000 to June 2009, 52 patients with a median age of 61 years met inclusion criteria. A single metastasis was resected in each patient. Thirty-four of the patients each had 1 lesion, 13 had 2 lesions, 3 had 3 lesions, and 2 had 4 lesions. A median dose of 1500 cGy (range 800–1800 cGy) was delivered to the resection bed targeting a median volume of 3.85 cm3 (range 0.08–22 cm3). With a median follow-up of 13 months, the median survival was 15.0 months. Four patients (7.7%) had a local recurrence within the surgical site. Twenty-three patients (44%) ultimately developed distant brain recurrences at a median of 16 months postresection, and 16 (30.7%) received salvage WBRT (8 for diffuse disease [> 3 lesions], 4 for local recurrence, and 4 for diffuse progression following salvage SRS). The median time to WBRT administration postresection was 8.7 months (range 2–43 months). On univariate analysis, patient factors of a solitary tumor (19.0 vs 12 months, p = 0.02), a recursive partitioning analysis (RPA) Class I (21 vs 13 months, p = 0.03), and no extracranial disease on presentation (22 vs 13 months, p = 0.01) were significantly associated with longer survival. Cox multivariate analysis showed a significant association with longer survival for the patient factors of no extracranial disease on presentation (p = 0.01) and solitary intracranial metastasis (p = 0.02). Among patients with no extracranial disease, a solitary intracranial metastasis conferred significant additional survival advantage (43 vs 10.5 months, p = 0.05, log-rank test). No factor (age, RPA class, tumor size or histological type, disease burden, extent of resection, or SRS dose or volume) was related to the need for salvage WBRT.

Conclusions

Adjuvant SRS to the metastatic intracranial operative bed results in a local recurrence rate equivalent to adjuvant WBRT. In combination with SRS for unresected lesions and routine imaging surveillance, this approach achieves robust overall survival (median 15 months) while sparing 70% of the patients WBRT and its potential acute and chronic toxicity.

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Robert Kellogg, Philip Lee, Christopher P. Deibert, Zachary Tempel, Nathan T. Zwagerman, Christopher M. Bonfield, Stephen Johnson and Stephanie Greene

OBJECTIVE

The authors reviewed 20 years’ experience with the surgical management of open myelomeningocele in a well-defined retrospective cohort from a single large academic medical center. Their goal was to define the characteristics of a modern cohort of children with myelomeningocele to allow for evidence-based decision-making for the treatment of these patients.

METHODS

After IRB approval was obtained, the authors queried an operative database maintained by the Department of Neurological Surgery at Children’s Hospital of Pittsburgh for patients who underwent closure of a myelomeningocele between 1995 and 2015. They identified 153 infants, and a retrospective chart review was performed.

RESULTS

Eighty-eight percent of the patients required placement of a ventriculoperitoneal shunt, and 15% of these patients acquired shunt-related infections. Eighteen percent of patients underwent Chiari malformation type II (CM-II) decompression. Sixteen percent of patients underwent a tethered cord release. Three percent of patients died within the 1st year of life. Predictors of an early demise included poor Apgar scores, large head circumference, and need for early CM-II decompression. Functional motor outcome was slightly better than predicted by anatomical level of defect.

CONCLUSIONS

Myelomeningoceles represent a severe birth defect with life-threatening complications. The authors provide long-term follow-up data and insight into factors that contribute to early death.

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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

OBJECTIVE

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.

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Mario Teo, Jeremiah N. Johnson, Teresa E. Bell-Stephens, Michael P. Marks, Huy M. Do, Robert L. Dodd, Michael B. Bober and Gary K. Steinberg

OBJECTIVE

Majewski osteodysplastic primordial dwarfism Type II (MOPD II) is a rare genetic disorder. Features of it include extremely small stature, severe microcephaly, and normal or near-normal intelligence. Previous studies have found that more than 50% of patients with MOPD II have intracranial vascular anomalies, but few successful surgical revascularization or aneurysm-clipping cases have been reported because of the diminutive arteries and narrow surgical corridors in these patients. Here, the authors report on a large series of patients with MOPD II who underwent surgery for an intracranial vascular anomaly.

METHODS

In conjunction with an approved prospective registry of patients with MOPD II, a prospectively collected institutional surgical database of children with MOPD II and intracranial vascular anomalies who underwent surgery was analyzed retrospectively to establish long-term outcomes.

RESULTS

Ten patients with MOPD II underwent surgery between 2005 and 2012; 5 patients had moyamoya disease (MMD), 2 had intracranial aneurysms, and 3 had both MMD and aneurysms. Patients presented with transient ischemic attack (TIA) (n = 2), ischemic stroke (n = 2), intraparenchymal hemorrhage from MMD (n = 1), and aneurysmal subarachnoid hemorrhage (n = 1), and 4 were diagnosed on screening. The mean age of the 8 patients with MMD, all of whom underwent extracranial-intracranial revascularization (14 indirect, 1 direct) was 9 years (range 1–17 years). The mean age of the 5 patients with aneurysms was 15.5 years (range 9–18 years). Two patients experienced postoperative complications (1 transient weakness after clipping, 1 femoral thrombosis that required surgical repair). During a mean follow-up of 5.9 years (range 3–10 years), 3 patients died (1 of subarachnoid hemorrhage, 1 of myocardial infarct, and 1 of respiratory failure), and 1 patient had continued TIAs. All of the surviving patients recovered to their neurological baseline.

CONCLUSIONS

Patients with MMD presented at a younger age than those in whom aneurysms were more prevalent. Microneurosurgery with either intracranial bypass or aneurysm clipping is extremely challenging but feasible at expert centers in patients with MOPD II, and good long-term outcomes are possible.

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Kathryn M. Wagner, Visish M. Srinivasan, Aditya Srivatsan, Michael G. Z. Ghali, Ajith J. Thomas, Alejandro Enriquez-Marulanda, Abdulrahman Y. Alturki, Christopher S. Ogilvy, Maxim Mokin, Anna L. Kuhn, Ajit Puri, Ramesh Grandhi, Stephen Chen, Jeremiah Johnson and Peter Kan

OBJECTIVE

With the increasing use of flow diversion as treatment for intracranial aneurysms, there is a concomitant increased vigilance in monitoring complications. The low porosity of flow diverters is concerning when the origins of vessels are covered, whether large circle of Willis branches or critical perforators. In this study, the authors report their experience with flow diverter coverage of the lenticulostriate vessels and evaluate their safety and outcomes.

METHODS

The authors retrospectively reviewed 5 institutional databases of all flow diversion cases from August 2012 to June 2018. Information regarding patient presentation, aneurysm location, treatment, and outcomes were recorded. Patients who were treated with flow diverters placed in the proximal middle cerebral artery (MCA), proximal anterior cerebral artery, or distal internal carotid artery leading to coverage of the medial and lateral lenticulostriate vessels were included. Clinical outcomes according to the modified Rankin Scale were reviewed. Univariate and multivariate analyses were performed to establish risk factors for lenticulostriate infarct.

RESULTS

Fifty-two patients were included in the analysis. Postprocedure cross-sectional images were available in 30 patients. Two patients experienced transient occlusion of the MCA during the procedure; one was asymptomatic, and the other had a clinical and radiographic ipsilateral internal capsule stroke. Five patients had transient symptoms without radiographic infarct in the lenticulostriate territory. Two patients experienced in-stent thrombosis, leading to clinical MCA infarcts (one in the ipsilateral caudate) after discontinuing antiplatelet therapy. Discontinuation of dual antiplatelet therapy prior to 6 months was the only variable that was significantly correlated with stroke outcome (p < 0.01, OR 0.3, 95% CI 0–0.43), and this significance persisted when controlled for other risk factors, including age, smoking status, and aneurysm location.

CONCLUSIONS

The use and versatility of flow diversion is increasing, and safety data are continuing to accumulate. Here, the authors provide early data on the safety of covering lenticulostriate vessels with flow diverters. The authors concluded that the coverage of these perforators does not routinely lead to clinically significant ischemia when dual antiplatelet therapy is continued for 6 months. Further evaluation is needed in larger cohorts and with imaging follow-up as experience develops in using these devices in more distal circulation.

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Brian L. Hoh, Yan Gong, Caitrin W. McDonough, Michael F. Waters, Adrienne J. Royster, Tiffany O. Sheehan, Ben Burkley, Taimour Y. Langaee, J Mocco, Scott L. Zuckerman, Nishit Mummareddy, Marcus L. Stephens II, Christie Ingram, Christian M. Shaffer, Joshua C. Denny, Murray H. Brilliant, Terrie E. Kitchner, James G. Linneman, Dan M. Roden and Julie A. Johnson

OBJECT

Symptomatic intracranial atherosclerotic disease (ICAD) has a high risk of recurrent stroke. Genetic polymorphisms in CYP2C19 and CES1 are associated with adverse outcomes in cardiovascular patients, but have not been studied in ICAD. The authors studied CYP2C19 and CES1 single-nucleotide polymorphisms (SNPs) in symptomatic ICAD patients.

METHODS

Genotype testing for CYP2C19*2, *3, *8, *17 and CES1 G143E was performed on 188 adult symptomatic ICAD patients from 3 medical centers who were medically managed with clopidogrel and aspirin. Testing was performed prospectively at 1 center, and retrospectively from a DNA sample biorepository at 2 centers. Multiple logistic regression and Cox regression analysis were performed to assess the association of these SNPs with the primary endpoint, which was a composite of transient ischemic attack (TIA), stroke, myocardial infarction, or death within 12 months.

RESULTS

The primary endpoint occurred in 14.9% of the 188 cases. In multiple logistic regression analysis, the presence of the CYP2C19 loss of function (LOF) alleles *2, *3, and *8 in the medically managed patients was associated with lower odds of primary endpoint compared with wild-type homozygotes (odds ratio [OR] 0.13, 95% CI 0.03–0.62, p = 0.0101). Cox regression analysis demonstrated the CYP2C19 LOF carriers had a lower risk for the primary endpoint, with hazard ratio (HR) of 0.27 (95% CI 0.08–0.95), p = 0.041. A sensitivity analysis of a secondary composite endpoint of TIA, stroke, or death demonstrated a significant trend in multiple logistic regression analysis of CYP2C19 variants, with lower odds of secondary endpoint in patients carrying at least 1 LOF allele (*2, *3, *8) than in wild-type homozygotes (OR 0.27, 95% CI 0.06–1.16, p = 0.078). Cox regression analysis demonstrated that the carriers of CYP2C19 LOF alleles had a lower risk forthe secondary composite endpoint (HR 0.22, 95% CI 0.05–1.04, p = 0.056).

CONCLUSIONS

This is the first study examining genetic variants and their effects in symptomatic ICAD. Variant alleles of CYP2C19 (*2, *3, *8) were associated with lower odds of the primary and secondary composite endpoints. However, the direction of the association was opposite of what is expected based on this SNP. This may reflect an incomplete understanding of this genetic variation and its effect in symptomatic ICAD and warrants further investigations.

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Oral Presentations

2010 AANS Annual Meeting Philadelphia, Pennsylvania May 1–5, 2010