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Stephen H. Martin and James R. Bloedel

✓ Experiments were performed to determine if changes in cortical evoked responses could be used to predict the extent of the neurological deficits following spinal cord injury by sudden inflation of a Fogarty balloon in the epidural space cephalad to a laminectomy. The cortical responses to stimulation of the posterior tibial nerve were recorded over the sigmoid gyrus at various times following the lesion and compared with the control response. Severe, irreversible neurological deficits occurred in cats in which the cortical response either could not be evoked immediately after injury or disappeared rapidly during this period. At the end of at least 6 weeks following injury, all of these animals were paraplegic and showed severe cystic degeneration of the spinal cord. In animals in which the post-injury cortical response did not completely disappear, only mild changes were observed in a spinal cord 6 weeks following injury. This technique may be helpful in ascertaining the severity and irreversibility of a traumatic spinal cord lesion; because the technique is simple, the method may prove helpful in the clinical management of patients with spinal cord injury.

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Leif-Erik Bohman, John Pierce, James H. Stephen, Sukhmeet Sandhu and John Y. K. Lee

Object

Fully endoscopicmicrovascular decompression (E-MVD) of the trigeminal nerve was initially described more than 1 decade ago, but has not yet gained wide acceptance. The authors present the experience of their first 47 consecutive E-MVDs for trigeminal neuralgia (TN).

Methods

All surgeries were performed by a single surgeon (J.Y.K.L.) at the Pennsylvania Hospital at the University of Pennsylvania. Patients prospectively completed pain scales before and after surgery by using the Brief Pain Inventory–Facial outcomes tool. All patients were called on the telephone, and the same outcome tool was administered without reference to their preoperative pain status.

Results

Forty-seven patients (17 men) were identified and enrolled. Forty (85%) had Burchiel Type 1 TN. Vascular compression was observed at surgery in 42 patients (89%). No surgery was aborted or converted to microscope. One patient suffered permanent hearing loss, for a permanent neurological morbidity rate of 2%. Overall improvement in pain outcomes was excellent, with a median maximum pain intensity preoperatively of 10 and postoperatively of 0 (p< 0.0001). The mean interference with global function scores were 6.2 preoperatively and reduced to 1.0 at last follow-up (p < 0.0001). The mean interference with facial function was 7.3 preoperatively and reduced to 1.2 at last follow-up (p < 0.0001). The mean follow-up period after surgery was 15 ± 8 months.

Conclusions

In experienced hands, E-MVD offers superb visualization and illumination and is both safe and effective, at least in the short term. Further longer-term study is needed to compare E-MVD to traditional microscopic MVD.

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Ajit Jada, Charles E. Mackel, Steven W. Hwang, Amer F. Samdani, James H. Stephen, James T. Bennett and Ali A. Baaj

Adolescent idiopathic scoliosis (AIS) is a 3D spinal deformity affecting children between the ages of 11 and 18, without an identifiable etiology. The authors here reviewed the available literature to provide spine surgeons with a summary and update on current management options.

Smaller thoracic and thoracolumbar curves can be managed conservatively with observation or bracing, but corrective surgery may be indicated for rapidly growing or larger curves. The authors summarize the atypical features to look for in patients who may warrant further investigation with MRI during diagnosis and review the fundamental principles of the surgical management of AIS.

Patients with AIS can be managed very well with a combination of conservative and surgical options. Outcomes for these children are excellent with sustained longer-term results.

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Daniela A. Bota, Daniela Alexandru, Stephen T. Keir, Darell Bigner, James Vredenburgh and Henry S. Friedman

Object

Recurrent malignant gliomas have inherent resistance to traditional chemotherapy. Novel therapies target specific molecular mechanisms involved in abnormal signaling and resistance to apoptosis. The proteasome is a key regulator of multiple cellular functions, and its inhibition in malignant astrocytic lines causes cell growth arrest and apoptotic cell death. The proteasome inhibitor bortezomib was reported to have very good in vitro activity against malignant glioma cell lines, with modest activity in animal models as well as in clinical trials as a single agent. In this paper, the authors describe the multiple effects of bortezomib in both in vitro and in vivo glioma models and offer a novel explanation for its seeming lack of activity.

Methods

Glioma stem-like cells (GSCs) were obtained from resected glioblastomas (GBMs) at surgery and expanded in culture. Stable glioma cell lines (U21 and D54) as well as temozolomide (TMZ)-resistant glioma cells derived from U251 and D54-MG were also cultured. GSCs from 2 different tumors, as well as D54 and U251 cells, were treated with bortezomib, and the effect of the drug was measured using an XTT cell viability assay. The activity of bortezomib was then determined in D54-MG and/or U251 cells using apoptosis analysis as well as caspase-3 activity and proteasome activity measurements. Human glioma xenograft models were created in nude mice by subcutaneous injection. Bevacizumab was administered via intraperitoneal injection at a dose of 5 mg/kg daily. Bortezomib was administered by intraperitoneal injection 1 hour after bevacizumab administration in doses of at a dose of 0.35 mg/kg on days 1, 4, 8, and 11 every 21 days. Tumors were measured twice weekly.

Results

Bortezomib induced caspase-3 activation and apoptotic cell death in stable glioma cell lines and in glioma stem-like cells (GSCs) derived from malignant tumor specimens Furthermore, TMZ-resistant glioma cell lines retained susceptibility to the proteasome inhibition. The bortezomib activity was directly proportional with the cells' baseline proteasome activity. The proteasome inhibition stimulated both hypoxia-inducible factor (HIF)–1α and vascular endothelial growth factor (VEGF) production in malignant GSCs. As such, the VEGF produced by GSCs stimulated endothelial cell growth, an effect that could be prevented by the addition of bevacizumab (VEGF antibody) to the media. Similarly, administration of bortezomib and bevacizumab to athymic mice carrying subcutaneous malignant glioma xenografts resulted in greater tumor inhibition and greater improvement in survival than administration of either drug alone. These data indicate that simultaneous proteasome inhibition and VEGF blockade offer increased benefit as a strategy for malignant glioma therapy.

Conclusions

The results of this study indicate that combination therapies based on bortezomib and bevacizumab might offer an increased benefit when the two agents are used in combination. These drugs have a complementary mechanism of action and therefore can be used together to treat TMZ-resistant malignant gliomas.

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Stephen K. Powers, Michael S. B. Edwards, James E. Boggan, Lawrence H. Pitts, Philip H. Gutin, Yoshio Hosobuchi, John E. Adams and Charles B. Wilson

✓ The argon surgical laser has been used in 68 neurosurgical procedures that included the removal of intracranial and intraspinal tumors, spinal cord fenestration for syringomyelia, and the production of dorsal root entry zone lesions. Characteristics that make the argon surgical laser a useful microneurosurgical instrument include the availability of a fiberoptic delivery system, a laser spot size that can be varied continuously between 0.15 and 1.5 mm, a single laser-aiming and treatment beam, the transmission of argon laser light through aqueous media such as irrigating or cerebrospinal fluids, and improved hemostasis compared to conventional techniques. The argon laser is limited primarily by its relatively low power output (less than 16 W), which makes the excision of large tumors difficult. However, even with these limitations, which can be used to advantage in the proper setting, the authors' laboratory and clinical experience suggests that the argon surgical laser may be useful in certain microneurosurgical operations.

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Stephen P. Lownie, Alan H. Menkis, Rosemary A. Craen, Bernard Mezon, James MacDonald and David A. Steinman

✓ Giant partially thrombosed intracranial aneurysms are a challenge to treat surgically, and they are also unsuitable for coil embolization. The current options for treatment include extracranial—intracranial bypass followed by parent artery occlusion or direct surgical occlusion in which deep hypothermic circulatory arrest is used.

The authors report the use of another approach in the treatment of a giant anterior circulation aneurysm: selective brain cooling accomplished by extracorporeal perfusion. This facilitated direct surgery on a 4.2-cm, partially thrombosed aneurysm of the middle cerebral artery (MCA). A brain temperature of 22°C was achieved after 20 minutes of perfusion with blood cooled using an extracorporeal technique of femoral—common carotid artery perfusion. This was followed by a 20-minute period of surgical trapping of the MCA, then evacuation and clip occlusion of the aneurysm. During the period of selective brain cooling the patient's core body temperature was maintained above 35°C.

This technique of selective brain cooling may be a useful alternative to currently available surgical and endovascular methods of treatment for giant aneurysms.

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Chun Po Yen, Stephen J. Monteith, James H. Nguyen, Jessica Rainey, David J. Schlesinger and Jason P. Sheehan

Object

The aim of this study was to evaluate the long-term imaging and clinical outcomes of intracranial arteriovenous malformations (AVMs) in children treated with Gamma Knife surgery (GKS).

Methods

Between 1989 and 2007, 200 patients with AVMs who were 18 years of age or younger were treated at the University of Virginia Health System. Excluding 14 patients who had not reached 2-year follow-up, 186 patients comprised this study. Hemorrhage was the most common presenting symptom leading to the diagnosis of AVMs (71.5%). The mean nidus volume was 3.2 cm3 at the time of GKS, and a mean prescription dose of 21.9 Gy was used.

Results

After initial GKS, 49.5% of patients achieved total angiographic obliteration. Forty-one patients whose AVM nidi remained patent underwent additional GKS. The obliteration rate increased to 58.6% after a second or multiple GKS. Subtotal obliteration was achieved in 9 patients (4.8%). Forty-nine patients (26.3%) still had a patent residual nidus. In 19 patients (10.2%), obliteration was confirmed on MR imaging only. Ten patients had 17 hemorrhages during the follow-up period. The hemorrhage rate was 5.4% within 2 years after GKS and 0.8% between 2 and 5 years. Six patients developed neurological deficits along with the radiation-induced changes. Two patients developed asymptomatic meningiomas 10 and 12 years after GKS. After a mean clinical follow-up of 98 months, less than 4% of patients had difficulty attending school or developing a career.

Conclusions

Gamma Knife surgery offers a reasonable chance of obliteration of an AVM in pediatric patients. The incidence of symptomatic radiation-induced changes is relatively low; however, long-term clinical and imaging follow-up is required to identify delayed cyst formation and secondary tumors.

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James L. West, Michael H. Soike, Jaclyn J. Renfrow, Michael D. Chan, Adrian W. Laxton and Stephen B. Tatter

OBJECTIVE

Rathke’s cleft cysts (RCCs) are benign lesions of the sella turcica that usually come to neurosurgical attention due to compression of the optic apparatus (OA) and headaches. Treatment options for these lesions include observation, aspiration of cyst contents, or open resection of the cyst with the cyst wall. All of these options involve the potential for cyst recurrence or enlargement. In this study the authors report on a potential new therapeutic option for RCCs, i.e., stereotactic radiosurgery (SRS).

METHODS

A retrospective review was conducted of 5 patients with histologically confirmed, multiply recurrent RCCs who were treated with single-fraction SRS at a tertiary referral academic medical center.

RESULTS

The total cohort consisted of 5 female patients with an average age of 31.8 years. The most common presenting symptom was headache followed by blurry vision. The symptoms were present on average for 7 months before intervention. The median number of surgeries prior to radiosurgery was 2. The average volume of lesion treated was 0.34 cm3. The median SRS dose was 12.5 Gy prescribed to the 50% isodose line with an average prescription coverage of 96.6%. The median dose to the OA was 5 Gy. At last follow-up, 3 of 5 cysts had completely regressed, 1 had regressed by more than 50% but was still present, and 1 was stable, with an overall mean follow-up duration of 34.2 months. There were no neurological, endocrinological, or visual complications attributable to SRS during the follow-up period.

CONCLUSIONS

RCCs can be a challenging clinical entity to treat, especially when they are multiply recurrent. In patients with an average of 2 previous surgeries for resection, a single SRS session prevented recurrence universally, with an average follow-up of almost 3 years. These results indicate that further investigation of the treatment of RCCs with SRS is indicated.

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Leslie N. Sutton, James H. Wood, Benjamin R. Brooks, Stephen J. Barrer, Mitchell Kline and Steven R. Cohen

✓ Immunoreactive myelin basic protein (MBP) levels were measured in cerebrospinal fluid (CSF) samples taken from 57 patients with active hydrocephalus (age range 3 weeks to 60 years). Of these patients, 28 (49%) had elevated MBP values (> 4.5 ng/ml). Elevated MBP levels were found in 44% of patients with congenital hydrocephalus, 75% of patients with posttraumatic hydrocephalus, 80% of patients with normal-pressure hydrocephalus, and 83% of patients with porencephaly. Also associated with abnormal MBP levels was the ventricular size as measured by computerized tomography scanning (χ2: p < 0.05): 36% of the patients with small ventricles (ventricle:brain ratio 0 to 0.4:1) had elevated MBP in the CSF, whereas 61% of those with moderate ventricles (0.41 to 0.6:1 ratio) and 100% of those with large ventricles (0.61 to 0.85:1 ratio) had abnormal values. Only 33% of those with maximal hydrocephalus (0.86 to 1.0:1 ratio) had elevated MBP levels, perhaps because of dilution effects. In three patients in whom CSF was obtained simultaneously by ventricular and lumbar punctures, the ventricular fluid had a consistently higher concentration of MBP, suggesting a cerebral origin. It is concluded that active hydrocephalus produces significant periventricular demyelination, probably as the result of mechanical stretching.

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James H. Stephen, Angela J. Sievert, Peter J. Madsen, Alexander R. Judkins, Adam C. Resnick, Phillip B. Storm, Elisabeth J. Rushing and Mariarita Santi

Object

Primary spinal cord ependymomas (EPNs) are rare in children, comprising classical WHO Grade II and III tumors and Grade I myxopapillary ependymomas (MEPNs). Despite their benign histology, recurrences and neural-axis dissemination have been reported in up to 33% MEPNs in the pediatric population. Treatment options beyond resection are limited, and little is known about their tumorigenesis. The purpose of this study was to explore the tumor biology and outcomes in a consecutive series of pediatric patients treated at a single institution.

Methods

The authors performed a retrospective clinicopathological review of 19 patients at a tertiary referral children's hospital for resection of a spinal cord ependymoma. The population included 8 patients with a pathological diagnosis of MEPN and 11 patients with a pathological diagnosis of spinal EPN (10 cases were Grade II and 1 case was Grade III). The upregulation of the following genes HOXB13, NEFL, PDGFRα, EGFR, EPHB3, AQP1, and JAGGED 1 was studied by immunohistochemistry from archived paraffin-embedded tumor samples of the entire cohort to compare the expression in MEPN versus EPN.

Results

Gross-total resection was achieved in 75% of patients presenting with MEPNs and in 100% of those with EPNs. The average follow-up period was 79 months for the MEPN subset and 53 months for Grade II/III EPNs. Overall survival for both subsets was 100%. However, event-free survival was only 50% for patients with MEPNs. Of note, in all cases involving MEPNs that recurred, the patients had undergone gross-total resection on initial surgery. In contrast, there were no tumor recurrences in patients with EPNs. Immunohistochemistry revealed no significant differences in protein expression between the two tumor types with the exception of EPHB3, which demonstrates a tendency to be positive in MEPNs (6 reactive tumors of 9) rather than in EPN (2 reactive tumors of 10).

Conclusions

The authors' experience shows that, following a gross-total resection, MEPNs are more likely to recur than their higher-grade counterpart, EPNs. This supports the recommendation for close long-term radiological follow-up of pediatric patients with MEPNs to monitor for recurrence, despite the tumor's low-grade histological feature. No significant difference in the protein expression of HOXB13, NEFL, PDGFRα, EGFR, EPHB3, AQP1, and JAGGED 1 was present in this selected cohort of pediatric patients.