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Russell R. Lonser, John A. Butman and Edward H. Oldfield

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Martin A. Baggenstos, John A. Butman, Edward H. Oldfield and Russell R. Lonser

✓Peritumoral cysts (those arising immediately adjacent to the tumor mass) are frequently associated with benign and malignant tumors of the brain and spinal cord (syringomyelia). The cystic component of central nervous system (CNS) tumors and associated peritumoral cysts are often the cause of clinical symptoms. Because of the common occurrence of peritumoral cysts with CNS neoplasms and the morbidity associated with them, advanced imaging, histological, and molecular techniques have been used to determine the mechanism underlying cyst formation and propagation. Based on evidence from such studies, edema appears to be a common precursor to peritumoral cyst formation in the CNS. Mediators of vascular permeability acting locally in the tumor and/or hydrodynamic forces within abnormal tumor vascula-ture appear to drive fluid extravasation. When these forces overcome the ability of surrounding tissue to resorb fluid, edema and subsequent cyst formation occur. These findings support the concept that the tumor itself is the source of the edema that precedes cyst formation and that resection of tumors or medical therapies directed at decreasing their vascular permeability will result in the resolution of edema and cysts.

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John A. Butman, Edjah Nduom, H. Jeffrey Kim and Russell R. Lonser

Object

To determine if physiologically based MRI sequences can be used to detect endolymphatic sac tumor (ELST)–associated hydrops, the authors performed contrast-enhanced delayed FLAIR imaging in consecutive ELST patients with clinical findings consistent with hydrops.

Methods

Consecutive patients with von Hippel-Lindau (VHL) disease and clinical findings of endolymphatic hydrops and ELSTs underwent contrast-enhanced delayed FLAIR MRI. Clinical, audiological, operative, and imaging findings were analyzed.

Results

Three patients (2 male, 1 female) with 4 ELSTs (1 patient had bilateral ELSTs) were identified who had clinical findings consistent with endolymphatic hydrops. Computed tomography and MRI evidence of an ELST was found in all patients. Their mean age at initial evaluation was 39.7 years (range 28–51 years). All patients demonstrated progressive sensorineural hearing loss that was associated with episodic vertigo and tinnitus. Contrast-enhanced delayed FLAIR MRI clearly demonstrated dilation of the membranous labyrinth consistent with hydrops in the affected ears but not the unaffected ears. Two patients underwent resection of the associated ELST that resulted in stabilization of progressive hearing loss, as well as amelioration of tinnitus and vertigo.

Conclusions

Contrast-enhanced delayed FLAIR MRI can be used to detect ELST-associated hydrops. Noninvasive MRI detection of hydrops can permit earlier detection of ELSTs in patients with VHL disease and provides direct insight into a mechanism that underlies ELST-associated audiovestibular morbidity.

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Gabriel C. Tender, John A. Butman, Edward H. Oldfield and Russell R. Lonser

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Ryszard M. Pluta, Scott D. Wait, John A. Butman, Kathleen A. Leppig, Alexander O. Vortmeyer, Edward H. Oldfield and Russell R. Lonser

Hemangioblastomas are histologically benign neoplasms that occur sporadically or as part of von Hippel–Lindau disease. Hemangioblastomas may occur anywhere along the neuraxis, but sacral hemangioblastomas are extremely rare. To identify features that will help guide the operative and clinical management of these lesions, the authors describe the management of a large von Hippel–Lindau disease–associated sacral hemangioblastoma and review the literature.

The authors present the case of a 38-year-old woman with von Hippel–Lindau disease and a 10-year history of progressive back pain, as well as left lower-extremity pain and numbness. Neurological examination revealed decreased sensation in the left S-1 and S-2 dermatomes. Magnetic resonance imaging demonstrated a large enhancing lesion in the sacral region, with associated erosion of the sacrum. The patient underwent arteriography and embolization of the tumor and then resection. The histopathological diagnosis was consistent with hemangioblastoma and showed intrafascicular tumor infiltration of the S-2 nerve root. At 1-year follow-up examination, pain had resolved and numbness improved.

Sacral nerve root hemangioblastomas may be safely removed in most patients, resulting in stabilization or improvement in symptomatology. Generally, hemangioblastomas of the sacral nerve roots should be removed when they cause symptoms. Because they originate from the nerve root, the nerve root from which the hemangioblastoma originates must be sacrificed to achieve complete resection.

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Rajiv R. Iyer, John A. Butman, Stuart Walbridge, Neville D. Gai, John D. Heiss and Russell R. Lonser

Object

Because convection-enhanced delivery relies on bulk flow of fluid in the interstitial spaces, MR imaging techniques that detect extracellular fluid and fluid movement may be useful for tracking convective drug distribution. To determine the tracking accuracy of T2-weighted and diffusion-weighted MR imaging sequences, the authors followed convective distribution of radiolabeled compounds using these imaging sequences in nonhuman primates.

Methods

Three nonhuman primates underwent thalamic convective infusions (5 infusions) with 14C-sucrose (MW 342 D) or 14C-dextran (MW 70,000 D) during serial MR imaging (T2- and diffusion-weighted imaging). Imaging, histological, and autoradiographic findings were analyzed.

Results

Real-time T2- and diffusion-weighted imaging clearly demonstrated the region of infusion, and serial images revealed progressive filling of the bilateral thalami during infusion. Imaging analysis for T2- and diffusion-weighted sequences revealed that the tissue volume of distribution (Vd) increased linearly with volume of infusion (Vi; R2 = 0.94, R2 = 0.91). Magnetic resonance imaging analysis demonstrated that the mean ± SD Vd/Vi ratios for T2-weighted (3.6 ± 0.5) and diffusion-weighted (3.3 ± 0.4) imaging were similar (p = 0.5). While 14C-sucrose and 14C-dextran were homogeneously distributed over the infused region, autoradiographic analysis revealed that T2-weighted and diffusion-weighted imaging significantly underestimated the Vd of both 14C-sucrose (mean differences 51.3% and 52.3%, respectively; p = 0.02) and 14C-dextran (mean differences 49.3% and 59.6%; respectively, p = 0.001).

Conclusions

Real-time T2- and diffusion-weighted MR imaging significantly underestimate tissue Vd during convection-enhanced delivery over a wide range of molecular sizes. Application of these imaging modalities may lead to inaccurate estimation of convective drug distribution.

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Davis P. Argersinger, Stuart Walbridge, Nicholas M. Wetjen, Alexander O. Vortmeyer, Tianxia Wu, John A. Butman and John D. Heiss

OBJECTIVE

Botulinum toxin serotype A (BoNT/A) was reported to raise the seizure threshold when injected into the seizure focus of a kindled rodent model. Delivering BoNT/A to the nonhuman primate (NHP) central nervous system via convection-enhanced delivery (CED) has not been performed. The objective of this study was to determine the toxicity and distribution characteristics of CED of BoNT/A into the NHP hippocampus and cisterna magna.

METHODS

Escalating BoNT/A doses were delivered by CED into the NHP hippocampus (n = 4) and cisterna magna (n = 5) for behavioral and histological assessment and to determine the highest nonlethal dose (LD0) and median lethal dose (LD50). Hippocampal BoNT/A was coinfused with Gd-albumin, a surrogate MRI tracer. Gd-albumin and radioiodinated BoNT/A (125I-BoNT/A) were coinfused into the hippocampus of 3 additional NHPs to determine BoNT/A distribution by in vivo MRI and postmortem quantitative autoradiography. Scintillation counting of CSF assessed the flow of 125I-BoNT/A from the hippocampus to CSF postinfusion.

RESULTS

LD0 and LD50 were 4.2 and 18 ng/kg, and 5 and > 5 ng/kg for the NHP hippocampus and cisterna magna, respectively. Gd-albumin and 125I-BoNT/A completely perfused the hippocampus (155–234 mm3) in 4 of 7 NHPs. Fifteen percent of BoNT/A entered CSF after hippocampal infusion. The MRI distribution volume of coinfused Gd-albumin (VdMRI) was similar to the quantitative autoradiography distribution of 125I-BoNT/A (VdQAR) (mean VdMRI = 139.5 mm3 [n = 7]; VdQAR = 134.8 mm3 [n = 3]; r = 1.00, p < 0.0001). No infusion-related toxicity was identified histologically except that directly attributable to needle placement.

CONCLUSIONS

Gd-albumin accurately tracked BoNT/A distribution on MRI. BoNT/A did not produce CNS toxicity. BoNT/A LD0 exceeded 10-fold the dose administered safely to humans for cosmesis and dystonia.

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Ryszard M. Pluta, John A. Butman, Bawarjan Schatlo, Dennis L. Johnson and Edward H. Oldfield

Object

Investigators in experimental and clinical studies have used the intrathecal route to deliver drugs to prevent or treat vasospasm. However, a clot near an artery or arteries after subarachnoid hemorrhage (SAH) may hamper distribution and limit the effects of intrathecally delivered compounds. In a primate model of right middle cerebral artery (MCA) SAH, the authors examined the distribution of Isovue-M 300 and 3% Evans blue after infusion into the cisterna magna CSF.

Methods

Ten cynomolgus monkeys were assigned to SAH and sham SAH surgery groups (5 in each group). Monkeys received CSF injections as long as 28 days after SAH and were killed 3 hours after the contrast/Evans blue injection. The authors assessed the distribution of contrast material on serial CT within 2 hours after contrast injection and during autopsy within 3 hours after Evans blue staining.

Results

Computed tomography cisternographies showed no contrast in the vicinity of the right MCA (p < 0.05 compared with left); the distribution of contrast surrounding the entire right cerebral hemisphere was substantially reduced. Postmortem analysis demonstrated much less Evans blue staining of the right hemisphere surface compared with the left. Furthermore, the Evans blue dye did not penetrate into the right sylvian fissure, which occurred surrounding the left MCA. The authors observed the same pattern of changes and differences in contrast distribution between SAH and sham SAH animals and between the right and the left hemispheres on Days 1, 3, 7, 14, 21, and 28 after SAH.

Conclusions

Intrathecal drug distribution is substantially limited by SAH. Thus, when using intrathecal drug delivery after SAH, vasoactive drugs are unlikely to reach the arteries that are at the highest risk of delayed cerebral vasospasm.

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David Croteau, Stuart Walbridge, Paul F. Morrison, John A. Butman, Alexander O. Vortmeyer, Dennis Johnson, Edward H. Oldfield and Russell R. Lonser

Object. Convection-enhanced delivery (CED) is increasingly used to distribute therapeutic agents to locations in the central nervous system. The optimal application of convective distribution of various agents requires the development of imaging tracers to monitor CED in vivo in real time. The authors examined the safety and utility of an iodine-based low-molecular-weight surrogate tracer for computerized tomography (CT) scanning during CED.

Methods. Various volumes (total volume range 90–150 µ1) of iopamidol (MW 777 D) were delivered to the cerebral white matter of four primates (Macaca mulatta) by using CED. The distribution of this imaging tracer was determined by in vivo real-time and postinfusion CT scanning (≤ 5 days after infusion [one animal]) as well as by quantitative autoradiography (14C-sucrose [all animals] and 14C-dextran [one animal]), and compared with a mathematical model. Clinical observation (≤ 5 months) and histopathological analyses were used to evaluate the safety and toxicity of the tracer delivery.

Real-time CT scanning of the tracer during infusion revealed a clearly definable region of perfusion. The volume of distribution (Vd) increased linearly (r2 = 0.97) with an increasing volume of infusion (Vi). The overall Vd/Vi ratio was 4.1 ± 0.7 (mean ± standard deviation) and the distribution of infusate was homogeneous. Quantitative autoradiography confirmed the accuracy of the imaged distribution for a small (sucrose, MW 359 D) and a large (dextran, MW 70 kD) molecule. The distribution of the infusate was identifiable up to 72 hours after infusion. There was no clinical or histopathological evidence of toxicity in any animal.

Conclusions. Real-time in vivo CT scanning of CED of iopamidol appears to be safe, feasible, and suitable for monitoring convective delivery of drugs with certain features and low infusion volumes.

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Russell R. Lonser, Scott D. Wait, John A. Butman, Alexander O. Vortmeyer, McClellan M. Walther, Lance S. Governale and Edward H. Oldfield

Object

Hemangioblastomas in the lumbosacral region are rare, and the authors of prior reports have not defined the surgical management, histopathological features, or outcome in a group of patients after resection of these tumors. To identify features that will help guide the operative and clinical management of these lesions, the authors reviewed data obtained in a series of patients with von Hippel—Lindau syndrome who underwent resection of lumbosacral nerve root hemangioblastomas.

Methods

Six consecutive patients (three men and three women; mean age at surgery 39 years [range 31–48 years]) who underwent operations for resection of lumbosacral nerve root hemangioblastomas were included in this study. The mean follow-up period was 23 months (range 6–45 months). Data derived from examination, hospital charts, operative findings, histopathological analysis, and magnetic resonance imaging were used to analyze surgical management and clinical outcome. The resected tumors were located in the lumbar (five cases) or sacral (one case) regions; the mean tumor size was 2728 mm3 (range 80–15,022 mm3). Consistent with central nervous system (CNS) regional variation of space available to accommodate the neural compressive effect of the hemangioblastoma size, the mean tumor volume (2728 mm3) of these symptomatic lesions was much larger than that of symptomatic hemangioblastomas resected in the other regions of the CNS. Histopathological examination showed infiltration of the associated nerve root by the hemangioblastoma in each case. In five of the six patients complete resection was achieved, and in one patient intradural exploration of two hemangioblastomas was performed, but resection was not achieved because of motor root involvement. In all cases involving complete resections the patients experienced symptomatic improvement.

Conclusions

Lumbosacral nerve root hemangioblastomas can be safely removed in most patients with von Hippel—Lindau syndrome. Generally, hemangioblastomas of the lumbosacral nerve roots should be resected when they become symptomatic. Because these neoplasms appear to originate from the nerve root, it is necessary to sacrifice the nerve root from which the hemangioblastoma originates to achieve complete resection.