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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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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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Russell R. Lonser, Martin Baggenstos, H. Jeffrey Kim, John A. Butman and Alexander O. Vortmeyer

Object

Although endolymphatic sac tumors (ELSTs) frequently destroy the posterior petrous bone and cause hearing loss, the anatomical origin of these neoplasms is unknown. To determine the precise topographic origin of ELSTs, the authors analyzed the imaging, operative, and pathological findings in patients with von Hippel–Lindau disease (VHL) and ELSTs.

Methods

Consecutive VHL patients with small (≤ 1.5 cm) ELSTs who underwent resection at the National Institutes of Health were included. Clinical, imaging, operative, and pathological findings were analyzed.

Results

Ten consecutive VHL patients (6 male and 4 female) with 10 small ELSTs (≤ 1.5 cm; 9 left, 1 right) were included. Serial imaging captured the development of 6 ELSTs and revealed that they originated within the intraosseous (vestibular aqueduct) portion of the endolymphatic duct/sac system. Imaging just before surgery demonstrated that the epicenters of 9 ELSTs (1 ELST was not visible on preoperative imaging) were in the vestibular aqueduct. Inspection during surgery established that all 10 ELSTs were limited to the intraosseous endolymphatic duct/sac and the immediately surrounding region. Histological analysis confirmed tumor within the intraosseous portion (vestibular aqueduct) of the endolymphatic duct/sac in all 10 patients.

Conclusions

ELSTs originate from endolymphatic epithelium within the vestibular aqueduct. High-resolution imaging through the region of the vestibular aqueduct is essential for diagnosis. Surgical exploration of the endolymphatic duct and sac is required for complete resection.

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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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Joshua M. Ammerman, Russell R. Lonser, James Dambrosia, John A. Butman and Edward H. Oldfield

Object

In the course of their lives most patients with von Hippel–Lindau (VHL) disease require treatment for several symptom-producing hemangioblastomas of the cerebellum, brainstem, or spinal cord. However, many tumors never produce symptoms and do not require treatment. Detection at an early stage of lesions that will later produce symptoms and ultimately require treatment would allow for earlier excision of hemangioblastomas of the spinal cord, brainstem, or cerebellum, and may identify cerebellar hemangioblastomas that can be treated with radiosurgery at a stage before treatment is contraindicated because of tumor size or the presence of an associated cyst.

Methods

To identify features predictive of symptom development that might allow for earlier treatment of smaller, presymptomatic hemangioblastomas in patients with VHL disease, the authors reviewed and analyzed the serial clinical and imaging findings in all patients with VHL disease who were followed up at the National Institutes of Health for more than 10 years. Features predictive of symptom formation were determined by recursive partition and regression analyses.

Nineteen patients (10 men and nine women; mean age 32.6 ± 11.6 years) harboring a total of 143 hemangioblastomas were identified (mean follow-up duration 12.4 ± 1.4 years). Hemangioblastomas were located in the cerebellum (68 hemangioblastomas, 48% of patients), brainstem (17 hemangioblastomas, 12% of patients), and spinal cord (58 hemangioblastomas, 40% of patients). Despite measurable growth in almost all hemangioblastomas (138 lesions, 97% of patients), only 58 (41% of patients) became symptomatic. Hemangioblastomas grew in a stuttering pattern. (mean growth period 13 ± 15 months, mean quiescent period 25 ± 19 months). Twenty-six (45%) of the hemangioblastomas that eventually produced symptoms were not among the tumors that were apparent on the initial MR imaging study. Depending on location, the hemangioblastoma size and/or tumor and cyst growth rates predicted symptom development and the need for treatment (p < 0.05). Cerebellar hemangioblastomas growing faster than 112 mm3/ month or larger than 69 mm3 with associated tumor and cyst growth rates greater than 14 mm3/month became symptomatic (100% sensitivity, 72% specificity). Brainstem hemangioblastomas larger than 245 mm3 with growth rates greater than 0.1 mm3/month became symptomatic (75% sensitivity, 89% specificity). Spinal hemangioblastomas larger than 22 mm3 became symptomatic (79% sensitivity, 94% specificity).

Conclusions

Because hemangioblastomas exhibit a stuttering growth pattern, frequently remain asymptomatic, and do not require treatment for long intervals, unqualified radiographic progression is not an indication for treatment. Basing the decision to intervene in individual tumors solely on radiographic progression would have resulted in approximately four additional procedures per patient during the 10-year study period. Threshold values are presented for tumor size and/or tumor and cyst growth rates that can be used to predict symptom formation and future need for treatment.

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Ashok R. Asthagiri, Gautam U. Mehta, John A. Butman, Martin Baggenstos, Edward H. Oldfield and Russell R. Lonser

Object

Despite the frequent multiplicity and development of new spinal cord hemangioblastomas that require multiple resections in patients with von Hippel-Lindau (VHL) disease, the long-term effects of spinal surgery on spinal column stability in this neoplasia disorder are not known. To determine the effect of multilevel cervical laminectomy for spinal cord tumor resection in VHL, the authors analyzed long-term clinical and radiographic outcomes.

Methods

The authors included consecutive patients enrolled in a prospective VHL disease natural history study who underwent cervical laminectomy(s) for spinal cord hemangioblastoma resection. Serial clinical examinations, neck disability indices, and radiographs (static and dynamic), as well as operative records, were analyzed.

Results

Twenty-five adult patients (16 female, 9 male) with VHL disease underwent 34 operations (mean 1.4 ± 0.7 [± SD]/patient) for the resection of cervical spinal cord hemangioblastomas (mean number of lamina removed/surgery 3.0 ± 1.3). The mean age at surgery was 33.9 ± 11.9 years (range 18–61 years), and the mean follow-up duration was 9.1 ± 5.6 years. At last follow-up, radiographic criteria indicated that 9 patients (36%) had spinal column instability, 13 patients (52%) developed a cervical spinal deformity, 4 patients (16%) developed moderate to severe neck disability, and 3 patients (12%) met the criteria for clinical instability. Removal of the C-2 lamina was associated with the development of clinical instability (p = 0.02, Fisher exact test); older age at surgery was associated with the development of cervical deformity (p = 0.05, logistic regression); and a greater number of operations (suboccipital–T4) were associated with increased neck disability indices (p = 0.01, linear regression).

Conclusions

Whereas patients with VHL disease will often require multiple laminectomies for cervical spinal cord hemangioblastoma resection, a limited number of patients (12%) will develop clinical instability. Because prophylactic cervical instrumentation confers limited benefit at the time of spinal cord tumor resection for most patients, and because these patients need life-long MR imaging of the spinal cord, the quality of which may be affected by instrumentation, longitudinal clinical and radiological evaluation may be used to determine which patients will require stabilization.