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  • Author or Editor: Ashok R. Asthagiri x
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John D. Heiss, Stuart Walbridge, Ashok R. Asthagiri and Russell R. Lonser

Object

Muscimol is a potent γ-aminobutyric acid-A receptor agonist that temporarily and selectively suppresses neurons. Targeted muscimol suppression of neuronal structures could provide insight into the pathophysiological processes and treatment of a variety of neurological disorders. To determine if muscimol delivered to the brain by convection-enhanced delivery could be monitored using a coinfused surrogate MR imaging tracer, the authors perfused the striata of primates with tritiated muscimol and Gd–diethylenetriamine pentaacetic acid (DTPA).

Methods

Three primates underwent convective coinfusion of 3H-muscimol (0.8 μM) and Gd-DTPA (5 mM) into the bilateral striata. Primates underwent serial MR imaging during infusion, and the animals were killed immediately after infusion. Postmortem quantitative autoradiography and histological analysis was performed.

Results

Real-time MR imaging revealed that infusate (tritiated muscimol and Gd-DTPA) distribution was clearly discernible from the noninfused parenchyma. Real-time MR imaging of the infusion revealed the precise region of anatomical perfusion in each animal. Imaging analysis during infusion revealed that the distribution volume (Vd) of infusate linearly increased (R = 0.92) with volume of infusion (Vi). Overall, the mean (± SD) Vd/Vi ratio was 8.2 ± 1.3. Autoradiographic analysis revealed that MR imaging of Gd-DTPA closely correlated with the distribution of 3H-muscimol, and precisely estimated its Vd (mean difference in Vd, 7.4%). Quantitative autoradiograms revealed that muscimol was homogeneously distributed over the perfused region in a square-shaped concentration profile.

Conclusions

Muscimol can be effectively delivered to clinically relevant volumes of the primate brain. Moreover, the distribution of muscimol can be tracked using coinfusion of Gd-DTPA and MR imaging. The ability to perform accurate monitoring and to control the anatomical extent of muscimol distribution during its convection-enhanced delivery will enhance safety, permit correlations of muscimol distribution with clinical effect, and should lead to an improved understanding of the pathophysiological processes underlying a variety of neurological disorders.

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Ashok R. Asthagiri, Stuart Walbridge, John D. Heiss and Russell R. Lonser

Object

Accurate real-time imaging of coinfused surrogate tracers can be used to determine the convective distribution of therapeutic agents. To assess the effect that a concentration of a Gd-based surrogate tracer has on the accuracy of determining the convective distribution, the authors infused different concentrations of Gd-diethylenetriamine pentaacetic acid (DTPA) in primates during MR imaging.

Methods

Five nonhuman primates underwent convective infusion (1 or 5 mM, 21–65 μl) of Gd-DTPA alone, Gd-DTPA and 14C-sucrose, or Gd-DTPA and 14C-dextran into the bilateral striata. Animals underwent real-time MR imaging during infusion (5 animals) and autoradiographic analysis (2 animals).

Results

Gadolinium-DTPA could be seen filling the striata at either concentration (1 or 5 mM) on real-time MR imaging. While the volume of distribution (Vd) increased linearly with the volume of infusion (Vi) for both concentrations of tracer (1 mM: R2 = 0.83; 5 mM: R2 = 0.96), the Vd/Vi ratio was significantly (p < 0.0001) less for the 1-mM (2.3 ± 1.0) as compared with the 5-mM (7.4 ± 1.9) concentration. Autoradiographic and MR volumetric analysis revealed that the 5-mM concentration most accurately estimated the Vd for both small (sucrose [359 D], 12% difference between imaging and autoradiographic distribution) and large (dextran [70 kD], 0.2% difference) molecules compared with the 1-mM concentration (sucrose, 65% difference; dextran, 68% difference).

Conclusions

The concentration of infused Gd-DTPA plays a critical role in accurately assessing the distribution of molecules delivered by CED. A 5-mM concentration of Gd-DTPA most accurately estimated the Vd over a wide range of molecular sizes.

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Donald Y. Ye, Kamran D. Bakhtian, Ashok R. Asthagiri and Russell R. Lonser

Object

Prior cases suggest that pregnancy increases the development and progression of CNS hemangioblastomas and/or peritumoral cysts. To determine the effect of pregnancy on CNS hemangioblastomas and peritumoral cysts, the authors prospectively evaluated serial clinical and imaging findings in patients with von Hippel-Lindau (VHL) disease who became pregnant and compared findings during pregnancy to findings in the same patients when they were not pregnant as well as to findings from a cohort of VHL patients who did not become pregnant.

Methods

Female VHL disease patients enrolled in a prospective natural history study who were of reproductive age (16–35 years at study entrance) were included. Analysis of serial clinical and imaging findings was performed.

Results

Thirty-six consecutive female VHL disease patients harboring 177 hemangioblastomas were included (mean follow-up [± SD] 7.5 ± 2.3 years). Nine patients (25%) became pregnant (pregnancy cohort). The mean rates of development of new hemangioblastomas and peritumoral cysts in these women during pregnancy (0.4 ± 0.4 tumors/year; 0.1 ± 0.2 cysts/year) did not differ significantly (p > 0.05) from the mean rates in the same group during nonpregnant periods (0.3 ± 0.4 tumors/year; 0.1 ± −0.1 cysts/year) or from the rate in the 27 patients who did not become pregnant (the no-pregnancy cohort: 0.3 ± 0.5 tumors/year; 0.1 ± 0.2 cysts/year). Hemangioblastoma growth rates were similar (p > 0.05) during pregnancy (mean 29.8% ± 42.7% increase in volume per year) compared with during nonpregnant periods (41.4% ± 51.4%) in the pregnancy cohort and the no-pregnancy cohort (34.3% ± 55.3%). Peritumoral cyst growth rates during pregnancy (571.0% ± 887.4%) were similar (p > 0.05) to those of the no-pregnancy cohort (483.9% ± 493.9%), but the rates were significantly higher for women in the pregnancy cohort during nonpregnant periods (2373.6% ± 3392.9%; p < 0.05 for comparison with no-pregnancy cohort). There was no significant difference (p > 0.05) in the need for resection or the mean age at resection between the pregnancy (28% of hemangioblastomas in cohort; mean patient age at resection 30.2 ± 2.6 years) and no-pregnancy cohorts (19%; 32.3 ± 5.6 years).

Conclusions

Pregnancy is not associated with increased hemangioblastoma or peritumoral cyst development or progression in patients with VHL disease.

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Robert M. Starke, John A. Jane Jr., Ashok R. Asthagiri and John A. Jane Sr.

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Alexander Ksendzovsky, Stuart Walbridge, Richard C. Saunders, Ashok R. Asthagiri, John D. Heiss and Russell R. Lonser

Object

Recent studies indicate that M13 bacteriophage, a very large nanoparticle, binds to β-amyloid and α-synuclein proteins, leading to plaque disaggregation in models of Alzheimer and Parkinson disease. To determine the feasibility, safety, and characteristics of convection-enhanced delivery (CED) of M13 bacteriophage to the brain, the authors perfused primate brains with bacteriophage.

Methods

Four nonhuman primates underwent CED of M13 bacteriophage (900 nm) to thalamic gray matter (4 infusions) and frontal white matter (3 infusions). Bacteriophage was coinfused with Gd-DTPA (1 mM), and serial MRI studies were performed during infusion. Animals were monitored for neurological deficits and were killed 3 days after infusion. Tissues were analyzed for bacteriophage distribution.

Results

Real-time T1-weighted MRI studies of coinfused Gd-DTPA during infusion demonstrated a discrete region of perfusion in both thalamic gray and frontal white matter. An MRI-volumetric analysis revealed that the mean volume of distribution (Vd) to volume of infusion (Vi) ratio of M13 bacteriophage was 2.3 ± 0.2 in gray matter and 1.9 ± 0.3 in white matter. The mean values are expressed ± SD. Immunohistochemical analysis demonstrated mean Vd:Vi ratios of 2.9 ± 0.2 in gray matter and 2.1 ± 0.3 in white matter. The Gd-DTPA accurately tracked M13 bacteriophage distribution (the mean difference between imaging and actual bacteriophage Vd was insignificant [p > 0.05], and was –2.2% ± 9.9% in thalamic gray matter and 9.1% ± 9.5% in frontal white matter). Immunohistochemical analysis revealed evidence of additional spread from the initial delivery site in white matter (mean Vd:Vi, 16.1 ± 9.1). All animals remained neurologically intact after infusion during the observation period, and histological studies revealed no evidence of toxicity.

Conclusions

The CED method can be used successfully and safely to distribute M13 bacteriophage in the brain. Furthermore, additional white matter spread after infusion cessation enhances distribution of this large nanoparticle. Real-time MRI studies of coinfused Gd-DTPA (1 mM) can be used for accurate tracking of distribution during infusion of M13 bacteriophage.

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J. Bradley Elder and E. Antonio Chiocca

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Gautam U. Mehta, Ashok R. Asthagiri, Kamran D. Bakhtian, Sungyoung Auh, Edward H. Oldfield and Russell R. Lonser

Object

Spinal cord hemangioblastomas are a common protean manifestation of von Hippel-Lindau (VHL) disease and can be associated with significant morbidity. To better define expected outcome and optimal management of these tumors in the context of this neoplasia syndrome, the authors analyzed the findings from patients with VHL disease who underwent resection of spinal cord hemangioblastomas.

Methods

Consecutive patients with VHL disease who underwent surgery for spinal cord hemangioblastomas with > 6 months follow-up were included in the study. Serial clinical examinations, functional scores, imaging findings, and operative records were analyzed.

Results

One hundred eight patients (57 male, 51 female) underwent 156 operations for resection of 218 spinal cord hemangioblastomas. One hundred forty-six operations (94%) were performed for symptom-producing tumors. The most common presenting symptoms included hypesthesia (64% of resections), hyperreflexia (57%), dysesthesia (43%), and weakness (36%). Mean follow-up was 7.0 ± 5.0 years (range 0.5–20.9 years). Complete resection was achieved for 217 tumors (99.5%). At 6-months follow-up, patients were stable or improved after 149 operations (96%) and worse after 7 operations (4%). Ventral tumors (OR 15.66, 95% CI 2.54–96.45; p = 0.003) or completely intramedullary tumors (OR 10.74, 95% CI 2.07–55.66; p = 0.005) were associated with an increased risk of postoperative worsening. The proportion of patients remaining functionally stable at 2, 5, 10, and 15 years' follow-up was 93, 86, 78, and 78%. Long-term functional decline was caused by extensive VHL-associated CNS disease (6 patients), VHL-associated visceral disease (1 patient), or non-VHL disease (2 patients).

Conclusions

Resection of symptomatic spinal cord hemangioblastomas is a safe and effective means of preserving neurological function in patients with VHL disease. Tumor location (ventral or completely intramedullary) can be used to assess functional risk associated with surgery. Long-term decline in neurological function is usually caused by VHL-associated disease progression.

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The transsphenoidal approach

A historical perspective

Adam S. Kanter, Aaron S. Dumont, Ashok R. Asthagiri, Rod J. Oskouian, John A. Jane Jr. and Edward R. Laws Jr.

Over the last century, the transsphenoidal approach has evolved into the first-line method of treatment for sellar as well as select groups of parasellar and suprasellar lesions. The journey to its current popularity has been marked by controversy and near abandonment in the late 1920s, followed by its renaissance in the late 1960s. Despite the profound skepticism with which this procedure was viewed, several visionary neurosurgeons persevered through its nadir in popularity, preserving this surgical corridor to the skull base. Advances in medical and surgical techniques, paralleling an improved understanding of pituitary pathophysiology, contributed to its resurgence. The transsphenoidal procedures now performed stem from an array of modifications and refinements accumulated through nearly 100 years of medical and surgical evolution. This era's critical innovations and neurosurgical personalities are the topic of this historical overview.

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Michael S. Dirks, John A. Butman, H. Jeffrey Kim, Tianxia Wu, Keaton Morgan, Anne P. Tran, Russell R. Lonser and Ashok R. Asthagiri

Object

Neurofibromatosis Type 2 (NF2) is a heritable tumor predisposition syndrome that leads to the development of multiple intracranial tumors, including meningiomas and schwannomas. Because the natural history of these tumors has not been determined, their optimal management has not been established. To define the natural history of NF2-associated intracranial tumors and to optimize management strategies, the authors evaluated long-term clinical and radiographic data in patients with NF2.

Methods

Consecutive NF2 patients with a minimum of 4 years of serial clinical and MRI follow-up were analyzed.

Results

Seventeen patients, 9 males and 8 females, were included in this analysis (mean follow-up 9.5 ± 4.8 years, range 4.0–20.7 years). The mean age at initial evaluation was 33.2 ± 15.5 years (range 12.3–57.6 years). Patients harbored 182 intracranial neoplasms, 164 of which were assessable for growth rate analysis (18 vestibular schwannomas [VSs], 11 nonvestibular cranial nerve [CN] schwannomas, and 135 meningiomas) and 152 of which were assessable for growth pattern analysis (15 VSs, 9 nonvestibular CN schwannomas, and 128 meningiomas). New tumors developed in patients over the course of the imaging follow-up: 66 meningiomas, 2 VSs, and 2 nonvestibular CN schwannomas. Overall, 45 tumors (29.6%) exhibited linear growth, 17 tumors (11.2%) exhibited exponential growth, and 90 tumors (59.2%) displayed a saltatory growth pattern characterized by alternating periods of growth and quiescence (mean quiescent period 2.3 ± 2.1 years, range 0.4–11.7 years). Further, the saltatory pattern was the most frequently identified growth pattern for each tumor type: meningiomas 60.9%, VSs 46.7%, and nonvestibular schwannoma 55.6%. A younger age at the onset of NF2-related symptoms (p = 0.01) and female sex (p = 0.05) were associated with an increased growth rate in meningiomas. The identification of saltatory growth in meningiomas increased with the duration of follow-up (p = 0.01).

Conclusions

Neurofibromatosis Type 2–associated intracranial tumors most frequently demonstrated a saltatory growth pattern. Because new tumors can develop in NF2 patients over their lifetime and because radiographic progression and symptom formation are unpredictable, resection may be best reserved for symptom-producing tumors. Moreover, establishing the efficacy of nonsurgical therapeutic interventions must be based on long-term follow-up (several years).