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Ronald I. Apfelbaum, Russell R. Lonser, Robert Veres, and Adrian Casey

Object

The management of odontoid fractures remains controversial. Only direct anterior screw fixation provides immediate stabilization of the spine and may preserve normal C1–2 motion. To determine the indications, optimum timing, and results for direct anterior screw fixation of odontoid fractures, the authors reviewed the surgery-related outcome of patients who underwent this procedure at two institutions.

Methods

One hundred forty-seven consecutive patients (98 males and 49 females) who underwent direct anterior screw fixation for a recent fracture (< 6 months postinjury [129 patients]) or remote (≥ 18 months postinjury [18 patients]) Type II (138 cases) or III (nine cases) odontoid fractures at the University of Utah (94 patients) and National Institute of Traumatology in Budapest, Hungary (53 patients) between 1986 and 1998 are included in this study (mean follow-up period 18.2 months). Data obtained from clinical examination, review of hospital charts, operative findings, and imaging studies were used to analyze the surgery-related results in these patients.

In patients with recent fractures there was an overall bone fusion rate of 88%. The rate of anatomical bone fusion of recent fractures was significantly (p ≤ 0.05) higher in fractures oriented in the horizontal and posterior oblique direction (as compared with anterior oblique), but this finding was independent (p ≥ 0.05) of age, sex, number of screws placed (one or two), and the degree or the direction of odontoid displacement. In patients with remote fractures there was a significantly lower rate of bone fusion (25%). Overall, complications related to hardware failure occurred in 14 patients (10%) and unrelated to hardware in three patients (2%). There was one death (1%) related to surgery.

Conclusions

Direct anterior screw fixation is an effective and safe method for treating recent odontoid fractures (< 6 months postinjury). It confers immediate stability, preserves C1–2 rotatory motion, and achieves a fusion rate that compares favorably with alternative treatment methods. In contradistinction, in patients with remote fractures (≥ 18 months postinjury) a significantly lower rate of fusion is found when using this technique, and these patients are believed to be poor candidates for this procedure.

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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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Gabriel C. Tender, Stuart Walbridge, Zoltan Olah, Laszlo Karai, Michael Iadarola, Edward H. Oldfield, and Russell R. Lonser

Object

Neuropathic pain is mediated by nociceptive neurons that selectively express the vanilloid receptor 1 (VR1). Resiniferatoxin (RTX) is an excitotoxic VR1 agonist that causes destruction of VR1-positive neurons. To determine whether RTX can be used to ablate VR1-positive neurons selectively and to eliminate hyperalgesia and neurogenic inflammation without affecting tactile sensation and motor function, the authors infused it unilaterally into the trigeminal ganglia in Rhesus monkeys.

Methods

Either RTX (three animals) or vehicle (one animal) was directly infused (20 μl) into the right trigeminal ganglion in Rhesus monkeys. Animals were tested postoperatively at 1, 4, and 7 weeks thereafter for touch and pain perception in the trigeminal distribution (application of saline and capsaicin to the cornea). The number of eye blinks, eye wipes, and duration of squinting were recorded. Neurogenic inflammation was tested using capsaicin cream. Animals were killed 4 (one monkey) and 12 (three monkeys) weeks postinfusion. Histological and immunohistochemical analyses were performed.

Throughout the duration of the study, response to high-intensity pain stimulation (capsaicin) was selectively and significantly reduced (p < 0.001, RTX-treated compared with vehicle-treated eye [mean ± standard deviation]): blinks, 25.7 ± 4.4 compared with 106.6 ± 20.8; eye wipes, 1.4 ± 0.8 compared with 19.3 ± 2.5; and squinting, 1.4 ± 0.6 seconds compared with 11.4 ± 1.6 seconds. Normal response to sensation was maintained. Animals showed no neurological deficit or sign of toxicity. Neurogenic inflammation was blocked on the RTX-treated side. Immunohistochemical analysis of the RTX-treated ganglia showed selective elimination of VR1-positive neurons.

Conclusions

Nociceptive neurons can be selectively ablated by intraganglionic RTX infusion, resulting in the elimination of high-intensity pain perception and neurogenic inflammation while maintaining normal sensation and motor function. Analysis of these findings indicated that intraganglionic RTX infusion may provide a new treatment for pain syndromes such as trigeminal neuralgia as well as others.

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H. Jeffrey Kim, John A. Butman, Brewer Carmen, Christopher Zalewski, Alexander O. Vortmeyer, Gladys Glenn, Edward H. Oldfield, and Russell R. Lonser

Object

Endolymphatic sac tumors (ELSTs), which often are associated with von Hippel–Lindau (VHL) disease, cause irreversible hearing loss and vestibulopathy. Clinical and imaging surveillance protocols provide new insights into the natural history, mechanisms of symptom formation, and indications for the treatment of ELSTs. To clarify the uncertainties associated with the pathophysiology and treatment of ELSTs, the authors describe a series of patients with VHL disease in whom serial examinations recorded the development of ELSTs.

Methods

Patients with VHL disease were included if serial clinical and imaging studies captured the development of ELSTs, and the patients underwent tumor resection. The patients' clinical, audiological, and imaging characteristics as well as their operative results were analyzed.

Five consecutive patients (three men and two women) with a mean age at surgery of 34.8 years and a follow-up period of 6 to 18 months were included in this study. Audiovestibular symptoms were present in three patients before a tumor was evident on neuroimaging. Imaging evidence of an intralabyrinthine hemorrhage coincided with a loss of hearing in three patients. Successful resection of the ELSTs was accomplished by performing a retrolabyrinthine posterior petrosectomy (RLPP). Hearing stabilized and vestibular symptoms resolved after surgery in all patients. No patient has experienced a recurrence.

Conclusions

Audiovestibular symptoms, including hearing loss, in patients with VHL disease can be the result of microscopic ELSTs. Once an ELST has been detected, it can be completely resected via an RLPP with preservation of hearing and amelioration of vestibular symptoms. Early detection and surgical treatment of small ELSTs, when hearing is still present, should reduce the incidence and severity of hearing loss, tinnitus, vertigo, and cranial nerve dysfunction, which are associated with these tumors.

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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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Russell R. Lonser, John A. Butman, Kristin Huntoon, Ashok R. Asthagiri, Tianxia Wu, Kamran D. Bakhtian, Emily Y. Chew, Zhengping Zhuang, W. Marston Linehan, and Edward H. Oldfield

Object

The tumors most frequently associated with von Hippel-Lindau (VHL) disease are hemangioblastomas. While they are associated with significant neurological impairment and mortality, their natural history and optimal management have not been fully defined.

Methods

Patients with VHL were enrolled in a prospective study designed to define the natural history of CNS hemangioblastomas. In the present analysis, serial imaging, laboratory, genetic, and clinical data were evaluated in those with at least 2 years of follow-up data.

Results

At study entrance 225 patients (111 males, 114 females) harbored 1921 CNS hemangioblastomas in the supratentorial compartment (21 tumors [1%]), cerebellum (865 [45%]), brainstem (129 [7%]), spinal cord (689 [36%]), cauda equina (212 [11%]), and nerve roots (5 [0.3%]; follow-up 15,819 hemangioblastoma-years). Increased tumor burden was associated with partial deletions in the VHL gene (p = 0.005) and male sex (p = 0.002). Hemangioblastoma development (median 0.3 new tumors/year) was associated with younger age (p < 0.0001) and more tumors at study entrance (p < 0.0001). While 1278 hemangioblastomas (51%) did not grow, 1227 hemangioblastomas (49%) grew in a saltatory (886 [72%]), linear (76 [6%]), or exponential (264 [22%]) pattern. Faster tumor growth was associated with male sex (p = 0.001), symptomatic tumors (p < 0.0001), and tumors associated with cysts (p < 0.0001). Location-dependent tumor size was the primary predictor of eventual symptom formation (159 symptomatic tumors [6.3%]; area under the curve > 0.9).

Conclusions

Central nervous system hemangioblastoma burden in VHL is associated with partial germline deletions and male sex. Unpredictable growth of hemangioblastomas compromises assessment of nonsurgical therapies. The judicious treatment of symptom-producing hemangioblastomas, while avoiding unnecessary treatment of asymptomatic tumors that may not progress, can provide clinical stability. Clinical trial registration no.: NCT00005902 (ClinicalTrials.gov).

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Russell R. Lonser, Malisa Sarntinoranont, Paul F. Morrison, and Edward H. Oldfield

Convection-enhanced delivery (CED) is a bulk flow–driven process. Its properties permit direct, homogeneous, targeted perfusion of CNS regions with putative therapeutics while bypassing the blood-brain barrier. Development of surrogate imaging tracers that are co-infused during drug delivery now permit accurate, noninvasive real-time tracking of convective infusate flow in nervous system tissues. The potential advantages of CED in the CNS over other currently available drug delivery techniques, including systemic delivery, intrathecal and/or intraventricular distribution, and polymer implantation, have led to its application in research studies and clinical trials. The authors review the biophysical principles of convective flow and the technology, properties, and clinical applications of convective delivery in the CNS.

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Prashant Chittiboina, Blake K. Montgomery, Corina Millo, Peter Herscovitch, and Russell R. Lonser

OBJECT

High-resolution PET (hrPET) performed using a high-resolution research tomograph is reported as having a resolution of 2 mm and could be used to detect corticotroph adenomas through uptake of18F-fluorodeoxyglucose (18F-FDG). To determine the sensitivity of this imaging modality, the authors compared18F-FDG hrPET and MRI detection of pituitary adenomas in Cushing disease (CD).

METHODS

Consecutive patients with CD who underwent preoperative18F-FDG hrPET and MRI (spin echo [SE] and spoiled gradient recalled [SPGR] sequences) were prospectively analyzed. Standardized uptake values (SUVs) were calculated from hrPET and were compared with MRI findings. Imaging findings were correlated to operative and histological findings.

RESULTS

Ten patients (7 females and 3 males) were included (mean age 30.8 ± 19.3 years; range 11–59 years). MRI revealed a pituitary adenoma in 4 patients (40% of patients) on SE and 7 patients (70%) on SPGR sequences.18F-FDG hrPET demonstrated increased18F-FDG uptake consistent with an adenoma in 4 patients (40%; adenoma size range 3–14 mm). Maximum SUV was significantly higher for18F-FDG hrPET–positive tumors (difference = 5.1, 95% CI 2.1–8.1; p = 0.004) than for18F-FDG hrPET–negative tumors.18F-FDG hrPET positivity was not associated with tumor volume (p = 0.2) or dural invasion (p = 0.5). Midnight and morning ACTH levels were associated with18F-FDG hrPET positivity (p = 0.01 and 0.04, respectively) and correlated with the maximum SUV (R = 0.9; p = 0.001) and average SUV (R = 0.8; p = 0.01). All18F-FDG hrPET–positive adenomas had a less than a 180% ACTH increase and18F-FDG hrPET–negative adenomas had a greater than 180% ACTH increase after CRH stimulation (p = 0.03). Three adenomas were detected on SPGR MRI sequences that were not detected by18F-FDG hrPET imaging. Two adenomas not detected on SE (but no adenomas not detected on SPGR) were detected on18F-FDG hrPET.

CONCLUSIONS

While18F-FDG hrPET imaging can detect small functioning corticotroph adenomas and is more sensitive than SE MRI, SPGR MRI is more sensitive than18F-FDG hrPET and SE MRI in the detection of CD-associated pituitary adenomas. Response to CRH stimulation can predict18F-FDG hrPET–positive adenomas in CD.

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Prashant Chittiboina, John D. Heiss, and Russell R. Lonser

An intraoperative MRI (iMRI)–compatible system has been developed for direct placement of convection-enhanced delivery (CED) cannulae using real-time imaging. To establish the precision and feasibility of this technology, the authors analyzed findings in patients who underwent direct iMRI CED cannula placement.

Three consecutive patients underwent iMRI-guided placement of CED infusion cannulae (6 cannulae) for treatment of diffuse intrinsic brainstem glioma (2 patients) or Parkinson's disease (1 patient). Convective infusion cannulae were guided to the target using the ClearPoint iMRI-based navigation platform (MRI Interventions, Inc.). Placement accuracy was analyzed.

Real-time iMRI during infusion cannula insertion allowed for monitoring of trajectory accuracy during placement. During cannula insertion, no reinsertions or changes due to errors in targeting were necessary. The mean radial error was 1.0 ± 0.5 mm (± SD). There was no correlation between the total length of the planned trajectory and the radial error (Pearson's coefficient: −0.40; p = 0.5). The mean anteroposterior and lateral errors were 0.9 ± 0.5 and 0.3 ± 0.2 mm, respectively. The mean in-plane distance error was 1.0 ± 0.4 mm. The mean tip error (scalar distance between the planned target and actual tip) was 1.9 ± 0.9 mm. There was no correlation between the length of the planned trajectory and any of the measured errors. No complications were associated with cannula placement.

Real-time iMRI-based targeting and monitoring of infusion cannula placement is a safe, effective, and accurate technique that should enable more selective perfusion of brain regions.