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Iman Feiz-Erfan, Eric M. Horn, Nicholas Theodore, Joseph M. Zabramski, Jeffrey D. Klopfenstein, Gregory P. Lekovic, Felipe C. Albuquerque, Shahram Partovi, Pamela W. Goslar and Scott R. Petersen

Object

Skull base fractures are often associated with potentially devastating injuries to major neural arteries in the head and neck, but the incidence and pattern of this association are unknown.

Methods

Between April and September 2002, 1738 Level 1 trauma patients were admitted to St. Joseph's Hospital and Medical Center in Phoenix, Arizona. Among them, a skull base fracture was diagnosed in 78 patients following computed tomography (CT) scans. Seven patients had no neurovascular imaging performed and were excluded. Altogether, 71 patients who received a diagnosis of skull base fractures after CT and who also underwent a neurovascular imaging study were included (54 men and 17 women, mean age 29 years, range 1–83 years). Patients underwent CT angiography, magnetic resonance angiography, or digital subtraction angiography of the head and craniovertebral junction, or combinations thereof.

Results

Nine neurovascular injuries were identified in six (8.5%) of the 71 patients. Fractures of the clivus were very likely to be associated with neurovascular injury (p < 0.001). A high risk of neurovascular injury showed a strong tendency to be associated with fractures of the sella turcica–sphenoid sinus complex (p = 0.07).

Conclusions

The risk of associated blunt neurovascular injury appears to be significant in Level 1 trauma patients in whom a diagnosis of skull base fracture has been made using CT. The incidence of neurovascular trauma is particularly high in patients with clival fractures. The authors recommend neurovascular imaging for Level 1 trauma patients with a high-risk fracture pattern of the central skull base to rule out cerebrovascular injuries.

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Mihaela A. Stavarache, Nicholas Petersen, Eric M. Jurgens, Elizabeth R. Milstein, Zachary B. Rosenfeld, Douglas J. Ballon and Michael G. Kaplitt

OBJECTIVE

Surgical infusion of gene therapy vectors has provided opportunities for biological manipulation of specific brain circuits in both animal models and human patients. Transient focal opening of the blood-brain barrier (BBB) by MR-guided focused ultrasound (MRgFUS) raises the possibility of noninvasive CNS gene therapy to target precise brain regions. However, variable efficiency and short follow-up of studies to date, along with recent suggestions of the potential for immune reactions following MRgFUS BBB disruption, all raise questions regarding the viability of this approach for clinical translation. The objective of the current study was to evaluate the efficiency, safety, and long-term stability of MRgFUS-mediated noninvasive gene therapy in the mammalian brain.

METHODS

Focused ultrasound under the control of MRI, in combination with microbubbles consisting of albumin-coated gas microspheres, was applied to rat striatum, followed by intravenous infusion of an adeno-associated virus serotype 1/2 (AAV1/2) vector expressing green fluorescent protein (GFP) as a marker. Following recovery, animals were followed from several hours up to 15 months. Immunostaining for GFP quantified transduction efficiency and stability of expression. Quantification of neuronal markers was used to determine histological safety over time, while inflammatory markers were examined for evidence of immune responses.

RESULTS

Transitory disruption of the BBB by MRgFUS resulted in efficient delivery of the AAV1/2 vector to the targeted rodent striatum, with 50%–75% of striatal neurons transduced on average. GFP transgene expression appeared to be stable over extended periods of time, from 2 weeks to 6 months, with evidence of ongoing stable expression as long as 16 months in a smaller cohort of animals. No evidence of substantial toxicity, tissue injury, or neuronal loss was observed. While transient inflammation from BBB disruption alone was noted for the first few days, consistent with prior observations, no evidence of brain inflammation was observed from 2 weeks to 6 months following MRgFUS BBB opening, despite delivery of a virus and expression of a foreign protein in target neurons.

CONCLUSIONS

This study demonstrates that transitory BBB disruption using MRgFUS can be a safe and efficient method for site-specific delivery of viral vectors to the brain, raising the potential for noninvasive focal human gene therapy for neurological disorders.