Clinical protocol. Gene therapy of Canavan disease: AAV-2 vector for neurosurgical delivery of aspartoacylase gene (ASPA) to the human brain.

This clinical protocol describes virus-based gene transfer for Canavan disease, a childhood leukodystrophy. Canavan disease, also known as Van Bogaert-Bertrand disease, is a monogeneic, autosomal recessive disease in which the gene coding for the enzyme aspartoacylase (ASPA) is defective. The lack of functional enzyme leads to an increase in the central nervous system of the substrate molecule, N-acetyl-aspartate (NAA), which impairs normal myelination and results in spongiform degeneration of the brain. No effective treatment currently exists; however, virus-based gene transfer has the potential to arrest or reverse the course of this otherwise fatal condition. This procedure involves neurosurgical administration of approximately 900 billion genomic particles (approximately 10 billion infectious particles) of recombinant adeno-associated virus (AAV) containing the aspartoacylase gene (ASPA) directly to affected regions of the brain in each of 21 patients with Canavan disease. Pre- and post-delivery assessments include a battery of noninvasive biochemical, radiological, and neurological tests. This gene transfer study represents the first clinical use of AAV in the human brain and the first instance of viral gene transfer for a neurodegenerative disease.

Direct comparison of two methods to measure T1: in vitro and in vivo values by echo-planar imaging and by segmented k-space imaging.

We test a hypothesis that proton T(1) is accurately measured independent of the physics inherent to the method. We used two well-validated but quite different imaging methods to measure T(1) in phantoms and in humans; an echo-planar imaging T-one measurement (EPITOME) method, and a segmented k-space acquisition precise and accurate inversion recovery (TurboPAIR) method. Agreement between the methods was generally excellent; the square of the correlation coefficient (r(2)) in phantoms was 0.9996. The r(2) in brain tissue of volunteers was 0.79 overall, and 0.85 if cortical gray matter and corpus callosum were excluded. Nevertheless, small but significant differences were observed between methods in vivo and T(1) measurements were sensitive to tissue type, although measurements could be made comparable. The major difference between the methods is that EPITOME takes 97 s to image 15 slices at low resolution, while TurboPAIR takes 240 s to image one slice at high resolution.

Brain T1 in young children with sickle cell disease: evidence of early abnormalities in brain development.

Measurement of tissue spin lattice relaxation time (T(1)) has been used to characterize brain development in healthy children. Here we report the first study of brain T(1) in young children with sickle cell disease (SCD). The T(1) in 10 tissue samples was measured by established techniques; 46 SCD patients under the age of 4 years were compared to 267 controls, including 55 well children under the age of 4 years. A model was developed to predict the relationship between age and brain T(1) in controls, then we compared patient T(1) to healthy normal T(1). Most white matter and gray matter tissues in infant patients (<2 years old), had T(1) values significantly higher than normal. For example, 15.0% of patient caudate T(1) values were above the upper bound of the 95% confidence interval for controls, but only 2.5% of normal values are expected to be this high (p = 0.0003). Among infant patients, brain T(1) was significantly higher than normal in every tissue (p < 0.01) except cortical gray matter. However, patient T(1) values declined rapidly to values lower than normal by about age 4. Our findings imply that patients follow an abnormal developmental trajectory beginning early in infancy.

Resident accuracy of joint line palpation using ultrasound verification.

OBJECTIVE: To determine the accuracy of knee and acromioclavicular (AC) joint line palpation in Physical Medicine and Rehabilitation (PM&R) residents using ultrasound (US) verification. DESIGN: Cohort study. SETTING: PM&R residency program at an academic institution. PARTICIPANTS: Twenty-four PM&R residents participating in a musculoskeletal US course (7 PGY-2, 8 PGY-3, and 9 PGY4 residents). METHODS: Twenty-four PM&R residents participating in an US course were asked to palpate the AC joint and lateral joint line of the knee in a female and male model before the start of the course. Once the presumed joint line was localized, the residents were asked to tape an 18-gauge, 1.5-inch, blunt-tip needle parallel to the joint line on the overlying skin. The accuracy of needle placement over the joint line was verified using US. MAIN OUTCOME MEASURES: US verification of correct needle placement over the joint line. RESULTS: Overall AC joint palpation accuracy was 16.7%, and knee lateral joint line palpation accuracy was 58.3%. Based on the resident level of education, using a value of P < .05, there were no statistically significant differences in the accuracy of joint line palpation. CONCLUSIONS: Residents in this study demonstrate poor accuracy of AC joint and lateral knee joint line identification by palpation, using US as the criterion standard for verification. There were no statistically significant differences in the accuracy rates of joint line palpation based on resident level of education. US may be a useful tool to use to advance the current methods of teaching the physical examination in medical education.

Priapism in children: treatment with embolotherapy.

BACKGROUND: Priapism is defined as involuntary, prolonged penile erection caused by factors other than sexual arousal, and is classified as either low-flow or high-flow. Embolotherapy is an accepted form of therapy in adults with high-flow priapism. Because the differences in etiology, management and outcome are significant, accurate and timely diagnosis is imperative. OBJECTIVE: The purpose of this report is to present our experience with embolotherapy for treatment of high-flow priapism in three children. PATIENTS AND METHODS: This was a retrospective study. During an 18-month period, three boys ranging in age from 6 to 15 years presented with priapism. All three children were treated with embolotherapy. RESULTS: All three children were successfully treated with angiography and embolotherapy. One boy had a presentation that initially raised the possibility of low-flow priapism. No complications occurred, and to date all children are able to maintain normal erections. CONCLUSION: Subselective transcatheter embolization is the procedure of choice for high-flow priapism. In cases where priapism persists despite adequate therapy, angiography might be useful to exclude high-flow disease. In children with high-flow priapism, selective occlusion of the penile arteriovenous fistula led to detumescence and normal erectile function.

Ultrasound of a torsed ovary: characteristic gray-scale appearance despite normal arterial and venous flow on Doppler.

BACKGROUND: We present the case of an 8-year-old girl with acute onset of intermittent lower abdominal pain. The gray-scale US examination showed an enlarged right ovary with peripheral cysts, reflecting ovarian congestion and strongly suggesting the diagnosis of torsion. Normal arterial and venous flow, however, was found on Doppler US. OBJECTIVE: To demonstrate the importance of gray-scale US findings despite the presence of blood flow found on Doppler US in salvaging a viable, torsed ovary. METHODS: Despite the Doppler findings, a presumptive diagnosis of ovarian torsion was made. RESULTS: Surgery confirmed the presence of a torsed ovary, which was viable and appeared normal after detorsion. CONCLUSION: This case illustrates that the gray-scale US appearance of the ovary can be more reliable than Doppler US for the diagnosis of ovarian torsion.

Dose reduction fluoroscopy in pediatrics.

BACKGROUND: It is essential that we find ways to reduce radiation exposure to children and maintain image quality. OBJECTIVES: We compared radiation dose, image quality, and spatial resolution when continuous and pulse fluoroscopy with a full and half dose are applied to a phantom. The film-screen technique was compared to fluoroscopy with the digitized spot technique (fluoro grab image) in procedures such as voiding cystourethrogram (VCUG). MATERIALS AND METHODS: Using a 15.1-cm Plexiglas phantom, we obtained dosimetry in milligrays (mGy), spatial resolution in number of line pairs per millimeter (lp/mm), and threshold contrast resolution in number of visible holes. To measure total radiation dose, we calculated the average elapsed fluoroscopy time for VCUG to be approximately 3 min and estimated the average number of exposures as 10. Dosimetry was obtained for full dose and half dose continuous, for 15 pulses per second (pps), 7.5 pps, and 3.75 pps. These were also calculated with normal, magnification 1, and magnification 2 factors. RESULTS: Results of the two most relevant parameters are shown: continuous full-dose fluoroscopy, 3 min, 10 photo spots, total dose of 28.7 mGy with 2 lp/mm of resolution and a threshold contrast of 2.2%, versus 3.75 pps half-dose fluoroscopy, 3 min, grab images, total dose of 3.7 mGy with 1.9 lp/mm of resolution and a threshold contrast of 2.3%. CONCLUSION: With minimal loss of resolution there is significant dose reduction (87%) when using 3.75 pps with digitized imaging.