Patient-specific analysis of the relationship between the volume of tissue activated during DBS and verbal fluency.

Deep brain stimulation (DBS) for the treatment of advanced Parkinson's disease involves implantation of a lead with four small contacts usually within the subthalamic nucleus (STN) or globus pallidus internus (GPi). While generally safe from a cognitive standpoint, STN DBS has been commonly associated with a decrease in the speeded production of words, a skill referred to as verbal fluency. Virtually all studies comparing presurgical to postsurgical verbal fluency performance have detected a decrease with DBS. The decline may be attributable in part to the surgical procedures, yet the relative contributions of stimulation effects are not known. In the present study, we used patient-specific DBS computer models to investigate the effects of stimulation on verbal fluency performance. Specifically, we investigated relationships of the volume and locus of activated STN tissue to verbal fluency outcome. Stimulation of different electrode contacts within the STN did not affect total verbal fluency scores. However, models of activation revealed subtle relationships between the locus and volume of activated tissue and verbal fluency performance. At ventral contacts, more tissue activation inside the STN was associated with decreased letter fluency performance. At optimal contacts, more tissue activation within the STN was associated with improved letter fluency performance. These findings suggest subtle effects of stimulation on verbal fluency performance, consistent with the functional nonmotor subregions/somatotopy of the STN.

Deep brain stimulation of the ventral internal capsule/ventral striatum for obsessive-compulsive disorder: worldwide experience.

Psychiatric neurosurgery teams in the United States and Europe have studied deep brain stimulation (DBS) of the ventral anterior limb of the internal capsule and adjacent ventral striatum (VC/VS) for severe and highly treatment-resistant obsessive-compulsive disorder. Four groups have collaborated most closely, in small-scale studies, over the past 8 years. First to begin was Leuven/Antwerp, followed by Butler Hospital/Brown Medical School, the Cleveland Clinic and most recently the University of Florida. These centers used comparable patient selection criteria and surgical targeting. Targeting, but not selection, evolved during this period. Here, we present combined long-term results of those studies, which reveal clinically significant symptom reductions and functional improvement in about two-thirds of patients. DBS was well tolerated overall and adverse effects were overwhelmingly transient. Results generally improved for patients implanted more recently, suggesting a 'learning curve' both within and across centers. This is well known from the development of DBS for movement disorders. The main factor accounting for these gains appears to be the refinement of the implantation site. Initially, an anterior-posterior location based on anterior capsulotomy lesions was used. In an attempt to improve results, more posterior sites were investigated resulting in the current target, at the junction of the anterior capsule, anterior commissure and posterior ventral striatum. Clinical results suggest that neural networks relevant to therapeutic improvement might be modulated more effectively at a more posterior target. Taken together, these data show that the procedure can be successfully implemented by dedicated interdisciplinary teams, and support its therapeutic promise.

The national DBS brain tissue network pilot study: need for more tissue and more standardization.

Over 70,000 DBS devices have been implanted worldwide; however, there remains a paucity of well-characterized post-mortem DBS brains available to researchers. We propose that the overall understanding of DBS can be improved through the establishment of a Deep Brain Stimulation-Brain Tissue Network (DBS-BTN), which will further our understanding of DBS and brain function. The objectives of the tissue bank are twofold: (a) to provide a complete (clinical, imaging and pathological) database for DBS brain tissue samples, and (b) to make available DBS tissue samples to researchers, which will help our understanding of disease and underlying brain circuitry. Standard operating procedures for processing DBS brains were developed as part of the pilot project. Complete data files were created for individual patients and included demographic information, clinical information, imaging data, pathology, and DBS lead locations/settings. 19 DBS brains were collected from 11 geographically dispersed centers from across the U.S. The average age at the time of death was 69.3 years (51-92, with a standard deviation or SD of 10.13). The male:female ratio was almost 3:1. Average post-mortem interval from death to brain collection was 10.6 h (SD of 7.17). The DBS targets included: subthalamic nucleus, globus pallidus interna, and ventralis intermedius nucleus of the thalamus. In 16.7% of cases the clinical diagnosis failed to match the pathological diagnosis. We provide neuropathological findings from the cohort, and perilead responses to DBS. One of the most important observations made in this pilot study was the missing data, which was approximately 25% of all available data fields. Preliminary results demonstrated the feasibility and utility of creating a National DBS-BTN resource for the scientific community. We plan to improve our techniques to remedy omitted clinical/research data, and expand the Network to include a larger donor pool. We will enhance sample preparation to facilitate advanced molecular studies and progenitor cell retrieval.

Mood and motor effects of thalamic deep brain stimulation surgery for essential tremor.

PURPOSE: The aim of this study was to evaluate the effects of unilateral and bilateral ventralis intermedius (Vim) deep brain stimulation (DBS) on mood and motor function. METHODS: Thirty-one consecutive medication refractory patients with essential tremor who underwent unilateral or bilateral Vim DBS at University of Florida and returned for at least 6 -month follow-up completed the Visual Analog Mood (VAMS), the Beck Depression Inventory (BDI), and the Tremor Rating Scale (TRS) before and after surgery. We excluded all patients who were implanted at other institutions. RESULTS: The tense subscale of the VAMS improved significantly in both the unilateral and bilateral DBS groups (P < 0.001). On the VAMS afraid subscale, only the bilateral group trended toward improvement (P = 0.075). There were no significant changes for either group for the happy, confused, sad, angry, energetic or tired VAMS scores. TRS subscale scores all improved after unilateral and bilateral Vim DBS surgery (P < 0.001). CONCLUSIONS: Feelings of tenseness, tremor severity and ADLs improved following unilateral or bilateral Vim DBS for ET.

Functional and Structural Connectivity Patterns Associated with Clinical Outcomes in Deep Brain Stimulation of the Globus Pallidus Internus for Generalized Dystonia.

BACKGROUND AND PURPOSE: Deep brain stimulation is a well-established treatment for generalized dystonia, but outcomes remain variable. Establishment of an imaging marker to guide device targeting and programming could possibly impact the efficacy of deep brain stimulation in dystonia, particularly in the absence of acute clinical markers to indicate benefit. We hypothesize that the stimulation-based functional and structural connectivity using resting-state fMRI and DTI can predict therapeutic outcomes in patients with generalized dystonia and deep brain stimulation. MATERIALS AND METHODS: We performed a retrospective analysis of 39 patients with inherited or idiopathic-isolated generalized dystonia who underwent bilateral globus pallidus internus deep brain stimulation. After electrode localization, the volumes of tissue activated were modeled and used as seed regions for functional and structural connectivity measures using a normative data base. Resulting connectivity maps were correlated with postoperative improvement in the Unified Dystonia Rating Scale score. RESULTS: Structural connectivity between the volumes of tissue activated and the primary sensorimotor cortex was correlated with Unified Dystonia Rating Scale improvement, while more anterior prefrontal connectivity was inversely correlated with Unified Dystonia Rating Scale improvement. Functional connectivity between the volumes of tissue activated and primary sensorimotor regions, motor thalamus, and cerebellum was most correlated with Unified Dystonia Rating Scale improvement; however, an inverse correlation with Unified Dystonia Rating Scale improvement was seen in the supplemental motor area and premotor cortex. CONCLUSIONS: Functional and structural connectivity with multiple nodes of the motor network is associated with motor improvement in patients with generalized dystonia undergoing deep brain stimulation. Results from this study may serve as a basis for future development of clinical markers to guide deep brain stimulation targeting and programming in dystonia.

Brain penetration effects of microelectrodes and DBS leads in STN or GPi.

OBJECTIVE: To determine how intraoperative microelectrode recordings (MER) and intraoperative lead placement acutely influence tremor, rigidity, and bradykinesia. Secondarily, to evaluate whether the longevity of the MER and lead placement effects were influenced by target location (subthalamic nucleus (STN) or globus pallidus interna (GPi)). BACKGROUND: Currently most groups who perform deep brain stimulation (DBS) for Parkinson disease (PD) use MER, as well as macrostimulation (test stimulation), to refine DBS lead position. Following MER and/or test stimulation, however, there may be a resultant "collision/implantation" or "microlesion" effect, thought to result from disruption of cells and/or fibres within the penetrated region. These effects have not been carefully quantified. METHODS: 47 consecutive patients with PD undergoing unilateral DBS for PD (STN or GPi DBS) were evaluated. Motor function was measured at six time points with a modified motor Unified Parkinson Disease Rating Scale (UPDRS): (1) preoperatively, (2) immediately after MER, (3) immediately after lead implantation/collision, (4) 4 months following surgery-off medications, on DBS (12 h medication washout), (5) 6 months postoperatively-off medication and off DBS (12 h washout) and (6) 6 months-on medication and off DBS (12 h washout). RESULTS: Significant improvements in motor scores (p<0.05) (tremor, rigidity, bradykinesia) were observed as a result of MER and lead placement. The improvements were similar in magnitude to what was observed at 4 and 6 months post-DBS following programming and medication optimisation. When washed out (medications and DBS) for 12 h, UPDRS motor scores were still improved compared with preoperative testing. There was a larger improvement in STN compared with GPi following MER (p<0.05) and a trend for significance following lead placement (p<0.08) but long term outcome was similar. CONCLUSION: This study demonstrated significant acute intraoperative penetration effects resulting from MER and lead placement/collision in PD. Clinicians rating patients in the operating suite should be aware of these effects, and should consider pre- and post-lead placement rating scales prior to activating DBS. The collision/implantation effects were greater intraoperatively with STN compared with GPi, and with greater disease duration there was a larger effect.

Perceptual characteristics of Parkinsonian speech: a comparison of the pharmacological effects of levodopa across speech and non-speech motor systems.

The purpose of this study was to: (1) define perceptual speech characteristics of idiopathic Parkinson disease (IPD) across 35 speech dimensions adapted from Darley et al. [19] and grouped under six speech-sign clusters (respiration, phonation, resonance, articulation, prosody and rate); (2) examine the effects of levodopa on the 35 perceptual speech dimensions and speech-sign clusters; and (3) to compare the relative effectiveness of levodopa on global motor functioning vs. speech production. Sixteen patients with IPD read the 'Grandfather Passage' both 'on' and 'off' levodopa. Three blinded speech-language pathologists performed perceptual speech analyses using a seven-point scale. The diagnosis of IPD was made by a movement disorders fellowship trained neurologist who applied UK Brain bank criteria and administered the Unified Parkinson Disease Rating Scale. Concordant with previous studies, the results of this experiment indicated that IPD disrupted multiple speech production subsystems, with prosody being the most severely affected domain. The perceptual dimensions that were most severely affected included: (1) sound imprecision; (2) mono-loudness; (3) mono-pitch; (4) reduced stress and (5) harsh voice. No significant differences were obtained between medicated states ('on'/'off') for any of the 35 individual speech dimensions and speech-sign clusters. Global motor function significantly improved following dopaminergic medications.

Segmentation of the Globus Pallidus Internus Using Probabilistic Diffusion Tractography for Deep Brain Stimulation Targeting in Parkinson Disease.

BACKGROUND AND PURPOSE: Although globus pallidus internus deep brain stimulation is a widely accepted treatment for Parkinson disease, there is persistent variability in outcomes that is not yet fully understood. In this pilot study, we aimed to investigate the potential role of globus pallidus internus segmentation using probabilistic tractography as a supplement to traditional targeting methods. MATERIALS AND METHODS: Eleven patients undergoing globus pallidus internus deep brain stimulation were included in this retrospective analysis. Using multidirection diffusion-weighted MR imaging, we performed probabilistic tractography at all individual globus pallidus internus voxels. Each globus pallidus internus voxel was then assigned to the 1 ROI with the greatest number of propagated paths. On the basis of deep brain stimulation programming settings, the volume of tissue activated was generated for each patient using a finite element method solution. For each patient, the volume of tissue activated within each of the 10 segmented globus pallidus internus regions was calculated and examined for association with a change in the Unified Parkinson Disease Rating Scale, Part III score before and after treatment. RESULTS: Increasing volume of tissue activated was most strongly correlated with a change in the Unified Parkinson Disease Rating Scale, Part III score for the primary motor region (Spearman r = 0.74, P = .010), followed by the supplementary motor area/premotor cortex (Spearman r = 0.47, P = .15). CONCLUSIONS: In this pilot study, we assessed a novel method of segmentation of the globus pallidus internus based on probabilistic tractography as a supplement to traditional targeting methods. Our results suggest that our method may be an independent predictor of deep brain stimulation outcome, and evaluation of a larger cohort or prospective study is warranted to validate these findings.

LRRK2 mutations in a clinic-based cohort of Parkinson's disease.

In the last decade, major breakthroughs in the understanding of genetic contributions to Parkinson's disease (PD) have been achieved. Recently, mutations in LRRK2, encoding dardarin, have been found to be responsible for an autosomal dominant parkinsonism (OMIM 607060). We screened 311 subjects (cases: n = 202, controls: n = 109) for the three previously reported LRRK2 mutations. Our investigation revealed a sporadic case of PD with a heterozygous mutation G2019S (c.6055G>A). Here, we present the clinical phenotype of this patient and discuss the implications of genetic testing for the G2019S mutation in patients with sporadic PD.

Mood and cognitive changes with deep brain stimulation. What we know and where we should go.

AIM: The aim of this study was to completely review the literature on cognitive and mood changes resulting from deep brain stimulation (DBS), and to examine the factors that might lead to these changes. DBS has been shown to improve motor symptoms in many movement disorders. Despite the widespread use of this technique, there are relatively few well controlled studies describing the potential cognitive, mood and behavioral consequences that may result from DBS. Additionally, the factors that may influence these changes have not been carefully studied. METHODS: A complete survey of the articles exploring the effects of DBS on mood and cognition was performed. Each study identified was examined and categories of factors that may have influenced mood and cognition were noted. These factors included surgical target, number of patients studied, whether procedures were unilateral or bilateral, average age of patients, diagnosis, condition of the DBS during the study (on or off), pre-operative screening tests (e.g., dementia rating scale, mini mental state exam), and changes on mood and cognitive tests (categorized as no change, improved, or worsened). Studies were divided into evidence-based categories. RESULTS: There are many mood and cognitive changes that may result from DBS. Due to methodological limitations of existing studies there are important unanswered questions about cognitive and mood changes resulting from this type of surgery. The predominant amount of data regarding changes in mood and cognition with DBS is level 3 or case based evidence. CONCLUSIONS: There exists a paucity of well-controlled studies addressing the mood and cognitive changes that result from DBS. Carefully performed prospective studies may help us to understand the effects of DBS on mood and cognition.

Brain synaptosomal, liver, plasma, and red blood cell lipids in piglets fed exclusively on a vegetable-oil-containing formula with and without fish-oil supplements.

Clinical studies showed that a decrease in red blood cell 22:6n-3 caused by feeding infants formula (F) can be prevented by supplementation with fish oil (F + O). It is not known whether fish-oil supplementation is able to support normal accretion of fatty acids with greater than or equal to 20 carbons (LCPs) in the brain. Therefore piglets were fed exclusively F + O, F, or sow milk (SM) for 15 d and their liver and brain synaptosomal fatty acids were determined. Feeding F + O corrected the low n-3 LCP in the liver phospholipid (PL) and synaptosomal phosphatidylethanolamine (PE) of piglets fed F compared with SM. An apparent compensatory increase in n-6 LCPs in liver PL and synaptosomal PE of piglets fed F compared with SM was suppressed by feeding F + O. F + O also reduced the ratio of plasma PL 20:4n-6 to 20:5n-3, important for eicosanoid metabolism. Supplementation of F with n-3 LCPs as fish oil, without n-6 LCPs, at levels giving normal brain n-3 LCP, may alter n-6 LCP accretion.

Effect of early introduction of formula vs fat-free parenteral nutrition on essential fatty acid status of preterm infants.

Previous studies have used relative (%) values of plasma 18:2n-6 (18:2 omega-6) and the ratio of 20:3n-9 to 20:4n-6 (triene/tetrene) to indicate the essential fatty acid (EFA: 18:2n-6 and 18:3n-3) status of preterm infants. The extent to which these indices reflect milligrams per liter quantities of n-6 and n-3 long-chain polyunsaturated derivatives of EFA (LCPs), required for cell membrane accretion, is unknown. Thus, 18:2n-6, the triene-tetrene ratio, and n-6 and n-3 LCPs were measured in plasma phospholipid of preterm infants' cord blood (n = 22) and of preterm infants fed formula (n = 12) or of preterm infants who received fat-free parenteral nutrition (n = 15) on postnatal day 3. Whether expressed as percent or milligrams per liter, 18:2n-6 was markedly higher and the triene-tetrene ratio lower in infants fed formula than in infants who had received no lipid. However, concentrations of n-6 and n-3 LCPs were similar in the two groups of infants and significantly higher than cord values. In the absence of an exogenous lipid source, it is suggested that tissue stores of LCPs are released in response to birth.

Plasma and red blood cell fatty acids of low-birth-weight infants fed their mother's expressed breast milk or preterm-infant formula.

The fatty acid composition of plasma phospholipids, red blood cell (RBC) phosphatidylcholine (PC), and phosphatidylethanolamine (PE) was determined for low-birth-weight (LBW) infants when full oral feeding commenced (day 0) and after a further 28 d (day 28). They were fed their mother's expressed breast milk (PTM, n = 9), formula (SCF, n = 16) with 2% 18:3n-3 fatty acids, 20% 18:2n-6 fatty acids, or a combination of SCF and PTM (n = 11). Concentrations of all 20- and 22-carbon n-6 and n-3 fatty acids were similar among the infant groups on days 0 and 28 (mean postnatal age 42 +/- 1.3 d). The results suggest that formula with greater than or equal to 2% 18:3n-3 and a ratio of 18:2n-6 to 18:3n-3 similar to that of human milk may permit incorporation of n-3 fatty acids in LBW infant tissues equivalent to that from human milk.

Calculation of cranial nerve complication probability for acoustic neuroma radiosurgery.

PURPOSE: Estimations of complications from stereotactic radiosurgery usually rely simply on dose-volume or dose-diameter isoeffect curves. Due to the sparse clinical data available, these curves have typically not considered the target location in the brain, target histology, or treatment plan conformality as parameters in the calculation. In this study, a predictive model was generated to estimate the probability of cranial neuropathies as a result of acoustic schwannoma radiosurgery. METHODS AND MATERIALS: The dose-volume histogram reduction scheme was used to calculate the normal tissue complication probability (NTCP) from brainstem dose-volume histograms. The model's fitting parameters were optimized to provide the best fit to the observed complication data for acoustic neuroma patients treated with stereotactic radiosurgery at the University of Florida. The calculation was then applied to the remainder of the patients in the database. RESULTS: The best fit to our clinical data was obtained using n = 0.04, m = 0.15, and alpha/beta = 2.1 Gy(-1). Although the fitting parameter m is relatively consistent with ranges found in the literature, both the volume parameter, n, and alpha/beta are much smaller than the values quoted in the literature. The fit to our clinical data indicates that brainstem, or possibly a specific portion of the brainstem, is more radiosensitive than the parameters in the literature indicate, and that there is very little volume effect; in other words, irradiation of a small fraction of the brainstem yields NTCPs that are nearly as high as those calculated for entire volume irradiation. These new fitting parameters are specific to acoustic neuroma radiosurgery, and the small volume effect that we observe may be an artifact of the fixed relationship of acoustic tumors to specific regions of the brainstem. Applying the model to our patient database, we calculate an average NTCP of 7.2% for patients who had no cranial nerve complications, and the average NTCP for was 66% for patients who sustained a cranial neuropathy. For the entire patient population, the actual percentage of patients suffering either facial or trigeminal neuropathy was 14.7%, whereas the calculated average NTCP was 14.8%. DISCUSSION: NTCP calculations using brainstem dose-volume histograms can be used to estimate the rate of cranial neuropathies from acoustic neuroma radiosurgery. More clinical data and further study will lead to refinement of the model with time.

Image localization for frameless stereotactic radiotherapy.

PURPOSE: Infrared light-emitting diodes (IRLEDs) have been used for optic-guided stereotactic radiotherapy localization at the University of Florida since 1995. The current paradigm requires stereotactic head ring placement for the patient's first fraction. The stereotactic coordinates and treatment plan are determined relative to this head ring. The IRLEDs are attached to the patient via a maxillary bite plate, and the position of the IRLEDs relative to linac isocenter is saved to file. These positions are then recalled for each subsequent treatment to position the patient for fractionated therapy. The purpose of this article was to report a method of predicting the desired IRLED locations without need for the invasive head ring. METHODS AND MATERIALS: To achieve the goal of frameless optic-guided radiotherapy, a method is required for direct localization of the IRLED positions from a CT scan. Because it is difficult to localize the exact point of light emission from a CT scan of an IRLED, a new bite plate was designed that contains eight aluminum fiducial markers along with the six IRLEDs. After a calibration procedure to establish the spatial relationship of the IRLEDs to the aluminum fiducial markers, the stereotactic coordinates of the IRLED light emission points are determined by localizing the aluminum fiducial markers in a stereotactic CT scan. RESULTS: To test the accuracy of direct CT determination of the IRLED positions, phantom tests were performed. The average accuracy of isocenter localization using the IRLED bite plate was 0.65 +/- 0. 17 mm for these phantom tests. In addition, the optic-guided system has a unique compatibility with the stereotactic head ring. Therefore, the isocentric localization capability was clinically tested using the stereotactic head ring as the absolute standard. The ongoing clinical trial has shown the frameless system to provide a patient localization accuracy of 1.11 +/- 0.3 mm compared with the head ring. CONCLUSION: Optic-guided radiotherapy using IRLEDs provides a mechanism through which setup accuracy may be improved over conventional techniques. To date, this optic-guided therapy has been used only as a hybrid system that requires use of the stereotactic head ring for the first fraction. This has limited its use in the routine clinical setting. Computation of the desired IRLED positions eliminates the need for the invasive head ring for the first fraction. This allows application of optic-guided therapy to a larger cohort of patients, and also facilitates the initiation of extracranial optic-guided radiotherapy.

A geometrically based method for automated radiosurgery planning.

PURPOSE: A geometrically based method of multiple isocenter linear accelerator radiosurgery treatment planning optimization was developed, based on a target's solid shape. METHODS AND MATERIALS: Our method uses an edge detection process to determine the optimal sphere packing arrangement with which to cover the planning target. The sphere packing arrangement is converted into a radiosurgery treatment plan by substituting the isocenter locations and collimator sizes for the spheres. RESULTS: This method is demonstrated on a set of 5 irregularly shaped phantom targets, as well as a set of 10 clinical example cases ranging from simple to very complex in planning difficulty. Using a prototype implementation of the method and standard dosimetric radiosurgery treatment planning tools, feasible treatment plans were developed for each target. The treatment plans generated for the phantom targets showed excellent dose conformity and acceptable dose homogeneity within the target volume. The algorithm was able to generate a radiosurgery plan conforming to the Radiation Therapy Oncology Group (RTOG) guidelines on radiosurgery for every clinical and phantom target examined. CONCLUSIONS: This automated planning method can serve as a valuable tool to assist treatment planners in rapidly and consistently designing conformal multiple isocenter radiosurgery treatment plans.

Analysis of risk factors associated with radiosurgery for vestibular schwannoma.

OBJECT: The aim of this study was to identify factors associated with delayed cranial neuropathy following radiosurgery for vestibular schwannoma (VS or acoustic neuroma) and to determine how such factors may be manipulated to minimize the incidence of radiosurgical complications while maintaining high rates of tumor control. METHODS: From July 1988 to June 1998, 149 cases of VS were treated using linear accelerator radiosurgery at the University of Florida. In each of these cases, the patient's tumor and brainstem were contoured in 1-mm slices on the original radiosurgical targeting images. Resulting tumor and brainstem volumes were coupled with the original radiosurgery plans to generate dose-volume histograms. Various tumor dimensions were also measured to estimate the length of cranial nerve that would be irradiated. Patient follow-up data, including evidence of cranial neuropathy and radiographic tumor control, were obtained from a prospectively maintained, computerized database. The authors performed statistical analyses to compare the incidence of posttreatment cranial neuropathies or tumor growth between patient strata defined by risk factors of interest. One hundred thirty-nine of the 149 patients were included in the analysis of complications. The median duration of clinical follow up for this group was 36 months (range 18-94 months). The tumor control analysis included 133 patients. The median duration of radiological follow up in this group was 34 months (range 6-94 months). The overall 2-year actuarial incidences of facial and trigeminal neuropathies were 11.8% and 9.5%, respectively. In 41 patients treated before 1994, the incidences of facial and trigeminal neuropathies were both 29%, but in the 108 patients treated since January 1994, these rates declined to 5% and 2%, respectively. An evaluation of multiple risk factor models showed that maximum radiation dose to the brainstem, treatment era (pre-1994 compared with 1994 or later), and prior surgical resection were all simultaneously informative predictors of cranial neuropathy risk. The radiation dose prescribed to the tumor margin could be substituted for the maximum dose to the brainstem with a small loss in predictive strength. The pons-petrous tumor diameter was an additional statistically significant simultaneous predictor of trigeminal neuropathy risk, whereas the distance from the brainstem to the end of the tumor in the petrous bone was an additional marginally significant simultaneous predictor of facial neuropathy risk. The overall radiological tumor control rate was 93% (59% tumors regressed, 34% remained stable, and 7.5% enlarged), and the 5-year actuarial tumor control rate was 87% (95% confidence interval [CI] 76-98%). Analysis revealed that a radiation dose cutpoint of 10 Gy compared with more than 10 Gy prescribed to the tumor margin yielded the greatest relative difference in tumor growth risk (relative risk 2.4, 95% CI 0.6-9.3), although this difference was not statistically significant (p = 0.207). CONCLUSIONS: Five points must be noted. 1) Radiosurgery is a safe, effective treatment for small VSs. 2) Reduction in the radiation dose has played the most important role in reducing the complications associated with VS radiosurgery. 3) The dose to the brainstem is a more informative predictor of postradiosurgical cranial neuropathy than the length of the nerve that is irradiated. 4) Prior resection increases the risk of late cranial neuropathies after radiosurgery. 5) A prescription dose of 12.5 Gy to the tumor margin resulted in the best combination of maximum tumor control and minimum complications in this series.

Weaning preterm infants: a randomised controlled trial.

OBJECTIVE: To assess the effect on growth and iron status in preterm infants of a specially devised weaning strategy compared with current best practices in infant feeding. The preterm weaning strategy recommended the early onset of weaning and the use of foods with a higher energy and protein content than standard milk formula, and foods that are rich sources of iron and zinc. SUBJECTS AND DESIGN: In a blinded, controlled study, 68 preterm infants (mean (SD) birth weight 1470 (430) g and mean (SD) gestational age 31.3 (2.9) weeks) were randomised to either the preterm weaning strategy group (n = 37) or a current best practice control group (n = 31), from hospital discharge until 1 year gestation corrected age (GCA). MAIN OUTCOME MEASURES: Weight, supine length, occipitofrontal head circumference, and intakes of energy, protein, and minerals were determined at 0, 6, and 12 months GCA. Levels of haemoglobin, serum iron, and serum ferritin were assayed at 0 and 6 months GCA. RESULTS: Significant positive effects of treatment included: greater increase in standard deviation length scores and length growth velocity; increased intake of energy, protein, and carbohydrate at 6 months GCA and iron at 12 months GCA; increased haemoglobin and serum iron levels at 6 months GCA. CONCLUSIONS: The preterm weaning strategy significantly influenced dietary intakes with consequent beneficial effects on growth in length and iron status. This strategy should be adopted as the basis of feeding guidelines for preterm infants after hospital discharge.

Linear accelerator radiosurgery in brain tumor management.

This article begins with a brief introduction to the concepts and techniques of linear accelerator-based stereotactic radiosurgery. The expanding role of radiosurgery in the treatment of brain tumors is explored in depth, including detailed discussions of the five intracranial neoplasms most frequently treated with radiosurgery. These include both benign (i.e., vestibular schwannoma, meningioma, pituitary adenoma) and malignant (i.e., cerebral metastasis, malignant glioma) pathologies. For each of these, a thorough review of published radiosurgical results is presented along with a discussion of common treatment modalities. The role of radiosurgery in the treatment of brain tumors continues to be defined, but an effort is made to provide reasonable indications for and against radiosurgery based on the current state of the art.

Advances in the nutrition of preterm infants.

The greatly improved survival rate of infants born both preterm and low birth weight (LBW) has led to the subsequent growth and development of these infants becoming an important focus for research. Preterm infants begin life with, or acquire as a result of their prematurity, greater morbidity than term born babies, growth deficits, an increased risk of developmental delay and an increased risk of later adult diseases compared with appropriate for gestational age (AGA) term born babies. Research in recent decades has confirmed that there are marked differences in the nutritional requirements of preterm LBW infants compared with their AGA term born counterparts, both in the neonatal period and probably for all of infancy. In addition to the increased requirement for energy and protein, preterm LBW infants demonstrate a greatly increased requirement for some of the mineral elements, particularly iron, zinc and calcium, when compared with the needs of term AGA infants. In the UK, feeding practices for preterm infants in neonatal units and throughout infancy after hospital discharge are variable and many questions remain as to the optimal nutritional regimen for preterm LBW infants (and for subgroups of these infants) at different stages of infancy. There is some concern that the 2002 World Health Organization recommendations on infant feeding may be applied to all infants, including preterm infants, without consideration of their special nutritional needs, which may further compromise their growth and development. A brief résumé of the work of prominent researchers in the field of preterm infant nutrition in the UK, notably Lucas, Cooke and Fewtrell, is included in the review, together with information from papers published by the authors of the review. The review concludes with a summary of the generally accepted recommendations on feeding preterm LBW infants after hospital discharge and information on some practical help available to the parents of these children and to health workers in the field.