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Objectives. International literature on temporomandibular disorders offers show a relationship between temporomandibular disorders and psychosocial factors. This study aims to go beyond this already known relationship (fully supported by previous literature) and shows how the application of an innovative therapeutic protocol for temporomandibular disorders (called MOBT; Myofunctional Orthognathodontic Biodynamic Therapy), may generate relevant effects in respect to anxiety, pain and disorders associated to temporomandibular disorders. Method. A total of 40 patients with TMD underwent a MOBT treatment in a private clinic in Italy, and completed a self-report questionnaire for evaluating anxiety and pain before and after the treatment. Results. Results showed that MOBT treatment gave a significant benefit for anxiety and pain in subjects with TMD symptoms, especially those with a high trait anxiety and severe correlated pains. Conclusion. MOBT appears to be an efficient therapeutic protocol for temporomandibular disorders. [ABSTRACT FROM AUTHOR]

The clivus is bone of the skull base located between the sella and the foramen magnum. It consists of both the sphenoid bone rostrally and the occipital bone caudally. Because of its deep central location near the brainstem, basilar artery, internal carotid arteries, cranial nerve VI (abducens), and cranial nerve XII (hypoglossal), treating clival lesions presents significant surgical challenges. Successful treatment often requires a multidisciplinary approach including otolaryngology, neurosurgery, radiology, oncology, pathology, palliative care, and anesthesiology. We report a 15 year-old female with a clival chordoma who underwent tumor resection via the expanded endoscopic endonasal approach (EEA). Given the proximity of the lesion to the abducens nerve, lower cranial nerves, and brainstem, intraoperative neu romonitoring (IONM) consisting of electromyography (EMG), motor-evoked potential (MEP) and somatosensory-evoked potential (SSEP) monitoring were utilized. As such, a propofol-remifentanil total intravenous anesthetic (TIVA) was used. To our knowledge, this is the first report detailing the anesthetic management of a pediatric patient undergoing a clival tumor resection via EEA. [ABSTRACT FROM AUTHOR]

Regional analgesia is an excellent alternative for patients who may have contraindications to intravenous narcotics for perioperative analgesia. The transversus (TAP) block is a peripheral nerve block which can provide sustained abdominal wall analgesia for lower and middle abdominal surgery and offers an alternative to parenteral opioids in these situations. We report a patient with spastic quadriplegia who presented for a baclofen pump revision surgery and had a history of suspected intravenous narcotic allergies. A TAP block was used to provide postoperative analgesia. Its application in such clinical scenarios is discussed. [ABSTRACT FROM AUTHOR]

Introduction: Craniosynostosis is the premature fusion of 1 or more cranial sutures. The presentation may vary, and there are differing opinions regarding surgical indications and timing. Though increased intracranial pressure (ICP) is a well-established risk of craniosynostosis, its response to treatment is not uniform. This study aims to identify the signs and symptoms indicative of increased ICP that are most likely to improve after craniosynostosis surgery., Methods: Pre- and post-operative data were retrospectively collected from patients at our institution with syndromic and non-syndromic craniosynostosis from January 2009 to June 2020. Demographics, symptoms (headache, nausea, emesis, and lethargy), signs (visual disturbances and papilledema), and imaging characteristics (copper beaten changes), if available, were analyzed., Results: One hundred fifty-three children with craniosynostosis were identified, and 56 with preoperative symptoms met inclusion criteria. Older age was significantly correlated with the number of symptoms improved postoperatively ( P = 0.015). Papilledema, headache, nausea, and irritability (if present preoperatively) were the features most likely to improve after craniosynostosis repair. Optic nerve or disc anomalies, feeding difficulties, seizures, and need for glasses were least likely to improve., Conclusions: Older children undergoing craniosynostosis surgery had a greater number of improved symptoms. Classical features of increased ICP were more likely to improve than developmental difficulties and multifactorial causes. These findings may be useful when considering craniosynostosis repair in a symptomatic child., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by Mutaz B. Habal, MD.)

Background: Asthma is a heterogeneous and complex disease in both its clinical course and response to treatment. IL-13 is central to Type 2 inflammation and contributes to many features of asthma. In a previous Phase 2 study, lebrikizumab, an anti-IL-13 monoclonal antibody, did not significantly improve FEV 1 in mild-to-moderate asthma patients not receiving ICS therapy. This Phase 3 study was designed to further assess the efficacy and safety of lebrikizumab in adult patients with mild-to-moderate asthma treated with daily short-acting β 2 -agonist therapy alone., Methods: Adult patients with mild-to-moderate asthma were randomised to receive lebrikizumab 125 mg subcutaneously (SC), placebo SC, or montelukast 10 mg orally for 12 weeks, with an 8-week follow-up period. The primary efficacy endpoint was absolute change in pre-bronchodilator FEV 1 from baseline at Week 12., Findings: A total of 310 patients were randomised and dosed in the study. The mean absolute change in FEV 1 from baseline at Week 12 was higher in the lebrikizumab-treated arm compared with placebo (150 mL versus 67 mL); however, this improvement did not achieve statistical significance (overall adjusted difference of 83 mL [95% CI: -3, 170]; p = .06). Montelukast did not improve FEV 1 as compared with placebo. Lebrikizumab was generally safe and well tolerated during the study., Interpretation: Lebrikizumab did not significantly improve FEV 1 in mild-to-moderate asthma patients at a dose expected to inhibit the IL-13 pathway. Inhibiting IL-13 in this patient population was not sufficient to improve lung function. These data support the findings of a previous trial of lebrikizumab in patients not receiving ICS., Clinical Trials Registry Number: This trial was registered under NCT02104674 at http://www.clinicaltrials.gov., (Copyright © 2017. Published by Elsevier Ltd.)

Background: Ventriculoperitoneal (VP) shunt placement, the mainstay of treatment for hydrocephalus, can place a substantial burden on patients and health care systems because of high complication and revision rates. We aimed to identify factors associated with 30-day VP shunt failure in children undergoing either initial placement or revision., Methods: VP shunt placements performed on patients in the 2012-2013 American College of Surgeons National Surgical Quality Improvement Program (NSQIP) Pediatric were identified., Results: VP shunts were placed in 3,984 patients either as an initial placement (n = 1,093) or as a revision (n = 2,891). Compared to the initial-placement group, the revision group was significantly more likely to experience shunt failure (14 vs. 8%, p < 0.0001). In the initial-placement group, congenital hydrocephalus was independently associated with shunt failure (OR 1.83; 95% CI 1.01-3.31, p = 0.047). In the revision group, cardiac risk factors (OR 1.38; 95% CI 1.00-1.90, p = 0.047), a chronic history of seizures (OR 1.33; 95% CI 1.04-1.71, p = 0.022), and a history of neuromuscular disease (OR 0.61; 95% CI 0.41-0.90, p = 0.014) were independently associated with shunt failure., Conclusions: Identifying the factors associated with VP shunt failure may allow the development of interventions to decrease failures. Further refinement of the collected variables in the NSQIP Pediatric specific to neurosurgical procedures is necessary to identify modifiable risk factors., (© 2016 S. Karger AG, Basel.)

Background: Emergency department visits and subsequent hospitalizations of young children after unsupervised ingestions of prescription medications are increasing despite widespread use of child-resistant packaging and caregiver education efforts. Data on the medications implicated in ingestions are limited but could help identify prevention priorities and intervention strategies., Methods: We used nationally representative adverse drug event data from the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance project and national retail pharmacy prescription data from IMS Health to estimate the frequency and rates of emergency hospitalizations for unsupervised prescription medication ingestions by young children (2007-2011)., Results: On the basis of 1513 surveillance cases, 9490 estimated emergency hospitalizations (95% confidence interval: 6420-12,560) occurred annually in the United States for unsupervised prescription medication ingestions among children aged <6 years from 2007 through 2011; 75.4% involved 1- or 2-year old children. Opioids (17.6%) and benzodiazepines (10.1%) were the most commonly implicated medication classes. The most commonly implicated active ingredients were buprenorphine (7.7%) and clonidine (7.4%). The top 12 active ingredients, alone or in combination with others, were implicated in nearly half (45.0%) of hospitalizations. Accounting for the number of unique patients who received dispensed prescriptions, the hospitalization rate for unsupervised ingestion of buprenorphine products was significantly higher than rates for all other commonly implicated medications and 97-fold higher than the rate for oxycodone products (200.1 vs 2.1 hospitalizations per 100,000 unique patients)., Conclusions: Focusing unsupervised ingestion prevention efforts on medications with the highest hospitalization rates may efficiently achieve large public health impact., (Copyright © 2014 by the American Academy of Pediatrics.)

Objective: To describe trends in outpatient prescription drug utilization in US children and the changes in major areas of pediatric therapeutic use for the years 2002 through 2010., Methods: Large prescription databases (the IMS Vector One: National and Total Patient Tracker) were used to examine national drug utilization patterns for the US pediatric population (ages 0-17 years) from 2002 through 2010., Results: In 2010, a total of 263.6 million prescriptions were dispensed to the US pediatric population, 7% lower than in 2002, while prescriptions dispensed to the adult population increased 22% during the same time. Analysis of pediatric drug utilization trends for the top 12 therapeutic areas in 2010 compared with 2002 showed decreases in systemic antibiotics (-14%), allergies (-61%), pain (-14%), depression (-5%), and cough/cold without expectorant (-42%) prescriptions, whereas asthma (14%), attention-deficit/hyperactivity disorder (46%), and contraceptive (93%) prescriptions increased. In 2010, amoxicillin was the most frequently dispensed prescription in infants (aged 0-23 months) and children (aged 2-11 years). Methylphenidate was the top prescription dispensed to adolescents (aged 12-17 years). Off-label use was identified, particularly for lansoprazole; ~358,000 prescriptions were dispensed in 2010 for infants <1 year old., Conclusions: Changes in the patterns of pediatric drug utilization were observed from 2002 to 2010. Changes include a decrease in antibiotic use and an increase in attention-deficit/hyperactivity disorder medication use during the examined time. This article provides an overview of pediatric outpatient drug utilization, which could set the stage for further in-depth analyses.

Background: Despite abundant published support of patch angioplasty during carotid endarterectomy (CEA), primary closure is still widely used. The reasons underlying the persistence of primary closure are not quite evident in the literature., Objective: To present our experience with primary closure in CEA, and provide a rationale for its persistent wide use., Methods: Medical records of all patients undergoing CEA by the senior author (R.F.) were retrospectively reviewed. Follow-up was supplemented with a telephone interview and completion of a structured questionnaire. A review of the current literature was performed., Results: From 1998 to 2010, the senior author performed 111 CEAs. Average cross-clamp time was 33 ± 11 minutes. Postoperative complications included 1 non-ST-elevation myocardial infarction and 2 strokes. No deaths, cranial-nerve deficits, or acute reocclusions were observed. After a mean follow-up of 64.6 months (7170.6 case-months), there were 3 contralateral strokes and 7 deaths. There were no ipsilateral strokes or restenoses >50%. Follow-up medication compliance was 94.6% for antiplatelet agents and 91.9% for statins. The outcomes of the current study were comparable to those of the available trials comparing patch angioplasty with primary closure. A careful evaluation of the literature revealed a number of reasons potentially explaining the persistent use of patch angioplasty., Conclusion: In conjunction with contemporary medical management, primary closure during CEA may yield results comparable or superior to patch angioplasty. Advantages of primary closure include shorter cross-clamp times and elimination of graft-specific complications.

Context: The thionamide antithyroid drugs methimazole and propylthiouracil are the mainstay of pharmacologic therapy for Graves' disease. However, little is known about the rate of use of these drugs and the prescribing practices of physicians treating hyperthyroidism., Objective: The objective of the study was to examine the frequency of methimazole and propylthiouracil use from years 1991 to 2008., Methods: The data were acquired by the U.S. Food and Drug Administration's Division of Epidemiology through two databases: IMS National Sales Perspectives and the Surveillance Data, Inc. Vector One: National database., Results: There was a 9-fold increase in the annual number of methimazole prescriptions during the study period, from 158,000 to 1.36 million per year. There was a 19% increase in the annual number of propylthiouracil prescriptions, from 348,000 to 415,000 per year. Propylthiouracil, which held two thirds of the market from 1991 to 1995, was surpassed by methimazole in 1996. Patient demographic data indicated that although 72% of methimazole prescriptions were for females, males were more likely to be on methimazole (82%) than females (74%) (P < 0.001, two tailed chi(2) test). The only demographic group in which methimazole use decreased was women of child-bearing age (5% decrease, P < 0.001, two tailed chi(2)). The incidence of hyperthyroidism in 2008 was estimated based on the number of new prescriptions of thionamides by age group and data from the 2008 U.S. census: 0.44 per 1000 for ages 0-11 yr, 0.26 per 1000 for ages 12-17 yr, 0.59 per 1000 for ages 18-44 yr, 0.78 per 1000 for ages 45-64 yr, and 1.01 per 1000 for ages 65+ yr., Conclusions: Methimazole has become the most frequently prescribed antithyroid drug. The remarkable increase in the total number of dispensed thionamide prescriptions over the last 18 yr may indicate a trend toward pharmacological treatment as primary treatment of Graves' disease in the United States.

Purpose: To determine if paroxetine versus non-paroxetine selective serotonin reuptake inhibitors (SSRIs) prescribing changed after the June 2003 FDA Paroxetine Public Health Advisory (PPHA) and if antidepressant and antipsychotic prescribing changed after the February 2004 FDA Advisory Committee Meeting (FDACM)., Methods: Ecologic analysis using estimates of patients dispensed antidepressants and antipsychotics, census data, and promotional spending data. Data sources were SDI: Vector One(R), US Census, and IMS Health(R). Measures were monthly use levels (number of patients dispensed antidepressants, antipsychotics, paroxetine, and non-paroxetine SSRIs prescriptions by age group per population count). Percent changes pre- to post-PPHA were used to assess changes in paroxetine versus non-paroxetine SSRIs prescribing. Interrupted time series (ITS) analysis was performed to examine use level changes post-FDACM by drug groups (all antidepressants and all antipsychotics)., Results: Post-PPHA mean paroxetine use levels decreased for all age groups (range: 5.5-34.1%). Mean non-paroxetine SSRIs use levels increased (range: 4.6-17.1%). Post-PPHA changes were greatest for 6-12 and 13-17 year olds. Decreased mean antidepressant drug use levels from pre- to post-FDACM were observed in all groups under 25 years old. A statistically significant decrease in the slopes from pre- to post-FDACM was observed for persons aged 13-17 and 18-24 years. The difference between the forecasted mean use level and the observed mean use level (in 12-month intervals) was statistically significant for all ages combined (-107.26; 95% CI: -166.32, -48.20) and 1-5 (-3.1; 95% CI: -4.62, -1.58), 6-12 (-36.02; 95% CI: -62.92, -9.12) and 25 years, and older groups (-83.17; 95% CI: -153.95, -12.39). For all age groups, decreases in the slopes of antipsychotic drugs use from pre- to post-FDACM were observed, although these slope changes were not statistically significant. The difference between the forecasted mean antipsychotic drugs use level and the observed mean use level (in 12-month intervals) was statistically significantly lower for all age groups., Conclusions: Antidepressant use changed post-PPHA and -FDACM, with a differential pattern by age. There was no evidence of increased antipsychotic use post-FDACM. Ecologic data cannot determine if changes were due to depression not treated with medications or the prescribing of fewer antidepressants for other conditions.

Background: The first clinical practice guidelines for management of atrial fibrillation (AF) were published in 2001. We explored the use of anticoagulants, rate-controlling drugs, and antiarrhythmic drugs in patients with AF during the 4 years surrounding publication of these guidelines., Methods: Mentions of warfarin, beta-blockers, digoxin, diltiazem, verapamil, and all class I and class III antiarrhythmic drugs made by US office-based physicians during patient visits for AF between October 1999 and September 2003 were evaluated using the IMS Health National Disease and Therapeutic Index (Plymouth Meeting, PA). Medication use by patient age, sex, and physician specialty was explored. Trends in use during the study period were estimated., Results: Warfarin was mentioned in an average of 37% of all AF-related visits across the observation period, with no statistically significant change over time. Digoxin was the most commonly mentioned rate-controlling drug in 23% of patient visits, followed by beta-blockers in 11% and calcium-channel blockers in 8%. Over the study period, mentions of digoxin significantly decreased, and mentions of beta-blockers significantly increased. Mentions of antiarrhythmic drugs were reported in an average of 12% of patient visits, with no significant change over the study period., Conclusions: Observed trends in use of digoxin, beta-blockers, and class Ia antiarrhythmic drugs were consistent with evidence-based recommendations. However, only approximately one third of patient visits for AF included mentions of warfarin, even among patients aged > or = 60 years. These results indicate the need for continued education and interventions, especially regarding stroke prevention, in patients with AF.

Purpose: To assess changes in isotretinoin prescribing following the implementation of the System to Manage Accutane Related Teratogenicity (SMART) risk management program., Methods: Using nationally representative commercial data resources on prescription drug dispensing patterns, surveys of office-based physician practices, and a large, claims database from a pharmacy benefits manager (PBM), we examined the total number of isotretinoin prescriptions (new and refill), prescriber speciality, and patient characteristics (age, gender, severity of acne indication) in the year before (April 2001-March 2002) and the year following (April 2002-March 2003) implementation of the SMART program., Results: In the 12-months prior to SMART, 1 508 000 prescriptions were dispensed for isotretinoin, declining approximately 23% to 1 160 000 prescriptions in the year following SMART. There was little or no change in prescriber specialty, severity of acne, and patient age and gender., Conclusion: SMART may have lead to a decrease in isotretinoin prescriptions. Further research is needed to determine whether the reduced number of isotretinoin prescriptions reflects appropriate use or inhibited use resulting in loss of access to the product's benefits., ((c) 2005 John Wiley & Sons, Ltd.)

Background: Stevens-Johnson syndrome and toxic epidermal necrolysis are closely related severe acute life-threatening, drug-induced skin disorders. The US FDA Adverse Events Reporting System (AERS) has received reports of Stevens-Johnson syndrome and toxic epidermal necrolysis associated with the use of the recently introduced selective cyclo-oxygenase (COX)-2 inhibitor NSAIDs, two of which are also sulfonamides., Objective: The objective of this study is to review cases of Stevens-Johnson syndrome and toxic epidermal necrolysis reported to the FDA associated with the use of the selective COX-2 inhibitor NSAIDs celecoxib, rofecoxib and valdecoxib, and to compare reporting rates of the two conditions associated with these drugs to each other, meloxicam (an oxicam NSAID that came on the US market at a similar time) and the background incidence rate., Methods: We reviewed all US cases of Stevens-Johnson syndrome and toxic epidermal necrolysis reported to the FDA AERS database associated with the use of celecoxib, rofecoxib, valdecoxib and meloxicam since these agents were first marketed. We utilised AERS and drug use data to calculate reporting rates for each drug after the first 2 years of marketing. We obtained the background rate from the medical literature., Results: Up to the end of March 2004, there were 63 cases of Stevens-Johnson syndrome/toxic epidermal necrolysis reported with valdecoxib use, 43 with celecoxib, 17 with rofecoxib (the non-sulfonamide coxib) and none for meloxicam. In the first 2 years of marketing the reporting rate for Stevens-Johnson syndrome/toxic epidermal necrolysis with valdecoxib was 49 cases per million person-years of use, 6 cases per million person-years for celecoxib and 3 cases per million person-years for rofecoxib. The reporting rates for the sulfonamide coxibs were substantially higher than the background rate of 1.9 cases per million population per year, with the valdecoxib rate being 8-9 times that of celecoxib and approximately 25 times that of the background rate., Conclusion: There is a strong association between Stevens-Johnson syndrome/toxic epidermal necrolysis and the use of the sulfonamide COX-2 inhibitors, particularly valdecoxib. Physicians should be aware of the possibility of this serious life-threatening event when prescribing these drugs and advise patients to discontinue use at the earliest possible sign or symptom.

Objective: To describe the use of oral antidiabetic drugs for management of type 2 diabetes in the U.S. from 1990 through 2001., Research Design and Methods: Data on oral antidiabetic drugs were derived from two pharmaceutical marketing databases from IMS Health, the National Prescription Audit Plus and the National Disease and Therapeutic Index., Results: In 1990, 23.4 million outpatient prescriptions of oral antidiabetic agents were dispensed. By 2001, this number had increased 3.9-fold, to 91.8 million prescriptions. Glipizide and glyburide, two sulfonylurea medications, accounted for approximately 77% of prescriptions of oral antidiabetic drugs in 1990 and 35.5% of prescriptions in 2001. By 2001, the biguanide metformin (approved in 1995) had captured approximately 33% of prescriptions, and the thiazolidinedione insulin sensitizers (rosiglitazone and pioglitazone marketed beginning in 1999) accounted for approximately 17% of market share. Compared with patients treated in 1990, those in 2001 were proportionately younger and they more often used oral antidiabetic drugs and insulin in combination. Internists and general and family practitioners were the primary prescribers of this class of drugs., Conclusions: Consistent with the reported increase in the prevalence of type 2 diabetes, the number of dispensed outpatient prescriptions of oral antidiabetic drugs increased rapidly between 1990 and 2001. This period was marked by an increase in the treatment of younger people and the use of oral antidiabetic drugs in combination. With the approval in the last decade of several new types of oral antidiabetic medications with different mechanisms of action, options for management of type 2 diabetes have expanded.

Meningioma has been included in the constellation of tumors associated with von Hippel-Lindau (VHL) disease in previously published reports. It is unclear whether these tumors are an uncommon component of VHL disease or are more readily detected in these patients because of the frequency with which they undergo central nervous system imaging as part of the routine management of VHL disease. The authors report the case of a patient with VHL disease in whom a progressively enlarging supratentorial mass developed and was diagnosed as a hemangioblastoma because of its appearance on serial magnetic resonance images. At surgery the tumor displayed the typical features of a meningioma and was given the histological diagnosis of fibrous meningioma. Single-stranded conformational polymorphism analysis of the tumor DNA revealed a loss of heterozygosity at the neurofibromatosis Type 2 gene locus, known to be associated with sporadically occurring meningiomas. Despite this finding, the VHL gene locus on the allele from the patient's unaffected parent was normal. Thus it is unlikely that the occurrence of this patient's fibrous meningioma was associated with underlying VHL disease. Given the high frequency of neuroimaging sessions in patients with VHL disease, some supratentorial lesions that have been given radiological diagnoses of hemangioblastomas may be incidental meningiomas.

Endolymphatic sac tumors (ELSTs) occur sporadically or in association with an autosomal dominantly inherited tumor syndrome, von Hippel-Lindau (VHL) disease. In VHL disease, a germline mutation of the VHL tumor suppressor gene is inherited, and loss of function of the wild-type allele occurs through genetic deletion with subsequent development of neoplastic growth. Genetic alterations associated with sporadic ELSTs are less well understood. In this study, we used tissue microdissection to selectively analyze neoplastic cells from four sporadic ELSTs. In two cases, we detected somatic mutations involving VHL gene exons 1 and 2, respectively. Additionally, one of these cases revealed deletion of the VHL gene locus. Two cases did not reveal VHL gene mutation; one of these two cases showed VHL gene deletion. These results suggest that mutations and allelic deletions of the VHL tumor suppressor gene play a role in the tumorigenesis of sporadic ELSTs.

Object: Although recent studies have shown that convection can be used to distribute macromolecules within the central nervous system (CNS) in a homogeneous, targeted fashion over clinically significant volumes and that the volume of infusion and target location (gray as opposed to white matter) influence distribution, little is known about other factors that may influence optimum use of convection-enhanced distribution. To understand the variables that affect convective delivery more fully, we examined the rate of infusion, delivery cannula size, concentration of infusate, and preinfusion sealing time., Methods: The authors used convection to deliver 4 microl of 14C-albumin to the striatum of 40 rats. The effect of the rate of infusion (0.1, 0.5, 1, and 5 microl/minute), cannula size (32, 28, and 22 gauge), concentration of infusate (100%, 50%, and 25%), and preinfusion sealing time (0 and 70 minutes) on convective delivery was examined using quantitative autoradiography, National Institutes of Health image analysis software, scintillation analysis, and histological analysis. Higher rates of infusion (1 and 5 microl/minute) caused significantly (p < 0.05) more leakback of infusate (22.7+/-11.7% and 30.3+/-7.8% [mean+/-standard deviation], respectively) compared with lower rates (0.1 microl/minute [4+/-3.6%] and 0.5 microl/minute [5.2+/-3.6%]). Recovery of infusate was significantly (p < 0.05) higher at the infusion rate of 0.1 microl/minute (95.1+/-2.8%) compared with higher rates (85.2+/-4%). The use of large cannulae (28 and 22 gauge) produced significantly (p < 0.05) more leakback (35.7+/-8.1% and 21.1+/-7.5%, respectively) than the smaller cannula (32 gauge [5.2+/-3.6%]). Varying the concentration of the infusate and the preinfusion sealing time did not alter the volume of distribution, regional distribution, or infusate recovery., Conclusions: Rate of infusion and cannula size can significantly affect convective distribution of molecules, whereas preinfusion sealing time and variations in infusate concentration have no effect in this small animal model. Understanding the parameters that influence convective delivery within the CNS can be used to enhance delivery of potentially therapeutic agents in an experimental setting and to indicate the variables that will need to be considered for optimum use of this approach for drug delivery in the clinical setting.

Object: Although many macromolecules have treatment potential for peripheral nerve disease, clinical use of these agents has been restricted because of limitations of delivery including systemic toxicity, heterogeneous dispersion, and inadequate distribution. In an effort to overcome these obstacles, the authors examined the use of convection to deliver and distribute macromolecules into peripheral nerves., Methods: For convective delivery, the authors used a gas-tight, noncompliant system that provided continuous flow through a small silica cannula (inner diameter 100 microm, outer diameter 170 microm) inserted into a peripheral nerve. Increases in the volume of infusion (Vi) (10, 20, 30, 40, and 80 microl) of 14C-labeled (nine nerves) or gadolinium-labeled (two nerves) albumin were infused unilaterally or bilaterally into the tibial nerves of six primates (Macaca mulatta) at 0.5 microl/minute. The volume of distribution (Vd), percentage recovery, and delivery homogeneity were determined using quantitative autoradiography, an imaging program developed by the National Institutes of Health, magnetic resonance (MR) imaging, scintillation counting, and kurtosis (K) analysis. One animal that was infused bilaterally with gadolinium-bound albumin (40 microl to each nerve) underwent MR imaging and was observed for 16 weeks after infusion. The Vd increased with the Vi in a logarithmic fashion. The mean Vd/Vi ratio over all Vi was 3.7+/-0.8 (mean+/-standard deviation). The concentration across the perfused region was homogeneous (K=-1.07). The infusate, which was limited circumferentially by the epineurium, followed the parallel arrangement of axonal fibers and filled long segments of nerve (up to 6.8 cm). Recovery of radioactivity was 75.8+/-9%. No neurological deficits arose from infusion., Conclusions: Convective delivery of macromolecules to peripheral nerves is safe and reliable. It overcomes obstacles associated with current delivery methods and allows selective regional delivery of putative therapeutic agents to long sections of nerve. This technique should permit the development of new treatments for numerous types of peripheral nerve lesions.