Publications by authors named "John Slevin"

59 Publications

Gait and Balance Changes with Investigational Peripheral Nerve Cell Therapy during Deep Brain Stimulation in People with Parkinson's Disease.

Brain Sci 2021 Apr 15;11(4). Epub 2021 Apr 15.

Brain Restoration Center, University of Kentucky, Lexington, KY 40536, USA.

Background: The efficacy of deep brain stimulation (DBS) and dopaminergic therapy is known to decrease over time. Hence, a new investigational approach combines implanting autologous injury-activated peripheral nerve grafts (APNG) at the time of bilateral DBS surgery to the globus pallidus interna.

Objectives: In a study where APNG was unilaterally implanted into the substantia nigra, we explored the effects on clinical gait and balance assessments over two years in 14 individuals with Parkinson's disease.

Methods: Computerized gait and balance evaluations were performed without medication, and stimulation was in the off state for at least 12 h to best assess the role of APNG implantation alone. We hypothesized that APNG might improve gait and balance deficits associated with PD.

Results: While people with a degenerative movement disorder typically worsen with time, none of the gait parameters significantly changed across visits in this 24 month study. The postural stability item in the UPDRS did not worsen from baseline to the 24-month follow-up. However, we measured gait and balance improvements in the two most affected individuals, who had moderate PD. In these two individuals, we observed an increase in gait velocity and step length that persisted over 6 and 24 months.

Conclusions: Participants did not show worsening of gait and balance performance in the off therapy state two years after surgery, while the two most severely affected participants showed improved performance. Further studies may better address the long-term maintanenace of these results.
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http://dx.doi.org/10.3390/brainsci11040500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071359PMC
April 2021

Ultrasound-Guided Biceps Tendon Sheath Injections Frequently Extravasate Into the Glenohumeral Joint.

Arthroscopy 2021 06 13;37(6):1711-1716. Epub 2021 Jan 13.

Madigan Army Medical Center, Joint Base Lewis-McChord, Washington, U.S.A.

Purpose: To evaluate the frequency of glenohumeral joint extravasation of ultrasound (US)-guided biceps tendon sheath injections.

Methods: Fifty shoulders with a clinical diagnosis of bicipital tenosynovitis pain received a US-guided biceps sheath injection with anesthetic, steroid, and contrast (5.0 mL mixture) followed immediately by orthogonal radiographs to localize the anatomic distribution of the injection. Radiographic evaluation of contrast localization was determined and interobserver reliability calculated.

Results: All 50 postinjection radiographs (100%) demonstrated contrast within the biceps tendon sheath. In addition, 30 of 50 (60%) radiographs also revealed contrast in the glenohumeral joint. Interobserver reliability for determination of intraarticular contrast was good (kappa value 0.87).

Conclusions: US-guided bicipital sheath injections reproducibly result in intrasheath placement of injection fluid. Bicipital sheath injections performed with 5 mL of volume result in partial extravasation into the joint 60% of the time. These data may be useful for surgeons who use the results of diagnostic biceps injections for diagnosis and surgical decision-making.

Level Of Evidence: III, prospective cohort study, diagnosis.
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http://dx.doi.org/10.1016/j.arthro.2020.12.238DOI Listing
June 2021

Encephalopathy and Complex Hyperkinesia in a Patient with Severe Acute Respiratory Syndrome Coronavirus-2 Infection.

J Mov Disord 2021 May 12;14(2):173-175. Epub 2021 Jan 12.

Department of Neurology, Kentucky Neuroscience Institute, University of Kentucky Chandler Medical Center, Lexington, KY, USA.

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http://dx.doi.org/10.14802/jmd.20084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175807PMC
May 2021

GDNF clinical trials for Parkinson's disease: a critical human dimension.

Cell Tissue Res 2020 10 24;382(1):65-70. Epub 2020 Aug 24.

Department of Neurology, Chandler Medical Center, University of Kentucky, Lexington, KY, USA.

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http://dx.doi.org/10.1007/s00441-020-03269-8DOI Listing
October 2020

Pregnancy outcomes in women with onset of type 1 diabetes mellitus less than 18 years of age.

BMJ Open Diabetes Res Care 2020 04;8(1)

Department of Paediatrics, University Hospital Limerick, Dooradoyle, Limerick, Ireland.

Background: Pregnancy in women with type 1 diabetes mellitus (T1DM) is associated with an increased risk of congenital malformations, obstetric complications and neonatal morbidity. This study aims to investigate maternal, perinatal and neonatal outcomes of pregnancies in women with onset of T1DM less than 18 years of age.

Methods: This retrospective cohort study extracted data regarding prenatal, intrapartum and postnatal outcomes of pregnancies in women with onset of T1DM<18 years identified from the diabetes in pregnancy register at University Maternity Hospital Limerick, treated from July 1, 2007 to July 1, 2017.

Results: Seventeen women with onset of T1DM <18 years gave birth to 23 live infants during the period studied. 73.9% of pregnancies were unplanned. Only 21.7% of pregnancies took preconceptual folic acid. 60.9% of infants required treatment for hypoglycemia.

Conclusion: The high prevalence of unplanned pregnancy and poor uptake of prepregnancy care must be improved on in order to improve outcomes for this high-risk group.
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http://dx.doi.org/10.1136/bmjdrc-2019-001080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213751PMC
April 2020

Pearls & Oy-sters: Progressive ataxia and palatal tremor: Imaging and disease course.

Neurology 2020 03 27;94(13):e1445-e1447. Epub 2020 Feb 27.

From the Departments of Neurology (S.P., P.G., S.J., F.D.R., J.T.S.) and Radiology (F.D.R.), University of Kentucky; and VA Medical Center (J.T.S.), Lexington, KY.

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http://dx.doi.org/10.1212/WNL.0000000000009178DOI Listing
March 2020

Modulation of epileptogenesis: A paradigm for the integration of enzyme-based microelectrode arrays and optogenetics.

Epilepsy Res 2020 01 26;159:106244. Epub 2019 Nov 26.

Epilepsy Center, University of Kentucky, Lexington, KY, 40536, United States; Department of Neurology, College of Medicine, University of Kentucky, Lexington, KY, 40536, United States; Veterans Affairs Medical Center, Lexington, KY, 40536, United States; Brain Restoration Center, University of Kentucky, Lexington, KY, 40356, United States. Electronic address:

Background: Genesis of acquired epilepsy includes transformations spanning genetic-to- network-level modifications, disrupting the regional excitatory/inhibitory balance. Methodology concurrently tracking changes at multiple levels is lacking. Here, viral vectors are used to differentially express two opsin proteins in neuronal populations within dentate gyrus (DG) of hippocampus. When activated, these opsins induced excitatory or inhibitory neural output that differentially affected neural networks and epileptogenesis. In vivo measures included behavioral observation coupled to real-time measures of regional glutamate flux using ceramic-based amperometric microelectrode arrays (MEAs).

Results: Using MEA technology, phasic increases of extracellular glutamate were recorded immediately upon application of blue light/488 nm to DG of rats previously transfected with an AAV 2/5 vector containing an (excitatory) channelrhodopsin-2 transcript. Rats receiving twice-daily 30-sec light stimulation to DG ipsilateral to viral transfection progressed through Racine seizure stages. AAV 2/5 (inhibitory) halorhodopsin-transfected rats receiving concomitant amygdalar kindling and DG light stimuli were kindled significantly more slowly than non-stimulated controls. In in vitro slice preparations, both excitatory and inhibitory responses were independently evoked in dentate granule cells during appropriate light stimulation. Latency to response and sensitivity of responses suggest a degree of neuron subtype-selective functional expression of the transcripts.

Conclusions: This study demonstrates the potential for coupling MEA technology and optogenetics for real-time neurotransmitter release measures and modification of seizure susceptibility in animal models of epileptogenesis. This microelectrode/optogenetic technology could prove useful for characterization of network and system level dysfunction in diseases involving imbalanced excitatory/inhibitory control of neuron populations and guide development of future treatment strategies.
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http://dx.doi.org/10.1016/j.eplepsyres.2019.106244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7451242PMC
January 2020

Investigating the role of early low-dose aspirin in diabetes: A phase III multicentre double-blinded placebo-controlled randomised trial of aspirin therapy initiated in the first trimester of diabetes pregnancy.

Contemp Clin Trials Commun 2019 Dec 15;16:100465. Epub 2019 Oct 15.

Our Lady of Lourdes Hospital, Drogheda, Ireland.

Background: Preeclampsia, preterm birth and low birth weight represent key contributing factors to perinatal morbidity and mortality. Pregnancies complicated by type 1 and type 2 diabetes are at increased risk of these complications, which are purported to be largely attributed to placental dysfunction. Studies investigating a potential role for aspirin therapy in optimizing perinatal outcome have consistently failed to demonstrate a benefit among women with pre-existing diabetes, and yet widespread aspirin administration has become common practice in many centres. This study seeks to examine the effect of aspirin therapy, administered from the first trimester until 36 weeks gestation, on perinatal outcome in women with established pre-pregnancy diabetes. Our hypothesis is that aspirin therapy will reduce complications mediated by placental dysfunction, and improve perinatal outcomes.

Methods: This phase III double-blinded, placebo-controlled randomized clinical trial will be conducted in seven tertiary-level perinatology centres in Ireland. Consenting participants who meet all eligibility criteria will be allocated randomly to either aspirin 150 mg once daily or matching placebo, commenced between 11 + 0 and 13 + 6 weeks. Allocation will take place electronically using software by Clininfo with randomization tables provided by the trial biostatistician. The primary outcome will be a composite clinical measure of placental dysfunction (preeclampsia, preterm birth before 34 weeks, birthweight below the 10th centile or perinatal mortality). This trial has been set up such that it is parallel in design and is a superiority study. No participants have been recruited yet. The trial has been registered with Eudra Clinical Trials - EudraCT Number 2018-000770-29. Funding for this trial was granted by the Health research Board (HRB) 1/9/2017(DIFA-2017-026).

Discussion: Aspirin therapy has been investigated for the prevention of preeclampsia owing to its reduction on thromboxane production. Previous studies have failed to demonstrate a beneficial effect of aspirin on perinatal outcome amongst women with type I or type II diabetes. It is plausible that the failure to observe benefit to date, among the limited aspirin studies that have included participants with diabetes, may be a consequence of aspirin initiation too late in pregnancy to exert any effect on placentation. We believe that if aspirin is to be used for the prevention of placental dysfunction, it must be initiated before the second active phase of trophoblast invasion, which takes place from 14 weeks' gestation onwards. No randomized trials investigating the role of aspirin in prevention of preeclampsia in pregnancies complicated by diabetes have previously initiated treatment in the first trimester, the gestational period at which it is most likely to exert an effect on placentation.
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http://dx.doi.org/10.1016/j.conctc.2019.100465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831706PMC
December 2019

Drug treatment strategies for depression in Parkinson disease.

Expert Opin Pharmacother 2019 08 23;20(11):1351-1363. Epub 2019 May 23.

c Departments of Neurology and Pharmacology and Nutritional Sciences , University of Kentucky College of Medicine , Lexington , KY , USA.

Introduction: Depression is a common non-motor symptom in Parkinson disease (PD), occurring in approximately 20% of patients with PD. While depression can occur anytime in the disease process, it predates PD diagnosis in about 30% of patients. Between 20% and 60% of depressed patients with PD are either without recognition or treatment of their depression.

Areas Covered: The pathophysiology of depression in PD is unclear. There are several structural changes seen in depressed patients with PD that are also seen in patients with depression. In addition, the neurotransmitters dopamine, serotonin, and norepinephrine are all depleted in PD. This article covers the pharmacological treatment of depression in PD; this involves standard antidepressant treatment such as selective serotonin reuptake inhibitors, tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors, and monoamine oxidase inhibitors. As with depression not associated with PD, most treatment is partially successful. Non-pharmacological approaches are also touched upon.

Expert Opinion: Most antidepressant therapy shows partial efficacy in patients with PD. However, there is a need for better study design as well as more comparative studies for the treatment of depression in PD. Biomarkers will help identify patients with PD and depression earlier in the future.
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http://dx.doi.org/10.1080/14656566.2019.1612877DOI Listing
August 2019

Martial arts technique for control of severe external bleeding.

Emerg Med J 2019 Mar 5;36(3):154-158. Epub 2019 Jan 5.

Department of Bioengineering, University of Washington, Seattle, Washington, USA.

Objectives: Haemorrhage control is a critical component of preventing traumatic death. Other than the battlefield, haemostatic devices, such as tourniquets or bandages, may not be available, allowing for significant avoidable blood loss. We hypothesised that compression of vascular pressure points using a position adapted from the martial art of Brazilian Jiu-Jitsu could be adapted to decrease blood flow velocity in major extremity arteries.

Methods: Knee mount compression was applied to the shoulder, groin and abdomen of healthy adult volunteer research subjects from Seattle, Washington, USA, from March through May 2018. Mean arterial blood flow velocity (MAV) was measured using ultrasound in the brachial and femoral arteries before and after compression. A MAV decrease greater than 20% with compression was deemed clinically relevant.

Results: For 11 subjects, median (IQR) MAV combining all anatomical locations tested was 29.2 (34.1, 24.1) cm/s at baseline and decreased to 3.3 (0, 19.1) cm/s during compression (Wilcoxon p<0.001). MAV was significantly decreased during compression for each individual anatomical position tested (Wilcoxon p≤0.004). Per cent (95% CI) MAV reduction was significantly greater than 20% for shoulder compression at 97.5%(94% to 100%) and groin compression at 78%(56% to 100%), but was not statistically greater for abdominal compression at 35%(12% to 57%). Complete vessel occlusion was most common with compression at the shoulder (73%), followed by groin (55%) and abdomen (9%) (χ² LR, p=0.018).

Conclusion: The Brazilian Jiu-Jitsu knee mount position can significantly decrease blood flow in major arteries of the extremities. This technique may be useful for bleeding control after injury.
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http://dx.doi.org/10.1136/emermed-2018-207966DOI Listing
March 2019

The Effect of Telerehabilitation on Missed Appointment Rates.

Int J Telerehabil 2018 11;10(2):65-72. Epub 2018 Dec 11.

DEPARTMENT OF VETERANS AFFAIRS MEDICAL CENTER, LEXINGTON, KY, USA.

The purpose of this study was to examine the effect of telerehabilitation on missed appointment rates in a rehabilitation clinic. Clients fail to attend scheduled appointments for a variety of reasons. Unmet appointments represent a loss of financial support as well as diminished efficiency and capacity to provide services. Speech therapy utilizing multiple appointments is most difficult to maintain during a treatment regimen. This may cause individuals to miss appointments and therefore not achieve desired results. For this study, researchers utilized an intense speech therapy technique, the Lee Silverman Voice Treatment (LSVT®) to measure compliance with scheduled appointments. Participants were randomized to either in-person treatment or telerehabilitation treatment at a site distant from the speech-language pathologist. Participants in the telerehabilitation (TR) condition completed significantly more appointments than participants in the in-person (IP) condition. When comparing results of treatment for each condition, there were no significant differences in outcome whether treated in the IP or TR condition of the study for monologue and picture description tasks, which are closely associated with conversational speech. There was a difference in the reading task with participants demonstrating significantly better post treatment results in the IP condition. The reason for this disparity is unclear and warrants further study.
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http://dx.doi.org/10.5195/ijt.2018.6258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296798PMC
December 2018

Reversible manifestations of extraparenchymal neurocysticercosis.

Clin Case Rep 2018 Jul 22;6(7):1400-1401. Epub 2018 May 22.

Department of Neurology Hospital de Especialidades Eugenio Espejo Quito Ecuador.

Movement disorders are uncommon manifestations of neurocysticercosis. When present, most are secondary to parenchymal lesions in the basal ganglia. Rarely, movement disorders can occur in racemose/extraparenchymal neurocysticercosis, an aggressive variant frequently associated with cerebrospinal fluid outflow obstruction and hydrocephalus. Appropriate treatment can reverse neurological manifestations.
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http://dx.doi.org/10.1002/ccr3.1602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028409PMC
July 2018

Management of combined factor V and factor VIII deficiency in pregnancy.

J Obstet Gynaecol 2019 Feb 18;39(2):271-272. Epub 2018 Apr 18.

a National Coagulation Centre , St. James's Hospital , Dublin , Ireland.

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http://dx.doi.org/10.1080/01443615.2018.1448766DOI Listing
February 2019

Long-term safety and efficacy of levodopa-carbidopa intestinal gel in advanced Parkinson's disease.

Mov Disord 2018 Jul 23;33(6):928-936. Epub 2018 Mar 23.

University of Cincinnati Academic Health Center, Cincinnati, Ohio, USA.

Background: Levodopa-carbidopa intestinal gel (designated as carbidopa-levodopa enteral suspension in the United States) provides stable plasma levodopa concentrations and reduces motor fluctuations in advanced Parkinson's disease patients through continuous delivery of levodopa via percutaneous endoscopic gastrojejunostomy. We report long-term safety and efficacy outcomes from an open-label phase 3 treatment program.

Methods: PD patients (n = 262) who completed a 12-week double-blind study and its 52-week open-label extension or a separate 54-week open-label study were enrolled in this ongoing phase 3 open-label, multinational study (NCT00660673). Safety and efficacy assessments were collected every 6 months.

Results: Mean total duration of exposure to levodopa-carbidopa intestinal gel was 4.1 years (range, 1.2 to 6.9 years). The overall discontinuation rate was 34% (average annual discontinuation rate, 10%). Although most patients (94%) reported an adverse event, the rate of adverse events decreased over time; 53% experienced a serious adverse event. Of patients in this extension study, 54% required jejunal tube replacement during the study, and 37% required percutaneous endoscopic gastrostomy tube replacement. Most patients were on levodopa monotherapy. Patients maintained reductions in "off" time and increases in mean "on" time without dyskinesia from initial levodopa-carbidopa intestinal gel infusion to he study end point (P < 0.001; n = 81). Activities of daily living and quality-of-life assessments demonstrated significant improvements that persisted through the study.

Conclusions: This long-term study demonstrates sustained and clinically meaningful benefits from levodopa-carbidopa intestinal gel in advanced PD patients. Although adverse event rates decreased over time, vigilance is required for device-related complications and adverse events. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27338DOI Listing
July 2018

Peripheral nerve grafts implanted into the substantia nigra in patients with Parkinson's disease during deep brain stimulation surgery: 1-year follow-up study of safety, feasibility, and clinical outcome.

J Neurosurg 2018 12;129(6):1550-1561

1Brain Restoration Center and.

OBJECTIVECurrently, there is no treatment that slows or halts the progression of Parkinson's disease. Delivery of various neurotrophic factors to restore dopaminergic function has become a focus of study in an effort to fill this unmet need for patients with Parkinson's disease. Schwann cells provide a readily available source of such factors. This study presents a 12-month evaluation of safety and feasibility, as well as the clinical response, of implanting autologous peripheral nerve grafts into the substantia nigra of patients with Parkinson's disease at the time of deep brain stimulation (DBS) surgery.METHODSStandard DBS surgery targeting the subthalamic nucleus was performed in 8 study participants. After DBS lead implantation, a section of the sural nerve containing Schwann cells was harvested and unilaterally grafted to the substantia nigra. Adverse events were continually monitored. Baseline clinical data were obtained during standard preoperative evaluations. Clinical outcome data were obtained with postoperative clinical evaluations, neuropsychological testing, and MRI at 1 year after surgery.RESULTSAll 8 participants were implanted with DBS systems and grafts. Adverse event profiles were comparable to those of standard DBS surgery with the exception of 1 superficial infection at the sural nerve harvest site. Three participants also reported numbness in the distribution of the sural nerve distal to the harvest site. Motor scores on Unified Parkinson's Disease Rating Scale (UPDRS) part III while the participant was off therapy at 12 months improved from baseline (mean ± SD 25.1 ± 15.9 points at 12 months vs 32.5 ± 9.7 points at baseline). An analysis of the lateralized UPDRS scores also showed a greater overall reduction in scores on the side contralateral to the graft.CONCLUSIONSPeripheral nerve graft delivery to the substantia nigra at the time of DBS surgery is feasible and safe based on the results of this initial pilot study. Clinical outcome data from this phase I trial suggests that grafting may have some clinical benefit and certainly warrants further study to determine if this is an efficacious and neurorestorative therapy.Clinical trial registration no.: NCT01833364 (clinicaltrials.gov).
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http://dx.doi.org/10.3171/2017.8.JNS163222DOI Listing
December 2018

Arthroscopic Surgery or Physical Therapy for Patients With Femoroacetabular Impingement Syndrome: A Randomized Controlled Trial With 2-Year Follow-up.

Am J Sports Med 2018 05 14;46(6):1306-1314. Epub 2018 Feb 14.

Department of Orthopaedics, Madigan Army Medical Center, Joint Base Lewis-McChord, Washington, USA.

Background: Arthroscopic hip surgery has risen 18-fold in the past decade; however, there is a dearth of clinical trials comparing surgery with nonoperative management.

Purpose: To determine the comparative effectiveness of surgery and physical therapy for femoroacetabular impingement syndrome.

Study Design: Randomized controlled trial; Level of evidence, 1.

Methods: Patients were recruited from a large military hospital after referral to the orthopaedic surgery clinic and were eligible for surgery. Of 104 eligible patients, 80 elected to participate, and the majority were active-duty service members (91.3%). No patients withdrew because of adverse events. The authors randomly selected patients to undergo either arthroscopic hip surgery (surgery group) or physical therapy (rehabilitation group). Patients in the rehabilitation group began a 12-session supervised clinic program within 3 weeks, and patients in the surgery group were scheduled for the next available surgery at a mean of 4 months after enrollment. Patient-reported outcomes of pain, disability, and perception of improvement over a 2-year period were collected. The primary outcome was the Hip Outcome Score (HOS; range, 0-100 [lower scores indicating greater disability]; 2 subscales: activities of daily living and sport). Secondary measures included the International Hip Outcome Tool (iHOT-33), Global Rating of Change (GRC), and return to work at 2 years. The primary analysis was on patients within their original randomization group.

Results: Statistically significant improvements were seen in both groups on the HOS and iHOT-33, but the mean difference was not significant between the groups at 2 years (HOS activities of daily living, 3.8 [95% CI, -6.0 to 13.6]; HOS sport, 1.8 [95% CI, -11.2 to 14.7]; iHOT-33, 6.3 [95% CI, -6.1 to 18.7]). The median GRC across all patients was that they "felt about the same" (GRC = 0). Two patients assigned to the surgery group did not undergo surgery, and 28 patients in the rehabilitation group ended up undergoing surgery. A sensitivity analysis of "actual surgery" to "no surgery" did not change the outcome. Twenty (33.3%) patients who underwent surgery and 4 (33.3%) who did not undergo surgery were medically separated from military service at 2 years.

Conclusion: There was no significant difference between the groups at 2 years. Most patients perceived little to no change in status at 2 years, and one-third of military patients were not medically fit for duty at 2 years. Limitations include a single hospital, a single surgeon, and a high rate of crossover. Registration: NCT01993615 ( ClinicalTrials.gov identifier).
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http://dx.doi.org/10.1177/0363546517751912DOI Listing
May 2018

Bilateral Radiation Optic Neuropathy Following Concurrent Chemotherapy and Radiation in Glioblastoma.

Neuroophthalmology 2017 Oct 30;41(5):287-290. Epub 2017 May 30.

Department of Neurology, University of Kentucky, Lexington, Kentucky, USA.

Radiation optic neuropathy (RON) is an iatrogenic complication that causes severe, irreversible vision loss within months to years following radiation to lesions close to the visual pathway. The authors describe a case of RON in glioblastoma after radio-sensitisation with temozolomide with sequential involvement of both optic nerves. This case provides a timeline for clinical and imaging findings with RON and specifically resolution of nerve enhancement. The authors also highlight the potential of an increase in incidence of RON in glioblastoma with advances in survival seen with greater use of second-line chemotherapy and even re-radiation.
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http://dx.doi.org/10.1080/01658107.2017.1322989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5762177PMC
October 2017

Effect of Levodopa-carbidopa Intestinal Gel on Non-motor Symptoms in Patients with Advanced Parkinson's Disease.

Mov Disord Clin Pract 2017 Nov-Dec;4(6):829-837. Epub 2017 Sep 20.

AbbVie Inc. North Chicago IL USA.

Background: Levodopa-carbidopa intestinal gel (LCIG; carbidopa-levodopa enteral suspension in the United States), delivered via percutaneous gastrojejunostomy (PEG-J) and titrated in the inpatient setting, is an established treatment option for advanced Parkinson's disease (PD) patients with motor fluctuations. However, long-term prospective data on the efficacy of LCIG on non-motor symptoms and the safety of outpatient titration are limited.

Methods: In this 60-week, open-label phase 3b study, LCIG titration was initiated in an outpatient setting following PEG-J placement in PD patients. The efficacy of LCIG on motor and non-motor symptoms, quality of life, and safety was assessed.

Results: Thirty-nine patients were enrolled in the study and 28 patients completed the treatment. A majority of patients (54%) completed outpatient titration within the first week of LCIG infusion. LCIG led to significant reductions from baseline in Non-Motor Symptom Scale (NMSS) total score (least squares mean ± SE = -17.6 ± 3.6, < 0.001) and 6 of the NMSS domain scores (sleep/fatigue, attention/memory, gastrointestinal tract, urinary, sexual function, miscellaneous) at week 12. These reductions were maintained at week 60 with the exception of the urinary domain. "Off" time (-4.9 ± 0.5 hours/day, < 0.001) and "On" time without troublesome dyskinesia (-4.3 ± 0.6 hours/day, < 0.001) were improved at week 60. Adverse events (AEs) were reported in 37 (95%) patients.

Conclusions: LCIG treatment led to reductions in non-motor symptom burden and motor fluctuations in advanced PD patients. The safety profile was consistent with previous studies that used inpatient titration and outpatient titration did not appear to pose additional risk.
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http://dx.doi.org/10.1002/mdc3.12526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5724683PMC
September 2017

Linking kindling to increased glutamate release in the dentate gyrus of the hippocampus through the STXBP5/tomosyn-1 gene.

Brain Behav 2017 09 13;7(9):e00795. Epub 2017 Aug 13.

Neurology Service Veterans Affairs Medical Center Lexington KY USA.

Introduction: In kindling, repeated electrical stimulation of certain brain areas causes progressive and permanent intensification of epileptiform activity resulting in generalized seizures. We focused on the role(s) of glutamate and a negative regulator of glutamate release, STXBP5/tomosyn-1, in kindling.

Methods: Stimulating electrodes were implanted in the amygdala and progression to two successive Racine stage 5 seizures was measured in wild-type and STXBP5/tomosyn-1 (Tom) animals. Glutamate release measurements were performed in distinct brain regions using a glutamate-selective microelectrode array (MEA).

Results: Naïve Tom mice had significant increases in KCl-evoked glutamate release compared to naïve wild type as measured by MEA of presynaptic release in the hippocampal dentate gyrus (DG). Kindling progression was considerably accelerated in Tom mice, requiring fewer stimuli to reach a fully kindled state. Following full kindling, MEA measurements of both kindled Tom and Tom mice showed significant increases in KCl-evoked and spontaneous glutamate release in the DG, indicating a correlation with the fully kindled state independent of genotype. Resting glutamate levels in all hippocampal subregions were significantly lower in the kindled Tom mice, suggesting possible changes in basal control of glutamate circuitry in the kindled Tom mice.

Conclusions: Our studies demonstrate that increased glutamate release in the hippocampal DG correlates with acceleration of the kindling process. Although STXBP5/tomosyn-1 loss increased evoked glutamate release in naïve animals contributing to their prokindling phenotype, the kindling process can override any attenuating effect of STXBP5/tomosyn-1. Loss of this "braking" effect of STXBP5/tomosyn-1 on kindling progression may set in motion an alternative but ultimately equally ineffective compensatory response, detected here as reduced basal glutamate release.
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http://dx.doi.org/10.1002/brb3.795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5607557PMC
September 2017

Three-Year Analysis of Value and Utilization After Development of an Ultrasound-Based Orthopedic Injection Clinic.

Mil Med 2017 09;182(9):e1965-e1968

Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425.

Introduction: Sonography is an effective method of diagnosing and treating musculoskeletal conditions, and the use of ultrasound has been shown to improve the accuracy, safety, and efficacy of both therapeutic and diagnostic injections. In 2012, we established an injection clinic at our institution to address our growing need for diagnostic and therapeutic injections.

Methods: We performed an analysis of value and utilization following the development of an orthopedic injection clinic. This included an evaluation of the cost of materials, equipment, and training required to develop and run the clinic, and an analysis of the services rendered and relative value units (RVUs) generated over 3 fiscal years (FYs).

Results: The cost to develop the clinic was $42,498.30. The cost to run the clinic thereafter was $16.90 to $21.60 per injection. By the end of FY 2012, 60% of providers performed at least 1 injection under ultrasound guidance. Every successive year thereafter, 100% of providers were using ultrasound guidance. In FY 2012, we performed 738 injections, 5.4% used ultrasound guidance and generated a total of 1,786.36 RVUs. In FY 2013, we performed 1,814 injections, 17.6% used ultrasound guidance, and generated a total of 7,224.5 RVUs. In FY 2014, we performed 2,821 injections, 25.2% used ultrasound guidance, and generated 13,786.82 RVUs. RVUs generated solely from ultrasound guided injections were 463.2 (2012), 3,694 (2013), 8,221.8 (2014). Injection accuracy was at least 98%. Average time until injection was 0 days.

Conclusion: The cost to start an injection clinic is modest, with the potential for large annual growth and early return on investment, and can generate significant revenue by recapturing RVUs that would otherwise be lost to outside referrals. Furthermore, it helps to increase clinic throughput, maximize services rendered during a single patient visit improving the overall quality of their encounter, expands the clinical practice of our midlevel providers, offloads clinical time for surgical providers, and can help expedite clinical decision making.
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http://dx.doi.org/10.7205/MILMED-D-17-00028DOI Listing
September 2017

Brain microvascular injury and white matter disease provoked by diabetes-associated hyperamylinemia.

Ann Neurol 2017 Aug 29;82(2):208-222. Epub 2017 Jul 29.

Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY.

Objective: The brain blood vessels of patients with type 2 diabetes and dementia have deposition of amylin, an amyloidogenic hormone cosecreted with insulin. It is not known whether vascular amylin deposition is a consequence or a trigger of vascular injury. We tested the hypothesis that the vascular amylin deposits cause endothelial dysfunction and microvascular injury and are modulated by amylin transport in the brain via plasma apolipoproteins.

Methods: Rats overexpressing amyloidogenic (human) amylin in the pancreas (HIP rats) and amylin knockout (AKO) rats intravenously infused with aggregated amylin were used for in vivo phenotyping. We also carried out biochemical analyses of human brain tissues and studied the effects of the aggregated amylin on endothelial cells ex vivo.

Results: Amylin deposition in brain blood vessels is associated with vessel wall disruption and abnormal surrounding neuropil in patients with type 2 diabetes and dementia, in HIP rats, and in AKO rats infused with aggregated amylin. HIP rats have brain microhemorrhages, white matter injury, and neurologic deficits. Vascular amylin deposition provokes loss of endothelial cell coverage and tight junctions. Intravenous infusion in AKO rats of human amylin, or combined human amylin and apolipoprotein E4, showed that amylin binds to plasma apolipoproteins. The intravenous infusion of apolipoprotein E4 exacerbated the brain accumulation of aggregated amylin and vascular pathology in HIP rats.

Interpretation: These data identify vascular amylin deposition as a trigger of brain endothelial dysfunction that is modulated by plasma apolipoproteins and represents a potential therapeutic target in diabetes-associated dementia and stroke. Ann Neurol 2017;82:208-222.
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http://dx.doi.org/10.1002/ana.24992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568970PMC
August 2017

Accuracy of Ultrasound-Guided Intra-articular Hip Injections Performed in the Orthopedic Clinic.

Orthopedics 2017 Mar 20;40(2):96-100. Epub 2016 Dec 20.

Intra-articular hip injections have proven clinical value for both diagnostic and therapeutic purposes. Historically, these injections have been performed by radiologists using fluoroscopic guidance. This necessitates a radiology referral, delays the injection, and represents lost productivity for the orthopedist. Ultrasound-guided intra-articular hip injections have been described in the radiology literature with excellent accuracy. These injections were performed by radiologists. The purpose of this study was to determine the accuracy of ultrasound-guided hip injections performed in the orthopedic clinic by orthopedic surgeons and orthopedic physician assistants. Fifty ultrasound-guided hip injections were performed using a standard technique. Contrast was included, and an anteroposterior pelvis radiograph was obtained immediately following injection. Diagnosis, body mass index, procedure time, and visual analog scale scores were recorded. Radiographs were reviewed independently by a musculoskeletal radiologist and an orthopedic surgeon to determine intra-articular placement of the injection. A total of 50 hips were injected. There was no identifiable contrast in 2 patients, leaving 48 hips for analysis. Of these, contrast was injected intra-articularly in 46 hips for an accuracy of 96%. Average procedural time was 2.6 minutes, and the average visual analog scale score was 1.9 during the procedure. Revenue value units ranged from 1.72-2.55 for ultrasound-guided hip injections. These findings indicate ultrasound-guided intra-articular hip injections performed in the orthopedic clinic by surgeons or physician assistants are accurate, efficient, and patient-friendly. Additionally, they preserve patient continuity and maintain productivity within the orthopedic clinic. [Orthopedics. 2017; 40(2):96-100.].
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http://dx.doi.org/10.3928/01477447-20161213-03DOI Listing
March 2017

Implantation of autologous peripheral nerve grafts into the substantia nigra of subjects with idiopathic Parkinson's disease treated with bilateral STN DBS: a report of safety and feasibility.

J Neurosurg 2017 04 6;126(4):1140-1147. Epub 2016 May 6.

Brain Restoration Center, and.

OBJECTIVE One avenue of intense efforts to treat Parkinson's disease (PD) involves the delivery of neurotrophic factors to restore dopaminergic cell function. A source of neurotrophic factors that could be used is the Schwann cell from the peripheral nervous system. The authors have begun an open-label safety study to examine the safety and feasibility of implanting an autologous peripheral nerve graft into the substantia nigra of PD patients undergoing deep brain stimulation (DBS) surgery. METHODS Multistage DBS surgery targeting the subthalamic nucleus was performed using standard procedures in 8 study participants. After the DBS leads were implanted, a section of sural nerve containing Schwann cells was excised and unilaterally delivered into the area of the substantia nigra. Adverse events were continuously monitored. RESULTS Eight of 8 participants were implanted with DBS systems and grafts. Adverse event profiles were comparable to those of standard DBS surgery. Postoperative MR images did not reveal edema, hemorrhage, or significant signal changes in the graft target region. Three participants reported a patch of numbness on the outside of the foot below the sural nerve harvest site. CONCLUSIONS Based on the safety outcome of the procedure, targeted peripheral nerve graft delivery to the substantia nigra at the time of DBS surgery is feasible and may provide a means to deliver neurorestorative therapy. Clinical trial registration no.: NCT01833364 ( clinicaltrials.gov ).
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http://dx.doi.org/10.3171/2016.2.JNS151988DOI Listing
April 2017

Two-year outcomes after arthroscopic surgery compared to physical therapy for femoracetabular impingement: A protocol for a randomized clinical trial.

BMC Musculoskelet Disord 2016 Feb 4;17:60. Epub 2016 Feb 4.

University of Southern California, Los Angeles, CA, 90089, USA.

Background: As the prevalence of hip pathology in the younger athletic population rises, the medical community continues to investigate effective intervention options. Femoracetabular impingement is the morphologically abnormal articulation of the femoral head against the acetabulum, and often implicated in pre-arthritic hip conditions of musculoskeletal nature. Arthroscopic surgical decompression and non-surgical rehabilitation programs focused on strengthening and stability are common interventions. However, they have never been directly compared in clinical trials. The primary purpose of this study will be to assess the difference in outcomes between these 2 commonly utilized interventions for femoracetabular impingement.

Methods: The study will be a single site, non-inferiority, randomized controlled trial comparing two different treatment approaches (surgical and nonsurgical) for FAI. The enrollment goal is for a total of 80 subjects with a diagnosis of Femoracetabular impingement that are surgical candidates and have failed 6 weeks of conservative treatment. This will be a convenience sample of consecutive patients that are Tricare beneficiaries and seeking care at Madigan Army Medical Center. Patients that meet the criteria will be screened, provide written consent before enrollment, and then randomized into one of two arms (Group I = hip arthroscopy, Group II = physical therapy). Group I will undergo hip arthroscopy with or without labral repair. Group II will follow an impairment based physical therapy program consisting of 2 sessions per week for 6 weeks. The primary outcome will be the Hip Outcome Score and secondary measures will include the International Hip Outcome Tool and the Global Rating of Change. Measures will be taken at baseline, 6 months, 1 and 2 years. Hip-related healthcare utilization between both groups will also be assessed at the end of 2 years.

Discussion: The current evidence to support both surgical and conservative interventions for femoroacetabular impingement is based on low-level research. To date, none of these interventions have been directly compared in a randomized clinical trial. Clinical trials are needed to help establish the value of these interventions in the management of femoracetabular impingement and to help define appropriate clinical pathways.

Trial Registration: NCT01993615 30 October 2013.
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http://dx.doi.org/10.1186/s12891-016-0914-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4743428PMC
February 2016

Effect of levodopa-carbidopa intestinal gel on dyskinesia in advanced Parkinson's disease patients.

Mov Disord 2016 Apr 28;31(4):530-7. Epub 2016 Jan 28.

AbbVie, Inc., North Chicago, Illinois, USA.

Objective: The purpose of this study was to assess the effect of levodopa-carbidopa intestinal gel (carbidopa-levodopa enteral suspension) in advanced Parkinson's disease patients with troublesome dyskinesia.

Methods: Post hoc analyses of patient data from a 12-week, randomized, double-blind study and a 54-week open-label study were performed. Efficacy was assessed in the subgroup of patients defined by ≥1 hour of "on" time with troublesome dyskinesia at baseline as recorded in Parkinson's disease symptom diaries (double blind: n = 11 levodopa-carbidopa intestinal gel, n = 12 oral levodopa-carbidopa; open label: n = 144 levodopa-carbidopa intestinal gel). The changes in "off" time, "on" time with and without troublesome dyskinesia, and the overall safety and tolerability of levodopa-carbidopa intestinal gel were analyzed.

Results: Although not significantly different from oral levodopa treatment (P > .05) in the double-blind study, levodopa-carbidopa intestinal gel treatment resulted in a reduction from baseline in "on" time with troublesome dyskinesia (mean [standard deviation] hours: baseline = 3.1 [1.7], change from baseline to final = -1.8 [1.8], P = .014), increase in "on" time without troublesome dyskinesia (baseline = 7.4 [2.2], change = 4.4 [3.6], P = .004), and decrease in "off" time (baseline = 5.5 [1.3], change = -2.7 [2.8], P = .015). Similar trends were found in the open-label study. An increase in levodopa-carbidopa intestinal gel dose was not significantly correlated with increased "on" time with troublesome dyskinesia in either study (double blind: r = -.073, P = .842; open label: r = -0.001, P = .992). Adverse events were usually mild to moderate in severity and related to the gastrointestinal procedure.

Conclusion: Our exploratory analyses suggest that optimizing levodopa delivery with levodopa-carbidopa intestinal gel may reduce troublesome dyskinesia in advanced Parkinson's disease.
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http://dx.doi.org/10.1002/mds.26528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5066747PMC
April 2016

Dopaminergic Modulation of Medial Prefrontal Cortex Deactivation in Parkinson Depression.

Parkinsons Dis 2015 17;2015:513452. Epub 2015 Dec 17.

Department of Neurology, University of Kentucky, Lexington, KY 40536, USA; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA; Department of Behavioral Science, University of Kentucky, Lexington, KY 40536, USA.

Parkinson's disease (PD) is associated with emotional abnormalities. Dopaminergic medications ameliorate Parkinsonian motor symptoms, but less is known regarding the impact of dopaminergic agents on affective processing, particularly in depressed PD (dPD) patients. The aim of this study was to examine the effects of dopaminergic pharmacotherapy on brain activation to emotional stimuli in depressed versus nondepressed Parkinson disease (ndPD) patients. Participants included 18 ndPD patients (11 men, 7 women) and 10 dPD patients (7 men, 3 women). Patients viewed photographs of emotional faces during functional MRI. Scans were performed while the patient was taking anti-Parkinson medication and the day after medication had been temporarily discontinued. Results indicate that dopaminergic medications have opposite effects in the prefrontal cortex depending upon depression status. DPD patients show greater deactivation in the ventromedial prefrontal cortex (VMPFC) on dopaminergic medications than off, while ndPD patients show greater deactivation in this region off drugs. The VMPFC is in the default-mode network (DMN). DMN activity is negatively correlated with activity in brain systems used for external visual attention. Thus dopaminergic medications may promote increased attention to external visual stimuli among dPD patients but impede normal suppression of DMN activity during external stimulation among ndPD patients.
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http://dx.doi.org/10.1155/2015/513452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4697088PMC
January 2016

Integrated safety of levodopa-carbidopa intestinal gel from prospective clinical trials.

Mov Disord 2016 Apr 23;31(4):538-46. Epub 2015 Dec 23.

AbbVie Inc, North Chicago, Illinois, USA.

Background: Continuous administration of levodopa-carbidopa intestinal gel (carbidopa-levodopa enteral suspension) through a percutaneous endoscopic gastrojejunostomy is a treatment option for advanced Parkinson disease (PD) patients with motor fluctuations resistant to standard oral medications. Safety data from 4 prospective studies were integrated to assess the safety of this therapy.

Methods: Safety data from 4 studies were summarized using 2 overlapping data sets, permitting the separation of procedure/device-associated (n = 395) from non-procedure/device adverse events (n = 412).

Results: At the data cutoff, median exposure to levodopa-carbidopa intestinal gel was 911 days (range, 1-1980 days) with 963 total patient-years of exposure. Procedure/device adverse events occurred in 300 patients (76%), and serious adverse events occurred in 68 (17%); most frequently reported procedure/device adverse events and serious adverse events were complications of device insertion (41% and 8%, respectively) and abdominal pain (36% and 4%, respectively). Non-procedure/device adverse events occurred in 92% (379), with most frequently reported being insomnia (23%) and falls (23%); 42% (171) had non-procedure/device serious adverse events, with most frequently reported being pneumonia (5%) and PD symptoms (2%). Adverse events led to discontinuation in 17% (72), most frequently because of complication of device insertion (2.4%). There were 34 treatment-emergent deaths (8.3%) in the overlapping data sets, 2 of which (0.5%) were considered "possibly related" to the treatment system.

Conclusion: In the largest collection of levodopa-carbidopa intestinal gel safety data from prospective clinical studies, procedure/device events were frequently reported and occasionally life threatening. Most non-procedure/device events were typical for levodopa treatment and an elderly population. These factors combined with high treatment efficacy led to a relatively low discontinuation rate in advanced PD patients.
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http://dx.doi.org/10.1002/mds.26485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5064722PMC
April 2016

Initiation and dose optimization for levodopa-carbidopa intestinal gel: Insights from phase 3 clinical trials.

Parkinsonism Relat Disord 2015 Jul 28;21(7):742-8. Epub 2015 Apr 28.

Department of Neurology, Westmead Hospital and Sydney Medical School, Sydney, Australia.

Background: Levodopa-carbidopa intestinal gel (LCIG) provides continuous infusion and reduces "off" time in advanced Parkinson's disease (PD) patients with motor fluctuations despite optimized pharmacotherapy.

Methods: Clinical experience with 2 LCIG dosing paradigms from phase 3 studies was examined. In an open-label, 54-week study, LCIG was initiated as daytime monotherapy via nasojejunal (NJ) tube then switched to percutaneous endoscopic gastrojejunostomy (PEG-J) tube; adjunctive therapy was permitted 28 days postPEG-J. In a 12-week, double-blind, placebo-controlled, double-dummy trial, patients continued stable doses of existing anti-PD medications, but LCIG replaced daytime oral levodopa-carbidopa and was initiated directly via PEG-J.

Results: In the open-label study, 92% of 354 patients received monotherapy at post-PEG-J week 4; mean titration duration was 7.6 days; dosing remained stable post-titration (mean total daily dose [TDD] was 1572 mg at last visit). In the double-blind trial, 84% received polypharmacy; mean titration took 7.1 days for the LCIG arm (TDD post-titration: 1181 mg; n = 37). At post-PEG-J week 4, mean "off" time with LCIG was reduced by 3.9 h (open-label/monotherapy study) and 3.7 h (double-blind/polypharmacy trial). NJ treatment (open-label study only) required an additional procedure with related adverse events (AEs) and withdrawals. The most common AEs during PEG-J weeks 1-4 in the open-label/monotherapy and double-blind/polypharmacy trials, respectively, were complication of device insertion (35%, 57%) and abdominal pain (26%, 51%). Discontinuations due to nonprocedure/nondevice AEs were low (2.2%, 2.7%).

Conclusion: These results support the option of initiating LCIG with or without NJ and as either monotherapy or polypharmacy.
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http://dx.doi.org/10.1016/j.parkreldis.2015.04.022DOI Listing
July 2015

Long-term safety and maintenance of efficacy of levodopa-carbidopa intestinal gel: an open-label extension of the double-blind pivotal study in advanced Parkinson's disease patients.

J Parkinsons Dis 2015 ;5(1):165-74

AbbVie Inc., North Chicago, IL, USA.

Background: Levodopa-carbidopa intestinal gel (LCIG) is delivered continuously via intrajejunal percutaneous gastrostomy tube.

Objective: To examine long-term safety, efficacy and quality of life of LCIG in an open-label extension study.

Methods: Patients received 52 weeks of open-label LCIG treatment following a 12-week double-blind, double-dummy trial in which they were randomized to either LCIG or immediate-release oral levodopa-carbidopa. Patient cohort designation was by receipt of LCIG in the preceding trial randomization (continuing-LCIG vs. LCIG-naïve patients).

Results: Sixty-two of 66 subjects in the double-blind proceeded to the open-label extension. Most subjects (95%) reported ≥1 adverse event (AE); only 3 subjects (4.8%) discontinued due to AEs. AE incidence declined gradually over 52 weeks. Serious AEs were reported by 23%. LCIG-naïve patients (N = 29) showed a decrease in "Off" time and an increase in "On" time without troublesome dyskinesia (change from baseline to final visit in mean [SD] hours = -2.34 [2.78] P < 0.001 and 2.19 [3.70] P = 0.005, respectively), while continuing-LCIG patients (N = 33) showed sustained "Off" time duration and further improvement in "On" time without troublesome dyskinesia (-0.42 [2.67] P = 0.377 and 1.00 [2.58] P = 0.036, respectively). The majority of patients in both groups (LCIG-naïve, continuing-LCIG, respectively) were rated 'Much Improved' or 'Very Much Improved' at final visit on the Clinical Global Impression-Improvement scale (69.0%, 69.7%).

Conclusions: Continuing-LCIG patients continued to derive benefit from LCIG while the magnitude of improvement among LCIG-naïve patients was similar to that observed for patients on LCIG in the preceding double-blind study. The overall AE profile was consistent with previous phase 3 clinical trials involving the LCIG system.
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http://dx.doi.org/10.3233/JPD-140456DOI Listing
November 2015

Tonic glutamate in CA1 of aging rats correlates with phasic glutamate dysregulation during seizure.

Epilepsia 2014 Nov 29;55(11):1817-25. Epub 2014 Sep 29.

Department of Anesthesiology, The Ohio State University Wexner Medical Center, Columbus, Ohio, U.S.A.

Objective: Characterize glutamate neurotransmission in the hippocampus of awake-behaving rodents during focal seizures in a model of aging.

Methods: We used enzyme-based ceramic microelectrode array technology to measure in vivo extracellular tonic glutamate levels and real-time phasic glutamate release and clearance events in the hippocampus of awake Fischer 344 rats. Local application of 4-aminopyridine (4-AP) into the CA1 region was used to induce focal motor seizures in different animal age groups representing young, late-middle aged and elderly humans.

Results: Rats with the highest preseizure tonic glutamate levels (all in late-middle aged or elderly groups) experienced the most persistent 4-AP-induced focal seizure motor activity (wet dog shakes) and greatest degree of acute seizure-associated disruption of glutamate neurotransmission measured as rapid transient changes in extracellular glutamate levels.

Significance: Increased seizure susceptibility was demonstrated in the rats with the highest baseline hippocampal extracellular glutamate levels, all of which were late-middle aged or aged animals. The manifestation of seizures behaviorally was associated with dynamic changes in glutamate neurotransmission. To our knowledge, this is the first report of a relationship between seizure susceptibility and alterations in both baseline tonic and phasic glutamate neurotransmission.
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http://dx.doi.org/10.1111/epi.12797DOI Listing
November 2014
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