SCIENCE TIMES
to the discrimination task on day 2. There was no significant difference between the caffeine and placebo groups, suggesting that caffeine does not have a direct effect on retrieval. Finally, to assess dosing, the team repeated the experiment using 100 mg, 200 mg, and 300 mg doses of caffeine. Ultimately, the 100 mg group did not significantly differ from placebo; and was significantly lower than the 200 mg group (P ¼ .03). The 300 mg group trended higher compared to placebo but was not significant (P ¼ .07), likely due to insufficient power. However, when the 200 mg and 300 mg groups were combined and compared to the 100 mg and placebo groups, significance was achieved (P ¼ .007), suggesting that 200 mg may be the minimum dose required to observe effect. The present study demonstrates that a 1-time dose of caffeine administered after an incidental learning task enhances a participant’s ability to differentiate similar images in a task 24 hours later. These results suggest that caffeine intake improves long-term memory consolidation. These results are compelling for both the neurosurgical patient and neurosurgeon alike. Caffeine has previously been shown to be neuroprotective in animal models of neurodegenerative disease, including Parkinson disease,5 Alzheimer disease,6 and even agerelated memory loss.7 These new findings, taken together with previous work studying caffeine and memory, demonstrate that caffeine likely has benefits beyond prevention of neuronal loss. Given that older adults have been shown to be more susceptible to performance-improving effects of caffeine,8 it is possible that the elderly population may also gain greater memory improvement than younger adults. Future studies are needed to articulate the mechanisms of caffeine’s effects on long-term memory, the temporal relationship between caffeine intake and memory processing, and the age dependence of caffeine’s potential benefits.
4. Yassa MA, Stark CE. Pattern separation in the hippocampus. Trends Neurosci. 2011;34(10): 515-525. 5. Chen JF, Xu K, Petzer JP, et al. Neuroprotection by caffeine and A(2A) adenosine receptor inactivation in a model of Parkinson’s disease. J Neurosci. 2001;21 (10):RC143. 6. Arendash GW, Schleif W, Rezai-Zadeh K, et al. Caffeine protects Alzheimer’s mice against cognitive impairment and reduces brain beta-amyloid production. Neuroscience. 2006;142(4): 941-952. 7. Sallaberry C, Nunes F, Costa MS, et al. Chronic caffeine prevents changes in inhibitory avoidance memory and hippocampal BDNF immunocontent in middle-aged rats. Neuropharmacology. 2013;64: 153-159. 8. Jarvis MJ. Does caffeine intake enhance absolute levels of cognitive performance? Psychopharmacology (Berl). 1993;110(1-2):45-52.
Lentiviral Vector-Based Gene Therapy in Parkinson Disease
D
espite the recent failure of the second Phase 2 trial of adeno-associated virus serotype 2 (AAV2) vector-mediated delivery of neurturin, expectations for the eventual success of gene therapy approaches
to treat Parkinson disease (PD) remain quite high. Currently, there are 2 clinical trials underway to study the delivery of other AAV2 vector-based therapeutics: aromaticL-amino acid decarboxylase (AADC), the final rate limiting enzyme in dopamine synthesis (NCT01973543), and glial cell-derived neurotrophic factor (GDNF), a potent neurotropic factor in the same family as neurturin (NCT01621581). These trials are employing convection-enhanced delivery via interventionalmagnetic resonance imaging for real-time imaging of vector distribution, in an attempt to overcome obstacles that may have prevented previous PD drug delivery trials from reaching efficacy goals. Whether replacing dopamine synthesis directly (AADC) or rescuing dopaminergic activity in the nigrostriatal pathway by trophic support (GDNF) is a better approach is an open question. It is possible that a combination of these strategies ultimately may be most effective. Expanding the strategy for replacement of dopamine synthesis, Palfi and colleagues1 reported the results of a 2-center (Créteil, France and Cambridge, United Kingdom), Phase 1/2 open label trial of ProSavin, a lentiviral vector that encodes not only AADC, but the other rate-limiting dopamine biosynthetic enzymes tyrosine hydroxylase and cyclohydrolase 1.
Kathleen M. Kelly, BA Charles B. Mikell, MD Guy M. McKhann, II, MD Columbia University Medical Center New York, New York
REFERENCES 1. Nehlig A. Is caffeine a cognitive enhancer? J Alzheimers Dis. 2010;20(suppl 1):S85-S94. 2. Borota D, Murray E, Keceli G, et al. Post-study caffeine administration enhances memory consolidation in humans. Nat Neurosci. 2014;17(2):201-203. 3. Pike Place Roast. Starbucks 2014. Available at: http:// www.starbucks.com/menu/drinks/brewed-coffee/pikeplace-roast-size¼2. Accessed March 21, 2014.
NEUROSURGERY
Figure 1. Trial design.1 Reprinted from The Lancet, Vol 383/edition number 9923, Palfi S, Gurruchaga JM, Ralph GS, et al., Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson’s disease: a dose escalation, open-label, phase 1/2 trial, Pages No. 1138-1146, Copyright (2014), with permission from Elsevier.
VOLUME 74 | NUMBER 6 | JUNE 2014 | N11
Copyright © Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited.
SCIENCE TIMES
Although lentiviral vectors have the advantage of being able to carry a larger genetic payload than AAV vectors, no clinical trial using in vivo administration of lentiviral vectors in any human disease had previously been reported. In this open-label, dose-escalation study with 12-month follow-up, 3 doses of ProSavin were assessed in 4 patient cohorts with bilateral delivery to the putamen. The primary endpoints were the number and severity of adverse events and change in Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores assessed at 6 months after vector administration. The most common therapy-related adverse events were increased on-medication dyskinesias, which resolved in each case with reduction of dopaminergic medication. Importantly, no patients developed off-medication dyskinesias or any signs of an inflammatory response to the viral vector. Off-medication UPDRS motor scores were significantly reduced at both 6 and 12 months in all patients, relative to their baselines (33% and 31%, respectively); however, no significant difference was seen between the different dose cohorts. The therapeutic goal of this gene therapy strategy was to produce a continuous and stable production of dopamine in the motor region of the putamen. Evaluation of this effect by Positron emission tomography scanning, however, produced conflicting results. There was no effect in 18F-levodopa uptake, an analog of levodopa used to evaluate striatal dopaminergic presynaptic function, after ProSavin administration. In contrast, 11C-raclopride binding, which assesses the degree of dopamine binding to the D2 dopamine receptor, increased in a dose-dependent manner. The authors hypothesize that the former finding was a result of an inability of cellular machinery in transduced neurons to store and accumulate radiolabeled dopamine. Patients in the highest dose cohort did have consistent requirement for a reduction in dopaminergic medication, the highest mean relative improvement in UPDRS motor scores, and a significant change in 11C-raclopride binding potentials. These findings suggest that the highest dose evaluated in this study resulted in the greatest level of dopaminergic activity, but this was not shown conclusively. Similarly, there was no dose-dependent effect on UPDRS motor scores, despite the fact that the authors introduced a “modified delivery method” in between the second and third cohorts “to increase the rate of delivery and enhance the distribution of the vector.” The supplementary methods indicate that this decision was based on non-human primate studies demonstrating similar vector distribution when
N12 | VOLUME 74 | NUMBER 6 | JUNE 2014
switching to a continuous infusion method, increasing the delivery rate to 3 mL/min, and decreasing the cannula diameter. The authors conclude the manuscript by stating, “Only when we have an optimum mode and dose of delivery will we proceed to a more definitive double-blind placebo controlled trial.” It should be noted that with regard to delivery, an optimized, interventional-magnetic resonance imaging-guided platform for convectionenhanced delivery of viral vectors has been described.2 Without real-time magnetic resonance imaging during infusion of the viral vector, it is not possible to determine if the infusate has been delivered to the target in the intended manner. Nonetheless, the work reported by Palfi and colleagues represents a significant advance in the field of neurosurgical gene therapy by demonstrating the safety of this first-in-man use of a lentiviral-based vector for a central nervous system disorder. As their report points out, the magnitude of clinical effects were within the placebo range reported in other clinical trials, and should be interpreted with caution. Fortunately, these investigators have described their intention to optimize the delivery of ProSavin before engaging in a blinded, randomized phase 2 trial to assess efficacy. Mark Richardson, MD, PhD University of Pittsburgh Pittsburgh, Pennsylvania
REFERENCES 1. Palfi S, Gurruchaga JM, Ralph GS, et al. Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson’s disease: a dose escalation, open-label, phase 1/2 trial. Lancet. 2014;383 (9923):1138-1146. 2. Richardson RM, Kells AP, Rosenbluth KH, et al. Interventional MRI-guided putaminal delivery of AAV2-GDNF for a planned clinical trial in Parkinson’s disease. Mol Ther. 2011;19(6):1048-1057.
Blinded Peer Assessment of Surgical Skill is Feasible and Can Predict Complication Rates: A Step Toward Measuring Surgical Quality
D
espite a growing emphasis on measuring and grading quality of surgical care, a tremendous knowledge gap exists regarding what constitutes quality care. How
to measure quality of care remains equally daunting in scope. Thus far, the focus has been on perioperative metrics that are relatively easy to measure and monitor such as deep venous thrombosis prophylaxis. It is doubtful that these perioperative factors will be dominant determinants of operative outcomes. While measuring intraoperative factors seems rational on the surface, huge complexities arise when one looks beyond the surface. Operative time, for example, can be a misleading measure of quality and may or may not relate directly to ultimate outcome. Even though volume has been grossly linked to outcomes, individual surgeon skills have been harder to define, study, and monitor. Which factors can affect surgeon skills and how these skills may relate to complications remains largely speculative. To investigate this important issue, Birkmeyer et al conducted a study to objectively assess the surgical performance of 20 bariatric surgeons located in Michigan, and to examine the relationship between their surgical skill and postoperative outcomes. The assessment of surgical skill was performed by at least 10 blinded peer surgeons, and the risk-adjusted complication rates were studied using a prospectively collected outcome registry. The results were published in the October 2013 issue of The New England Journal of Medicine.1 Twenty of 63 bariatric surgeons in Michigan who perform laparoscopic gastric bypass surgeries volunteered to participate in the study. Between August 2006 and 2012, the 20 participating surgeons performed bypass procedures on 10 343 patients who were prospectively enrolled in the Michigan Bariatric Surgery Collaborative (MBSC) registry.2,3 The authors used this registry to study postoperative complications and to correlate them with surgical performance. Initially, to assess the surgical skill of the participating surgeons, each surgeon was asked to submit an operative video of his/her choice. These videos were edited to include only important elements of the procedure (range of video time was 25-40 minutes). Each video was rated by at least 10 independent peer surgeons who were blinded to both the operator and the surgical outcome of the procedure. The authors used the average grading of all peer surgeons for each video. The grading was performed using a 5-point, likert-type scale derived from the validated Objective Structured Assessment of Technical Skills (OSATS).4-6 The scale involved five main items: instrument handling, tissue exposure, time and motion, gentleness, and flow of operation, in addition to an overall skill rating score. Using the MBSC database, the authors studied the surgical outcomes of procedures
www.neurosurgery-online.com
Copyright © Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited.
to the discrimination task on day 2. There was no significant difference between the caffeine and placebo groups, suggesting that caffeine does not have a direct effect on retrieval. Finally, to assess dosing, the team repeated the experiment using 100 mg, 200 mg, and 300 mg doses of caffeine. Ultimately, the 100 mg group did not significantly differ from placebo; and was significantly lower than the 200 mg group (P ¼ .03). The 300 mg group trended higher compared to placebo but was not significant (P ¼ .07), likely due to insufficient power. However, when the 200 mg and 300 mg groups were combined and compared to the 100 mg and placebo groups, significance was achieved (P ¼ .007), suggesting that 200 mg may be the minimum dose required to observe effect. The present study demonstrates that a 1-time dose of caffeine administered after an incidental learning task enhances a participant’s ability to differentiate similar images in a task 24 hours later. These results suggest that caffeine intake improves long-term memory consolidation. These results are compelling for both the neurosurgical patient and neurosurgeon alike. Caffeine has previously been shown to be neuroprotective in animal models of neurodegenerative disease, including Parkinson disease,5 Alzheimer disease,6 and even agerelated memory loss.7 These new findings, taken together with previous work studying caffeine and memory, demonstrate that caffeine likely has benefits beyond prevention of neuronal loss. Given that older adults have been shown to be more susceptible to performance-improving effects of caffeine,8 it is possible that the elderly population may also gain greater memory improvement than younger adults. Future studies are needed to articulate the mechanisms of caffeine’s effects on long-term memory, the temporal relationship between caffeine intake and memory processing, and the age dependence of caffeine’s potential benefits.
4. Yassa MA, Stark CE. Pattern separation in the hippocampus. Trends Neurosci. 2011;34(10): 515-525. 5. Chen JF, Xu K, Petzer JP, et al. Neuroprotection by caffeine and A(2A) adenosine receptor inactivation in a model of Parkinson’s disease. J Neurosci. 2001;21 (10):RC143. 6. Arendash GW, Schleif W, Rezai-Zadeh K, et al. Caffeine protects Alzheimer’s mice against cognitive impairment and reduces brain beta-amyloid production. Neuroscience. 2006;142(4): 941-952. 7. Sallaberry C, Nunes F, Costa MS, et al. Chronic caffeine prevents changes in inhibitory avoidance memory and hippocampal BDNF immunocontent in middle-aged rats. Neuropharmacology. 2013;64: 153-159. 8. Jarvis MJ. Does caffeine intake enhance absolute levels of cognitive performance? Psychopharmacology (Berl). 1993;110(1-2):45-52.
Lentiviral Vector-Based Gene Therapy in Parkinson Disease
D
espite the recent failure of the second Phase 2 trial of adeno-associated virus serotype 2 (AAV2) vector-mediated delivery of neurturin, expectations for the eventual success of gene therapy approaches
to treat Parkinson disease (PD) remain quite high. Currently, there are 2 clinical trials underway to study the delivery of other AAV2 vector-based therapeutics: aromaticL-amino acid decarboxylase (AADC), the final rate limiting enzyme in dopamine synthesis (NCT01973543), and glial cell-derived neurotrophic factor (GDNF), a potent neurotropic factor in the same family as neurturin (NCT01621581). These trials are employing convection-enhanced delivery via interventionalmagnetic resonance imaging for real-time imaging of vector distribution, in an attempt to overcome obstacles that may have prevented previous PD drug delivery trials from reaching efficacy goals. Whether replacing dopamine synthesis directly (AADC) or rescuing dopaminergic activity in the nigrostriatal pathway by trophic support (GDNF) is a better approach is an open question. It is possible that a combination of these strategies ultimately may be most effective. Expanding the strategy for replacement of dopamine synthesis, Palfi and colleagues1 reported the results of a 2-center (Créteil, France and Cambridge, United Kingdom), Phase 1/2 open label trial of ProSavin, a lentiviral vector that encodes not only AADC, but the other rate-limiting dopamine biosynthetic enzymes tyrosine hydroxylase and cyclohydrolase 1.
Kathleen M. Kelly, BA Charles B. Mikell, MD Guy M. McKhann, II, MD Columbia University Medical Center New York, New York
REFERENCES 1. Nehlig A. Is caffeine a cognitive enhancer? J Alzheimers Dis. 2010;20(suppl 1):S85-S94. 2. Borota D, Murray E, Keceli G, et al. Post-study caffeine administration enhances memory consolidation in humans. Nat Neurosci. 2014;17(2):201-203. 3. Pike Place Roast. Starbucks 2014. Available at: http:// www.starbucks.com/menu/drinks/brewed-coffee/pikeplace-roast-size¼2. Accessed March 21, 2014.
NEUROSURGERY
Figure 1. Trial design.1 Reprinted from The Lancet, Vol 383/edition number 9923, Palfi S, Gurruchaga JM, Ralph GS, et al., Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson’s disease: a dose escalation, open-label, phase 1/2 trial, Pages No. 1138-1146, Copyright (2014), with permission from Elsevier.
VOLUME 74 | NUMBER 6 | JUNE 2014 | N11
Copyright © Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited.
SCIENCE TIMES
Although lentiviral vectors have the advantage of being able to carry a larger genetic payload than AAV vectors, no clinical trial using in vivo administration of lentiviral vectors in any human disease had previously been reported. In this open-label, dose-escalation study with 12-month follow-up, 3 doses of ProSavin were assessed in 4 patient cohorts with bilateral delivery to the putamen. The primary endpoints were the number and severity of adverse events and change in Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores assessed at 6 months after vector administration. The most common therapy-related adverse events were increased on-medication dyskinesias, which resolved in each case with reduction of dopaminergic medication. Importantly, no patients developed off-medication dyskinesias or any signs of an inflammatory response to the viral vector. Off-medication UPDRS motor scores were significantly reduced at both 6 and 12 months in all patients, relative to their baselines (33% and 31%, respectively); however, no significant difference was seen between the different dose cohorts. The therapeutic goal of this gene therapy strategy was to produce a continuous and stable production of dopamine in the motor region of the putamen. Evaluation of this effect by Positron emission tomography scanning, however, produced conflicting results. There was no effect in 18F-levodopa uptake, an analog of levodopa used to evaluate striatal dopaminergic presynaptic function, after ProSavin administration. In contrast, 11C-raclopride binding, which assesses the degree of dopamine binding to the D2 dopamine receptor, increased in a dose-dependent manner. The authors hypothesize that the former finding was a result of an inability of cellular machinery in transduced neurons to store and accumulate radiolabeled dopamine. Patients in the highest dose cohort did have consistent requirement for a reduction in dopaminergic medication, the highest mean relative improvement in UPDRS motor scores, and a significant change in 11C-raclopride binding potentials. These findings suggest that the highest dose evaluated in this study resulted in the greatest level of dopaminergic activity, but this was not shown conclusively. Similarly, there was no dose-dependent effect on UPDRS motor scores, despite the fact that the authors introduced a “modified delivery method” in between the second and third cohorts “to increase the rate of delivery and enhance the distribution of the vector.” The supplementary methods indicate that this decision was based on non-human primate studies demonstrating similar vector distribution when
N12 | VOLUME 74 | NUMBER 6 | JUNE 2014
switching to a continuous infusion method, increasing the delivery rate to 3 mL/min, and decreasing the cannula diameter. The authors conclude the manuscript by stating, “Only when we have an optimum mode and dose of delivery will we proceed to a more definitive double-blind placebo controlled trial.” It should be noted that with regard to delivery, an optimized, interventional-magnetic resonance imaging-guided platform for convectionenhanced delivery of viral vectors has been described.2 Without real-time magnetic resonance imaging during infusion of the viral vector, it is not possible to determine if the infusate has been delivered to the target in the intended manner. Nonetheless, the work reported by Palfi and colleagues represents a significant advance in the field of neurosurgical gene therapy by demonstrating the safety of this first-in-man use of a lentiviral-based vector for a central nervous system disorder. As their report points out, the magnitude of clinical effects were within the placebo range reported in other clinical trials, and should be interpreted with caution. Fortunately, these investigators have described their intention to optimize the delivery of ProSavin before engaging in a blinded, randomized phase 2 trial to assess efficacy. Mark Richardson, MD, PhD University of Pittsburgh Pittsburgh, Pennsylvania
REFERENCES 1. Palfi S, Gurruchaga JM, Ralph GS, et al. Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson’s disease: a dose escalation, open-label, phase 1/2 trial. Lancet. 2014;383 (9923):1138-1146. 2. Richardson RM, Kells AP, Rosenbluth KH, et al. Interventional MRI-guided putaminal delivery of AAV2-GDNF for a planned clinical trial in Parkinson’s disease. Mol Ther. 2011;19(6):1048-1057.
Blinded Peer Assessment of Surgical Skill is Feasible and Can Predict Complication Rates: A Step Toward Measuring Surgical Quality
D
espite a growing emphasis on measuring and grading quality of surgical care, a tremendous knowledge gap exists regarding what constitutes quality care. How
to measure quality of care remains equally daunting in scope. Thus far, the focus has been on perioperative metrics that are relatively easy to measure and monitor such as deep venous thrombosis prophylaxis. It is doubtful that these perioperative factors will be dominant determinants of operative outcomes. While measuring intraoperative factors seems rational on the surface, huge complexities arise when one looks beyond the surface. Operative time, for example, can be a misleading measure of quality and may or may not relate directly to ultimate outcome. Even though volume has been grossly linked to outcomes, individual surgeon skills have been harder to define, study, and monitor. Which factors can affect surgeon skills and how these skills may relate to complications remains largely speculative. To investigate this important issue, Birkmeyer et al conducted a study to objectively assess the surgical performance of 20 bariatric surgeons located in Michigan, and to examine the relationship between their surgical skill and postoperative outcomes. The assessment of surgical skill was performed by at least 10 blinded peer surgeons, and the risk-adjusted complication rates were studied using a prospectively collected outcome registry. The results were published in the October 2013 issue of The New England Journal of Medicine.1 Twenty of 63 bariatric surgeons in Michigan who perform laparoscopic gastric bypass surgeries volunteered to participate in the study. Between August 2006 and 2012, the 20 participating surgeons performed bypass procedures on 10 343 patients who were prospectively enrolled in the Michigan Bariatric Surgery Collaborative (MBSC) registry.2,3 The authors used this registry to study postoperative complications and to correlate them with surgical performance. Initially, to assess the surgical skill of the participating surgeons, each surgeon was asked to submit an operative video of his/her choice. These videos were edited to include only important elements of the procedure (range of video time was 25-40 minutes). Each video was rated by at least 10 independent peer surgeons who were blinded to both the operator and the surgical outcome of the procedure. The authors used the average grading of all peer surgeons for each video. The grading was performed using a 5-point, likert-type scale derived from the validated Objective Structured Assessment of Technical Skills (OSATS).4-6 The scale involved five main items: instrument handling, tissue exposure, time and motion, gentleness, and flow of operation, in addition to an overall skill rating score. Using the MBSC database, the authors studied the surgical outcomes of procedures
www.neurosurgery-online.com
Copyright © Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited.
