VIENNA—Early-onset idiopathic epi­lepsy occurring before age 7 nearly doubles the likelihood that a child with autism spectrum disorder (ASD) will later develop comorbid ADHD, reported Johnny Downs, MD, a child psychiatrist at King’s College in London, at the 29th Annual Congress of the European College of Neuropsychopharmacology.

Comorbid ADHD is common in the setting of ASD. In a search for risk factors for the comorbid condition, Dr. Downs and his colleagues reviewed the physical health records prior to age 7 of 3,032 patients with ASD referred at ages 3 to 17 to child and adolescent mental health services clinics serving South London. “That’s information that often doesn’t make it into the clinical psychiatric record,” said Dr. Downs.

Half of the 3,032 subjects were diagnosed with ASD at ages 6 to 12 and another 39% at ages 13 to 17. During five years of prospective follow-up after being diagnosed with ASD, 25.5% of patients were diagnosed with comorbid ADHD. When reviewing early physical health records, researchers observed that 114 (3.76%) of study participants had experienced early-onset epilepsy before age 7.

A large sample size allowed for robust multivariate adjustment for potential confounders. In a multivariate analysis, patients with ASD and a history of early-onset epilepsy were at a significant 1.75-fold increased risk for subsequent comorbid ADHD. The analysis was adjusted for family history of epilepsy, sociodemographic factors, intellectual disability, previous head injury, perinatal complications, CNS tumors, early meningitis, and other confounders.

Compared with white subjects with ASD, the risk of developing comorbid ADHD was reduced by 37% in black patients and by 52% in Asian patients with ASD.

“The take-home message would be if you’ve got social and communication difficulties in a young child appearing at the age of 5, 6, or 7, and there’s a history of seizures, we are seeing from observational data that the child is at increased risk of ADHD over the age of 7,” said Dr. Downs.

—Bruce Jancin

VIENNA—Early-onset idiopathic epi­lepsy occurring before age 7 nearly doubles the likelihood that a child with autism spectrum disorder (ASD) will later develop comorbid ADHD, reported Johnny Downs, MD, a child psychiatrist at King’s College in London, at the 29th Annual Congress of the European College of Neuropsychopharmacology.

Comorbid ADHD is common in the setting of ASD. In a search for risk factors for the comorbid condition, Dr. Downs and his colleagues reviewed the physical health records prior to age 7 of 3,032 patients with ASD referred at ages 3 to 17 to child and adolescent mental health services clinics serving South London. “That’s information that often doesn’t make it into the clinical psychiatric record,” said Dr. Downs.

Half of the 3,032 subjects were diagnosed with ASD at ages 6 to 12 and another 39% at ages 13 to 17. During five years of prospective follow-up after being diagnosed with ASD, 25.5% of patients were diagnosed with comorbid ADHD. When reviewing early physical health records, researchers observed that 114 (3.76%) of study participants had experienced early-onset epilepsy before age 7.

A large sample size allowed for robust multivariate adjustment for potential confounders. In a multivariate analysis, patients with ASD and a history of early-onset epilepsy were at a significant 1.75-fold increased risk for subsequent comorbid ADHD. The analysis was adjusted for family history of epilepsy, sociodemographic factors, intellectual disability, previous head injury, perinatal complications, CNS tumors, early meningitis, and other confounders.

Compared with white subjects with ASD, the risk of developing comorbid ADHD was reduced by 37% in black patients and by 52% in Asian patients with ASD.

“The take-home message would be if you’ve got social and communication difficulties in a young child appearing at the age of 5, 6, or 7, and there’s a history of seizures, we are seeing from observational data that the child is at increased risk of ADHD over the age of 7,” said Dr. Downs.

—Bruce Jancin

VIENNA—Early-onset idiopathic epi­lepsy occurring before age 7 nearly doubles the likelihood that a child with autism spectrum disorder (ASD) will later develop comorbid ADHD, reported Johnny Downs, MD, a child psychiatrist at King’s College in London, at the 29th Annual Congress of the European College of Neuropsychopharmacology.

Comorbid ADHD is common in the setting of ASD. In a search for risk factors for the comorbid condition, Dr. Downs and his colleagues reviewed the physical health records prior to age 7 of 3,032 patients with ASD referred at ages 3 to 17 to child and adolescent mental health services clinics serving South London. “That’s information that often doesn’t make it into the clinical psychiatric record,” said Dr. Downs.

Half of the 3,032 subjects were diagnosed with ASD at ages 6 to 12 and another 39% at ages 13 to 17. During five years of prospective follow-up after being diagnosed with ASD, 25.5% of patients were diagnosed with comorbid ADHD. When reviewing early physical health records, researchers observed that 114 (3.76%) of study participants had experienced early-onset epilepsy before age 7.

A large sample size allowed for robust multivariate adjustment for potential confounders. In a multivariate analysis, patients with ASD and a history of early-onset epilepsy were at a significant 1.75-fold increased risk for subsequent comorbid ADHD. The analysis was adjusted for family history of epilepsy, sociodemographic factors, intellectual disability, previous head injury, perinatal complications, CNS tumors, early meningitis, and other confounders.

Compared with white subjects with ASD, the risk of developing comorbid ADHD was reduced by 37% in black patients and by 52% in Asian patients with ASD.

“The take-home message would be if you’ve got social and communication difficulties in a young child appearing at the age of 5, 6, or 7, and there’s a history of seizures, we are seeing from observational data that the child is at increased risk of ADHD over the age of 7,” said Dr. Downs.

—Bruce Jancin

The current labeling for the antimalarial mefloquine is inconsistent internationally with medication guides regarding certain adverse reactions, including depression and anxiety, according to a review of drug labels and medication guides from six English-speaking countries.

Neuropsychiatric reactions have been reported by 29% to 77% of mefloquine users at prophylactic doses of 250 mg per week, wrote Remington L. Nevin, MD, MPH, of Johns Hopkins University in Baltimore, and Aricia M. Byrd, an MD student at Trinity School of Medicine, Kingstown, St. Vincent and the Grenadines. “Neuropsychiatric adverse reactions may occur early during use – frequently within the first three doses – and may even occur after only a single dose,” the researchers said (Neurol Ther. 2016 Jun;5[1]:69-83).

In addition, data suggest that the neuropsychiatric adverse reactions, including nightmares and cognitive dysfunction, can last many years after the drug has been discontinued, and a black box warning was added to the U.S. label in 2013 to emphasize the potential long-term impact, Dr. Nevin and Ms. Byrd reported.

In this study, Dr. Nevin and Ms. Byrd compared prescribing information and patient safety guidance in the United States and five other English-speaking countries: the United Kingdom, Ireland, Australia, Canada, and New Zealand.

At the time of the study, mefloquine was licensed in all six countries, but the innovator product was withdrawn from the United States in 2011 and from Canada in 2013.

In addition to the United States, the United Kingdom and Ireland recommended discontinuing mefloquine at the onset of any general neurologic or psychiatric symptoms, the researchers noted.

All six countries were in complete agreement with corresponding medication guides and drug labeling that recommended discontinuing mefloquine or consulting a healthcare provider if adverse reactions occurred within four high level group terms (HLGTs): anxiety disorders and symptoms, changes in physical activity, depressed mood disorders and disturbances, and deliria (including confusion).

Three of the six countries (the United States, the United Kingdom, and Ireland) show partial agreement in medication guides and drug labeling recommendations to discontinue the drug or consult a healthcare provider in the instance of three other HLGTs: disturbances in thinking and perception, personality disorders and disturbances in behavior, and suicidal and self-injurious behaviors not elsewhere classified. The United Kingdom and Ireland also showed partial agreement in corresponding medication guides and drug labeling, drug discontinuation, or consulting a healthcare provider for the following adverse reactions: neuromuscular disorders, sleep disorders and disturbances, and peripheral neuropathies.

In the United States alone, medication guides and drug labeling corresponded in terms of drug discontinuation or healthcare provider consultation in cases of cranial nerve disorders, excluding neoplasms and neurologic disorders not elsewhere classified. For nine other areas of adverse reactions, medication guidelines recommended healthcare provider consultation, but no corresponding guidance was found on the drug labeling.

The review was limited by several factors, including the use of data from only six countries and the subjective interpretation of the language used in the drug labeling and medication guides, the researchers noted.

However, the results “suggest opportunities for physicians in these countries to improve patient counseling by specifically emphasizing the need to discontinue at the onset of these adverse reactions,” they said.

“The results of this analysis also suggest opportunities for international drug regulators to clarify language in future updates to remaining mefloquine drug labels and medication guides to better reflect national risk-benefit considerations for continued use of the drug,” they concluded.

Dr. Nevin disclosed that he has been retained as consultant and expert witness in legal cases involving antimalarial drug toxicity claims. Ms. Byrd had no financial conflicts to disclose.
 

The current labeling for the antimalarial mefloquine is inconsistent internationally with medication guides regarding certain adverse reactions, including depression and anxiety, according to a review of drug labels and medication guides from six English-speaking countries.

Neuropsychiatric reactions have been reported by 29% to 77% of mefloquine users at prophylactic doses of 250 mg per week, wrote Remington L. Nevin, MD, MPH, of Johns Hopkins University in Baltimore, and Aricia M. Byrd, an MD student at Trinity School of Medicine, Kingstown, St. Vincent and the Grenadines. “Neuropsychiatric adverse reactions may occur early during use – frequently within the first three doses – and may even occur after only a single dose,” the researchers said (Neurol Ther. 2016 Jun;5[1]:69-83).

In addition, data suggest that the neuropsychiatric adverse reactions, including nightmares and cognitive dysfunction, can last many years after the drug has been discontinued, and a black box warning was added to the U.S. label in 2013 to emphasize the potential long-term impact, Dr. Nevin and Ms. Byrd reported.

In this study, Dr. Nevin and Ms. Byrd compared prescribing information and patient safety guidance in the United States and five other English-speaking countries: the United Kingdom, Ireland, Australia, Canada, and New Zealand.

At the time of the study, mefloquine was licensed in all six countries, but the innovator product was withdrawn from the United States in 2011 and from Canada in 2013.

In addition to the United States, the United Kingdom and Ireland recommended discontinuing mefloquine at the onset of any general neurologic or psychiatric symptoms, the researchers noted.

All six countries were in complete agreement with corresponding medication guides and drug labeling that recommended discontinuing mefloquine or consulting a healthcare provider if adverse reactions occurred within four high level group terms (HLGTs): anxiety disorders and symptoms, changes in physical activity, depressed mood disorders and disturbances, and deliria (including confusion).

Three of the six countries (the United States, the United Kingdom, and Ireland) show partial agreement in medication guides and drug labeling recommendations to discontinue the drug or consult a healthcare provider in the instance of three other HLGTs: disturbances in thinking and perception, personality disorders and disturbances in behavior, and suicidal and self-injurious behaviors not elsewhere classified. The United Kingdom and Ireland also showed partial agreement in corresponding medication guides and drug labeling, drug discontinuation, or consulting a healthcare provider for the following adverse reactions: neuromuscular disorders, sleep disorders and disturbances, and peripheral neuropathies.

In the United States alone, medication guides and drug labeling corresponded in terms of drug discontinuation or healthcare provider consultation in cases of cranial nerve disorders, excluding neoplasms and neurologic disorders not elsewhere classified. For nine other areas of adverse reactions, medication guidelines recommended healthcare provider consultation, but no corresponding guidance was found on the drug labeling.

The review was limited by several factors, including the use of data from only six countries and the subjective interpretation of the language used in the drug labeling and medication guides, the researchers noted.

However, the results “suggest opportunities for physicians in these countries to improve patient counseling by specifically emphasizing the need to discontinue at the onset of these adverse reactions,” they said.

“The results of this analysis also suggest opportunities for international drug regulators to clarify language in future updates to remaining mefloquine drug labels and medication guides to better reflect national risk-benefit considerations for continued use of the drug,” they concluded.

Dr. Nevin disclosed that he has been retained as consultant and expert witness in legal cases involving antimalarial drug toxicity claims. Ms. Byrd had no financial conflicts to disclose.
 

The current labeling for the antimalarial mefloquine is inconsistent internationally with medication guides regarding certain adverse reactions, including depression and anxiety, according to a review of drug labels and medication guides from six English-speaking countries.

Neuropsychiatric reactions have been reported by 29% to 77% of mefloquine users at prophylactic doses of 250 mg per week, wrote Remington L. Nevin, MD, MPH, of Johns Hopkins University in Baltimore, and Aricia M. Byrd, an MD student at Trinity School of Medicine, Kingstown, St. Vincent and the Grenadines. “Neuropsychiatric adverse reactions may occur early during use – frequently within the first three doses – and may even occur after only a single dose,” the researchers said (Neurol Ther. 2016 Jun;5[1]:69-83).

In addition, data suggest that the neuropsychiatric adverse reactions, including nightmares and cognitive dysfunction, can last many years after the drug has been discontinued, and a black box warning was added to the U.S. label in 2013 to emphasize the potential long-term impact, Dr. Nevin and Ms. Byrd reported.

In this study, Dr. Nevin and Ms. Byrd compared prescribing information and patient safety guidance in the United States and five other English-speaking countries: the United Kingdom, Ireland, Australia, Canada, and New Zealand.

At the time of the study, mefloquine was licensed in all six countries, but the innovator product was withdrawn from the United States in 2011 and from Canada in 2013.

In addition to the United States, the United Kingdom and Ireland recommended discontinuing mefloquine at the onset of any general neurologic or psychiatric symptoms, the researchers noted.

All six countries were in complete agreement with corresponding medication guides and drug labeling that recommended discontinuing mefloquine or consulting a healthcare provider if adverse reactions occurred within four high level group terms (HLGTs): anxiety disorders and symptoms, changes in physical activity, depressed mood disorders and disturbances, and deliria (including confusion).

Three of the six countries (the United States, the United Kingdom, and Ireland) show partial agreement in medication guides and drug labeling recommendations to discontinue the drug or consult a healthcare provider in the instance of three other HLGTs: disturbances in thinking and perception, personality disorders and disturbances in behavior, and suicidal and self-injurious behaviors not elsewhere classified. The United Kingdom and Ireland also showed partial agreement in corresponding medication guides and drug labeling, drug discontinuation, or consulting a healthcare provider for the following adverse reactions: neuromuscular disorders, sleep disorders and disturbances, and peripheral neuropathies.

In the United States alone, medication guides and drug labeling corresponded in terms of drug discontinuation or healthcare provider consultation in cases of cranial nerve disorders, excluding neoplasms and neurologic disorders not elsewhere classified. For nine other areas of adverse reactions, medication guidelines recommended healthcare provider consultation, but no corresponding guidance was found on the drug labeling.

The review was limited by several factors, including the use of data from only six countries and the subjective interpretation of the language used in the drug labeling and medication guides, the researchers noted.

However, the results “suggest opportunities for physicians in these countries to improve patient counseling by specifically emphasizing the need to discontinue at the onset of these adverse reactions,” they said.

“The results of this analysis also suggest opportunities for international drug regulators to clarify language in future updates to remaining mefloquine drug labels and medication guides to better reflect national risk-benefit considerations for continued use of the drug,” they concluded.

Dr. Nevin disclosed that he has been retained as consultant and expert witness in legal cases involving antimalarial drug toxicity claims. Ms. Byrd had no financial conflicts to disclose.
 

This article by Adam Weizman and colleagues is the first of a three-part series that will provide practical advice for practices that wish to develop a quality initiative. The first article, “Launching a quality improvement initiative” describes the infrastructure, personnel, and structure needed to approach an identified problem within a practice (variability in adenoma detection rates). This case-based approach helps us understand the step-by-step approach needed to reduce variability and improve quality. The authors present a plan (road map) in a straightforward and practical way that seems simple, but if followed carefully, leads to success. These articles are rich in resources and link to state-of-the-art advice.

John I. Allen, MD, MBA, AGAF, Special Section Editor

There has been increasing focus on measuring quality indicators in gastroenterology over the past few years. The adenoma detection rate (ADR) has emerged as one of the most important quality indicators because it is supported by robust clinical evidence.^1-3 With every 1% increase in ADR, a 3% reduction in interval colorectal cancer has been noted.³ As such, an ADR of 25% has been designated as an important quality target for all endoscopists who perform colorectal cancer screening.¹

You work at a community hospital in a large, metropolitan area. Your colleagues in a number of other departments across your hospital have been increasingly interested in quality improvement (QI) and have launched QI interventions, although none in your department. Moreover, there have been reforms in how hospital endoscopy units are funded in your jurisdiction, with a move toward volume-based funding with a quality overlay. In an effort to improve efficiency and better characterize performance, the hospital has been auditing the performance of all endoscopists at your institution over the past year. Among the eight endoscopists who work at your hospital, the overall ADR has been found to be 19%, decreasing to less than the generally accepted benchmark.¹

In response to the results of the audit in your unit, you decide that you would like to develop an initiative to improve your group’s ADR.

Forming a quality improvement team

The first step in any QI project is to establish an improvement team. This working group consists of individuals with specific roles who perform interdependent tasks and share a common goal.⁴ Usually, frontline health care workers who are impacted most by the quality-of-care problem form the foundation of the team. A team lead is identified who will oversee the project. Content experts are also helpful members of the team who may have particular expertise in the clinical domain that will be the focus of the project. In addition, an improvement adviser, an individual with some expertise in QI, is needed on the team. This adviser may be from within your department or from outside. Although they may not possess expertise in the clinical problem you are trying to tackle, they should have skills in QI methodology and process to aid the team. An executive sponsor also needs to be identified. This should be an influential and well-respected individual who holds a senior administrative position at your institution who can help the team overcome barriers and secure resources. Physician engagement is a critical, often-overlooked step in any improvement effort. Regardless of the initiative, physicians continue to have tremendous influence over hospital-based outcomes.⁵ Identifying a physician champion, a prominent and respected physician at your organization to help spread the importance of your efforts and create a burning platform for change, is helpful. It also is valuable to have a patient on the improvement team to provide unique perspectives that only the end user of health care can convey and to ensure that the project is patient centered, as all improvement efforts should be.⁶

Improvement framework

Before starting any improvement effort, there are several important considerations that need to be addressed when choosing a quality improvement target.7 It is important to have a good understanding of the burden and severity of the problem. This often requires audit and measuring. For example, although we may think there is a problem with ADR in our endoscopy unit based on a general impression, it is critical to have data to support this suspicion. This is part of a current state analysis (discussed later). It also is important to select a quality-of-care problem that is under you or your group’s direct control. For example, it would be difficult to initiate a quality improvement project aimed at changing the practice of radiology reporting as a gastroenterologist. It is important to pick a problem that is focused and within a narrow scope that is feasible to address and then improve. Consideration of the unintended consequences of an improvement initiative often is overlooked, but needs to be considered because not all that comes out of quality improvement efforts is good. Finally, the likelihood of success of a quality initiative is increased significantly if it can generate momentum and lead to other interventions both within your department and beyond.

There are several specific improvement frameworks that can be used by a team to address a quality-of-care problem and perform a quality improvement project. The framework chosen depends on the type of problem that is being targeted and the training of the individuals on the improvement team. Three of the most commonly used improvement frameworks include the following: 1) Six Sigma; 2) Lean; and 3) Model for Improvement.

AGA Institute

Six Sigma

Six Sigma is focused on improvement by reducing variability.⁸ It is a highly analytic framework relying on statistical analysis and mathematical modeling. It is best suited for projects in which the root cause and contributors to the target problem remain unclear and the aim of the intervention is to reduce variation.

Lean

Lean emphasizes improvement through elimination of waste and classifies all parts of any process as value added and nonvalue added.⁹ It is estimated that 95% of activities in any health care process are nonvalue added and the objective of Lean is to identify opportunities to simplify and create efficiencies. It is best suited for target problems that directly can be observed and mapped out, for example, process of care, flow, and efficiency of an endoscopy unit.

Model for Improvement

The Model for Improvement has been popularized by the Institute for Healthcare Improvement.^10,11 It is well suited for health care teams, and its advantages are its adaptability to many improvement targets and lack of extensive training, consultant support, or statistical training as required by the previous frameworks mentioned earlier. As a result, it is the most commonly used improvement framework.

Using the Model for Improvement

The Model for Improvement is organized around three main questions: 1) What are we trying to accomplish? 2) How will we know that a change is an improvement? and 3) What changes can result in improvement?

Question 1: What are we trying to accomplish?

The first stage using the Model for Improvement is developing a clear project aim. A good aim statement should be specific in defining what measures one is hoping to improve and setting a concrete deadline by which to achieve it.^10,11 It should answer the questions of what the team is trying to improve, by how much, and by what date. It is more effective for the target to be an ambitious, stretch goal to ensure the effort is worth the resources and time that will be invested by the team. Not only does a good aim statement serve as the foundation for the project, but it can redirect the team if the improvement effort is getting off track. In the earlier example of improving ADR, an aim statement could be “to increase the ADR of all endoscopists who perform colonoscopy at your hospital to 25% over a 12-month period.”

Question 2: How will we know that a change is an improvement?

This step involves defining measures that will allow you to understand if changes implemented are impacting the system within which your target problem resides and if this represents an improvement. This usually involves continuous, real-time measurement. Outcome measures are clinically relevant outcomes and are the ultimate goal of what the project team is trying to accomplish. In the example of ADR, this could be the proportion of endoscopists at your institution with an ADR greater than 25%. Process measures are relevant to the system within which you are working and your target problem resides. Typically, the intervention that you implement will have impact that is measurable much earlier by process outcomes than outcomes measures, which are usually a downstream effect. As such, an improvement project still may be a success if it shows improvements in process measures only. For example, the proportion of endoscopists measuring withdrawal time would be a process measure in an intervention aimed at improving ADR. In time, improvement in process measures may translate to improvements in the outcome measure. Balancing measures are indicators of unintended consequences of the project. Not all that comes from an improvement effort is necessarily positive. If improvements in certain process measures come at the cost of harms shown by the balancing measures, such as deterioration in staff satisfaction or increase in time per procedure, the improvement project may not be worth continuing.

Importance of understanding the target problem: Current-state analysis

In contrast to classic enumerative research in which the clinical environment can be well controlled, quality improvement work focuses on sampling and intervening upon a less controlled and dynamic process or system with the intent of improving it.¹⁰ Just as treatment strategies in clinical medicine are based on diagnostic testing, so too in quality improvement work, the strategy of diagnosing the current state allows for linking the root cause of quality problems with solutions that can induce positive change.

Several common diagnostic tools are used to identify root causes of quality and safety issues. These include the following: 1) process mapping, 2) cause-and-effect diagrams, and 3) Pareto charts.

Process mapping

Process maps are tools used to understand the system that is being studied. A process map is a graphic depiction of the flow through a process, which creates a collaborative awareness of the current state and identifies opportunities for improvement. It is important that multiple individuals who have knowledge of the process in question are involved in its creation. Process maps are created by first establishing the start and end of the process. Second, the high-level steps are included. Third, a more detailed set of steps can be included within each of the high-level steps.

Cause-and-effect diagrams

Cause-and-effect diagrams, also known as Ishikawa or fishbone diagrams, are helpful brainstorming tools used to graphically display and explore potential causes of a target problem. They illustrate that there often are many contributing factors to one underlying problem and the relationship between contributing factors. Classic examples of categories include equipment, environment, materials, methods and process, people, and measurement.¹⁰ Figure 1 provides an example of these tools in an effort to improve ADR.
 

To identify the most important contributors to the target problem and thus where to focus improvement efforts, a Pareto chart, a bar graph that places all defects/causes in the order of the frequency in which they occur, is constructed. The x-axis is a list of possible defects (Figure 1). The y-axis is the frequency with which any one defect is occurring, and the third (x-2) axis is the cumulative frequency. In theory, it is expected that there will be a vital few defects that account for 80% of all occurrences (referred to by some as the 80:20 rule).10, 11 Populating this graph requires measurement, which, as discussed earlier, is the key to understanding any problem. Measurement can be accomplished through direct observation/audit, chart review, and/or multivoting.

Question 3: What changes can result in improvement?

Once the improvement team has defined an aim and established its family of measures, it is time to develop and implement an intervention. Rather than investing time and resources into one intervention that may or may not be successful, it is preferable to perform small change cycles in which the intervention is conducted on a small scale, refined, and either repeated or changed. As a result, most quality improvement projects consist of an iterative process. The Model for Improvement defines four steps that allow the improvement team to perform this: Plan, do, study, act (PDSA).^4,10,11 The first two questions listed earlier allowed the improvement team to plan the intervention. The next step, do, involves implementing your project on a small scale, thereby testing your change while collecting continuous measurements. Study involves interpreting your data using both conventional methods and several improvement-specific methods (discussed later) that help answer the question of how will we know that a change is improvement? Finally, act involves making a conclusion about your first PDSA cycle, helping to inform subsequent cycles. This results in a series of small, rapid cycle changes, one building on the next, that lead to implementation of change(s) that ultimately serve to address your improvement problem and your project aim.

A change concept is an approach known to be useful in developing specific changes that result in improvement. Change concepts are used as a starting point to generate change ideas. A number of change concepts spanning nine main categories have been defined by the Associates for Process Improvement,¹⁰ including eliminating waste, improving work flow, managing variation, and designing systems to prevent error. For the purpose of improving ADR, your team may choose a few change concepts and ideas based on the diagnostic work-up. For example, the change concept of designing the system to prevent errors through standardizing withdrawal time for all physicians may lead to an improvement in ADR. This then is linked to the change idea of audible timers placed in endoscopy suites to ensure longer withdrawal times.¹² The impact of this change would be measured and the next cycle would build on these results.
 

Summary and next steps

In this first article of the series, the QI team moved forward with their aim to increase ADR. A root cause analysis was undertaken using multiple diagnostic tools including a fishbone diagram and a Pareto chart. Finally, change ideas were generated based on the earlier-described root causes and established change concepts. The next steps involve undertaking PDSA cycles to test change ideas and monitor for improvement.

References

1. Rex, D.K., Schoenfeld, P.S., Cohen, J. et al. Quality indicators for colonoscopy. Gastrointest Endosc. 2015;81:31-53.

2. Rex, D.K., Bond, J.H., Winawer, S. et al. Quality in the technical performance of colonoscopy and the continuous quality improvement process for colonoscopy: recommendations of the U.S. Multi-Society Task Force on Colorectal Cancer. Am J Gastroenterol. 2002;97:1296-308.

3. Corley, D., Jensen, C.D., Marks, A.R. et al. Adenoma detection rate and risk of colorectal cancer and death. N Engl J Med. 2014;370:1298-306.
4. Kotter, J.P. Leading change. Harvard Business Review Press, Boston; 2012

5. Taitz, J.M., Lee, T.H., and Sequist, T.D. A framework for engaging physicians in quality and safety. BMJ Qual Saf. 2012;21:722-8.

6. Carman, K.L., Dardess, P., Maurer, M. et al. Patient and family engagement: a framework for understanding the elements and developing interventions and policies. Health Aff (Millwood). 2013;33:223-31.

7.Ranji, S.R. and Shojania, S.G. Implementing patient safety interventions in your hospital: what to try and what to avoid. Med Clin North Am. 2008;92:275-93.

8. Antony, J. Six Sigma vs Lean: some perspectives from leading academics and practitioners. Int J Product Perform Manage. 2011;60:185-90.

9. Bercaw, R. Taking improvement from the assembly line to healthcare: the application of lean within the healthcare industry. Taylor and Francis, Boca Raton, FL; 2012

10. Langley, G.J., Nolan, K.M., Nolan, T.W. et al. The improvement guide: a practical approach to enhancing organizational performance. Jossey-Bass, San Francisco; 2009

11. Berwick, D.M. A primer on leading the improvement of systems. BMJ. 1996;312:619-22.

12. Corley, D.A., Jensen, C.D., and Marks, A.R. Can we improve adenoma detection rates? A systematic review of intervention studies. Gastrointest Endosc. 2011;74:656-65.

Dr. Weizman is at the Mount Sinai Hospital Centre for Inflammatory Bowel Disease, and Institute of Health Policy, Management and Evaluation, department of medicine; Dr. Mosko is in the division of gastroenterology, St. Michael’s Hospital, department of medicine, and Institute of Health Policy, Management and Evaluation; Dr. Bollegala is in the division of gastroenterology, Women’s College Hospital, department of medicine; Dr. Bernstein is in the division of gastroenterology, Sunnybrook Health Sciences Centre, department of medicine; Dr. Brahmania is at the Toronto Center for Liver Diseases, division of gastroenterology, University Health Network, department of medicine; Dr. Liu is in the division of gastroenterology, University Health Network, department of medicine; Dr. Steinhart is at Mount Sinai Hospital Centre for Inflammatory Bowel Disease, department of medicine, and Institute of Health Policy, Management and Evaluation; Dr. Silver is in the division of nephrology, St. Michael’s Hospital; Dr. Bell is in the division of internal medicine, Mount Sinai Hospital, department of medicine, and Institute of Health Policy, Management and Evaluation; and Dr. Nguyen is at Mount Sinai Hospital Centre for Inflammatory Bowel Disease, department of medicine and Institute of Health Policy, Management and Evaluation; all are at the University of Toronto. Dr. Steinhart is an advisory board member for Abbvie, Janssen, Takeda, Shire, Allergan, Pfizer, Merck, Ferring, and Pharmascience; has received research grants from Abbvie, Amgen, Genentech, Cellgene, Arena Pharmaceuticals, Red Hill Biopharma, Millenium, Roche, and Centocor; and has received speaking honoraria from Abbvie, Janssen, Takeda, Shire, Pfizer, Merck, and Ferring.

The remaining authors declare no conflicts for this article.

This article by Adam Weizman and colleagues is the first of a three-part series that will provide practical advice for practices that wish to develop a quality initiative. The first article, “Launching a quality improvement initiative” describes the infrastructure, personnel, and structure needed to approach an identified problem within a practice (variability in adenoma detection rates). This case-based approach helps us understand the step-by-step approach needed to reduce variability and improve quality. The authors present a plan (road map) in a straightforward and practical way that seems simple, but if followed carefully, leads to success. These articles are rich in resources and link to state-of-the-art advice.

John I. Allen, MD, MBA, AGAF, Special Section Editor

There has been increasing focus on measuring quality indicators in gastroenterology over the past few years. The adenoma detection rate (ADR) has emerged as one of the most important quality indicators because it is supported by robust clinical evidence.^1-3 With every 1% increase in ADR, a 3% reduction in interval colorectal cancer has been noted.³ As such, an ADR of 25% has been designated as an important quality target for all endoscopists who perform colorectal cancer screening.¹

You work at a community hospital in a large, metropolitan area. Your colleagues in a number of other departments across your hospital have been increasingly interested in quality improvement (QI) and have launched QI interventions, although none in your department. Moreover, there have been reforms in how hospital endoscopy units are funded in your jurisdiction, with a move toward volume-based funding with a quality overlay. In an effort to improve efficiency and better characterize performance, the hospital has been auditing the performance of all endoscopists at your institution over the past year. Among the eight endoscopists who work at your hospital, the overall ADR has been found to be 19%, decreasing to less than the generally accepted benchmark.¹

In response to the results of the audit in your unit, you decide that you would like to develop an initiative to improve your group’s ADR.

Forming a quality improvement team

The first step in any QI project is to establish an improvement team. This working group consists of individuals with specific roles who perform interdependent tasks and share a common goal.⁴ Usually, frontline health care workers who are impacted most by the quality-of-care problem form the foundation of the team. A team lead is identified who will oversee the project. Content experts are also helpful members of the team who may have particular expertise in the clinical domain that will be the focus of the project. In addition, an improvement adviser, an individual with some expertise in QI, is needed on the team. This adviser may be from within your department or from outside. Although they may not possess expertise in the clinical problem you are trying to tackle, they should have skills in QI methodology and process to aid the team. An executive sponsor also needs to be identified. This should be an influential and well-respected individual who holds a senior administrative position at your institution who can help the team overcome barriers and secure resources. Physician engagement is a critical, often-overlooked step in any improvement effort. Regardless of the initiative, physicians continue to have tremendous influence over hospital-based outcomes.⁵ Identifying a physician champion, a prominent and respected physician at your organization to help spread the importance of your efforts and create a burning platform for change, is helpful. It also is valuable to have a patient on the improvement team to provide unique perspectives that only the end user of health care can convey and to ensure that the project is patient centered, as all improvement efforts should be.⁶

Improvement framework

Before starting any improvement effort, there are several important considerations that need to be addressed when choosing a quality improvement target.7 It is important to have a good understanding of the burden and severity of the problem. This often requires audit and measuring. For example, although we may think there is a problem with ADR in our endoscopy unit based on a general impression, it is critical to have data to support this suspicion. This is part of a current state analysis (discussed later). It also is important to select a quality-of-care problem that is under you or your group’s direct control. For example, it would be difficult to initiate a quality improvement project aimed at changing the practice of radiology reporting as a gastroenterologist. It is important to pick a problem that is focused and within a narrow scope that is feasible to address and then improve. Consideration of the unintended consequences of an improvement initiative often is overlooked, but needs to be considered because not all that comes out of quality improvement efforts is good. Finally, the likelihood of success of a quality initiative is increased significantly if it can generate momentum and lead to other interventions both within your department and beyond.

There are several specific improvement frameworks that can be used by a team to address a quality-of-care problem and perform a quality improvement project. The framework chosen depends on the type of problem that is being targeted and the training of the individuals on the improvement team. Three of the most commonly used improvement frameworks include the following: 1) Six Sigma; 2) Lean; and 3) Model for Improvement.

AGA Institute

Six Sigma

Six Sigma is focused on improvement by reducing variability.⁸ It is a highly analytic framework relying on statistical analysis and mathematical modeling. It is best suited for projects in which the root cause and contributors to the target problem remain unclear and the aim of the intervention is to reduce variation.

Lean

Lean emphasizes improvement through elimination of waste and classifies all parts of any process as value added and nonvalue added.⁹ It is estimated that 95% of activities in any health care process are nonvalue added and the objective of Lean is to identify opportunities to simplify and create efficiencies. It is best suited for target problems that directly can be observed and mapped out, for example, process of care, flow, and efficiency of an endoscopy unit.

Model for Improvement

The Model for Improvement has been popularized by the Institute for Healthcare Improvement.^10,11 It is well suited for health care teams, and its advantages are its adaptability to many improvement targets and lack of extensive training, consultant support, or statistical training as required by the previous frameworks mentioned earlier. As a result, it is the most commonly used improvement framework.

Using the Model for Improvement

The Model for Improvement is organized around three main questions: 1) What are we trying to accomplish? 2) How will we know that a change is an improvement? and 3) What changes can result in improvement?

Question 1: What are we trying to accomplish?

The first stage using the Model for Improvement is developing a clear project aim. A good aim statement should be specific in defining what measures one is hoping to improve and setting a concrete deadline by which to achieve it.^10,11 It should answer the questions of what the team is trying to improve, by how much, and by what date. It is more effective for the target to be an ambitious, stretch goal to ensure the effort is worth the resources and time that will be invested by the team. Not only does a good aim statement serve as the foundation for the project, but it can redirect the team if the improvement effort is getting off track. In the earlier example of improving ADR, an aim statement could be “to increase the ADR of all endoscopists who perform colonoscopy at your hospital to 25% over a 12-month period.”

Question 2: How will we know that a change is an improvement?

This step involves defining measures that will allow you to understand if changes implemented are impacting the system within which your target problem resides and if this represents an improvement. This usually involves continuous, real-time measurement. Outcome measures are clinically relevant outcomes and are the ultimate goal of what the project team is trying to accomplish. In the example of ADR, this could be the proportion of endoscopists at your institution with an ADR greater than 25%. Process measures are relevant to the system within which you are working and your target problem resides. Typically, the intervention that you implement will have impact that is measurable much earlier by process outcomes than outcomes measures, which are usually a downstream effect. As such, an improvement project still may be a success if it shows improvements in process measures only. For example, the proportion of endoscopists measuring withdrawal time would be a process measure in an intervention aimed at improving ADR. In time, improvement in process measures may translate to improvements in the outcome measure. Balancing measures are indicators of unintended consequences of the project. Not all that comes from an improvement effort is necessarily positive. If improvements in certain process measures come at the cost of harms shown by the balancing measures, such as deterioration in staff satisfaction or increase in time per procedure, the improvement project may not be worth continuing.

Importance of understanding the target problem: Current-state analysis

In contrast to classic enumerative research in which the clinical environment can be well controlled, quality improvement work focuses on sampling and intervening upon a less controlled and dynamic process or system with the intent of improving it.¹⁰ Just as treatment strategies in clinical medicine are based on diagnostic testing, so too in quality improvement work, the strategy of diagnosing the current state allows for linking the root cause of quality problems with solutions that can induce positive change.

Several common diagnostic tools are used to identify root causes of quality and safety issues. These include the following: 1) process mapping, 2) cause-and-effect diagrams, and 3) Pareto charts.

Process mapping

Process maps are tools used to understand the system that is being studied. A process map is a graphic depiction of the flow through a process, which creates a collaborative awareness of the current state and identifies opportunities for improvement. It is important that multiple individuals who have knowledge of the process in question are involved in its creation. Process maps are created by first establishing the start and end of the process. Second, the high-level steps are included. Third, a more detailed set of steps can be included within each of the high-level steps.

Cause-and-effect diagrams

Cause-and-effect diagrams, also known as Ishikawa or fishbone diagrams, are helpful brainstorming tools used to graphically display and explore potential causes of a target problem. They illustrate that there often are many contributing factors to one underlying problem and the relationship between contributing factors. Classic examples of categories include equipment, environment, materials, methods and process, people, and measurement.¹⁰ Figure 1 provides an example of these tools in an effort to improve ADR.
 

To identify the most important contributors to the target problem and thus where to focus improvement efforts, a Pareto chart, a bar graph that places all defects/causes in the order of the frequency in which they occur, is constructed. The x-axis is a list of possible defects (Figure 1). The y-axis is the frequency with which any one defect is occurring, and the third (x-2) axis is the cumulative frequency. In theory, it is expected that there will be a vital few defects that account for 80% of all occurrences (referred to by some as the 80:20 rule).10, 11 Populating this graph requires measurement, which, as discussed earlier, is the key to understanding any problem. Measurement can be accomplished through direct observation/audit, chart review, and/or multivoting.

Question 3: What changes can result in improvement?

Once the improvement team has defined an aim and established its family of measures, it is time to develop and implement an intervention. Rather than investing time and resources into one intervention that may or may not be successful, it is preferable to perform small change cycles in which the intervention is conducted on a small scale, refined, and either repeated or changed. As a result, most quality improvement projects consist of an iterative process. The Model for Improvement defines four steps that allow the improvement team to perform this: Plan, do, study, act (PDSA).^4,10,11 The first two questions listed earlier allowed the improvement team to plan the intervention. The next step, do, involves implementing your project on a small scale, thereby testing your change while collecting continuous measurements. Study involves interpreting your data using both conventional methods and several improvement-specific methods (discussed later) that help answer the question of how will we know that a change is improvement? Finally, act involves making a conclusion about your first PDSA cycle, helping to inform subsequent cycles. This results in a series of small, rapid cycle changes, one building on the next, that lead to implementation of change(s) that ultimately serve to address your improvement problem and your project aim.

A change concept is an approach known to be useful in developing specific changes that result in improvement. Change concepts are used as a starting point to generate change ideas. A number of change concepts spanning nine main categories have been defined by the Associates for Process Improvement,¹⁰ including eliminating waste, improving work flow, managing variation, and designing systems to prevent error. For the purpose of improving ADR, your team may choose a few change concepts and ideas based on the diagnostic work-up. For example, the change concept of designing the system to prevent errors through standardizing withdrawal time for all physicians may lead to an improvement in ADR. This then is linked to the change idea of audible timers placed in endoscopy suites to ensure longer withdrawal times.¹² The impact of this change would be measured and the next cycle would build on these results.
 

Summary and next steps

In this first article of the series, the QI team moved forward with their aim to increase ADR. A root cause analysis was undertaken using multiple diagnostic tools including a fishbone diagram and a Pareto chart. Finally, change ideas were generated based on the earlier-described root causes and established change concepts. The next steps involve undertaking PDSA cycles to test change ideas and monitor for improvement.

References

1. Rex, D.K., Schoenfeld, P.S., Cohen, J. et al. Quality indicators for colonoscopy. Gastrointest Endosc. 2015;81:31-53.

2. Rex, D.K., Bond, J.H., Winawer, S. et al. Quality in the technical performance of colonoscopy and the continuous quality improvement process for colonoscopy: recommendations of the U.S. Multi-Society Task Force on Colorectal Cancer. Am J Gastroenterol. 2002;97:1296-308.

3. Corley, D., Jensen, C.D., Marks, A.R. et al. Adenoma detection rate and risk of colorectal cancer and death. N Engl J Med. 2014;370:1298-306.
4. Kotter, J.P. Leading change. Harvard Business Review Press, Boston; 2012

5. Taitz, J.M., Lee, T.H., and Sequist, T.D. A framework for engaging physicians in quality and safety. BMJ Qual Saf. 2012;21:722-8.

6. Carman, K.L., Dardess, P., Maurer, M. et al. Patient and family engagement: a framework for understanding the elements and developing interventions and policies. Health Aff (Millwood). 2013;33:223-31.

7.Ranji, S.R. and Shojania, S.G. Implementing patient safety interventions in your hospital: what to try and what to avoid. Med Clin North Am. 2008;92:275-93.

8. Antony, J. Six Sigma vs Lean: some perspectives from leading academics and practitioners. Int J Product Perform Manage. 2011;60:185-90.

9. Bercaw, R. Taking improvement from the assembly line to healthcare: the application of lean within the healthcare industry. Taylor and Francis, Boca Raton, FL; 2012

10. Langley, G.J., Nolan, K.M., Nolan, T.W. et al. The improvement guide: a practical approach to enhancing organizational performance. Jossey-Bass, San Francisco; 2009

11. Berwick, D.M. A primer on leading the improvement of systems. BMJ. 1996;312:619-22.

12. Corley, D.A., Jensen, C.D., and Marks, A.R. Can we improve adenoma detection rates? A systematic review of intervention studies. Gastrointest Endosc. 2011;74:656-65.

Dr. Weizman is at the Mount Sinai Hospital Centre for Inflammatory Bowel Disease, and Institute of Health Policy, Management and Evaluation, department of medicine; Dr. Mosko is in the division of gastroenterology, St. Michael’s Hospital, department of medicine, and Institute of Health Policy, Management and Evaluation; Dr. Bollegala is in the division of gastroenterology, Women’s College Hospital, department of medicine; Dr. Bernstein is in the division of gastroenterology, Sunnybrook Health Sciences Centre, department of medicine; Dr. Brahmania is at the Toronto Center for Liver Diseases, division of gastroenterology, University Health Network, department of medicine; Dr. Liu is in the division of gastroenterology, University Health Network, department of medicine; Dr. Steinhart is at Mount Sinai Hospital Centre for Inflammatory Bowel Disease, department of medicine, and Institute of Health Policy, Management and Evaluation; Dr. Silver is in the division of nephrology, St. Michael’s Hospital; Dr. Bell is in the division of internal medicine, Mount Sinai Hospital, department of medicine, and Institute of Health Policy, Management and Evaluation; and Dr. Nguyen is at Mount Sinai Hospital Centre for Inflammatory Bowel Disease, department of medicine and Institute of Health Policy, Management and Evaluation; all are at the University of Toronto. Dr. Steinhart is an advisory board member for Abbvie, Janssen, Takeda, Shire, Allergan, Pfizer, Merck, Ferring, and Pharmascience; has received research grants from Abbvie, Amgen, Genentech, Cellgene, Arena Pharmaceuticals, Red Hill Biopharma, Millenium, Roche, and Centocor; and has received speaking honoraria from Abbvie, Janssen, Takeda, Shire, Pfizer, Merck, and Ferring.

The remaining authors declare no conflicts for this article.

This article by Adam Weizman and colleagues is the first of a three-part series that will provide practical advice for practices that wish to develop a quality initiative. The first article, “Launching a quality improvement initiative” describes the infrastructure, personnel, and structure needed to approach an identified problem within a practice (variability in adenoma detection rates). This case-based approach helps us understand the step-by-step approach needed to reduce variability and improve quality. The authors present a plan (road map) in a straightforward and practical way that seems simple, but if followed carefully, leads to success. These articles are rich in resources and link to state-of-the-art advice.

John I. Allen, MD, MBA, AGAF, Special Section Editor

There has been increasing focus on measuring quality indicators in gastroenterology over the past few years. The adenoma detection rate (ADR) has emerged as one of the most important quality indicators because it is supported by robust clinical evidence.^1-3 With every 1% increase in ADR, a 3% reduction in interval colorectal cancer has been noted.³ As such, an ADR of 25% has been designated as an important quality target for all endoscopists who perform colorectal cancer screening.¹

You work at a community hospital in a large, metropolitan area. Your colleagues in a number of other departments across your hospital have been increasingly interested in quality improvement (QI) and have launched QI interventions, although none in your department. Moreover, there have been reforms in how hospital endoscopy units are funded in your jurisdiction, with a move toward volume-based funding with a quality overlay. In an effort to improve efficiency and better characterize performance, the hospital has been auditing the performance of all endoscopists at your institution over the past year. Among the eight endoscopists who work at your hospital, the overall ADR has been found to be 19%, decreasing to less than the generally accepted benchmark.¹

In response to the results of the audit in your unit, you decide that you would like to develop an initiative to improve your group’s ADR.

Forming a quality improvement team

The first step in any QI project is to establish an improvement team. This working group consists of individuals with specific roles who perform interdependent tasks and share a common goal.⁴ Usually, frontline health care workers who are impacted most by the quality-of-care problem form the foundation of the team. A team lead is identified who will oversee the project. Content experts are also helpful members of the team who may have particular expertise in the clinical domain that will be the focus of the project. In addition, an improvement adviser, an individual with some expertise in QI, is needed on the team. This adviser may be from within your department or from outside. Although they may not possess expertise in the clinical problem you are trying to tackle, they should have skills in QI methodology and process to aid the team. An executive sponsor also needs to be identified. This should be an influential and well-respected individual who holds a senior administrative position at your institution who can help the team overcome barriers and secure resources. Physician engagement is a critical, often-overlooked step in any improvement effort. Regardless of the initiative, physicians continue to have tremendous influence over hospital-based outcomes.⁵ Identifying a physician champion, a prominent and respected physician at your organization to help spread the importance of your efforts and create a burning platform for change, is helpful. It also is valuable to have a patient on the improvement team to provide unique perspectives that only the end user of health care can convey and to ensure that the project is patient centered, as all improvement efforts should be.⁶

Improvement framework

Before starting any improvement effort, there are several important considerations that need to be addressed when choosing a quality improvement target.7 It is important to have a good understanding of the burden and severity of the problem. This often requires audit and measuring. For example, although we may think there is a problem with ADR in our endoscopy unit based on a general impression, it is critical to have data to support this suspicion. This is part of a current state analysis (discussed later). It also is important to select a quality-of-care problem that is under you or your group’s direct control. For example, it would be difficult to initiate a quality improvement project aimed at changing the practice of radiology reporting as a gastroenterologist. It is important to pick a problem that is focused and within a narrow scope that is feasible to address and then improve. Consideration of the unintended consequences of an improvement initiative often is overlooked, but needs to be considered because not all that comes out of quality improvement efforts is good. Finally, the likelihood of success of a quality initiative is increased significantly if it can generate momentum and lead to other interventions both within your department and beyond.

There are several specific improvement frameworks that can be used by a team to address a quality-of-care problem and perform a quality improvement project. The framework chosen depends on the type of problem that is being targeted and the training of the individuals on the improvement team. Three of the most commonly used improvement frameworks include the following: 1) Six Sigma; 2) Lean; and 3) Model for Improvement.

AGA Institute

Six Sigma

Six Sigma is focused on improvement by reducing variability.⁸ It is a highly analytic framework relying on statistical analysis and mathematical modeling. It is best suited for projects in which the root cause and contributors to the target problem remain unclear and the aim of the intervention is to reduce variation.

Lean

Lean emphasizes improvement through elimination of waste and classifies all parts of any process as value added and nonvalue added.⁹ It is estimated that 95% of activities in any health care process are nonvalue added and the objective of Lean is to identify opportunities to simplify and create efficiencies. It is best suited for target problems that directly can be observed and mapped out, for example, process of care, flow, and efficiency of an endoscopy unit.

Model for Improvement

The Model for Improvement has been popularized by the Institute for Healthcare Improvement.^10,11 It is well suited for health care teams, and its advantages are its adaptability to many improvement targets and lack of extensive training, consultant support, or statistical training as required by the previous frameworks mentioned earlier. As a result, it is the most commonly used improvement framework.

Using the Model for Improvement

The Model for Improvement is organized around three main questions: 1) What are we trying to accomplish? 2) How will we know that a change is an improvement? and 3) What changes can result in improvement?

Question 1: What are we trying to accomplish?

The first stage using the Model for Improvement is developing a clear project aim. A good aim statement should be specific in defining what measures one is hoping to improve and setting a concrete deadline by which to achieve it.^10,11 It should answer the questions of what the team is trying to improve, by how much, and by what date. It is more effective for the target to be an ambitious, stretch goal to ensure the effort is worth the resources and time that will be invested by the team. Not only does a good aim statement serve as the foundation for the project, but it can redirect the team if the improvement effort is getting off track. In the earlier example of improving ADR, an aim statement could be “to increase the ADR of all endoscopists who perform colonoscopy at your hospital to 25% over a 12-month period.”

Question 2: How will we know that a change is an improvement?

This step involves defining measures that will allow you to understand if changes implemented are impacting the system within which your target problem resides and if this represents an improvement. This usually involves continuous, real-time measurement. Outcome measures are clinically relevant outcomes and are the ultimate goal of what the project team is trying to accomplish. In the example of ADR, this could be the proportion of endoscopists at your institution with an ADR greater than 25%. Process measures are relevant to the system within which you are working and your target problem resides. Typically, the intervention that you implement will have impact that is measurable much earlier by process outcomes than outcomes measures, which are usually a downstream effect. As such, an improvement project still may be a success if it shows improvements in process measures only. For example, the proportion of endoscopists measuring withdrawal time would be a process measure in an intervention aimed at improving ADR. In time, improvement in process measures may translate to improvements in the outcome measure. Balancing measures are indicators of unintended consequences of the project. Not all that comes from an improvement effort is necessarily positive. If improvements in certain process measures come at the cost of harms shown by the balancing measures, such as deterioration in staff satisfaction or increase in time per procedure, the improvement project may not be worth continuing.

Importance of understanding the target problem: Current-state analysis

In contrast to classic enumerative research in which the clinical environment can be well controlled, quality improvement work focuses on sampling and intervening upon a less controlled and dynamic process or system with the intent of improving it.¹⁰ Just as treatment strategies in clinical medicine are based on diagnostic testing, so too in quality improvement work, the strategy of diagnosing the current state allows for linking the root cause of quality problems with solutions that can induce positive change.

Several common diagnostic tools are used to identify root causes of quality and safety issues. These include the following: 1) process mapping, 2) cause-and-effect diagrams, and 3) Pareto charts.

Process mapping

Process maps are tools used to understand the system that is being studied. A process map is a graphic depiction of the flow through a process, which creates a collaborative awareness of the current state and identifies opportunities for improvement. It is important that multiple individuals who have knowledge of the process in question are involved in its creation. Process maps are created by first establishing the start and end of the process. Second, the high-level steps are included. Third, a more detailed set of steps can be included within each of the high-level steps.

Cause-and-effect diagrams

Cause-and-effect diagrams, also known as Ishikawa or fishbone diagrams, are helpful brainstorming tools used to graphically display and explore potential causes of a target problem. They illustrate that there often are many contributing factors to one underlying problem and the relationship between contributing factors. Classic examples of categories include equipment, environment, materials, methods and process, people, and measurement.¹⁰ Figure 1 provides an example of these tools in an effort to improve ADR.
 

To identify the most important contributors to the target problem and thus where to focus improvement efforts, a Pareto chart, a bar graph that places all defects/causes in the order of the frequency in which they occur, is constructed. The x-axis is a list of possible defects (Figure 1). The y-axis is the frequency with which any one defect is occurring, and the third (x-2) axis is the cumulative frequency. In theory, it is expected that there will be a vital few defects that account for 80% of all occurrences (referred to by some as the 80:20 rule).10, 11 Populating this graph requires measurement, which, as discussed earlier, is the key to understanding any problem. Measurement can be accomplished through direct observation/audit, chart review, and/or multivoting.

Question 3: What changes can result in improvement?

Once the improvement team has defined an aim and established its family of measures, it is time to develop and implement an intervention. Rather than investing time and resources into one intervention that may or may not be successful, it is preferable to perform small change cycles in which the intervention is conducted on a small scale, refined, and either repeated or changed. As a result, most quality improvement projects consist of an iterative process. The Model for Improvement defines four steps that allow the improvement team to perform this: Plan, do, study, act (PDSA).^4,10,11 The first two questions listed earlier allowed the improvement team to plan the intervention. The next step, do, involves implementing your project on a small scale, thereby testing your change while collecting continuous measurements. Study involves interpreting your data using both conventional methods and several improvement-specific methods (discussed later) that help answer the question of how will we know that a change is improvement? Finally, act involves making a conclusion about your first PDSA cycle, helping to inform subsequent cycles. This results in a series of small, rapid cycle changes, one building on the next, that lead to implementation of change(s) that ultimately serve to address your improvement problem and your project aim.

A change concept is an approach known to be useful in developing specific changes that result in improvement. Change concepts are used as a starting point to generate change ideas. A number of change concepts spanning nine main categories have been defined by the Associates for Process Improvement,¹⁰ including eliminating waste, improving work flow, managing variation, and designing systems to prevent error. For the purpose of improving ADR, your team may choose a few change concepts and ideas based on the diagnostic work-up. For example, the change concept of designing the system to prevent errors through standardizing withdrawal time for all physicians may lead to an improvement in ADR. This then is linked to the change idea of audible timers placed in endoscopy suites to ensure longer withdrawal times.¹² The impact of this change would be measured and the next cycle would build on these results.
 

Summary and next steps

In this first article of the series, the QI team moved forward with their aim to increase ADR. A root cause analysis was undertaken using multiple diagnostic tools including a fishbone diagram and a Pareto chart. Finally, change ideas were generated based on the earlier-described root causes and established change concepts. The next steps involve undertaking PDSA cycles to test change ideas and monitor for improvement.

References

1. Rex, D.K., Schoenfeld, P.S., Cohen, J. et al. Quality indicators for colonoscopy. Gastrointest Endosc. 2015;81:31-53.

2. Rex, D.K., Bond, J.H., Winawer, S. et al. Quality in the technical performance of colonoscopy and the continuous quality improvement process for colonoscopy: recommendations of the U.S. Multi-Society Task Force on Colorectal Cancer. Am J Gastroenterol. 2002;97:1296-308.

3. Corley, D., Jensen, C.D., Marks, A.R. et al. Adenoma detection rate and risk of colorectal cancer and death. N Engl J Med. 2014;370:1298-306.
4. Kotter, J.P. Leading change. Harvard Business Review Press, Boston; 2012

5. Taitz, J.M., Lee, T.H., and Sequist, T.D. A framework for engaging physicians in quality and safety. BMJ Qual Saf. 2012;21:722-8.

6. Carman, K.L., Dardess, P., Maurer, M. et al. Patient and family engagement: a framework for understanding the elements and developing interventions and policies. Health Aff (Millwood). 2013;33:223-31.

7.Ranji, S.R. and Shojania, S.G. Implementing patient safety interventions in your hospital: what to try and what to avoid. Med Clin North Am. 2008;92:275-93.

8. Antony, J. Six Sigma vs Lean: some perspectives from leading academics and practitioners. Int J Product Perform Manage. 2011;60:185-90.

9. Bercaw, R. Taking improvement from the assembly line to healthcare: the application of lean within the healthcare industry. Taylor and Francis, Boca Raton, FL; 2012

10. Langley, G.J., Nolan, K.M., Nolan, T.W. et al. The improvement guide: a practical approach to enhancing organizational performance. Jossey-Bass, San Francisco; 2009

11. Berwick, D.M. A primer on leading the improvement of systems. BMJ. 1996;312:619-22.

12. Corley, D.A., Jensen, C.D., and Marks, A.R. Can we improve adenoma detection rates? A systematic review of intervention studies. Gastrointest Endosc. 2011;74:656-65.

Dr. Weizman is at the Mount Sinai Hospital Centre for Inflammatory Bowel Disease, and Institute of Health Policy, Management and Evaluation, department of medicine; Dr. Mosko is in the division of gastroenterology, St. Michael’s Hospital, department of medicine, and Institute of Health Policy, Management and Evaluation; Dr. Bollegala is in the division of gastroenterology, Women’s College Hospital, department of medicine; Dr. Bernstein is in the division of gastroenterology, Sunnybrook Health Sciences Centre, department of medicine; Dr. Brahmania is at the Toronto Center for Liver Diseases, division of gastroenterology, University Health Network, department of medicine; Dr. Liu is in the division of gastroenterology, University Health Network, department of medicine; Dr. Steinhart is at Mount Sinai Hospital Centre for Inflammatory Bowel Disease, department of medicine, and Institute of Health Policy, Management and Evaluation; Dr. Silver is in the division of nephrology, St. Michael’s Hospital; Dr. Bell is in the division of internal medicine, Mount Sinai Hospital, department of medicine, and Institute of Health Policy, Management and Evaluation; and Dr. Nguyen is at Mount Sinai Hospital Centre for Inflammatory Bowel Disease, department of medicine and Institute of Health Policy, Management and Evaluation; all are at the University of Toronto. Dr. Steinhart is an advisory board member for Abbvie, Janssen, Takeda, Shire, Allergan, Pfizer, Merck, Ferring, and Pharmascience; has received research grants from Abbvie, Amgen, Genentech, Cellgene, Arena Pharmaceuticals, Red Hill Biopharma, Millenium, Roche, and Centocor; and has received speaking honoraria from Abbvie, Janssen, Takeda, Shire, Pfizer, Merck, and Ferring.

The remaining authors declare no conflicts for this article.

LONDON—Higher levels of a neuronal protein were found in the blood of patients with relapsing-remitting multiple sclerosis (RRMS) than in healthy subjects in a proof-of-concept study reported at the 32nd Annual Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Blood levels of neurofilament light chain (NfL) were 28.1 and 12.5 pg/mL, respectively, and were also found to be higher in patients with RRMS with greater disease activity seen on MRI.

As the number of gadolinium-enhancing (Gd+) lesions increased, so did the blood concentration of NfL, which was 23.9 pg/mL in patients with no Gd+ lesions, 26.7 pg/mL in those with one Gd+ lesion, 33.4 pg/mL in those with two to three Gd+ lesions, and 55.9 pg/mL in those with more than three Gd+ lesions.

“These findings support a role for NfL as a peripheral biomarker for MS,” said Jens Kuhle, MD, of University Hospital Basel in Switzerland. “There is an urgent unmet need for reliable biomarkers of neurodegeneration, besides efforts that are being done in MRI, optical coherence tomography, and evoked potentials.

“NfL is an exclusively neuronal protein. It is expressed in the cytosol of neurons, it is released upon cell injury into the CSF, and obviously it also appears in the blood circulation.” NfL in the CSF thus reflects nerve damage and had been seen in patients with MS and several other neurologic diseases, including Alzheimer’s disease, Parkinson’s disease, and ALS.

Until recently, however, it was not possible to detect NfL in the blood, as levels are around 50 to 100 times lower than in the CSF, but Dr. Kuhle and his associates have shown that an electrochemiluminescence immunoassay could detect increasing NfL levels with increasing disease activity. In the current study, Dr. Kuhle and colleagues used a Single Molecule Array Immunoassay (Quanterix). This test is based on an enzyme-linked immunoassay with more than 280,000 wells and was developed to be an ultrasensitive diagnostic platform to measure minute quantities of individual proteins. Dr. Kuhle noted that it had “significantly increased sensitivity to measure NfL in blood,” when compared with conventional enzyme-linked immunosorbent assay (ELISA) or electrochemiluminescence.

Two to three consecutive blood samples taken from 149 patients with RRMS participating in the phase III FREEDOMS trial were obtained and compared with samples from 29 similarly aged healthy individuals without MS obtained from a separate biobank.

Patients with two or more relapses in the previous 24 months had significantly higher NfL levels than those with one relapse or no relapses. Serum NfL also significantly increased with the Expanded Disability Status Scale score recorded at the time the blood samples were taken.

Furthermore, “blood NfL levels predicted subsequent brain atrophy rates,” Dr. Kuhle reported, with NfL levels at six months being highly predictive of brain volume changes at 24 months.

And, in this preliminary dataset, patients who had been treated with fingolimod versus placebo during the FREEDOMS trial had lower NfL levels at six, 12, and 24 months. Dr. Kuhle observed that the findings of this study were corroborated by other study data presented at the ECTRIMS meeting.

The FREEDOMS trial was sponsored by Novartis. Dr. Kuhle received research support and consulting fees from Biogen, Novartis, and Protagen. He also disclosed receiving speaker fees and travel expenses from Novartis and several other pharmaceutical companies. Several of Dr. Kuhle’s coinvestigators were employees of Novartis.

—Sara Freeman

LONDON—Higher levels of a neuronal protein were found in the blood of patients with relapsing-remitting multiple sclerosis (RRMS) than in healthy subjects in a proof-of-concept study reported at the 32nd Annual Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Blood levels of neurofilament light chain (NfL) were 28.1 and 12.5 pg/mL, respectively, and were also found to be higher in patients with RRMS with greater disease activity seen on MRI.

As the number of gadolinium-enhancing (Gd+) lesions increased, so did the blood concentration of NfL, which was 23.9 pg/mL in patients with no Gd+ lesions, 26.7 pg/mL in those with one Gd+ lesion, 33.4 pg/mL in those with two to three Gd+ lesions, and 55.9 pg/mL in those with more than three Gd+ lesions.

“These findings support a role for NfL as a peripheral biomarker for MS,” said Jens Kuhle, MD, of University Hospital Basel in Switzerland. “There is an urgent unmet need for reliable biomarkers of neurodegeneration, besides efforts that are being done in MRI, optical coherence tomography, and evoked potentials.

“NfL is an exclusively neuronal protein. It is expressed in the cytosol of neurons, it is released upon cell injury into the CSF, and obviously it also appears in the blood circulation.” NfL in the CSF thus reflects nerve damage and had been seen in patients with MS and several other neurologic diseases, including Alzheimer’s disease, Parkinson’s disease, and ALS.

Until recently, however, it was not possible to detect NfL in the blood, as levels are around 50 to 100 times lower than in the CSF, but Dr. Kuhle and his associates have shown that an electrochemiluminescence immunoassay could detect increasing NfL levels with increasing disease activity. In the current study, Dr. Kuhle and colleagues used a Single Molecule Array Immunoassay (Quanterix). This test is based on an enzyme-linked immunoassay with more than 280,000 wells and was developed to be an ultrasensitive diagnostic platform to measure minute quantities of individual proteins. Dr. Kuhle noted that it had “significantly increased sensitivity to measure NfL in blood,” when compared with conventional enzyme-linked immunosorbent assay (ELISA) or electrochemiluminescence.

Two to three consecutive blood samples taken from 149 patients with RRMS participating in the phase III FREEDOMS trial were obtained and compared with samples from 29 similarly aged healthy individuals without MS obtained from a separate biobank.

Patients with two or more relapses in the previous 24 months had significantly higher NfL levels than those with one relapse or no relapses. Serum NfL also significantly increased with the Expanded Disability Status Scale score recorded at the time the blood samples were taken.

Furthermore, “blood NfL levels predicted subsequent brain atrophy rates,” Dr. Kuhle reported, with NfL levels at six months being highly predictive of brain volume changes at 24 months.

And, in this preliminary dataset, patients who had been treated with fingolimod versus placebo during the FREEDOMS trial had lower NfL levels at six, 12, and 24 months. Dr. Kuhle observed that the findings of this study were corroborated by other study data presented at the ECTRIMS meeting.

The FREEDOMS trial was sponsored by Novartis. Dr. Kuhle received research support and consulting fees from Biogen, Novartis, and Protagen. He also disclosed receiving speaker fees and travel expenses from Novartis and several other pharmaceutical companies. Several of Dr. Kuhle’s coinvestigators were employees of Novartis.

—Sara Freeman

LONDON—Higher levels of a neuronal protein were found in the blood of patients with relapsing-remitting multiple sclerosis (RRMS) than in healthy subjects in a proof-of-concept study reported at the 32nd Annual Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Blood levels of neurofilament light chain (NfL) were 28.1 and 12.5 pg/mL, respectively, and were also found to be higher in patients with RRMS with greater disease activity seen on MRI.

As the number of gadolinium-enhancing (Gd+) lesions increased, so did the blood concentration of NfL, which was 23.9 pg/mL in patients with no Gd+ lesions, 26.7 pg/mL in those with one Gd+ lesion, 33.4 pg/mL in those with two to three Gd+ lesions, and 55.9 pg/mL in those with more than three Gd+ lesions.

“These findings support a role for NfL as a peripheral biomarker for MS,” said Jens Kuhle, MD, of University Hospital Basel in Switzerland. “There is an urgent unmet need for reliable biomarkers of neurodegeneration, besides efforts that are being done in MRI, optical coherence tomography, and evoked potentials.

“NfL is an exclusively neuronal protein. It is expressed in the cytosol of neurons, it is released upon cell injury into the CSF, and obviously it also appears in the blood circulation.” NfL in the CSF thus reflects nerve damage and had been seen in patients with MS and several other neurologic diseases, including Alzheimer’s disease, Parkinson’s disease, and ALS.

Until recently, however, it was not possible to detect NfL in the blood, as levels are around 50 to 100 times lower than in the CSF, but Dr. Kuhle and his associates have shown that an electrochemiluminescence immunoassay could detect increasing NfL levels with increasing disease activity. In the current study, Dr. Kuhle and colleagues used a Single Molecule Array Immunoassay (Quanterix). This test is based on an enzyme-linked immunoassay with more than 280,000 wells and was developed to be an ultrasensitive diagnostic platform to measure minute quantities of individual proteins. Dr. Kuhle noted that it had “significantly increased sensitivity to measure NfL in blood,” when compared with conventional enzyme-linked immunosorbent assay (ELISA) or electrochemiluminescence.

Two to three consecutive blood samples taken from 149 patients with RRMS participating in the phase III FREEDOMS trial were obtained and compared with samples from 29 similarly aged healthy individuals without MS obtained from a separate biobank.

Patients with two or more relapses in the previous 24 months had significantly higher NfL levels than those with one relapse or no relapses. Serum NfL also significantly increased with the Expanded Disability Status Scale score recorded at the time the blood samples were taken.

Furthermore, “blood NfL levels predicted subsequent brain atrophy rates,” Dr. Kuhle reported, with NfL levels at six months being highly predictive of brain volume changes at 24 months.

And, in this preliminary dataset, patients who had been treated with fingolimod versus placebo during the FREEDOMS trial had lower NfL levels at six, 12, and 24 months. Dr. Kuhle observed that the findings of this study were corroborated by other study data presented at the ECTRIMS meeting.

The FREEDOMS trial was sponsored by Novartis. Dr. Kuhle received research support and consulting fees from Biogen, Novartis, and Protagen. He also disclosed receiving speaker fees and travel expenses from Novartis and several other pharmaceutical companies. Several of Dr. Kuhle’s coinvestigators were employees of Novartis.

—Sara Freeman

Rejuvenation of the periocular area is in high demand among patients who want to look and feel their best. Physicians should understand the complicated anatomy surrounding the eyes before attempting to inject this area with facial fillers, both to understand the aging process and to minimize treatment complications.

Basic Oculoplastic and Orbital Anatomy

The injector should understand the anatomy of the periocular muscles, the orbital osteology, and the secretory and lacrimal system, in addition to the fat, ligaments, and vascular anatomy in this area.¹

The eyes are surrounded by fat compartments that provide glide planes for the motion of the eyelids and globe. There are 2 upper eyelid fat-pads—nasal and central [preaponeurotic])—in the upper lid, leaving room for the lacrimal gland laterally. There are 3 fat compartments—nasal, central, and lateral—in the lower eyelid. The nasal and central compartments are separated by the inferior oblique muscle, which elevates and extorts the eye. The orbital septum holds the fat-pads in place in the orbit. The brow fat-pad is the retro-orbicularis oculi fat-pad (ROOF). There are fat compartments that lie in the subcutaneous space along the entire forehead and in the temple. The suborbicularis oculi fat-pad (SOOF) lies over the malar eminence. Superficial and deep submuscular fat compartments of the face have been described.² Deep fat compartments also have been examined on computed tomography.³

Orbital circulation comes from the internal carotid artery and anastomoses with the supply from the external carotid artery to supply the orbit. The first branch off of the carotid artery is the ophthalmic artery, and the first branch off of the ophthalmic artery is the central retinal artery that enters the optic nerve sheath 1 cm behind the globe to supply the retina. The supraorbital and supratrochlear arteries branch off of the ophthalmic artery and supply the forehead. The supraorbital artery runs through the supraorbital notch (foramen in 8%)¹ and can usually be palpated with one’s finger. There are 15 to 20 short posterior ciliary arteries leading to the choroid, 2 long posterior ciliary arteries to the iris circle, and 7 anterior ciliary arteries to the extraocular muscles. The superior and inferior venous systems drain into the cavernous sinus.⁴

The ligaments are important to signs of facial aging because tissue atrophy occurs along them. The main orbital ligaments are the lateral orbital thickening (known as the LOT) that adheres the eyelids to the lateral orbital rim and the orbitomalar ligament (orbicularis retaining ligament), which is a condensation fibrous tissue that attaches the skin to the inferior orbital rim and orbital septum along the arcus marginalis and defines the superior edge of the SOOF.⁵ The zygomatic ligament not only suspends the zygomaticus major and zygomaticus minor muscles to the malar eminence but there are osseocutaneous attachments that connect the skin over the zygoma’s malar eminence and demarcate the inferior edge of the SOOF.⁶

Periocular Aging

The skin, fat, muscles, and bones change and rotate with aging, and not all orbits age in the same manner. Older patients with dermatochalasis (excess skin fat and muscle) often undergo rejuvenation with blepharoplasty, a brow-lift, and a midface-lift, but many atrophic changes can be improved with facial fillers.^7,8

As adults age, the soft tissue along the ligaments begins to show atrophy, prime signs of aging that are often improved with fillers. Atrophy along the orbitomalar ligament along the infraorbital rim creates a depressed tear trough, which is an early sign of aging. A 3-point grading system reported by Hirmand⁸ describes the severity of progressive hallowing. There also is atrophy along the zygomatic cutaneous ligament that creates the malar hollow. The SOOF appears to be more prominent when these areas above and below show atrophy, which creates the look of an unwanted bag known as a festoon. Additionally, there is atrophy along the superior orbital notch where the ophthalmic branch of the trigeminal nerve (V1) and the supraorbital artery traverse. Soft-tissue atrophy along the supraorbital notch resembles the peak at the top of the letter A, giving the slang term A-frame deformity.

Periocular fat can atrophy, hypertrophy, herniate forward as the septum weakens, or become ptotic. Some patients develop hypertrophy and herniation of the superior and inferior orbital fat-pads, while others develop unwanted atrophy leaving a hollow superior orbit and loss of support to the levator muscle that contributes to eyelid ptosis. The frontalis fat deflates, leaving veins, arteries, and the hypertrophied corrugators unwantedly visible. Loss of subcutaneous fat in the glabella contributes to the formation of frown lines between the brows (also called number 11’s). The ROOF deflates in some patients adding to brow ptosis. Loss of the facial frame occurs when temple fat atrophies.

Skeletal rotation also occurs. Throughout a patient’s life, the skeleton remodels itself via activity of osteoclasts and osteoblasts. Pessa et al^9,10 has described the expansion of the anterior orbital aperture superomedially and inferolaterally as well as maxillary retrusion that results in angular changes of the midface in relation to the orbital rim. Lambros’ algorithm describes the rotational changes of the cranium where the superior orbit protrudes as the maxilla retreats posteriorly.^9-11 The equator of the globe does not change its distance from the ROOF of the orbit, presumably because of its suspension in the orbit by the optic nerve after it passes through the optic canal and trochlea via the superior oblique muscle, but the distance of the inferior equator of the globe to the floor of the orbit increases as the floor of the orbit descends.¹²

Dermal Fillers for Periocular Rejuvenation

Hyaluronic acid (HA) was first pioneered for use in humans in the late 1970s by ophthalmologists for anterior segment surgery.^13-15 Biocompatibility for orthopedic and dermal applications was explored in the early 1990s.¹⁶

At this time, no dermal filler is approved by the US Food and Drug Administration for use in the periorbital area. Some fillers are approved for subdermal areas extending to the preperiosteal plane and can be used in the midface such as HA fillers (eg, Restylane Lyft [Galderma Laboratories, LP]), Juvéderm Voluma XC [Allergan, Inc]), poly-L-lactic acid (PLLA), and calcium hydroxylapatite (CaHA). No dermal fillers are approved for use in the forehead, glabella, or temples. Their use is becoming increasingly popular but is considered off label. In addition, cannulas are not approved for use in these areas. Cannulas may be beneficial in that they are thought to create less bruising and have less chance of entering a vessel than needles, but some injectors prefer needles because they are stiffer and therefore more precise.

The ideal filler for the tear trough, superior sulcus, ROOF, over the orbitomalar ligament, forehead, and glabella is one that is somewhat moldable but does not migrate, is not hydrophilic, is smooth to inject, and is reversible should there be any complications. No single filler fits this ideal description, but HAs typically are the first choice.

In vitro studies to determine the stiffness (G') and the ability to flow (viscosity) have been performed.^17,18 Calcium hydroxylapatite has the most stiffness, while Belotero Balance (Merz Aesthetics) and Juvéderm Ultra XC (Allergan, Inc) are more soft¹⁷ (Table). These guidelines are important but may not correlate directly with how the fillers behave in vivo as demonstrated in animal models.¹⁸

Periocular Injection Considerations

An experienced injector is one who has developed not only an artistic eye for the face and excellent sense of anatomy but also has a sensitive ability to predict the filler-tissue interaction based on tactile feedback dependent on 3 main qualities: (1) stiffness and viscosity of the filler, (2) gauge of the needle or cannula, and (3) depth of the needle in the tissue. Periocular injections of dermal fillers can be delivered with needles or cannulas, diluted or undiluted. Smaller-gauge needles require more force than larger-gauge needles and cannulas that flow more freely. A needle in the dense dermis will require more force than one placed in the loose subcutaneous space.

The tear trough is generally preferable to fill with a mid-level G' HA filler that is less apt to migrate. A neutral gaze during the injection is preferred because closing or moving the eyes can distort the position of the inferior orbital fat-pads (Figure 1). A needle or cannula can be used, diluted or undiluted. The tear trough can be filled with the injection directed horizontally or vertically via a fanning technique. If needles are used, the skin should be stretched to view the 3 to 5 vertical veins and then the needle should be advanced beneath them to avoid bruising. Avoidance of hydrophilic fillers in the tear trough is important to avoid edema. The superior sulcus can be filled both anteriorly and posteriorly to the septum, which is a highly advanced injection for experienced injectors because of the proximity to the supratrochlear and supraorbital arteries as well as the superior ophthalmic vein (Figure 2). Sharp creases such as deep lateral periocular rhytides known as crow’s-feet are nicely filled with intradermal HAs with a low G'.

Image courtesy of Julie A. Woodward, MD.

Adding volume to the midface is important because it is the continuum of the lower eyelid. Fillers can be injected into multiple levels in this area: deep (to act as pillars to lift the malar eminence and replace bone that has rotated and soft tissue that has become atrophic or descended) and subcutaneous (to efface soft tissue along the zygomatic cutaneous ligament). Higher G' HA fillers and CaHA often are used in the midface along with PLLA. Facial framing of the temples, lateral cheeks, and preauricular area is often accomplished with PLLA but also can be done with mid to high G' HA fillers or CaHA. A cannula may be used to undermine and break apart the zygomatic cutaneous ligament’s cutaneous attachments prior to delivery of the filler in the subcutaneous plane.²⁶ If not done, filler may track away from the hollow area where the ligament is attached and instead move to adjacent areas that will accentuate the hollow and make it look worse.

The temples and lateral face often are filled with PLLA for framing. Mid or high G' HA fillers and CaHA also are used in the temples both beneath the temporalis muscle and also above the deep temporalis fascia or sometimes in the subcutaneous plane.²⁷

Prevention and Management of Periocular Complications

Blindness is the most devastating periocular complication of facial fillers, which is caused by retrograde arterial embolization followed by anterograde flow into the ophthalmic then central retinal arteries. Injectables that have caused blindness include (in descending order of frequency) fat, HA, collagen, paraffin, polymethyl methacrylate, silicone, PLLA, CaHA, polyacrylamide hydrogel, and micronized acellular dermal matrix. Of the 98 cases of blindness from periocular complications from dermal fillers reported in the world literature, the order of affected sites include the glabella (38 cases), nose (25), nasolabial folds (13), superior forehead (12), infraorbital rim (6), temples (1), malar area (1), lip (1), and chin (1). Prevention includes avoidance of danger zone arteries including the supratrochlear, supraorbital, dorsal nasal, angular, infraorbital, zygomaticofacial and zygomaticotemporal arteries.²⁸

Avoiding the average critical volume of 0.84 in any single aliquot dispensed is key to avoid filling of these periocular arteries to the critical bifurcation point that can result in anterograde flow into the eye (Freudenthal Nicolau syndrome). The smallest supratrochlear artery’s volume in this study was 0.04 cc, so aliquots that do not exceed 0.03 cc are ideal.^29,30

The injector should always be thinking about the anatomy of the danger zones (eg, infratrochlear and supratrochlear arteries, supraorbital artery, frontal branch of the superficial temporal artery, lacrimal artery, dorsal nasal artery, infraorbital artery, angular artery, zygomaticofacial artery, zygomaticotemporal artery)(Figure 3).

Image courtesy of Julie A. Woodward, MD.

Conclusion

In summary, periocular injections of facial fillers are useful tools for rejuvenation of the upper face when used with great caution and respect for anatomy.

Rejuvenation of the periocular area is in high demand among patients who want to look and feel their best. Physicians should understand the complicated anatomy surrounding the eyes before attempting to inject this area with facial fillers, both to understand the aging process and to minimize treatment complications.

Basic Oculoplastic and Orbital Anatomy

The injector should understand the anatomy of the periocular muscles, the orbital osteology, and the secretory and lacrimal system, in addition to the fat, ligaments, and vascular anatomy in this area.¹

The eyes are surrounded by fat compartments that provide glide planes for the motion of the eyelids and globe. There are 2 upper eyelid fat-pads—nasal and central [preaponeurotic])—in the upper lid, leaving room for the lacrimal gland laterally. There are 3 fat compartments—nasal, central, and lateral—in the lower eyelid. The nasal and central compartments are separated by the inferior oblique muscle, which elevates and extorts the eye. The orbital septum holds the fat-pads in place in the orbit. The brow fat-pad is the retro-orbicularis oculi fat-pad (ROOF). There are fat compartments that lie in the subcutaneous space along the entire forehead and in the temple. The suborbicularis oculi fat-pad (SOOF) lies over the malar eminence. Superficial and deep submuscular fat compartments of the face have been described.² Deep fat compartments also have been examined on computed tomography.³

Orbital circulation comes from the internal carotid artery and anastomoses with the supply from the external carotid artery to supply the orbit. The first branch off of the carotid artery is the ophthalmic artery, and the first branch off of the ophthalmic artery is the central retinal artery that enters the optic nerve sheath 1 cm behind the globe to supply the retina. The supraorbital and supratrochlear arteries branch off of the ophthalmic artery and supply the forehead. The supraorbital artery runs through the supraorbital notch (foramen in 8%)¹ and can usually be palpated with one’s finger. There are 15 to 20 short posterior ciliary arteries leading to the choroid, 2 long posterior ciliary arteries to the iris circle, and 7 anterior ciliary arteries to the extraocular muscles. The superior and inferior venous systems drain into the cavernous sinus.⁴

The ligaments are important to signs of facial aging because tissue atrophy occurs along them. The main orbital ligaments are the lateral orbital thickening (known as the LOT) that adheres the eyelids to the lateral orbital rim and the orbitomalar ligament (orbicularis retaining ligament), which is a condensation fibrous tissue that attaches the skin to the inferior orbital rim and orbital septum along the arcus marginalis and defines the superior edge of the SOOF.⁵ The zygomatic ligament not only suspends the zygomaticus major and zygomaticus minor muscles to the malar eminence but there are osseocutaneous attachments that connect the skin over the zygoma’s malar eminence and demarcate the inferior edge of the SOOF.⁶

Periocular Aging

The skin, fat, muscles, and bones change and rotate with aging, and not all orbits age in the same manner. Older patients with dermatochalasis (excess skin fat and muscle) often undergo rejuvenation with blepharoplasty, a brow-lift, and a midface-lift, but many atrophic changes can be improved with facial fillers.^7,8

As adults age, the soft tissue along the ligaments begins to show atrophy, prime signs of aging that are often improved with fillers. Atrophy along the orbitomalar ligament along the infraorbital rim creates a depressed tear trough, which is an early sign of aging. A 3-point grading system reported by Hirmand⁸ describes the severity of progressive hallowing. There also is atrophy along the zygomatic cutaneous ligament that creates the malar hollow. The SOOF appears to be more prominent when these areas above and below show atrophy, which creates the look of an unwanted bag known as a festoon. Additionally, there is atrophy along the superior orbital notch where the ophthalmic branch of the trigeminal nerve (V1) and the supraorbital artery traverse. Soft-tissue atrophy along the supraorbital notch resembles the peak at the top of the letter A, giving the slang term A-frame deformity.

Periocular fat can atrophy, hypertrophy, herniate forward as the septum weakens, or become ptotic. Some patients develop hypertrophy and herniation of the superior and inferior orbital fat-pads, while others develop unwanted atrophy leaving a hollow superior orbit and loss of support to the levator muscle that contributes to eyelid ptosis. The frontalis fat deflates, leaving veins, arteries, and the hypertrophied corrugators unwantedly visible. Loss of subcutaneous fat in the glabella contributes to the formation of frown lines between the brows (also called number 11’s). The ROOF deflates in some patients adding to brow ptosis. Loss of the facial frame occurs when temple fat atrophies.

Skeletal rotation also occurs. Throughout a patient’s life, the skeleton remodels itself via activity of osteoclasts and osteoblasts. Pessa et al^9,10 has described the expansion of the anterior orbital aperture superomedially and inferolaterally as well as maxillary retrusion that results in angular changes of the midface in relation to the orbital rim. Lambros’ algorithm describes the rotational changes of the cranium where the superior orbit protrudes as the maxilla retreats posteriorly.^9-11 The equator of the globe does not change its distance from the ROOF of the orbit, presumably because of its suspension in the orbit by the optic nerve after it passes through the optic canal and trochlea via the superior oblique muscle, but the distance of the inferior equator of the globe to the floor of the orbit increases as the floor of the orbit descends.¹²

Dermal Fillers for Periocular Rejuvenation

Hyaluronic acid (HA) was first pioneered for use in humans in the late 1970s by ophthalmologists for anterior segment surgery.^13-15 Biocompatibility for orthopedic and dermal applications was explored in the early 1990s.¹⁶

At this time, no dermal filler is approved by the US Food and Drug Administration for use in the periorbital area. Some fillers are approved for subdermal areas extending to the preperiosteal plane and can be used in the midface such as HA fillers (eg, Restylane Lyft [Galderma Laboratories, LP]), Juvéderm Voluma XC [Allergan, Inc]), poly-L-lactic acid (PLLA), and calcium hydroxylapatite (CaHA). No dermal fillers are approved for use in the forehead, glabella, or temples. Their use is becoming increasingly popular but is considered off label. In addition, cannulas are not approved for use in these areas. Cannulas may be beneficial in that they are thought to create less bruising and have less chance of entering a vessel than needles, but some injectors prefer needles because they are stiffer and therefore more precise.

The ideal filler for the tear trough, superior sulcus, ROOF, over the orbitomalar ligament, forehead, and glabella is one that is somewhat moldable but does not migrate, is not hydrophilic, is smooth to inject, and is reversible should there be any complications. No single filler fits this ideal description, but HAs typically are the first choice.

In vitro studies to determine the stiffness (G') and the ability to flow (viscosity) have been performed.^17,18 Calcium hydroxylapatite has the most stiffness, while Belotero Balance (Merz Aesthetics) and Juvéderm Ultra XC (Allergan, Inc) are more soft¹⁷ (Table). These guidelines are important but may not correlate directly with how the fillers behave in vivo as demonstrated in animal models.¹⁸

Periocular Injection Considerations

An experienced injector is one who has developed not only an artistic eye for the face and excellent sense of anatomy but also has a sensitive ability to predict the filler-tissue interaction based on tactile feedback dependent on 3 main qualities: (1) stiffness and viscosity of the filler, (2) gauge of the needle or cannula, and (3) depth of the needle in the tissue. Periocular injections of dermal fillers can be delivered with needles or cannulas, diluted or undiluted. Smaller-gauge needles require more force than larger-gauge needles and cannulas that flow more freely. A needle in the dense dermis will require more force than one placed in the loose subcutaneous space.

The tear trough is generally preferable to fill with a mid-level G' HA filler that is less apt to migrate. A neutral gaze during the injection is preferred because closing or moving the eyes can distort the position of the inferior orbital fat-pads (Figure 1). A needle or cannula can be used, diluted or undiluted. The tear trough can be filled with the injection directed horizontally or vertically via a fanning technique. If needles are used, the skin should be stretched to view the 3 to 5 vertical veins and then the needle should be advanced beneath them to avoid bruising. Avoidance of hydrophilic fillers in the tear trough is important to avoid edema. The superior sulcus can be filled both anteriorly and posteriorly to the septum, which is a highly advanced injection for experienced injectors because of the proximity to the supratrochlear and supraorbital arteries as well as the superior ophthalmic vein (Figure 2). Sharp creases such as deep lateral periocular rhytides known as crow’s-feet are nicely filled with intradermal HAs with a low G'.

Image courtesy of Julie A. Woodward, MD.

Adding volume to the midface is important because it is the continuum of the lower eyelid. Fillers can be injected into multiple levels in this area: deep (to act as pillars to lift the malar eminence and replace bone that has rotated and soft tissue that has become atrophic or descended) and subcutaneous (to efface soft tissue along the zygomatic cutaneous ligament). Higher G' HA fillers and CaHA often are used in the midface along with PLLA. Facial framing of the temples, lateral cheeks, and preauricular area is often accomplished with PLLA but also can be done with mid to high G' HA fillers or CaHA. A cannula may be used to undermine and break apart the zygomatic cutaneous ligament’s cutaneous attachments prior to delivery of the filler in the subcutaneous plane.²⁶ If not done, filler may track away from the hollow area where the ligament is attached and instead move to adjacent areas that will accentuate the hollow and make it look worse.

The temples and lateral face often are filled with PLLA for framing. Mid or high G' HA fillers and CaHA also are used in the temples both beneath the temporalis muscle and also above the deep temporalis fascia or sometimes in the subcutaneous plane.²⁷

Prevention and Management of Periocular Complications

Blindness is the most devastating periocular complication of facial fillers, which is caused by retrograde arterial embolization followed by anterograde flow into the ophthalmic then central retinal arteries. Injectables that have caused blindness include (in descending order of frequency) fat, HA, collagen, paraffin, polymethyl methacrylate, silicone, PLLA, CaHA, polyacrylamide hydrogel, and micronized acellular dermal matrix. Of the 98 cases of blindness from periocular complications from dermal fillers reported in the world literature, the order of affected sites include the glabella (38 cases), nose (25), nasolabial folds (13), superior forehead (12), infraorbital rim (6), temples (1), malar area (1), lip (1), and chin (1). Prevention includes avoidance of danger zone arteries including the supratrochlear, supraorbital, dorsal nasal, angular, infraorbital, zygomaticofacial and zygomaticotemporal arteries.²⁸

Avoiding the average critical volume of 0.84 in any single aliquot dispensed is key to avoid filling of these periocular arteries to the critical bifurcation point that can result in anterograde flow into the eye (Freudenthal Nicolau syndrome). The smallest supratrochlear artery’s volume in this study was 0.04 cc, so aliquots that do not exceed 0.03 cc are ideal.^29,30

The injector should always be thinking about the anatomy of the danger zones (eg, infratrochlear and supratrochlear arteries, supraorbital artery, frontal branch of the superficial temporal artery, lacrimal artery, dorsal nasal artery, infraorbital artery, angular artery, zygomaticofacial artery, zygomaticotemporal artery)(Figure 3).

Image courtesy of Julie A. Woodward, MD.

Conclusion

In summary, periocular injections of facial fillers are useful tools for rejuvenation of the upper face when used with great caution and respect for anatomy.

Rejuvenation of the periocular area is in high demand among patients who want to look and feel their best. Physicians should understand the complicated anatomy surrounding the eyes before attempting to inject this area with facial fillers, both to understand the aging process and to minimize treatment complications.

Basic Oculoplastic and Orbital Anatomy

The injector should understand the anatomy of the periocular muscles, the orbital osteology, and the secretory and lacrimal system, in addition to the fat, ligaments, and vascular anatomy in this area.¹

The eyes are surrounded by fat compartments that provide glide planes for the motion of the eyelids and globe. There are 2 upper eyelid fat-pads—nasal and central [preaponeurotic])—in the upper lid, leaving room for the lacrimal gland laterally. There are 3 fat compartments—nasal, central, and lateral—in the lower eyelid. The nasal and central compartments are separated by the inferior oblique muscle, which elevates and extorts the eye. The orbital septum holds the fat-pads in place in the orbit. The brow fat-pad is the retro-orbicularis oculi fat-pad (ROOF). There are fat compartments that lie in the subcutaneous space along the entire forehead and in the temple. The suborbicularis oculi fat-pad (SOOF) lies over the malar eminence. Superficial and deep submuscular fat compartments of the face have been described.² Deep fat compartments also have been examined on computed tomography.³

Orbital circulation comes from the internal carotid artery and anastomoses with the supply from the external carotid artery to supply the orbit. The first branch off of the carotid artery is the ophthalmic artery, and the first branch off of the ophthalmic artery is the central retinal artery that enters the optic nerve sheath 1 cm behind the globe to supply the retina. The supraorbital and supratrochlear arteries branch off of the ophthalmic artery and supply the forehead. The supraorbital artery runs through the supraorbital notch (foramen in 8%)¹ and can usually be palpated with one’s finger. There are 15 to 20 short posterior ciliary arteries leading to the choroid, 2 long posterior ciliary arteries to the iris circle, and 7 anterior ciliary arteries to the extraocular muscles. The superior and inferior venous systems drain into the cavernous sinus.⁴

The ligaments are important to signs of facial aging because tissue atrophy occurs along them. The main orbital ligaments are the lateral orbital thickening (known as the LOT) that adheres the eyelids to the lateral orbital rim and the orbitomalar ligament (orbicularis retaining ligament), which is a condensation fibrous tissue that attaches the skin to the inferior orbital rim and orbital septum along the arcus marginalis and defines the superior edge of the SOOF.⁵ The zygomatic ligament not only suspends the zygomaticus major and zygomaticus minor muscles to the malar eminence but there are osseocutaneous attachments that connect the skin over the zygoma’s malar eminence and demarcate the inferior edge of the SOOF.⁶

Periocular Aging

The skin, fat, muscles, and bones change and rotate with aging, and not all orbits age in the same manner. Older patients with dermatochalasis (excess skin fat and muscle) often undergo rejuvenation with blepharoplasty, a brow-lift, and a midface-lift, but many atrophic changes can be improved with facial fillers.^7,8

As adults age, the soft tissue along the ligaments begins to show atrophy, prime signs of aging that are often improved with fillers. Atrophy along the orbitomalar ligament along the infraorbital rim creates a depressed tear trough, which is an early sign of aging. A 3-point grading system reported by Hirmand⁸ describes the severity of progressive hallowing. There also is atrophy along the zygomatic cutaneous ligament that creates the malar hollow. The SOOF appears to be more prominent when these areas above and below show atrophy, which creates the look of an unwanted bag known as a festoon. Additionally, there is atrophy along the superior orbital notch where the ophthalmic branch of the trigeminal nerve (V1) and the supraorbital artery traverse. Soft-tissue atrophy along the supraorbital notch resembles the peak at the top of the letter A, giving the slang term A-frame deformity.

Periocular fat can atrophy, hypertrophy, herniate forward as the septum weakens, or become ptotic. Some patients develop hypertrophy and herniation of the superior and inferior orbital fat-pads, while others develop unwanted atrophy leaving a hollow superior orbit and loss of support to the levator muscle that contributes to eyelid ptosis. The frontalis fat deflates, leaving veins, arteries, and the hypertrophied corrugators unwantedly visible. Loss of subcutaneous fat in the glabella contributes to the formation of frown lines between the brows (also called number 11’s). The ROOF deflates in some patients adding to brow ptosis. Loss of the facial frame occurs when temple fat atrophies.

Skeletal rotation also occurs. Throughout a patient’s life, the skeleton remodels itself via activity of osteoclasts and osteoblasts. Pessa et al^9,10 has described the expansion of the anterior orbital aperture superomedially and inferolaterally as well as maxillary retrusion that results in angular changes of the midface in relation to the orbital rim. Lambros’ algorithm describes the rotational changes of the cranium where the superior orbit protrudes as the maxilla retreats posteriorly.^9-11 The equator of the globe does not change its distance from the ROOF of the orbit, presumably because of its suspension in the orbit by the optic nerve after it passes through the optic canal and trochlea via the superior oblique muscle, but the distance of the inferior equator of the globe to the floor of the orbit increases as the floor of the orbit descends.¹²

Dermal Fillers for Periocular Rejuvenation

Hyaluronic acid (HA) was first pioneered for use in humans in the late 1970s by ophthalmologists for anterior segment surgery.^13-15 Biocompatibility for orthopedic and dermal applications was explored in the early 1990s.¹⁶

At this time, no dermal filler is approved by the US Food and Drug Administration for use in the periorbital area. Some fillers are approved for subdermal areas extending to the preperiosteal plane and can be used in the midface such as HA fillers (eg, Restylane Lyft [Galderma Laboratories, LP]), Juvéderm Voluma XC [Allergan, Inc]), poly-L-lactic acid (PLLA), and calcium hydroxylapatite (CaHA). No dermal fillers are approved for use in the forehead, glabella, or temples. Their use is becoming increasingly popular but is considered off label. In addition, cannulas are not approved for use in these areas. Cannulas may be beneficial in that they are thought to create less bruising and have less chance of entering a vessel than needles, but some injectors prefer needles because they are stiffer and therefore more precise.

The ideal filler for the tear trough, superior sulcus, ROOF, over the orbitomalar ligament, forehead, and glabella is one that is somewhat moldable but does not migrate, is not hydrophilic, is smooth to inject, and is reversible should there be any complications. No single filler fits this ideal description, but HAs typically are the first choice.

In vitro studies to determine the stiffness (G') and the ability to flow (viscosity) have been performed.^17,18 Calcium hydroxylapatite has the most stiffness, while Belotero Balance (Merz Aesthetics) and Juvéderm Ultra XC (Allergan, Inc) are more soft¹⁷ (Table). These guidelines are important but may not correlate directly with how the fillers behave in vivo as demonstrated in animal models.¹⁸

Periocular Injection Considerations

An experienced injector is one who has developed not only an artistic eye for the face and excellent sense of anatomy but also has a sensitive ability to predict the filler-tissue interaction based on tactile feedback dependent on 3 main qualities: (1) stiffness and viscosity of the filler, (2) gauge of the needle or cannula, and (3) depth of the needle in the tissue. Periocular injections of dermal fillers can be delivered with needles or cannulas, diluted or undiluted. Smaller-gauge needles require more force than larger-gauge needles and cannulas that flow more freely. A needle in the dense dermis will require more force than one placed in the loose subcutaneous space.

The tear trough is generally preferable to fill with a mid-level G' HA filler that is less apt to migrate. A neutral gaze during the injection is preferred because closing or moving the eyes can distort the position of the inferior orbital fat-pads (Figure 1). A needle or cannula can be used, diluted or undiluted. The tear trough can be filled with the injection directed horizontally or vertically via a fanning technique. If needles are used, the skin should be stretched to view the 3 to 5 vertical veins and then the needle should be advanced beneath them to avoid bruising. Avoidance of hydrophilic fillers in the tear trough is important to avoid edema. The superior sulcus can be filled both anteriorly and posteriorly to the septum, which is a highly advanced injection for experienced injectors because of the proximity to the supratrochlear and supraorbital arteries as well as the superior ophthalmic vein (Figure 2). Sharp creases such as deep lateral periocular rhytides known as crow’s-feet are nicely filled with intradermal HAs with a low G'.

Image courtesy of Julie A. Woodward, MD.

Adding volume to the midface is important because it is the continuum of the lower eyelid. Fillers can be injected into multiple levels in this area: deep (to act as pillars to lift the malar eminence and replace bone that has rotated and soft tissue that has become atrophic or descended) and subcutaneous (to efface soft tissue along the zygomatic cutaneous ligament). Higher G' HA fillers and CaHA often are used in the midface along with PLLA. Facial framing of the temples, lateral cheeks, and preauricular area is often accomplished with PLLA but also can be done with mid to high G' HA fillers or CaHA. A cannula may be used to undermine and break apart the zygomatic cutaneous ligament’s cutaneous attachments prior to delivery of the filler in the subcutaneous plane.²⁶ If not done, filler may track away from the hollow area where the ligament is attached and instead move to adjacent areas that will accentuate the hollow and make it look worse.

The temples and lateral face often are filled with PLLA for framing. Mid or high G' HA fillers and CaHA also are used in the temples both beneath the temporalis muscle and also above the deep temporalis fascia or sometimes in the subcutaneous plane.²⁷

Prevention and Management of Periocular Complications

Blindness is the most devastating periocular complication of facial fillers, which is caused by retrograde arterial embolization followed by anterograde flow into the ophthalmic then central retinal arteries. Injectables that have caused blindness include (in descending order of frequency) fat, HA, collagen, paraffin, polymethyl methacrylate, silicone, PLLA, CaHA, polyacrylamide hydrogel, and micronized acellular dermal matrix. Of the 98 cases of blindness from periocular complications from dermal fillers reported in the world literature, the order of affected sites include the glabella (38 cases), nose (25), nasolabial folds (13), superior forehead (12), infraorbital rim (6), temples (1), malar area (1), lip (1), and chin (1). Prevention includes avoidance of danger zone arteries including the supratrochlear, supraorbital, dorsal nasal, angular, infraorbital, zygomaticofacial and zygomaticotemporal arteries.²⁸

Avoiding the average critical volume of 0.84 in any single aliquot dispensed is key to avoid filling of these periocular arteries to the critical bifurcation point that can result in anterograde flow into the eye (Freudenthal Nicolau syndrome). The smallest supratrochlear artery’s volume in this study was 0.04 cc, so aliquots that do not exceed 0.03 cc are ideal.^29,30

The injector should always be thinking about the anatomy of the danger zones (eg, infratrochlear and supratrochlear arteries, supraorbital artery, frontal branch of the superficial temporal artery, lacrimal artery, dorsal nasal artery, infraorbital artery, angular artery, zygomaticofacial artery, zygomaticotemporal artery)(Figure 3).

Image courtesy of Julie A. Woodward, MD.

Conclusion

In summary, periocular injections of facial fillers are useful tools for rejuvenation of the upper face when used with great caution and respect for anatomy.

For years, we advocated to repeal the sustainable growth rate (SGR) payment formula. Congress, by passing the MACRA legislation, eliminated SGR but created a new process that links provider reimbursement to value (quality and cost). Value-based reimbursement is here to stay. We now must help CMS devise reasonable linkages that will truly improve patient care, yet keep us in business. MACRA’s final rule is an improvement over the preliminary rule published earlier this spring. Gastroenterologists that plan to practice (and accept Medicare reimbursement) must educate themselves about both the incentive portion (MIPS) and alternative payment models.

http://healthaffairs.org/healthpolicybriefs/brief_pdfs/healthpolicybrief_156.pdf

https://blog.cms.gov/2016/10/14/a-letter-from-cms-to-medicare-clinicians-in-the-quality-payment-program/

https://innovation.cms.gov/initiatives/Transforming-Clinical-Practices/

I hope you will take it to heart that we are moving into a new world of care delivery and payment. We need physician leaders and innovators to make sure this works well for our patients and our profession.

John I. Allen MD, MBA, AGAF
Editor in Chief

For years, we advocated to repeal the sustainable growth rate (SGR) payment formula. Congress, by passing the MACRA legislation, eliminated SGR but created a new process that links provider reimbursement to value (quality and cost). Value-based reimbursement is here to stay. We now must help CMS devise reasonable linkages that will truly improve patient care, yet keep us in business. MACRA’s final rule is an improvement over the preliminary rule published earlier this spring. Gastroenterologists that plan to practice (and accept Medicare reimbursement) must educate themselves about both the incentive portion (MIPS) and alternative payment models.

http://healthaffairs.org/healthpolicybriefs/brief_pdfs/healthpolicybrief_156.pdf

https://blog.cms.gov/2016/10/14/a-letter-from-cms-to-medicare-clinicians-in-the-quality-payment-program/

https://innovation.cms.gov/initiatives/Transforming-Clinical-Practices/

I hope you will take it to heart that we are moving into a new world of care delivery and payment. We need physician leaders and innovators to make sure this works well for our patients and our profession.

John I. Allen MD, MBA, AGAF
Editor in Chief

For years, we advocated to repeal the sustainable growth rate (SGR) payment formula. Congress, by passing the MACRA legislation, eliminated SGR but created a new process that links provider reimbursement to value (quality and cost). Value-based reimbursement is here to stay. We now must help CMS devise reasonable linkages that will truly improve patient care, yet keep us in business. MACRA’s final rule is an improvement over the preliminary rule published earlier this spring. Gastroenterologists that plan to practice (and accept Medicare reimbursement) must educate themselves about both the incentive portion (MIPS) and alternative payment models.

http://healthaffairs.org/healthpolicybriefs/brief_pdfs/healthpolicybrief_156.pdf

https://blog.cms.gov/2016/10/14/a-letter-from-cms-to-medicare-clinicians-in-the-quality-payment-program/

https://innovation.cms.gov/initiatives/Transforming-Clinical-Practices/

I hope you will take it to heart that we are moving into a new world of care delivery and payment. We need physician leaders and innovators to make sure this works well for our patients and our profession.

John I. Allen MD, MBA, AGAF
Editor in Chief

PORTLAND, OR—Performing deep brain stimulation (DBS) surgery for Parkinson’s disease using intraoperative CT imaging while the patient is under general anesthesia had clinical advantages and no disadvantages over surgery using microelectrode recording (MER) for lead placement with the patient awake, in a prospective, open-label study of 64 patients. The study was presented at the Fourth World Parkinson Congress.

The change in motor scores following surgery was the same for asleep and awake patients, said study coauthor Shannon Anderson, a physician assistant at Oregon Health & Science University in Portland. “What was surprising to us was that verbal fluency ... the ability to come up with the right word, actually improved in our asleep DBS group, which is a huge complication for patients [and] has a really negative impact on their life.”

Awake surgery with MER for lead targeting has been the preferred method. Surgery under general anesthesia with intraoperative CT (ICT) has been known to have lower morbidity and be more cost effective, but comparative clinical outcomes were previously not known.

Patients with Parkinson’s disease and motor complications (n = 64) were enrolled prospectively at Oregon Health & Science University. Thirty received asleep procedures under general anesthesia with ICT guidance for lead targeting to the globus pallidus pars interna (GPi; n = 21) or to the subthalamic nucleus (STN; n = 9). Thirty-four patients received DBS devices with MER guidance (15 STN; 19 GPi). At baseline, the two groups were similar in age (mean age, 61.1 and 62.7) and off-medication motor subscale scores of the Unified Parkinson’s Disease Rating Scale (mUPDRS; mean, 43.0 and 43.5). The university investigators optimized the DBS parameters at one, two, three, and six months after implantation. The same surgeon performed all the procedures at the same medical center.

Motor improvements were similar between the asleep and awake cohorts. At six months, the ICT (asleep) group experienced a mean improvement in motor abilities of 14.3 on the mUPDRS off medication and on DBS, compared with an improvement of 17.6 for the MER (awake) group.

Greater Fluency With Asleep DBS

Asleep DBS with ICT resulted in improvements in aspects of language, whereas awake patients lost language abilities. The asleep group showed a 0.8-point increase in phonemic fluency and a 1.0-point increase in semantic fluency at six months versus a worsening on both language measures (–3.5 points and –4.7 points, respectively) if DBS was performed via MER on awake patients.

Both cohorts showed significant improvements on the 39-item Parkinson’s Disease Questionnaire at six months. The cohorts did not differ in their degrees of improvement. Similarly, both had improvements on scores of activities of daily living, and both cohorts had a 4 to 4.5 hours per day increase in on time without dyskinesia and a 2.6 to 3.5 hours per day decrease in on time with dyskinesia.

Patients tolerated asleep DBS well, and there were no serious complications.

Surgery while patients are asleep is much shorter. “It is about two hours long, as opposed to four, five, sometimes eight, 10 hours with the awake. There [are fewer] complications, so less risk of hemorrhage or seizures or things like that,” Ms. Anderson said. A separate study found that asleep surgery results in more accurate placement of the electrodes. “All of those things considered, we feel the asleep version is definitely the superior choice between the two,” she said.

Being asleep is much more comfortable for the patient, added study leader Matthew Brodsky, MD, Associate Professor of Neurology at Oregon Health & Science University. “But the biggest advantage is that it is a single pass into the brain as opposed to multiple passes.” The average number of passes using MER is two to three per side of the brain, and in some centers, four or more. “Problems such as speech prosody are related to pokes in the brain, if you will, rather than stimulation,” he said.

Ms. Anderson said MER “is a fantastic research tool, and it gives us a lot of information on the electrophysiology, but really, there is no need for it in the clinical application of DBS.”

Based on the asleep procedure’s accuracy, lower rate of complications, shorter operating room time, and noninferiority in terms of motor outcomes, she said, “Our recommendation is that in more centers, more neurosurgeons be trained in this technique .... We would like to see the clinical field move toward that area and really reserve MER for the research side of things.”

A Barrier for Patients

“If you talk to folks who are considering brain surgery for their Parkinson’s, for some of them, the idea of being awake in the operating room and undergoing this is a barrier that they cannot quite overcome,” Dr. Brodsky said. “So, having this as an option makes it easier for them to sign up for the process.”

Richard Smeyne, PhD, Director of the Jefferson Comprehensive Parkinson’s Center at Thomas Jefferson University in Philadelphia, said that the asleep procedure is the newer one and can target either the GPi or the STN. “The asleep DBS seems to have a little bit better improvement on speech afterwards than the awake DBS, and there could be several causes of this,” he said. “Some might be operative, in that you can make smaller holes, you can get really nice guidance, you do not have to sort of move around as in the awake DBS.”

In addition, CT scanning with the patients asleep in the operating room allows more time in the scanner and greater precision in anatomical placement of the DBS leads.

“If I had to choose, looking at this particular study, it would suggest that the asleep DBS is actually a better overall way to go,” Dr. Smeyne said. However, he had no objection to awake procedures “if the neurosurgeon has a record of good results with it .... But if you have the option ... that becomes an individual choice that you should discuss with the neurosurgeon.”

Some of the work presented in the study was supported by a research grant from Medtronic.

—Daniel M. Keller

PORTLAND, OR—Performing deep brain stimulation (DBS) surgery for Parkinson’s disease using intraoperative CT imaging while the patient is under general anesthesia had clinical advantages and no disadvantages over surgery using microelectrode recording (MER) for lead placement with the patient awake, in a prospective, open-label study of 64 patients. The study was presented at the Fourth World Parkinson Congress.

The change in motor scores following surgery was the same for asleep and awake patients, said study coauthor Shannon Anderson, a physician assistant at Oregon Health & Science University in Portland. “What was surprising to us was that verbal fluency ... the ability to come up with the right word, actually improved in our asleep DBS group, which is a huge complication for patients [and] has a really negative impact on their life.”

Awake surgery with MER for lead targeting has been the preferred method. Surgery under general anesthesia with intraoperative CT (ICT) has been known to have lower morbidity and be more cost effective, but comparative clinical outcomes were previously not known.

Patients with Parkinson’s disease and motor complications (n = 64) were enrolled prospectively at Oregon Health & Science University. Thirty received asleep procedures under general anesthesia with ICT guidance for lead targeting to the globus pallidus pars interna (GPi; n = 21) or to the subthalamic nucleus (STN; n = 9). Thirty-four patients received DBS devices with MER guidance (15 STN; 19 GPi). At baseline, the two groups were similar in age (mean age, 61.1 and 62.7) and off-medication motor subscale scores of the Unified Parkinson’s Disease Rating Scale (mUPDRS; mean, 43.0 and 43.5). The university investigators optimized the DBS parameters at one, two, three, and six months after implantation. The same surgeon performed all the procedures at the same medical center.

Motor improvements were similar between the asleep and awake cohorts. At six months, the ICT (asleep) group experienced a mean improvement in motor abilities of 14.3 on the mUPDRS off medication and on DBS, compared with an improvement of 17.6 for the MER (awake) group.

Greater Fluency With Asleep DBS

Asleep DBS with ICT resulted in improvements in aspects of language, whereas awake patients lost language abilities. The asleep group showed a 0.8-point increase in phonemic fluency and a 1.0-point increase in semantic fluency at six months versus a worsening on both language measures (–3.5 points and –4.7 points, respectively) if DBS was performed via MER on awake patients.

Both cohorts showed significant improvements on the 39-item Parkinson’s Disease Questionnaire at six months. The cohorts did not differ in their degrees of improvement. Similarly, both had improvements on scores of activities of daily living, and both cohorts had a 4 to 4.5 hours per day increase in on time without dyskinesia and a 2.6 to 3.5 hours per day decrease in on time with dyskinesia.

Patients tolerated asleep DBS well, and there were no serious complications.

Surgery while patients are asleep is much shorter. “It is about two hours long, as opposed to four, five, sometimes eight, 10 hours with the awake. There [are fewer] complications, so less risk of hemorrhage or seizures or things like that,” Ms. Anderson said. A separate study found that asleep surgery results in more accurate placement of the electrodes. “All of those things considered, we feel the asleep version is definitely the superior choice between the two,” she said.

Being asleep is much more comfortable for the patient, added study leader Matthew Brodsky, MD, Associate Professor of Neurology at Oregon Health & Science University. “But the biggest advantage is that it is a single pass into the brain as opposed to multiple passes.” The average number of passes using MER is two to three per side of the brain, and in some centers, four or more. “Problems such as speech prosody are related to pokes in the brain, if you will, rather than stimulation,” he said.

Ms. Anderson said MER “is a fantastic research tool, and it gives us a lot of information on the electrophysiology, but really, there is no need for it in the clinical application of DBS.”

Based on the asleep procedure’s accuracy, lower rate of complications, shorter operating room time, and noninferiority in terms of motor outcomes, she said, “Our recommendation is that in more centers, more neurosurgeons be trained in this technique .... We would like to see the clinical field move toward that area and really reserve MER for the research side of things.”

A Barrier for Patients

“If you talk to folks who are considering brain surgery for their Parkinson’s, for some of them, the idea of being awake in the operating room and undergoing this is a barrier that they cannot quite overcome,” Dr. Brodsky said. “So, having this as an option makes it easier for them to sign up for the process.”

Richard Smeyne, PhD, Director of the Jefferson Comprehensive Parkinson’s Center at Thomas Jefferson University in Philadelphia, said that the asleep procedure is the newer one and can target either the GPi or the STN. “The asleep DBS seems to have a little bit better improvement on speech afterwards than the awake DBS, and there could be several causes of this,” he said. “Some might be operative, in that you can make smaller holes, you can get really nice guidance, you do not have to sort of move around as in the awake DBS.”

In addition, CT scanning with the patients asleep in the operating room allows more time in the scanner and greater precision in anatomical placement of the DBS leads.

“If I had to choose, looking at this particular study, it would suggest that the asleep DBS is actually a better overall way to go,” Dr. Smeyne said. However, he had no objection to awake procedures “if the neurosurgeon has a record of good results with it .... But if you have the option ... that becomes an individual choice that you should discuss with the neurosurgeon.”

Some of the work presented in the study was supported by a research grant from Medtronic.

—Daniel M. Keller

PORTLAND, OR—Performing deep brain stimulation (DBS) surgery for Parkinson’s disease using intraoperative CT imaging while the patient is under general anesthesia had clinical advantages and no disadvantages over surgery using microelectrode recording (MER) for lead placement with the patient awake, in a prospective, open-label study of 64 patients. The study was presented at the Fourth World Parkinson Congress.

The change in motor scores following surgery was the same for asleep and awake patients, said study coauthor Shannon Anderson, a physician assistant at Oregon Health & Science University in Portland. “What was surprising to us was that verbal fluency ... the ability to come up with the right word, actually improved in our asleep DBS group, which is a huge complication for patients [and] has a really negative impact on their life.”

Awake surgery with MER for lead targeting has been the preferred method. Surgery under general anesthesia with intraoperative CT (ICT) has been known to have lower morbidity and be more cost effective, but comparative clinical outcomes were previously not known.

Patients with Parkinson’s disease and motor complications (n = 64) were enrolled prospectively at Oregon Health & Science University. Thirty received asleep procedures under general anesthesia with ICT guidance for lead targeting to the globus pallidus pars interna (GPi; n = 21) or to the subthalamic nucleus (STN; n = 9). Thirty-four patients received DBS devices with MER guidance (15 STN; 19 GPi). At baseline, the two groups were similar in age (mean age, 61.1 and 62.7) and off-medication motor subscale scores of the Unified Parkinson’s Disease Rating Scale (mUPDRS; mean, 43.0 and 43.5). The university investigators optimized the DBS parameters at one, two, three, and six months after implantation. The same surgeon performed all the procedures at the same medical center.

Motor improvements were similar between the asleep and awake cohorts. At six months, the ICT (asleep) group experienced a mean improvement in motor abilities of 14.3 on the mUPDRS off medication and on DBS, compared with an improvement of 17.6 for the MER (awake) group.

Greater Fluency With Asleep DBS

Asleep DBS with ICT resulted in improvements in aspects of language, whereas awake patients lost language abilities. The asleep group showed a 0.8-point increase in phonemic fluency and a 1.0-point increase in semantic fluency at six months versus a worsening on both language measures (–3.5 points and –4.7 points, respectively) if DBS was performed via MER on awake patients.

Both cohorts showed significant improvements on the 39-item Parkinson’s Disease Questionnaire at six months. The cohorts did not differ in their degrees of improvement. Similarly, both had improvements on scores of activities of daily living, and both cohorts had a 4 to 4.5 hours per day increase in on time without dyskinesia and a 2.6 to 3.5 hours per day decrease in on time with dyskinesia.

Patients tolerated asleep DBS well, and there were no serious complications.

Surgery while patients are asleep is much shorter. “It is about two hours long, as opposed to four, five, sometimes eight, 10 hours with the awake. There [are fewer] complications, so less risk of hemorrhage or seizures or things like that,” Ms. Anderson said. A separate study found that asleep surgery results in more accurate placement of the electrodes. “All of those things considered, we feel the asleep version is definitely the superior choice between the two,” she said.

Being asleep is much more comfortable for the patient, added study leader Matthew Brodsky, MD, Associate Professor of Neurology at Oregon Health & Science University. “But the biggest advantage is that it is a single pass into the brain as opposed to multiple passes.” The average number of passes using MER is two to three per side of the brain, and in some centers, four or more. “Problems such as speech prosody are related to pokes in the brain, if you will, rather than stimulation,” he said.

Ms. Anderson said MER “is a fantastic research tool, and it gives us a lot of information on the electrophysiology, but really, there is no need for it in the clinical application of DBS.”

Based on the asleep procedure’s accuracy, lower rate of complications, shorter operating room time, and noninferiority in terms of motor outcomes, she said, “Our recommendation is that in more centers, more neurosurgeons be trained in this technique .... We would like to see the clinical field move toward that area and really reserve MER for the research side of things.”

A Barrier for Patients

“If you talk to folks who are considering brain surgery for their Parkinson’s, for some of them, the idea of being awake in the operating room and undergoing this is a barrier that they cannot quite overcome,” Dr. Brodsky said. “So, having this as an option makes it easier for them to sign up for the process.”

Richard Smeyne, PhD, Director of the Jefferson Comprehensive Parkinson’s Center at Thomas Jefferson University in Philadelphia, said that the asleep procedure is the newer one and can target either the GPi or the STN. “The asleep DBS seems to have a little bit better improvement on speech afterwards than the awake DBS, and there could be several causes of this,” he said. “Some might be operative, in that you can make smaller holes, you can get really nice guidance, you do not have to sort of move around as in the awake DBS.”

In addition, CT scanning with the patients asleep in the operating room allows more time in the scanner and greater precision in anatomical placement of the DBS leads.

“If I had to choose, looking at this particular study, it would suggest that the asleep DBS is actually a better overall way to go,” Dr. Smeyne said. However, he had no objection to awake procedures “if the neurosurgeon has a record of good results with it .... But if you have the option ... that becomes an individual choice that you should discuss with the neurosurgeon.”

Some of the work presented in the study was supported by a research grant from Medtronic.

—Daniel M. Keller

HILTON HEAD, SC—Biologics, stem cells, and gene therapy may hold promise as treatments for neuromuscular disorders. Ongoing clinical trials are poised to inform treatment strategies and may identify new therapies for amyotrophic lateral sclerosis (ALS), myasthenia gravis, muscular dystrophy, and neuropathy, according to a lecture delivered at the 39th Annual Contemporary Clinical Neurology Symposium.

Recent developments in neuromuscular disorders include the FDA’s approval of a new drug for Duchenne muscular dystrophy and the publication of a randomized trial that found that thymectomy improves clinical outcomes in patients with myasthenia gravis.

ALS

In ALS, many drugs have been studied with little success, said Amanda C. Peltier, MD, Associate Professor of Neurology at Vanderbilt University in Nashville. Riluzole, an approved drug for ALS that may result in a three-month increase in life expectancy or time to mechanical ventilation, targets excitotoxicity. Other drugs targeting excitotoxicity (eg, ceftriaxone and talampanel) have not been found to be effective, however. Agents that target oxidative stress, inflammatory response, protein degradation pathways, mitochondrial dysfunction, and apoptotic pathways have not provided benefit, Dr. Peltier said.

Most trials in ALS use time to mechanical ventilation, time to death, or rate of decline on the ALS Functional Rating Scale as end points. These end points are “very gross measures of how people do,” and researchers are seeking better ways to measure progression in ALS, she said.

Two phase II stem cell studies in ALS are ongoing—the BrainStorm trial in Hassadah, Israel, and the Neuralstem Trial at Emory University and the University of Michigan. Safety data for the Neuralstem Trial that were presented at the 68th Annual Meeting of the American Academy of Neurology (AAN) showed that patients experienced no significant worsening after injections of stem cells in the cervical and lumbar cord. Dose escalation therapy currently is being tested.

Several phase III studies in ALS are under way, including a study of tirasemtiv, an activator of the skeletal muscle troponin complex. “The goal of this [therapy] is to increase muscle force in ALS patients. It is not actually acting at the motor neuron itself,” Dr. Peltier said. In addition, investigators are re-studying creatine, an organic acid involved in ATP formation, at doses of 5 g to 10 g per day. Researchers also are studying masitinib, a biologic targeting inflammation.

Muscular Dystrophies

“There is more gene therapy going on in muscular dystrophy than has ever happened in my lifetime,” Dr. Peltier said. Neuromuscular diseases are caused by genetic mutations in structural proteins that connect the muscle cell membrane to the actin–myosin complex. Dystrophin, one of the largest proteins in the body, is mutated in Duchenne muscular dystrophy and Becker muscular dystrophy.

Some patients with Duchenne muscular dystrophy have a frameshift mutation that results in nonfunctional dystrophin. One treatment strategy entails using an antisense oligonucleotide fragment that binds to messenger RNA to create a more functional protein. “The biggest problem is that those mutations are not the vast majority of mutations in Duchenne,” said Dr. Peltier. “A large proportion of our Duchenne patients are not going to be able to benefit from this technology.”

The FDA on September 19 approved eteplirsen (Exondys 51) injection to treat patients with Duchenne muscular dystrophy who have a confirmed mutation of the dystrophin gene that is amenable to exon 51 skipping. About 13% of people with Duchenne muscular dystrophy have this mutation. The FDA approved eteplirsen under an accelerated pathway that provides patients with access to the drug while the drug developer conducts trials to verify clinical benefit. The FDA said that the approval was based on an increase of dystrophin in skeletal muscle that was observed in some treated patients. Clinical benefit of eteplirsen has not been established.

“The approval of eteplirsen is a positive first step in gene therapy,” Dr. Peltier said. “The FDA is requiring further clinical trials to establish whether clinical improvement will occur, and hopefully these [trials] will be positive.” Gene therapy may have applications for treating other dystrophies and genetic disorders, and the FDA is considering gene therapy for spinal muscular atrophy that is based on increasing messenger RNA transcripts. “Hopefully this is a signal that the FDA is open to gene therapy for these devastating neuromuscular disorders,” she said.

Idebenone, an analog of coenzyme Q10, may reduce loss of respiratory function in patients with Duchenne muscular dystrophy, according to a post hoc analysis of the phase III Duchenne Muscular Dystrophy Long-term Idebenone Study (DELOS). Patients who received idebenone had a lower risk of bronchopulmonary adverse events and a reduced need for systemic antibiotics, compared with patients who received placebo.

Ataluren, a drug intended to make red blood cells less sensitive to premature stop codons, resulted in faster walk times in the Ataluren Confirmatory Trial in Duchenne Muscular Dystrophy (ACT DMD) study. “So far, it seems to be promising,” Dr. Peltier said.

Many patients with Becker or Duchenne muscular dystrophy develop cardiomyopathy. Drugs that typically are used for heart failure and ischemic cardiomyopathy have not been studied in this patient population, however. An ongoing study comparing ACE inhibitors and beta blockers aims to determine the best strategy for treating cardiomyopathy in this population, she said.

In addition, investigators are studying whether follistatin, delivered by an adeno-associated virus, inhibits the degradation of muscle cells in muscular dystrophy and sporadic inclusion body myositis. A recombinant version of histidyl-tRNA synthetase, aTyr1940, is being studied in facioscapulohumeral muscular dystrophy and limb girdle dystrophies.

Among patients with myotonic dystrophy, a small study found that methylphenidate significantly reduces daytime sleepiness, Dr. Peltier said.

Biologics

Several biologics are being studied as treatments for various neuromuscular disorders. In a phase III study in patients with refractory generalized myasthenia gravis, eculizumab, which inhibits complements and the membrane attack complex, did not result in a significant improvement in Myasthenia Gravis–Activities of Daily Living Profile score. Eculizumab did, however, significantly improve a secondary end point, Quantitative Myasthenia Gravis total score.

A phase II trial to evaluate rituximab in myasthenia gravis has completed enrollment. Results may be available in approximately a year. Rituximab also is being studied in juvenile and adult dermatomyositis and chronic inflammatory demyelinating polyneuropathy (CIDP), Dr. Peltier said.

Etanercept and infliximab, treatments for rheumatoid arthritis that act on tumor necrosis factor alpha, are being studied in dermatomyositis and polymyositis. Tocilizumab, a treatment for rheumatoid arthritis that inhibits IL-6 receptors, is being studied in those disorders as well.

Alemtuzumab has been shown to stabilize quantitative muscle testing in sporadic inclusion body myositis and may be helpful in refractory CIDP, Dr. Peltier said.

Myasthenia Gravis

Researchers in August published the results of a randomized trial that found that thymectomy improves clinical outcomes over three years in patients with nonthymomatous myasthenia gravis. Patients who underwent thymectomy and received alternate-day prednisone had a lower time-weighted average Quantitative Myasthenia Gravis score, compared with patients who received alternate-day prednisone alone. Thymectomy had been a mainstay in the treatment of myasthenia gravis, although prior nonrandomized studies had not provided conclusive evidence of its benefit. “The MGTX trial was based on the traditional method of thymectomy requiring sternotomy,” she said. “Further trials comparing the effectiveness of full sternotomy versus newer methods utilizing transcervical approaches or partial sternotomy will most likely be coming.”

A trial of subcutaneous IV immunoglobulin (IVIg) in myasthenia gravis is enrolling patients. Additional data to support the use of IVIg in myasthenia gravis would improve patient outcomes due to the ease of delivering IVIg versus plasma exchange, Dr. Peltier said.

Neuropathy

Investigators have pooled data for patients with neuropathy who have received IVIg. The INSIGHTS Quality Improvement Registry includes data from 585 patients. Researchers have found that patients who fulfill European Federation of Neurological Societies or AAN definite or probable criteria for CIDP or multifocal motor neuropathy respond better to IVIg. This finding “makes sense,” Dr. Peltier said. “If we are more confident of the diagnosis, then it is very likely that IVIg will perform better.”

Among patients with type 2 diabetic neuropathy, exercise significantly improves epidermal nerve fiber density. “Exercise has been interesting, in that it may actually reverse some of the effects” of neuropathy in type 2 diabetes, Dr. Peltier said. “It may be that you will see more exercise studies in the future.”

—Jake Remaly

HILTON HEAD, SC—Biologics, stem cells, and gene therapy may hold promise as treatments for neuromuscular disorders. Ongoing clinical trials are poised to inform treatment strategies and may identify new therapies for amyotrophic lateral sclerosis (ALS), myasthenia gravis, muscular dystrophy, and neuropathy, according to a lecture delivered at the 39th Annual Contemporary Clinical Neurology Symposium.

Recent developments in neuromuscular disorders include the FDA’s approval of a new drug for Duchenne muscular dystrophy and the publication of a randomized trial that found that thymectomy improves clinical outcomes in patients with myasthenia gravis.

ALS

In ALS, many drugs have been studied with little success, said Amanda C. Peltier, MD, Associate Professor of Neurology at Vanderbilt University in Nashville. Riluzole, an approved drug for ALS that may result in a three-month increase in life expectancy or time to mechanical ventilation, targets excitotoxicity. Other drugs targeting excitotoxicity (eg, ceftriaxone and talampanel) have not been found to be effective, however. Agents that target oxidative stress, inflammatory response, protein degradation pathways, mitochondrial dysfunction, and apoptotic pathways have not provided benefit, Dr. Peltier said.

Most trials in ALS use time to mechanical ventilation, time to death, or rate of decline on the ALS Functional Rating Scale as end points. These end points are “very gross measures of how people do,” and researchers are seeking better ways to measure progression in ALS, she said.

Two phase II stem cell studies in ALS are ongoing—the BrainStorm trial in Hassadah, Israel, and the Neuralstem Trial at Emory University and the University of Michigan. Safety data for the Neuralstem Trial that were presented at the 68th Annual Meeting of the American Academy of Neurology (AAN) showed that patients experienced no significant worsening after injections of stem cells in the cervical and lumbar cord. Dose escalation therapy currently is being tested.

Several phase III studies in ALS are under way, including a study of tirasemtiv, an activator of the skeletal muscle troponin complex. “The goal of this [therapy] is to increase muscle force in ALS patients. It is not actually acting at the motor neuron itself,” Dr. Peltier said. In addition, investigators are re-studying creatine, an organic acid involved in ATP formation, at doses of 5 g to 10 g per day. Researchers also are studying masitinib, a biologic targeting inflammation.

Muscular Dystrophies

“There is more gene therapy going on in muscular dystrophy than has ever happened in my lifetime,” Dr. Peltier said. Neuromuscular diseases are caused by genetic mutations in structural proteins that connect the muscle cell membrane to the actin–myosin complex. Dystrophin, one of the largest proteins in the body, is mutated in Duchenne muscular dystrophy and Becker muscular dystrophy.

Some patients with Duchenne muscular dystrophy have a frameshift mutation that results in nonfunctional dystrophin. One treatment strategy entails using an antisense oligonucleotide fragment that binds to messenger RNA to create a more functional protein. “The biggest problem is that those mutations are not the vast majority of mutations in Duchenne,” said Dr. Peltier. “A large proportion of our Duchenne patients are not going to be able to benefit from this technology.”

The FDA on September 19 approved eteplirsen (Exondys 51) injection to treat patients with Duchenne muscular dystrophy who have a confirmed mutation of the dystrophin gene that is amenable to exon 51 skipping. About 13% of people with Duchenne muscular dystrophy have this mutation. The FDA approved eteplirsen under an accelerated pathway that provides patients with access to the drug while the drug developer conducts trials to verify clinical benefit. The FDA said that the approval was based on an increase of dystrophin in skeletal muscle that was observed in some treated patients. Clinical benefit of eteplirsen has not been established.

“The approval of eteplirsen is a positive first step in gene therapy,” Dr. Peltier said. “The FDA is requiring further clinical trials to establish whether clinical improvement will occur, and hopefully these [trials] will be positive.” Gene therapy may have applications for treating other dystrophies and genetic disorders, and the FDA is considering gene therapy for spinal muscular atrophy that is based on increasing messenger RNA transcripts. “Hopefully this is a signal that the FDA is open to gene therapy for these devastating neuromuscular disorders,” she said.

Idebenone, an analog of coenzyme Q10, may reduce loss of respiratory function in patients with Duchenne muscular dystrophy, according to a post hoc analysis of the phase III Duchenne Muscular Dystrophy Long-term Idebenone Study (DELOS). Patients who received idebenone had a lower risk of bronchopulmonary adverse events and a reduced need for systemic antibiotics, compared with patients who received placebo.

Ataluren, a drug intended to make red blood cells less sensitive to premature stop codons, resulted in faster walk times in the Ataluren Confirmatory Trial in Duchenne Muscular Dystrophy (ACT DMD) study. “So far, it seems to be promising,” Dr. Peltier said.

Many patients with Becker or Duchenne muscular dystrophy develop cardiomyopathy. Drugs that typically are used for heart failure and ischemic cardiomyopathy have not been studied in this patient population, however. An ongoing study comparing ACE inhibitors and beta blockers aims to determine the best strategy for treating cardiomyopathy in this population, she said.

In addition, investigators are studying whether follistatin, delivered by an adeno-associated virus, inhibits the degradation of muscle cells in muscular dystrophy and sporadic inclusion body myositis. A recombinant version of histidyl-tRNA synthetase, aTyr1940, is being studied in facioscapulohumeral muscular dystrophy and limb girdle dystrophies.

Among patients with myotonic dystrophy, a small study found that methylphenidate significantly reduces daytime sleepiness, Dr. Peltier said.

Biologics

Several biologics are being studied as treatments for various neuromuscular disorders. In a phase III study in patients with refractory generalized myasthenia gravis, eculizumab, which inhibits complements and the membrane attack complex, did not result in a significant improvement in Myasthenia Gravis–Activities of Daily Living Profile score. Eculizumab did, however, significantly improve a secondary end point, Quantitative Myasthenia Gravis total score.

A phase II trial to evaluate rituximab in myasthenia gravis has completed enrollment. Results may be available in approximately a year. Rituximab also is being studied in juvenile and adult dermatomyositis and chronic inflammatory demyelinating polyneuropathy (CIDP), Dr. Peltier said.

Etanercept and infliximab, treatments for rheumatoid arthritis that act on tumor necrosis factor alpha, are being studied in dermatomyositis and polymyositis. Tocilizumab, a treatment for rheumatoid arthritis that inhibits IL-6 receptors, is being studied in those disorders as well.

Alemtuzumab has been shown to stabilize quantitative muscle testing in sporadic inclusion body myositis and may be helpful in refractory CIDP, Dr. Peltier said.

Myasthenia Gravis

Researchers in August published the results of a randomized trial that found that thymectomy improves clinical outcomes over three years in patients with nonthymomatous myasthenia gravis. Patients who underwent thymectomy and received alternate-day prednisone had a lower time-weighted average Quantitative Myasthenia Gravis score, compared with patients who received alternate-day prednisone alone. Thymectomy had been a mainstay in the treatment of myasthenia gravis, although prior nonrandomized studies had not provided conclusive evidence of its benefit. “The MGTX trial was based on the traditional method of thymectomy requiring sternotomy,” she said. “Further trials comparing the effectiveness of full sternotomy versus newer methods utilizing transcervical approaches or partial sternotomy will most likely be coming.”

A trial of subcutaneous IV immunoglobulin (IVIg) in myasthenia gravis is enrolling patients. Additional data to support the use of IVIg in myasthenia gravis would improve patient outcomes due to the ease of delivering IVIg versus plasma exchange, Dr. Peltier said.

Neuropathy

Investigators have pooled data for patients with neuropathy who have received IVIg. The INSIGHTS Quality Improvement Registry includes data from 585 patients. Researchers have found that patients who fulfill European Federation of Neurological Societies or AAN definite or probable criteria for CIDP or multifocal motor neuropathy respond better to IVIg. This finding “makes sense,” Dr. Peltier said. “If we are more confident of the diagnosis, then it is very likely that IVIg will perform better.”

Among patients with type 2 diabetic neuropathy, exercise significantly improves epidermal nerve fiber density. “Exercise has been interesting, in that it may actually reverse some of the effects” of neuropathy in type 2 diabetes, Dr. Peltier said. “It may be that you will see more exercise studies in the future.”

—Jake Remaly

HILTON HEAD, SC—Biologics, stem cells, and gene therapy may hold promise as treatments for neuromuscular disorders. Ongoing clinical trials are poised to inform treatment strategies and may identify new therapies for amyotrophic lateral sclerosis (ALS), myasthenia gravis, muscular dystrophy, and neuropathy, according to a lecture delivered at the 39th Annual Contemporary Clinical Neurology Symposium.

Recent developments in neuromuscular disorders include the FDA’s approval of a new drug for Duchenne muscular dystrophy and the publication of a randomized trial that found that thymectomy improves clinical outcomes in patients with myasthenia gravis.

ALS

In ALS, many drugs have been studied with little success, said Amanda C. Peltier, MD, Associate Professor of Neurology at Vanderbilt University in Nashville. Riluzole, an approved drug for ALS that may result in a three-month increase in life expectancy or time to mechanical ventilation, targets excitotoxicity. Other drugs targeting excitotoxicity (eg, ceftriaxone and talampanel) have not been found to be effective, however. Agents that target oxidative stress, inflammatory response, protein degradation pathways, mitochondrial dysfunction, and apoptotic pathways have not provided benefit, Dr. Peltier said.

Most trials in ALS use time to mechanical ventilation, time to death, or rate of decline on the ALS Functional Rating Scale as end points. These end points are “very gross measures of how people do,” and researchers are seeking better ways to measure progression in ALS, she said.

Two phase II stem cell studies in ALS are ongoing—the BrainStorm trial in Hassadah, Israel, and the Neuralstem Trial at Emory University and the University of Michigan. Safety data for the Neuralstem Trial that were presented at the 68th Annual Meeting of the American Academy of Neurology (AAN) showed that patients experienced no significant worsening after injections of stem cells in the cervical and lumbar cord. Dose escalation therapy currently is being tested.

Several phase III studies in ALS are under way, including a study of tirasemtiv, an activator of the skeletal muscle troponin complex. “The goal of this [therapy] is to increase muscle force in ALS patients. It is not actually acting at the motor neuron itself,” Dr. Peltier said. In addition, investigators are re-studying creatine, an organic acid involved in ATP formation, at doses of 5 g to 10 g per day. Researchers also are studying masitinib, a biologic targeting inflammation.

Muscular Dystrophies

“There is more gene therapy going on in muscular dystrophy than has ever happened in my lifetime,” Dr. Peltier said. Neuromuscular diseases are caused by genetic mutations in structural proteins that connect the muscle cell membrane to the actin–myosin complex. Dystrophin, one of the largest proteins in the body, is mutated in Duchenne muscular dystrophy and Becker muscular dystrophy.

Some patients with Duchenne muscular dystrophy have a frameshift mutation that results in nonfunctional dystrophin. One treatment strategy entails using an antisense oligonucleotide fragment that binds to messenger RNA to create a more functional protein. “The biggest problem is that those mutations are not the vast majority of mutations in Duchenne,” said Dr. Peltier. “A large proportion of our Duchenne patients are not going to be able to benefit from this technology.”

The FDA on September 19 approved eteplirsen (Exondys 51) injection to treat patients with Duchenne muscular dystrophy who have a confirmed mutation of the dystrophin gene that is amenable to exon 51 skipping. About 13% of people with Duchenne muscular dystrophy have this mutation. The FDA approved eteplirsen under an accelerated pathway that provides patients with access to the drug while the drug developer conducts trials to verify clinical benefit. The FDA said that the approval was based on an increase of dystrophin in skeletal muscle that was observed in some treated patients. Clinical benefit of eteplirsen has not been established.

“The approval of eteplirsen is a positive first step in gene therapy,” Dr. Peltier said. “The FDA is requiring further clinical trials to establish whether clinical improvement will occur, and hopefully these [trials] will be positive.” Gene therapy may have applications for treating other dystrophies and genetic disorders, and the FDA is considering gene therapy for spinal muscular atrophy that is based on increasing messenger RNA transcripts. “Hopefully this is a signal that the FDA is open to gene therapy for these devastating neuromuscular disorders,” she said.

Idebenone, an analog of coenzyme Q10, may reduce loss of respiratory function in patients with Duchenne muscular dystrophy, according to a post hoc analysis of the phase III Duchenne Muscular Dystrophy Long-term Idebenone Study (DELOS). Patients who received idebenone had a lower risk of bronchopulmonary adverse events and a reduced need for systemic antibiotics, compared with patients who received placebo.

Ataluren, a drug intended to make red blood cells less sensitive to premature stop codons, resulted in faster walk times in the Ataluren Confirmatory Trial in Duchenne Muscular Dystrophy (ACT DMD) study. “So far, it seems to be promising,” Dr. Peltier said.

Many patients with Becker or Duchenne muscular dystrophy develop cardiomyopathy. Drugs that typically are used for heart failure and ischemic cardiomyopathy have not been studied in this patient population, however. An ongoing study comparing ACE inhibitors and beta blockers aims to determine the best strategy for treating cardiomyopathy in this population, she said.

In addition, investigators are studying whether follistatin, delivered by an adeno-associated virus, inhibits the degradation of muscle cells in muscular dystrophy and sporadic inclusion body myositis. A recombinant version of histidyl-tRNA synthetase, aTyr1940, is being studied in facioscapulohumeral muscular dystrophy and limb girdle dystrophies.

Among patients with myotonic dystrophy, a small study found that methylphenidate significantly reduces daytime sleepiness, Dr. Peltier said.

Biologics

Several biologics are being studied as treatments for various neuromuscular disorders. In a phase III study in patients with refractory generalized myasthenia gravis, eculizumab, which inhibits complements and the membrane attack complex, did not result in a significant improvement in Myasthenia Gravis–Activities of Daily Living Profile score. Eculizumab did, however, significantly improve a secondary end point, Quantitative Myasthenia Gravis total score.

A phase II trial to evaluate rituximab in myasthenia gravis has completed enrollment. Results may be available in approximately a year. Rituximab also is being studied in juvenile and adult dermatomyositis and chronic inflammatory demyelinating polyneuropathy (CIDP), Dr. Peltier said.

Etanercept and infliximab, treatments for rheumatoid arthritis that act on tumor necrosis factor alpha, are being studied in dermatomyositis and polymyositis. Tocilizumab, a treatment for rheumatoid arthritis that inhibits IL-6 receptors, is being studied in those disorders as well.

Alemtuzumab has been shown to stabilize quantitative muscle testing in sporadic inclusion body myositis and may be helpful in refractory CIDP, Dr. Peltier said.

Myasthenia Gravis

Researchers in August published the results of a randomized trial that found that thymectomy improves clinical outcomes over three years in patients with nonthymomatous myasthenia gravis. Patients who underwent thymectomy and received alternate-day prednisone had a lower time-weighted average Quantitative Myasthenia Gravis score, compared with patients who received alternate-day prednisone alone. Thymectomy had been a mainstay in the treatment of myasthenia gravis, although prior nonrandomized studies had not provided conclusive evidence of its benefit. “The MGTX trial was based on the traditional method of thymectomy requiring sternotomy,” she said. “Further trials comparing the effectiveness of full sternotomy versus newer methods utilizing transcervical approaches or partial sternotomy will most likely be coming.”

A trial of subcutaneous IV immunoglobulin (IVIg) in myasthenia gravis is enrolling patients. Additional data to support the use of IVIg in myasthenia gravis would improve patient outcomes due to the ease of delivering IVIg versus plasma exchange, Dr. Peltier said.

Neuropathy

Investigators have pooled data for patients with neuropathy who have received IVIg. The INSIGHTS Quality Improvement Registry includes data from 585 patients. Researchers have found that patients who fulfill European Federation of Neurological Societies or AAN definite or probable criteria for CIDP or multifocal motor neuropathy respond better to IVIg. This finding “makes sense,” Dr. Peltier said. “If we are more confident of the diagnosis, then it is very likely that IVIg will perform better.”

Among patients with type 2 diabetic neuropathy, exercise significantly improves epidermal nerve fiber density. “Exercise has been interesting, in that it may actually reverse some of the effects” of neuropathy in type 2 diabetes, Dr. Peltier said. “It may be that you will see more exercise studies in the future.”

—Jake Remaly

Historically, a variety of tools have been used to alter one’s appearance for cultural or religious purposes or to conform to standards of beauty. As a defining feature of the face, the lips provide a unique opportunity for facial aesthetic enhancement. There has been a paradigm shift in medicine favoring preventative health and a desire to slow and even reverse the aging process.¹ Acknowledging that product technology, skill sets, and cultural ideals continually evolve, this article highlights perioral anatomy, explains aging of the lower face, and reviews techniques to achieve perioral rejuvenation through volume restoration and muscle control.

Perioral Anatomy

The layers of the lips include the epidermis, subcutaneous tissue, orbicularis oris muscle fibers, and mucosa. The upper lip extends from the base of the nose to the mucosa inferiorly and to the nasolabial folds laterally. The curvilinear lower lip extends from the mucosa to the mandible inferiorly and to the oral commissures laterally.² Circumferential at the vermilion-cutaneous junction, a raised area of pale skin known as the white roll accentuates the vermilion border and provides an important landmark during lip augmentation.³ At the upper lip, this elevation of the vermilion joins at a V-shaped depression centrally to form the Cupid’s bow. The cutaneous upper lip has 2 raised vertical pillars known as the philtral columns, which are formed from decussating fibers of the orbicularis oris muscle.² The resultant midline depression is the philtrum. These defining features of the upper lip are to be preserved during augmentation procedures (Figure 1).⁴

The superior and inferior labial arteries, both branches of the facial artery, supply the upper and lower lip, respectively. The anastomotic arch of the superior labial artery is susceptible to injury from deep injection of the upper lip between the muscle layer and mucosa; therefore, caution must be exercised in this area.⁵ Injections into the vermilion and lower lip can be safely performed with less concern for vascular compromise. The vermilion derives its red color from the translucency of capillaries in the superficial papillae.² The capillary plexus at the papillae and rich sensory nerve network render the lip a highly vascular and sensitive structure.

Aging of the Lower Face

Subcutaneous fat atrophy, loss of elasticity, gravitational forces, and remodeling of the skeletal foundation all contribute to aging of the lower face. Starting as early as the third decade of life, intrinsic factors including hormonal changes and genetically determined processes produce alterations in skin quality and structure. Similarly, extrinsic aging through environmental influences, namely exposure to UV radiation and smoking, accelerate the loss of skin integrity.⁶

The decreased laxity of the skin in combination with repeated contraction of the orbicularis oris muscle results in perioral rhytides.⁷ For women in particular, vertically oriented perioral rhytides develop above the vermilion; terminal hair follicles, thicker skin, and a greater density of subcutaneous fat are presumptive protective factors for males.⁸ With time, the cutaneous portion of the upper lip lengthens and there is redistribution of volume with effacement of the upper lip vermilion.⁹ Additionally, the demarcation of the vermilion becomes blurred secondary to pallor, flattening of the philtral columns, and loss of projection of the Cupid’s bow.¹⁰

Downturning of the oral commissures is observed secondary to a combination of gravity, bone resorption, and soft tissue volume loss. Hyperactivity of the depressor anguli oris muscle exacerbates the mesolabial folds, producing marionette lines and a saddened expression.⁷ With ongoing volume loss and ligament laxity, tissue redistributes near the jaws and chin, giving rise to jowls. Similarly, perioral volume loss and descent of the malar fat-pad deepen the nasolabial folds in the aging midface.⁶

The main objective of perioral rejuvenation is to reinstate a harmonious refreshed look to the lower face; however, aesthetic analysis should occur within the context of the face as a whole, as the lips should complement the surrounding perioral cosmetic unit and overall skeletal foundation of the face. To accomplish this goal, the dermatologist’s armamentarium contains a broad variety of approaches including restriction of muscle movement, volume restoration, and surface contouring.

Volume Restoration

Treatment Options

In 2015, hyaluronic acid (HA) fillers constituted 80% of all injectable soft-tissue fillers, an 8% increase from 2014.¹¹ Hyaluronic acid has achieved immense popularity as a temporary dermal filler given its biocompatibility, longevity, and reversibility via hyaluronidase.¹²

Hyaluronic acid is a naturally occurring glycosaminoglycan that comprises the connective tissue matrix. The molecular composition affords HA its hydrophilic property, which augments dermal volume.⁷ Endogenous HA has a short half-life, and chemical modification by a cross-linking process extends longevity by 6 to 12 months. The various HA fillers are distinguished by method of purification, size of molecules, concentration and degree of cross-linking, and viscosity.^7,13,14 These differences dictate overall clinical performance such as flow properties, longevity, and stability. As a general rule, a high-viscosity product is more appropriate for deeper augmentation; fillers with low viscosity are more appropriate for correction of shallow defects.¹ Table 1 lists the HA fillers that are currently approved by the US Food and Drug Administration for lip augmentation and/or perioral rhytides in adults 21 years and older.^15-17

Randomized controlled trials comparing the efficacy, longevity, and tolerability of different HA products are lacking in the literature and, where present, have strong industry influence.^18,19 The advent of assessment scales has provided an objective evaluation of perioral and lip augmentation, facilitating comparisons between products in both clinical research and practice.²⁰

Semipermanent biostimulatory dermal fillers such as calcium hydroxylapatite and poly-L-lactic acid are not recommended for lip augmentation due to an increased incidence of submucosal nodule formation.^6,14,21 Likewise, permanent fillers are not recommended given their irreversibility and risk of nodule formation around the lips.^14,22 Nonetheless, liquid silicone (purified polydimethylsiloxane) administered via a microdroplet technique (0.01 mL of silicone at a time, no more than 1 cc per lip per session) has been used off label as a permanent filling agent for lip augmentation with limited complications.²³ Regardless, trepidations about its use with respect to reported risks continue to limit its application.²²

Similarly, surgical lip implants such as expanded polytetrafluoroethylene is an option for a subset of patients desiring permanent enhancement but are less commonly utilized given the side-effect profile, irreversibility, and relatively invasive nature of the procedure.²² Lastly, autologous fat transfer has been used in correction of the nasolabial and mesolabial folds as well as in lip augmentation; however, irregular surface contours and unpredictable longevity secondary to postinjection resorption (20%–90%) has limited its popularity.^3,14,21

HA Injection Technique

With respect to HA fillers in the perioral area, numerous approaches have been described.^10,22 The techniques in Table 2 provide a foundation for lip rejuvenation.

Several injection techniques exist, including serial puncture, linear threading, cross-hatching, and fanning in a retrograde or anterograde manner.²⁴ A blunt microcannula (27 gauge, 38 mm) may be used in place of sharp needles and offers the benefit of increased patient comfort, reduced edema and ecchymosis, and shortened recovery period.^25,26 Gentle massage of the product after injection can assist with an even contour. Lastly, a key determinant of successful outcomes is using an adequate volume of HA filler (1–2 mL for shaping the vermilion border and volumizing the lips).²⁷ Figure 2 highlights a clinical example of HA filler for lip augmentation.

Fortunately, most complications encountered with HA lip augmentation are mild and transient. The most commonly observed side effects include injection-site reactions such as pain, erythema, and edema. Similarly, most adverse effects are related to injection technique. All HA fillers are prone to the Tyndall effect, a consequence of too superficial an injection plane. Patients with history of recurrent herpes simplex virus infections should receive prophylactic antiviral therapy.¹²

Muscle Control

An emerging concept in rejuvenation of the lower face recognizes not only restoration of volume but also control of muscle movement. Local injection of botulinum toxin type A induces relaxation of hyperfunctional facial muscles through temporary inhibition of neurotransmitter release.⁶ The potential for paralysis of the oral cavity may limit the application of botulinum toxin type A in that region.⁷ Nonetheless, the off-label potential of botulinum toxin type A has expanded to include several targets in the lower face. The orbicularis oris muscle is targeted to soften perioral rhytides. Conservative dosing (1–2 U per lip quadrant or approximately 5 U total) and superficial injection is emphasized in this area.²⁷ Similarly, the depressor anguli oris muscle is targeted by injection of 4 U bilaterally to soften the marionette lines. In the chin area, the mentalis muscle can be targeted by injection of 2 U deep into each belly of the muscle to reduce the mental crease and dimpling.²⁸ Combination treatment with dermal filler and neurotoxin demonstrates effects that last longer than either modality alone without additional adverse events.²⁹ With combination therapy, guidelines suggest treating with filler first.²⁷

Conclusion

A greater understanding of the extrinsic and intrinsic factors that contribute to the structural and surface changes of the aging face coupled with a preference for minimally invasive procedures has revolutionized the dermatologist’s approach to perioral rejuvenation. Serving as a focal point of the face, the lips and perioral skin are well poised to benefit from this paradigm shift. A multifaceted approach utilizing dermal fillers and neurotoxins may be most appropriate and has demonstrated optimal outcomes in facial aesthetics.

Historically, a variety of tools have been used to alter one’s appearance for cultural or religious purposes or to conform to standards of beauty. As a defining feature of the face, the lips provide a unique opportunity for facial aesthetic enhancement. There has been a paradigm shift in medicine favoring preventative health and a desire to slow and even reverse the aging process.¹ Acknowledging that product technology, skill sets, and cultural ideals continually evolve, this article highlights perioral anatomy, explains aging of the lower face, and reviews techniques to achieve perioral rejuvenation through volume restoration and muscle control.

Perioral Anatomy

The layers of the lips include the epidermis, subcutaneous tissue, orbicularis oris muscle fibers, and mucosa. The upper lip extends from the base of the nose to the mucosa inferiorly and to the nasolabial folds laterally. The curvilinear lower lip extends from the mucosa to the mandible inferiorly and to the oral commissures laterally.² Circumferential at the vermilion-cutaneous junction, a raised area of pale skin known as the white roll accentuates the vermilion border and provides an important landmark during lip augmentation.³ At the upper lip, this elevation of the vermilion joins at a V-shaped depression centrally to form the Cupid’s bow. The cutaneous upper lip has 2 raised vertical pillars known as the philtral columns, which are formed from decussating fibers of the orbicularis oris muscle.² The resultant midline depression is the philtrum. These defining features of the upper lip are to be preserved during augmentation procedures (Figure 1).⁴

The superior and inferior labial arteries, both branches of the facial artery, supply the upper and lower lip, respectively. The anastomotic arch of the superior labial artery is susceptible to injury from deep injection of the upper lip between the muscle layer and mucosa; therefore, caution must be exercised in this area.⁵ Injections into the vermilion and lower lip can be safely performed with less concern for vascular compromise. The vermilion derives its red color from the translucency of capillaries in the superficial papillae.² The capillary plexus at the papillae and rich sensory nerve network render the lip a highly vascular and sensitive structure.

Aging of the Lower Face

Subcutaneous fat atrophy, loss of elasticity, gravitational forces, and remodeling of the skeletal foundation all contribute to aging of the lower face. Starting as early as the third decade of life, intrinsic factors including hormonal changes and genetically determined processes produce alterations in skin quality and structure. Similarly, extrinsic aging through environmental influences, namely exposure to UV radiation and smoking, accelerate the loss of skin integrity.⁶

The decreased laxity of the skin in combination with repeated contraction of the orbicularis oris muscle results in perioral rhytides.⁷ For women in particular, vertically oriented perioral rhytides develop above the vermilion; terminal hair follicles, thicker skin, and a greater density of subcutaneous fat are presumptive protective factors for males.⁸ With time, the cutaneous portion of the upper lip lengthens and there is redistribution of volume with effacement of the upper lip vermilion.⁹ Additionally, the demarcation of the vermilion becomes blurred secondary to pallor, flattening of the philtral columns, and loss of projection of the Cupid’s bow.¹⁰

Downturning of the oral commissures is observed secondary to a combination of gravity, bone resorption, and soft tissue volume loss. Hyperactivity of the depressor anguli oris muscle exacerbates the mesolabial folds, producing marionette lines and a saddened expression.⁷ With ongoing volume loss and ligament laxity, tissue redistributes near the jaws and chin, giving rise to jowls. Similarly, perioral volume loss and descent of the malar fat-pad deepen the nasolabial folds in the aging midface.⁶

The main objective of perioral rejuvenation is to reinstate a harmonious refreshed look to the lower face; however, aesthetic analysis should occur within the context of the face as a whole, as the lips should complement the surrounding perioral cosmetic unit and overall skeletal foundation of the face. To accomplish this goal, the dermatologist’s armamentarium contains a broad variety of approaches including restriction of muscle movement, volume restoration, and surface contouring.

Volume Restoration

Treatment Options

In 2015, hyaluronic acid (HA) fillers constituted 80% of all injectable soft-tissue fillers, an 8% increase from 2014.¹¹ Hyaluronic acid has achieved immense popularity as a temporary dermal filler given its biocompatibility, longevity, and reversibility via hyaluronidase.¹²

Hyaluronic acid is a naturally occurring glycosaminoglycan that comprises the connective tissue matrix. The molecular composition affords HA its hydrophilic property, which augments dermal volume.⁷ Endogenous HA has a short half-life, and chemical modification by a cross-linking process extends longevity by 6 to 12 months. The various HA fillers are distinguished by method of purification, size of molecules, concentration and degree of cross-linking, and viscosity.^7,13,14 These differences dictate overall clinical performance such as flow properties, longevity, and stability. As a general rule, a high-viscosity product is more appropriate for deeper augmentation; fillers with low viscosity are more appropriate for correction of shallow defects.¹ Table 1 lists the HA fillers that are currently approved by the US Food and Drug Administration for lip augmentation and/or perioral rhytides in adults 21 years and older.^15-17

Randomized controlled trials comparing the efficacy, longevity, and tolerability of different HA products are lacking in the literature and, where present, have strong industry influence.^18,19 The advent of assessment scales has provided an objective evaluation of perioral and lip augmentation, facilitating comparisons between products in both clinical research and practice.²⁰

Semipermanent biostimulatory dermal fillers such as calcium hydroxylapatite and poly-L-lactic acid are not recommended for lip augmentation due to an increased incidence of submucosal nodule formation.^6,14,21 Likewise, permanent fillers are not recommended given their irreversibility and risk of nodule formation around the lips.^14,22 Nonetheless, liquid silicone (purified polydimethylsiloxane) administered via a microdroplet technique (0.01 mL of silicone at a time, no more than 1 cc per lip per session) has been used off label as a permanent filling agent for lip augmentation with limited complications.²³ Regardless, trepidations about its use with respect to reported risks continue to limit its application.²²

Similarly, surgical lip implants such as expanded polytetrafluoroethylene is an option for a subset of patients desiring permanent enhancement but are less commonly utilized given the side-effect profile, irreversibility, and relatively invasive nature of the procedure.²² Lastly, autologous fat transfer has been used in correction of the nasolabial and mesolabial folds as well as in lip augmentation; however, irregular surface contours and unpredictable longevity secondary to postinjection resorption (20%–90%) has limited its popularity.^3,14,21

HA Injection Technique

With respect to HA fillers in the perioral area, numerous approaches have been described.^10,22 The techniques in Table 2 provide a foundation for lip rejuvenation.

Several injection techniques exist, including serial puncture, linear threading, cross-hatching, and fanning in a retrograde or anterograde manner.²⁴ A blunt microcannula (27 gauge, 38 mm) may be used in place of sharp needles and offers the benefit of increased patient comfort, reduced edema and ecchymosis, and shortened recovery period.^25,26 Gentle massage of the product after injection can assist with an even contour. Lastly, a key determinant of successful outcomes is using an adequate volume of HA filler (1–2 mL for shaping the vermilion border and volumizing the lips).²⁷ Figure 2 highlights a clinical example of HA filler for lip augmentation.

Fortunately, most complications encountered with HA lip augmentation are mild and transient. The most commonly observed side effects include injection-site reactions such as pain, erythema, and edema. Similarly, most adverse effects are related to injection technique. All HA fillers are prone to the Tyndall effect, a consequence of too superficial an injection plane. Patients with history of recurrent herpes simplex virus infections should receive prophylactic antiviral therapy.¹²

Muscle Control

An emerging concept in rejuvenation of the lower face recognizes not only restoration of volume but also control of muscle movement. Local injection of botulinum toxin type A induces relaxation of hyperfunctional facial muscles through temporary inhibition of neurotransmitter release.⁶ The potential for paralysis of the oral cavity may limit the application of botulinum toxin type A in that region.⁷ Nonetheless, the off-label potential of botulinum toxin type A has expanded to include several targets in the lower face. The orbicularis oris muscle is targeted to soften perioral rhytides. Conservative dosing (1–2 U per lip quadrant or approximately 5 U total) and superficial injection is emphasized in this area.²⁷ Similarly, the depressor anguli oris muscle is targeted by injection of 4 U bilaterally to soften the marionette lines. In the chin area, the mentalis muscle can be targeted by injection of 2 U deep into each belly of the muscle to reduce the mental crease and dimpling.²⁸ Combination treatment with dermal filler and neurotoxin demonstrates effects that last longer than either modality alone without additional adverse events.²⁹ With combination therapy, guidelines suggest treating with filler first.²⁷

Conclusion

A greater understanding of the extrinsic and intrinsic factors that contribute to the structural and surface changes of the aging face coupled with a preference for minimally invasive procedures has revolutionized the dermatologist’s approach to perioral rejuvenation. Serving as a focal point of the face, the lips and perioral skin are well poised to benefit from this paradigm shift. A multifaceted approach utilizing dermal fillers and neurotoxins may be most appropriate and has demonstrated optimal outcomes in facial aesthetics.

Historically, a variety of tools have been used to alter one’s appearance for cultural or religious purposes or to conform to standards of beauty. As a defining feature of the face, the lips provide a unique opportunity for facial aesthetic enhancement. There has been a paradigm shift in medicine favoring preventative health and a desire to slow and even reverse the aging process.¹ Acknowledging that product technology, skill sets, and cultural ideals continually evolve, this article highlights perioral anatomy, explains aging of the lower face, and reviews techniques to achieve perioral rejuvenation through volume restoration and muscle control.

Perioral Anatomy

The layers of the lips include the epidermis, subcutaneous tissue, orbicularis oris muscle fibers, and mucosa. The upper lip extends from the base of the nose to the mucosa inferiorly and to the nasolabial folds laterally. The curvilinear lower lip extends from the mucosa to the mandible inferiorly and to the oral commissures laterally.² Circumferential at the vermilion-cutaneous junction, a raised area of pale skin known as the white roll accentuates the vermilion border and provides an important landmark during lip augmentation.³ At the upper lip, this elevation of the vermilion joins at a V-shaped depression centrally to form the Cupid’s bow. The cutaneous upper lip has 2 raised vertical pillars known as the philtral columns, which are formed from decussating fibers of the orbicularis oris muscle.² The resultant midline depression is the philtrum. These defining features of the upper lip are to be preserved during augmentation procedures (Figure 1).⁴

The superior and inferior labial arteries, both branches of the facial artery, supply the upper and lower lip, respectively. The anastomotic arch of the superior labial artery is susceptible to injury from deep injection of the upper lip between the muscle layer and mucosa; therefore, caution must be exercised in this area.⁵ Injections into the vermilion and lower lip can be safely performed with less concern for vascular compromise. The vermilion derives its red color from the translucency of capillaries in the superficial papillae.² The capillary plexus at the papillae and rich sensory nerve network render the lip a highly vascular and sensitive structure.

Aging of the Lower Face

Subcutaneous fat atrophy, loss of elasticity, gravitational forces, and remodeling of the skeletal foundation all contribute to aging of the lower face. Starting as early as the third decade of life, intrinsic factors including hormonal changes and genetically determined processes produce alterations in skin quality and structure. Similarly, extrinsic aging through environmental influences, namely exposure to UV radiation and smoking, accelerate the loss of skin integrity.⁶

The decreased laxity of the skin in combination with repeated contraction of the orbicularis oris muscle results in perioral rhytides.⁷ For women in particular, vertically oriented perioral rhytides develop above the vermilion; terminal hair follicles, thicker skin, and a greater density of subcutaneous fat are presumptive protective factors for males.⁸ With time, the cutaneous portion of the upper lip lengthens and there is redistribution of volume with effacement of the upper lip vermilion.⁹ Additionally, the demarcation of the vermilion becomes blurred secondary to pallor, flattening of the philtral columns, and loss of projection of the Cupid’s bow.¹⁰

Downturning of the oral commissures is observed secondary to a combination of gravity, bone resorption, and soft tissue volume loss. Hyperactivity of the depressor anguli oris muscle exacerbates the mesolabial folds, producing marionette lines and a saddened expression.⁷ With ongoing volume loss and ligament laxity, tissue redistributes near the jaws and chin, giving rise to jowls. Similarly, perioral volume loss and descent of the malar fat-pad deepen the nasolabial folds in the aging midface.⁶

The main objective of perioral rejuvenation is to reinstate a harmonious refreshed look to the lower face; however, aesthetic analysis should occur within the context of the face as a whole, as the lips should complement the surrounding perioral cosmetic unit and overall skeletal foundation of the face. To accomplish this goal, the dermatologist’s armamentarium contains a broad variety of approaches including restriction of muscle movement, volume restoration, and surface contouring.

Volume Restoration

Treatment Options

In 2015, hyaluronic acid (HA) fillers constituted 80% of all injectable soft-tissue fillers, an 8% increase from 2014.¹¹ Hyaluronic acid has achieved immense popularity as a temporary dermal filler given its biocompatibility, longevity, and reversibility via hyaluronidase.¹²

Hyaluronic acid is a naturally occurring glycosaminoglycan that comprises the connective tissue matrix. The molecular composition affords HA its hydrophilic property, which augments dermal volume.⁷ Endogenous HA has a short half-life, and chemical modification by a cross-linking process extends longevity by 6 to 12 months. The various HA fillers are distinguished by method of purification, size of molecules, concentration and degree of cross-linking, and viscosity.^7,13,14 These differences dictate overall clinical performance such as flow properties, longevity, and stability. As a general rule, a high-viscosity product is more appropriate for deeper augmentation; fillers with low viscosity are more appropriate for correction of shallow defects.¹ Table 1 lists the HA fillers that are currently approved by the US Food and Drug Administration for lip augmentation and/or perioral rhytides in adults 21 years and older.^15-17

Randomized controlled trials comparing the efficacy, longevity, and tolerability of different HA products are lacking in the literature and, where present, have strong industry influence.^18,19 The advent of assessment scales has provided an objective evaluation of perioral and lip augmentation, facilitating comparisons between products in both clinical research and practice.²⁰

Semipermanent biostimulatory dermal fillers such as calcium hydroxylapatite and poly-L-lactic acid are not recommended for lip augmentation due to an increased incidence of submucosal nodule formation.^6,14,21 Likewise, permanent fillers are not recommended given their irreversibility and risk of nodule formation around the lips.^14,22 Nonetheless, liquid silicone (purified polydimethylsiloxane) administered via a microdroplet technique (0.01 mL of silicone at a time, no more than 1 cc per lip per session) has been used off label as a permanent filling agent for lip augmentation with limited complications.²³ Regardless, trepidations about its use with respect to reported risks continue to limit its application.²²

Similarly, surgical lip implants such as expanded polytetrafluoroethylene is an option for a subset of patients desiring permanent enhancement but are less commonly utilized given the side-effect profile, irreversibility, and relatively invasive nature of the procedure.²² Lastly, autologous fat transfer has been used in correction of the nasolabial and mesolabial folds as well as in lip augmentation; however, irregular surface contours and unpredictable longevity secondary to postinjection resorption (20%–90%) has limited its popularity.^3,14,21

HA Injection Technique

With respect to HA fillers in the perioral area, numerous approaches have been described.^10,22 The techniques in Table 2 provide a foundation for lip rejuvenation.

Several injection techniques exist, including serial puncture, linear threading, cross-hatching, and fanning in a retrograde or anterograde manner.²⁴ A blunt microcannula (27 gauge, 38 mm) may be used in place of sharp needles and offers the benefit of increased patient comfort, reduced edema and ecchymosis, and shortened recovery period.^25,26 Gentle massage of the product after injection can assist with an even contour. Lastly, a key determinant of successful outcomes is using an adequate volume of HA filler (1–2 mL for shaping the vermilion border and volumizing the lips).²⁷ Figure 2 highlights a clinical example of HA filler for lip augmentation.

Fortunately, most complications encountered with HA lip augmentation are mild and transient. The most commonly observed side effects include injection-site reactions such as pain, erythema, and edema. Similarly, most adverse effects are related to injection technique. All HA fillers are prone to the Tyndall effect, a consequence of too superficial an injection plane. Patients with history of recurrent herpes simplex virus infections should receive prophylactic antiviral therapy.¹²

Muscle Control

An emerging concept in rejuvenation of the lower face recognizes not only restoration of volume but also control of muscle movement. Local injection of botulinum toxin type A induces relaxation of hyperfunctional facial muscles through temporary inhibition of neurotransmitter release.⁶ The potential for paralysis of the oral cavity may limit the application of botulinum toxin type A in that region.⁷ Nonetheless, the off-label potential of botulinum toxin type A has expanded to include several targets in the lower face. The orbicularis oris muscle is targeted to soften perioral rhytides. Conservative dosing (1–2 U per lip quadrant or approximately 5 U total) and superficial injection is emphasized in this area.²⁷ Similarly, the depressor anguli oris muscle is targeted by injection of 4 U bilaterally to soften the marionette lines. In the chin area, the mentalis muscle can be targeted by injection of 2 U deep into each belly of the muscle to reduce the mental crease and dimpling.²⁸ Combination treatment with dermal filler and neurotoxin demonstrates effects that last longer than either modality alone without additional adverse events.²⁹ With combination therapy, guidelines suggest treating with filler first.²⁷

Conclusion

A greater understanding of the extrinsic and intrinsic factors that contribute to the structural and surface changes of the aging face coupled with a preference for minimally invasive procedures has revolutionized the dermatologist’s approach to perioral rejuvenation. Serving as a focal point of the face, the lips and perioral skin are well poised to benefit from this paradigm shift. A multifaceted approach utilizing dermal fillers and neurotoxins may be most appropriate and has demonstrated optimal outcomes in facial aesthetics.

More than 40 AGA members, representing 24 states, visited Capitol Hill earlier this fall to fight for the science and practice of gastroenterology during AGA’s annual Advocacy Day.

NIH funding

AGA members met with lawmakers and their staffs on Sept. 16 to discuss the success that research and medical breakthroughs have had for their patients and encouraged Congress to support increased funding for NIH. Many members of Congress support increased funding for NIH, but a small group of House members is preventing passage of a bill that would increase funding for the institute by $1.25 billion in fiscal year (FY) 2017. The Senate Appropriations Committee passed a bill in June, on a vote of 29-1, to increase funding for NIH by $2 billion. Advocacy Day attendees urged their congressional offices to support the higher Senate number.

MACRA implementation

Members also discussed the need for congressional oversight to ensure that the Medicare Access & CHIP Reauthorization Act of 2015 (MACRA) law is being implemented as Congress intended. They shared their concerns over the impact this law could have on gastroenterologists, especially those in small or solo practices, and emphasized the need for CMS to provide flexibility to physicians to enable them to comply with the new requirements.

Participants highlighted the recent announcement that CMS will allow physicians more options for reporting in the first year as a positive sign that it is listening to the concerns voiced by Congress and the physician community on the regulatory burdens. AGA members also discussed the barriers that currently exist in qualifying as a specialty-focused alternative payment model (APM) and the need for continued flexibility to ensure that all physicians have the opportunity to participate in more value-based payment models.

Virtual advocacy

In conjunction with the Capitol Hill meetings, all AGA members were invited to participate in a Virtual Advocacy Day campaign. This additional component allowed all members to contact their members of Congress via email to voice their concerns about sustainable NIH funding for FY 2017 and the need for more congressional oversight of MACRA.

It’s not too late for you to show your support for the science and practice of GI. Contact your congressional representatives in support of important issues at www.gastroadvocacy.org/actionalerts.aspx.

More than 40 AGA members, representing 24 states, visited Capitol Hill earlier this fall to fight for the science and practice of gastroenterology during AGA’s annual Advocacy Day.

NIH funding

AGA members met with lawmakers and their staffs on Sept. 16 to discuss the success that research and medical breakthroughs have had for their patients and encouraged Congress to support increased funding for NIH. Many members of Congress support increased funding for NIH, but a small group of House members is preventing passage of a bill that would increase funding for the institute by $1.25 billion in fiscal year (FY) 2017. The Senate Appropriations Committee passed a bill in June, on a vote of 29-1, to increase funding for NIH by $2 billion. Advocacy Day attendees urged their congressional offices to support the higher Senate number.

MACRA implementation

Members also discussed the need for congressional oversight to ensure that the Medicare Access & CHIP Reauthorization Act of 2015 (MACRA) law is being implemented as Congress intended. They shared their concerns over the impact this law could have on gastroenterologists, especially those in small or solo practices, and emphasized the need for CMS to provide flexibility to physicians to enable them to comply with the new requirements.

Participants highlighted the recent announcement that CMS will allow physicians more options for reporting in the first year as a positive sign that it is listening to the concerns voiced by Congress and the physician community on the regulatory burdens. AGA members also discussed the barriers that currently exist in qualifying as a specialty-focused alternative payment model (APM) and the need for continued flexibility to ensure that all physicians have the opportunity to participate in more value-based payment models.

Virtual advocacy

In conjunction with the Capitol Hill meetings, all AGA members were invited to participate in a Virtual Advocacy Day campaign. This additional component allowed all members to contact their members of Congress via email to voice their concerns about sustainable NIH funding for FY 2017 and the need for more congressional oversight of MACRA.

It’s not too late for you to show your support for the science and practice of GI. Contact your congressional representatives in support of important issues at www.gastroadvocacy.org/actionalerts.aspx.

More than 40 AGA members, representing 24 states, visited Capitol Hill earlier this fall to fight for the science and practice of gastroenterology during AGA’s annual Advocacy Day.

NIH funding

AGA members met with lawmakers and their staffs on Sept. 16 to discuss the success that research and medical breakthroughs have had for their patients and encouraged Congress to support increased funding for NIH. Many members of Congress support increased funding for NIH, but a small group of House members is preventing passage of a bill that would increase funding for the institute by $1.25 billion in fiscal year (FY) 2017. The Senate Appropriations Committee passed a bill in June, on a vote of 29-1, to increase funding for NIH by $2 billion. Advocacy Day attendees urged their congressional offices to support the higher Senate number.

MACRA implementation

Members also discussed the need for congressional oversight to ensure that the Medicare Access & CHIP Reauthorization Act of 2015 (MACRA) law is being implemented as Congress intended. They shared their concerns over the impact this law could have on gastroenterologists, especially those in small or solo practices, and emphasized the need for CMS to provide flexibility to physicians to enable them to comply with the new requirements.

Participants highlighted the recent announcement that CMS will allow physicians more options for reporting in the first year as a positive sign that it is listening to the concerns voiced by Congress and the physician community on the regulatory burdens. AGA members also discussed the barriers that currently exist in qualifying as a specialty-focused alternative payment model (APM) and the need for continued flexibility to ensure that all physicians have the opportunity to participate in more value-based payment models.

Virtual advocacy

In conjunction with the Capitol Hill meetings, all AGA members were invited to participate in a Virtual Advocacy Day campaign. This additional component allowed all members to contact their members of Congress via email to voice their concerns about sustainable NIH funding for FY 2017 and the need for more congressional oversight of MACRA.

It’s not too late for you to show your support for the science and practice of GI. Contact your congressional representatives in support of important issues at www.gastroadvocacy.org/actionalerts.aspx.