The mnemonic CUT DOWNTIME, which I have adapted and modi­fied from the book Lean Healthcare Deployment and Sustainability,¹ breaks down waste in health care—an activity that adds no value to a service—into 11 major categories (Table). This mnemonic provides the busy practitioner a simple framework for improving quality and efficiency of services by identifying and eliminating wastes the Lean way.

Disclosure
The author reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

The mnemonic CUT DOWNTIME, which I have adapted and modi­fied from the book Lean Healthcare Deployment and Sustainability,¹ breaks down waste in health care—an activity that adds no value to a service—into 11 major categories (Table). This mnemonic provides the busy practitioner a simple framework for improving quality and efficiency of services by identifying and eliminating wastes the Lean way.

Disclosure
The author reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

The mnemonic CUT DOWNTIME, which I have adapted and modi­fied from the book Lean Healthcare Deployment and Sustainability,¹ breaks down waste in health care—an activity that adds no value to a service—into 11 major categories (Table). This mnemonic provides the busy practitioner a simple framework for improving quality and efficiency of services by identifying and eliminating wastes the Lean way.

Disclosure
The author reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

The Social Security Administration (SSA) does not provide much guid­ance on the contentious issue of determining payeeship for disability ben­eficiaries. The only description available is stated on the “Physician/medical officer’s statement of patient’s capability to man­age benefits” (form SSA-787): “By capable we mean that the patient: Is able to under­stand and act on the ordinary affairs of life, such as providing for own adequate food, housing, etc., and is able, in spite of physi­cal impairments, to manage funds or direct others how to manage them.”

Physicians will be asked to make a capa­bility statement if they are performing a consultative examination for SSA or if their patient:
   • is applying for benefits
   • needs to have a payee.

Regrettably, the published literature on capability is scant.^1,2 Based on decades of personal experience, here is the approach I have adopted to determine capability.

Diagnoses, circumstances, and clini­cal syndromes that strongly suggest the need for a payee include those listed in the Table.

The psychiatric rehabilitation agency I work at adheres to a recovery model. I consult with caseworkers on the issue of capability, but generally endorse a “team” recommendation for initiating or termi­nating payeeship. A number of factors are involved:

Adherence to recovery means that we encourage autonomy; we do not attempt to prevent every bad decision.

Demands for money from the patient and demands to terminate payeeship can be strident and potentially violent.

Confrontations over payeeship can be a safety risk for family or staff who have been acting as the payee. 

Guardianship (or conservatorship) is a judicially determined restriction of financial decision-making.

Payeeship is an extrajudicial restriction of financial decision-making. Treating physicians, understandably, may feel uneasy restricting the rights of a patient. Additionally, there is ethical stress when a physician does anything that might compromise the primacy of the treatment relationship.

If all parties agree that payeeship should be terminated, I recommend the payee (whether the family or an institutional payee) begin a 3-month trial, during which the payee does not pay bills or keep a bud­get. The patient receives his (her) money in a lump sum at the beginning of the month, which begins a naturalistic trial of the patient’s capability to pay rent and budget adequately for all other necessities. If the patient demonstrates capability, I sign the SSA-787 form.

Offering a structured plan for restor­ing a patient’s benefits could defuse hostile demands.

Disclosure
The author reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

The Social Security Administration (SSA) does not provide much guid­ance on the contentious issue of determining payeeship for disability ben­eficiaries. The only description available is stated on the “Physician/medical officer’s statement of patient’s capability to man­age benefits” (form SSA-787): “By capable we mean that the patient: Is able to under­stand and act on the ordinary affairs of life, such as providing for own adequate food, housing, etc., and is able, in spite of physi­cal impairments, to manage funds or direct others how to manage them.”

Physicians will be asked to make a capa­bility statement if they are performing a consultative examination for SSA or if their patient:
   • is applying for benefits
   • needs to have a payee.

Regrettably, the published literature on capability is scant.^1,2 Based on decades of personal experience, here is the approach I have adopted to determine capability.

Diagnoses, circumstances, and clini­cal syndromes that strongly suggest the need for a payee include those listed in the Table.

The psychiatric rehabilitation agency I work at adheres to a recovery model. I consult with caseworkers on the issue of capability, but generally endorse a “team” recommendation for initiating or termi­nating payeeship. A number of factors are involved:

Adherence to recovery means that we encourage autonomy; we do not attempt to prevent every bad decision.

Demands for money from the patient and demands to terminate payeeship can be strident and potentially violent.

Confrontations over payeeship can be a safety risk for family or staff who have been acting as the payee. 

Guardianship (or conservatorship) is a judicially determined restriction of financial decision-making.

Payeeship is an extrajudicial restriction of financial decision-making. Treating physicians, understandably, may feel uneasy restricting the rights of a patient. Additionally, there is ethical stress when a physician does anything that might compromise the primacy of the treatment relationship.

If all parties agree that payeeship should be terminated, I recommend the payee (whether the family or an institutional payee) begin a 3-month trial, during which the payee does not pay bills or keep a bud­get. The patient receives his (her) money in a lump sum at the beginning of the month, which begins a naturalistic trial of the patient’s capability to pay rent and budget adequately for all other necessities. If the patient demonstrates capability, I sign the SSA-787 form.

Offering a structured plan for restor­ing a patient’s benefits could defuse hostile demands.

Disclosure
The author reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

The Social Security Administration (SSA) does not provide much guid­ance on the contentious issue of determining payeeship for disability ben­eficiaries. The only description available is stated on the “Physician/medical officer’s statement of patient’s capability to man­age benefits” (form SSA-787): “By capable we mean that the patient: Is able to under­stand and act on the ordinary affairs of life, such as providing for own adequate food, housing, etc., and is able, in spite of physi­cal impairments, to manage funds or direct others how to manage them.”

Physicians will be asked to make a capa­bility statement if they are performing a consultative examination for SSA or if their patient:
   • is applying for benefits
   • needs to have a payee.

Regrettably, the published literature on capability is scant.^1,2 Based on decades of personal experience, here is the approach I have adopted to determine capability.

Diagnoses, circumstances, and clini­cal syndromes that strongly suggest the need for a payee include those listed in the Table.

The psychiatric rehabilitation agency I work at adheres to a recovery model. I consult with caseworkers on the issue of capability, but generally endorse a “team” recommendation for initiating or termi­nating payeeship. A number of factors are involved:

Adherence to recovery means that we encourage autonomy; we do not attempt to prevent every bad decision.

Demands for money from the patient and demands to terminate payeeship can be strident and potentially violent.

Confrontations over payeeship can be a safety risk for family or staff who have been acting as the payee. 

Guardianship (or conservatorship) is a judicially determined restriction of financial decision-making.

Payeeship is an extrajudicial restriction of financial decision-making. Treating physicians, understandably, may feel uneasy restricting the rights of a patient. Additionally, there is ethical stress when a physician does anything that might compromise the primacy of the treatment relationship.

If all parties agree that payeeship should be terminated, I recommend the payee (whether the family or an institutional payee) begin a 3-month trial, during which the payee does not pay bills or keep a bud­get. The patient receives his (her) money in a lump sum at the beginning of the month, which begins a naturalistic trial of the patient’s capability to pay rent and budget adequately for all other necessities. If the patient demonstrates capability, I sign the SSA-787 form.

Offering a structured plan for restor­ing a patient’s benefits could defuse hostile demands.

Disclosure
The author reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Dear Dr. Mossman,

I practice in a state that allows medical mari­juana use. A few of my patients have asked me to help them obtain marijuana for their conditions. How risky would it be to oblige?

Submitted by “Dr. J”

In recent years, public debate about mar­ijuana has acquired 2 new dimensions: (1) the wishes and medical needs of peo­ple who seek marijuana for its purported health benefits, and (2) the role of physi­cians who practice where “medical mari­juana” is legal. This article, the authors’ joint effort to address Dr. J’s concerns, hits 3 topics:
   • the intersection of marijuana policy and health care in the United States
   • the risks and possible benefits of mari­juana use
   • the medicolegal problems faced by physicians who might advise patients to use marijuana.

Legal haze
Two cannabinoids—dronabinol and nabi­lone—have received FDA approval as appetite enhancers and anti-nausea agents. Third-party payors usually cover these types of medications, but no insurer pays for medical marijuana.¹ The Controlled Substances Act of 1970² classified mari­juana as a Schedule I drug because of its abuse potential, lack of accepted medical applications, and uncertain safety. The FDA has not approved marijuana use for any medical condition.

Although people commonly speak of “prescribing” marijuana, physicians cannot legally do this in the United States. What physicians may do, in the 23 states that allow medical marijuana, is recommend or certify a patient’s marijuana use—an action that has constitutional protection under the First Amendment’s freedom of speech clause.^3,4

A physician may complete documenta­tion that a patient has one of the qualifying medical conditions for which the jurisdic­tion has legalized medical marijuana. Either the patient or the physician then submits that documentation to the appropriate gov­ernment agency (eg, the state’s department of health).

If the documentation receives approval, the agency will issue the patient a registra­tion card that allows possession of medi­cal marijuana, with which the patient can obtain or grow a small amount of mari­juana. The cannabinoid content of mari­juana products varies considerably,⁵ and physicians who certify marijuana typi­cally defer dosage recommendations to the patient or the dispensary.¹

In states that allow medical marijuana, users may assert an affirmative defense of medical necessity if they face criminal pros­ecution.^3,6 Possession of marijuana remains illegal under federal law, however, regard­less of one’s reason for having it.^7,8 Since October 2009, the Attorney General’s office has discouraged federal prosecutions of per­sons “whose actions are in clear and unam­biguous compliance with existing state laws providing for the medical use of mari­juana.”⁹ But given the remaining conflicts between state and federal laws, “the legal implications of certifying patients for medi­cal marijuana remain unclear.”¹⁰

Physicians have few resources to instruct them on the legal risks of certifying medical marijuana. When Canada legalized medical marijuana, the organization that provides malpractice insurance to Canadian physi­cians told its members that “prescribing medical marijuana cannot be compared to prescribing prescription drugs” and rec­ommended that physicians obtain signed release forms documenting that they have discussed the risks of medical marijuana with patients.¹¹ For some risky approved drugs, the FDA has established a risk evalu­ation and mitigation strategy, but no such guidance is available for marijuana.

Highlighting the benefits and risks
Proponents of medical marijuana claim that Cannabis can help patients, and dispas­sionate experts acknowledge that at least modest evidence supports the benefits of using “marijuana for nausea and vomit­ing related to chemotherapy, specific pain syndromes, and spasticity from multiple sclerosis.”¹⁰ For several other conditions— HIV/AIDS, depression, anxiety disor­ders, sleep disorders, psychosis, Tourette syndrome—evidence of benefit is poor.¹² Rigorous evaluation of medical marijuana is difficult because the plant contains hun­dreds of active chemical compounds. The chemical content of marijuana is highly variable, depending on its preparation and administration,^10,13—one reason why only a few good randomized controlled trials of marijuana have been conducted.

Marijuana has several side effects and carries many health risks (Table 1).^4,14-20

On the highway: Marijuana and driving
Marijuana use impairs driving ability.¹⁴ Following enactment of more lenient mari­juana laws, several states have reported higher numbers of fatally injured drivers who tested positive for Cannabis^21-23 and had a positive screen of tetrahydrocannabi­nol (THC) in driving under the influence cases.^24,25 One study showed that a blood THC concentration >5 ng/mL (comparable to a blood alcohol concentration of 0.15%) increased the crash odds ratio to 6.^6.25,26

Marijuana impairs reaction time, informa­tion processing, motor performance, atten­tion, and visual processing.^14,16,27,28 Drivers who are under the influence of marijuana make more driving errors, despite being cautious about how they react to traffic.²⁹ Even after weeks of abstinence, previ­ous daily users of marijuana display some cognitive processing and driving-related impairments.^30,31

Courts have found physicians negligent if their patients’ treatment-induced driving impairments injured others when the risk of driving-related injury was foreseeable.³² The Massachusetts case of Coombes v Florio³³ lik­ened the physician’s duty to that of a liquor store that sells alcohol to a minor who sub­sequently crashes, or to a father who did not lock his firearms away from his violent adult son.

Three variables influence a court’s judgment about whether risk is “foresee­able”: “the relative knowledge of the risk as between lay persons and physicians, whether the patient has previously used the medication and/or experienced the adverse effect, and whether a warning would other­wise have been futile.”³⁴ A physician who certified a patient to use marijuana without adequately explaining the risks of driv­ing might be vulnerable to a lawsuit if the patient’s driving accident occurred while the patient was under the influence of the drug. Recommending marijuana as a treat­ment also could lead to a malpractice action if a patient experienced and was harmed by the drug’s adverse effects.

Other drags
Another malpractice risk stems from mari­juana’s addiction potential. Although many people think Cannabis isn’t addictive, nearly 10% of all marijuana users develop depen­dence.^10,17 Regular Cannabis users are more likely to use alcohol, tobacco, and “recre­ational” drugs,^17,35 and using alcohol and marijuana together greatly heightens the risk of driving accidents.^14,15 Although we know of no case that relates directly to mari­juana, physicians have faced lawsuits for injuries stemming from a patient’s addiction to prescription drugs,36 particularly when the patient’s behavior should have led the physician to suspect abuse or overuse.³⁷

When certifying marijuana use, physi­cians have the same obligations that apply to more conventional medical treatment:
   • establishing a proper physician–patient relationship
   • taking an appropriate history
   • conducting a proper examination
   • reviewing records
   • developing a comprehensive treatment plan
   • weighing risks and alternatives
   • providing follow-up care.

Neglecting these steps could lead to medical board sanctions and suspension or revocation of a medical license.¹³

The blunt reality
We advise against recommending mari­juana for your patients. But if you have exhausted the alternatives, see marijuana as the last resort, and believe that taking the risk is worth the potential benefit, you can take some steps to reduce your legal risk (Table 2,^1,32,37,38 and Table 3¹³).

Bottom LinE
Medical marijuana is a controversial topic that demands more rigorous research and regulatory consideration. In the present climate, cautious physicians will avoid recommending marijuana to their patients. If you think that a patient has a medical indication, with no treatment option better than medical marijuana, be sure to understand the medical and legal ramifications before you authorize its use.

Disclosures
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dear Dr. Mossman,

I practice in a state that allows medical mari­juana use. A few of my patients have asked me to help them obtain marijuana for their conditions. How risky would it be to oblige?

Submitted by “Dr. J”

In recent years, public debate about mar­ijuana has acquired 2 new dimensions: (1) the wishes and medical needs of peo­ple who seek marijuana for its purported health benefits, and (2) the role of physi­cians who practice where “medical mari­juana” is legal. This article, the authors’ joint effort to address Dr. J’s concerns, hits 3 topics:
   • the intersection of marijuana policy and health care in the United States
   • the risks and possible benefits of mari­juana use
   • the medicolegal problems faced by physicians who might advise patients to use marijuana.

Legal haze
Two cannabinoids—dronabinol and nabi­lone—have received FDA approval as appetite enhancers and anti-nausea agents. Third-party payors usually cover these types of medications, but no insurer pays for medical marijuana.¹ The Controlled Substances Act of 1970² classified mari­juana as a Schedule I drug because of its abuse potential, lack of accepted medical applications, and uncertain safety. The FDA has not approved marijuana use for any medical condition.

Although people commonly speak of “prescribing” marijuana, physicians cannot legally do this in the United States. What physicians may do, in the 23 states that allow medical marijuana, is recommend or certify a patient’s marijuana use—an action that has constitutional protection under the First Amendment’s freedom of speech clause.^3,4

A physician may complete documenta­tion that a patient has one of the qualifying medical conditions for which the jurisdic­tion has legalized medical marijuana. Either the patient or the physician then submits that documentation to the appropriate gov­ernment agency (eg, the state’s department of health).

If the documentation receives approval, the agency will issue the patient a registra­tion card that allows possession of medi­cal marijuana, with which the patient can obtain or grow a small amount of mari­juana. The cannabinoid content of mari­juana products varies considerably,⁵ and physicians who certify marijuana typi­cally defer dosage recommendations to the patient or the dispensary.¹

In states that allow medical marijuana, users may assert an affirmative defense of medical necessity if they face criminal pros­ecution.^3,6 Possession of marijuana remains illegal under federal law, however, regard­less of one’s reason for having it.^7,8 Since October 2009, the Attorney General’s office has discouraged federal prosecutions of per­sons “whose actions are in clear and unam­biguous compliance with existing state laws providing for the medical use of mari­juana.”⁹ But given the remaining conflicts between state and federal laws, “the legal implications of certifying patients for medi­cal marijuana remain unclear.”¹⁰

Physicians have few resources to instruct them on the legal risks of certifying medical marijuana. When Canada legalized medical marijuana, the organization that provides malpractice insurance to Canadian physi­cians told its members that “prescribing medical marijuana cannot be compared to prescribing prescription drugs” and rec­ommended that physicians obtain signed release forms documenting that they have discussed the risks of medical marijuana with patients.¹¹ For some risky approved drugs, the FDA has established a risk evalu­ation and mitigation strategy, but no such guidance is available for marijuana.

Highlighting the benefits and risks
Proponents of medical marijuana claim that Cannabis can help patients, and dispas­sionate experts acknowledge that at least modest evidence supports the benefits of using “marijuana for nausea and vomit­ing related to chemotherapy, specific pain syndromes, and spasticity from multiple sclerosis.”¹⁰ For several other conditions— HIV/AIDS, depression, anxiety disor­ders, sleep disorders, psychosis, Tourette syndrome—evidence of benefit is poor.¹² Rigorous evaluation of medical marijuana is difficult because the plant contains hun­dreds of active chemical compounds. The chemical content of marijuana is highly variable, depending on its preparation and administration,^10,13—one reason why only a few good randomized controlled trials of marijuana have been conducted.

Marijuana has several side effects and carries many health risks (Table 1).^4,14-20

On the highway: Marijuana and driving
Marijuana use impairs driving ability.¹⁴ Following enactment of more lenient mari­juana laws, several states have reported higher numbers of fatally injured drivers who tested positive for Cannabis^21-23 and had a positive screen of tetrahydrocannabi­nol (THC) in driving under the influence cases.^24,25 One study showed that a blood THC concentration >5 ng/mL (comparable to a blood alcohol concentration of 0.15%) increased the crash odds ratio to 6.^6.25,26

Marijuana impairs reaction time, informa­tion processing, motor performance, atten­tion, and visual processing.^14,16,27,28 Drivers who are under the influence of marijuana make more driving errors, despite being cautious about how they react to traffic.²⁹ Even after weeks of abstinence, previ­ous daily users of marijuana display some cognitive processing and driving-related impairments.^30,31

Courts have found physicians negligent if their patients’ treatment-induced driving impairments injured others when the risk of driving-related injury was foreseeable.³² The Massachusetts case of Coombes v Florio³³ lik­ened the physician’s duty to that of a liquor store that sells alcohol to a minor who sub­sequently crashes, or to a father who did not lock his firearms away from his violent adult son.

Three variables influence a court’s judgment about whether risk is “foresee­able”: “the relative knowledge of the risk as between lay persons and physicians, whether the patient has previously used the medication and/or experienced the adverse effect, and whether a warning would other­wise have been futile.”³⁴ A physician who certified a patient to use marijuana without adequately explaining the risks of driv­ing might be vulnerable to a lawsuit if the patient’s driving accident occurred while the patient was under the influence of the drug. Recommending marijuana as a treat­ment also could lead to a malpractice action if a patient experienced and was harmed by the drug’s adverse effects.

Other drags
Another malpractice risk stems from mari­juana’s addiction potential. Although many people think Cannabis isn’t addictive, nearly 10% of all marijuana users develop depen­dence.^10,17 Regular Cannabis users are more likely to use alcohol, tobacco, and “recre­ational” drugs,^17,35 and using alcohol and marijuana together greatly heightens the risk of driving accidents.^14,15 Although we know of no case that relates directly to mari­juana, physicians have faced lawsuits for injuries stemming from a patient’s addiction to prescription drugs,36 particularly when the patient’s behavior should have led the physician to suspect abuse or overuse.³⁷

When certifying marijuana use, physi­cians have the same obligations that apply to more conventional medical treatment:
   • establishing a proper physician–patient relationship
   • taking an appropriate history
   • conducting a proper examination
   • reviewing records
   • developing a comprehensive treatment plan
   • weighing risks and alternatives
   • providing follow-up care.

Neglecting these steps could lead to medical board sanctions and suspension or revocation of a medical license.¹³

The blunt reality
We advise against recommending mari­juana for your patients. But if you have exhausted the alternatives, see marijuana as the last resort, and believe that taking the risk is worth the potential benefit, you can take some steps to reduce your legal risk (Table 2,^1,32,37,38 and Table 3¹³).

Bottom LinE
Medical marijuana is a controversial topic that demands more rigorous research and regulatory consideration. In the present climate, cautious physicians will avoid recommending marijuana to their patients. If you think that a patient has a medical indication, with no treatment option better than medical marijuana, be sure to understand the medical and legal ramifications before you authorize its use.

Disclosures
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dear Dr. Mossman,

I practice in a state that allows medical mari­juana use. A few of my patients have asked me to help them obtain marijuana for their conditions. How risky would it be to oblige?

Submitted by “Dr. J”

In recent years, public debate about mar­ijuana has acquired 2 new dimensions: (1) the wishes and medical needs of peo­ple who seek marijuana for its purported health benefits, and (2) the role of physi­cians who practice where “medical mari­juana” is legal. This article, the authors’ joint effort to address Dr. J’s concerns, hits 3 topics:
   • the intersection of marijuana policy and health care in the United States
   • the risks and possible benefits of mari­juana use
   • the medicolegal problems faced by physicians who might advise patients to use marijuana.

Legal haze
Two cannabinoids—dronabinol and nabi­lone—have received FDA approval as appetite enhancers and anti-nausea agents. Third-party payors usually cover these types of medications, but no insurer pays for medical marijuana.¹ The Controlled Substances Act of 1970² classified mari­juana as a Schedule I drug because of its abuse potential, lack of accepted medical applications, and uncertain safety. The FDA has not approved marijuana use for any medical condition.

Although people commonly speak of “prescribing” marijuana, physicians cannot legally do this in the United States. What physicians may do, in the 23 states that allow medical marijuana, is recommend or certify a patient’s marijuana use—an action that has constitutional protection under the First Amendment’s freedom of speech clause.^3,4

A physician may complete documenta­tion that a patient has one of the qualifying medical conditions for which the jurisdic­tion has legalized medical marijuana. Either the patient or the physician then submits that documentation to the appropriate gov­ernment agency (eg, the state’s department of health).

If the documentation receives approval, the agency will issue the patient a registra­tion card that allows possession of medi­cal marijuana, with which the patient can obtain or grow a small amount of mari­juana. The cannabinoid content of mari­juana products varies considerably,⁵ and physicians who certify marijuana typi­cally defer dosage recommendations to the patient or the dispensary.¹

In states that allow medical marijuana, users may assert an affirmative defense of medical necessity if they face criminal pros­ecution.^3,6 Possession of marijuana remains illegal under federal law, however, regard­less of one’s reason for having it.^7,8 Since October 2009, the Attorney General’s office has discouraged federal prosecutions of per­sons “whose actions are in clear and unam­biguous compliance with existing state laws providing for the medical use of mari­juana.”⁹ But given the remaining conflicts between state and federal laws, “the legal implications of certifying patients for medi­cal marijuana remain unclear.”¹⁰

Physicians have few resources to instruct them on the legal risks of certifying medical marijuana. When Canada legalized medical marijuana, the organization that provides malpractice insurance to Canadian physi­cians told its members that “prescribing medical marijuana cannot be compared to prescribing prescription drugs” and rec­ommended that physicians obtain signed release forms documenting that they have discussed the risks of medical marijuana with patients.¹¹ For some risky approved drugs, the FDA has established a risk evalu­ation and mitigation strategy, but no such guidance is available for marijuana.

Highlighting the benefits and risks
Proponents of medical marijuana claim that Cannabis can help patients, and dispas­sionate experts acknowledge that at least modest evidence supports the benefits of using “marijuana for nausea and vomit­ing related to chemotherapy, specific pain syndromes, and spasticity from multiple sclerosis.”¹⁰ For several other conditions— HIV/AIDS, depression, anxiety disor­ders, sleep disorders, psychosis, Tourette syndrome—evidence of benefit is poor.¹² Rigorous evaluation of medical marijuana is difficult because the plant contains hun­dreds of active chemical compounds. The chemical content of marijuana is highly variable, depending on its preparation and administration,^10,13—one reason why only a few good randomized controlled trials of marijuana have been conducted.

Marijuana has several side effects and carries many health risks (Table 1).^4,14-20

On the highway: Marijuana and driving
Marijuana use impairs driving ability.¹⁴ Following enactment of more lenient mari­juana laws, several states have reported higher numbers of fatally injured drivers who tested positive for Cannabis^21-23 and had a positive screen of tetrahydrocannabi­nol (THC) in driving under the influence cases.^24,25 One study showed that a blood THC concentration >5 ng/mL (comparable to a blood alcohol concentration of 0.15%) increased the crash odds ratio to 6.^6.25,26

Marijuana impairs reaction time, informa­tion processing, motor performance, atten­tion, and visual processing.^14,16,27,28 Drivers who are under the influence of marijuana make more driving errors, despite being cautious about how they react to traffic.²⁹ Even after weeks of abstinence, previ­ous daily users of marijuana display some cognitive processing and driving-related impairments.^30,31

Courts have found physicians negligent if their patients’ treatment-induced driving impairments injured others when the risk of driving-related injury was foreseeable.³² The Massachusetts case of Coombes v Florio³³ lik­ened the physician’s duty to that of a liquor store that sells alcohol to a minor who sub­sequently crashes, or to a father who did not lock his firearms away from his violent adult son.

Three variables influence a court’s judgment about whether risk is “foresee­able”: “the relative knowledge of the risk as between lay persons and physicians, whether the patient has previously used the medication and/or experienced the adverse effect, and whether a warning would other­wise have been futile.”³⁴ A physician who certified a patient to use marijuana without adequately explaining the risks of driv­ing might be vulnerable to a lawsuit if the patient’s driving accident occurred while the patient was under the influence of the drug. Recommending marijuana as a treat­ment also could lead to a malpractice action if a patient experienced and was harmed by the drug’s adverse effects.

Other drags
Another malpractice risk stems from mari­juana’s addiction potential. Although many people think Cannabis isn’t addictive, nearly 10% of all marijuana users develop depen­dence.^10,17 Regular Cannabis users are more likely to use alcohol, tobacco, and “recre­ational” drugs,^17,35 and using alcohol and marijuana together greatly heightens the risk of driving accidents.^14,15 Although we know of no case that relates directly to mari­juana, physicians have faced lawsuits for injuries stemming from a patient’s addiction to prescription drugs,36 particularly when the patient’s behavior should have led the physician to suspect abuse or overuse.³⁷

When certifying marijuana use, physi­cians have the same obligations that apply to more conventional medical treatment:
   • establishing a proper physician–patient relationship
   • taking an appropriate history
   • conducting a proper examination
   • reviewing records
   • developing a comprehensive treatment plan
   • weighing risks and alternatives
   • providing follow-up care.

Neglecting these steps could lead to medical board sanctions and suspension or revocation of a medical license.¹³

The blunt reality
We advise against recommending mari­juana for your patients. But if you have exhausted the alternatives, see marijuana as the last resort, and believe that taking the risk is worth the potential benefit, you can take some steps to reduce your legal risk (Table 2,^1,32,37,38 and Table 3¹³).

Bottom LinE
Medical marijuana is a controversial topic that demands more rigorous research and regulatory consideration. In the present climate, cautious physicians will avoid recommending marijuana to their patients. If you think that a patient has a medical indication, with no treatment option better than medical marijuana, be sure to understand the medical and legal ramifications before you authorize its use.

Disclosures
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

As I was writing my introduction to this current edition of the Master Class in Gynecologic Surgery, focusing on minimally invasive surgery for the obese female patient, I was listening to Chuck Todd, host of “Meet the Press.” Instantaneously, television and my thoughts became one; in the last segment of the program, Mr. Todd discussed what he was able to consume for $50 at the Iowa State Fair. I learned that his diet that day consisted of a pork chop on a stick, mac and cheese, a bacon-wrapped corn dog, cheese on a stick with jalapeños, a deep-fried Twinkie, and even fried apple pie with bacon. While Mr. Todd is thin and healthy, the array of foods at the fair reflects our nation’s penchant toward fast food that is fat laden and fried. Though our county is not alone in the world, obesity has reached epidemic proportion in the United States.

According to a May 2015 Department of Health & Human Services report on the health status of the nation, 69% of adults in the United States are overweight and 35% are obese. As a result, the minimally invasive gynecologic surgeon is dealing with an increasing population of women with comorbidities related to their obesity that can confound surgery outcomes. Moreover, anatomic landmarks that the young medical student learns in his or her first anatomy classes are modified due to the size of panniculus and the migration of the umbilicus relative to the bifurcation of the aorta.

I asked Dr. Amina Ahmed to join me in discussing the management of the obese patient undergoing minimally invasive gynecologic surgery. After completing her fellowship in gynecologic oncology, Dr. Ahmed has been on staff at both the University of Iowa Hospitals and Clinics, Iowa City, and Advocate Lutheran General Hospital, Park Ridge, Ill. She will soon join the gynecologic oncology faculty at Rush University Medical Center, Chicago. Given the increased rate of obesity in both Chicago and Iowa, Dr. Ahmed has become an expert in this area in a short period of time.

Dr. Miller is a clinical associate professor at the University of Illinois at Chicago, immediate past president of the International Society for Gynecologic Endoscopy (ISGE), and a past president of the AAGL. He is a reproductive endocrinologist and minimally invasive gynecologic surgeon in private practice in Naperville, Ill., and Schaumburg, Ill.; director of minimally invasive gynecologic surgery and the director of the AAGL/SRS fellowship in minimally invasive gynecologic surgery at Advocate Lutheran General Hospital, Park Ridge, Ill; and the medical editor of this column, Master Class. Dr. Miller disclosed that he is a consultant and on the speakers bureau for Ethicon and Intuitive Surgical, and is a consultant for Covidien.

As I was writing my introduction to this current edition of the Master Class in Gynecologic Surgery, focusing on minimally invasive surgery for the obese female patient, I was listening to Chuck Todd, host of “Meet the Press.” Instantaneously, television and my thoughts became one; in the last segment of the program, Mr. Todd discussed what he was able to consume for $50 at the Iowa State Fair. I learned that his diet that day consisted of a pork chop on a stick, mac and cheese, a bacon-wrapped corn dog, cheese on a stick with jalapeños, a deep-fried Twinkie, and even fried apple pie with bacon. While Mr. Todd is thin and healthy, the array of foods at the fair reflects our nation’s penchant toward fast food that is fat laden and fried. Though our county is not alone in the world, obesity has reached epidemic proportion in the United States.

According to a May 2015 Department of Health & Human Services report on the health status of the nation, 69% of adults in the United States are overweight and 35% are obese. As a result, the minimally invasive gynecologic surgeon is dealing with an increasing population of women with comorbidities related to their obesity that can confound surgery outcomes. Moreover, anatomic landmarks that the young medical student learns in his or her first anatomy classes are modified due to the size of panniculus and the migration of the umbilicus relative to the bifurcation of the aorta.

I asked Dr. Amina Ahmed to join me in discussing the management of the obese patient undergoing minimally invasive gynecologic surgery. After completing her fellowship in gynecologic oncology, Dr. Ahmed has been on staff at both the University of Iowa Hospitals and Clinics, Iowa City, and Advocate Lutheran General Hospital, Park Ridge, Ill. She will soon join the gynecologic oncology faculty at Rush University Medical Center, Chicago. Given the increased rate of obesity in both Chicago and Iowa, Dr. Ahmed has become an expert in this area in a short period of time.

Dr. Miller is a clinical associate professor at the University of Illinois at Chicago, immediate past president of the International Society for Gynecologic Endoscopy (ISGE), and a past president of the AAGL. He is a reproductive endocrinologist and minimally invasive gynecologic surgeon in private practice in Naperville, Ill., and Schaumburg, Ill.; director of minimally invasive gynecologic surgery and the director of the AAGL/SRS fellowship in minimally invasive gynecologic surgery at Advocate Lutheran General Hospital, Park Ridge, Ill; and the medical editor of this column, Master Class. Dr. Miller disclosed that he is a consultant and on the speakers bureau for Ethicon and Intuitive Surgical, and is a consultant for Covidien.

As I was writing my introduction to this current edition of the Master Class in Gynecologic Surgery, focusing on minimally invasive surgery for the obese female patient, I was listening to Chuck Todd, host of “Meet the Press.” Instantaneously, television and my thoughts became one; in the last segment of the program, Mr. Todd discussed what he was able to consume for $50 at the Iowa State Fair. I learned that his diet that day consisted of a pork chop on a stick, mac and cheese, a bacon-wrapped corn dog, cheese on a stick with jalapeños, a deep-fried Twinkie, and even fried apple pie with bacon. While Mr. Todd is thin and healthy, the array of foods at the fair reflects our nation’s penchant toward fast food that is fat laden and fried. Though our county is not alone in the world, obesity has reached epidemic proportion in the United States.

According to a May 2015 Department of Health & Human Services report on the health status of the nation, 69% of adults in the United States are overweight and 35% are obese. As a result, the minimally invasive gynecologic surgeon is dealing with an increasing population of women with comorbidities related to their obesity that can confound surgery outcomes. Moreover, anatomic landmarks that the young medical student learns in his or her first anatomy classes are modified due to the size of panniculus and the migration of the umbilicus relative to the bifurcation of the aorta.

I asked Dr. Amina Ahmed to join me in discussing the management of the obese patient undergoing minimally invasive gynecologic surgery. After completing her fellowship in gynecologic oncology, Dr. Ahmed has been on staff at both the University of Iowa Hospitals and Clinics, Iowa City, and Advocate Lutheran General Hospital, Park Ridge, Ill. She will soon join the gynecologic oncology faculty at Rush University Medical Center, Chicago. Given the increased rate of obesity in both Chicago and Iowa, Dr. Ahmed has become an expert in this area in a short period of time.

Dr. Miller is a clinical associate professor at the University of Illinois at Chicago, immediate past president of the International Society for Gynecologic Endoscopy (ISGE), and a past president of the AAGL. He is a reproductive endocrinologist and minimally invasive gynecologic surgeon in private practice in Naperville, Ill., and Schaumburg, Ill.; director of minimally invasive gynecologic surgery and the director of the AAGL/SRS fellowship in minimally invasive gynecologic surgery at Advocate Lutheran General Hospital, Park Ridge, Ill; and the medical editor of this column, Master Class. Dr. Miller disclosed that he is a consultant and on the speakers bureau for Ethicon and Intuitive Surgical, and is a consultant for Covidien.

The current epidemic of obesity presents gynecologic surgeons with the challenge of safely and successfully performing minimally invasive surgery in women who are morbidly or superobese.

In 2004, the prevalence of a body mass index greater than 40 kg/m² was almost 7.0% in females in the United States (JAMA. 2006 Apr 5;295[13]:1549-55.). Most recently, 8.3% of women were reported to have a BMI greater than 40 (JAMA. 2014 Feb 26;311[8]:806-14.). This is a value that the World Health Organization defines as Class III obesity and that, according to further stratification reported in the surgical literature, includes the categories of morbid obesity (40-44.9), superobesity (greater than 45), and super-superobesity (greater than 60).

As a gynecologic oncologist, I see firsthand the impact of obesity on the risk of multiple gynecologic conditions and female cancers, including endometrial cancer, as well as the benefits of a minimally invasive approach. I frequently perform hysterectomies via the minimally invasive approach to treat precancer and cancer of the uterus in morbidly and superobese women who have significant central adiposity.

MIGS benefits in the obese

In the past 15 years, and particularly in the past decade, evidence that obese patients benefit from laparoscopic surgery compared with traditional laparotomy has increased. I consider minimally invasive surgery the standard of care for women with endometrial cancer, regardless of the BMI.

As Dr. Stacey A. Scheib and her colleagues wrote in a recent review on laparoscopy in the morbidly obese, most of the gynecologic literature comparing laparoscopic surgery with laparotomy in this population is focused on gynecologic oncology because obesity is so strongly associated with endometrial and other cancers in women (J Minim Invasive Gynecol. 2014 Mar-Apr;21[2]:182-95.). In one prospective study of women with clinical stage I endometrial cancer and BMIs between 28 and 60, those who underwent laparoscopic surgery – 40 of 42 women over 2 years – had significantly longer operative times but less operative morbidity, shorter hospital stays, faster recovery and better postsurgical quality of life, compared with women who had undergone laparotomy in the previous 2 years. The control patients also had clinical stage I endometrial cancer and similar BMIs (Gynecol Oncol. 2000 Sep;78[3 Pt 1]:329-35.).

Research comparing robotics and conventional laparoscopy in obese gynecologic surgery patients is limited, and findings are inconsistent. It will remain difficult to compare the two approaches because few surgeons are equally skilled in both approaches and because the learning curve for conventional laparoscopy is so much steeper than for robotics.

I favor the robotic approach for morbidly and superobese patients for its superior visualization and ergonomics.

Patient positioning

It is important to use an operative bed that will accommodate the weight and width of obese patients and enable Trendelenburg positioning of up to 45 degrees. We use a bariatric bed with a 1,000-pound weight limit.

Obese patients are at greater risk for neuromuscular injuries and pressure sores, so careful patient positioning and padding of pressure points is critically important. We have found a surgical bean bag to be much more effective in preventing slippage for the morbidly or superobese patient than is egg-crate foam. The bean bag conforms nicely to the shape of the patient’s back, neck, and arms when it is appropriately desufflated. After desufflation, the bean bag must be well taped onto the operative bed.

I sometimes use shoulder blocks for extra assurance. When used, these braces must be attached to the bean bag and not to the patient.

We typically pad the arms completely with gel pads or foam before the bean bag is desufflated. We also often pad the knees and calves before the legs are placed and secured in stirrups made for the morbidly obese, with the buttocks slightly off the table.

In a review of literature on obesity and laparoscopy outcomes, Dr. Georgine Lamvu and her associates recommended that the arms be tucked in the “military” position, along the length of the body (Am J Obstet Gynecol. 2004 Aug;191[2]:669-74.). To ensure that both arms are properly tucked against the length of the body, we use bed extenders or sleds to widen the bed as necessary.

Abdominal access

I use the open Hasson technique in my obese patients and enter the peritoneum under direct visualization. In patients with high levels of morbid obesity, I have found it helpful to retract the adipose tissue using thin Breisky vaginal retractors. These retractors can hold the adipose tissue away from the fascia to facilitate entry into the abdominal cavity via the open technique.

Utilizing the umbilicus as the initial entry point – often desirable in minimally invasive surgery – is frequently not possible in morbidly obese patients because as BMI increases, the umbilicus migrates toward the pubic bone and away from the aortic bifurcation. In patients who were overweight (BMI greater than 25), Dr. W.W. Hurd and his associates noted a repositioning of the umbilicus below the aortic bifurcation of 2 cm or greater (Obstet Gynecol. 1992 Jul;80[1]:48-51.).

Instead, a supraumbilical or left upper quadrant site for initial entry enables optimal triangulation of trocars and visualization of disease. The trocars must then be placed more lateral and cephalad than in thinner women. In doing so, risk to the inferior epigastric is mitigated. Moreover, longer trocar lengths (150 mm) may be required.

To utilize an umbilical entry, it is imperative that the panniculus be placed cephalad to a position between the two anterior iliac spines (Obstet Gynecol. 1998 Nov;92[5]:869-72.). By doing this, the umbilicus is now repositioned relative to the bifurcation of the aorta similar to the thinner patient. This can either be accomplished using assistants to move the panniculus cephalad or taping the panniculus.

Alternatively, if the Hasson technique is not utilized, a Veress needle (50 mm in length) may be used. Based on MRI and CT visualization, Dr. Hurd has long recommended using a 90-degree angle in the obese population, compared with a 45-degree angle in nonobese women (J Reprod Med. 1991;36[7]:473-6.).

I usually place the patient into a moderate Trendelenburg position before docking the robot and observe the patient’s cardiac and respiratory responses to the induction of anesthesia. Adjustments in the degree of Trendelenburg positioning, the insufflation pressure level, and the ventilation settings can then be made if necessary. Occasionally I will decrease the insufflation pressure from 15 to 12 mm Hg, for instance, to accommodate ventilation needs.

A note from Dr. Charles E. Miller, Master Class Medical Editor

It must be recognized that not all physicians agree with the use of shoulder braces. In a review of literature on brachial plexus injuries in gynecologic surgery during 1980-2012, Dr. Nigel Pereira and his associates identified eight case reports, all of which involved Trendelenburg positioning and seven of which utilized shoulder braces. In their evaluation of the literature, the authors concluded that “the force of the shoulder braces on the clavicle and scapula opposes the force of gravity on the humerus, thereby stretching the brachial plexus and leading to nerve injury. This is particularly exaggerated when the arm is hyperabducted (less than 90 degrees), the head is laterally flexed to the opposite side, or the abducted arm is sagging.”

The authors also point out that longer times spent under general anesthesia (commensurate with increased operating times) increase the risk of brachial plexus injury “by increasing joint mobility (particularly when muscle relaxants are used) because the neighboring bony structure is more likely to compress or impinge on the brachial plexus” (CRSLS e2014.00077. [doi:10.4293/CRSLS.2014.00077]).

More pearls from Dr. Miller

Preoperative care. Prior to surgery it is important to examine a patient’s panniculus closely for evidence of infection. As the area underneath the panniculus receives little oxygen, it is at greater risk for both bacterial and fungal infections. If infection is noted, treatment prior to surgery is strongly recommended. Moreover, as the skin under the panniculus is often times “broken down,” which can compromise healing, lateral incisions should not be made in this area.

Since obese women have more severe comorbidities (such as metabolic syndrome, obstructed sleep apnea, coronary artery disease, poorly controlled hypertension, and a difficult airway) and a greater risk of perioperative complications than women who are not obese, they generally require a more-extensive preoperative work-up and additional perioperative considerations. If the minimally invasive gynecologic surgeon is uncomfortable with evaluation of cardiac and pulmonary status, medical clearance and perioperative consultation with an anesthesiologist prior to surgery is strongly recommended.

Perioperative care. There are no studies in the literature supporting the use of antibiotic prophylaxis prior to surgery despite the increased risk of postoperative wound infection in morbidly obese patients. Increased risk of surgical site infection post abdominal hysterectomy has been noted in women with a BMI greater than 35. Therefore, consideration should be given to the use of prophylactic antibiotics. For patients weighing more than 80 kg, I advise using 2 gm prophylactic cefazolin; increase this to 3 gm in patients that weigh more than 120 kg.

The morbidly obese patient is also at greater risk of deep venous thrombosis, especially when the procedure is lengthy. Sequential compression devices are essential. Moreover, use of such antithrombotic agents as Lovenox [enoxaparin] and heparin should be considered until the patient is ambulating.

Postoperative care. It is imperative to stress the need for extensive pulmonary toilet or hygiene (i.e., coughing and breathing deeply to clear mucus and secretions from the airways) as well as early ambulation. The patient should also be counseled to use pain medication judiciously. And until the patient is mobile, the use of antithrombotic agents, such as Lovenox and heparin, should be continued.

Dr. Ahmed reports that she has no disclosures related to this Master Class. Dr. Miller disclosed that he is a consultant and is on the speakers bureau for Ethicon and Intuitive Surgical, and is a consultant for Covidien. Email Dr. Ahmed and Dr. Miller at [email protected].

The current epidemic of obesity presents gynecologic surgeons with the challenge of safely and successfully performing minimally invasive surgery in women who are morbidly or superobese.

In 2004, the prevalence of a body mass index greater than 40 kg/m² was almost 7.0% in females in the United States (JAMA. 2006 Apr 5;295[13]:1549-55.). Most recently, 8.3% of women were reported to have a BMI greater than 40 (JAMA. 2014 Feb 26;311[8]:806-14.). This is a value that the World Health Organization defines as Class III obesity and that, according to further stratification reported in the surgical literature, includes the categories of morbid obesity (40-44.9), superobesity (greater than 45), and super-superobesity (greater than 60).

As a gynecologic oncologist, I see firsthand the impact of obesity on the risk of multiple gynecologic conditions and female cancers, including endometrial cancer, as well as the benefits of a minimally invasive approach. I frequently perform hysterectomies via the minimally invasive approach to treat precancer and cancer of the uterus in morbidly and superobese women who have significant central adiposity.

MIGS benefits in the obese

In the past 15 years, and particularly in the past decade, evidence that obese patients benefit from laparoscopic surgery compared with traditional laparotomy has increased. I consider minimally invasive surgery the standard of care for women with endometrial cancer, regardless of the BMI.

As Dr. Stacey A. Scheib and her colleagues wrote in a recent review on laparoscopy in the morbidly obese, most of the gynecologic literature comparing laparoscopic surgery with laparotomy in this population is focused on gynecologic oncology because obesity is so strongly associated with endometrial and other cancers in women (J Minim Invasive Gynecol. 2014 Mar-Apr;21[2]:182-95.). In one prospective study of women with clinical stage I endometrial cancer and BMIs between 28 and 60, those who underwent laparoscopic surgery – 40 of 42 women over 2 years – had significantly longer operative times but less operative morbidity, shorter hospital stays, faster recovery and better postsurgical quality of life, compared with women who had undergone laparotomy in the previous 2 years. The control patients also had clinical stage I endometrial cancer and similar BMIs (Gynecol Oncol. 2000 Sep;78[3 Pt 1]:329-35.).

Research comparing robotics and conventional laparoscopy in obese gynecologic surgery patients is limited, and findings are inconsistent. It will remain difficult to compare the two approaches because few surgeons are equally skilled in both approaches and because the learning curve for conventional laparoscopy is so much steeper than for robotics.

I favor the robotic approach for morbidly and superobese patients for its superior visualization and ergonomics.

Patient positioning

It is important to use an operative bed that will accommodate the weight and width of obese patients and enable Trendelenburg positioning of up to 45 degrees. We use a bariatric bed with a 1,000-pound weight limit.

Obese patients are at greater risk for neuromuscular injuries and pressure sores, so careful patient positioning and padding of pressure points is critically important. We have found a surgical bean bag to be much more effective in preventing slippage for the morbidly or superobese patient than is egg-crate foam. The bean bag conforms nicely to the shape of the patient’s back, neck, and arms when it is appropriately desufflated. After desufflation, the bean bag must be well taped onto the operative bed.

I sometimes use shoulder blocks for extra assurance. When used, these braces must be attached to the bean bag and not to the patient.

We typically pad the arms completely with gel pads or foam before the bean bag is desufflated. We also often pad the knees and calves before the legs are placed and secured in stirrups made for the morbidly obese, with the buttocks slightly off the table.

In a review of literature on obesity and laparoscopy outcomes, Dr. Georgine Lamvu and her associates recommended that the arms be tucked in the “military” position, along the length of the body (Am J Obstet Gynecol. 2004 Aug;191[2]:669-74.). To ensure that both arms are properly tucked against the length of the body, we use bed extenders or sleds to widen the bed as necessary.

Abdominal access

I use the open Hasson technique in my obese patients and enter the peritoneum under direct visualization. In patients with high levels of morbid obesity, I have found it helpful to retract the adipose tissue using thin Breisky vaginal retractors. These retractors can hold the adipose tissue away from the fascia to facilitate entry into the abdominal cavity via the open technique.

Utilizing the umbilicus as the initial entry point – often desirable in minimally invasive surgery – is frequently not possible in morbidly obese patients because as BMI increases, the umbilicus migrates toward the pubic bone and away from the aortic bifurcation. In patients who were overweight (BMI greater than 25), Dr. W.W. Hurd and his associates noted a repositioning of the umbilicus below the aortic bifurcation of 2 cm or greater (Obstet Gynecol. 1992 Jul;80[1]:48-51.).

Instead, a supraumbilical or left upper quadrant site for initial entry enables optimal triangulation of trocars and visualization of disease. The trocars must then be placed more lateral and cephalad than in thinner women. In doing so, risk to the inferior epigastric is mitigated. Moreover, longer trocar lengths (150 mm) may be required.

To utilize an umbilical entry, it is imperative that the panniculus be placed cephalad to a position between the two anterior iliac spines (Obstet Gynecol. 1998 Nov;92[5]:869-72.). By doing this, the umbilicus is now repositioned relative to the bifurcation of the aorta similar to the thinner patient. This can either be accomplished using assistants to move the panniculus cephalad or taping the panniculus.

Alternatively, if the Hasson technique is not utilized, a Veress needle (50 mm in length) may be used. Based on MRI and CT visualization, Dr. Hurd has long recommended using a 90-degree angle in the obese population, compared with a 45-degree angle in nonobese women (J Reprod Med. 1991;36[7]:473-6.).

I usually place the patient into a moderate Trendelenburg position before docking the robot and observe the patient’s cardiac and respiratory responses to the induction of anesthesia. Adjustments in the degree of Trendelenburg positioning, the insufflation pressure level, and the ventilation settings can then be made if necessary. Occasionally I will decrease the insufflation pressure from 15 to 12 mm Hg, for instance, to accommodate ventilation needs.

A note from Dr. Charles E. Miller, Master Class Medical Editor

It must be recognized that not all physicians agree with the use of shoulder braces. In a review of literature on brachial plexus injuries in gynecologic surgery during 1980-2012, Dr. Nigel Pereira and his associates identified eight case reports, all of which involved Trendelenburg positioning and seven of which utilized shoulder braces. In their evaluation of the literature, the authors concluded that “the force of the shoulder braces on the clavicle and scapula opposes the force of gravity on the humerus, thereby stretching the brachial plexus and leading to nerve injury. This is particularly exaggerated when the arm is hyperabducted (less than 90 degrees), the head is laterally flexed to the opposite side, or the abducted arm is sagging.”

The authors also point out that longer times spent under general anesthesia (commensurate with increased operating times) increase the risk of brachial plexus injury “by increasing joint mobility (particularly when muscle relaxants are used) because the neighboring bony structure is more likely to compress or impinge on the brachial plexus” (CRSLS e2014.00077. [doi:10.4293/CRSLS.2014.00077]).

More pearls from Dr. Miller

Preoperative care. Prior to surgery it is important to examine a patient’s panniculus closely for evidence of infection. As the area underneath the panniculus receives little oxygen, it is at greater risk for both bacterial and fungal infections. If infection is noted, treatment prior to surgery is strongly recommended. Moreover, as the skin under the panniculus is often times “broken down,” which can compromise healing, lateral incisions should not be made in this area.

Since obese women have more severe comorbidities (such as metabolic syndrome, obstructed sleep apnea, coronary artery disease, poorly controlled hypertension, and a difficult airway) and a greater risk of perioperative complications than women who are not obese, they generally require a more-extensive preoperative work-up and additional perioperative considerations. If the minimally invasive gynecologic surgeon is uncomfortable with evaluation of cardiac and pulmonary status, medical clearance and perioperative consultation with an anesthesiologist prior to surgery is strongly recommended.

Perioperative care. There are no studies in the literature supporting the use of antibiotic prophylaxis prior to surgery despite the increased risk of postoperative wound infection in morbidly obese patients. Increased risk of surgical site infection post abdominal hysterectomy has been noted in women with a BMI greater than 35. Therefore, consideration should be given to the use of prophylactic antibiotics. For patients weighing more than 80 kg, I advise using 2 gm prophylactic cefazolin; increase this to 3 gm in patients that weigh more than 120 kg.

The morbidly obese patient is also at greater risk of deep venous thrombosis, especially when the procedure is lengthy. Sequential compression devices are essential. Moreover, use of such antithrombotic agents as Lovenox [enoxaparin] and heparin should be considered until the patient is ambulating.

Postoperative care. It is imperative to stress the need for extensive pulmonary toilet or hygiene (i.e., coughing and breathing deeply to clear mucus and secretions from the airways) as well as early ambulation. The patient should also be counseled to use pain medication judiciously. And until the patient is mobile, the use of antithrombotic agents, such as Lovenox and heparin, should be continued.

Dr. Ahmed reports that she has no disclosures related to this Master Class. Dr. Miller disclosed that he is a consultant and is on the speakers bureau for Ethicon and Intuitive Surgical, and is a consultant for Covidien. Email Dr. Ahmed and Dr. Miller at [email protected].

The current epidemic of obesity presents gynecologic surgeons with the challenge of safely and successfully performing minimally invasive surgery in women who are morbidly or superobese.

In 2004, the prevalence of a body mass index greater than 40 kg/m² was almost 7.0% in females in the United States (JAMA. 2006 Apr 5;295[13]:1549-55.). Most recently, 8.3% of women were reported to have a BMI greater than 40 (JAMA. 2014 Feb 26;311[8]:806-14.). This is a value that the World Health Organization defines as Class III obesity and that, according to further stratification reported in the surgical literature, includes the categories of morbid obesity (40-44.9), superobesity (greater than 45), and super-superobesity (greater than 60).

As a gynecologic oncologist, I see firsthand the impact of obesity on the risk of multiple gynecologic conditions and female cancers, including endometrial cancer, as well as the benefits of a minimally invasive approach. I frequently perform hysterectomies via the minimally invasive approach to treat precancer and cancer of the uterus in morbidly and superobese women who have significant central adiposity.

MIGS benefits in the obese

In the past 15 years, and particularly in the past decade, evidence that obese patients benefit from laparoscopic surgery compared with traditional laparotomy has increased. I consider minimally invasive surgery the standard of care for women with endometrial cancer, regardless of the BMI.

As Dr. Stacey A. Scheib and her colleagues wrote in a recent review on laparoscopy in the morbidly obese, most of the gynecologic literature comparing laparoscopic surgery with laparotomy in this population is focused on gynecologic oncology because obesity is so strongly associated with endometrial and other cancers in women (J Minim Invasive Gynecol. 2014 Mar-Apr;21[2]:182-95.). In one prospective study of women with clinical stage I endometrial cancer and BMIs between 28 and 60, those who underwent laparoscopic surgery – 40 of 42 women over 2 years – had significantly longer operative times but less operative morbidity, shorter hospital stays, faster recovery and better postsurgical quality of life, compared with women who had undergone laparotomy in the previous 2 years. The control patients also had clinical stage I endometrial cancer and similar BMIs (Gynecol Oncol. 2000 Sep;78[3 Pt 1]:329-35.).

Research comparing robotics and conventional laparoscopy in obese gynecologic surgery patients is limited, and findings are inconsistent. It will remain difficult to compare the two approaches because few surgeons are equally skilled in both approaches and because the learning curve for conventional laparoscopy is so much steeper than for robotics.

I favor the robotic approach for morbidly and superobese patients for its superior visualization and ergonomics.

Patient positioning

It is important to use an operative bed that will accommodate the weight and width of obese patients and enable Trendelenburg positioning of up to 45 degrees. We use a bariatric bed with a 1,000-pound weight limit.

Obese patients are at greater risk for neuromuscular injuries and pressure sores, so careful patient positioning and padding of pressure points is critically important. We have found a surgical bean bag to be much more effective in preventing slippage for the morbidly or superobese patient than is egg-crate foam. The bean bag conforms nicely to the shape of the patient’s back, neck, and arms when it is appropriately desufflated. After desufflation, the bean bag must be well taped onto the operative bed.

I sometimes use shoulder blocks for extra assurance. When used, these braces must be attached to the bean bag and not to the patient.

We typically pad the arms completely with gel pads or foam before the bean bag is desufflated. We also often pad the knees and calves before the legs are placed and secured in stirrups made for the morbidly obese, with the buttocks slightly off the table.

In a review of literature on obesity and laparoscopy outcomes, Dr. Georgine Lamvu and her associates recommended that the arms be tucked in the “military” position, along the length of the body (Am J Obstet Gynecol. 2004 Aug;191[2]:669-74.). To ensure that both arms are properly tucked against the length of the body, we use bed extenders or sleds to widen the bed as necessary.

Abdominal access

I use the open Hasson technique in my obese patients and enter the peritoneum under direct visualization. In patients with high levels of morbid obesity, I have found it helpful to retract the adipose tissue using thin Breisky vaginal retractors. These retractors can hold the adipose tissue away from the fascia to facilitate entry into the abdominal cavity via the open technique.

Utilizing the umbilicus as the initial entry point – often desirable in minimally invasive surgery – is frequently not possible in morbidly obese patients because as BMI increases, the umbilicus migrates toward the pubic bone and away from the aortic bifurcation. In patients who were overweight (BMI greater than 25), Dr. W.W. Hurd and his associates noted a repositioning of the umbilicus below the aortic bifurcation of 2 cm or greater (Obstet Gynecol. 1992 Jul;80[1]:48-51.).

Instead, a supraumbilical or left upper quadrant site for initial entry enables optimal triangulation of trocars and visualization of disease. The trocars must then be placed more lateral and cephalad than in thinner women. In doing so, risk to the inferior epigastric is mitigated. Moreover, longer trocar lengths (150 mm) may be required.

To utilize an umbilical entry, it is imperative that the panniculus be placed cephalad to a position between the two anterior iliac spines (Obstet Gynecol. 1998 Nov;92[5]:869-72.). By doing this, the umbilicus is now repositioned relative to the bifurcation of the aorta similar to the thinner patient. This can either be accomplished using assistants to move the panniculus cephalad or taping the panniculus.

Alternatively, if the Hasson technique is not utilized, a Veress needle (50 mm in length) may be used. Based on MRI and CT visualization, Dr. Hurd has long recommended using a 90-degree angle in the obese population, compared with a 45-degree angle in nonobese women (J Reprod Med. 1991;36[7]:473-6.).

I usually place the patient into a moderate Trendelenburg position before docking the robot and observe the patient’s cardiac and respiratory responses to the induction of anesthesia. Adjustments in the degree of Trendelenburg positioning, the insufflation pressure level, and the ventilation settings can then be made if necessary. Occasionally I will decrease the insufflation pressure from 15 to 12 mm Hg, for instance, to accommodate ventilation needs.

A note from Dr. Charles E. Miller, Master Class Medical Editor

It must be recognized that not all physicians agree with the use of shoulder braces. In a review of literature on brachial plexus injuries in gynecologic surgery during 1980-2012, Dr. Nigel Pereira and his associates identified eight case reports, all of which involved Trendelenburg positioning and seven of which utilized shoulder braces. In their evaluation of the literature, the authors concluded that “the force of the shoulder braces on the clavicle and scapula opposes the force of gravity on the humerus, thereby stretching the brachial plexus and leading to nerve injury. This is particularly exaggerated when the arm is hyperabducted (less than 90 degrees), the head is laterally flexed to the opposite side, or the abducted arm is sagging.”

The authors also point out that longer times spent under general anesthesia (commensurate with increased operating times) increase the risk of brachial plexus injury “by increasing joint mobility (particularly when muscle relaxants are used) because the neighboring bony structure is more likely to compress or impinge on the brachial plexus” (CRSLS e2014.00077. [doi:10.4293/CRSLS.2014.00077]).

More pearls from Dr. Miller

Preoperative care. Prior to surgery it is important to examine a patient’s panniculus closely for evidence of infection. As the area underneath the panniculus receives little oxygen, it is at greater risk for both bacterial and fungal infections. If infection is noted, treatment prior to surgery is strongly recommended. Moreover, as the skin under the panniculus is often times “broken down,” which can compromise healing, lateral incisions should not be made in this area.

Since obese women have more severe comorbidities (such as metabolic syndrome, obstructed sleep apnea, coronary artery disease, poorly controlled hypertension, and a difficult airway) and a greater risk of perioperative complications than women who are not obese, they generally require a more-extensive preoperative work-up and additional perioperative considerations. If the minimally invasive gynecologic surgeon is uncomfortable with evaluation of cardiac and pulmonary status, medical clearance and perioperative consultation with an anesthesiologist prior to surgery is strongly recommended.

Perioperative care. There are no studies in the literature supporting the use of antibiotic prophylaxis prior to surgery despite the increased risk of postoperative wound infection in morbidly obese patients. Increased risk of surgical site infection post abdominal hysterectomy has been noted in women with a BMI greater than 35. Therefore, consideration should be given to the use of prophylactic antibiotics. For patients weighing more than 80 kg, I advise using 2 gm prophylactic cefazolin; increase this to 3 gm in patients that weigh more than 120 kg.

The morbidly obese patient is also at greater risk of deep venous thrombosis, especially when the procedure is lengthy. Sequential compression devices are essential. Moreover, use of such antithrombotic agents as Lovenox [enoxaparin] and heparin should be considered until the patient is ambulating.

Postoperative care. It is imperative to stress the need for extensive pulmonary toilet or hygiene (i.e., coughing and breathing deeply to clear mucus and secretions from the airways) as well as early ambulation. The patient should also be counseled to use pain medication judiciously. And until the patient is mobile, the use of antithrombotic agents, such as Lovenox and heparin, should be continued.

Dr. Ahmed reports that she has no disclosures related to this Master Class. Dr. Miller disclosed that he is a consultant and is on the speakers bureau for Ethicon and Intuitive Surgical, and is a consultant for Covidien. Email Dr. Ahmed and Dr. Miller at [email protected].

CASE Insurer denies drug coverage
Ms. X, age 65, has a 35-year history of bipolar I disorder (BD I) characterized by psychotic mania and severe suicidal depression. For the past year, her symptoms have been well controlled with aripiprazole, 5 mg/d; trazodone, 50 mg at bedtime; and citalopram, 20 mg/d. Because her health insurance has changed, Ms. X asks to be switched to an alternative antipsychotic because the new provider denied coverage of aripiprazole.

While taking aripiprazole, Ms. X did not report any extrapyramidal side effects, including tardive dyskinesia. Her Abnormal Involuntary Movement Scale (AIMS) score is 4. No significant abnormal movements were noted on examination during previous medica­tion management sessions.

We decide to replace aripiprazole with que­tiapine, 50 mg/d. At a 2-week follow-up visit, Ms. X is noted to have euphoric mood and reduced need to sleep, flight of ideas, increased talkativeness, and paranoia. We also notice that she has significant tongue rolling and lip smacking, which she says started 10 days after changing from aripiprazole to quetiapine. Her AIMS score is 17.

What could be causing Ms. X’s tongue rolling and lip smacking?
   a) an irreversible syndrome usually starting after 1 or 2 years of continuous exposure to antipsychotics
   b) a self-limited condition expected to resolve completely within 12 weeks
   c) an acute manifestation of an antipsychotic that can respond to an anticholinergic agent
   d) none of the above

The authors’ observations
Tardive dyskinesia (TD) refers to at least moderate abnormal involuntary move­ments in ≥1 areas of the body or at least mild movements in ≥2 areas of the body, developing after ≥3 months of cumulative exposure (continuous or discontinuous) to dopamine D2 receptor-blocking agents.¹ AIMS is a 14-item, clinician-administered questionnaire designed to evaluate such movements and track their severity over time. The first 10 items are rated on 5-point scale (0 = none; 1 = minimal; 2 = mild; 3 = moderate; 4 = severe), with items 1 to 4 assessing orofacial movements, 5 to 7 assess­ing extremity and truncal movements, and 8 to 10 assessing overall severity, impair­ment, and subjective distress. Items 11 to 13 assess dental status because lack of teeth can result in oral movements mimicking TDs. The last item assesses whether these move­ments disappear during sleep.

HISTORY Poor response
Ms. X was given a diagnosis of BD I at age 30; she first started taking antipsychotics 10 years later. Previous psychotropic trials included lamotrigine, divalproex sodium, risperidone, and ziprasidone, which were ineffective or poorly tolerated. Her medical history includes obstructive sleep apnea, narcolepsy, type 2 diabetes mellitus, hypertension, dyslipid­emia, fibromyalgia, gastroesophageal reflux disease, and hypothyroidism. She takes met­formin, omeprazole, pravastatin, carvedilol, insulin, levothyroxine, methylphenidate (for hypersomnia), and enalapril.

What is the next best step in management?
   a) discontinue quetiapine
   b) replace quetiapine with clozapine
   c) increase quetiapine to target manic symptoms and reassess in a few weeks
   d) continue quetiapine and treat abnormal movements with benztropine

TREATMENT Increase dosage
We increase quetiapine to 150 mg/d to target Ms. X’s manic symptoms. She is scheduled for a follow-up visit in 4 weeks but is instructed to return to the clinic earlier if her manic symp­toms do not improve. At the 4-week follow-up visit, Ms. X does not have any abnormal move­ments and her manic symptoms have resolved. Her AIMS score is 4. Her husband reports that her abnormal movements resolved 4 days after increasing quetiapine to 150 mg/d.

The authors’ observations
Second-generation antipsychotics are known to have a lower risk of extrapyrami­dal adverse reactions compared with older first-generation antipsychotics.^2,3 TD differs from other extrapyramidal symptoms (EPS) because of its delayed onset. Risk factors for TD include:
   • female sex
   • age >50
   • history of brain damage
   • long-term antipsychotic use
   • diagnosis of a mood disorder.

Gardos et al⁴ described 2 other forms of delayed dyskinesias related to antipsy­chotic use but resulting from antipsychotic discontinuation: withdrawal dyskinesia and covert dyskinesia. Evidence for these types of antipsychotic discontinuation syn­dromes mostly is anecdotal.^5,6Table 1 high­lights 3 different types of dyskinesias and their management.

Withdrawal dyskinesia has been described as a syndrome resembling TD that appears after discontinuation or dos­age reduction of an antipsychotic in a patient who does not have an earlier TD diagnosis.⁷ The prevalence of withdrawal dyskinesia among patients undergoing antipsychotic discontinuation is approximately 30%.⁸ Cases of withdrawal dyskinesia are self-limited and resolve in 1 to 3 months.^9,10 We believe that Ms. X’s movement disorder was withdrawal dyskinesia from aripiprazole because her symptoms started 10 days after the drug was discontinued, and was self-limited and reversible.

Similar to TD, withdrawal dyskinesia can present in different forms:
   • tongue protrusion movements
   • facial grimacing
   • ticks
   • chorea
   • tremors
   • athetosis
   • involuntary vocalizations
   • abnormal movements of hands and legs
   • “dyspnea” due to involvement of respiratory musculature.^5,11

There may be a sex difference in duration of withdrawal dyskinesias, because symp­toms persist longer in females.⁹

Although covert dyskinesia also develops after discontinuation or dosage reduction of a dopamine-blocking agent, the symptoms usually are permanent, and could require reintroducing the antipsychotic or manage­ment with evidence-based treatments for TD, such as tetrabenazine or amantadine.^6,12

What is the cause of Ms. X’s abnormal involuntary movements?
   a) quetiapine-induced D2 receptor hypersensitivity
   b) aripiprazole-induced cholinergic overactivity
   c) quetiapine-induced cholinergic overactivity
   d) aripiprazole-induced D2 receptor hypersensitivity

The authors’ observations
Pathophysiology of this condition is unknown but different theories have been proposed. D2 receptor up-regulation and hypersensitivity to compensate for chronic D2 receptor blockade by antipsychotics is a commonly cited theory.^7,13 Discontinuation of an antipsychotic can make this D2 recep­tor up-regulation and hypersensitivity manifest as withdrawal dyskinesia by cre­ating a temporary hyperdopaminergic state in basal ganglia. Other theories implicate decrease of γ-aminobutyric acid (GABA) in the globus pallidus (GP) and substantia nigra (SN) regions of the brain, and oxida­tive damage to GABAergic interneurons in GP and SN from excess production of cat­echolamines in response to chronic dopa­mine blockade.¹⁴

It has been proposed that patients with withdrawal dyskinesia might be in an early phase of D2 receptor modulation that, if con­tinued because of use of the antipsychotic implicated in withdrawal dyskinesia, can lead to development of TD.^4,7,8 A feature of withdrawal dyskinesia that differentiates it from TD is that it usually remits spontane­ously within several weeks to a few months.^4,7 Because of this characteristic, Schultz et al⁸ propose that, if withdrawal dyskinesia is identified early in treatment, it may be possi­ble to prevent development of persistent TD.

Look carefully for dyskinetic movements in patients who have recently discontinued or decreased the dosage of their antipsy­chotic. Non-compliance and partial compliance are common problems among patients taking an antipsychotic.¹⁵ Therefore, careful watchfulness for withdrawal dyskinesias at all times can be beneficial. Inquiring about recent history of these dyskinesias in such patients is probably more useful than an exam because the dyskinesias may not be evident on exam when these patients show up for their follow-up visit, because of their self-limited nature.⁸

Treatment options
If a patient is noted to have a withdrawal-emergent dyskinesia, a clinician has options to prevent TD, including:
   • decreasing the dosage of the antipsychotic
   • switching from a typical antipsychotic to an atypical antipsychotic
   • switching from one atypical to another with lesser affinity for striatal D2 recep­tor, such as clozapine or quetiapine.^16,17

In addition, researchers are investigating the use of vitamin B6, Ginkgo biloba, aman­tadine, levetiracetam, melatonin, tetrabena­zine, zonisamide, branched chain amino acids, clonazepam, and vitamin E as treat­ment alternatives for TD.

Tetrabenazine acts by blocking vesicu­lar monoamine transporter type 2, thereby inhibiting release of monoamines, includ­ing dopamine into synaptic cleft area in basal ganglia.¹⁸ Clonazepam’s benefit for TD relates to its facilitation of GABAergic neuro­transmission, because reduced GABAergic transmission in GP and SN has been associ­ ated with hyperkinetic movements, includ­ing TD.¹⁴Ginkgo biloba and melatonin exert their beneficial effects in TD through their antioxidant function.¹⁴

The agents listed in Table 2¹⁹ could be used on a short-term basis for symptomatic treatment of withdrawal dyskinesias.^1,18,20

Withdrawal dyskinesia has been reported with aripiprazole discontinuation and is thought to be related to aripiprazole’s strong affinity for D2 receptors.²¹ Aripiprazole at dosages of 15 to 30 mg/d can occupy more than 80% of the striatal D2 dopamine recep­tors. The dosage of ≥30 mg/d can lead to receptor occupancy of >90%.²² Studies have shown that EPS correlate with D2 receptor occupancy in steady-state conditions, and occupancy exceeding 80% results in these symptoms.²²

Compared with aripiprazole, quetiapine has weak affinity for D2 receptors (Table 3), making it an unlikely culprit if dyskine­sia emerges within 2 weeks of initation.²² We believe that, in Ms. X’s case, quetiapine might have masked the severity of aripip­razole withdrawal dyskinesia by causing some degree of D2 receptor blockade. It may have decreased the duration of withdrawal dyskinesia by the same effect on D2 recep­tors. It may have lasted longer if aripiprazole was not replaced by another antipsychotic. This is particularly evident because dys­kinesia improved quickly when quetiap­ine was titrated to 150 mg/d. The higher quetiapine dosage of 150 mg/d is closer to 5 mg/d of aripiprazole in terms of D2 recep­tor occupancy and affinity. However, que­tiapine is weaker than aripiprazole in terms of D2 receptor occupancy at all dosages, and therefore less likely to cause EPS.¹⁶

Evidence suggests that reversible withdrawal dyskinesia could represent a prodrome to irreversible TD. Therefore, keeping a watchful eye for these move­ments during the exam, along with spe­cific inquiry about withdrawal dyskinesias while taking a history at every follow-up visit, is important because doing so can:
   • inform the clinician about partial compliance or noncompliance to these medications, which could lead to treat­ment failure
   • help prevent development of irrevers­ible TD syndrome.

Ms. X’s case reminds clinicians (1) to be aware of this unexpected side effect occur­ring even with second-generation antipsy­chotics and (2) that they should consider EPS in patients while they are discontinu­ing their drugs. Furthermore, it is impor­tant for clinical and medicolegal reasons to inform our patients that different forms of dyskinesias can be potential side effects of antipsychotics.

Bottom Line
Dyskinesias can result from withdrawal of both typical and atypical antipsychotics, and usually are self-limited. Withdrawal dyskinesia may represent a prodrome to tardive dyskinesia; early recognition may aid in preventing development of persistent tardive dyskinesia.

Related Resources
• Abnormal Involuntary Movement Scale. http://www.cqaimh.org/pdf/toolaims.pdf.
• Goldberg JF, Ernst CL. Managing the side effects of psychotro­pic medications. Arlington, VA: American Psychiatric Publishing, Inc; 2012.
• Tarsay D. Tardive dyskinesia: prevention and treatment. http:// www.uptodate.com/contents/tardive-dyskinesia-prevention-and-treatment?topicKey=NEURO%2F4908&elapsedTimeMs=3 &view=print&displayedView=full#.

Drug Brand Names
Amantadine • Symmetrel
Aripiprazole • Abilify
Benztropine • Cogentin
Carvedilol • Coreg
Citalopram • Celexa
Clonazepam • Klonopin
Clozapine • Clozaril
Divalproex sodium • Depakote
Donepezil • Aricept
Enalapril • Vasotec
Haloperidol • Haldol
Lamotrigine • Lamictal
Levetiracetam • Keppra
Levothyroxine • Levoxyl, Synthroid
Metformin • Glucophage
Methylphenidate • Ritalin
Olanzapine • Zyprexa
Omeprazole • Prilosec
Pravastatin • Pravachol
Quetiapine • Seroquel
Risperidone • Risperdal
Tetrabenazine • Xenazine
Trazodone • Desyrel, Oleptro
Ziprasidone • Geodon
Zonisamide • Zonegran

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE Insurer denies drug coverage
Ms. X, age 65, has a 35-year history of bipolar I disorder (BD I) characterized by psychotic mania and severe suicidal depression. For the past year, her symptoms have been well controlled with aripiprazole, 5 mg/d; trazodone, 50 mg at bedtime; and citalopram, 20 mg/d. Because her health insurance has changed, Ms. X asks to be switched to an alternative antipsychotic because the new provider denied coverage of aripiprazole.

While taking aripiprazole, Ms. X did not report any extrapyramidal side effects, including tardive dyskinesia. Her Abnormal Involuntary Movement Scale (AIMS) score is 4. No significant abnormal movements were noted on examination during previous medica­tion management sessions.

We decide to replace aripiprazole with que­tiapine, 50 mg/d. At a 2-week follow-up visit, Ms. X is noted to have euphoric mood and reduced need to sleep, flight of ideas, increased talkativeness, and paranoia. We also notice that she has significant tongue rolling and lip smacking, which she says started 10 days after changing from aripiprazole to quetiapine. Her AIMS score is 17.

What could be causing Ms. X’s tongue rolling and lip smacking?
   a) an irreversible syndrome usually starting after 1 or 2 years of continuous exposure to antipsychotics
   b) a self-limited condition expected to resolve completely within 12 weeks
   c) an acute manifestation of an antipsychotic that can respond to an anticholinergic agent
   d) none of the above

The authors’ observations
Tardive dyskinesia (TD) refers to at least moderate abnormal involuntary move­ments in ≥1 areas of the body or at least mild movements in ≥2 areas of the body, developing after ≥3 months of cumulative exposure (continuous or discontinuous) to dopamine D2 receptor-blocking agents.¹ AIMS is a 14-item, clinician-administered questionnaire designed to evaluate such movements and track their severity over time. The first 10 items are rated on 5-point scale (0 = none; 1 = minimal; 2 = mild; 3 = moderate; 4 = severe), with items 1 to 4 assessing orofacial movements, 5 to 7 assess­ing extremity and truncal movements, and 8 to 10 assessing overall severity, impair­ment, and subjective distress. Items 11 to 13 assess dental status because lack of teeth can result in oral movements mimicking TDs. The last item assesses whether these move­ments disappear during sleep.

HISTORY Poor response
Ms. X was given a diagnosis of BD I at age 30; she first started taking antipsychotics 10 years later. Previous psychotropic trials included lamotrigine, divalproex sodium, risperidone, and ziprasidone, which were ineffective or poorly tolerated. Her medical history includes obstructive sleep apnea, narcolepsy, type 2 diabetes mellitus, hypertension, dyslipid­emia, fibromyalgia, gastroesophageal reflux disease, and hypothyroidism. She takes met­formin, omeprazole, pravastatin, carvedilol, insulin, levothyroxine, methylphenidate (for hypersomnia), and enalapril.

What is the next best step in management?
   a) discontinue quetiapine
   b) replace quetiapine with clozapine
   c) increase quetiapine to target manic symptoms and reassess in a few weeks
   d) continue quetiapine and treat abnormal movements with benztropine

TREATMENT Increase dosage
We increase quetiapine to 150 mg/d to target Ms. X’s manic symptoms. She is scheduled for a follow-up visit in 4 weeks but is instructed to return to the clinic earlier if her manic symp­toms do not improve. At the 4-week follow-up visit, Ms. X does not have any abnormal move­ments and her manic symptoms have resolved. Her AIMS score is 4. Her husband reports that her abnormal movements resolved 4 days after increasing quetiapine to 150 mg/d.

The authors’ observations
Second-generation antipsychotics are known to have a lower risk of extrapyrami­dal adverse reactions compared with older first-generation antipsychotics.^2,3 TD differs from other extrapyramidal symptoms (EPS) because of its delayed onset. Risk factors for TD include:
   • female sex
   • age >50
   • history of brain damage
   • long-term antipsychotic use
   • diagnosis of a mood disorder.

Gardos et al⁴ described 2 other forms of delayed dyskinesias related to antipsy­chotic use but resulting from antipsychotic discontinuation: withdrawal dyskinesia and covert dyskinesia. Evidence for these types of antipsychotic discontinuation syn­dromes mostly is anecdotal.^5,6Table 1 high­lights 3 different types of dyskinesias and their management.

Withdrawal dyskinesia has been described as a syndrome resembling TD that appears after discontinuation or dos­age reduction of an antipsychotic in a patient who does not have an earlier TD diagnosis.⁷ The prevalence of withdrawal dyskinesia among patients undergoing antipsychotic discontinuation is approximately 30%.⁸ Cases of withdrawal dyskinesia are self-limited and resolve in 1 to 3 months.^9,10 We believe that Ms. X’s movement disorder was withdrawal dyskinesia from aripiprazole because her symptoms started 10 days after the drug was discontinued, and was self-limited and reversible.

Similar to TD, withdrawal dyskinesia can present in different forms:
   • tongue protrusion movements
   • facial grimacing
   • ticks
   • chorea
   • tremors
   • athetosis
   • involuntary vocalizations
   • abnormal movements of hands and legs
   • “dyspnea” due to involvement of respiratory musculature.^5,11

There may be a sex difference in duration of withdrawal dyskinesias, because symp­toms persist longer in females.⁹

Although covert dyskinesia also develops after discontinuation or dosage reduction of a dopamine-blocking agent, the symptoms usually are permanent, and could require reintroducing the antipsychotic or manage­ment with evidence-based treatments for TD, such as tetrabenazine or amantadine.^6,12

What is the cause of Ms. X’s abnormal involuntary movements?
   a) quetiapine-induced D2 receptor hypersensitivity
   b) aripiprazole-induced cholinergic overactivity
   c) quetiapine-induced cholinergic overactivity
   d) aripiprazole-induced D2 receptor hypersensitivity

The authors’ observations
Pathophysiology of this condition is unknown but different theories have been proposed. D2 receptor up-regulation and hypersensitivity to compensate for chronic D2 receptor blockade by antipsychotics is a commonly cited theory.^7,13 Discontinuation of an antipsychotic can make this D2 recep­tor up-regulation and hypersensitivity manifest as withdrawal dyskinesia by cre­ating a temporary hyperdopaminergic state in basal ganglia. Other theories implicate decrease of γ-aminobutyric acid (GABA) in the globus pallidus (GP) and substantia nigra (SN) regions of the brain, and oxida­tive damage to GABAergic interneurons in GP and SN from excess production of cat­echolamines in response to chronic dopa­mine blockade.¹⁴

It has been proposed that patients with withdrawal dyskinesia might be in an early phase of D2 receptor modulation that, if con­tinued because of use of the antipsychotic implicated in withdrawal dyskinesia, can lead to development of TD.^4,7,8 A feature of withdrawal dyskinesia that differentiates it from TD is that it usually remits spontane­ously within several weeks to a few months.^4,7 Because of this characteristic, Schultz et al⁸ propose that, if withdrawal dyskinesia is identified early in treatment, it may be possi­ble to prevent development of persistent TD.

Look carefully for dyskinetic movements in patients who have recently discontinued or decreased the dosage of their antipsy­chotic. Non-compliance and partial compliance are common problems among patients taking an antipsychotic.¹⁵ Therefore, careful watchfulness for withdrawal dyskinesias at all times can be beneficial. Inquiring about recent history of these dyskinesias in such patients is probably more useful than an exam because the dyskinesias may not be evident on exam when these patients show up for their follow-up visit, because of their self-limited nature.⁸

Treatment options
If a patient is noted to have a withdrawal-emergent dyskinesia, a clinician has options to prevent TD, including:
   • decreasing the dosage of the antipsychotic
   • switching from a typical antipsychotic to an atypical antipsychotic
   • switching from one atypical to another with lesser affinity for striatal D2 recep­tor, such as clozapine or quetiapine.^16,17

In addition, researchers are investigating the use of vitamin B6, Ginkgo biloba, aman­tadine, levetiracetam, melatonin, tetrabena­zine, zonisamide, branched chain amino acids, clonazepam, and vitamin E as treat­ment alternatives for TD.

Tetrabenazine acts by blocking vesicu­lar monoamine transporter type 2, thereby inhibiting release of monoamines, includ­ing dopamine into synaptic cleft area in basal ganglia.¹⁸ Clonazepam’s benefit for TD relates to its facilitation of GABAergic neuro­transmission, because reduced GABAergic transmission in GP and SN has been associ­ ated with hyperkinetic movements, includ­ing TD.¹⁴Ginkgo biloba and melatonin exert their beneficial effects in TD through their antioxidant function.¹⁴

The agents listed in Table 2¹⁹ could be used on a short-term basis for symptomatic treatment of withdrawal dyskinesias.^1,18,20

Withdrawal dyskinesia has been reported with aripiprazole discontinuation and is thought to be related to aripiprazole’s strong affinity for D2 receptors.²¹ Aripiprazole at dosages of 15 to 30 mg/d can occupy more than 80% of the striatal D2 dopamine recep­tors. The dosage of ≥30 mg/d can lead to receptor occupancy of >90%.²² Studies have shown that EPS correlate with D2 receptor occupancy in steady-state conditions, and occupancy exceeding 80% results in these symptoms.²²

Compared with aripiprazole, quetiapine has weak affinity for D2 receptors (Table 3), making it an unlikely culprit if dyskine­sia emerges within 2 weeks of initation.²² We believe that, in Ms. X’s case, quetiapine might have masked the severity of aripip­razole withdrawal dyskinesia by causing some degree of D2 receptor blockade. It may have decreased the duration of withdrawal dyskinesia by the same effect on D2 recep­tors. It may have lasted longer if aripiprazole was not replaced by another antipsychotic. This is particularly evident because dys­kinesia improved quickly when quetiap­ine was titrated to 150 mg/d. The higher quetiapine dosage of 150 mg/d is closer to 5 mg/d of aripiprazole in terms of D2 recep­tor occupancy and affinity. However, que­tiapine is weaker than aripiprazole in terms of D2 receptor occupancy at all dosages, and therefore less likely to cause EPS.¹⁶

Evidence suggests that reversible withdrawal dyskinesia could represent a prodrome to irreversible TD. Therefore, keeping a watchful eye for these move­ments during the exam, along with spe­cific inquiry about withdrawal dyskinesias while taking a history at every follow-up visit, is important because doing so can:
   • inform the clinician about partial compliance or noncompliance to these medications, which could lead to treat­ment failure
   • help prevent development of irrevers­ible TD syndrome.

Ms. X’s case reminds clinicians (1) to be aware of this unexpected side effect occur­ring even with second-generation antipsy­chotics and (2) that they should consider EPS in patients while they are discontinu­ing their drugs. Furthermore, it is impor­tant for clinical and medicolegal reasons to inform our patients that different forms of dyskinesias can be potential side effects of antipsychotics.

Bottom Line
Dyskinesias can result from withdrawal of both typical and atypical antipsychotics, and usually are self-limited. Withdrawal dyskinesia may represent a prodrome to tardive dyskinesia; early recognition may aid in preventing development of persistent tardive dyskinesia.

Related Resources
• Abnormal Involuntary Movement Scale. http://www.cqaimh.org/pdf/toolaims.pdf.
• Goldberg JF, Ernst CL. Managing the side effects of psychotro­pic medications. Arlington, VA: American Psychiatric Publishing, Inc; 2012.
• Tarsay D. Tardive dyskinesia: prevention and treatment. http:// www.uptodate.com/contents/tardive-dyskinesia-prevention-and-treatment?topicKey=NEURO%2F4908&elapsedTimeMs=3 &view=print&displayedView=full#.

Drug Brand Names
Amantadine • Symmetrel
Aripiprazole • Abilify
Benztropine • Cogentin
Carvedilol • Coreg
Citalopram • Celexa
Clonazepam • Klonopin
Clozapine • Clozaril
Divalproex sodium • Depakote
Donepezil • Aricept
Enalapril • Vasotec
Haloperidol • Haldol
Lamotrigine • Lamictal
Levetiracetam • Keppra
Levothyroxine • Levoxyl, Synthroid
Metformin • Glucophage
Methylphenidate • Ritalin
Olanzapine • Zyprexa
Omeprazole • Prilosec
Pravastatin • Pravachol
Quetiapine • Seroquel
Risperidone • Risperdal
Tetrabenazine • Xenazine
Trazodone • Desyrel, Oleptro
Ziprasidone • Geodon
Zonisamide • Zonegran

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE Insurer denies drug coverage
Ms. X, age 65, has a 35-year history of bipolar I disorder (BD I) characterized by psychotic mania and severe suicidal depression. For the past year, her symptoms have been well controlled with aripiprazole, 5 mg/d; trazodone, 50 mg at bedtime; and citalopram, 20 mg/d. Because her health insurance has changed, Ms. X asks to be switched to an alternative antipsychotic because the new provider denied coverage of aripiprazole.

While taking aripiprazole, Ms. X did not report any extrapyramidal side effects, including tardive dyskinesia. Her Abnormal Involuntary Movement Scale (AIMS) score is 4. No significant abnormal movements were noted on examination during previous medica­tion management sessions.

We decide to replace aripiprazole with que­tiapine, 50 mg/d. At a 2-week follow-up visit, Ms. X is noted to have euphoric mood and reduced need to sleep, flight of ideas, increased talkativeness, and paranoia. We also notice that she has significant tongue rolling and lip smacking, which she says started 10 days after changing from aripiprazole to quetiapine. Her AIMS score is 17.

What could be causing Ms. X’s tongue rolling and lip smacking?
   a) an irreversible syndrome usually starting after 1 or 2 years of continuous exposure to antipsychotics
   b) a self-limited condition expected to resolve completely within 12 weeks
   c) an acute manifestation of an antipsychotic that can respond to an anticholinergic agent
   d) none of the above

The authors’ observations
Tardive dyskinesia (TD) refers to at least moderate abnormal involuntary move­ments in ≥1 areas of the body or at least mild movements in ≥2 areas of the body, developing after ≥3 months of cumulative exposure (continuous or discontinuous) to dopamine D2 receptor-blocking agents.¹ AIMS is a 14-item, clinician-administered questionnaire designed to evaluate such movements and track their severity over time. The first 10 items are rated on 5-point scale (0 = none; 1 = minimal; 2 = mild; 3 = moderate; 4 = severe), with items 1 to 4 assessing orofacial movements, 5 to 7 assess­ing extremity and truncal movements, and 8 to 10 assessing overall severity, impair­ment, and subjective distress. Items 11 to 13 assess dental status because lack of teeth can result in oral movements mimicking TDs. The last item assesses whether these move­ments disappear during sleep.

HISTORY Poor response
Ms. X was given a diagnosis of BD I at age 30; she first started taking antipsychotics 10 years later. Previous psychotropic trials included lamotrigine, divalproex sodium, risperidone, and ziprasidone, which were ineffective or poorly tolerated. Her medical history includes obstructive sleep apnea, narcolepsy, type 2 diabetes mellitus, hypertension, dyslipid­emia, fibromyalgia, gastroesophageal reflux disease, and hypothyroidism. She takes met­formin, omeprazole, pravastatin, carvedilol, insulin, levothyroxine, methylphenidate (for hypersomnia), and enalapril.

What is the next best step in management?
   a) discontinue quetiapine
   b) replace quetiapine with clozapine
   c) increase quetiapine to target manic symptoms and reassess in a few weeks
   d) continue quetiapine and treat abnormal movements with benztropine

TREATMENT Increase dosage
We increase quetiapine to 150 mg/d to target Ms. X’s manic symptoms. She is scheduled for a follow-up visit in 4 weeks but is instructed to return to the clinic earlier if her manic symp­toms do not improve. At the 4-week follow-up visit, Ms. X does not have any abnormal move­ments and her manic symptoms have resolved. Her AIMS score is 4. Her husband reports that her abnormal movements resolved 4 days after increasing quetiapine to 150 mg/d.

The authors’ observations
Second-generation antipsychotics are known to have a lower risk of extrapyrami­dal adverse reactions compared with older first-generation antipsychotics.^2,3 TD differs from other extrapyramidal symptoms (EPS) because of its delayed onset. Risk factors for TD include:
   • female sex
   • age >50
   • history of brain damage
   • long-term antipsychotic use
   • diagnosis of a mood disorder.

Gardos et al⁴ described 2 other forms of delayed dyskinesias related to antipsy­chotic use but resulting from antipsychotic discontinuation: withdrawal dyskinesia and covert dyskinesia. Evidence for these types of antipsychotic discontinuation syn­dromes mostly is anecdotal.^5,6Table 1 high­lights 3 different types of dyskinesias and their management.

Withdrawal dyskinesia has been described as a syndrome resembling TD that appears after discontinuation or dos­age reduction of an antipsychotic in a patient who does not have an earlier TD diagnosis.⁷ The prevalence of withdrawal dyskinesia among patients undergoing antipsychotic discontinuation is approximately 30%.⁸ Cases of withdrawal dyskinesia are self-limited and resolve in 1 to 3 months.^9,10 We believe that Ms. X’s movement disorder was withdrawal dyskinesia from aripiprazole because her symptoms started 10 days after the drug was discontinued, and was self-limited and reversible.

Similar to TD, withdrawal dyskinesia can present in different forms:
   • tongue protrusion movements
   • facial grimacing
   • ticks
   • chorea
   • tremors
   • athetosis
   • involuntary vocalizations
   • abnormal movements of hands and legs
   • “dyspnea” due to involvement of respiratory musculature.^5,11

There may be a sex difference in duration of withdrawal dyskinesias, because symp­toms persist longer in females.⁹

Although covert dyskinesia also develops after discontinuation or dosage reduction of a dopamine-blocking agent, the symptoms usually are permanent, and could require reintroducing the antipsychotic or manage­ment with evidence-based treatments for TD, such as tetrabenazine or amantadine.^6,12

What is the cause of Ms. X’s abnormal involuntary movements?
   a) quetiapine-induced D2 receptor hypersensitivity
   b) aripiprazole-induced cholinergic overactivity
   c) quetiapine-induced cholinergic overactivity
   d) aripiprazole-induced D2 receptor hypersensitivity

The authors’ observations
Pathophysiology of this condition is unknown but different theories have been proposed. D2 receptor up-regulation and hypersensitivity to compensate for chronic D2 receptor blockade by antipsychotics is a commonly cited theory.^7,13 Discontinuation of an antipsychotic can make this D2 recep­tor up-regulation and hypersensitivity manifest as withdrawal dyskinesia by cre­ating a temporary hyperdopaminergic state in basal ganglia. Other theories implicate decrease of γ-aminobutyric acid (GABA) in the globus pallidus (GP) and substantia nigra (SN) regions of the brain, and oxida­tive damage to GABAergic interneurons in GP and SN from excess production of cat­echolamines in response to chronic dopa­mine blockade.¹⁴

It has been proposed that patients with withdrawal dyskinesia might be in an early phase of D2 receptor modulation that, if con­tinued because of use of the antipsychotic implicated in withdrawal dyskinesia, can lead to development of TD.^4,7,8 A feature of withdrawal dyskinesia that differentiates it from TD is that it usually remits spontane­ously within several weeks to a few months.^4,7 Because of this characteristic, Schultz et al⁸ propose that, if withdrawal dyskinesia is identified early in treatment, it may be possi­ble to prevent development of persistent TD.

Look carefully for dyskinetic movements in patients who have recently discontinued or decreased the dosage of their antipsy­chotic. Non-compliance and partial compliance are common problems among patients taking an antipsychotic.¹⁵ Therefore, careful watchfulness for withdrawal dyskinesias at all times can be beneficial. Inquiring about recent history of these dyskinesias in such patients is probably more useful than an exam because the dyskinesias may not be evident on exam when these patients show up for their follow-up visit, because of their self-limited nature.⁸

Treatment options
If a patient is noted to have a withdrawal-emergent dyskinesia, a clinician has options to prevent TD, including:
   • decreasing the dosage of the antipsychotic
   • switching from a typical antipsychotic to an atypical antipsychotic
   • switching from one atypical to another with lesser affinity for striatal D2 recep­tor, such as clozapine or quetiapine.^16,17

In addition, researchers are investigating the use of vitamin B6, Ginkgo biloba, aman­tadine, levetiracetam, melatonin, tetrabena­zine, zonisamide, branched chain amino acids, clonazepam, and vitamin E as treat­ment alternatives for TD.

Tetrabenazine acts by blocking vesicu­lar monoamine transporter type 2, thereby inhibiting release of monoamines, includ­ing dopamine into synaptic cleft area in basal ganglia.¹⁸ Clonazepam’s benefit for TD relates to its facilitation of GABAergic neuro­transmission, because reduced GABAergic transmission in GP and SN has been associ­ ated with hyperkinetic movements, includ­ing TD.¹⁴Ginkgo biloba and melatonin exert their beneficial effects in TD through their antioxidant function.¹⁴

The agents listed in Table 2¹⁹ could be used on a short-term basis for symptomatic treatment of withdrawal dyskinesias.^1,18,20

Withdrawal dyskinesia has been reported with aripiprazole discontinuation and is thought to be related to aripiprazole’s strong affinity for D2 receptors.²¹ Aripiprazole at dosages of 15 to 30 mg/d can occupy more than 80% of the striatal D2 dopamine recep­tors. The dosage of ≥30 mg/d can lead to receptor occupancy of >90%.²² Studies have shown that EPS correlate with D2 receptor occupancy in steady-state conditions, and occupancy exceeding 80% results in these symptoms.²²

Compared with aripiprazole, quetiapine has weak affinity for D2 receptors (Table 3), making it an unlikely culprit if dyskine­sia emerges within 2 weeks of initation.²² We believe that, in Ms. X’s case, quetiapine might have masked the severity of aripip­razole withdrawal dyskinesia by causing some degree of D2 receptor blockade. It may have decreased the duration of withdrawal dyskinesia by the same effect on D2 recep­tors. It may have lasted longer if aripiprazole was not replaced by another antipsychotic. This is particularly evident because dys­kinesia improved quickly when quetiap­ine was titrated to 150 mg/d. The higher quetiapine dosage of 150 mg/d is closer to 5 mg/d of aripiprazole in terms of D2 recep­tor occupancy and affinity. However, que­tiapine is weaker than aripiprazole in terms of D2 receptor occupancy at all dosages, and therefore less likely to cause EPS.¹⁶

Evidence suggests that reversible withdrawal dyskinesia could represent a prodrome to irreversible TD. Therefore, keeping a watchful eye for these move­ments during the exam, along with spe­cific inquiry about withdrawal dyskinesias while taking a history at every follow-up visit, is important because doing so can:
   • inform the clinician about partial compliance or noncompliance to these medications, which could lead to treat­ment failure
   • help prevent development of irrevers­ible TD syndrome.

Ms. X’s case reminds clinicians (1) to be aware of this unexpected side effect occur­ring even with second-generation antipsy­chotics and (2) that they should consider EPS in patients while they are discontinu­ing their drugs. Furthermore, it is impor­tant for clinical and medicolegal reasons to inform our patients that different forms of dyskinesias can be potential side effects of antipsychotics.

Bottom Line
Dyskinesias can result from withdrawal of both typical and atypical antipsychotics, and usually are self-limited. Withdrawal dyskinesia may represent a prodrome to tardive dyskinesia; early recognition may aid in preventing development of persistent tardive dyskinesia.

Related Resources
• Abnormal Involuntary Movement Scale. http://www.cqaimh.org/pdf/toolaims.pdf.
• Goldberg JF, Ernst CL. Managing the side effects of psychotro­pic medications. Arlington, VA: American Psychiatric Publishing, Inc; 2012.
• Tarsay D. Tardive dyskinesia: prevention and treatment. http:// www.uptodate.com/contents/tardive-dyskinesia-prevention-and-treatment?topicKey=NEURO%2F4908&elapsedTimeMs=3 &view=print&displayedView=full#.

Drug Brand Names
Amantadine • Symmetrel
Aripiprazole • Abilify
Benztropine • Cogentin
Carvedilol • Coreg
Citalopram • Celexa
Clonazepam • Klonopin
Clozapine • Clozaril
Divalproex sodium • Depakote
Donepezil • Aricept
Enalapril • Vasotec
Haloperidol • Haldol
Lamotrigine • Lamictal
Levetiracetam • Keppra
Levothyroxine • Levoxyl, Synthroid
Metformin • Glucophage
Methylphenidate • Ritalin
Olanzapine • Zyprexa
Omeprazole • Prilosec
Pravastatin • Pravachol
Quetiapine • Seroquel
Risperidone • Risperdal
Tetrabenazine • Xenazine
Trazodone • Desyrel, Oleptro
Ziprasidone • Geodon
Zonisamide • Zonegran

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Cryosurgery followed by topical ingenol mebutate cleared extensive regions of actinic keratosis, which helped reveal residual squamous cell carcinomas, according to a report in the August issue of the Journal of Drugs in Dermatology.

The findings show that ingenol mebutate can clear multiple AKs and reduce the number of scarring biopsies required to identify SCCs, said Dr. Miriam S. Bettencourt, a dermatologist in group practice in Henderson, Nev. “In our dermatology clinic, many of the patients with a long history of AK who were treated with ingenol mebutate used sequentially after cryosurgery have achieved complete or partial clearance of AKs.”

Ingenol mebutate gel after cryosurgery cleared AKs more effectively than cryosurgery alone in a recent phase III trial (J Drugs Dermatol. 2014 Jun;13[6]741-7), Dr. Bettencourt noted. She described six men and one woman who each had at least 10 recurrent or hyperkeratotic AKs and previously had undergone cryosurgery. She treated all patients with cryosurgery, followed 2 weeks later by two or three once-daily applications of ingenol mebutate gel at strengths of 0.05% or 0.015%, respectively (J Drugs Dermatol. 2015 Aug;14[8];813-8). One course of ingenol mebutate gel cleared 50%-100% of AKs, Dr. Bettencourt said. She treated residual AKs with cryosurgery, and five patients also received at least one more course of ingenol mebutate to re-treat a partially cleared area or to treat a separate area. Shave biopsies of 10 residual suspicious lesions taken 3-8 months later all revealed invasive SCCs, which were treated with Mohs micrographic surgery (MMS). “These lesions may have been preexisting at the time of topical treatment but not readily recognized as suspicious in the heavily actinically damaged skin, in which suspected or small SCCs may be adjacent to or obscured by AKs,” she said. “Alternatively, these tumors may have been spontaneous new SCCs. In either case, we suggest that effective clearance of AKs from the palette of sun-damaged skin with ingenol mebutate permitted prompt recognition of these lesions as suspicious, and led to further diagnosis and treatment with MMS.”

All patients developed mild to moderate localized redness, flaking, and crusting starting on the second day of ingenol mebutate treatment and resolving within a week of finishing the course, Dr. Bettencourt said.

She reported that she had no relevant financial conflicts.

Cryosurgery followed by topical ingenol mebutate cleared extensive regions of actinic keratosis, which helped reveal residual squamous cell carcinomas, according to a report in the August issue of the Journal of Drugs in Dermatology.

The findings show that ingenol mebutate can clear multiple AKs and reduce the number of scarring biopsies required to identify SCCs, said Dr. Miriam S. Bettencourt, a dermatologist in group practice in Henderson, Nev. “In our dermatology clinic, many of the patients with a long history of AK who were treated with ingenol mebutate used sequentially after cryosurgery have achieved complete or partial clearance of AKs.”

Ingenol mebutate gel after cryosurgery cleared AKs more effectively than cryosurgery alone in a recent phase III trial (J Drugs Dermatol. 2014 Jun;13[6]741-7), Dr. Bettencourt noted. She described six men and one woman who each had at least 10 recurrent or hyperkeratotic AKs and previously had undergone cryosurgery. She treated all patients with cryosurgery, followed 2 weeks later by two or three once-daily applications of ingenol mebutate gel at strengths of 0.05% or 0.015%, respectively (J Drugs Dermatol. 2015 Aug;14[8];813-8). One course of ingenol mebutate gel cleared 50%-100% of AKs, Dr. Bettencourt said. She treated residual AKs with cryosurgery, and five patients also received at least one more course of ingenol mebutate to re-treat a partially cleared area or to treat a separate area. Shave biopsies of 10 residual suspicious lesions taken 3-8 months later all revealed invasive SCCs, which were treated with Mohs micrographic surgery (MMS). “These lesions may have been preexisting at the time of topical treatment but not readily recognized as suspicious in the heavily actinically damaged skin, in which suspected or small SCCs may be adjacent to or obscured by AKs,” she said. “Alternatively, these tumors may have been spontaneous new SCCs. In either case, we suggest that effective clearance of AKs from the palette of sun-damaged skin with ingenol mebutate permitted prompt recognition of these lesions as suspicious, and led to further diagnosis and treatment with MMS.”

All patients developed mild to moderate localized redness, flaking, and crusting starting on the second day of ingenol mebutate treatment and resolving within a week of finishing the course, Dr. Bettencourt said.

She reported that she had no relevant financial conflicts.

Cryosurgery followed by topical ingenol mebutate cleared extensive regions of actinic keratosis, which helped reveal residual squamous cell carcinomas, according to a report in the August issue of the Journal of Drugs in Dermatology.

The findings show that ingenol mebutate can clear multiple AKs and reduce the number of scarring biopsies required to identify SCCs, said Dr. Miriam S. Bettencourt, a dermatologist in group practice in Henderson, Nev. “In our dermatology clinic, many of the patients with a long history of AK who were treated with ingenol mebutate used sequentially after cryosurgery have achieved complete or partial clearance of AKs.”

Ingenol mebutate gel after cryosurgery cleared AKs more effectively than cryosurgery alone in a recent phase III trial (J Drugs Dermatol. 2014 Jun;13[6]741-7), Dr. Bettencourt noted. She described six men and one woman who each had at least 10 recurrent or hyperkeratotic AKs and previously had undergone cryosurgery. She treated all patients with cryosurgery, followed 2 weeks later by two or three once-daily applications of ingenol mebutate gel at strengths of 0.05% or 0.015%, respectively (J Drugs Dermatol. 2015 Aug;14[8];813-8). One course of ingenol mebutate gel cleared 50%-100% of AKs, Dr. Bettencourt said. She treated residual AKs with cryosurgery, and five patients also received at least one more course of ingenol mebutate to re-treat a partially cleared area or to treat a separate area. Shave biopsies of 10 residual suspicious lesions taken 3-8 months later all revealed invasive SCCs, which were treated with Mohs micrographic surgery (MMS). “These lesions may have been preexisting at the time of topical treatment but not readily recognized as suspicious in the heavily actinically damaged skin, in which suspected or small SCCs may be adjacent to or obscured by AKs,” she said. “Alternatively, these tumors may have been spontaneous new SCCs. In either case, we suggest that effective clearance of AKs from the palette of sun-damaged skin with ingenol mebutate permitted prompt recognition of these lesions as suspicious, and led to further diagnosis and treatment with MMS.”

All patients developed mild to moderate localized redness, flaking, and crusting starting on the second day of ingenol mebutate treatment and resolving within a week of finishing the course, Dr. Bettencourt said.

She reported that she had no relevant financial conflicts.

ANSWER: D
 
Critique

This patient has vitamin B12 deficiency, which is common in the elderly. In addition, gastrectomy can produce cobalamin deficiency due to lack of gastrin and pepsin resulting in impaired release of dietary B12 from ingested proteins. Also, the lack of intrinsic factor will result in impaired absorption of B12. B12 and folate are required to metabolize homocysteine to methionine. Therefore, with deficiency of either folate or B12, there is an increase in serum homocysteine levels. B12 is also a cofactor in the synthesis of succinyl-CoA from methylmalonyl-CoA and therefore, with B12 deficiency, methylmalonic acid levels are also elevated. Hypoglycemia would not explain this constellation of symptoms. Microscopic colitis causes diarrhea but does not cause dementia or cognitive impairment, glossitis, or taste disturbances. The dominant micronutrient deficiencies with celiac disease are iron and calcium malabsorption, and while B12 deficiency is possible with extensive disease, it is not seen as commonly, and celiac would not be the most likely etiology for her B12 deficiency.
 
Reference

1. Sumner, A.E., Chin, M.M., Abrahm, J.L., et al. Elevated methylmalonic acid and total homocysteine levels show high prevalence of B12 deficiency after gastric surgery. Ann. Intern. Med. 1996;124:469.

ANSWER: D
 
Critique

This patient has vitamin B12 deficiency, which is common in the elderly. In addition, gastrectomy can produce cobalamin deficiency due to lack of gastrin and pepsin resulting in impaired release of dietary B12 from ingested proteins. Also, the lack of intrinsic factor will result in impaired absorption of B12. B12 and folate are required to metabolize homocysteine to methionine. Therefore, with deficiency of either folate or B12, there is an increase in serum homocysteine levels. B12 is also a cofactor in the synthesis of succinyl-CoA from methylmalonyl-CoA and therefore, with B12 deficiency, methylmalonic acid levels are also elevated. Hypoglycemia would not explain this constellation of symptoms. Microscopic colitis causes diarrhea but does not cause dementia or cognitive impairment, glossitis, or taste disturbances. The dominant micronutrient deficiencies with celiac disease are iron and calcium malabsorption, and while B12 deficiency is possible with extensive disease, it is not seen as commonly, and celiac would not be the most likely etiology for her B12 deficiency.
 
Reference

1. Sumner, A.E., Chin, M.M., Abrahm, J.L., et al. Elevated methylmalonic acid and total homocysteine levels show high prevalence of B12 deficiency after gastric surgery. Ann. Intern. Med. 1996;124:469.

ANSWER: D
 
Critique

This patient has vitamin B12 deficiency, which is common in the elderly. In addition, gastrectomy can produce cobalamin deficiency due to lack of gastrin and pepsin resulting in impaired release of dietary B12 from ingested proteins. Also, the lack of intrinsic factor will result in impaired absorption of B12. B12 and folate are required to metabolize homocysteine to methionine. Therefore, with deficiency of either folate or B12, there is an increase in serum homocysteine levels. B12 is also a cofactor in the synthesis of succinyl-CoA from methylmalonyl-CoA and therefore, with B12 deficiency, methylmalonic acid levels are also elevated. Hypoglycemia would not explain this constellation of symptoms. Microscopic colitis causes diarrhea but does not cause dementia or cognitive impairment, glossitis, or taste disturbances. The dominant micronutrient deficiencies with celiac disease are iron and calcium malabsorption, and while B12 deficiency is possible with extensive disease, it is not seen as commonly, and celiac would not be the most likely etiology for her B12 deficiency.
 
Reference

1. Sumner, A.E., Chin, M.M., Abrahm, J.L., et al. Elevated methylmalonic acid and total homocysteine levels show high prevalence of B12 deficiency after gastric surgery. Ann. Intern. Med. 1996;124:469.

ANSWER: D
 
Critique

Cystic fibrosis (CF) is the correct diagnosis here even in the absence of respiratory symptoms; failure to thrive with malabsorption, elevated liver chemistries, and protein malnutrition (low serum albumin) are all suggestive of CF. Additionally, profound hypoalbuminemia and anemia have been reported with the use of soy protein-based formulas in infants with CF. Although celiac disease can have a very early onset, this may obviously only follow ingestion of gluten, so it is not a diagnostic possibility in the case of this formula-fed child. Poor feeding technique is a cause of failure to thrive in early infancy, but here we have good oral intake also suggesting an absorption issue. Giardiasis may have caused this child's symptoms, as this parasitic infection may result in malabsorption, but at this early age this is a highly unlikely explanation, especially in developed countries. Milk protein allergy-induced enteropathy is also possible in this case but is less likely with heme-negative stool and elevated liver chemistries.
 
Reference

1. Messick, J. A 21st century approach to cystic fibrosis: optimizing outcomes across the disease spectrum. J. Pediatr. Gastroenterol. Nutr. 2010;51(Suppl 7):S1-7.

ANSWER: D
 
Critique

Cystic fibrosis (CF) is the correct diagnosis here even in the absence of respiratory symptoms; failure to thrive with malabsorption, elevated liver chemistries, and protein malnutrition (low serum albumin) are all suggestive of CF. Additionally, profound hypoalbuminemia and anemia have been reported with the use of soy protein-based formulas in infants with CF. Although celiac disease can have a very early onset, this may obviously only follow ingestion of gluten, so it is not a diagnostic possibility in the case of this formula-fed child. Poor feeding technique is a cause of failure to thrive in early infancy, but here we have good oral intake also suggesting an absorption issue. Giardiasis may have caused this child's symptoms, as this parasitic infection may result in malabsorption, but at this early age this is a highly unlikely explanation, especially in developed countries. Milk protein allergy-induced enteropathy is also possible in this case but is less likely with heme-negative stool and elevated liver chemistries.
 
Reference

1. Messick, J. A 21st century approach to cystic fibrosis: optimizing outcomes across the disease spectrum. J. Pediatr. Gastroenterol. Nutr. 2010;51(Suppl 7):S1-7.

ANSWER: D
 
Critique

Cystic fibrosis (CF) is the correct diagnosis here even in the absence of respiratory symptoms; failure to thrive with malabsorption, elevated liver chemistries, and protein malnutrition (low serum albumin) are all suggestive of CF. Additionally, profound hypoalbuminemia and anemia have been reported with the use of soy protein-based formulas in infants with CF. Although celiac disease can have a very early onset, this may obviously only follow ingestion of gluten, so it is not a diagnostic possibility in the case of this formula-fed child. Poor feeding technique is a cause of failure to thrive in early infancy, but here we have good oral intake also suggesting an absorption issue. Giardiasis may have caused this child's symptoms, as this parasitic infection may result in malabsorption, but at this early age this is a highly unlikely explanation, especially in developed countries. Milk protein allergy-induced enteropathy is also possible in this case but is less likely with heme-negative stool and elevated liver chemistries.
 
Reference

1. Messick, J. A 21st century approach to cystic fibrosis: optimizing outcomes across the disease spectrum. J. Pediatr. Gastroenterol. Nutr. 2010;51(Suppl 7):S1-7.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common pediatric psychiatric dis­orders, occurring in approximately 5% of children.¹ The disorder persists into adulthood in about one-half of those who are affected in childhood.² In adults and children, diagnosis continues to be based on the examiner’s subjec­tive assessment. (Box 1^3-9 describes how ADHD presents a compli­cated, moving target for the diagnostician.)

Patients who have ADHD are rarely studied with imag­ing; there are no established imaging findings associated with an ADHD diagnosis. Over the past 20 years, however, significant research has shown that molecular alterations along the dopaminergic−frontostriatal pathways occur in association with the behavioral constellation of ADHD symptoms—suggesting a pathophysiologic mechanism for this disorder.

In this article, we describe molecular findings from nuclear medicine imaging in ADHD. We also summarize imaging evidence for dysfunction of the dopaminergic-frontostriatal neural circuits as central in the pathophysiol­ogy of ADHD, with special focus on the dopamine reuptake transporter (DaT). Box 2^10,11 reviews our key observations and looks at the future of imaging in the management of ADHD.

Dopaminergic theory of ADHD
The executive functions that are disordered in ADHD (impulse control, judgment, main­taining attention) are thought to be centered in the infraorbital, dorsolateral, and medial frontal lobes. Neurotransmitters that have been implicated in the pathophysiology of ADHD include norepinephrine¹² and dopa­mine¹³; medications that selectively block reuptake of these neurotransmitters are used to treat ADHD.^14,15 Only the dopamine system has been extensively evaluated with molecular imaging techniques.

Because methylphenidate, a potent selec­tive dopamine reuptake inhibitor, has been shown to reduce disordered executive func­tional behaviors in ADHD, considerable imaging research has focused on the dopa­minergic neural circuits in the frontostriatal regions of the brain. The dopaminergic the­ory of ADHD is based on the hypothesis that alterations in the density or function of these circuits are responsible for behaviors that constitute ADHD.

Despite decades of efforts to delineate the underlying pathophysiology and neu­rochemistry of ADHD, no single unifying theory accounts for all imaging findings in all patients. This might be in part because of imprecision inherent in psychiatric diag­noses that are based on subjective observa­tions. The behavioral criteria for ADHD can manifest in several disorders. For example, anxiety-related symptoms seen in post­traumatic stress disorder, social anxiety disorder, and panic disorder also present as behaviors similar to those in ADHD diag­nostic criteria.

Molecular imaging might provide a window into the underlying pathophysiol­ogy of ADHD and, by identifying objective findings, (1) allow for patient stratification based on underlying physiologic subtypes, (2) refine diagnostic criteria, and (3) predict treatment response.

Nuclear medicine findings
In general, nuclear medicine investiga­tions of ADHD can be divided into studies of changes in regional cerebral blood flow (rCBF) or glucose metabolism (rCGM) and those that have assessed the concentration of synaptic structures, using highly specific radiolabeled ligands. Both kinds of studies provide limited anatomic resolution, unless co-registered with MRI or CT scans and either single photon emission computed tomography (SPECT) or positron emission tomography (PET).

Synaptic imaging using radiolabeled ligands with high biologic specificity for synaptic structures has high molecular resolution—that is, radiolabeled ligands used for selective imaging of the dopamine transporter or receptor do not identify sero­tonin transporters or receptors, and vice versa. (Details of SPECT and PET tech­niques are beyond the scope of this article but can be found in standard nuclear medi­cine textbooks.)

SPECT and PET of rCBF
Early investigations of rCBF in ADHD were performed using inhaled radioactive xenon-133 gas.¹⁶ Later, rCBF was assessed using fat-soluble radiolabeled ligands that rapidly distribute in the brain in proportion to blood flow by crossing the blood−brain barrier. Labeled with radioactive 99m-technetium, these ligands cross rapidly into brain cells after IV injection. Once intracellular, cova­lent bonds within the ligands cleave into 2 charged particles that do not easily recross the cell membrane. There is little redistribu­tion of tracer after initial uptake.

The imaging data set that results can be reconstructed as (1) surface images, on which defects indicate areas of reduced rCBF, or (2) tomographic slices on which color scales indicate relative rCBF values (Figure 1). Because of the minimal redistribution of the tracer, SPECT images obtained 1 or 2 hours after injection provide a snapshot of rCBF at the time tracer is injected. Patients can be injected under various conditions, such as at rest with eyes and ears open in a dimly lit, quiet room, and then under cognitive stress (Figure 2), such as performing a computer-based attention and impulse con­trol task, or during stimulant treatment.

Numerous investigators have found reduced frontal or striatal rCBF, or both, in patients with ADHD, unilaterally on the right¹⁷ or left,^18,19 or bilaterally.²⁰ Additionally, with stimulant therapy, normalization of striatal and frontal rCBF has been demon­strated^14,19—changes that correlate with reso­lution of behavioral symptoms of ADHD with stimulant treatment.²¹

SPECT of 32 boys with previously untreated ADHD. Kim et al²¹ found that the presence of reduced right or left, or both, frontal rCBF, which normal­ized with 8 weeks of stimulant therapy, predicted symptom improvement in 85% of patients. Absence of improve­ment of reduced frontal rCBF had a 75% negative predictive value for treatment response. (Additionally, hyperperfusion of the somatosensory cortex has been demonstrated in children with ADHD,^16,22 suggesting increased responsiveness to extraneous environmental input.)

SPECT of 40 untreated pediatric patients compared with 17 age-matched controls. Using SPECT, Lee et al²³ reported rCBF reductions in the orbitofrontal cortex and the medial temporal gyrus of participants; reductions corresponded to areas of motor and impulsivity control. The researchers also demonstrated increased rCBF in the somato­sensory area.

After methylphenidate treatment, blood flow to these areas normalized, and rCBF to higher visual and superior prefrontal areas decreased. Substantial clinical improve­ment occurred in 64% of patients—suggest­ing methylphenidate treatment of ADHD works by (1) increasing function of areas of the brain that control impulses, motor activ­ity, and attention, and (2) reducing function to sensory areas that lead to distraction by extraneous environmental sensory input.

O-15-labeled water PET of 10 adults with ADHD. Schweitzer et al²⁴ found that participants who demonstrated improve­ment in behavioral symptoms with chronic stimulant therapy had reduced rCBF in the striata at baseline—again, suggesting that baseline hypometabolism in the striata is associated with ADHD.

PET of regional cerebral glucose metabolism
Cerebral metabolism requires a constant supply of glucose; regional differences in cerebral glucose metabolism can be assessed directly with positron-emitting F-18-fluoro-2-deoxyglucose. Although metabolically inert, this agent is transported intracellularly simi­lar to glucose; once phosphorylated within brain cells, however, it can no longer undergo further metabolism or redistribution.

Studies using PET to assess rCGM were some of the earliest molecular imaging appli­cations in ADHD. Zametkin et al²⁵ reported low global cerebral glucose utilization in adults, but not adolescents,²⁶ with ADHD. However, further study, with normalization of the PET data, confirmed reduced rCGM in the left prefrontal cortex in both adolescents²⁶ and adults,²⁷ indicating hypometabolism of cortical areas associated with impulse con­trol and attention in ADHD. In adolescents, symptom severity was inversely related to rCBF in the left anterior frontal cortex.

Synaptic imaging
Nuclear imaging has been used to study several components of the striatal dopami­nergic synapse, including:
   • dopamine substrates, using fluorine- 18-labeled dopa or carbon-11-labeled dopa
   • dopamine receptors, using carbon- 11-labeled raclopride or iodine-123 iodobenzamide
   • the tDaT, using iodine-123 ioflupane, 99m-technetium TRODAT, or carbon-11 cocaine (Figure 3).

All of these synaptic imaging agents were used mainly as research tools until 2011, when the FDA approved the SPECT imag­ing agent iodine-123 ioflupane (DaTscan) for clinical use in assessment of Parkinson’s disease.²⁸ This commercially available agent has high specificity for the DaT, with little background activity noted on SPECT imag­ing (Figure 4).

Dopamine transporter imaging
Because the site of action of methylpheni­date is the DaT, imaging this component of the striatal dopaminergic synapse has been an area of intense investigation in ADHD. Located almost exclusively in the striata, DaT reduces synaptic concentrations of dopamine by means of reuptake channels in the cell membrane.²⁹ By reversibly bind­ing to, and occupying sites on, the DaT, methylphenidate impedes dopamine reup­take, which results in increased availability of dopamine at the synapse.³⁰

By demonstrating an increase in stria­tal DaT density in patients with ADHD— first reported by Dougherty et al³¹ using iodine-123 altropane (a dopaminergic uptake inhibitor) in 6 adults with ADHD—inves­tigators have hypothesized that excessive expression of the DaT protein in the striata, which may result from genetic or environ­mental factors, is a central causative agent of ADHD.³² Subsequent studies, however, have yielded contradictory findings: Hesse et al,³³ using SPECT imaging, and Volkow et al,³⁴ using carbon-11 cocaine PET imaging, found reduced DaT density in, respectively, 9 and 26 patients with ADHD.

To clarify the role of DaT levels in the eti­ology of ADHD and to explain discrepant results, Fusar-Poli et al³⁵ performed a meta-analysis of 9 published papers that reported the results of DaT imaging in a total of 169 ADHD patients and 129 controls. They noted that these studies included 6 differ­ent imaging agents and protocols. Patients were stimulant therapy-naïve (n = 137) or drug-free (refrained from stimulant therapy for a time [n = 32]). The team found that the degree of elevation of the striatal DaT con­centration correlated with a history of stimu­lant exposure, and that the drug-naïve group had a reduced DaT level.

Fusar-Poli’s hypothesis? Elevated DaT lev­els result from up-regulation in the presence of chronic methylphenidate therapy, which accounts for early reports that demonstrated increased striatal DaT density. Clinically, up-regulation might explain the lack of sustained relief of behavioral symptoms with stimulant therapy in 20% of patients with ADHD who showed clinical improvement initially.³⁶

Only limited conclusions can be drawn about the role of DaT levels in ADHD, given the small number of patients studied in pub­lished reports. In addition, the Fusar-Poli meta-analysis has come under strong criti­cism because of methodological errors with improper patient inclusion and characteriza­tion of treatment status,³⁷ calling into question the investigators’ conclusions.

Does the DaT level hold promise for practice? Despite a lack of clarity about the significance of DaT level in the etiology of ADHD, knowledge of a patient’s level might prove useful in predicting which patients will respond to methylphenidate. Namely, several researchers have found that:
   • an elevated baseline level of DaT (before stimulant therapy) correlates with robust clinical response
   • absence of an elevated baseline DaT level suggests that symptomatic improvement with stimulant therapy in unlikely.^38-40

Dresel et al³⁸ evaluated 17 drug-naïve adults, newly diagnosed with ADHD, using 99m-technetium TRODAT SPECT before and after methylphenidate therapy. They found a 15% increase in specific DaT binding in patients with ADHD, compared with con­trols, at baseline. After treatment, the research­ers observed a 28% reduction in specific DaT binding—a significant change from baseline that correlated with behavioral response.

Study: SPECT in 18 adults with ADHD given methylphenidate. Krause³⁹ used the same SPECT agent to study 18 adults before they received methylphenidate and 10 weeks after treatment. Participants were categorized as responders or nonresponders based on clinical assessment of ADHD symptoms after those 10 weeks. All 12 responders had an elevated striatal DaT concentration at baseline. Of the 6 nonresponders, 5 had a normal level of striatal DaT compared with age-matched controls.

Study: 22 Adult ADHD patients evalu­ated with 99m-technetium TRODAT SPECT. The same group of investigators⁴⁰ presented imaging findings in 22 additional adult patients. Seventeen had an elevated striatal DaT level, 16 of whom responded to stimulant therapy. The remaining 5 patients had reduced striatal DaT at base­line; none had a good clinical response to methylphenidate.

The positive clinical response to methylphenidate in 67%³⁷ and 77%⁴⁰ of patients is in good agreement with results from larger studies, which reported that approximately 75% of patients with ADHD show prompt clinical improvement with stimulants.⁴¹ Improvement might be related to an increase in functioning of the frontostriatal dopami­nergic circuit that is seen with stimulant therapy. Increased availability of dopamine at the synapse, resulting from stimulant blockade of the dopamine reuptake trans­porter, produces increased dopamine neu­rotransmission and increased activation of frontostriatal circuits.

In another study, rCBF in frontostriatal circuits was determined to be inversely proportional to DaT density; rCBF normalized with stimulant therapy.⁴²

Will imaging pave the way for therapeu­tic stratification? Baseline determinations of striatal DaT concentration with SPECT imaging might make it possible to stratify patients with ADHD symptoms into those likely to show significant behavioral symp­tom response to methylphenidate and those who are not likely to respond. There might be an objective imaging finding—striatal DaT density—that allows clinicians to dis­tinguish stimulant-responsive ADHD from stimulant-unresponsive ADHD.

Dopamine substrate imaging
Radiolabeled dopa (carbon-11 or fluorine-18) is transported into presynaptic dopaminer­gic neurons in the striatum, where it is decar­boxylated, converted to radio-dopamine, and stored within vesicles until released in response to neuronal excitation. Semi-quantitative assessment is achieved with calculation of specific (striatal) to nonspecific (background) uptake ratios. Increased val­ues are thought to indicate increased density of dopaminergic neurons.⁴³

Ernst et al⁴⁴ reported a 50% decrease in specific fluorine-18 dopa uptake in the left prefrontal cortex in 17 drug-naïve adults with ADHD, compared with 23 controls. The same team reported increased midbrain fluorine-18 dopa levels in 10 adolescents with ADHD—48% higher, overall, than what was seen in 10 controls.⁴³ They hypoth­esized that these opposite results were the results of a reduction in the dopaminergic neuronal density in adults, which might be part of the natural history of ADHD, or a normal age-related reduction in neuronal density, or both. Increased dopa levels in the team’s adolescent group were hypothesized to reflect up-regulation in dopamine syn­thesis due to low synaptic dopamine con­centrations that might result from increased dopamine reuptake.

Dopamine-receptor imaging
The 5 distinct dopamine receptors (D1, D2, D3, D4, and D5) can be grouped into 2 subtypes, based on their coupling with G proteins. D1 and D5 constitute a group; D2, D3, and D4, a second group.

The D1 receptor is the most common dopamine receptor in the brain and is widely distributed in the striatum and pre­frontal cerebral cortex. D1 receptor knock­out mice demonstrate hyperactivity and poorer performance on learning tasks and are used as an animal model for ADHD.⁴⁵ D1 has been imaged using C-11 SCH 23390 PET⁴⁶ in rats, but its role in ADHD has yet to be evaluated. D5 is the most recently cloned and most widely distributed of the known dopamine receptors; however, there are no imaging studies of the D5 receptor.¹³

D2 receptors are present in presynaptic and postsynaptic neurons⁴⁷ in the neocor­tex, substantia nigra, nucleus accumbens, and olfactory tubercle, as well as in other structures.⁴⁸ Presynaptic D2 receptors act as autoregulators, inhibiting dopaminergic synthesis, firing rate, and release.⁴⁹

Using C-11 raclopride PET imaging, Lou et al⁵⁰ reported high D2/3 receptor availabil­ity in adolescents who had a history of peri­natal cerebral ischemia. They found that this availability is associated with an increase in the severity of ADHD symptoms. They pro­posed that the increase in “empty” receptor density might have been caused by perinatal ischemia-induced presynaptic dopaminer­gic neuronal loss or an increase in presynap­tic dopamine reuptake (Figure 5⁵⁰). Either mechanism could result in up-regulation in postsynaptic D2/3 receptors.

Volkow et al⁵¹ reported that D2 receptor density correlated with methylphenidate-induced changes in rCBF in frontal and tem­poral lobes in humans. They postulated that the variable therapeutic effects of methyl­phenidate seen in ADHD patients might be related to variations in baseline D2 receptor availability.

Lou et al⁵⁰ reported elevated D2 recep­tor density, demonstrated using carbon-11 raclopride, in children with ADHD, com­pared with normal adults.

Further support for a relationship between D2-receptor density and symptom­atic improvement with methylphenidate in ADHD was presented by Ilgin et al⁵² using iodine-123 iodobenzamide SPECT. They found elevated D2 receptor levels in 9 drug-naïve children with ADHD, which is 20% to 60% above what is seen in unaffected chil­dren. They noted that these patients showed improvement in hyperactivity when treated with methylphenidate.

In a similar study of 20 drug-naïve adults, Volkow et al⁵³ found that durable symptom­atic improvement with methylphenidate therapy was associated with increased D2 receptor availability.

Summing up
Striatal DaT is the most likely synaptic tar­get for stratifying patients with ADHD, now that a dopamine transporter imaging agent is available commercially. Stratification might allow for refinement in the diagnostic categorization of ADHD, with introduction of stimulant-responsive and stimulant-unresponsive subtypes that are based on DaT imaging findings.

Bottom Line
Given recent advances showing molecular alterations in the dopaminergic-frontostriatal pathway as central to attention-deficit/hyperactivity disorder, molecular imaging might be useful as an objective study for diagnosis.

Related Resources
• Schweitzer JB, Lee DO, Hanford RB, et al. A positron emis­sion tomography study of methylphenidate in adults with ADHD: alterations in resting blood flow and predict­ing treatment response. Neuropsychopharmacology. 2003;28(5):967-973.
• Raz A. Brain imaging data of ADHD. Psychiatric Times. http://www.psychiatrictimes.com/adhd/brain-imaging-data-adhd.

Drug Brand Names
Iodine-123 ioflupane • Methylphenidate • Ritalin DaTscan

Acknowledgment
Kylee M. L. Unsdorfer, a medical student at Northeast Ohio Medical University, helped prepare the manuscript of this article.

Disclosures
Dr. Thacker reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.
Dr. Binkovitz received 4 doses of ioflupane I123I (DaTscan) from General Electric for investigator-initiated research, used for animal imaging in 2012.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common pediatric psychiatric dis­orders, occurring in approximately 5% of children.¹ The disorder persists into adulthood in about one-half of those who are affected in childhood.² In adults and children, diagnosis continues to be based on the examiner’s subjec­tive assessment. (Box 1^3-9 describes how ADHD presents a compli­cated, moving target for the diagnostician.)

Patients who have ADHD are rarely studied with imag­ing; there are no established imaging findings associated with an ADHD diagnosis. Over the past 20 years, however, significant research has shown that molecular alterations along the dopaminergic−frontostriatal pathways occur in association with the behavioral constellation of ADHD symptoms—suggesting a pathophysiologic mechanism for this disorder.

In this article, we describe molecular findings from nuclear medicine imaging in ADHD. We also summarize imaging evidence for dysfunction of the dopaminergic-frontostriatal neural circuits as central in the pathophysiol­ogy of ADHD, with special focus on the dopamine reuptake transporter (DaT). Box 2^10,11 reviews our key observations and looks at the future of imaging in the management of ADHD.

Dopaminergic theory of ADHD
The executive functions that are disordered in ADHD (impulse control, judgment, main­taining attention) are thought to be centered in the infraorbital, dorsolateral, and medial frontal lobes. Neurotransmitters that have been implicated in the pathophysiology of ADHD include norepinephrine¹² and dopa­mine¹³; medications that selectively block reuptake of these neurotransmitters are used to treat ADHD.^14,15 Only the dopamine system has been extensively evaluated with molecular imaging techniques.

Because methylphenidate, a potent selec­tive dopamine reuptake inhibitor, has been shown to reduce disordered executive func­tional behaviors in ADHD, considerable imaging research has focused on the dopa­minergic neural circuits in the frontostriatal regions of the brain. The dopaminergic the­ory of ADHD is based on the hypothesis that alterations in the density or function of these circuits are responsible for behaviors that constitute ADHD.

Despite decades of efforts to delineate the underlying pathophysiology and neu­rochemistry of ADHD, no single unifying theory accounts for all imaging findings in all patients. This might be in part because of imprecision inherent in psychiatric diag­noses that are based on subjective observa­tions. The behavioral criteria for ADHD can manifest in several disorders. For example, anxiety-related symptoms seen in post­traumatic stress disorder, social anxiety disorder, and panic disorder also present as behaviors similar to those in ADHD diag­nostic criteria.

Molecular imaging might provide a window into the underlying pathophysiol­ogy of ADHD and, by identifying objective findings, (1) allow for patient stratification based on underlying physiologic subtypes, (2) refine diagnostic criteria, and (3) predict treatment response.

Nuclear medicine findings
In general, nuclear medicine investiga­tions of ADHD can be divided into studies of changes in regional cerebral blood flow (rCBF) or glucose metabolism (rCGM) and those that have assessed the concentration of synaptic structures, using highly specific radiolabeled ligands. Both kinds of studies provide limited anatomic resolution, unless co-registered with MRI or CT scans and either single photon emission computed tomography (SPECT) or positron emission tomography (PET).

Synaptic imaging using radiolabeled ligands with high biologic specificity for synaptic structures has high molecular resolution—that is, radiolabeled ligands used for selective imaging of the dopamine transporter or receptor do not identify sero­tonin transporters or receptors, and vice versa. (Details of SPECT and PET tech­niques are beyond the scope of this article but can be found in standard nuclear medi­cine textbooks.)

SPECT and PET of rCBF
Early investigations of rCBF in ADHD were performed using inhaled radioactive xenon-133 gas.¹⁶ Later, rCBF was assessed using fat-soluble radiolabeled ligands that rapidly distribute in the brain in proportion to blood flow by crossing the blood−brain barrier. Labeled with radioactive 99m-technetium, these ligands cross rapidly into brain cells after IV injection. Once intracellular, cova­lent bonds within the ligands cleave into 2 charged particles that do not easily recross the cell membrane. There is little redistribu­tion of tracer after initial uptake.

The imaging data set that results can be reconstructed as (1) surface images, on which defects indicate areas of reduced rCBF, or (2) tomographic slices on which color scales indicate relative rCBF values (Figure 1). Because of the minimal redistribution of the tracer, SPECT images obtained 1 or 2 hours after injection provide a snapshot of rCBF at the time tracer is injected. Patients can be injected under various conditions, such as at rest with eyes and ears open in a dimly lit, quiet room, and then under cognitive stress (Figure 2), such as performing a computer-based attention and impulse con­trol task, or during stimulant treatment.

Numerous investigators have found reduced frontal or striatal rCBF, or both, in patients with ADHD, unilaterally on the right¹⁷ or left,^18,19 or bilaterally.²⁰ Additionally, with stimulant therapy, normalization of striatal and frontal rCBF has been demon­strated^14,19—changes that correlate with reso­lution of behavioral symptoms of ADHD with stimulant treatment.²¹

SPECT of 32 boys with previously untreated ADHD. Kim et al²¹ found that the presence of reduced right or left, or both, frontal rCBF, which normal­ized with 8 weeks of stimulant therapy, predicted symptom improvement in 85% of patients. Absence of improve­ment of reduced frontal rCBF had a 75% negative predictive value for treatment response. (Additionally, hyperperfusion of the somatosensory cortex has been demonstrated in children with ADHD,^16,22 suggesting increased responsiveness to extraneous environmental input.)

SPECT of 40 untreated pediatric patients compared with 17 age-matched controls. Using SPECT, Lee et al²³ reported rCBF reductions in the orbitofrontal cortex and the medial temporal gyrus of participants; reductions corresponded to areas of motor and impulsivity control. The researchers also demonstrated increased rCBF in the somato­sensory area.

After methylphenidate treatment, blood flow to these areas normalized, and rCBF to higher visual and superior prefrontal areas decreased. Substantial clinical improve­ment occurred in 64% of patients—suggest­ing methylphenidate treatment of ADHD works by (1) increasing function of areas of the brain that control impulses, motor activ­ity, and attention, and (2) reducing function to sensory areas that lead to distraction by extraneous environmental sensory input.

O-15-labeled water PET of 10 adults with ADHD. Schweitzer et al²⁴ found that participants who demonstrated improve­ment in behavioral symptoms with chronic stimulant therapy had reduced rCBF in the striata at baseline—again, suggesting that baseline hypometabolism in the striata is associated with ADHD.

PET of regional cerebral glucose metabolism
Cerebral metabolism requires a constant supply of glucose; regional differences in cerebral glucose metabolism can be assessed directly with positron-emitting F-18-fluoro-2-deoxyglucose. Although metabolically inert, this agent is transported intracellularly simi­lar to glucose; once phosphorylated within brain cells, however, it can no longer undergo further metabolism or redistribution.

Studies using PET to assess rCGM were some of the earliest molecular imaging appli­cations in ADHD. Zametkin et al²⁵ reported low global cerebral glucose utilization in adults, but not adolescents,²⁶ with ADHD. However, further study, with normalization of the PET data, confirmed reduced rCGM in the left prefrontal cortex in both adolescents²⁶ and adults,²⁷ indicating hypometabolism of cortical areas associated with impulse con­trol and attention in ADHD. In adolescents, symptom severity was inversely related to rCBF in the left anterior frontal cortex.

Synaptic imaging
Nuclear imaging has been used to study several components of the striatal dopami­nergic synapse, including:
   • dopamine substrates, using fluorine- 18-labeled dopa or carbon-11-labeled dopa
   • dopamine receptors, using carbon- 11-labeled raclopride or iodine-123 iodobenzamide
   • the tDaT, using iodine-123 ioflupane, 99m-technetium TRODAT, or carbon-11 cocaine (Figure 3).

All of these synaptic imaging agents were used mainly as research tools until 2011, when the FDA approved the SPECT imag­ing agent iodine-123 ioflupane (DaTscan) for clinical use in assessment of Parkinson’s disease.²⁸ This commercially available agent has high specificity for the DaT, with little background activity noted on SPECT imag­ing (Figure 4).

Dopamine transporter imaging
Because the site of action of methylpheni­date is the DaT, imaging this component of the striatal dopaminergic synapse has been an area of intense investigation in ADHD. Located almost exclusively in the striata, DaT reduces synaptic concentrations of dopamine by means of reuptake channels in the cell membrane.²⁹ By reversibly bind­ing to, and occupying sites on, the DaT, methylphenidate impedes dopamine reup­take, which results in increased availability of dopamine at the synapse.³⁰

By demonstrating an increase in stria­tal DaT density in patients with ADHD— first reported by Dougherty et al³¹ using iodine-123 altropane (a dopaminergic uptake inhibitor) in 6 adults with ADHD—inves­tigators have hypothesized that excessive expression of the DaT protein in the striata, which may result from genetic or environ­mental factors, is a central causative agent of ADHD.³² Subsequent studies, however, have yielded contradictory findings: Hesse et al,³³ using SPECT imaging, and Volkow et al,³⁴ using carbon-11 cocaine PET imaging, found reduced DaT density in, respectively, 9 and 26 patients with ADHD.

To clarify the role of DaT levels in the eti­ology of ADHD and to explain discrepant results, Fusar-Poli et al³⁵ performed a meta-analysis of 9 published papers that reported the results of DaT imaging in a total of 169 ADHD patients and 129 controls. They noted that these studies included 6 differ­ent imaging agents and protocols. Patients were stimulant therapy-naïve (n = 137) or drug-free (refrained from stimulant therapy for a time [n = 32]). The team found that the degree of elevation of the striatal DaT con­centration correlated with a history of stimu­lant exposure, and that the drug-naïve group had a reduced DaT level.

Fusar-Poli’s hypothesis? Elevated DaT lev­els result from up-regulation in the presence of chronic methylphenidate therapy, which accounts for early reports that demonstrated increased striatal DaT density. Clinically, up-regulation might explain the lack of sustained relief of behavioral symptoms with stimulant therapy in 20% of patients with ADHD who showed clinical improvement initially.³⁶

Only limited conclusions can be drawn about the role of DaT levels in ADHD, given the small number of patients studied in pub­lished reports. In addition, the Fusar-Poli meta-analysis has come under strong criti­cism because of methodological errors with improper patient inclusion and characteriza­tion of treatment status,³⁷ calling into question the investigators’ conclusions.

Does the DaT level hold promise for practice? Despite a lack of clarity about the significance of DaT level in the etiology of ADHD, knowledge of a patient’s level might prove useful in predicting which patients will respond to methylphenidate. Namely, several researchers have found that:
   • an elevated baseline level of DaT (before stimulant therapy) correlates with robust clinical response
   • absence of an elevated baseline DaT level suggests that symptomatic improvement with stimulant therapy in unlikely.^38-40

Dresel et al³⁸ evaluated 17 drug-naïve adults, newly diagnosed with ADHD, using 99m-technetium TRODAT SPECT before and after methylphenidate therapy. They found a 15% increase in specific DaT binding in patients with ADHD, compared with con­trols, at baseline. After treatment, the research­ers observed a 28% reduction in specific DaT binding—a significant change from baseline that correlated with behavioral response.

Study: SPECT in 18 adults with ADHD given methylphenidate. Krause³⁹ used the same SPECT agent to study 18 adults before they received methylphenidate and 10 weeks after treatment. Participants were categorized as responders or nonresponders based on clinical assessment of ADHD symptoms after those 10 weeks. All 12 responders had an elevated striatal DaT concentration at baseline. Of the 6 nonresponders, 5 had a normal level of striatal DaT compared with age-matched controls.

Study: 22 Adult ADHD patients evalu­ated with 99m-technetium TRODAT SPECT. The same group of investigators⁴⁰ presented imaging findings in 22 additional adult patients. Seventeen had an elevated striatal DaT level, 16 of whom responded to stimulant therapy. The remaining 5 patients had reduced striatal DaT at base­line; none had a good clinical response to methylphenidate.

The positive clinical response to methylphenidate in 67%³⁷ and 77%⁴⁰ of patients is in good agreement with results from larger studies, which reported that approximately 75% of patients with ADHD show prompt clinical improvement with stimulants.⁴¹ Improvement might be related to an increase in functioning of the frontostriatal dopami­nergic circuit that is seen with stimulant therapy. Increased availability of dopamine at the synapse, resulting from stimulant blockade of the dopamine reuptake trans­porter, produces increased dopamine neu­rotransmission and increased activation of frontostriatal circuits.

In another study, rCBF in frontostriatal circuits was determined to be inversely proportional to DaT density; rCBF normalized with stimulant therapy.⁴²

Will imaging pave the way for therapeu­tic stratification? Baseline determinations of striatal DaT concentration with SPECT imaging might make it possible to stratify patients with ADHD symptoms into those likely to show significant behavioral symp­tom response to methylphenidate and those who are not likely to respond. There might be an objective imaging finding—striatal DaT density—that allows clinicians to dis­tinguish stimulant-responsive ADHD from stimulant-unresponsive ADHD.

Dopamine substrate imaging
Radiolabeled dopa (carbon-11 or fluorine-18) is transported into presynaptic dopaminer­gic neurons in the striatum, where it is decar­boxylated, converted to radio-dopamine, and stored within vesicles until released in response to neuronal excitation. Semi-quantitative assessment is achieved with calculation of specific (striatal) to nonspecific (background) uptake ratios. Increased val­ues are thought to indicate increased density of dopaminergic neurons.⁴³

Ernst et al⁴⁴ reported a 50% decrease in specific fluorine-18 dopa uptake in the left prefrontal cortex in 17 drug-naïve adults with ADHD, compared with 23 controls. The same team reported increased midbrain fluorine-18 dopa levels in 10 adolescents with ADHD—48% higher, overall, than what was seen in 10 controls.⁴³ They hypoth­esized that these opposite results were the results of a reduction in the dopaminergic neuronal density in adults, which might be part of the natural history of ADHD, or a normal age-related reduction in neuronal density, or both. Increased dopa levels in the team’s adolescent group were hypothesized to reflect up-regulation in dopamine syn­thesis due to low synaptic dopamine con­centrations that might result from increased dopamine reuptake.

Dopamine-receptor imaging
The 5 distinct dopamine receptors (D1, D2, D3, D4, and D5) can be grouped into 2 subtypes, based on their coupling with G proteins. D1 and D5 constitute a group; D2, D3, and D4, a second group.

The D1 receptor is the most common dopamine receptor in the brain and is widely distributed in the striatum and pre­frontal cerebral cortex. D1 receptor knock­out mice demonstrate hyperactivity and poorer performance on learning tasks and are used as an animal model for ADHD.⁴⁵ D1 has been imaged using C-11 SCH 23390 PET⁴⁶ in rats, but its role in ADHD has yet to be evaluated. D5 is the most recently cloned and most widely distributed of the known dopamine receptors; however, there are no imaging studies of the D5 receptor.¹³

D2 receptors are present in presynaptic and postsynaptic neurons⁴⁷ in the neocor­tex, substantia nigra, nucleus accumbens, and olfactory tubercle, as well as in other structures.⁴⁸ Presynaptic D2 receptors act as autoregulators, inhibiting dopaminergic synthesis, firing rate, and release.⁴⁹

Using C-11 raclopride PET imaging, Lou et al⁵⁰ reported high D2/3 receptor availabil­ity in adolescents who had a history of peri­natal cerebral ischemia. They found that this availability is associated with an increase in the severity of ADHD symptoms. They pro­posed that the increase in “empty” receptor density might have been caused by perinatal ischemia-induced presynaptic dopaminer­gic neuronal loss or an increase in presynap­tic dopamine reuptake (Figure 5⁵⁰). Either mechanism could result in up-regulation in postsynaptic D2/3 receptors.

Volkow et al⁵¹ reported that D2 receptor density correlated with methylphenidate-induced changes in rCBF in frontal and tem­poral lobes in humans. They postulated that the variable therapeutic effects of methyl­phenidate seen in ADHD patients might be related to variations in baseline D2 receptor availability.

Lou et al⁵⁰ reported elevated D2 recep­tor density, demonstrated using carbon-11 raclopride, in children with ADHD, com­pared with normal adults.

Further support for a relationship between D2-receptor density and symptom­atic improvement with methylphenidate in ADHD was presented by Ilgin et al⁵² using iodine-123 iodobenzamide SPECT. They found elevated D2 receptor levels in 9 drug-naïve children with ADHD, which is 20% to 60% above what is seen in unaffected chil­dren. They noted that these patients showed improvement in hyperactivity when treated with methylphenidate.

In a similar study of 20 drug-naïve adults, Volkow et al⁵³ found that durable symptom­atic improvement with methylphenidate therapy was associated with increased D2 receptor availability.

Summing up
Striatal DaT is the most likely synaptic tar­get for stratifying patients with ADHD, now that a dopamine transporter imaging agent is available commercially. Stratification might allow for refinement in the diagnostic categorization of ADHD, with introduction of stimulant-responsive and stimulant-unresponsive subtypes that are based on DaT imaging findings.

Bottom Line
Given recent advances showing molecular alterations in the dopaminergic-frontostriatal pathway as central to attention-deficit/hyperactivity disorder, molecular imaging might be useful as an objective study for diagnosis.

Related Resources
• Schweitzer JB, Lee DO, Hanford RB, et al. A positron emis­sion tomography study of methylphenidate in adults with ADHD: alterations in resting blood flow and predict­ing treatment response. Neuropsychopharmacology. 2003;28(5):967-973.
• Raz A. Brain imaging data of ADHD. Psychiatric Times. http://www.psychiatrictimes.com/adhd/brain-imaging-data-adhd.

Drug Brand Names
Iodine-123 ioflupane • Methylphenidate • Ritalin DaTscan

Acknowledgment
Kylee M. L. Unsdorfer, a medical student at Northeast Ohio Medical University, helped prepare the manuscript of this article.

Disclosures
Dr. Thacker reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.
Dr. Binkovitz received 4 doses of ioflupane I123I (DaTscan) from General Electric for investigator-initiated research, used for animal imaging in 2012.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common pediatric psychiatric dis­orders, occurring in approximately 5% of children.¹ The disorder persists into adulthood in about one-half of those who are affected in childhood.² In adults and children, diagnosis continues to be based on the examiner’s subjec­tive assessment. (Box 1^3-9 describes how ADHD presents a compli­cated, moving target for the diagnostician.)

Patients who have ADHD are rarely studied with imag­ing; there are no established imaging findings associated with an ADHD diagnosis. Over the past 20 years, however, significant research has shown that molecular alterations along the dopaminergic−frontostriatal pathways occur in association with the behavioral constellation of ADHD symptoms—suggesting a pathophysiologic mechanism for this disorder.

In this article, we describe molecular findings from nuclear medicine imaging in ADHD. We also summarize imaging evidence for dysfunction of the dopaminergic-frontostriatal neural circuits as central in the pathophysiol­ogy of ADHD, with special focus on the dopamine reuptake transporter (DaT). Box 2^10,11 reviews our key observations and looks at the future of imaging in the management of ADHD.

Dopaminergic theory of ADHD
The executive functions that are disordered in ADHD (impulse control, judgment, main­taining attention) are thought to be centered in the infraorbital, dorsolateral, and medial frontal lobes. Neurotransmitters that have been implicated in the pathophysiology of ADHD include norepinephrine¹² and dopa­mine¹³; medications that selectively block reuptake of these neurotransmitters are used to treat ADHD.^14,15 Only the dopamine system has been extensively evaluated with molecular imaging techniques.

Because methylphenidate, a potent selec­tive dopamine reuptake inhibitor, has been shown to reduce disordered executive func­tional behaviors in ADHD, considerable imaging research has focused on the dopa­minergic neural circuits in the frontostriatal regions of the brain. The dopaminergic the­ory of ADHD is based on the hypothesis that alterations in the density or function of these circuits are responsible for behaviors that constitute ADHD.

Despite decades of efforts to delineate the underlying pathophysiology and neu­rochemistry of ADHD, no single unifying theory accounts for all imaging findings in all patients. This might be in part because of imprecision inherent in psychiatric diag­noses that are based on subjective observa­tions. The behavioral criteria for ADHD can manifest in several disorders. For example, anxiety-related symptoms seen in post­traumatic stress disorder, social anxiety disorder, and panic disorder also present as behaviors similar to those in ADHD diag­nostic criteria.

Molecular imaging might provide a window into the underlying pathophysiol­ogy of ADHD and, by identifying objective findings, (1) allow for patient stratification based on underlying physiologic subtypes, (2) refine diagnostic criteria, and (3) predict treatment response.

Nuclear medicine findings
In general, nuclear medicine investiga­tions of ADHD can be divided into studies of changes in regional cerebral blood flow (rCBF) or glucose metabolism (rCGM) and those that have assessed the concentration of synaptic structures, using highly specific radiolabeled ligands. Both kinds of studies provide limited anatomic resolution, unless co-registered with MRI or CT scans and either single photon emission computed tomography (SPECT) or positron emission tomography (PET).

Synaptic imaging using radiolabeled ligands with high biologic specificity for synaptic structures has high molecular resolution—that is, radiolabeled ligands used for selective imaging of the dopamine transporter or receptor do not identify sero­tonin transporters or receptors, and vice versa. (Details of SPECT and PET tech­niques are beyond the scope of this article but can be found in standard nuclear medi­cine textbooks.)

SPECT and PET of rCBF
Early investigations of rCBF in ADHD were performed using inhaled radioactive xenon-133 gas.¹⁶ Later, rCBF was assessed using fat-soluble radiolabeled ligands that rapidly distribute in the brain in proportion to blood flow by crossing the blood−brain barrier. Labeled with radioactive 99m-technetium, these ligands cross rapidly into brain cells after IV injection. Once intracellular, cova­lent bonds within the ligands cleave into 2 charged particles that do not easily recross the cell membrane. There is little redistribu­tion of tracer after initial uptake.

The imaging data set that results can be reconstructed as (1) surface images, on which defects indicate areas of reduced rCBF, or (2) tomographic slices on which color scales indicate relative rCBF values (Figure 1). Because of the minimal redistribution of the tracer, SPECT images obtained 1 or 2 hours after injection provide a snapshot of rCBF at the time tracer is injected. Patients can be injected under various conditions, such as at rest with eyes and ears open in a dimly lit, quiet room, and then under cognitive stress (Figure 2), such as performing a computer-based attention and impulse con­trol task, or during stimulant treatment.

Numerous investigators have found reduced frontal or striatal rCBF, or both, in patients with ADHD, unilaterally on the right¹⁷ or left,^18,19 or bilaterally.²⁰ Additionally, with stimulant therapy, normalization of striatal and frontal rCBF has been demon­strated^14,19—changes that correlate with reso­lution of behavioral symptoms of ADHD with stimulant treatment.²¹

SPECT of 32 boys with previously untreated ADHD. Kim et al²¹ found that the presence of reduced right or left, or both, frontal rCBF, which normal­ized with 8 weeks of stimulant therapy, predicted symptom improvement in 85% of patients. Absence of improve­ment of reduced frontal rCBF had a 75% negative predictive value for treatment response. (Additionally, hyperperfusion of the somatosensory cortex has been demonstrated in children with ADHD,^16,22 suggesting increased responsiveness to extraneous environmental input.)

SPECT of 40 untreated pediatric patients compared with 17 age-matched controls. Using SPECT, Lee et al²³ reported rCBF reductions in the orbitofrontal cortex and the medial temporal gyrus of participants; reductions corresponded to areas of motor and impulsivity control. The researchers also demonstrated increased rCBF in the somato­sensory area.

After methylphenidate treatment, blood flow to these areas normalized, and rCBF to higher visual and superior prefrontal areas decreased. Substantial clinical improve­ment occurred in 64% of patients—suggest­ing methylphenidate treatment of ADHD works by (1) increasing function of areas of the brain that control impulses, motor activ­ity, and attention, and (2) reducing function to sensory areas that lead to distraction by extraneous environmental sensory input.

O-15-labeled water PET of 10 adults with ADHD. Schweitzer et al²⁴ found that participants who demonstrated improve­ment in behavioral symptoms with chronic stimulant therapy had reduced rCBF in the striata at baseline—again, suggesting that baseline hypometabolism in the striata is associated with ADHD.

PET of regional cerebral glucose metabolism
Cerebral metabolism requires a constant supply of glucose; regional differences in cerebral glucose metabolism can be assessed directly with positron-emitting F-18-fluoro-2-deoxyglucose. Although metabolically inert, this agent is transported intracellularly simi­lar to glucose; once phosphorylated within brain cells, however, it can no longer undergo further metabolism or redistribution.

Studies using PET to assess rCGM were some of the earliest molecular imaging appli­cations in ADHD. Zametkin et al²⁵ reported low global cerebral glucose utilization in adults, but not adolescents,²⁶ with ADHD. However, further study, with normalization of the PET data, confirmed reduced rCGM in the left prefrontal cortex in both adolescents²⁶ and adults,²⁷ indicating hypometabolism of cortical areas associated with impulse con­trol and attention in ADHD. In adolescents, symptom severity was inversely related to rCBF in the left anterior frontal cortex.

Synaptic imaging
Nuclear imaging has been used to study several components of the striatal dopami­nergic synapse, including:
   • dopamine substrates, using fluorine- 18-labeled dopa or carbon-11-labeled dopa
   • dopamine receptors, using carbon- 11-labeled raclopride or iodine-123 iodobenzamide
   • the tDaT, using iodine-123 ioflupane, 99m-technetium TRODAT, or carbon-11 cocaine (Figure 3).

All of these synaptic imaging agents were used mainly as research tools until 2011, when the FDA approved the SPECT imag­ing agent iodine-123 ioflupane (DaTscan) for clinical use in assessment of Parkinson’s disease.²⁸ This commercially available agent has high specificity for the DaT, with little background activity noted on SPECT imag­ing (Figure 4).

Dopamine transporter imaging
Because the site of action of methylpheni­date is the DaT, imaging this component of the striatal dopaminergic synapse has been an area of intense investigation in ADHD. Located almost exclusively in the striata, DaT reduces synaptic concentrations of dopamine by means of reuptake channels in the cell membrane.²⁹ By reversibly bind­ing to, and occupying sites on, the DaT, methylphenidate impedes dopamine reup­take, which results in increased availability of dopamine at the synapse.³⁰

By demonstrating an increase in stria­tal DaT density in patients with ADHD— first reported by Dougherty et al³¹ using iodine-123 altropane (a dopaminergic uptake inhibitor) in 6 adults with ADHD—inves­tigators have hypothesized that excessive expression of the DaT protein in the striata, which may result from genetic or environ­mental factors, is a central causative agent of ADHD.³² Subsequent studies, however, have yielded contradictory findings: Hesse et al,³³ using SPECT imaging, and Volkow et al,³⁴ using carbon-11 cocaine PET imaging, found reduced DaT density in, respectively, 9 and 26 patients with ADHD.

To clarify the role of DaT levels in the eti­ology of ADHD and to explain discrepant results, Fusar-Poli et al³⁵ performed a meta-analysis of 9 published papers that reported the results of DaT imaging in a total of 169 ADHD patients and 129 controls. They noted that these studies included 6 differ­ent imaging agents and protocols. Patients were stimulant therapy-naïve (n = 137) or drug-free (refrained from stimulant therapy for a time [n = 32]). The team found that the degree of elevation of the striatal DaT con­centration correlated with a history of stimu­lant exposure, and that the drug-naïve group had a reduced DaT level.

Fusar-Poli’s hypothesis? Elevated DaT lev­els result from up-regulation in the presence of chronic methylphenidate therapy, which accounts for early reports that demonstrated increased striatal DaT density. Clinically, up-regulation might explain the lack of sustained relief of behavioral symptoms with stimulant therapy in 20% of patients with ADHD who showed clinical improvement initially.³⁶

Only limited conclusions can be drawn about the role of DaT levels in ADHD, given the small number of patients studied in pub­lished reports. In addition, the Fusar-Poli meta-analysis has come under strong criti­cism because of methodological errors with improper patient inclusion and characteriza­tion of treatment status,³⁷ calling into question the investigators’ conclusions.

Does the DaT level hold promise for practice? Despite a lack of clarity about the significance of DaT level in the etiology of ADHD, knowledge of a patient’s level might prove useful in predicting which patients will respond to methylphenidate. Namely, several researchers have found that:
   • an elevated baseline level of DaT (before stimulant therapy) correlates with robust clinical response
   • absence of an elevated baseline DaT level suggests that symptomatic improvement with stimulant therapy in unlikely.^38-40

Dresel et al³⁸ evaluated 17 drug-naïve adults, newly diagnosed with ADHD, using 99m-technetium TRODAT SPECT before and after methylphenidate therapy. They found a 15% increase in specific DaT binding in patients with ADHD, compared with con­trols, at baseline. After treatment, the research­ers observed a 28% reduction in specific DaT binding—a significant change from baseline that correlated with behavioral response.

Study: SPECT in 18 adults with ADHD given methylphenidate. Krause³⁹ used the same SPECT agent to study 18 adults before they received methylphenidate and 10 weeks after treatment. Participants were categorized as responders or nonresponders based on clinical assessment of ADHD symptoms after those 10 weeks. All 12 responders had an elevated striatal DaT concentration at baseline. Of the 6 nonresponders, 5 had a normal level of striatal DaT compared with age-matched controls.

Study: 22 Adult ADHD patients evalu­ated with 99m-technetium TRODAT SPECT. The same group of investigators⁴⁰ presented imaging findings in 22 additional adult patients. Seventeen had an elevated striatal DaT level, 16 of whom responded to stimulant therapy. The remaining 5 patients had reduced striatal DaT at base­line; none had a good clinical response to methylphenidate.

The positive clinical response to methylphenidate in 67%³⁷ and 77%⁴⁰ of patients is in good agreement with results from larger studies, which reported that approximately 75% of patients with ADHD show prompt clinical improvement with stimulants.⁴¹ Improvement might be related to an increase in functioning of the frontostriatal dopami­nergic circuit that is seen with stimulant therapy. Increased availability of dopamine at the synapse, resulting from stimulant blockade of the dopamine reuptake trans­porter, produces increased dopamine neu­rotransmission and increased activation of frontostriatal circuits.

In another study, rCBF in frontostriatal circuits was determined to be inversely proportional to DaT density; rCBF normalized with stimulant therapy.⁴²

Will imaging pave the way for therapeu­tic stratification? Baseline determinations of striatal DaT concentration with SPECT imaging might make it possible to stratify patients with ADHD symptoms into those likely to show significant behavioral symp­tom response to methylphenidate and those who are not likely to respond. There might be an objective imaging finding—striatal DaT density—that allows clinicians to dis­tinguish stimulant-responsive ADHD from stimulant-unresponsive ADHD.

Dopamine substrate imaging
Radiolabeled dopa (carbon-11 or fluorine-18) is transported into presynaptic dopaminer­gic neurons in the striatum, where it is decar­boxylated, converted to radio-dopamine, and stored within vesicles until released in response to neuronal excitation. Semi-quantitative assessment is achieved with calculation of specific (striatal) to nonspecific (background) uptake ratios. Increased val­ues are thought to indicate increased density of dopaminergic neurons.⁴³

Ernst et al⁴⁴ reported a 50% decrease in specific fluorine-18 dopa uptake in the left prefrontal cortex in 17 drug-naïve adults with ADHD, compared with 23 controls. The same team reported increased midbrain fluorine-18 dopa levels in 10 adolescents with ADHD—48% higher, overall, than what was seen in 10 controls.⁴³ They hypoth­esized that these opposite results were the results of a reduction in the dopaminergic neuronal density in adults, which might be part of the natural history of ADHD, or a normal age-related reduction in neuronal density, or both. Increased dopa levels in the team’s adolescent group were hypothesized to reflect up-regulation in dopamine syn­thesis due to low synaptic dopamine con­centrations that might result from increased dopamine reuptake.

Dopamine-receptor imaging
The 5 distinct dopamine receptors (D1, D2, D3, D4, and D5) can be grouped into 2 subtypes, based on their coupling with G proteins. D1 and D5 constitute a group; D2, D3, and D4, a second group.

The D1 receptor is the most common dopamine receptor in the brain and is widely distributed in the striatum and pre­frontal cerebral cortex. D1 receptor knock­out mice demonstrate hyperactivity and poorer performance on learning tasks and are used as an animal model for ADHD.⁴⁵ D1 has been imaged using C-11 SCH 23390 PET⁴⁶ in rats, but its role in ADHD has yet to be evaluated. D5 is the most recently cloned and most widely distributed of the known dopamine receptors; however, there are no imaging studies of the D5 receptor.¹³

D2 receptors are present in presynaptic and postsynaptic neurons⁴⁷ in the neocor­tex, substantia nigra, nucleus accumbens, and olfactory tubercle, as well as in other structures.⁴⁸ Presynaptic D2 receptors act as autoregulators, inhibiting dopaminergic synthesis, firing rate, and release.⁴⁹

Using C-11 raclopride PET imaging, Lou et al⁵⁰ reported high D2/3 receptor availabil­ity in adolescents who had a history of peri­natal cerebral ischemia. They found that this availability is associated with an increase in the severity of ADHD symptoms. They pro­posed that the increase in “empty” receptor density might have been caused by perinatal ischemia-induced presynaptic dopaminer­gic neuronal loss or an increase in presynap­tic dopamine reuptake (Figure 5⁵⁰). Either mechanism could result in up-regulation in postsynaptic D2/3 receptors.

Volkow et al⁵¹ reported that D2 receptor density correlated with methylphenidate-induced changes in rCBF in frontal and tem­poral lobes in humans. They postulated that the variable therapeutic effects of methyl­phenidate seen in ADHD patients might be related to variations in baseline D2 receptor availability.

Lou et al⁵⁰ reported elevated D2 recep­tor density, demonstrated using carbon-11 raclopride, in children with ADHD, com­pared with normal adults.

Further support for a relationship between D2-receptor density and symptom­atic improvement with methylphenidate in ADHD was presented by Ilgin et al⁵² using iodine-123 iodobenzamide SPECT. They found elevated D2 receptor levels in 9 drug-naïve children with ADHD, which is 20% to 60% above what is seen in unaffected chil­dren. They noted that these patients showed improvement in hyperactivity when treated with methylphenidate.

In a similar study of 20 drug-naïve adults, Volkow et al⁵³ found that durable symptom­atic improvement with methylphenidate therapy was associated with increased D2 receptor availability.

Summing up
Striatal DaT is the most likely synaptic tar­get for stratifying patients with ADHD, now that a dopamine transporter imaging agent is available commercially. Stratification might allow for refinement in the diagnostic categorization of ADHD, with introduction of stimulant-responsive and stimulant-unresponsive subtypes that are based on DaT imaging findings.

Bottom Line
Given recent advances showing molecular alterations in the dopaminergic-frontostriatal pathway as central to attention-deficit/hyperactivity disorder, molecular imaging might be useful as an objective study for diagnosis.

Related Resources
• Schweitzer JB, Lee DO, Hanford RB, et al. A positron emis­sion tomography study of methylphenidate in adults with ADHD: alterations in resting blood flow and predict­ing treatment response. Neuropsychopharmacology. 2003;28(5):967-973.
• Raz A. Brain imaging data of ADHD. Psychiatric Times. http://www.psychiatrictimes.com/adhd/brain-imaging-data-adhd.

Drug Brand Names
Iodine-123 ioflupane • Methylphenidate • Ritalin DaTscan

Acknowledgment
Kylee M. L. Unsdorfer, a medical student at Northeast Ohio Medical University, helped prepare the manuscript of this article.

Disclosures
Dr. Thacker reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.
Dr. Binkovitz received 4 doses of ioflupane I123I (DaTscan) from General Electric for investigator-initiated research, used for animal imaging in 2012.