Case-Based Review

Series Editor: Arthur T. Skarin, MD, FACP, FCCP

Neuroendocrine tumors (NETs) are a rare, heterogeneous group of neoplasms that arise from neuroendocrine cells located throughout the body. These tumors are characterized by variable but most often indolent biologic behavior. They are also classically characterized by their ability to secrete peptides, resulting in distinctive hormonal syndromes. Although NETs have been considered rare, recent studies suggest that they are more common than previously suspected. An analysis of the Surveillance, Epidemiology, and End Results (SEER) database demonstrated a significant increase in the incidence of NETs over time with an age-adjusted annual incidence in the United States of 5.25 cases per 100,000 population. The increase in incidence is likely attributable to increasing awareness, improved diagnostic strategies, and possibly other undetermined environmental and genetic factors.

To read the full article in PDF:

Click here

Series Editor: Arthur T. Skarin, MD, FACP, FCCP

Neuroendocrine tumors (NETs) are a rare, heterogeneous group of neoplasms that arise from neuroendocrine cells located throughout the body. These tumors are characterized by variable but most often indolent biologic behavior. They are also classically characterized by their ability to secrete peptides, resulting in distinctive hormonal syndromes. Although NETs have been considered rare, recent studies suggest that they are more common than previously suspected. An analysis of the Surveillance, Epidemiology, and End Results (SEER) database demonstrated a significant increase in the incidence of NETs over time with an age-adjusted annual incidence in the United States of 5.25 cases per 100,000 population. The increase in incidence is likely attributable to increasing awareness, improved diagnostic strategies, and possibly other undetermined environmental and genetic factors.

To read the full article in PDF:

Click here

Series Editor: Arthur T. Skarin, MD, FACP, FCCP

Neuroendocrine tumors (NETs) are a rare, heterogeneous group of neoplasms that arise from neuroendocrine cells located throughout the body. These tumors are characterized by variable but most often indolent biologic behavior. They are also classically characterized by their ability to secrete peptides, resulting in distinctive hormonal syndromes. Although NETs have been considered rare, recent studies suggest that they are more common than previously suspected. An analysis of the Surveillance, Epidemiology, and End Results (SEER) database demonstrated a significant increase in the incidence of NETs over time with an age-adjusted annual incidence in the United States of 5.25 cases per 100,000 population. The increase in incidence is likely attributable to increasing awareness, improved diagnostic strategies, and possibly other undetermined environmental and genetic factors.

To read the full article in PDF:

Click here

Case Agitated and violent
Mr. C, age 19, presents with anxiety, agitation, isolation, social withdrawal, and paranoia. He is admitted to the inpatient unit after attempting to punch his father and place him in a headlock. Mr. C has no history of mental illness, no signifi­cant medical history, and no significant family history of mental illness.

The treatment team determines that this is Mr. C’s first psychotic break. He is given a diag­nosis of psychosis, not otherwise specified and started on risperidone, titrated to 2 mg/d, later discontinued secondary to tachycardia. He is then started on haloperidol, 5 mg/d titrated to 10 mg/d, and psychotic symptoms abate. Mr. C is discharged with a plan to receive follow-up care at an outpatient mental health center.

One year later, Mr. C is readmitted with a similar presentation: paranoia, agitation, anxi­ety, and isolation. After discharge, he starts an intensive outpatient program (IOP) for long-term treatment of adults who have a diagnosis of a schizophrenia spectrum disorder.

Several medication trials ensue, includ­ing risperidone, escitalopram, citalopram, fluphenazine, lorazepam, quetiapine, and haloperidol. Despite these trials over the course of 2 years, Mr. C continues to display paranoia and agitation, and is unable to resume academic and community activities. Within the IOP, Mr. C is placed in a vocational training program and struggles to remain stable enough to continue his job at a small greenhouse.

Concurrently, Mr. C is noted to be abusing alcohol. After the IOP treatment team expresses concern about his abuse, he reduces alcohol intake and he and his parents are educated on the impact of alcohol use on schizophrenia.

Which treatment option would you choose next?
   a) initiate a trial of clozapine
   b) try a long-acting injectable antipsychotic
   c) recommend inpatient treatment

The authors’ observations
Clozapine is an atypical antipsychotic that is FDA-approved for treatment-resistant schizophrenia; it also helps reduce recur­rent suicidal behavior in patients with schizophrenia or schizoaffective disorder.

Clozapine works by blocking D2 recep­tors, thereby reducing positive symptoms. It also blocks serotonin 2A receptors, which enhances dopamine release in certain brain regions, thereby reducing motor side effects. Interactions at 5-HT2C and 5-HT1A recep­tors may address cognitive and affective symptoms. Clozapine can help relieve nega­tive symptoms and can decrease aggression. Because it has a low risk of tardive dyskine­sia, clozapine is useful when treating patients with treatment-resistant schizophrenia.^1-3

Treatment Quick heart rate
Mr. C’s IOP treatment team considers a clo­zapine trial because previous medication tri­als failed. All paperwork for the registry and screening labs are completed and Mr. C is started on clozapine.

Mr. C’s clozapine dosages are:
   • Days 1 to 9: 25 mg/d
   • Days 10 to 16: 50 mg/d
   • Days 17 to 23: 75 mg/d
   • Days 24 to 32: 100 mg/d
   • Days 33 to 37: 125 mg/d
   • Day 38: 150 mg/d.

On Day 45 of the clozapine trial, Mr. C is increasingly paranoid toward his father and thinks that his father is controlling his thoughts. Mr. C tells the attending psychiatrist that he ingested a handful of clonazepam and considered putting a bag over his head with the intent to commit suicide. Mr. C is admitted to the inpatient unit.

Admission vitals recorded a heart rate of 72 beats per minute but, later that day, the rate was recorded in the vital sign book as 137 beats per minute. The treatment team considers dehydration, anxiety, and staff error; Mr. C is observed carefully. Over the next 2 days, heart rate remains between 102 and 119 beats per minute.

Because of persistent tachycardia, the team orders lab studies, a medical consult, and an electrocardiogram (ECG). Thyroid panel, elec­trolytes, and clozapine level are within normal limits; ECG is unremarkable.

Although tachycardia is a known side effect of clozapine,^3,4 we order an echocar­diogram because of Mr. C’s young age and non-diagnostic laboratory workup. The echo study demonstrates reduced left-ventricular ejection fraction (LVEF) of 45%. Tests for HIV infection and Lyme disease are negative. The cardiology team diagnoses cardiomyopathy of unknown origin.

Although Mr. C has a history of alcohol abuse, the cardiology team believes that alco­hol consumption does not adequately explain the cardiomyopathy, given his young age and the limited number of lifetime drinking-years (approximately 4 or 5); the team determines that clozapine is causing secondary cardiomy­opathy and tachycardia, leading to reduced LVEF. Clozapine is stopped because the rec­ommended treatment for toxic secondary cardiomyopathy is to remove the offending agent. At this point, the clozapine dosage is 250 mg/d.

At the medical team’s recommendation, Mr. C is started on metoprolol, a beta blocker, at 25 mg/d.

The etiology of secondary cardiomyopathy includes all of the following except:
   a) tachycardia-induced
   b) autoimmune
   c) radiation-induced
   d) infiltrative
   e) endomyocardial

The authors’ observations
Cardiomyopathies are diseases of the heart muscle causing mechanical and electrical dysfunction. This group of diseases has a range of symptoms, causes, and treatments. Disease manifests typically as arrhythmia, systolic dysfunction, or diastolic dysfunc­tion. Classification systems are based on origin, anatomy, physiology, primary treat­ments, method of diagnosis, biopsy, histopa­thology, and symptomatic state.

The American Heart Association Scientific Statement5 distinguishes cardiomyopathies by degree of organ involvement. Diseases confined to the heart are defined as primary cardiomyopathy, which may have a genetic, acquired, or mixed cause. Acquired causes include inflammatory (myocarditis), stress (Takotsubo), peripartum, and tachycardia. Cardiomyopathies that are part of general­ized systemic disorders are defined as sec­ondary cardiomyopathy (Table 1).

Secondary cardiomyopathies have many causes. These include toxicity (medica­tions or alcohol), cancer therapy, infiltra­tive, storage disease, and endomyocardial, inflammatory, autoimmune, endocrine, and neurologic diseases.⁵

Evaluation of suspected cardiomyopathy begins with a history and physical focused on identifying causative factors. Selective testing, based on pretest probabilities, might include lab testing, ECG, and echocardiogra­phy, and can narrow the differential diagno­sis. When toxin-induced cardiomyopathy is suspected, withdrawing the toxin and moni­toring for improvement is recommended. The treatment and prognosis for cardiomy­opathies vary, based on the cause.⁶

Review of the literature
After 23 cases of fatal and non-fatal myo­carditis were found in a study of 8,000 patients starting clozapine,⁷ manufacturers in Australia introduced clinical guidelines. Before initiating clozapine, they recom­mended, clinicians should:
   • screen for cardiac symptoms
   • screen for a family history of heart disease
   • obtain baseline ECG
   • obtain baseline markers of myocardial damage (troponin assay and serum creatinine)
   • obtain baseline echocardiogram
   • repeat cardiac monitoring after the first and second week and then repeat in 6 months
   • maintain a high degree of vigilance for signs and symptoms of cardiac toxicity throughout clozapine treatment.^8,9

After studying 38 cases of clozap­ine-induced myocarditis—3 fatal— Ronaldson et al¹⁰ listed primary diag­nostic features as:  
   • tachycardia (heart rate >100 beats per minute)  
   • heart rate >120 beats per minute  
   • temperature >37°C  
   • chest pain  
   • troponin I/T level >2 ng/mL  
   • C-reactive protein (CRP) > 100 mg/L  
   • erythrocyte sedimentation rate >50 mm/h.

Among non-fatal cases, symptoms abated after clozapine was discontinued. In 36 of the 38 cases, symptoms emerged 14 to 22 days after clozapine was started. For tachycardia to be considered a diagnostic feature, it must persist for at least 24 hours; if the heart rate is ≥120 beats per minute, however, persistence is not a criterion. It was thought that elevated CRP might herald disease onset; the authors suggest that CRP >50 mg/L should warrant increased monitoring with daily ECG and troponin levels.

Authors’ recommendations include:  
   • measuring troponin and CRP and order an ECG at baseline and at 7, 14, 21, and 28 days  
   • examining patient for signs and symp­toms of illness at these same intervals  
   • considering chest pain or fever as an indicator of cardiomyopathy  
   • asking patients to report any illness during this 4-week period  
   • if ECG is abnormal or troponin ele­vated, decreasing clozapine pending further investigation.¹⁰ 

When medications fail
We had to discontinue Mr. C’s clozapine, which meant that the therapeutic relation­ship established between him and the psy­chology fellow became an important and, at times, the only bond between him and the medical team while olanzapine was initiated. The alliance between patient and clinician is an important factor for positive prognosis in mental health treatment.^11-13 Priebe and McCabe¹⁴ asked if the therapeu­tic relationship in psychiatry is “the basis of therapy or therapy itself?” In a review of studies that used an operationalized mea­surement of the therapeutic relationship in treating severe mental illness, the authors concluded that the therapeutic relation­ship is a reliable predictor of outcome.¹⁵

In Mr. C’s case, the psychology fellow, who also works with the Partial Hospitalization Program/Intensive Outpatient Program (PHP/IOP), joined the treatment team on the inpatient unit a few days into hospitalization. Eleven meetings, includ­ing a discharge session, were held between the psychology fellow and the patient during the inpatient hospitaliza­tion. Mr. C also participated in a daily group session, facilitated by the psychol­ogy fellow.

Maintaining recognition of the bound­ary disturbance that characterizes schizo­phrenic psychoses was important for Mr. C. As Auerhahn and Moskowitz¹⁶ wrote, the inpatient therapist can be transformed by the schizophrenia patient into the all-knowing, all-powerful early mother, which could contribute to substantial improvement in the patient’s functioning and report of symptoms, only to have the patient’s symp­toms return after discharge.

In an effort to evaluate the duration, fre­quency, and intensity of Mr. C’s symptom experience, a goal of Mr. C’s hospitalization was to attach words to his internal states, including mood and intensity of paranoid ideation. We showed Mr. C directly and indi­rectly that reporting intensification of symp­toms and decreased functioning would not result in abandonment or punishment, and worked to demonstrate through our actions that the treatment team differs from Mr. C’s view of the world as dangerous and others as hostile and omnipotent.


Treatment Developing language
Initially, Mr. C gives a number (from 1 to 10) to describe his mood, 10 being the happiest he has ever felt and 1 being the most depressed. The treatment team discusses how important it is that Mr. C know his feelings and be able to convey to others how he feels.

Over time, Mr. C is encouraged to attach a feeling word to the number, and by discharge, he stops using numbers and responds to inqui­ries about his feelings with a mood word. This practice has been reinforced with the patient in the IOP program, allowing him to continue practicing linking his internal state with feeling words.

During hospitalization, Mr. C becomes more vocal about his level of paranoia and is now more likely to seek support when he first expe­riences a paranoid thought, rather than waiting until after he is paranoid and agitated. Mr. C is encouraged to monitor his thoughts and feel­ings, and to practice coping strategies he has identified as helpful, including deep breathing, meditation, listening to music, and reminding himself that he is safe.

The treatment team responds to Mr. C’s reports of paranoid ideation (eg, “Some of the other patients were talking about me today”) by processing the affect, and hypothesizing other explanations for these events to slow down “jumping to conclusions,” which is a common part of the paranoid experience.¹⁷ Additionally, all meetings with the cardiology team are processed and Mr. C receives psychoeduca­tion about his heart function. Joint sessions with the psychiatry resident and psychology fellow allow Mr. C to ask medical questions and immediately process his reactions, which likely ameliorated his anxiety and allowed him to continue connecting with, identifying, and verbalizing his internal experiences. Given his history of paranoia, sessions also showed that Mr. C is an active participant in his treatment, with the hope of lessening his belief that bad things happen to him and that they are out of his control.

We maintain frequent contact with Mr. C’s parents to update them on their son’s function­ing and to discuss treatment interventions that were helpful and the family could implement when Mr. C returns home. Discharge medica­tions are discussed.

After 24 days in the inpatient unit, Mr. C is discharged to the IOP program. The psychology fellow walks Mr. C to the IOP program, where he transitioned immediately from inpatient to the IOP daily schedule of groups and an appointment with the program psychiatrist. The psychology fellow also arranged for and participated in the family meeting with Mr. C’s parents, sister, and treatment providers in the IOP program after his first day back at the IOP.

Throughout his hospitalization, Mr. C had no symptoms of cardiomyopathy, without exercise intolerance, shortness of breath, fatigue, or fever. He is discharged with follow-up care at his outpatient program at the PHP level of care and a follow-up echocardiogram and cardiology appointment are scheduled for 6 weeks later.

The authors' observations
Throughout Mr. C’s hospitalization, the intersections among psychiatry, psychol­ogy, cardiology, and internal medicine were apparent and necessary for treat­ment. No one specialty was able to com­pletely direct this patient’s care without the expertise of, and input from, others. When it looked like all medications had failed, the relationship between the patient and the psychology fellow and the appli­cation of previously learned coping strate­gies prevented acute decompensation.

Clozapine is FDA-approved for treatment-resistant schizophrenia and often is a last resort to help patients remain sta­ble. When clozapine is chosen, it is impor­tant to be aware of its side-effect profile (Table 2,¹ and Table 3,^1-3) and the need for monitoring. The importance of relying on colleagues from other specialties to assist in the effective monitoring process cannot be overstated. This multidisciplinary team ensured that Mr. C did not experience acute decompensation during this process. Cardiac function improved, with an LVEF of 50% after clozapine was discontinued. Mr. C has not needed hospitalization again.

Follow-up appointment with cardiology and repeat echocardiography were scheduled for 6 weeks after discharge. The follow-up echocardiogram showed improvement (LVEF, 50%). Mr. C continues to do well and remains a client at the IOP program.

Bottom Line
Clozapine often is used as a last resort for patients with treatment-resistant schizophrenia, but its side-effect profile requires careful management and monitoring. If a patient taking clozapine shows tachycardia, consider cardiomyopathy. Evaluation might include lab testing, electrocardiography, and echocardiography. Symptoms often resolve when clozapine is discontinued.

Related Resources
• Citrome L. Clozapine for schizophrenia: life-threatening or life-saving treatment? Current Psychiatry. 2009;8(12):56-63.
• Layland JJ, Liew D, Prior DL. Clozapine-induced cardiotoxicity: a clinical update. Med J Aust. 2009;190(4):190-192.

Drug Brand Names
Benztropine • Cogentin               Fluphenazine • Prolixin
Chlorpromazine • Thorazine        Haloperidol • Haldol
Citalopram • Celexa                    Lorazepam • Ativan
Clonazepam • Klonopin               Metoprolol • Lopressor
Clozapine • Clozaril                    Olanzapine • Zyprexa
Duloxetine • Cymbalta                Quetiapine • Seroquel
Escitalopram • Lexapro               Risperidone • Risperdal

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

Case Agitated and violent
Mr. C, age 19, presents with anxiety, agitation, isolation, social withdrawal, and paranoia. He is admitted to the inpatient unit after attempting to punch his father and place him in a headlock. Mr. C has no history of mental illness, no signifi­cant medical history, and no significant family history of mental illness.

The treatment team determines that this is Mr. C’s first psychotic break. He is given a diag­nosis of psychosis, not otherwise specified and started on risperidone, titrated to 2 mg/d, later discontinued secondary to tachycardia. He is then started on haloperidol, 5 mg/d titrated to 10 mg/d, and psychotic symptoms abate. Mr. C is discharged with a plan to receive follow-up care at an outpatient mental health center.

One year later, Mr. C is readmitted with a similar presentation: paranoia, agitation, anxi­ety, and isolation. After discharge, he starts an intensive outpatient program (IOP) for long-term treatment of adults who have a diagnosis of a schizophrenia spectrum disorder.

Several medication trials ensue, includ­ing risperidone, escitalopram, citalopram, fluphenazine, lorazepam, quetiapine, and haloperidol. Despite these trials over the course of 2 years, Mr. C continues to display paranoia and agitation, and is unable to resume academic and community activities. Within the IOP, Mr. C is placed in a vocational training program and struggles to remain stable enough to continue his job at a small greenhouse.

Concurrently, Mr. C is noted to be abusing alcohol. After the IOP treatment team expresses concern about his abuse, he reduces alcohol intake and he and his parents are educated on the impact of alcohol use on schizophrenia.

Which treatment option would you choose next?
   a) initiate a trial of clozapine
   b) try a long-acting injectable antipsychotic
   c) recommend inpatient treatment

The authors’ observations
Clozapine is an atypical antipsychotic that is FDA-approved for treatment-resistant schizophrenia; it also helps reduce recur­rent suicidal behavior in patients with schizophrenia or schizoaffective disorder.

Clozapine works by blocking D2 recep­tors, thereby reducing positive symptoms. It also blocks serotonin 2A receptors, which enhances dopamine release in certain brain regions, thereby reducing motor side effects. Interactions at 5-HT2C and 5-HT1A recep­tors may address cognitive and affective symptoms. Clozapine can help relieve nega­tive symptoms and can decrease aggression. Because it has a low risk of tardive dyskine­sia, clozapine is useful when treating patients with treatment-resistant schizophrenia.^1-3

Treatment Quick heart rate
Mr. C’s IOP treatment team considers a clo­zapine trial because previous medication tri­als failed. All paperwork for the registry and screening labs are completed and Mr. C is started on clozapine.

Mr. C’s clozapine dosages are:
   • Days 1 to 9: 25 mg/d
   • Days 10 to 16: 50 mg/d
   • Days 17 to 23: 75 mg/d
   • Days 24 to 32: 100 mg/d
   • Days 33 to 37: 125 mg/d
   • Day 38: 150 mg/d.

On Day 45 of the clozapine trial, Mr. C is increasingly paranoid toward his father and thinks that his father is controlling his thoughts. Mr. C tells the attending psychiatrist that he ingested a handful of clonazepam and considered putting a bag over his head with the intent to commit suicide. Mr. C is admitted to the inpatient unit.

Admission vitals recorded a heart rate of 72 beats per minute but, later that day, the rate was recorded in the vital sign book as 137 beats per minute. The treatment team considers dehydration, anxiety, and staff error; Mr. C is observed carefully. Over the next 2 days, heart rate remains between 102 and 119 beats per minute.

Because of persistent tachycardia, the team orders lab studies, a medical consult, and an electrocardiogram (ECG). Thyroid panel, elec­trolytes, and clozapine level are within normal limits; ECG is unremarkable.

Although tachycardia is a known side effect of clozapine,^3,4 we order an echocar­diogram because of Mr. C’s young age and non-diagnostic laboratory workup. The echo study demonstrates reduced left-ventricular ejection fraction (LVEF) of 45%. Tests for HIV infection and Lyme disease are negative. The cardiology team diagnoses cardiomyopathy of unknown origin.

Although Mr. C has a history of alcohol abuse, the cardiology team believes that alco­hol consumption does not adequately explain the cardiomyopathy, given his young age and the limited number of lifetime drinking-years (approximately 4 or 5); the team determines that clozapine is causing secondary cardiomy­opathy and tachycardia, leading to reduced LVEF. Clozapine is stopped because the rec­ommended treatment for toxic secondary cardiomyopathy is to remove the offending agent. At this point, the clozapine dosage is 250 mg/d.

At the medical team’s recommendation, Mr. C is started on metoprolol, a beta blocker, at 25 mg/d.

The etiology of secondary cardiomyopathy includes all of the following except:
   a) tachycardia-induced
   b) autoimmune
   c) radiation-induced
   d) infiltrative
   e) endomyocardial

The authors’ observations
Cardiomyopathies are diseases of the heart muscle causing mechanical and electrical dysfunction. This group of diseases has a range of symptoms, causes, and treatments. Disease manifests typically as arrhythmia, systolic dysfunction, or diastolic dysfunc­tion. Classification systems are based on origin, anatomy, physiology, primary treat­ments, method of diagnosis, biopsy, histopa­thology, and symptomatic state.

The American Heart Association Scientific Statement5 distinguishes cardiomyopathies by degree of organ involvement. Diseases confined to the heart are defined as primary cardiomyopathy, which may have a genetic, acquired, or mixed cause. Acquired causes include inflammatory (myocarditis), stress (Takotsubo), peripartum, and tachycardia. Cardiomyopathies that are part of general­ized systemic disorders are defined as sec­ondary cardiomyopathy (Table 1).

Secondary cardiomyopathies have many causes. These include toxicity (medica­tions or alcohol), cancer therapy, infiltra­tive, storage disease, and endomyocardial, inflammatory, autoimmune, endocrine, and neurologic diseases.⁵

Evaluation of suspected cardiomyopathy begins with a history and physical focused on identifying causative factors. Selective testing, based on pretest probabilities, might include lab testing, ECG, and echocardiogra­phy, and can narrow the differential diagno­sis. When toxin-induced cardiomyopathy is suspected, withdrawing the toxin and moni­toring for improvement is recommended. The treatment and prognosis for cardiomy­opathies vary, based on the cause.⁶

Review of the literature
After 23 cases of fatal and non-fatal myo­carditis were found in a study of 8,000 patients starting clozapine,⁷ manufacturers in Australia introduced clinical guidelines. Before initiating clozapine, they recom­mended, clinicians should:
   • screen for cardiac symptoms
   • screen for a family history of heart disease
   • obtain baseline ECG
   • obtain baseline markers of myocardial damage (troponin assay and serum creatinine)
   • obtain baseline echocardiogram
   • repeat cardiac monitoring after the first and second week and then repeat in 6 months
   • maintain a high degree of vigilance for signs and symptoms of cardiac toxicity throughout clozapine treatment.^8,9

After studying 38 cases of clozap­ine-induced myocarditis—3 fatal— Ronaldson et al¹⁰ listed primary diag­nostic features as:  
   • tachycardia (heart rate >100 beats per minute)  
   • heart rate >120 beats per minute  
   • temperature >37°C  
   • chest pain  
   • troponin I/T level >2 ng/mL  
   • C-reactive protein (CRP) > 100 mg/L  
   • erythrocyte sedimentation rate >50 mm/h.

Among non-fatal cases, symptoms abated after clozapine was discontinued. In 36 of the 38 cases, symptoms emerged 14 to 22 days after clozapine was started. For tachycardia to be considered a diagnostic feature, it must persist for at least 24 hours; if the heart rate is ≥120 beats per minute, however, persistence is not a criterion. It was thought that elevated CRP might herald disease onset; the authors suggest that CRP >50 mg/L should warrant increased monitoring with daily ECG and troponin levels.

Authors’ recommendations include:  
   • measuring troponin and CRP and order an ECG at baseline and at 7, 14, 21, and 28 days  
   • examining patient for signs and symp­toms of illness at these same intervals  
   • considering chest pain or fever as an indicator of cardiomyopathy  
   • asking patients to report any illness during this 4-week period  
   • if ECG is abnormal or troponin ele­vated, decreasing clozapine pending further investigation.¹⁰ 

When medications fail
We had to discontinue Mr. C’s clozapine, which meant that the therapeutic relation­ship established between him and the psy­chology fellow became an important and, at times, the only bond between him and the medical team while olanzapine was initiated. The alliance between patient and clinician is an important factor for positive prognosis in mental health treatment.^11-13 Priebe and McCabe¹⁴ asked if the therapeu­tic relationship in psychiatry is “the basis of therapy or therapy itself?” In a review of studies that used an operationalized mea­surement of the therapeutic relationship in treating severe mental illness, the authors concluded that the therapeutic relation­ship is a reliable predictor of outcome.¹⁵

In Mr. C’s case, the psychology fellow, who also works with the Partial Hospitalization Program/Intensive Outpatient Program (PHP/IOP), joined the treatment team on the inpatient unit a few days into hospitalization. Eleven meetings, includ­ing a discharge session, were held between the psychology fellow and the patient during the inpatient hospitaliza­tion. Mr. C also participated in a daily group session, facilitated by the psychol­ogy fellow.

Maintaining recognition of the bound­ary disturbance that characterizes schizo­phrenic psychoses was important for Mr. C. As Auerhahn and Moskowitz¹⁶ wrote, the inpatient therapist can be transformed by the schizophrenia patient into the all-knowing, all-powerful early mother, which could contribute to substantial improvement in the patient’s functioning and report of symptoms, only to have the patient’s symp­toms return after discharge.

In an effort to evaluate the duration, fre­quency, and intensity of Mr. C’s symptom experience, a goal of Mr. C’s hospitalization was to attach words to his internal states, including mood and intensity of paranoid ideation. We showed Mr. C directly and indi­rectly that reporting intensification of symp­toms and decreased functioning would not result in abandonment or punishment, and worked to demonstrate through our actions that the treatment team differs from Mr. C’s view of the world as dangerous and others as hostile and omnipotent.


Treatment Developing language
Initially, Mr. C gives a number (from 1 to 10) to describe his mood, 10 being the happiest he has ever felt and 1 being the most depressed. The treatment team discusses how important it is that Mr. C know his feelings and be able to convey to others how he feels.

Over time, Mr. C is encouraged to attach a feeling word to the number, and by discharge, he stops using numbers and responds to inqui­ries about his feelings with a mood word. This practice has been reinforced with the patient in the IOP program, allowing him to continue practicing linking his internal state with feeling words.

During hospitalization, Mr. C becomes more vocal about his level of paranoia and is now more likely to seek support when he first expe­riences a paranoid thought, rather than waiting until after he is paranoid and agitated. Mr. C is encouraged to monitor his thoughts and feel­ings, and to practice coping strategies he has identified as helpful, including deep breathing, meditation, listening to music, and reminding himself that he is safe.

The treatment team responds to Mr. C’s reports of paranoid ideation (eg, “Some of the other patients were talking about me today”) by processing the affect, and hypothesizing other explanations for these events to slow down “jumping to conclusions,” which is a common part of the paranoid experience.¹⁷ Additionally, all meetings with the cardiology team are processed and Mr. C receives psychoeduca­tion about his heart function. Joint sessions with the psychiatry resident and psychology fellow allow Mr. C to ask medical questions and immediately process his reactions, which likely ameliorated his anxiety and allowed him to continue connecting with, identifying, and verbalizing his internal experiences. Given his history of paranoia, sessions also showed that Mr. C is an active participant in his treatment, with the hope of lessening his belief that bad things happen to him and that they are out of his control.

We maintain frequent contact with Mr. C’s parents to update them on their son’s function­ing and to discuss treatment interventions that were helpful and the family could implement when Mr. C returns home. Discharge medica­tions are discussed.

After 24 days in the inpatient unit, Mr. C is discharged to the IOP program. The psychology fellow walks Mr. C to the IOP program, where he transitioned immediately from inpatient to the IOP daily schedule of groups and an appointment with the program psychiatrist. The psychology fellow also arranged for and participated in the family meeting with Mr. C’s parents, sister, and treatment providers in the IOP program after his first day back at the IOP.

Throughout his hospitalization, Mr. C had no symptoms of cardiomyopathy, without exercise intolerance, shortness of breath, fatigue, or fever. He is discharged with follow-up care at his outpatient program at the PHP level of care and a follow-up echocardiogram and cardiology appointment are scheduled for 6 weeks later.

The authors' observations
Throughout Mr. C’s hospitalization, the intersections among psychiatry, psychol­ogy, cardiology, and internal medicine were apparent and necessary for treat­ment. No one specialty was able to com­pletely direct this patient’s care without the expertise of, and input from, others. When it looked like all medications had failed, the relationship between the patient and the psychology fellow and the appli­cation of previously learned coping strate­gies prevented acute decompensation.

Clozapine is FDA-approved for treatment-resistant schizophrenia and often is a last resort to help patients remain sta­ble. When clozapine is chosen, it is impor­tant to be aware of its side-effect profile (Table 2,¹ and Table 3,^1-3) and the need for monitoring. The importance of relying on colleagues from other specialties to assist in the effective monitoring process cannot be overstated. This multidisciplinary team ensured that Mr. C did not experience acute decompensation during this process. Cardiac function improved, with an LVEF of 50% after clozapine was discontinued. Mr. C has not needed hospitalization again.

Follow-up appointment with cardiology and repeat echocardiography were scheduled for 6 weeks after discharge. The follow-up echocardiogram showed improvement (LVEF, 50%). Mr. C continues to do well and remains a client at the IOP program.

Bottom Line
Clozapine often is used as a last resort for patients with treatment-resistant schizophrenia, but its side-effect profile requires careful management and monitoring. If a patient taking clozapine shows tachycardia, consider cardiomyopathy. Evaluation might include lab testing, electrocardiography, and echocardiography. Symptoms often resolve when clozapine is discontinued.

Related Resources
• Citrome L. Clozapine for schizophrenia: life-threatening or life-saving treatment? Current Psychiatry. 2009;8(12):56-63.
• Layland JJ, Liew D, Prior DL. Clozapine-induced cardiotoxicity: a clinical update. Med J Aust. 2009;190(4):190-192.

Drug Brand Names
Benztropine • Cogentin               Fluphenazine • Prolixin
Chlorpromazine • Thorazine        Haloperidol • Haldol
Citalopram • Celexa                    Lorazepam • Ativan
Clonazepam • Klonopin               Metoprolol • Lopressor
Clozapine • Clozaril                    Olanzapine • Zyprexa
Duloxetine • Cymbalta                Quetiapine • Seroquel
Escitalopram • Lexapro               Risperidone • Risperdal

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

Case Agitated and violent
Mr. C, age 19, presents with anxiety, agitation, isolation, social withdrawal, and paranoia. He is admitted to the inpatient unit after attempting to punch his father and place him in a headlock. Mr. C has no history of mental illness, no signifi­cant medical history, and no significant family history of mental illness.

The treatment team determines that this is Mr. C’s first psychotic break. He is given a diag­nosis of psychosis, not otherwise specified and started on risperidone, titrated to 2 mg/d, later discontinued secondary to tachycardia. He is then started on haloperidol, 5 mg/d titrated to 10 mg/d, and psychotic symptoms abate. Mr. C is discharged with a plan to receive follow-up care at an outpatient mental health center.

One year later, Mr. C is readmitted with a similar presentation: paranoia, agitation, anxi­ety, and isolation. After discharge, he starts an intensive outpatient program (IOP) for long-term treatment of adults who have a diagnosis of a schizophrenia spectrum disorder.

Several medication trials ensue, includ­ing risperidone, escitalopram, citalopram, fluphenazine, lorazepam, quetiapine, and haloperidol. Despite these trials over the course of 2 years, Mr. C continues to display paranoia and agitation, and is unable to resume academic and community activities. Within the IOP, Mr. C is placed in a vocational training program and struggles to remain stable enough to continue his job at a small greenhouse.

Concurrently, Mr. C is noted to be abusing alcohol. After the IOP treatment team expresses concern about his abuse, he reduces alcohol intake and he and his parents are educated on the impact of alcohol use on schizophrenia.

Which treatment option would you choose next?
   a) initiate a trial of clozapine
   b) try a long-acting injectable antipsychotic
   c) recommend inpatient treatment

The authors’ observations
Clozapine is an atypical antipsychotic that is FDA-approved for treatment-resistant schizophrenia; it also helps reduce recur­rent suicidal behavior in patients with schizophrenia or schizoaffective disorder.

Clozapine works by blocking D2 recep­tors, thereby reducing positive symptoms. It also blocks serotonin 2A receptors, which enhances dopamine release in certain brain regions, thereby reducing motor side effects. Interactions at 5-HT2C and 5-HT1A recep­tors may address cognitive and affective symptoms. Clozapine can help relieve nega­tive symptoms and can decrease aggression. Because it has a low risk of tardive dyskine­sia, clozapine is useful when treating patients with treatment-resistant schizophrenia.^1-3

Treatment Quick heart rate
Mr. C’s IOP treatment team considers a clo­zapine trial because previous medication tri­als failed. All paperwork for the registry and screening labs are completed and Mr. C is started on clozapine.

Mr. C’s clozapine dosages are:
   • Days 1 to 9: 25 mg/d
   • Days 10 to 16: 50 mg/d
   • Days 17 to 23: 75 mg/d
   • Days 24 to 32: 100 mg/d
   • Days 33 to 37: 125 mg/d
   • Day 38: 150 mg/d.

On Day 45 of the clozapine trial, Mr. C is increasingly paranoid toward his father and thinks that his father is controlling his thoughts. Mr. C tells the attending psychiatrist that he ingested a handful of clonazepam and considered putting a bag over his head with the intent to commit suicide. Mr. C is admitted to the inpatient unit.

Admission vitals recorded a heart rate of 72 beats per minute but, later that day, the rate was recorded in the vital sign book as 137 beats per minute. The treatment team considers dehydration, anxiety, and staff error; Mr. C is observed carefully. Over the next 2 days, heart rate remains between 102 and 119 beats per minute.

Because of persistent tachycardia, the team orders lab studies, a medical consult, and an electrocardiogram (ECG). Thyroid panel, elec­trolytes, and clozapine level are within normal limits; ECG is unremarkable.

Although tachycardia is a known side effect of clozapine,^3,4 we order an echocar­diogram because of Mr. C’s young age and non-diagnostic laboratory workup. The echo study demonstrates reduced left-ventricular ejection fraction (LVEF) of 45%. Tests for HIV infection and Lyme disease are negative. The cardiology team diagnoses cardiomyopathy of unknown origin.

Although Mr. C has a history of alcohol abuse, the cardiology team believes that alco­hol consumption does not adequately explain the cardiomyopathy, given his young age and the limited number of lifetime drinking-years (approximately 4 or 5); the team determines that clozapine is causing secondary cardiomy­opathy and tachycardia, leading to reduced LVEF. Clozapine is stopped because the rec­ommended treatment for toxic secondary cardiomyopathy is to remove the offending agent. At this point, the clozapine dosage is 250 mg/d.

At the medical team’s recommendation, Mr. C is started on metoprolol, a beta blocker, at 25 mg/d.

The etiology of secondary cardiomyopathy includes all of the following except:
   a) tachycardia-induced
   b) autoimmune
   c) radiation-induced
   d) infiltrative
   e) endomyocardial

The authors’ observations
Cardiomyopathies are diseases of the heart muscle causing mechanical and electrical dysfunction. This group of diseases has a range of symptoms, causes, and treatments. Disease manifests typically as arrhythmia, systolic dysfunction, or diastolic dysfunc­tion. Classification systems are based on origin, anatomy, physiology, primary treat­ments, method of diagnosis, biopsy, histopa­thology, and symptomatic state.

The American Heart Association Scientific Statement5 distinguishes cardiomyopathies by degree of organ involvement. Diseases confined to the heart are defined as primary cardiomyopathy, which may have a genetic, acquired, or mixed cause. Acquired causes include inflammatory (myocarditis), stress (Takotsubo), peripartum, and tachycardia. Cardiomyopathies that are part of general­ized systemic disorders are defined as sec­ondary cardiomyopathy (Table 1).

Secondary cardiomyopathies have many causes. These include toxicity (medica­tions or alcohol), cancer therapy, infiltra­tive, storage disease, and endomyocardial, inflammatory, autoimmune, endocrine, and neurologic diseases.⁵

Evaluation of suspected cardiomyopathy begins with a history and physical focused on identifying causative factors. Selective testing, based on pretest probabilities, might include lab testing, ECG, and echocardiogra­phy, and can narrow the differential diagno­sis. When toxin-induced cardiomyopathy is suspected, withdrawing the toxin and moni­toring for improvement is recommended. The treatment and prognosis for cardiomy­opathies vary, based on the cause.⁶

Review of the literature
After 23 cases of fatal and non-fatal myo­carditis were found in a study of 8,000 patients starting clozapine,⁷ manufacturers in Australia introduced clinical guidelines. Before initiating clozapine, they recom­mended, clinicians should:
   • screen for cardiac symptoms
   • screen for a family history of heart disease
   • obtain baseline ECG
   • obtain baseline markers of myocardial damage (troponin assay and serum creatinine)
   • obtain baseline echocardiogram
   • repeat cardiac monitoring after the first and second week and then repeat in 6 months
   • maintain a high degree of vigilance for signs and symptoms of cardiac toxicity throughout clozapine treatment.^8,9

After studying 38 cases of clozap­ine-induced myocarditis—3 fatal— Ronaldson et al¹⁰ listed primary diag­nostic features as:  
   • tachycardia (heart rate >100 beats per minute)  
   • heart rate >120 beats per minute  
   • temperature >37°C  
   • chest pain  
   • troponin I/T level >2 ng/mL  
   • C-reactive protein (CRP) > 100 mg/L  
   • erythrocyte sedimentation rate >50 mm/h.

Among non-fatal cases, symptoms abated after clozapine was discontinued. In 36 of the 38 cases, symptoms emerged 14 to 22 days after clozapine was started. For tachycardia to be considered a diagnostic feature, it must persist for at least 24 hours; if the heart rate is ≥120 beats per minute, however, persistence is not a criterion. It was thought that elevated CRP might herald disease onset; the authors suggest that CRP >50 mg/L should warrant increased monitoring with daily ECG and troponin levels.

Authors’ recommendations include:  
   • measuring troponin and CRP and order an ECG at baseline and at 7, 14, 21, and 28 days  
   • examining patient for signs and symp­toms of illness at these same intervals  
   • considering chest pain or fever as an indicator of cardiomyopathy  
   • asking patients to report any illness during this 4-week period  
   • if ECG is abnormal or troponin ele­vated, decreasing clozapine pending further investigation.¹⁰ 

When medications fail
We had to discontinue Mr. C’s clozapine, which meant that the therapeutic relation­ship established between him and the psy­chology fellow became an important and, at times, the only bond between him and the medical team while olanzapine was initiated. The alliance between patient and clinician is an important factor for positive prognosis in mental health treatment.^11-13 Priebe and McCabe¹⁴ asked if the therapeu­tic relationship in psychiatry is “the basis of therapy or therapy itself?” In a review of studies that used an operationalized mea­surement of the therapeutic relationship in treating severe mental illness, the authors concluded that the therapeutic relation­ship is a reliable predictor of outcome.¹⁵

In Mr. C’s case, the psychology fellow, who also works with the Partial Hospitalization Program/Intensive Outpatient Program (PHP/IOP), joined the treatment team on the inpatient unit a few days into hospitalization. Eleven meetings, includ­ing a discharge session, were held between the psychology fellow and the patient during the inpatient hospitaliza­tion. Mr. C also participated in a daily group session, facilitated by the psychol­ogy fellow.

Maintaining recognition of the bound­ary disturbance that characterizes schizo­phrenic psychoses was important for Mr. C. As Auerhahn and Moskowitz¹⁶ wrote, the inpatient therapist can be transformed by the schizophrenia patient into the all-knowing, all-powerful early mother, which could contribute to substantial improvement in the patient’s functioning and report of symptoms, only to have the patient’s symp­toms return after discharge.

In an effort to evaluate the duration, fre­quency, and intensity of Mr. C’s symptom experience, a goal of Mr. C’s hospitalization was to attach words to his internal states, including mood and intensity of paranoid ideation. We showed Mr. C directly and indi­rectly that reporting intensification of symp­toms and decreased functioning would not result in abandonment or punishment, and worked to demonstrate through our actions that the treatment team differs from Mr. C’s view of the world as dangerous and others as hostile and omnipotent.


Treatment Developing language
Initially, Mr. C gives a number (from 1 to 10) to describe his mood, 10 being the happiest he has ever felt and 1 being the most depressed. The treatment team discusses how important it is that Mr. C know his feelings and be able to convey to others how he feels.

Over time, Mr. C is encouraged to attach a feeling word to the number, and by discharge, he stops using numbers and responds to inqui­ries about his feelings with a mood word. This practice has been reinforced with the patient in the IOP program, allowing him to continue practicing linking his internal state with feeling words.

During hospitalization, Mr. C becomes more vocal about his level of paranoia and is now more likely to seek support when he first expe­riences a paranoid thought, rather than waiting until after he is paranoid and agitated. Mr. C is encouraged to monitor his thoughts and feel­ings, and to practice coping strategies he has identified as helpful, including deep breathing, meditation, listening to music, and reminding himself that he is safe.

The treatment team responds to Mr. C’s reports of paranoid ideation (eg, “Some of the other patients were talking about me today”) by processing the affect, and hypothesizing other explanations for these events to slow down “jumping to conclusions,” which is a common part of the paranoid experience.¹⁷ Additionally, all meetings with the cardiology team are processed and Mr. C receives psychoeduca­tion about his heart function. Joint sessions with the psychiatry resident and psychology fellow allow Mr. C to ask medical questions and immediately process his reactions, which likely ameliorated his anxiety and allowed him to continue connecting with, identifying, and verbalizing his internal experiences. Given his history of paranoia, sessions also showed that Mr. C is an active participant in his treatment, with the hope of lessening his belief that bad things happen to him and that they are out of his control.

We maintain frequent contact with Mr. C’s parents to update them on their son’s function­ing and to discuss treatment interventions that were helpful and the family could implement when Mr. C returns home. Discharge medica­tions are discussed.

After 24 days in the inpatient unit, Mr. C is discharged to the IOP program. The psychology fellow walks Mr. C to the IOP program, where he transitioned immediately from inpatient to the IOP daily schedule of groups and an appointment with the program psychiatrist. The psychology fellow also arranged for and participated in the family meeting with Mr. C’s parents, sister, and treatment providers in the IOP program after his first day back at the IOP.

Throughout his hospitalization, Mr. C had no symptoms of cardiomyopathy, without exercise intolerance, shortness of breath, fatigue, or fever. He is discharged with follow-up care at his outpatient program at the PHP level of care and a follow-up echocardiogram and cardiology appointment are scheduled for 6 weeks later.

The authors' observations
Throughout Mr. C’s hospitalization, the intersections among psychiatry, psychol­ogy, cardiology, and internal medicine were apparent and necessary for treat­ment. No one specialty was able to com­pletely direct this patient’s care without the expertise of, and input from, others. When it looked like all medications had failed, the relationship between the patient and the psychology fellow and the appli­cation of previously learned coping strate­gies prevented acute decompensation.

Clozapine is FDA-approved for treatment-resistant schizophrenia and often is a last resort to help patients remain sta­ble. When clozapine is chosen, it is impor­tant to be aware of its side-effect profile (Table 2,¹ and Table 3,^1-3) and the need for monitoring. The importance of relying on colleagues from other specialties to assist in the effective monitoring process cannot be overstated. This multidisciplinary team ensured that Mr. C did not experience acute decompensation during this process. Cardiac function improved, with an LVEF of 50% after clozapine was discontinued. Mr. C has not needed hospitalization again.

Follow-up appointment with cardiology and repeat echocardiography were scheduled for 6 weeks after discharge. The follow-up echocardiogram showed improvement (LVEF, 50%). Mr. C continues to do well and remains a client at the IOP program.

Bottom Line
Clozapine often is used as a last resort for patients with treatment-resistant schizophrenia, but its side-effect profile requires careful management and monitoring. If a patient taking clozapine shows tachycardia, consider cardiomyopathy. Evaluation might include lab testing, electrocardiography, and echocardiography. Symptoms often resolve when clozapine is discontinued.

Related Resources
• Citrome L. Clozapine for schizophrenia: life-threatening or life-saving treatment? Current Psychiatry. 2009;8(12):56-63.
• Layland JJ, Liew D, Prior DL. Clozapine-induced cardiotoxicity: a clinical update. Med J Aust. 2009;190(4):190-192.

Drug Brand Names
Benztropine • Cogentin               Fluphenazine • Prolixin
Chlorpromazine • Thorazine        Haloperidol • Haldol
Citalopram • Celexa                    Lorazepam • Ativan
Clonazepam • Klonopin               Metoprolol • Lopressor
Clozapine • Clozaril                    Olanzapine • Zyprexa
Duloxetine • Cymbalta                Quetiapine • Seroquel
Escitalopram • Lexapro               Risperidone • Risperdal

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

Series Editor: Arthur T. Skarin, MD, FACP, FCCP

Primary central nervous system tumors are relatively rare, but they can cause significant morbidity. They are also among the most lethal of all neoplasms. Brain tumors are the second most common cause of death due to intracranial disease, second only to stroke. The estimated annual incidence of primary brain tumors is approximately 21 per 100,000 individuals in the United States. The incidence of brain tumors varies by gender, age, race, ethnicity, and geography and has increased over time. Gliomas and germ cell tumors are more common in men, whereas meningiomas are twice as common in women. The only validated environmental risk factor for primary brain tumors is exposure to ionizing radiation.

To read the full article in PDF:

Click here

Series Editor: Arthur T. Skarin, MD, FACP, FCCP

Primary central nervous system tumors are relatively rare, but they can cause significant morbidity. They are also among the most lethal of all neoplasms. Brain tumors are the second most common cause of death due to intracranial disease, second only to stroke. The estimated annual incidence of primary brain tumors is approximately 21 per 100,000 individuals in the United States. The incidence of brain tumors varies by gender, age, race, ethnicity, and geography and has increased over time. Gliomas and germ cell tumors are more common in men, whereas meningiomas are twice as common in women. The only validated environmental risk factor for primary brain tumors is exposure to ionizing radiation.

To read the full article in PDF:

Click here

Series Editor: Arthur T. Skarin, MD, FACP, FCCP

Primary central nervous system tumors are relatively rare, but they can cause significant morbidity. They are also among the most lethal of all neoplasms. Brain tumors are the second most common cause of death due to intracranial disease, second only to stroke. The estimated annual incidence of primary brain tumors is approximately 21 per 100,000 individuals in the United States. The incidence of brain tumors varies by gender, age, race, ethnicity, and geography and has increased over time. Gliomas and germ cell tumors are more common in men, whereas meningiomas are twice as common in women. The only validated environmental risk factor for primary brain tumors is exposure to ionizing radiation.

To read the full article in PDF:

Click here

Case Forgetful and depressed
Mr. B, age 55, has been a patient at our clinic for 8 years, where he has been under our care for treatment-resistant depression and opi­oid addiction [read about earlier events in his case in “A life of drugs and ‘downtime’” Current Psychiatry, August 2007, p. 98-103].¹ He reports feeling intermittently depressed since his teens and has had 3 near-fatal suicide attempts.

Three years ago, Mr. B reported severe depressive symptoms and short-term memory loss, which undermined his job performance and contributed to interpersonal conflict with his wife. The episode has been continuously severe for 10 months. He was taking sertra­line, 150 mg/d, and duloxetine, 60 mg/d, for major depressive disorder (MDD) and sublin­gual buprenorphine/naloxone, 20 mg/d, for opioid dependence, which was in sustained full remission.² Mr. B scored 24/30 in the Mini- Mental State Examination, indicating mild cognitive deficit. Negative results of a com­plete routine laboratory workup rule out an organic cause for his deteriorating cognition.

How would you diagnose Mr. B’s condition at this point?
   a) treatment-resistant MDD
   b) cognitive disorder not otherwise specified
   c) opioid use disorder
   d) a and c

The authors' observations
Relapse is a core feature of substance use dis­orders (SUDs) that contributes significantly to the longstanding functional impairment in patients with a mood disorder. With the relapse rate following substance use treat­ment estimated at more than 60%,³ SUDs often are described as chronic relapsing conditions. In chronic stress, corticotropin-releasing factor (CRF) is over-sensitized; we believe that acute stress can cause an unhealthy response to an over-expressed CRF system.

To prevent relapse in patients with an over-expressed CRF system, it is crucial to manage stress. One treatment option to con­sider in preventing relapse is mindfulness-based interventions (MBI). Mindfulness has been described as “paying attention in a particular way: on purpose, in the present moment, and non-judgmentally.” In the event of a relapse, awareness and acceptance fostered by mindfulness may aid in recogniz­ing and minimizing unhealthy responses, such as negative thinking that can increase the risk of relapse.

History Remission, then relapse
Mr. B was admitted to inpatient psychiatric unit after a near-fatal suicide attempt 8 years ago and given a diagnosis of MDD recurrent, severe with­out psychotic features. Trials of sertraline, bupro­pion, trazodone, quetiapine, and aripiprazole were ineffective.

Before he presented to our clinic 8 years ago, Mr. B had been taking venlafaxine, 75 mg/d, and mirtazapine, 30 mg at bedtime. His previous outpatient psychiatrist added methylphenidate, 40 mg/d, to augment the antidepressants, but this did not alleviate Mr. B’s depression.

At age 40, he entered a methadone pro­gram, began working steadily, and got married. Five years later, he stopped methadone (it is unclear from the chart if his psychiatrist initiated this change). Mr. B’s depression persisted while using opioids and became worse after stopping methadone.

We considered electroconvulsive therapy (ECT) at the time, but switching the anti­depressant or starting ECT would address only the persistent depression; buprenor­phine/naloxone would target opioid crav­ing. We started a trial of buprenorphine/ naloxone, a partial μ opioid agonist and ĸ opioid antagonist; ĸ receptor antagonism serves as an antidepressant. He responded well to augmentation of his current regimen (mirtazapine, 30 mg at bedtime, and venlafax­ine, 225 mg/d) with buprenorphine/naloxone, 16 mg/d.^4,5 he reported no anergia and said he felt more motivated and productive.

Mr. B took buprenorphine/naloxone, 32 mg/d, for 4 years until, because of concern for daytime sedation, his outpatient psychia­trist reduced the dose to 20 mg/d. With the lower dosage of buprenorphine/naloxone ini­tiated 4 years ago, Mr. B reported irritability, anhedonia, insomnia, increased self-criticism, and decreased self-care.

How would you treat Mr. B’s depression at this point?
   a) switch to a daytime antidepressant
   b) adjust the dosage of buprenorphine/ naloxone
   c) try ECT
   d) try mindfulness-based cognitive therapy

The authors’ observations
Mindfulness meditation (MM) is a medi­tation practice that cultivates awareness. While learning MM, the practitioner inten­tionally focuses on awareness—a way of purposely paying attention to the present moment, non-judgmentally, to nurture calmness and self-acceptance. Being con­scious of what the practitioner is doing while he is doing it is the core of mindful­ness practice.⁶

Mindfulness-based interventions. We rec­ommended the following forms of MBI to treat Mr. B:  
   • Mindfulness-based cognitive therapy (MBCT). MBCT is designed to help people who suffer repeated bouts of depression and chronic unhappiness. It combines the ideas of cognitive-behavioral therapy (CBT) with MM practices and attitudes based on culti­vating mindfulness.⁷  
   • Mindfulness-based stress reduction (MBSR). MBSR brings together MM and physical/breathing exercises to relax body and mind.⁶

Chronic stress and drug addiction
The literature demonstrates a significant association between acute and chronic stress and motivation to abuse substances. Stress mobilizes the CRF system to stimulate the hypothalamic-pituitary-adrenal (HPA) axis, and extra-hypothalamic actions of CRF can kindle the neuronal circuits responsible for stress-induced anxiety, dysphoria, and drug abuse behaviors.⁸

A study to evaluate effects of mindful­ness on young adult romantic partners’ HPA responses to conflict stress showed that MM has sex-specific effects on neu­roendocrine response to interpersonal stress.⁹ Research has shown that MM practice can decrease stress, increase well-being, and affect brain structure and func­tion.¹⁰ Meta-analysis of studies of animal models and humans described how spe­cific interventions intended to encourage pro-social behavior and well-being might produce plasticity-related changes in the brain.¹¹ This work concluded that, by tak­ing responsibility for the mind and the brain by participating in regular mental exercise, plastic changes in the brain pro­moted could produce lasting beneficial consequences for social and emotional behavior.¹¹

What could be perpetuating Mr. B’s depression?
   a) psychosocial stressors
   b) over-expression of CRF gene due to psychosocial stressors
   c) a and b

Treatment Mindfulness practice
Mr. B was started on CBT to manage anxiety symptoms and cognitive distortions. After 2 months, he reports no improvements in anx­iety, depression, or cognitive distortions.

We consider MBI for Mr. B, which was devel­oped by Segal et al⁷ to help prevent relapse of depression and gain the benefits of MM. There is evidence that MBI can prevent relapse of SUDs.¹² Mr. B’s MBI practice is based on MBCT, as outlined by Segal et al.⁷ He attends biweekly, 45-minute therapy sessions at our outpatient clinic. During these sessions, MM is practiced for 10 minutes under a psychiatrist’s supervision. The MBCT manual calls for 45 minutes of MM practice but, during the 10-minute ses­sion, we instruct Mr. B to independently prac­tice MM at home. Mr. B is assessed for relapses, and drug cravings; a urine toxicology screen is performed every 6 months.

We score Mr. B’s day-to-day level of mindful­ness experience, depression, and anxiety symp­toms before starting MBI and after 8 weeks of practicing MBI (Figure 1). Mindfulness is scored with the Mindful Attention Awareness Scale (MAAS), a valid, reliable scale.¹³ The MAAS comprises 15 items designed to reflect mindfulness in everyday experiences, includ­ing awareness and attention to thoughts, emotions, actions, and physical states. Items are rated on a 6-point Likert-type scale of 1 (“almost never”) to 6 (“almost always”). A typ­ical item on MAAS is “I find myself doing things without paying attention.”

Depression and anxiety symptoms are mea­sured using the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder Scale-7 (GAD-7) Item Scale. Mr. B scores a 23 on PHQ-9, indicating severe depression (he reports that he finds it ‘‘extremely difficult” to function) (Figure 2).

There is evidence to support the use of PHQ-9 for measurement-based care in the psychiatric population.¹⁴ PHQ-9 does not capture anxiety, which is a strong predicator of suicidal behavior; therefore, we use GAD-7 to measure the sever­ity of Mr. B’s subjective anxiety.¹⁵ He scores a 14 on GAD-7 and reports that it is “very difficult” for him to function.

Mr. B is retested after 8 weeks. During those 8 weeks, he was instructed by audio guidance in body scan technique. He practices MBI tech­niques for 45 minutes every morning between 5 AM and 6 AM.⁶

After 3 months of MBI, Mr. B is promoted at work and reports that he is handling more responsibilities. He is stressed at his new job and, subsequently, experiences a relapse of anxiety symptoms and insomnia. Partly, this is because Mr. B is not able to consistently practice MBI and misses a few outpatient appointments. In the meantime, he has difficulties with sleep and con­centration and anxiety symptoms.

The treating psychiatrist reassures Mr. B and provides support to restart MBI. He man­ages to attend outpatient clinic appointments consistently and shows interest in practicing MBI daily. Later, he reports practicing MBI con­sistently along with his routine treatment at our clinic. The timeline of Mr. B’s history and treatment are summarized in Figure 3.

The authors’ observations
Mr. B’s CRF may have been down-regulated by MBI. This, in turn, decreased his depres­sive and anxiety symptoms, thereby helping to prevent relapse of depression and sub­stance abuse. He benefited from MBI prac­tices in several areas of his life, which can be described with the acronym FACES.¹⁰

Flexible. Mr. B became more cogni­tively flexible. He started to realize that “thoughts are not facts.”⁷ This change was reflected in his relationship with his wife. His wife came to one of our sessions because she noticed significant change in his attitude toward her. Their marriage of 15 years was riddled with conflict and his wife was excited to see the improvement he achieved within the short time of prac­ticing MBI.

Adaptive. He became more adaptive to changes at the work place and reported that he is enjoying his work. This is a change from his feeling that his job was a burden, as he observed in our earlier sessions.

Coherent. He became more cognitively rational. He reported improvement in his memory and concentration. Five months after initiation of MBI and MM training, he was promoted and could cope with the stress at work.

Energized. Initially, he had said that he never wanted to be part of his extended family. During a session toward the end of the treatment, he mentioned that he made an effort to contact his extended family and reported that he found it more meaningful now to be reconnected with them.

Stable. He became more emotionally stable. He did not have the urge to use drugs and he did not relapse.

As we hypothesized, for Mr. B, practic­ing MBI was associated with abstinence from substance use, increased mindfulness, acceptance of mental health problems, and remission of psychiatric symptoms.

Bottom Line
Mindfulness-based interventions provide patients with tools to target symptoms such as poor affect regulation, poor impulse control, and rumination. Evidence supports that using MBI in addition to the usual treatment can prevent relapse of a substance use disorder.

Related Resources
• Sipe WE, Eisendrath SJ. Mindfulness-based cognitive therapy: theory and practice. Can J Psychiatry. 2012;57(2):63-69.• Lau MA, Grabovac AD. Mindfulness-based interventions: Effective for depression and anxiety. Current Psychiatry. 2009;8(12):39-55.

Drug Brand Names
Aripiprazole • Abilify                               Mirtazapine • Remeron
Buprenorphine/naloxone •                       Quetiapine • Seroquel
Suboxone              
Bupropion • Wellbutrin                            Sertraline • Zoloft
Duloxetine • Cymbalta                            Trazodone • Desyrel
Methadone • Dolophine                           Venlafaxine • Effexor
Methylphenidate • Ritalin, Concerta

Acknowledgement
The manuscript preparation of Maju Mathew Koola, MD, DPM was supported by the NIMH T32 grant MH067533-07 (PI: William T. Carpenter, MD) and the American Psychiatric Association/Kempf Fund Award for Research Development in Psychobiological Psychiatry (PI: Koola). The treating Psychiatrist PGY-5 (2011-2012) Addiction Psychiatry fellow (Dr. Varghese) was supervised by Dr. Eiger. Drs. Koola and Varghese contributed equally with the manuscript preparation and are joint first authors. Dr. Varghese received a second prize for a poster presentation of this case re­port at the 34th Indo American Psychiatric Association meeting in San Francisco, CA, May 19, 2013. Christina Mathew, MD, also contributed with manuscript preparation.

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

Case Forgetful and depressed
Mr. B, age 55, has been a patient at our clinic for 8 years, where he has been under our care for treatment-resistant depression and opi­oid addiction [read about earlier events in his case in “A life of drugs and ‘downtime’” Current Psychiatry, August 2007, p. 98-103].¹ He reports feeling intermittently depressed since his teens and has had 3 near-fatal suicide attempts.

Three years ago, Mr. B reported severe depressive symptoms and short-term memory loss, which undermined his job performance and contributed to interpersonal conflict with his wife. The episode has been continuously severe for 10 months. He was taking sertra­line, 150 mg/d, and duloxetine, 60 mg/d, for major depressive disorder (MDD) and sublin­gual buprenorphine/naloxone, 20 mg/d, for opioid dependence, which was in sustained full remission.² Mr. B scored 24/30 in the Mini- Mental State Examination, indicating mild cognitive deficit. Negative results of a com­plete routine laboratory workup rule out an organic cause for his deteriorating cognition.

How would you diagnose Mr. B’s condition at this point?
   a) treatment-resistant MDD
   b) cognitive disorder not otherwise specified
   c) opioid use disorder
   d) a and c

The authors' observations
Relapse is a core feature of substance use dis­orders (SUDs) that contributes significantly to the longstanding functional impairment in patients with a mood disorder. With the relapse rate following substance use treat­ment estimated at more than 60%,³ SUDs often are described as chronic relapsing conditions. In chronic stress, corticotropin-releasing factor (CRF) is over-sensitized; we believe that acute stress can cause an unhealthy response to an over-expressed CRF system.

To prevent relapse in patients with an over-expressed CRF system, it is crucial to manage stress. One treatment option to con­sider in preventing relapse is mindfulness-based interventions (MBI). Mindfulness has been described as “paying attention in a particular way: on purpose, in the present moment, and non-judgmentally.” In the event of a relapse, awareness and acceptance fostered by mindfulness may aid in recogniz­ing and minimizing unhealthy responses, such as negative thinking that can increase the risk of relapse.

History Remission, then relapse
Mr. B was admitted to inpatient psychiatric unit after a near-fatal suicide attempt 8 years ago and given a diagnosis of MDD recurrent, severe with­out psychotic features. Trials of sertraline, bupro­pion, trazodone, quetiapine, and aripiprazole were ineffective.

Before he presented to our clinic 8 years ago, Mr. B had been taking venlafaxine, 75 mg/d, and mirtazapine, 30 mg at bedtime. His previous outpatient psychiatrist added methylphenidate, 40 mg/d, to augment the antidepressants, but this did not alleviate Mr. B’s depression.

At age 40, he entered a methadone pro­gram, began working steadily, and got married. Five years later, he stopped methadone (it is unclear from the chart if his psychiatrist initiated this change). Mr. B’s depression persisted while using opioids and became worse after stopping methadone.

We considered electroconvulsive therapy (ECT) at the time, but switching the anti­depressant or starting ECT would address only the persistent depression; buprenor­phine/naloxone would target opioid crav­ing. We started a trial of buprenorphine/ naloxone, a partial μ opioid agonist and ĸ opioid antagonist; ĸ receptor antagonism serves as an antidepressant. He responded well to augmentation of his current regimen (mirtazapine, 30 mg at bedtime, and venlafax­ine, 225 mg/d) with buprenorphine/naloxone, 16 mg/d.^4,5 he reported no anergia and said he felt more motivated and productive.

Mr. B took buprenorphine/naloxone, 32 mg/d, for 4 years until, because of concern for daytime sedation, his outpatient psychia­trist reduced the dose to 20 mg/d. With the lower dosage of buprenorphine/naloxone ini­tiated 4 years ago, Mr. B reported irritability, anhedonia, insomnia, increased self-criticism, and decreased self-care.

How would you treat Mr. B’s depression at this point?
   a) switch to a daytime antidepressant
   b) adjust the dosage of buprenorphine/ naloxone
   c) try ECT
   d) try mindfulness-based cognitive therapy

The authors’ observations
Mindfulness meditation (MM) is a medi­tation practice that cultivates awareness. While learning MM, the practitioner inten­tionally focuses on awareness—a way of purposely paying attention to the present moment, non-judgmentally, to nurture calmness and self-acceptance. Being con­scious of what the practitioner is doing while he is doing it is the core of mindful­ness practice.⁶

Mindfulness-based interventions. We rec­ommended the following forms of MBI to treat Mr. B:  
   • Mindfulness-based cognitive therapy (MBCT). MBCT is designed to help people who suffer repeated bouts of depression and chronic unhappiness. It combines the ideas of cognitive-behavioral therapy (CBT) with MM practices and attitudes based on culti­vating mindfulness.⁷  
   • Mindfulness-based stress reduction (MBSR). MBSR brings together MM and physical/breathing exercises to relax body and mind.⁶

Chronic stress and drug addiction
The literature demonstrates a significant association between acute and chronic stress and motivation to abuse substances. Stress mobilizes the CRF system to stimulate the hypothalamic-pituitary-adrenal (HPA) axis, and extra-hypothalamic actions of CRF can kindle the neuronal circuits responsible for stress-induced anxiety, dysphoria, and drug abuse behaviors.⁸

A study to evaluate effects of mindful­ness on young adult romantic partners’ HPA responses to conflict stress showed that MM has sex-specific effects on neu­roendocrine response to interpersonal stress.⁹ Research has shown that MM practice can decrease stress, increase well-being, and affect brain structure and func­tion.¹⁰ Meta-analysis of studies of animal models and humans described how spe­cific interventions intended to encourage pro-social behavior and well-being might produce plasticity-related changes in the brain.¹¹ This work concluded that, by tak­ing responsibility for the mind and the brain by participating in regular mental exercise, plastic changes in the brain pro­moted could produce lasting beneficial consequences for social and emotional behavior.¹¹

What could be perpetuating Mr. B’s depression?
   a) psychosocial stressors
   b) over-expression of CRF gene due to psychosocial stressors
   c) a and b

Treatment Mindfulness practice
Mr. B was started on CBT to manage anxiety symptoms and cognitive distortions. After 2 months, he reports no improvements in anx­iety, depression, or cognitive distortions.

We consider MBI for Mr. B, which was devel­oped by Segal et al⁷ to help prevent relapse of depression and gain the benefits of MM. There is evidence that MBI can prevent relapse of SUDs.¹² Mr. B’s MBI practice is based on MBCT, as outlined by Segal et al.⁷ He attends biweekly, 45-minute therapy sessions at our outpatient clinic. During these sessions, MM is practiced for 10 minutes under a psychiatrist’s supervision. The MBCT manual calls for 45 minutes of MM practice but, during the 10-minute ses­sion, we instruct Mr. B to independently prac­tice MM at home. Mr. B is assessed for relapses, and drug cravings; a urine toxicology screen is performed every 6 months.

We score Mr. B’s day-to-day level of mindful­ness experience, depression, and anxiety symp­toms before starting MBI and after 8 weeks of practicing MBI (Figure 1). Mindfulness is scored with the Mindful Attention Awareness Scale (MAAS), a valid, reliable scale.¹³ The MAAS comprises 15 items designed to reflect mindfulness in everyday experiences, includ­ing awareness and attention to thoughts, emotions, actions, and physical states. Items are rated on a 6-point Likert-type scale of 1 (“almost never”) to 6 (“almost always”). A typ­ical item on MAAS is “I find myself doing things without paying attention.”

Depression and anxiety symptoms are mea­sured using the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder Scale-7 (GAD-7) Item Scale. Mr. B scores a 23 on PHQ-9, indicating severe depression (he reports that he finds it ‘‘extremely difficult” to function) (Figure 2).

There is evidence to support the use of PHQ-9 for measurement-based care in the psychiatric population.¹⁴ PHQ-9 does not capture anxiety, which is a strong predicator of suicidal behavior; therefore, we use GAD-7 to measure the sever­ity of Mr. B’s subjective anxiety.¹⁵ He scores a 14 on GAD-7 and reports that it is “very difficult” for him to function.

Mr. B is retested after 8 weeks. During those 8 weeks, he was instructed by audio guidance in body scan technique. He practices MBI tech­niques for 45 minutes every morning between 5 AM and 6 AM.⁶

After 3 months of MBI, Mr. B is promoted at work and reports that he is handling more responsibilities. He is stressed at his new job and, subsequently, experiences a relapse of anxiety symptoms and insomnia. Partly, this is because Mr. B is not able to consistently practice MBI and misses a few outpatient appointments. In the meantime, he has difficulties with sleep and con­centration and anxiety symptoms.

The treating psychiatrist reassures Mr. B and provides support to restart MBI. He man­ages to attend outpatient clinic appointments consistently and shows interest in practicing MBI daily. Later, he reports practicing MBI con­sistently along with his routine treatment at our clinic. The timeline of Mr. B’s history and treatment are summarized in Figure 3.

The authors’ observations
Mr. B’s CRF may have been down-regulated by MBI. This, in turn, decreased his depres­sive and anxiety symptoms, thereby helping to prevent relapse of depression and sub­stance abuse. He benefited from MBI prac­tices in several areas of his life, which can be described with the acronym FACES.¹⁰

Flexible. Mr. B became more cogni­tively flexible. He started to realize that “thoughts are not facts.”⁷ This change was reflected in his relationship with his wife. His wife came to one of our sessions because she noticed significant change in his attitude toward her. Their marriage of 15 years was riddled with conflict and his wife was excited to see the improvement he achieved within the short time of prac­ticing MBI.

Adaptive. He became more adaptive to changes at the work place and reported that he is enjoying his work. This is a change from his feeling that his job was a burden, as he observed in our earlier sessions.

Coherent. He became more cognitively rational. He reported improvement in his memory and concentration. Five months after initiation of MBI and MM training, he was promoted and could cope with the stress at work.

Energized. Initially, he had said that he never wanted to be part of his extended family. During a session toward the end of the treatment, he mentioned that he made an effort to contact his extended family and reported that he found it more meaningful now to be reconnected with them.

Stable. He became more emotionally stable. He did not have the urge to use drugs and he did not relapse.

As we hypothesized, for Mr. B, practic­ing MBI was associated with abstinence from substance use, increased mindfulness, acceptance of mental health problems, and remission of psychiatric symptoms.

Bottom Line
Mindfulness-based interventions provide patients with tools to target symptoms such as poor affect regulation, poor impulse control, and rumination. Evidence supports that using MBI in addition to the usual treatment can prevent relapse of a substance use disorder.

Related Resources
• Sipe WE, Eisendrath SJ. Mindfulness-based cognitive therapy: theory and practice. Can J Psychiatry. 2012;57(2):63-69.• Lau MA, Grabovac AD. Mindfulness-based interventions: Effective for depression and anxiety. Current Psychiatry. 2009;8(12):39-55.

Drug Brand Names
Aripiprazole • Abilify                               Mirtazapine • Remeron
Buprenorphine/naloxone •                       Quetiapine • Seroquel
Suboxone              
Bupropion • Wellbutrin                            Sertraline • Zoloft
Duloxetine • Cymbalta                            Trazodone • Desyrel
Methadone • Dolophine                           Venlafaxine • Effexor
Methylphenidate • Ritalin, Concerta

Acknowledgement
The manuscript preparation of Maju Mathew Koola, MD, DPM was supported by the NIMH T32 grant MH067533-07 (PI: William T. Carpenter, MD) and the American Psychiatric Association/Kempf Fund Award for Research Development in Psychobiological Psychiatry (PI: Koola). The treating Psychiatrist PGY-5 (2011-2012) Addiction Psychiatry fellow (Dr. Varghese) was supervised by Dr. Eiger. Drs. Koola and Varghese contributed equally with the manuscript preparation and are joint first authors. Dr. Varghese received a second prize for a poster presentation of this case re­port at the 34th Indo American Psychiatric Association meeting in San Francisco, CA, May 19, 2013. Christina Mathew, MD, also contributed with manuscript preparation.

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

Case Forgetful and depressed
Mr. B, age 55, has been a patient at our clinic for 8 years, where he has been under our care for treatment-resistant depression and opi­oid addiction [read about earlier events in his case in “A life of drugs and ‘downtime’” Current Psychiatry, August 2007, p. 98-103].¹ He reports feeling intermittently depressed since his teens and has had 3 near-fatal suicide attempts.

Three years ago, Mr. B reported severe depressive symptoms and short-term memory loss, which undermined his job performance and contributed to interpersonal conflict with his wife. The episode has been continuously severe for 10 months. He was taking sertra­line, 150 mg/d, and duloxetine, 60 mg/d, for major depressive disorder (MDD) and sublin­gual buprenorphine/naloxone, 20 mg/d, for opioid dependence, which was in sustained full remission.² Mr. B scored 24/30 in the Mini- Mental State Examination, indicating mild cognitive deficit. Negative results of a com­plete routine laboratory workup rule out an organic cause for his deteriorating cognition.

How would you diagnose Mr. B’s condition at this point?
   a) treatment-resistant MDD
   b) cognitive disorder not otherwise specified
   c) opioid use disorder
   d) a and c

The authors' observations
Relapse is a core feature of substance use dis­orders (SUDs) that contributes significantly to the longstanding functional impairment in patients with a mood disorder. With the relapse rate following substance use treat­ment estimated at more than 60%,³ SUDs often are described as chronic relapsing conditions. In chronic stress, corticotropin-releasing factor (CRF) is over-sensitized; we believe that acute stress can cause an unhealthy response to an over-expressed CRF system.

To prevent relapse in patients with an over-expressed CRF system, it is crucial to manage stress. One treatment option to con­sider in preventing relapse is mindfulness-based interventions (MBI). Mindfulness has been described as “paying attention in a particular way: on purpose, in the present moment, and non-judgmentally.” In the event of a relapse, awareness and acceptance fostered by mindfulness may aid in recogniz­ing and minimizing unhealthy responses, such as negative thinking that can increase the risk of relapse.

History Remission, then relapse
Mr. B was admitted to inpatient psychiatric unit after a near-fatal suicide attempt 8 years ago and given a diagnosis of MDD recurrent, severe with­out psychotic features. Trials of sertraline, bupro­pion, trazodone, quetiapine, and aripiprazole were ineffective.

Before he presented to our clinic 8 years ago, Mr. B had been taking venlafaxine, 75 mg/d, and mirtazapine, 30 mg at bedtime. His previous outpatient psychiatrist added methylphenidate, 40 mg/d, to augment the antidepressants, but this did not alleviate Mr. B’s depression.

At age 40, he entered a methadone pro­gram, began working steadily, and got married. Five years later, he stopped methadone (it is unclear from the chart if his psychiatrist initiated this change). Mr. B’s depression persisted while using opioids and became worse after stopping methadone.

We considered electroconvulsive therapy (ECT) at the time, but switching the anti­depressant or starting ECT would address only the persistent depression; buprenor­phine/naloxone would target opioid crav­ing. We started a trial of buprenorphine/ naloxone, a partial μ opioid agonist and ĸ opioid antagonist; ĸ receptor antagonism serves as an antidepressant. He responded well to augmentation of his current regimen (mirtazapine, 30 mg at bedtime, and venlafax­ine, 225 mg/d) with buprenorphine/naloxone, 16 mg/d.^4,5 he reported no anergia and said he felt more motivated and productive.

Mr. B took buprenorphine/naloxone, 32 mg/d, for 4 years until, because of concern for daytime sedation, his outpatient psychia­trist reduced the dose to 20 mg/d. With the lower dosage of buprenorphine/naloxone ini­tiated 4 years ago, Mr. B reported irritability, anhedonia, insomnia, increased self-criticism, and decreased self-care.

How would you treat Mr. B’s depression at this point?
   a) switch to a daytime antidepressant
   b) adjust the dosage of buprenorphine/ naloxone
   c) try ECT
   d) try mindfulness-based cognitive therapy

The authors’ observations
Mindfulness meditation (MM) is a medi­tation practice that cultivates awareness. While learning MM, the practitioner inten­tionally focuses on awareness—a way of purposely paying attention to the present moment, non-judgmentally, to nurture calmness and self-acceptance. Being con­scious of what the practitioner is doing while he is doing it is the core of mindful­ness practice.⁶

Mindfulness-based interventions. We rec­ommended the following forms of MBI to treat Mr. B:  
   • Mindfulness-based cognitive therapy (MBCT). MBCT is designed to help people who suffer repeated bouts of depression and chronic unhappiness. It combines the ideas of cognitive-behavioral therapy (CBT) with MM practices and attitudes based on culti­vating mindfulness.⁷  
   • Mindfulness-based stress reduction (MBSR). MBSR brings together MM and physical/breathing exercises to relax body and mind.⁶

Chronic stress and drug addiction
The literature demonstrates a significant association between acute and chronic stress and motivation to abuse substances. Stress mobilizes the CRF system to stimulate the hypothalamic-pituitary-adrenal (HPA) axis, and extra-hypothalamic actions of CRF can kindle the neuronal circuits responsible for stress-induced anxiety, dysphoria, and drug abuse behaviors.⁸

A study to evaluate effects of mindful­ness on young adult romantic partners’ HPA responses to conflict stress showed that MM has sex-specific effects on neu­roendocrine response to interpersonal stress.⁹ Research has shown that MM practice can decrease stress, increase well-being, and affect brain structure and func­tion.¹⁰ Meta-analysis of studies of animal models and humans described how spe­cific interventions intended to encourage pro-social behavior and well-being might produce plasticity-related changes in the brain.¹¹ This work concluded that, by tak­ing responsibility for the mind and the brain by participating in regular mental exercise, plastic changes in the brain pro­moted could produce lasting beneficial consequences for social and emotional behavior.¹¹

What could be perpetuating Mr. B’s depression?
   a) psychosocial stressors
   b) over-expression of CRF gene due to psychosocial stressors
   c) a and b

Treatment Mindfulness practice
Mr. B was started on CBT to manage anxiety symptoms and cognitive distortions. After 2 months, he reports no improvements in anx­iety, depression, or cognitive distortions.

We consider MBI for Mr. B, which was devel­oped by Segal et al⁷ to help prevent relapse of depression and gain the benefits of MM. There is evidence that MBI can prevent relapse of SUDs.¹² Mr. B’s MBI practice is based on MBCT, as outlined by Segal et al.⁷ He attends biweekly, 45-minute therapy sessions at our outpatient clinic. During these sessions, MM is practiced for 10 minutes under a psychiatrist’s supervision. The MBCT manual calls for 45 minutes of MM practice but, during the 10-minute ses­sion, we instruct Mr. B to independently prac­tice MM at home. Mr. B is assessed for relapses, and drug cravings; a urine toxicology screen is performed every 6 months.

We score Mr. B’s day-to-day level of mindful­ness experience, depression, and anxiety symp­toms before starting MBI and after 8 weeks of practicing MBI (Figure 1). Mindfulness is scored with the Mindful Attention Awareness Scale (MAAS), a valid, reliable scale.¹³ The MAAS comprises 15 items designed to reflect mindfulness in everyday experiences, includ­ing awareness and attention to thoughts, emotions, actions, and physical states. Items are rated on a 6-point Likert-type scale of 1 (“almost never”) to 6 (“almost always”). A typ­ical item on MAAS is “I find myself doing things without paying attention.”

Depression and anxiety symptoms are mea­sured using the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder Scale-7 (GAD-7) Item Scale. Mr. B scores a 23 on PHQ-9, indicating severe depression (he reports that he finds it ‘‘extremely difficult” to function) (Figure 2).

There is evidence to support the use of PHQ-9 for measurement-based care in the psychiatric population.¹⁴ PHQ-9 does not capture anxiety, which is a strong predicator of suicidal behavior; therefore, we use GAD-7 to measure the sever­ity of Mr. B’s subjective anxiety.¹⁵ He scores a 14 on GAD-7 and reports that it is “very difficult” for him to function.

Mr. B is retested after 8 weeks. During those 8 weeks, he was instructed by audio guidance in body scan technique. He practices MBI tech­niques for 45 minutes every morning between 5 AM and 6 AM.⁶

After 3 months of MBI, Mr. B is promoted at work and reports that he is handling more responsibilities. He is stressed at his new job and, subsequently, experiences a relapse of anxiety symptoms and insomnia. Partly, this is because Mr. B is not able to consistently practice MBI and misses a few outpatient appointments. In the meantime, he has difficulties with sleep and con­centration and anxiety symptoms.

The treating psychiatrist reassures Mr. B and provides support to restart MBI. He man­ages to attend outpatient clinic appointments consistently and shows interest in practicing MBI daily. Later, he reports practicing MBI con­sistently along with his routine treatment at our clinic. The timeline of Mr. B’s history and treatment are summarized in Figure 3.

The authors’ observations
Mr. B’s CRF may have been down-regulated by MBI. This, in turn, decreased his depres­sive and anxiety symptoms, thereby helping to prevent relapse of depression and sub­stance abuse. He benefited from MBI prac­tices in several areas of his life, which can be described with the acronym FACES.¹⁰

Flexible. Mr. B became more cogni­tively flexible. He started to realize that “thoughts are not facts.”⁷ This change was reflected in his relationship with his wife. His wife came to one of our sessions because she noticed significant change in his attitude toward her. Their marriage of 15 years was riddled with conflict and his wife was excited to see the improvement he achieved within the short time of prac­ticing MBI.

Adaptive. He became more adaptive to changes at the work place and reported that he is enjoying his work. This is a change from his feeling that his job was a burden, as he observed in our earlier sessions.

Coherent. He became more cognitively rational. He reported improvement in his memory and concentration. Five months after initiation of MBI and MM training, he was promoted and could cope with the stress at work.

Energized. Initially, he had said that he never wanted to be part of his extended family. During a session toward the end of the treatment, he mentioned that he made an effort to contact his extended family and reported that he found it more meaningful now to be reconnected with them.

Stable. He became more emotionally stable. He did not have the urge to use drugs and he did not relapse.

As we hypothesized, for Mr. B, practic­ing MBI was associated with abstinence from substance use, increased mindfulness, acceptance of mental health problems, and remission of psychiatric symptoms.

Bottom Line
Mindfulness-based interventions provide patients with tools to target symptoms such as poor affect regulation, poor impulse control, and rumination. Evidence supports that using MBI in addition to the usual treatment can prevent relapse of a substance use disorder.

Related Resources
• Sipe WE, Eisendrath SJ. Mindfulness-based cognitive therapy: theory and practice. Can J Psychiatry. 2012;57(2):63-69.• Lau MA, Grabovac AD. Mindfulness-based interventions: Effective for depression and anxiety. Current Psychiatry. 2009;8(12):39-55.

Drug Brand Names
Aripiprazole • Abilify                               Mirtazapine • Remeron
Buprenorphine/naloxone •                       Quetiapine • Seroquel
Suboxone              
Bupropion • Wellbutrin                            Sertraline • Zoloft
Duloxetine • Cymbalta                            Trazodone • Desyrel
Methadone • Dolophine                           Venlafaxine • Effexor
Methylphenidate • Ritalin, Concerta

Acknowledgement
The manuscript preparation of Maju Mathew Koola, MD, DPM was supported by the NIMH T32 grant MH067533-07 (PI: William T. Carpenter, MD) and the American Psychiatric Association/Kempf Fund Award for Research Development in Psychobiological Psychiatry (PI: Koola). The treating Psychiatrist PGY-5 (2011-2012) Addiction Psychiatry fellow (Dr. Varghese) was supervised by Dr. Eiger. Drs. Koola and Varghese contributed equally with the manuscript preparation and are joint first authors. Dr. Varghese received a second prize for a poster presentation of this case re­port at the 34th Indo American Psychiatric Association meeting in San Francisco, CA, May 19, 2013. Christina Mathew, MD, also contributed with manuscript preparation.

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

From the Department of Pediatrics, University of Wisconsin, Madison, WI.

Abstract

• Objective: To provide information that will assist clinicians in assessing and addressing risk for obesity-related comorbidities in adolescents.
• Methods: Review of the literature.
• Results: Childhood obesity is a major public health concern. Prevention of obesity or early detection of its health consequences are important responsibilities or opportunities for primary care clinicians. While body mass index (BMI) screening is valuable, insulin resistance and other obesity-related comorbidities can develop even when BMI falls below the 95th percentile threshold for obesity. Detailed history and physical examination can help identify comorbidities and guide diagnostic evaluation. Referral to multidisciplinary clinics specializing in childhood obesity is warranted when obesity is particularly severe, comorbidities are present at baseline, or no improvement is noted after 6 months of intense lifestyle intervention.
• Conclusion: For optimal health outcomes, management of adolescent obesity and associated comorbidities is should be adapted based on an individual’s overall risk rather than BMI alone.

Case Study

Initial Presentation

A 14-year-old Hispanic male presents for a well child check.

History and Physical Examination

The patient and his mother have no complaints or concerns. A comprehensive review of systems is positive for fatigue and snoring but is otherwise unremarkable. Past medical history is unremarkable except for mild intermittent asthma. Family history is positive for type 2 diabetes in paternal grandmother and a maternal uncle and cardiovascular disease and hypertension in multiple extended family members. Both maternal and paternal grandparents are from Mexico.

Vital signs are within normal limits. Height is 160 cm (30th percentile for age), weight is 58.4 kg (75th percentile for age), and body mass index (BMI) is 22.8 kg/m² (85th percentile for age). Blood pressure is 127/81 mm Hg (95th percentile for age and gender). Physical exam is pertinent for acanthosis nigricans on neck and axilla and nonviolaceous striae on abdomen. Waist circumference is 88 cm (90th percentile for age and ethnicity). Otherwise, physical exam is within normal limits.

• Does this child’s physical examination findings pose a cause for concern?

Yes. A key concept is that while obesity is widespread, the adverse health complications of adiposity and overnutrition affect some children much earlier and more profoundly than others. Some children exhibit adiposity-associated comorbidities even prior to meeting obesity criteria defined by BMI. Careful history and examination can help identify those most at risk for developing adiposity-associated comorbidities, prompting earlier intervention and, when appropriate, subspecialty referral.

Obesity is caused by a complex interplay of genetic, environmental, and metabolic programming, especially early in life, and lifestyle habits [1,2]. The vast majority of obesity is due to excess nutrition leading to energy imbalance, while less than 1% is due to endocrine or syndromic causes [3]. Obesity is defined as excessive body fat and is often estimated indirectly by using a surrogate marker, BMI. Diagnostically, a BMI > 95th percentile for age on sex-specific CDC growth charts is defined as obese, while a BMI from the 85th to 94th percentile is defined as overweight [4]. Using these criteria, the prevalence of childhood obesity more than tripled in the past 3 decades [5], leading to its classification as an epidemic and public health crisis [2]. Today, an estimated 12.5 million American children are obese [5]. For adolescents specifically, the prevalence of obesity is 18.4%, with more than one-third overweight [6].

Childhood obesity is associated with both short- and long-term morbidities including insulin resistance and type 2 diabetes, hypertension, dyslipidemia, asthma, obstructive sleep apnea, psychosocial problems, and decreased quality of life [7,8]. Obese children, particularly older children and adolescents, are more likely become obese adults [2,7]. Obesity in adulthood is associated with both significant morbidity and premature death [9]. Individual characteristics such as lifestyle habits, fitness level, and genetic predisposition influence the likelihood of development of both obesity and associated comorbidities [10].

The burden of obesity and its associated comorbidities are not equally distributed among racial/ethnic and socioeconomic groups. Hispanic and non-Hispanic black children are much more likely to be obese and overweight than non-Hispanic white children [6]. Low socioeconomic status is associated with increased rates of obesity in certain subgroups, including adolescents [2]. In addition, certain ethnic/racial minorities are more likely to develop obesity-associated comorbidities, such as insulin resistance, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD). With regard to insulin resistance and development of type 2 diabetes, the risk is greatest in Native Americans, but there is also increased risk in Hispanic/Latinos, non-Hispanic blacks, and Asian Americans as compared with non-Hispanic whites [11–13]. Collectively, these findings highlight the need for individualized assessment and the importance of obesity prevention and early intervention to improve long-term health outcomes. Primary care providers play a pivotal role in this process of preventing, identifying and treating childhood obesity and associated comorbidities [14]. In the case history, the child’s ethnicity, family history, and borderline overweight BMI indicate a high risk for future obesity-related morbidity and a critical opportunity for prevention intervention.

• What are the initial steps a practitioner can take to address overweight and obesity?

To encourage the development of healthy lifestyles and prevention of obesity, dietary and exercise counseling should be routinely provided as part of anticipatory guidance to all children and families regardless of weight status. It is critical to recognize individuals at high risk for becoming obese starting early in life. Risk factors for obesity in healthy weight children include rapid crossing of BMI percentiles, obese parent(s), maternal history of gestational diabetes during pregnancy, ethnicity, sedentary lifestyle, and excessive caloric intake [2]. Identification of these high-risk individuals can prompt more intensive counseling and early intervention with the goal of preventing the development of obesity and its complications. The use of automated BMI calculation and electronic medical records can facilitate identification of overweight and obesity status when already present and improve counseling rates [15].

Obesity due to excess nutrition is typically associated with linear growth acceleration that occurs subsequent to and to a lesser degree than the percentile shift in weight gain. A declining height velocity associated with obesity, therefore, is concerning and should prompt investigation for endocrine disease such as hypothyroidism, glucocorticoid excess, and growth hormone deficiency. Additional factors that warrant further investigation and/or referral include growth trajectory significantly below genetic potential, developmental delay, and dysmorphic features. A complete physical examination should be performed to evaluate for signs consistent with these conditions (eg, violaceous striae in glucocorticoid excess, microcephaly, and small hands/feet in Prader-Willi syndrome), and signs of obesity-associated comorbidities (eg, acanthosis nigricans). Accurate height, weight, BMI calculation, and blood pressure assessment using an appropriately sized cuff are essential.

While BMI screening is valuable, as noted above it is important to appreciate that insulin resistance (and other obesity-related comorbidities) can develop even when BMI is below the 95th percentile. Detailed history and physical examination can help identify these comorbidities of excess adiposity and guide diagnostic evaluation. Independent risk factors for insulin resistance and the development of type 2 diabetes include family history of diabetes, minority race/ethnicity, elevated waist circumference, and poor fitness level [18–20].

Further History

The patient reports skipping breakfast on most days, eats lunch at school, and snacks on chips and soda after school. Dinner is variable but usually contains carbohydrates and a protein and rarely includes vegetables. Family eats “take-out” about 3 times per week. Patient reports spending 3 hours a day watching television and playing on computer. He had gym last semester but currently reports very limited to no physical activity on most days.

•  What are effective ways to raise the issue of obesity during an office visit?

Despite the strong connection of obesity with adverse health outcomes, discussion of obesity in routine office settings can be difficult and is often limited by many factors such as time, training, availability of support services, perceived lack of patient motivation, and low outcome expectations [21,22]. Perhaps most challenging is tactfully handling the stigma associated with obesity, which can make discussion awkward and difficult for patients, parents, and providers. To do this, efforts to choose words that convey a nonjudgmental message while maintaining focus on obesity as a health concern are helpful. For example, terms such as “fat” and “obese” are often perceived as stigmatizing and blaming while using the term “unhealthy weight” is less pejorative and can be motivating [23]. It can also be important to acknowledge and emphasize that some individuals are more susceptible to weight gain and its consequences than others and as a result can tolerate fewer calories without unwanted weight gain and health problems. These approaches shift the focus of the discussion toward the goal of restoring and preserving health rather than changing physical appearance without placing blame on the individual and/or family. Motivational interviewing techniques which can be performed effectively even in short office visits can help to actively engage families, reveal familial perception of obesity and assess readiness to change [2]. Their use may also improve the efficacy of other interventions [24].

Case Continued

The patient and his mother were asked if they had any concerns today, including concerns about future health. Mother expressed worry about the potential for diabetes given their family history. The clinician used this as an opportunity to discuss pertinent factors associated with insulin resistance and type 2 diabetes, including modifiable factors such as diet, fitness level, and weight.

•  Should this non-obese adolescent be assessed for obesity comorbidities?

Yes. While there are multiple guidelines available for pediatric screening, all highlight the importance of obtaining individualized risk assessment to guide the extent of diagnostic workup. An Expert Committee comprised of representatives from 15 professional organizations appointed 3 writing groups to review the literature and recommend approaches to prevention, assessment, and treatment. Because effective strategies remain poorly defined, the writing groups used both available evidence and expert opinion to develop the recommendations [2]. In addition to routine blood pressure monitoring and universal lipid screening, the Expert Committee recommends obtaining additional laboratory assessment for obese children (BMI ≥ 95th percentile) including a fasting glucose and ALT/AST levels every 2 years starting at age 10 years. For overweight children (BMI > 85th percentile), the Expert Committee recommends obtaining these studies if additional risk factors are present [2]. The American Diabetes Association (ADA) recommends obtaining diabetes screening in all children classified as overweight (defined as either a BMI > 85th percentile for age and sex, weight for height > 85th percentile, or weight > 120% of ideal for height) once every 3 years beginning at age 10 or at pubertal onset (whichever is earliest) when 2 additional risk factors for diabetes are also present, including: (1) history of type 2 diabetes in a first- or second-degree relative, (2) race/ethnicity with increased risk for diabetes development (eg, Native American, African American, Latino, Asian American), (3) signs of insulin resistance or conditions associated with insulin resistance (eg, small for gestational age, polycystic ovary syndrome, hypertension) and (4) maternal history of gestational diabetes during pregnancy [25]. The ADA recommendations for diabetes screening test include either fasting plasma glucose, HgA1C, or oral glucose tolerance test [25].

With a BMI at the 85th percentile, on initial assessment our patient might be perceived as being at moderate or even low risk for obesity and its associated comorbidities. However, a more careful review has elicited several additional risk factors suggesting more appropriate classification in the high-risk category. First, family history of type 2 diabetes on both sides of his family suggests a degree of genetic predisposition. Second, Hispanic ethnicity is known to be independently associated with insulin resistance, type 2 diabetes, and NAFLD [26]. Moreover, physical exam findings of an elevated waist circumference (90th percentile for age and ethnicity [27]) and acanthosis nigricans are also supportive of insulin resistance. As a result, despite having a BMI at the 85th percentile, this adolescent is at high risk and further evaluation is warranted based on both Expert Committee and ADA guidelines. Detailed discussion of certain risk factors is outlined below.

Pattern of Adipose Tissue Distribution: Utility of BMI and Waist Circumference

BMI is a clinical tool that serves as a surrogate marker of adiposity, but since it does not directly measure body fat it provides a statistical, rather than inherent, description of risk. While it is a relatively specific marker (~95%) with moderately high sensitivity and positive predictive value (~70–80%) at BMI levels > 95th percentile, sensitivity and positive predictive value decrease substantially at lower BMI percentiles (PPV 18% in a sample of overweight children) [28]. Current CDC BMI percentile charts consider age and gender differences but do not take into account sexual maturation level or race/ethnicity, both of which are independently correlated with BMI [29]. That is, children with similar BMIs of the same age and sex may exhibit varying degrees of adiposity and risk attributable to their pubertal stage and/or ethnicity [30]. For example, many studies have demonstrated that at the same BMI percentile, Asian Americans tend to have more adiposity compared with non-Hispanic whites [31], whereas African Americans tend to have more fat-free mass compared with non-Hispanic whites [32]. As a result of these differences, some advocate for adjusting cut-offs for BMI based on ethnicity and/or utilizing alternative measures of adiposity such as waist circumference or waist to hip ratio. However, in order for these latter methods to be useful, standardized methods of measurement and normative reference values must be developed. In summary, though BMI can be a useful screening tool, it is an indirect measure of adiposity and cannot discern adipose distribution. Therefore, it is important to remember that when used alone, BMI may overlook children with high inherent risk for disease.

Abdominal adiposity is associated with increased metabolic risk, including insulin resistance, type 2 diabetes, hypertension, cardiovascular disease, and mortality [33]. Waist circumference, a marker of abdominal/truncal obesity, has been considered as a potential marker in place of or in combination with BMI to identify children with increased metabolic risk. In adults, it is well established that an elevated waist circumference is associated with increased health risk, even among those within a normal-weight BMI category [34], and it is recommended that waist circumference in addition to BMI be used to assess health risk [35]. Many studies have documented similar associations between increased waist circumference and metabolic risk factors in childhood and adolescence [36–38]. Specifically, waist circumference is an independent predictor of both insulin sensitivity and increased visceral adiposity tissue (VAT) in children and adolescents [39]. Waist circumference can provide valuable information beyond BMI alone and may be beneficial in the clinical setting in identifying adolescents at risk for obesity-associated comorbidities.

The use of waist circumference in routine clinical settings is complicated and limited by many factors. First, there is no universal method for waist circumference measurement. For example, the WHO recommends measurement at the midpoint between the superior iliac crest and inferior most rib, while the NIH and NHANES recommend measurement immediately above the iliac crest [40]. Since nationally representative data published by Fernandez et al [27] uses the latter method for waist circumference measurement, we recommend this method to allow for comparison of waist circumference percentile with available data for age, sex, and ethnicity. Second, while absolute waist circumference values are used as cut-offs in adulthood, in childhood use of waist circumference percentiles would be more appropriate to account for expected increases during childhood and changes related to pubertal stage. Unfortunately, a lack of standardized waist circumference percentile charts makes meaningful interpretation of waist circumference difficult. Moreover, even if standardized waist circumference percentile charts were developed, there are currently no accepted standards defining an abnormally elevated waist circumference percentile.

Many studies have identified increased metabolic risk factors associated with a waist circumference at or above the 90th percentile for age [41–43]. Based on these studies, the International Diabetes Federation uses waist circumference > 90th percentile as part of the criteria for metabolic syndrome in adolescents. While this ensures a high degree of specificity, use of waist circumference at the 75th percentile would allow for increased sensitivity. For example, Lee et al found that for insulin resistance use of waist circumference at the 75th percentile compared with the 90th percentile increased sensitivity from 61.3% to 86.1% while decreasing specificity from 91.4% to 71.5% [44]. Thus, for individuals at low risk based on history and clinical findings, a waist circumference threshold at the 90th percentile might be reasonable, while for individuals with additional risk factors for insulin resistance use of a lower waist circumference threshold (such as the 75th percentile) may be beneficial. Finally, since risk for insulin resistance and type 2 diabetes varies by race/ethnicity, which may correspond with visceral fat deposition, utilizing various threshold cut-offs based on race/ethnicity has been proposed by some. However, current data do not support this practice [44]. In summary, though there are many challenges to using waist circumference measurements in routine settings, if performed correctly determination of elevated waist circumference measurement can provide some additional information on an individual’s overall risk for complications of obesity.

Acanthosis Nigricans as an Indicator of Insulin Resistance

Insulin resistance, independent of adiposity, is associated with increased risk for type 2 diabetes, cardiovascular disease, ovarian hyperandrogenism, and certain forms of cancer [45]. Identification of insulin resistance in the clinical setting can lead to appropriate intervention (both lifestyle and, when warranted, pharmacologic) to reduce insulin resistance and improve health outcomes. Several risk factors for insulin resistance have been discussed above. Acanthosis nigricans, which is characterized by thick, velvety hyperpigmentation of the skin in intertriginous areas such as the neck and axilla, is an additional finding that is associated with insulin resistance. Its pathogenesis is felt to be related to activation of the IGF-1 receptor by high levels of circulating insulin [46]. Acanthosis nigricans is independently associated with fasting insulin levels and impaired glucose tolerance [47,48]. In addition to increased insulin resistance, one study found that 1 in 4 youths with acanthosis nigricans demonstrated abnormalities in glucose homeostasis and identified 2 individuals with diabetes who would not have been diagnosed based on fasting glucose levels alone [48]. The presence of acanthosis nigricans should alert the clinician to the likelihood of insulin resistance and prompt further investigation. Of note, the prevalence of acanthosis nigricans is increased among African American and Hispanic patients [49,50].

• What laboratory evaluation is warranted and practical in the office setting?

Laboratory evaluation is warranted when obesity or risk factors for comorbidities of obesity are present. At minimum, this should include lipid screening, liver enzymes (ALT and AST), and fasting glucose as outlined above. This approach, however, fails to identify all individuals with obesity-associated comorbidities. ALT is only moderately sensitive in detecting NAFLD [51], and fasting glucose levels only become abnormal when compensation for the degree of insulin resistance is inadequate to maintain normal fasting glucose homeostasis. As a result, while abnormal results on screening are suggestive of disease, normal results do not necessarily confer its absence. Thus, for high-risk subjects, additional testing and/or referral should be considered.

The hyperinsulinemic euglycemic clamp is the “gold standard” for measuring insulin sensitivity, but it is labor intensive and impractical in routine clinical settings. Alter-native approaches using surrogate markers have commonly been utilized, including fasting insulin and glucose levels and 2-hour oral glucose tolerance test (OGTT). The utility of these approaches in the clinical setting has been limited by several factors, including lack of a universal insulin assay. However, despite these limitations, obtaining fasting insulin in addition to fasting glucose or performing 2-hour OGTT can be useful in providing crude estimates of insulin resistance in certain high-risk subpopulations [52,53]. Recently, the ADA added HgA1C measurement as diagnostic criteria for pre-diabetes (5.7%–6.4%) and diabetes (> 6.5%) [54]. Benefits of HgA1C measurement include reliable measurements in nonfasting conditions and reflection of glucose over time. Studies in pediatric patients have shown the usefulness of HgA1C as a measure of future glucose intolerance or diabetes [55]. When fasting insulin or HgA1C are elevated and/or OGTT is abnormal, this suggests the presence of insulin resistance and need for intervention.

Proposed guideline criteria for the diagnosis of “metabolic syndrome” in adolescents include the following: (1) glucose intolerance, (2) elevated waist circumference or BMI, (3) hypertriglyceridemia, (4) low HDL, and 5) hypertension. There is no universal definition for metabolic syndrome in childhood and adolescence, and cut-off values in each category vary by study group [41–43,56]. When insulin resistance is present, it should alert the clinician to the increased likelihood for metabolic syndrome and NAFLD, and additional screening should be performed accordingly. NAFLD is present in about 25% of all overweight children and is strongly associated with insulin resistance and the metabolic syndrome [57]. Hispanic patients have an increased prevalence of NAFLD compared with patients of other ethnicities [58,59]. Elevated liver transaminases (AST and ALT) are commonly used to screen for NAFLD. However, since these markers are indicative of hepatocellular damage, they may remain within normal limits and correlate poorly with early steatosis [51]. Alternative approaches have been proposed in high-risk populations to detect early steatosis and improve long-term prognosis [60].

Case Continued

The patient underwent laboratory assessment that included fasting glucose and insulin, fasting lipid panel, and ALT. Results were suggestive of insulin resistance and metabolic syndrome and included the following: fasting glucose 108 mg/dL, fasting insulin 65 uIU/mL (reference range 3–25), HgA1C 5.9% (reference range 4.2–5.8), total cholesterol 178 mg/dL, HDL cholesterol 35 mg/dL, LDL cholesterol 110 mg/dL, triglycerides 157 mg/dL, and ALT 40 u/L. Blood pressure, as noted above, is at the 95th percentile for age and height.

• What is the recommended approach to intervention? When is referral warranted?

Staged Obesity Treatment

The initial stage, termed “Prevention Plus,” is similar to obesity prevention strategies and is focused on institution of healthy dietary and activity lifestyle habits tailored to the individual and family. Frequent follow-up and monitoring can be helpful and should be offered to families. Failure to demonstrate progress after 3 to 6 months warrants advancement to Stage 2, “Structured Weight Management,” which includes a planned diet with structured meals and snacks, reduction of screen time to 1 hour or less, 60 minutes of supervised physical activity, use of logs to document diet and activity levels, monthly follow-ups and positive reinforcement for achieving goals. Consultation with a dietician and health psychologist/counseling can be helpful at this level.

If no progress is noted after 3 to 6 months, progression to Stage 3, “Comprehensive Multidisciplinary Intervention,” is recommended. This stage emphasizes the importance of a multidisciplinary team including behavioral counselor, registered dietician and exercise specialist in addition to a medical provider. Current evidence suggests modest improvement of obesity and related comorbidities in adolescents participating in multidisciplinary weight management programs [62,63]. While these interventions can be implemented in community settings, coordination in this setting can be difficult and implementation more commonly involves weight management programs in tertiary care centers. Access to such programs can be limited by geographic accessibility, insurance coverage and physician awareness of available programs/resources [64]. Utilization of technology such as telemedicine visits is one way to overcome limited access [65]. Finally, Stage 4 “Tertiary Care Intervention”, involving discussion of pharmacologic or intensive/surgical weight loss options, can be considered for those who fail to show progression after successful intervention of previous stages.

Specialty Referral

Referral to multidisciplinary clinics specializing in childhood obesity is warranted when obesity is particularly severe, comorbidities are present at baseline, or no improvement is noted after 6 months of intense lifestyle intervention. Insulin resistance evidenced by impaired glucose tolerance (abnormal fasting or 2-hour glucose levels), HgA1C in the pre-diabetes range or higher (> 5.7%), or persistently elevated fasting insulin levels after 3 to 6 months of intensive lifestyle modification should prompt referral for consideration of metformin initiation. Metformin can reduce insulin resistance in children and may reduce progression from impaired glucose tolerance to diabetes [66]. For dyslipidemia related to metabolic syndrome, lifestyle interventions are most likely to be efficacious. Referral to preventative cardiology for consideration of pharmacologic intervention should be considered when severe hypertriglyceridemia is present (> 400 mg/dL) or LDL remains elevated after implementation of healthy lifestyle interventions. Elevations in ALT are highly specific for NAFLD and should prompt referral to gastroenterology. In addition, given the poor sensitivity of ALT for detection of early hepatic steatosis, referral might be considered when ALT is in the high normal ranges, especially in those with increased risk such as Hispanic patients [67]. Finally, when signs of obstructive sleep apnea are present, a sleep study should be performed. In summary, while specialty referral can aid targeted treatment of obesity-related morbidities, the central role of the primary care clinician in anticipating and preventing or minimizing their occurrence remains paramount.

Case Conclusion

The patient was referred to a multidisciplinary obesity clinic where he and his family met with dietician, exercise physiologist, health psychologist, and endocrinologist. Healthy lifestyle modifications with specific goals were instituted, including elimination of all calorie-containing beverages (except daily recommended intake of fat-free milk) and initiation of physical activity for 30 minutes a day 5 days per week. He was started on metformin due to glucose intolerance and increased risk for diabetes. Follow-up occurred at monthly intervals for the first 3 months. Additional goals and lifestyle interventions were implemented at each follow-up. At 6 months’ follow-up, the patient’s height was 164 cm, weight was stable at 58.4 kg and BMI was 21.7 (79th percentile). Blood pressure was slightly improved at 123/80 mm Hg. Repeat labs showed mild but consistent improvement in all areas. Specifically, fasting glucose 100 mg/dL, fasting insulin 40 uIU/mL, HgA1C 5.6%, total cholesterol 162 mg/dL, HDL cholesterol 40 mg/dL, LDL cholesterol 105 mg/dL, triglycerides 140 mg/dL, and ALT 38 u/L. The patient continues to be monitored closely with goal to improve metabolic health and long-term health outcomes.

Summary

Childhood obesity is a major public health concern. The health impact of obesity on children is broad and profound. Since treatment of obesity is often unsuccessful, prevention of obesity or early detection of its health consequences are crucial responsibilities and opportunities for primary care clinicians. While clinical guidelines can be instructive, application of clinical guidelines must be tailored to individual adolescent patients according to accompanying risk factors. This review aims to help clinicians stratify risk based on susceptibility to development of insulin resistance and other morbidities associated with adolescent obesity. While the enormity of the obesity epidemic can appear overwhelming to primary care providers, they remain in the best position to initiate early intervention strategies. Coordinating care between primary care providers and specialty clinics will continue to be an important partnership for the care of those experiencing health-threatening effects of adolescent obesity.

Corresponding author: Aaron L Carrel, MD, University of Wisconsin, 600 Highland Ave, H4-436, Madison, WI 53792.

Financial disclosures: Drs. Seibert and Carrel have received fellowship grants from Genentech.

From the Department of Pediatrics, University of Wisconsin, Madison, WI.

Abstract

• Objective: To provide information that will assist clinicians in assessing and addressing risk for obesity-related comorbidities in adolescents.
• Methods: Review of the literature.
• Results: Childhood obesity is a major public health concern. Prevention of obesity or early detection of its health consequences are important responsibilities or opportunities for primary care clinicians. While body mass index (BMI) screening is valuable, insulin resistance and other obesity-related comorbidities can develop even when BMI falls below the 95th percentile threshold for obesity. Detailed history and physical examination can help identify comorbidities and guide diagnostic evaluation. Referral to multidisciplinary clinics specializing in childhood obesity is warranted when obesity is particularly severe, comorbidities are present at baseline, or no improvement is noted after 6 months of intense lifestyle intervention.
• Conclusion: For optimal health outcomes, management of adolescent obesity and associated comorbidities is should be adapted based on an individual’s overall risk rather than BMI alone.

Case Study

Initial Presentation

A 14-year-old Hispanic male presents for a well child check.

History and Physical Examination

The patient and his mother have no complaints or concerns. A comprehensive review of systems is positive for fatigue and snoring but is otherwise unremarkable. Past medical history is unremarkable except for mild intermittent asthma. Family history is positive for type 2 diabetes in paternal grandmother and a maternal uncle and cardiovascular disease and hypertension in multiple extended family members. Both maternal and paternal grandparents are from Mexico.

Vital signs are within normal limits. Height is 160 cm (30th percentile for age), weight is 58.4 kg (75th percentile for age), and body mass index (BMI) is 22.8 kg/m² (85th percentile for age). Blood pressure is 127/81 mm Hg (95th percentile for age and gender). Physical exam is pertinent for acanthosis nigricans on neck and axilla and nonviolaceous striae on abdomen. Waist circumference is 88 cm (90th percentile for age and ethnicity). Otherwise, physical exam is within normal limits.

• Does this child’s physical examination findings pose a cause for concern?

Yes. A key concept is that while obesity is widespread, the adverse health complications of adiposity and overnutrition affect some children much earlier and more profoundly than others. Some children exhibit adiposity-associated comorbidities even prior to meeting obesity criteria defined by BMI. Careful history and examination can help identify those most at risk for developing adiposity-associated comorbidities, prompting earlier intervention and, when appropriate, subspecialty referral.

Obesity is caused by a complex interplay of genetic, environmental, and metabolic programming, especially early in life, and lifestyle habits [1,2]. The vast majority of obesity is due to excess nutrition leading to energy imbalance, while less than 1% is due to endocrine or syndromic causes [3]. Obesity is defined as excessive body fat and is often estimated indirectly by using a surrogate marker, BMI. Diagnostically, a BMI > 95th percentile for age on sex-specific CDC growth charts is defined as obese, while a BMI from the 85th to 94th percentile is defined as overweight [4]. Using these criteria, the prevalence of childhood obesity more than tripled in the past 3 decades [5], leading to its classification as an epidemic and public health crisis [2]. Today, an estimated 12.5 million American children are obese [5]. For adolescents specifically, the prevalence of obesity is 18.4%, with more than one-third overweight [6].

Childhood obesity is associated with both short- and long-term morbidities including insulin resistance and type 2 diabetes, hypertension, dyslipidemia, asthma, obstructive sleep apnea, psychosocial problems, and decreased quality of life [7,8]. Obese children, particularly older children and adolescents, are more likely become obese adults [2,7]. Obesity in adulthood is associated with both significant morbidity and premature death [9]. Individual characteristics such as lifestyle habits, fitness level, and genetic predisposition influence the likelihood of development of both obesity and associated comorbidities [10].

The burden of obesity and its associated comorbidities are not equally distributed among racial/ethnic and socioeconomic groups. Hispanic and non-Hispanic black children are much more likely to be obese and overweight than non-Hispanic white children [6]. Low socioeconomic status is associated with increased rates of obesity in certain subgroups, including adolescents [2]. In addition, certain ethnic/racial minorities are more likely to develop obesity-associated comorbidities, such as insulin resistance, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD). With regard to insulin resistance and development of type 2 diabetes, the risk is greatest in Native Americans, but there is also increased risk in Hispanic/Latinos, non-Hispanic blacks, and Asian Americans as compared with non-Hispanic whites [11–13]. Collectively, these findings highlight the need for individualized assessment and the importance of obesity prevention and early intervention to improve long-term health outcomes. Primary care providers play a pivotal role in this process of preventing, identifying and treating childhood obesity and associated comorbidities [14]. In the case history, the child’s ethnicity, family history, and borderline overweight BMI indicate a high risk for future obesity-related morbidity and a critical opportunity for prevention intervention.

• What are the initial steps a practitioner can take to address overweight and obesity?

To encourage the development of healthy lifestyles and prevention of obesity, dietary and exercise counseling should be routinely provided as part of anticipatory guidance to all children and families regardless of weight status. It is critical to recognize individuals at high risk for becoming obese starting early in life. Risk factors for obesity in healthy weight children include rapid crossing of BMI percentiles, obese parent(s), maternal history of gestational diabetes during pregnancy, ethnicity, sedentary lifestyle, and excessive caloric intake [2]. Identification of these high-risk individuals can prompt more intensive counseling and early intervention with the goal of preventing the development of obesity and its complications. The use of automated BMI calculation and electronic medical records can facilitate identification of overweight and obesity status when already present and improve counseling rates [15].

Obesity due to excess nutrition is typically associated with linear growth acceleration that occurs subsequent to and to a lesser degree than the percentile shift in weight gain. A declining height velocity associated with obesity, therefore, is concerning and should prompt investigation for endocrine disease such as hypothyroidism, glucocorticoid excess, and growth hormone deficiency. Additional factors that warrant further investigation and/or referral include growth trajectory significantly below genetic potential, developmental delay, and dysmorphic features. A complete physical examination should be performed to evaluate for signs consistent with these conditions (eg, violaceous striae in glucocorticoid excess, microcephaly, and small hands/feet in Prader-Willi syndrome), and signs of obesity-associated comorbidities (eg, acanthosis nigricans). Accurate height, weight, BMI calculation, and blood pressure assessment using an appropriately sized cuff are essential.

While BMI screening is valuable, as noted above it is important to appreciate that insulin resistance (and other obesity-related comorbidities) can develop even when BMI is below the 95th percentile. Detailed history and physical examination can help identify these comorbidities of excess adiposity and guide diagnostic evaluation. Independent risk factors for insulin resistance and the development of type 2 diabetes include family history of diabetes, minority race/ethnicity, elevated waist circumference, and poor fitness level [18–20].

Further History

The patient reports skipping breakfast on most days, eats lunch at school, and snacks on chips and soda after school. Dinner is variable but usually contains carbohydrates and a protein and rarely includes vegetables. Family eats “take-out” about 3 times per week. Patient reports spending 3 hours a day watching television and playing on computer. He had gym last semester but currently reports very limited to no physical activity on most days.

•  What are effective ways to raise the issue of obesity during an office visit?

Despite the strong connection of obesity with adverse health outcomes, discussion of obesity in routine office settings can be difficult and is often limited by many factors such as time, training, availability of support services, perceived lack of patient motivation, and low outcome expectations [21,22]. Perhaps most challenging is tactfully handling the stigma associated with obesity, which can make discussion awkward and difficult for patients, parents, and providers. To do this, efforts to choose words that convey a nonjudgmental message while maintaining focus on obesity as a health concern are helpful. For example, terms such as “fat” and “obese” are often perceived as stigmatizing and blaming while using the term “unhealthy weight” is less pejorative and can be motivating [23]. It can also be important to acknowledge and emphasize that some individuals are more susceptible to weight gain and its consequences than others and as a result can tolerate fewer calories without unwanted weight gain and health problems. These approaches shift the focus of the discussion toward the goal of restoring and preserving health rather than changing physical appearance without placing blame on the individual and/or family. Motivational interviewing techniques which can be performed effectively even in short office visits can help to actively engage families, reveal familial perception of obesity and assess readiness to change [2]. Their use may also improve the efficacy of other interventions [24].

Case Continued

The patient and his mother were asked if they had any concerns today, including concerns about future health. Mother expressed worry about the potential for diabetes given their family history. The clinician used this as an opportunity to discuss pertinent factors associated with insulin resistance and type 2 diabetes, including modifiable factors such as diet, fitness level, and weight.

•  Should this non-obese adolescent be assessed for obesity comorbidities?

Yes. While there are multiple guidelines available for pediatric screening, all highlight the importance of obtaining individualized risk assessment to guide the extent of diagnostic workup. An Expert Committee comprised of representatives from 15 professional organizations appointed 3 writing groups to review the literature and recommend approaches to prevention, assessment, and treatment. Because effective strategies remain poorly defined, the writing groups used both available evidence and expert opinion to develop the recommendations [2]. In addition to routine blood pressure monitoring and universal lipid screening, the Expert Committee recommends obtaining additional laboratory assessment for obese children (BMI ≥ 95th percentile) including a fasting glucose and ALT/AST levels every 2 years starting at age 10 years. For overweight children (BMI > 85th percentile), the Expert Committee recommends obtaining these studies if additional risk factors are present [2]. The American Diabetes Association (ADA) recommends obtaining diabetes screening in all children classified as overweight (defined as either a BMI > 85th percentile for age and sex, weight for height > 85th percentile, or weight > 120% of ideal for height) once every 3 years beginning at age 10 or at pubertal onset (whichever is earliest) when 2 additional risk factors for diabetes are also present, including: (1) history of type 2 diabetes in a first- or second-degree relative, (2) race/ethnicity with increased risk for diabetes development (eg, Native American, African American, Latino, Asian American), (3) signs of insulin resistance or conditions associated with insulin resistance (eg, small for gestational age, polycystic ovary syndrome, hypertension) and (4) maternal history of gestational diabetes during pregnancy [25]. The ADA recommendations for diabetes screening test include either fasting plasma glucose, HgA1C, or oral glucose tolerance test [25].

With a BMI at the 85th percentile, on initial assessment our patient might be perceived as being at moderate or even low risk for obesity and its associated comorbidities. However, a more careful review has elicited several additional risk factors suggesting more appropriate classification in the high-risk category. First, family history of type 2 diabetes on both sides of his family suggests a degree of genetic predisposition. Second, Hispanic ethnicity is known to be independently associated with insulin resistance, type 2 diabetes, and NAFLD [26]. Moreover, physical exam findings of an elevated waist circumference (90th percentile for age and ethnicity [27]) and acanthosis nigricans are also supportive of insulin resistance. As a result, despite having a BMI at the 85th percentile, this adolescent is at high risk and further evaluation is warranted based on both Expert Committee and ADA guidelines. Detailed discussion of certain risk factors is outlined below.

Pattern of Adipose Tissue Distribution: Utility of BMI and Waist Circumference

BMI is a clinical tool that serves as a surrogate marker of adiposity, but since it does not directly measure body fat it provides a statistical, rather than inherent, description of risk. While it is a relatively specific marker (~95%) with moderately high sensitivity and positive predictive value (~70–80%) at BMI levels > 95th percentile, sensitivity and positive predictive value decrease substantially at lower BMI percentiles (PPV 18% in a sample of overweight children) [28]. Current CDC BMI percentile charts consider age and gender differences but do not take into account sexual maturation level or race/ethnicity, both of which are independently correlated with BMI [29]. That is, children with similar BMIs of the same age and sex may exhibit varying degrees of adiposity and risk attributable to their pubertal stage and/or ethnicity [30]. For example, many studies have demonstrated that at the same BMI percentile, Asian Americans tend to have more adiposity compared with non-Hispanic whites [31], whereas African Americans tend to have more fat-free mass compared with non-Hispanic whites [32]. As a result of these differences, some advocate for adjusting cut-offs for BMI based on ethnicity and/or utilizing alternative measures of adiposity such as waist circumference or waist to hip ratio. However, in order for these latter methods to be useful, standardized methods of measurement and normative reference values must be developed. In summary, though BMI can be a useful screening tool, it is an indirect measure of adiposity and cannot discern adipose distribution. Therefore, it is important to remember that when used alone, BMI may overlook children with high inherent risk for disease.

Abdominal adiposity is associated with increased metabolic risk, including insulin resistance, type 2 diabetes, hypertension, cardiovascular disease, and mortality [33]. Waist circumference, a marker of abdominal/truncal obesity, has been considered as a potential marker in place of or in combination with BMI to identify children with increased metabolic risk. In adults, it is well established that an elevated waist circumference is associated with increased health risk, even among those within a normal-weight BMI category [34], and it is recommended that waist circumference in addition to BMI be used to assess health risk [35]. Many studies have documented similar associations between increased waist circumference and metabolic risk factors in childhood and adolescence [36–38]. Specifically, waist circumference is an independent predictor of both insulin sensitivity and increased visceral adiposity tissue (VAT) in children and adolescents [39]. Waist circumference can provide valuable information beyond BMI alone and may be beneficial in the clinical setting in identifying adolescents at risk for obesity-associated comorbidities.

The use of waist circumference in routine clinical settings is complicated and limited by many factors. First, there is no universal method for waist circumference measurement. For example, the WHO recommends measurement at the midpoint between the superior iliac crest and inferior most rib, while the NIH and NHANES recommend measurement immediately above the iliac crest [40]. Since nationally representative data published by Fernandez et al [27] uses the latter method for waist circumference measurement, we recommend this method to allow for comparison of waist circumference percentile with available data for age, sex, and ethnicity. Second, while absolute waist circumference values are used as cut-offs in adulthood, in childhood use of waist circumference percentiles would be more appropriate to account for expected increases during childhood and changes related to pubertal stage. Unfortunately, a lack of standardized waist circumference percentile charts makes meaningful interpretation of waist circumference difficult. Moreover, even if standardized waist circumference percentile charts were developed, there are currently no accepted standards defining an abnormally elevated waist circumference percentile.

Many studies have identified increased metabolic risk factors associated with a waist circumference at or above the 90th percentile for age [41–43]. Based on these studies, the International Diabetes Federation uses waist circumference > 90th percentile as part of the criteria for metabolic syndrome in adolescents. While this ensures a high degree of specificity, use of waist circumference at the 75th percentile would allow for increased sensitivity. For example, Lee et al found that for insulin resistance use of waist circumference at the 75th percentile compared with the 90th percentile increased sensitivity from 61.3% to 86.1% while decreasing specificity from 91.4% to 71.5% [44]. Thus, for individuals at low risk based on history and clinical findings, a waist circumference threshold at the 90th percentile might be reasonable, while for individuals with additional risk factors for insulin resistance use of a lower waist circumference threshold (such as the 75th percentile) may be beneficial. Finally, since risk for insulin resistance and type 2 diabetes varies by race/ethnicity, which may correspond with visceral fat deposition, utilizing various threshold cut-offs based on race/ethnicity has been proposed by some. However, current data do not support this practice [44]. In summary, though there are many challenges to using waist circumference measurements in routine settings, if performed correctly determination of elevated waist circumference measurement can provide some additional information on an individual’s overall risk for complications of obesity.

Acanthosis Nigricans as an Indicator of Insulin Resistance

Insulin resistance, independent of adiposity, is associated with increased risk for type 2 diabetes, cardiovascular disease, ovarian hyperandrogenism, and certain forms of cancer [45]. Identification of insulin resistance in the clinical setting can lead to appropriate intervention (both lifestyle and, when warranted, pharmacologic) to reduce insulin resistance and improve health outcomes. Several risk factors for insulin resistance have been discussed above. Acanthosis nigricans, which is characterized by thick, velvety hyperpigmentation of the skin in intertriginous areas such as the neck and axilla, is an additional finding that is associated with insulin resistance. Its pathogenesis is felt to be related to activation of the IGF-1 receptor by high levels of circulating insulin [46]. Acanthosis nigricans is independently associated with fasting insulin levels and impaired glucose tolerance [47,48]. In addition to increased insulin resistance, one study found that 1 in 4 youths with acanthosis nigricans demonstrated abnormalities in glucose homeostasis and identified 2 individuals with diabetes who would not have been diagnosed based on fasting glucose levels alone [48]. The presence of acanthosis nigricans should alert the clinician to the likelihood of insulin resistance and prompt further investigation. Of note, the prevalence of acanthosis nigricans is increased among African American and Hispanic patients [49,50].

• What laboratory evaluation is warranted and practical in the office setting?

Laboratory evaluation is warranted when obesity or risk factors for comorbidities of obesity are present. At minimum, this should include lipid screening, liver enzymes (ALT and AST), and fasting glucose as outlined above. This approach, however, fails to identify all individuals with obesity-associated comorbidities. ALT is only moderately sensitive in detecting NAFLD [51], and fasting glucose levels only become abnormal when compensation for the degree of insulin resistance is inadequate to maintain normal fasting glucose homeostasis. As a result, while abnormal results on screening are suggestive of disease, normal results do not necessarily confer its absence. Thus, for high-risk subjects, additional testing and/or referral should be considered.

The hyperinsulinemic euglycemic clamp is the “gold standard” for measuring insulin sensitivity, but it is labor intensive and impractical in routine clinical settings. Alter-native approaches using surrogate markers have commonly been utilized, including fasting insulin and glucose levels and 2-hour oral glucose tolerance test (OGTT). The utility of these approaches in the clinical setting has been limited by several factors, including lack of a universal insulin assay. However, despite these limitations, obtaining fasting insulin in addition to fasting glucose or performing 2-hour OGTT can be useful in providing crude estimates of insulin resistance in certain high-risk subpopulations [52,53]. Recently, the ADA added HgA1C measurement as diagnostic criteria for pre-diabetes (5.7%–6.4%) and diabetes (> 6.5%) [54]. Benefits of HgA1C measurement include reliable measurements in nonfasting conditions and reflection of glucose over time. Studies in pediatric patients have shown the usefulness of HgA1C as a measure of future glucose intolerance or diabetes [55]. When fasting insulin or HgA1C are elevated and/or OGTT is abnormal, this suggests the presence of insulin resistance and need for intervention.

Proposed guideline criteria for the diagnosis of “metabolic syndrome” in adolescents include the following: (1) glucose intolerance, (2) elevated waist circumference or BMI, (3) hypertriglyceridemia, (4) low HDL, and 5) hypertension. There is no universal definition for metabolic syndrome in childhood and adolescence, and cut-off values in each category vary by study group [41–43,56]. When insulin resistance is present, it should alert the clinician to the increased likelihood for metabolic syndrome and NAFLD, and additional screening should be performed accordingly. NAFLD is present in about 25% of all overweight children and is strongly associated with insulin resistance and the metabolic syndrome [57]. Hispanic patients have an increased prevalence of NAFLD compared with patients of other ethnicities [58,59]. Elevated liver transaminases (AST and ALT) are commonly used to screen for NAFLD. However, since these markers are indicative of hepatocellular damage, they may remain within normal limits and correlate poorly with early steatosis [51]. Alternative approaches have been proposed in high-risk populations to detect early steatosis and improve long-term prognosis [60].

Case Continued

The patient underwent laboratory assessment that included fasting glucose and insulin, fasting lipid panel, and ALT. Results were suggestive of insulin resistance and metabolic syndrome and included the following: fasting glucose 108 mg/dL, fasting insulin 65 uIU/mL (reference range 3–25), HgA1C 5.9% (reference range 4.2–5.8), total cholesterol 178 mg/dL, HDL cholesterol 35 mg/dL, LDL cholesterol 110 mg/dL, triglycerides 157 mg/dL, and ALT 40 u/L. Blood pressure, as noted above, is at the 95th percentile for age and height.

• What is the recommended approach to intervention? When is referral warranted?

Staged Obesity Treatment

The initial stage, termed “Prevention Plus,” is similar to obesity prevention strategies and is focused on institution of healthy dietary and activity lifestyle habits tailored to the individual and family. Frequent follow-up and monitoring can be helpful and should be offered to families. Failure to demonstrate progress after 3 to 6 months warrants advancement to Stage 2, “Structured Weight Management,” which includes a planned diet with structured meals and snacks, reduction of screen time to 1 hour or less, 60 minutes of supervised physical activity, use of logs to document diet and activity levels, monthly follow-ups and positive reinforcement for achieving goals. Consultation with a dietician and health psychologist/counseling can be helpful at this level.

If no progress is noted after 3 to 6 months, progression to Stage 3, “Comprehensive Multidisciplinary Intervention,” is recommended. This stage emphasizes the importance of a multidisciplinary team including behavioral counselor, registered dietician and exercise specialist in addition to a medical provider. Current evidence suggests modest improvement of obesity and related comorbidities in adolescents participating in multidisciplinary weight management programs [62,63]. While these interventions can be implemented in community settings, coordination in this setting can be difficult and implementation more commonly involves weight management programs in tertiary care centers. Access to such programs can be limited by geographic accessibility, insurance coverage and physician awareness of available programs/resources [64]. Utilization of technology such as telemedicine visits is one way to overcome limited access [65]. Finally, Stage 4 “Tertiary Care Intervention”, involving discussion of pharmacologic or intensive/surgical weight loss options, can be considered for those who fail to show progression after successful intervention of previous stages.

Specialty Referral

Referral to multidisciplinary clinics specializing in childhood obesity is warranted when obesity is particularly severe, comorbidities are present at baseline, or no improvement is noted after 6 months of intense lifestyle intervention. Insulin resistance evidenced by impaired glucose tolerance (abnormal fasting or 2-hour glucose levels), HgA1C in the pre-diabetes range or higher (> 5.7%), or persistently elevated fasting insulin levels after 3 to 6 months of intensive lifestyle modification should prompt referral for consideration of metformin initiation. Metformin can reduce insulin resistance in children and may reduce progression from impaired glucose tolerance to diabetes [66]. For dyslipidemia related to metabolic syndrome, lifestyle interventions are most likely to be efficacious. Referral to preventative cardiology for consideration of pharmacologic intervention should be considered when severe hypertriglyceridemia is present (> 400 mg/dL) or LDL remains elevated after implementation of healthy lifestyle interventions. Elevations in ALT are highly specific for NAFLD and should prompt referral to gastroenterology. In addition, given the poor sensitivity of ALT for detection of early hepatic steatosis, referral might be considered when ALT is in the high normal ranges, especially in those with increased risk such as Hispanic patients [67]. Finally, when signs of obstructive sleep apnea are present, a sleep study should be performed. In summary, while specialty referral can aid targeted treatment of obesity-related morbidities, the central role of the primary care clinician in anticipating and preventing or minimizing their occurrence remains paramount.

Case Conclusion

The patient was referred to a multidisciplinary obesity clinic where he and his family met with dietician, exercise physiologist, health psychologist, and endocrinologist. Healthy lifestyle modifications with specific goals were instituted, including elimination of all calorie-containing beverages (except daily recommended intake of fat-free milk) and initiation of physical activity for 30 minutes a day 5 days per week. He was started on metformin due to glucose intolerance and increased risk for diabetes. Follow-up occurred at monthly intervals for the first 3 months. Additional goals and lifestyle interventions were implemented at each follow-up. At 6 months’ follow-up, the patient’s height was 164 cm, weight was stable at 58.4 kg and BMI was 21.7 (79th percentile). Blood pressure was slightly improved at 123/80 mm Hg. Repeat labs showed mild but consistent improvement in all areas. Specifically, fasting glucose 100 mg/dL, fasting insulin 40 uIU/mL, HgA1C 5.6%, total cholesterol 162 mg/dL, HDL cholesterol 40 mg/dL, LDL cholesterol 105 mg/dL, triglycerides 140 mg/dL, and ALT 38 u/L. The patient continues to be monitored closely with goal to improve metabolic health and long-term health outcomes.

Summary

Childhood obesity is a major public health concern. The health impact of obesity on children is broad and profound. Since treatment of obesity is often unsuccessful, prevention of obesity or early detection of its health consequences are crucial responsibilities and opportunities for primary care clinicians. While clinical guidelines can be instructive, application of clinical guidelines must be tailored to individual adolescent patients according to accompanying risk factors. This review aims to help clinicians stratify risk based on susceptibility to development of insulin resistance and other morbidities associated with adolescent obesity. While the enormity of the obesity epidemic can appear overwhelming to primary care providers, they remain in the best position to initiate early intervention strategies. Coordinating care between primary care providers and specialty clinics will continue to be an important partnership for the care of those experiencing health-threatening effects of adolescent obesity.

Corresponding author: Aaron L Carrel, MD, University of Wisconsin, 600 Highland Ave, H4-436, Madison, WI 53792.

Financial disclosures: Drs. Seibert and Carrel have received fellowship grants from Genentech.

From the Department of Pediatrics, University of Wisconsin, Madison, WI.

Abstract

• Objective: To provide information that will assist clinicians in assessing and addressing risk for obesity-related comorbidities in adolescents.
• Methods: Review of the literature.
• Results: Childhood obesity is a major public health concern. Prevention of obesity or early detection of its health consequences are important responsibilities or opportunities for primary care clinicians. While body mass index (BMI) screening is valuable, insulin resistance and other obesity-related comorbidities can develop even when BMI falls below the 95th percentile threshold for obesity. Detailed history and physical examination can help identify comorbidities and guide diagnostic evaluation. Referral to multidisciplinary clinics specializing in childhood obesity is warranted when obesity is particularly severe, comorbidities are present at baseline, or no improvement is noted after 6 months of intense lifestyle intervention.
• Conclusion: For optimal health outcomes, management of adolescent obesity and associated comorbidities is should be adapted based on an individual’s overall risk rather than BMI alone.

Case Study

Initial Presentation

A 14-year-old Hispanic male presents for a well child check.

History and Physical Examination

The patient and his mother have no complaints or concerns. A comprehensive review of systems is positive for fatigue and snoring but is otherwise unremarkable. Past medical history is unremarkable except for mild intermittent asthma. Family history is positive for type 2 diabetes in paternal grandmother and a maternal uncle and cardiovascular disease and hypertension in multiple extended family members. Both maternal and paternal grandparents are from Mexico.

Vital signs are within normal limits. Height is 160 cm (30th percentile for age), weight is 58.4 kg (75th percentile for age), and body mass index (BMI) is 22.8 kg/m² (85th percentile for age). Blood pressure is 127/81 mm Hg (95th percentile for age and gender). Physical exam is pertinent for acanthosis nigricans on neck and axilla and nonviolaceous striae on abdomen. Waist circumference is 88 cm (90th percentile for age and ethnicity). Otherwise, physical exam is within normal limits.

• Does this child’s physical examination findings pose a cause for concern?

Yes. A key concept is that while obesity is widespread, the adverse health complications of adiposity and overnutrition affect some children much earlier and more profoundly than others. Some children exhibit adiposity-associated comorbidities even prior to meeting obesity criteria defined by BMI. Careful history and examination can help identify those most at risk for developing adiposity-associated comorbidities, prompting earlier intervention and, when appropriate, subspecialty referral.

Obesity is caused by a complex interplay of genetic, environmental, and metabolic programming, especially early in life, and lifestyle habits [1,2]. The vast majority of obesity is due to excess nutrition leading to energy imbalance, while less than 1% is due to endocrine or syndromic causes [3]. Obesity is defined as excessive body fat and is often estimated indirectly by using a surrogate marker, BMI. Diagnostically, a BMI > 95th percentile for age on sex-specific CDC growth charts is defined as obese, while a BMI from the 85th to 94th percentile is defined as overweight [4]. Using these criteria, the prevalence of childhood obesity more than tripled in the past 3 decades [5], leading to its classification as an epidemic and public health crisis [2]. Today, an estimated 12.5 million American children are obese [5]. For adolescents specifically, the prevalence of obesity is 18.4%, with more than one-third overweight [6].

Childhood obesity is associated with both short- and long-term morbidities including insulin resistance and type 2 diabetes, hypertension, dyslipidemia, asthma, obstructive sleep apnea, psychosocial problems, and decreased quality of life [7,8]. Obese children, particularly older children and adolescents, are more likely become obese adults [2,7]. Obesity in adulthood is associated with both significant morbidity and premature death [9]. Individual characteristics such as lifestyle habits, fitness level, and genetic predisposition influence the likelihood of development of both obesity and associated comorbidities [10].

The burden of obesity and its associated comorbidities are not equally distributed among racial/ethnic and socioeconomic groups. Hispanic and non-Hispanic black children are much more likely to be obese and overweight than non-Hispanic white children [6]. Low socioeconomic status is associated with increased rates of obesity in certain subgroups, including adolescents [2]. In addition, certain ethnic/racial minorities are more likely to develop obesity-associated comorbidities, such as insulin resistance, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD). With regard to insulin resistance and development of type 2 diabetes, the risk is greatest in Native Americans, but there is also increased risk in Hispanic/Latinos, non-Hispanic blacks, and Asian Americans as compared with non-Hispanic whites [11–13]. Collectively, these findings highlight the need for individualized assessment and the importance of obesity prevention and early intervention to improve long-term health outcomes. Primary care providers play a pivotal role in this process of preventing, identifying and treating childhood obesity and associated comorbidities [14]. In the case history, the child’s ethnicity, family history, and borderline overweight BMI indicate a high risk for future obesity-related morbidity and a critical opportunity for prevention intervention.

• What are the initial steps a practitioner can take to address overweight and obesity?

To encourage the development of healthy lifestyles and prevention of obesity, dietary and exercise counseling should be routinely provided as part of anticipatory guidance to all children and families regardless of weight status. It is critical to recognize individuals at high risk for becoming obese starting early in life. Risk factors for obesity in healthy weight children include rapid crossing of BMI percentiles, obese parent(s), maternal history of gestational diabetes during pregnancy, ethnicity, sedentary lifestyle, and excessive caloric intake [2]. Identification of these high-risk individuals can prompt more intensive counseling and early intervention with the goal of preventing the development of obesity and its complications. The use of automated BMI calculation and electronic medical records can facilitate identification of overweight and obesity status when already present and improve counseling rates [15].

Obesity due to excess nutrition is typically associated with linear growth acceleration that occurs subsequent to and to a lesser degree than the percentile shift in weight gain. A declining height velocity associated with obesity, therefore, is concerning and should prompt investigation for endocrine disease such as hypothyroidism, glucocorticoid excess, and growth hormone deficiency. Additional factors that warrant further investigation and/or referral include growth trajectory significantly below genetic potential, developmental delay, and dysmorphic features. A complete physical examination should be performed to evaluate for signs consistent with these conditions (eg, violaceous striae in glucocorticoid excess, microcephaly, and small hands/feet in Prader-Willi syndrome), and signs of obesity-associated comorbidities (eg, acanthosis nigricans). Accurate height, weight, BMI calculation, and blood pressure assessment using an appropriately sized cuff are essential.

While BMI screening is valuable, as noted above it is important to appreciate that insulin resistance (and other obesity-related comorbidities) can develop even when BMI is below the 95th percentile. Detailed history and physical examination can help identify these comorbidities of excess adiposity and guide diagnostic evaluation. Independent risk factors for insulin resistance and the development of type 2 diabetes include family history of diabetes, minority race/ethnicity, elevated waist circumference, and poor fitness level [18–20].

Further History

The patient reports skipping breakfast on most days, eats lunch at school, and snacks on chips and soda after school. Dinner is variable but usually contains carbohydrates and a protein and rarely includes vegetables. Family eats “take-out” about 3 times per week. Patient reports spending 3 hours a day watching television and playing on computer. He had gym last semester but currently reports very limited to no physical activity on most days.

•  What are effective ways to raise the issue of obesity during an office visit?

Despite the strong connection of obesity with adverse health outcomes, discussion of obesity in routine office settings can be difficult and is often limited by many factors such as time, training, availability of support services, perceived lack of patient motivation, and low outcome expectations [21,22]. Perhaps most challenging is tactfully handling the stigma associated with obesity, which can make discussion awkward and difficult for patients, parents, and providers. To do this, efforts to choose words that convey a nonjudgmental message while maintaining focus on obesity as a health concern are helpful. For example, terms such as “fat” and “obese” are often perceived as stigmatizing and blaming while using the term “unhealthy weight” is less pejorative and can be motivating [23]. It can also be important to acknowledge and emphasize that some individuals are more susceptible to weight gain and its consequences than others and as a result can tolerate fewer calories without unwanted weight gain and health problems. These approaches shift the focus of the discussion toward the goal of restoring and preserving health rather than changing physical appearance without placing blame on the individual and/or family. Motivational interviewing techniques which can be performed effectively even in short office visits can help to actively engage families, reveal familial perception of obesity and assess readiness to change [2]. Their use may also improve the efficacy of other interventions [24].

Case Continued

The patient and his mother were asked if they had any concerns today, including concerns about future health. Mother expressed worry about the potential for diabetes given their family history. The clinician used this as an opportunity to discuss pertinent factors associated with insulin resistance and type 2 diabetes, including modifiable factors such as diet, fitness level, and weight.

•  Should this non-obese adolescent be assessed for obesity comorbidities?

Yes. While there are multiple guidelines available for pediatric screening, all highlight the importance of obtaining individualized risk assessment to guide the extent of diagnostic workup. An Expert Committee comprised of representatives from 15 professional organizations appointed 3 writing groups to review the literature and recommend approaches to prevention, assessment, and treatment. Because effective strategies remain poorly defined, the writing groups used both available evidence and expert opinion to develop the recommendations [2]. In addition to routine blood pressure monitoring and universal lipid screening, the Expert Committee recommends obtaining additional laboratory assessment for obese children (BMI ≥ 95th percentile) including a fasting glucose and ALT/AST levels every 2 years starting at age 10 years. For overweight children (BMI > 85th percentile), the Expert Committee recommends obtaining these studies if additional risk factors are present [2]. The American Diabetes Association (ADA) recommends obtaining diabetes screening in all children classified as overweight (defined as either a BMI > 85th percentile for age and sex, weight for height > 85th percentile, or weight > 120% of ideal for height) once every 3 years beginning at age 10 or at pubertal onset (whichever is earliest) when 2 additional risk factors for diabetes are also present, including: (1) history of type 2 diabetes in a first- or second-degree relative, (2) race/ethnicity with increased risk for diabetes development (eg, Native American, African American, Latino, Asian American), (3) signs of insulin resistance or conditions associated with insulin resistance (eg, small for gestational age, polycystic ovary syndrome, hypertension) and (4) maternal history of gestational diabetes during pregnancy [25]. The ADA recommendations for diabetes screening test include either fasting plasma glucose, HgA1C, or oral glucose tolerance test [25].

With a BMI at the 85th percentile, on initial assessment our patient might be perceived as being at moderate or even low risk for obesity and its associated comorbidities. However, a more careful review has elicited several additional risk factors suggesting more appropriate classification in the high-risk category. First, family history of type 2 diabetes on both sides of his family suggests a degree of genetic predisposition. Second, Hispanic ethnicity is known to be independently associated with insulin resistance, type 2 diabetes, and NAFLD [26]. Moreover, physical exam findings of an elevated waist circumference (90th percentile for age and ethnicity [27]) and acanthosis nigricans are also supportive of insulin resistance. As a result, despite having a BMI at the 85th percentile, this adolescent is at high risk and further evaluation is warranted based on both Expert Committee and ADA guidelines. Detailed discussion of certain risk factors is outlined below.

Pattern of Adipose Tissue Distribution: Utility of BMI and Waist Circumference

BMI is a clinical tool that serves as a surrogate marker of adiposity, but since it does not directly measure body fat it provides a statistical, rather than inherent, description of risk. While it is a relatively specific marker (~95%) with moderately high sensitivity and positive predictive value (~70–80%) at BMI levels > 95th percentile, sensitivity and positive predictive value decrease substantially at lower BMI percentiles (PPV 18% in a sample of overweight children) [28]. Current CDC BMI percentile charts consider age and gender differences but do not take into account sexual maturation level or race/ethnicity, both of which are independently correlated with BMI [29]. That is, children with similar BMIs of the same age and sex may exhibit varying degrees of adiposity and risk attributable to their pubertal stage and/or ethnicity [30]. For example, many studies have demonstrated that at the same BMI percentile, Asian Americans tend to have more adiposity compared with non-Hispanic whites [31], whereas African Americans tend to have more fat-free mass compared with non-Hispanic whites [32]. As a result of these differences, some advocate for adjusting cut-offs for BMI based on ethnicity and/or utilizing alternative measures of adiposity such as waist circumference or waist to hip ratio. However, in order for these latter methods to be useful, standardized methods of measurement and normative reference values must be developed. In summary, though BMI can be a useful screening tool, it is an indirect measure of adiposity and cannot discern adipose distribution. Therefore, it is important to remember that when used alone, BMI may overlook children with high inherent risk for disease.

Abdominal adiposity is associated with increased metabolic risk, including insulin resistance, type 2 diabetes, hypertension, cardiovascular disease, and mortality [33]. Waist circumference, a marker of abdominal/truncal obesity, has been considered as a potential marker in place of or in combination with BMI to identify children with increased metabolic risk. In adults, it is well established that an elevated waist circumference is associated with increased health risk, even among those within a normal-weight BMI category [34], and it is recommended that waist circumference in addition to BMI be used to assess health risk [35]. Many studies have documented similar associations between increased waist circumference and metabolic risk factors in childhood and adolescence [36–38]. Specifically, waist circumference is an independent predictor of both insulin sensitivity and increased visceral adiposity tissue (VAT) in children and adolescents [39]. Waist circumference can provide valuable information beyond BMI alone and may be beneficial in the clinical setting in identifying adolescents at risk for obesity-associated comorbidities.

The use of waist circumference in routine clinical settings is complicated and limited by many factors. First, there is no universal method for waist circumference measurement. For example, the WHO recommends measurement at the midpoint between the superior iliac crest and inferior most rib, while the NIH and NHANES recommend measurement immediately above the iliac crest [40]. Since nationally representative data published by Fernandez et al [27] uses the latter method for waist circumference measurement, we recommend this method to allow for comparison of waist circumference percentile with available data for age, sex, and ethnicity. Second, while absolute waist circumference values are used as cut-offs in adulthood, in childhood use of waist circumference percentiles would be more appropriate to account for expected increases during childhood and changes related to pubertal stage. Unfortunately, a lack of standardized waist circumference percentile charts makes meaningful interpretation of waist circumference difficult. Moreover, even if standardized waist circumference percentile charts were developed, there are currently no accepted standards defining an abnormally elevated waist circumference percentile.

Many studies have identified increased metabolic risk factors associated with a waist circumference at or above the 90th percentile for age [41–43]. Based on these studies, the International Diabetes Federation uses waist circumference > 90th percentile as part of the criteria for metabolic syndrome in adolescents. While this ensures a high degree of specificity, use of waist circumference at the 75th percentile would allow for increased sensitivity. For example, Lee et al found that for insulin resistance use of waist circumference at the 75th percentile compared with the 90th percentile increased sensitivity from 61.3% to 86.1% while decreasing specificity from 91.4% to 71.5% [44]. Thus, for individuals at low risk based on history and clinical findings, a waist circumference threshold at the 90th percentile might be reasonable, while for individuals with additional risk factors for insulin resistance use of a lower waist circumference threshold (such as the 75th percentile) may be beneficial. Finally, since risk for insulin resistance and type 2 diabetes varies by race/ethnicity, which may correspond with visceral fat deposition, utilizing various threshold cut-offs based on race/ethnicity has been proposed by some. However, current data do not support this practice [44]. In summary, though there are many challenges to using waist circumference measurements in routine settings, if performed correctly determination of elevated waist circumference measurement can provide some additional information on an individual’s overall risk for complications of obesity.

Acanthosis Nigricans as an Indicator of Insulin Resistance

Insulin resistance, independent of adiposity, is associated with increased risk for type 2 diabetes, cardiovascular disease, ovarian hyperandrogenism, and certain forms of cancer [45]. Identification of insulin resistance in the clinical setting can lead to appropriate intervention (both lifestyle and, when warranted, pharmacologic) to reduce insulin resistance and improve health outcomes. Several risk factors for insulin resistance have been discussed above. Acanthosis nigricans, which is characterized by thick, velvety hyperpigmentation of the skin in intertriginous areas such as the neck and axilla, is an additional finding that is associated with insulin resistance. Its pathogenesis is felt to be related to activation of the IGF-1 receptor by high levels of circulating insulin [46]. Acanthosis nigricans is independently associated with fasting insulin levels and impaired glucose tolerance [47,48]. In addition to increased insulin resistance, one study found that 1 in 4 youths with acanthosis nigricans demonstrated abnormalities in glucose homeostasis and identified 2 individuals with diabetes who would not have been diagnosed based on fasting glucose levels alone [48]. The presence of acanthosis nigricans should alert the clinician to the likelihood of insulin resistance and prompt further investigation. Of note, the prevalence of acanthosis nigricans is increased among African American and Hispanic patients [49,50].

• What laboratory evaluation is warranted and practical in the office setting?

Laboratory evaluation is warranted when obesity or risk factors for comorbidities of obesity are present. At minimum, this should include lipid screening, liver enzymes (ALT and AST), and fasting glucose as outlined above. This approach, however, fails to identify all individuals with obesity-associated comorbidities. ALT is only moderately sensitive in detecting NAFLD [51], and fasting glucose levels only become abnormal when compensation for the degree of insulin resistance is inadequate to maintain normal fasting glucose homeostasis. As a result, while abnormal results on screening are suggestive of disease, normal results do not necessarily confer its absence. Thus, for high-risk subjects, additional testing and/or referral should be considered.

The hyperinsulinemic euglycemic clamp is the “gold standard” for measuring insulin sensitivity, but it is labor intensive and impractical in routine clinical settings. Alter-native approaches using surrogate markers have commonly been utilized, including fasting insulin and glucose levels and 2-hour oral glucose tolerance test (OGTT). The utility of these approaches in the clinical setting has been limited by several factors, including lack of a universal insulin assay. However, despite these limitations, obtaining fasting insulin in addition to fasting glucose or performing 2-hour OGTT can be useful in providing crude estimates of insulin resistance in certain high-risk subpopulations [52,53]. Recently, the ADA added HgA1C measurement as diagnostic criteria for pre-diabetes (5.7%–6.4%) and diabetes (> 6.5%) [54]. Benefits of HgA1C measurement include reliable measurements in nonfasting conditions and reflection of glucose over time. Studies in pediatric patients have shown the usefulness of HgA1C as a measure of future glucose intolerance or diabetes [55]. When fasting insulin or HgA1C are elevated and/or OGTT is abnormal, this suggests the presence of insulin resistance and need for intervention.

Proposed guideline criteria for the diagnosis of “metabolic syndrome” in adolescents include the following: (1) glucose intolerance, (2) elevated waist circumference or BMI, (3) hypertriglyceridemia, (4) low HDL, and 5) hypertension. There is no universal definition for metabolic syndrome in childhood and adolescence, and cut-off values in each category vary by study group [41–43,56]. When insulin resistance is present, it should alert the clinician to the increased likelihood for metabolic syndrome and NAFLD, and additional screening should be performed accordingly. NAFLD is present in about 25% of all overweight children and is strongly associated with insulin resistance and the metabolic syndrome [57]. Hispanic patients have an increased prevalence of NAFLD compared with patients of other ethnicities [58,59]. Elevated liver transaminases (AST and ALT) are commonly used to screen for NAFLD. However, since these markers are indicative of hepatocellular damage, they may remain within normal limits and correlate poorly with early steatosis [51]. Alternative approaches have been proposed in high-risk populations to detect early steatosis and improve long-term prognosis [60].

Case Continued

The patient underwent laboratory assessment that included fasting glucose and insulin, fasting lipid panel, and ALT. Results were suggestive of insulin resistance and metabolic syndrome and included the following: fasting glucose 108 mg/dL, fasting insulin 65 uIU/mL (reference range 3–25), HgA1C 5.9% (reference range 4.2–5.8), total cholesterol 178 mg/dL, HDL cholesterol 35 mg/dL, LDL cholesterol 110 mg/dL, triglycerides 157 mg/dL, and ALT 40 u/L. Blood pressure, as noted above, is at the 95th percentile for age and height.

• What is the recommended approach to intervention? When is referral warranted?

Staged Obesity Treatment

The initial stage, termed “Prevention Plus,” is similar to obesity prevention strategies and is focused on institution of healthy dietary and activity lifestyle habits tailored to the individual and family. Frequent follow-up and monitoring can be helpful and should be offered to families. Failure to demonstrate progress after 3 to 6 months warrants advancement to Stage 2, “Structured Weight Management,” which includes a planned diet with structured meals and snacks, reduction of screen time to 1 hour or less, 60 minutes of supervised physical activity, use of logs to document diet and activity levels, monthly follow-ups and positive reinforcement for achieving goals. Consultation with a dietician and health psychologist/counseling can be helpful at this level.

If no progress is noted after 3 to 6 months, progression to Stage 3, “Comprehensive Multidisciplinary Intervention,” is recommended. This stage emphasizes the importance of a multidisciplinary team including behavioral counselor, registered dietician and exercise specialist in addition to a medical provider. Current evidence suggests modest improvement of obesity and related comorbidities in adolescents participating in multidisciplinary weight management programs [62,63]. While these interventions can be implemented in community settings, coordination in this setting can be difficult and implementation more commonly involves weight management programs in tertiary care centers. Access to such programs can be limited by geographic accessibility, insurance coverage and physician awareness of available programs/resources [64]. Utilization of technology such as telemedicine visits is one way to overcome limited access [65]. Finally, Stage 4 “Tertiary Care Intervention”, involving discussion of pharmacologic or intensive/surgical weight loss options, can be considered for those who fail to show progression after successful intervention of previous stages.

Specialty Referral

Referral to multidisciplinary clinics specializing in childhood obesity is warranted when obesity is particularly severe, comorbidities are present at baseline, or no improvement is noted after 6 months of intense lifestyle intervention. Insulin resistance evidenced by impaired glucose tolerance (abnormal fasting or 2-hour glucose levels), HgA1C in the pre-diabetes range or higher (> 5.7%), or persistently elevated fasting insulin levels after 3 to 6 months of intensive lifestyle modification should prompt referral for consideration of metformin initiation. Metformin can reduce insulin resistance in children and may reduce progression from impaired glucose tolerance to diabetes [66]. For dyslipidemia related to metabolic syndrome, lifestyle interventions are most likely to be efficacious. Referral to preventative cardiology for consideration of pharmacologic intervention should be considered when severe hypertriglyceridemia is present (> 400 mg/dL) or LDL remains elevated after implementation of healthy lifestyle interventions. Elevations in ALT are highly specific for NAFLD and should prompt referral to gastroenterology. In addition, given the poor sensitivity of ALT for detection of early hepatic steatosis, referral might be considered when ALT is in the high normal ranges, especially in those with increased risk such as Hispanic patients [67]. Finally, when signs of obstructive sleep apnea are present, a sleep study should be performed. In summary, while specialty referral can aid targeted treatment of obesity-related morbidities, the central role of the primary care clinician in anticipating and preventing or minimizing their occurrence remains paramount.

Case Conclusion

The patient was referred to a multidisciplinary obesity clinic where he and his family met with dietician, exercise physiologist, health psychologist, and endocrinologist. Healthy lifestyle modifications with specific goals were instituted, including elimination of all calorie-containing beverages (except daily recommended intake of fat-free milk) and initiation of physical activity for 30 minutes a day 5 days per week. He was started on metformin due to glucose intolerance and increased risk for diabetes. Follow-up occurred at monthly intervals for the first 3 months. Additional goals and lifestyle interventions were implemented at each follow-up. At 6 months’ follow-up, the patient’s height was 164 cm, weight was stable at 58.4 kg and BMI was 21.7 (79th percentile). Blood pressure was slightly improved at 123/80 mm Hg. Repeat labs showed mild but consistent improvement in all areas. Specifically, fasting glucose 100 mg/dL, fasting insulin 40 uIU/mL, HgA1C 5.6%, total cholesterol 162 mg/dL, HDL cholesterol 40 mg/dL, LDL cholesterol 105 mg/dL, triglycerides 140 mg/dL, and ALT 38 u/L. The patient continues to be monitored closely with goal to improve metabolic health and long-term health outcomes.

Summary

Childhood obesity is a major public health concern. The health impact of obesity on children is broad and profound. Since treatment of obesity is often unsuccessful, prevention of obesity or early detection of its health consequences are crucial responsibilities and opportunities for primary care clinicians. While clinical guidelines can be instructive, application of clinical guidelines must be tailored to individual adolescent patients according to accompanying risk factors. This review aims to help clinicians stratify risk based on susceptibility to development of insulin resistance and other morbidities associated with adolescent obesity. While the enormity of the obesity epidemic can appear overwhelming to primary care providers, they remain in the best position to initiate early intervention strategies. Coordinating care between primary care providers and specialty clinics will continue to be an important partnership for the care of those experiencing health-threatening effects of adolescent obesity.

Corresponding author: Aaron L Carrel, MD, University of Wisconsin, 600 Highland Ave, H4-436, Madison, WI 53792.

Financial disclosures: Drs. Seibert and Carrel have received fellowship grants from Genentech.

Series Editor: Arthur T. Skarin, MD, FACP, FCCP

Melanoma is the sixth most common cancer in the United States and the leading cause of deaths among all cutaneous malignancies. In 2012, it was estimated that approximately 75,000 individuals were diagnosed with melanoma and more than 9000 died. The incidence of melanoma is rising the fastest among all major malignancies, and the lifetime risk of melanoma among men and women now exceeds 1 in 68, as compared with 1:1500 in 1930.4 The incidence of melanoma is predicted to continue increasing, and there has been no corresponding decrease in mortality. This case-based review summarizes the etiology, risk factors, clinical presentation, and management of cutaneous melanomas, which comprise the majority of melanoma cases. The biology and management for other noncutaneous melanomas (such as mucosal or ocular melanomas) are beyond the scope of this review.

To read the full article in PDF:

Click here

Series Editor: Arthur T. Skarin, MD, FACP, FCCP

Melanoma is the sixth most common cancer in the United States and the leading cause of deaths among all cutaneous malignancies. In 2012, it was estimated that approximately 75,000 individuals were diagnosed with melanoma and more than 9000 died. The incidence of melanoma is rising the fastest among all major malignancies, and the lifetime risk of melanoma among men and women now exceeds 1 in 68, as compared with 1:1500 in 1930.4 The incidence of melanoma is predicted to continue increasing, and there has been no corresponding decrease in mortality. This case-based review summarizes the etiology, risk factors, clinical presentation, and management of cutaneous melanomas, which comprise the majority of melanoma cases. The biology and management for other noncutaneous melanomas (such as mucosal or ocular melanomas) are beyond the scope of this review.

To read the full article in PDF:

Click here

Series Editor: Arthur T. Skarin, MD, FACP, FCCP

Melanoma is the sixth most common cancer in the United States and the leading cause of deaths among all cutaneous malignancies. In 2012, it was estimated that approximately 75,000 individuals were diagnosed with melanoma and more than 9000 died. The incidence of melanoma is rising the fastest among all major malignancies, and the lifetime risk of melanoma among men and women now exceeds 1 in 68, as compared with 1:1500 in 1930.4 The incidence of melanoma is predicted to continue increasing, and there has been no corresponding decrease in mortality. This case-based review summarizes the etiology, risk factors, clinical presentation, and management of cutaneous melanomas, which comprise the majority of melanoma cases. The biology and management for other noncutaneous melanomas (such as mucosal or ocular melanomas) are beyond the scope of this review.

To read the full article in PDF:

Click here

CASE Nearly naked
Mr. A, age 68, is found sitting in his car, wear­ing only a jacket, underpants, and boots. He speaks of spreading a message about Osama bin Laden and “taking a census.” Police officers bring him to a hospital emergency depart­ment for evaluation.

The examining clinician determines that Mr. A is a danger to himself and others because of mental illness, leading to admission to our state psychiatric hospital.

Mr. A’s wife describes recent spend­ing sprees with large purchases. She had obtained a restraining order against her hus­band because of his threatening remarks and behaviors. Within days of the order issuance, he got a home equity loan and purchased a $300,000 house.

The medical history is notable for type 2 diabetes mellitus. Although he is not tak­ing medications, his blood sugar is well controlled. Other than an initial resting heart rate of 116 beats per minute, vital signs are stable and within normal lim­its. Physical examination is unremarkable. Screening laboratory studies are notable for mildly elevated hepatic function, which approaches normal range several days after admission.

Mr. A reports a remote history of alcohol abuse but says he had not been drinking recently, and does not detail his pattern of use. Urine toxicology screen is negative for all substances of abuse.

Mental status examination reveals dishev­eled appearance, motor agitation, pressured speech, labile affect, loosening of associa­tions, grandiose delusions, and auditory hal­lucinations. Mr. A’s thought processes are grossly disorganized, such that we could not gather a meaningful history. He believes God is speaking directly to him about plans to build a carousel at Disney World. He makes strange gestures with his hands throughout the inter­view, as if attempting to trace the shapes of letters and numbers. He frequently speaks of seeing an array of colors. Cognitive examina­tion reveals a score of 5 of 30 on the Montreal Cognitive Assessment (Figure 1), indicating a severe impairment in neurocognitive func­tioning. He demonstrates limited insight and markedly impaired judgment, and denies hav­ing a mental illness.

What should be the next step in managing Mr. A?
a) obtain records from other facilities and collateral history
b) start an antipsychotic
c) order a brain MRI
d) start an alcohol withdrawal protocol

The authors’ observations
Mr. A showed elements of mania, psycho­sis, and delirium. We considered a broad differential diagnosis (Table). Mr. A initially could not provide reliable or accurate information. The least invasive next step was to obtain additional history from his wife and other medical records to refine the differential diagnosis.

HISTORY Bizarre behavior
Mr. A allows staff to speak with his wife and obtain records from a psychiatric hospitaliza­tion 3 years earlier. Mrs. A reports significant and rapid changes in her husband’s behav­ior and personality over 3 months, but does not describe a recent alcohol relapse. Mr. A sleeps very little, remaining awake and active throughout the night. He frequently rear­ranges the furniture in their home for no clear reason. Once, he knocked on the door of a young female neighbor asking if she found him attractive.

Mr. A has a significant criminal history. Approximately 30 years ago, he was charged with attempted murder of his ex-wife and he had faced charges of attempted kidnapping and assaulting a police officer. However, he has no recent legal issues.

Mr. A has a history of episodes that are simi­lar to this presentation. Seven years ago, he impulsively purchased a $650,000 house after his fourth wife died. He then had a $90,000 heart-shaped pool installed. He also drove a tractor through his stepdaughter’s car for no apparent reason. Also, 3 years ago, he displayed symptoms similar to his current presentation, including insomnia, irritability, and grandios­ity. He engaged in strange behaviors, such as dressing up and imitating homeless people at his church.

During the hospitalization 3 years ago, cli­nicians gave Mr. A a diagnosis of bipolar dis­order, current episode manic, and delirium of an unclear cause. A medical workup, includ­ing brain MRI, did not uncover a basis for his delirium. Antipsychotics (risperidone and per­phenazine) and mood stabilizers (lithium and valproic acid), stabilized his condition; after 7 weeks, Mr. A was discharged, but he did not pursue outpatient psychiatric care.

What is the most likely DSM-5 diagnosis?
   a) major neurocognitive disorder (dementia)
   b) alcohol use disorder (eg, Wernicke- Korsakoff syndrome)
   c) delirium secondary to mania
   d) psychotic disorder

The authors’ observations
DSM-5¹ suggests a stepwise approach to diagnosis, with consideration of:
   • signs and symptoms
   • substance use
   • general medical condition
   • developmental conflict or stage
   • whether a mental disorder is present.

Mr. A’s age and severe cognitive impair­ment raise the possibility of dementia. Rapid onset, history of similar episodes, and apparent inter-episode recovery make dementia unlikely. The history of alcohol abuse and mildly elevated hepatic func­tion tests suggest a substance use disorder such as Wernicke-Korsakoff syndrome or a withdrawal syndrome. However, there is no evidence of excessive alcohol use over the past several months, toxicology studies were negative, and vital signs were stable. General medical causes for Mr. A’s presen­tation, such as hypoglycemia, head trauma, intracranial infection, and metabolic dis­turbance were considered, but physical examination and laboratory studies did not suggest any condition that would explain his condition.

Mr. A’s previous psychiatric hospitaliza­tion is critical in clarifying the more likely diagnosis. A similar presentation yielded the diagnosis of bipolar disorder, manic phase. Our working diagnosis, therefore, was bipolar disorder with features of delir­ious mania.

Delirious mania
Delirious mania was first described by Luther Bell in 1849 and is characterized by an acute and simultaneous onset of mania— severe insomnia, poor judgment, grandios­ity, excitement, emotional lability, bizarre hallucinations, and delusions—and delir­ium—altered consciousness, disorientation, and confusion.^2,3 Although there are no diag­nostic criteria, some authors suggest that delirious mania is characterized by inappro­priate toileting, denudation, profound lack of sleep, and episodic memory impairment that can last hours or days.⁴ Catatonia fre­quently is seen with delirious mania.⁵ Initial case descriptions described a high mortality rate, approaching 75% of patients.⁶ There is little published literature and no classifica­tion of delirious mania in DSM-5.1 Estimates are that delirium is concomitant in 20% to 33% of patients with mania.^7,8

Several theories try to clarify the underly­ing etiology of delirious mania. Jacobowski et al⁹ summarized the etiology and pro­posed that it is:
   • 1 of 3 types of mania, including: acute and delusional manias, as initially pro­posed by Kraeplin
   • a severe form of catatonia
   • a condition akin to, but distinct from, delirium with similar underlying medi­cal causes
   • a primary psychiatric disorder under­lying the cause of delirium.

EVALUATION Brain changes
For several days, Mr. A continues to engage in strange behavior. He tries to take patients’ belongings, is denudative, crawls on floors, licks walls, is unable to feed himself, and exhib­its odd motor movements with purposeless motor activity.

We consult our internal medicine team to iden­tify treatable, medical causes. Results of serum B12, thyroid-stimulating hormone, and rapid plasma reagin studies are within normal limits. Urinalysis is negative. A brain MRI reveals numerous white-matter T2-weighted and FLAIR hyperintensities, indicating small-vessel ischemic changes that are consistent with the findings of an MRI 3 years ago. A sleep-deprived EEG with temporal leads obtained on Day 4 of hospitalization demonstrates a diffusely slow and marginally to poorly organized background, believed to indicate global cerebral dysfunction that is most consistent with nonfocal global encephalopathy. There is no seizure activity. We do not perform a lumbar puncture because of Mr. A’s absence of focal neurologic deficits, lack of fever, and normal white blood cell count.

What is the most appropriate treatment?
   a) electroconvulsive therapy (ECT)
   b) high-dose benzodiazepine
   c) mood stabilizer
   d) antipsychotic

The authors’ observations
We strongly suspect that Mr. A has delirious mania. Symptoms and signs of mania include labile mood, excessive spending, grandios­ity, insomnia, and psychosis together with delirium (marked disorientation, confusion). We ascribed Mr. A’s odd motor behaviors to catatonia, a hallmark of delirious mania. The literature has little description of EEG find­ings in suspected cases of delirious mania; however, abnormal EEG tracings have been reported.¹⁰ We also speculated that Mr. A’s EEG reflected effects produced by his pre­scribed antipsychotic regimen.

Treatment
There is no clear consensus on treating deliri­ous mania. Because catatonia is a key feature of delirious mania—whether etiologically or as a prominent sign of the condition—ECT and benzodiazepines are proposed as pri­mary treatments. In a study of 16 patients with delirious mania, Karmacharya et al4 found ECT to be effective, with patients showing improvement after 1 to 4 treat­ments. Lee et al¹⁰ reported similar findings. Although a high-dose benzodiazepine is not as effective as ECT, a 1-time oral dose of 3 to 4 mg of lorazepam has been used to treat delirious mania.

The efficacy of antipsychotic and mood-stabilizing pharmacotherapy is not clear. Bond³ described 3 cases in which patients were treated effectively with a typical anti­psychotic (haloperidol or chlorpromazine) and lithium. Jung and Lee_¹¹demonstrated the efficacy of atypical antipsychotics, with a marked improvement in symptoms within 1 week. However, other studies do not sup­port these findings. Karmacharya et al⁴ found that typical antipsychotics 1) make the clinical picture worse by increasing extrapy­ramidal symptoms and 2) produce incon­sistent effects. Mood stabilizers sometimes proved beneficial.

Karmacharya et al⁴ further argued that the delay in improvement seen with any antipsychotics and mood stabilizers suggest they should not be considered a first-line treatment. These discordant findings are the result of a small number of studies and a lack of understanding of the exact nature of delirious mania.


TREATMENT Quick Response
Mr. A’s symptoms rapidly resolve with a com­bination of quetiapine, 800 mg/d, haloperidol, 10 mg/d, and lithium, 1,200 mg/d. His mood returns to euthymia and his psychotic symptoms abate. He is able to attend to all activities of daily living. Mental status clears and he is fully oriented and able to hold a logical conversation. He scores 28 out of 30 on a subsequent Montreal Cognitive Assessment, administered 11 days after the ini­tial assessment (Figure 2), indicating normal neurocognitive function. He returns to his baseline level of functioning and is discharged in psychiatrically stable condition. Mr. A has no recollection of the bizarre behaviors he dis­played earlier in his hospitalization.

The authors’ observations
We started Mr. A on antipsychotics because of his initial level of agitation. In reviewing pharmacotherapy options for Mr. A’s mania and delirium, we contemplated several options. Quetiapine and lithium were cho­sen after a review of outside hospital records demonstrated a combination of a mood sta­bilizer and an antipsychotic was effective in treating a previous similar episode, which led to remission of Mr. A’s symptoms. We chose quetiapine because of it highly sedat­ing properties, suspecting that it would help treat his insomnia. We thought that the risk that lithium would make delirium worse was mitigated by Mr. A’s previous therapeu­tic response to it. Haloperidol was added for treating delirium, given its more potent D2 antagonism. Mr. A responded quickly to these interventions.

We did not consider ECT at the begin­ning of Mr. A’s admission, and we avoided sedative-hypnotic agents because we were concerned that a benzodiazepine might make his delirium worse. In light of avail­able data suggesting that ECT and ben­zodiazepines are preferred treatments for delirious mania, it is noteworthy that Mr. A responded so robustly and rapidly to an antipsychotic and a mood stabilizer.

Bottom Line
Consider delirious mania in any patient who has a history of bipolar disorder presenting with co-occuring symptoms of mania and delirium. Collateral information is vital to establishing a diagnosis. With suspected delirium, rule out concomitant reversible medical problems. Electroconvulsive therapy, high-dose benzodiazepines, antipsychotics, and mood stabilizers have shown efficacy.

Related Resources
• Nunes AL, Cheniaux E. Delirium and mania with catatonic fea­tures in a Brazilian patient: response to ECT. J Neuropsychiatry Clin Neurosci. 2014;26(1):E1-E3.
• Danivas V, Behere RV, Varambally S, et al. Electroconvulsive ther­apy in the treatment of delirious mania: a report of 2 patients. J ECT. 2010;26(4):278-279.

Drug Brand Names
Chlorpromazine • Thorazine               Perphenazine • Trilafon
Haloperidol • Haldol                           Quetiapine • Seroquel
Lithium • Eskalith                              Risperidone • Risperdal
Lorazepam • Ativan                           Valproic acid • Depakene

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

CASE Nearly naked
Mr. A, age 68, is found sitting in his car, wear­ing only a jacket, underpants, and boots. He speaks of spreading a message about Osama bin Laden and “taking a census.” Police officers bring him to a hospital emergency depart­ment for evaluation.

The examining clinician determines that Mr. A is a danger to himself and others because of mental illness, leading to admission to our state psychiatric hospital.

Mr. A’s wife describes recent spend­ing sprees with large purchases. She had obtained a restraining order against her hus­band because of his threatening remarks and behaviors. Within days of the order issuance, he got a home equity loan and purchased a $300,000 house.

The medical history is notable for type 2 diabetes mellitus. Although he is not tak­ing medications, his blood sugar is well controlled. Other than an initial resting heart rate of 116 beats per minute, vital signs are stable and within normal lim­its. Physical examination is unremarkable. Screening laboratory studies are notable for mildly elevated hepatic function, which approaches normal range several days after admission.

Mr. A reports a remote history of alcohol abuse but says he had not been drinking recently, and does not detail his pattern of use. Urine toxicology screen is negative for all substances of abuse.

Mental status examination reveals dishev­eled appearance, motor agitation, pressured speech, labile affect, loosening of associa­tions, grandiose delusions, and auditory hal­lucinations. Mr. A’s thought processes are grossly disorganized, such that we could not gather a meaningful history. He believes God is speaking directly to him about plans to build a carousel at Disney World. He makes strange gestures with his hands throughout the inter­view, as if attempting to trace the shapes of letters and numbers. He frequently speaks of seeing an array of colors. Cognitive examina­tion reveals a score of 5 of 30 on the Montreal Cognitive Assessment (Figure 1), indicating a severe impairment in neurocognitive func­tioning. He demonstrates limited insight and markedly impaired judgment, and denies hav­ing a mental illness.

What should be the next step in managing Mr. A?
a) obtain records from other facilities and collateral history
b) start an antipsychotic
c) order a brain MRI
d) start an alcohol withdrawal protocol

The authors’ observations
Mr. A showed elements of mania, psycho­sis, and delirium. We considered a broad differential diagnosis (Table). Mr. A initially could not provide reliable or accurate information. The least invasive next step was to obtain additional history from his wife and other medical records to refine the differential diagnosis.

HISTORY Bizarre behavior
Mr. A allows staff to speak with his wife and obtain records from a psychiatric hospitaliza­tion 3 years earlier. Mrs. A reports significant and rapid changes in her husband’s behav­ior and personality over 3 months, but does not describe a recent alcohol relapse. Mr. A sleeps very little, remaining awake and active throughout the night. He frequently rear­ranges the furniture in their home for no clear reason. Once, he knocked on the door of a young female neighbor asking if she found him attractive.

Mr. A has a significant criminal history. Approximately 30 years ago, he was charged with attempted murder of his ex-wife and he had faced charges of attempted kidnapping and assaulting a police officer. However, he has no recent legal issues.

Mr. A has a history of episodes that are simi­lar to this presentation. Seven years ago, he impulsively purchased a $650,000 house after his fourth wife died. He then had a $90,000 heart-shaped pool installed. He also drove a tractor through his stepdaughter’s car for no apparent reason. Also, 3 years ago, he displayed symptoms similar to his current presentation, including insomnia, irritability, and grandios­ity. He engaged in strange behaviors, such as dressing up and imitating homeless people at his church.

During the hospitalization 3 years ago, cli­nicians gave Mr. A a diagnosis of bipolar dis­order, current episode manic, and delirium of an unclear cause. A medical workup, includ­ing brain MRI, did not uncover a basis for his delirium. Antipsychotics (risperidone and per­phenazine) and mood stabilizers (lithium and valproic acid), stabilized his condition; after 7 weeks, Mr. A was discharged, but he did not pursue outpatient psychiatric care.

What is the most likely DSM-5 diagnosis?
   a) major neurocognitive disorder (dementia)
   b) alcohol use disorder (eg, Wernicke- Korsakoff syndrome)
   c) delirium secondary to mania
   d) psychotic disorder

The authors’ observations
DSM-5¹ suggests a stepwise approach to diagnosis, with consideration of:
   • signs and symptoms
   • substance use
   • general medical condition
   • developmental conflict or stage
   • whether a mental disorder is present.

Mr. A’s age and severe cognitive impair­ment raise the possibility of dementia. Rapid onset, history of similar episodes, and apparent inter-episode recovery make dementia unlikely. The history of alcohol abuse and mildly elevated hepatic func­tion tests suggest a substance use disorder such as Wernicke-Korsakoff syndrome or a withdrawal syndrome. However, there is no evidence of excessive alcohol use over the past several months, toxicology studies were negative, and vital signs were stable. General medical causes for Mr. A’s presen­tation, such as hypoglycemia, head trauma, intracranial infection, and metabolic dis­turbance were considered, but physical examination and laboratory studies did not suggest any condition that would explain his condition.

Mr. A’s previous psychiatric hospitaliza­tion is critical in clarifying the more likely diagnosis. A similar presentation yielded the diagnosis of bipolar disorder, manic phase. Our working diagnosis, therefore, was bipolar disorder with features of delir­ious mania.

Delirious mania
Delirious mania was first described by Luther Bell in 1849 and is characterized by an acute and simultaneous onset of mania— severe insomnia, poor judgment, grandios­ity, excitement, emotional lability, bizarre hallucinations, and delusions—and delir­ium—altered consciousness, disorientation, and confusion.^2,3 Although there are no diag­nostic criteria, some authors suggest that delirious mania is characterized by inappro­priate toileting, denudation, profound lack of sleep, and episodic memory impairment that can last hours or days.⁴ Catatonia fre­quently is seen with delirious mania.⁵ Initial case descriptions described a high mortality rate, approaching 75% of patients.⁶ There is little published literature and no classifica­tion of delirious mania in DSM-5.1 Estimates are that delirium is concomitant in 20% to 33% of patients with mania.^7,8

Several theories try to clarify the underly­ing etiology of delirious mania. Jacobowski et al⁹ summarized the etiology and pro­posed that it is:
   • 1 of 3 types of mania, including: acute and delusional manias, as initially pro­posed by Kraeplin
   • a severe form of catatonia
   • a condition akin to, but distinct from, delirium with similar underlying medi­cal causes
   • a primary psychiatric disorder under­lying the cause of delirium.

EVALUATION Brain changes
For several days, Mr. A continues to engage in strange behavior. He tries to take patients’ belongings, is denudative, crawls on floors, licks walls, is unable to feed himself, and exhib­its odd motor movements with purposeless motor activity.

We consult our internal medicine team to iden­tify treatable, medical causes. Results of serum B12, thyroid-stimulating hormone, and rapid plasma reagin studies are within normal limits. Urinalysis is negative. A brain MRI reveals numerous white-matter T2-weighted and FLAIR hyperintensities, indicating small-vessel ischemic changes that are consistent with the findings of an MRI 3 years ago. A sleep-deprived EEG with temporal leads obtained on Day 4 of hospitalization demonstrates a diffusely slow and marginally to poorly organized background, believed to indicate global cerebral dysfunction that is most consistent with nonfocal global encephalopathy. There is no seizure activity. We do not perform a lumbar puncture because of Mr. A’s absence of focal neurologic deficits, lack of fever, and normal white blood cell count.

What is the most appropriate treatment?
   a) electroconvulsive therapy (ECT)
   b) high-dose benzodiazepine
   c) mood stabilizer
   d) antipsychotic

The authors’ observations
We strongly suspect that Mr. A has delirious mania. Symptoms and signs of mania include labile mood, excessive spending, grandios­ity, insomnia, and psychosis together with delirium (marked disorientation, confusion). We ascribed Mr. A’s odd motor behaviors to catatonia, a hallmark of delirious mania. The literature has little description of EEG find­ings in suspected cases of delirious mania; however, abnormal EEG tracings have been reported.¹⁰ We also speculated that Mr. A’s EEG reflected effects produced by his pre­scribed antipsychotic regimen.

Treatment
There is no clear consensus on treating deliri­ous mania. Because catatonia is a key feature of delirious mania—whether etiologically or as a prominent sign of the condition—ECT and benzodiazepines are proposed as pri­mary treatments. In a study of 16 patients with delirious mania, Karmacharya et al4 found ECT to be effective, with patients showing improvement after 1 to 4 treat­ments. Lee et al¹⁰ reported similar findings. Although a high-dose benzodiazepine is not as effective as ECT, a 1-time oral dose of 3 to 4 mg of lorazepam has been used to treat delirious mania.

The efficacy of antipsychotic and mood-stabilizing pharmacotherapy is not clear. Bond³ described 3 cases in which patients were treated effectively with a typical anti­psychotic (haloperidol or chlorpromazine) and lithium. Jung and Lee_¹¹demonstrated the efficacy of atypical antipsychotics, with a marked improvement in symptoms within 1 week. However, other studies do not sup­port these findings. Karmacharya et al⁴ found that typical antipsychotics 1) make the clinical picture worse by increasing extrapy­ramidal symptoms and 2) produce incon­sistent effects. Mood stabilizers sometimes proved beneficial.

Karmacharya et al⁴ further argued that the delay in improvement seen with any antipsychotics and mood stabilizers suggest they should not be considered a first-line treatment. These discordant findings are the result of a small number of studies and a lack of understanding of the exact nature of delirious mania.


TREATMENT Quick Response
Mr. A’s symptoms rapidly resolve with a com­bination of quetiapine, 800 mg/d, haloperidol, 10 mg/d, and lithium, 1,200 mg/d. His mood returns to euthymia and his psychotic symptoms abate. He is able to attend to all activities of daily living. Mental status clears and he is fully oriented and able to hold a logical conversation. He scores 28 out of 30 on a subsequent Montreal Cognitive Assessment, administered 11 days after the ini­tial assessment (Figure 2), indicating normal neurocognitive function. He returns to his baseline level of functioning and is discharged in psychiatrically stable condition. Mr. A has no recollection of the bizarre behaviors he dis­played earlier in his hospitalization.

The authors’ observations
We started Mr. A on antipsychotics because of his initial level of agitation. In reviewing pharmacotherapy options for Mr. A’s mania and delirium, we contemplated several options. Quetiapine and lithium were cho­sen after a review of outside hospital records demonstrated a combination of a mood sta­bilizer and an antipsychotic was effective in treating a previous similar episode, which led to remission of Mr. A’s symptoms. We chose quetiapine because of it highly sedat­ing properties, suspecting that it would help treat his insomnia. We thought that the risk that lithium would make delirium worse was mitigated by Mr. A’s previous therapeu­tic response to it. Haloperidol was added for treating delirium, given its more potent D2 antagonism. Mr. A responded quickly to these interventions.

We did not consider ECT at the begin­ning of Mr. A’s admission, and we avoided sedative-hypnotic agents because we were concerned that a benzodiazepine might make his delirium worse. In light of avail­able data suggesting that ECT and ben­zodiazepines are preferred treatments for delirious mania, it is noteworthy that Mr. A responded so robustly and rapidly to an antipsychotic and a mood stabilizer.

Bottom Line
Consider delirious mania in any patient who has a history of bipolar disorder presenting with co-occuring symptoms of mania and delirium. Collateral information is vital to establishing a diagnosis. With suspected delirium, rule out concomitant reversible medical problems. Electroconvulsive therapy, high-dose benzodiazepines, antipsychotics, and mood stabilizers have shown efficacy.

Related Resources
• Nunes AL, Cheniaux E. Delirium and mania with catatonic fea­tures in a Brazilian patient: response to ECT. J Neuropsychiatry Clin Neurosci. 2014;26(1):E1-E3.
• Danivas V, Behere RV, Varambally S, et al. Electroconvulsive ther­apy in the treatment of delirious mania: a report of 2 patients. J ECT. 2010;26(4):278-279.

Drug Brand Names
Chlorpromazine • Thorazine               Perphenazine • Trilafon
Haloperidol • Haldol                           Quetiapine • Seroquel
Lithium • Eskalith                              Risperidone • Risperdal
Lorazepam • Ativan                           Valproic acid • Depakene

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

CASE Nearly naked
Mr. A, age 68, is found sitting in his car, wear­ing only a jacket, underpants, and boots. He speaks of spreading a message about Osama bin Laden and “taking a census.” Police officers bring him to a hospital emergency depart­ment for evaluation.

The examining clinician determines that Mr. A is a danger to himself and others because of mental illness, leading to admission to our state psychiatric hospital.

Mr. A’s wife describes recent spend­ing sprees with large purchases. She had obtained a restraining order against her hus­band because of his threatening remarks and behaviors. Within days of the order issuance, he got a home equity loan and purchased a $300,000 house.

The medical history is notable for type 2 diabetes mellitus. Although he is not tak­ing medications, his blood sugar is well controlled. Other than an initial resting heart rate of 116 beats per minute, vital signs are stable and within normal lim­its. Physical examination is unremarkable. Screening laboratory studies are notable for mildly elevated hepatic function, which approaches normal range several days after admission.

Mr. A reports a remote history of alcohol abuse but says he had not been drinking recently, and does not detail his pattern of use. Urine toxicology screen is negative for all substances of abuse.

Mental status examination reveals dishev­eled appearance, motor agitation, pressured speech, labile affect, loosening of associa­tions, grandiose delusions, and auditory hal­lucinations. Mr. A’s thought processes are grossly disorganized, such that we could not gather a meaningful history. He believes God is speaking directly to him about plans to build a carousel at Disney World. He makes strange gestures with his hands throughout the inter­view, as if attempting to trace the shapes of letters and numbers. He frequently speaks of seeing an array of colors. Cognitive examina­tion reveals a score of 5 of 30 on the Montreal Cognitive Assessment (Figure 1), indicating a severe impairment in neurocognitive func­tioning. He demonstrates limited insight and markedly impaired judgment, and denies hav­ing a mental illness.

What should be the next step in managing Mr. A?
a) obtain records from other facilities and collateral history
b) start an antipsychotic
c) order a brain MRI
d) start an alcohol withdrawal protocol

The authors’ observations
Mr. A showed elements of mania, psycho­sis, and delirium. We considered a broad differential diagnosis (Table). Mr. A initially could not provide reliable or accurate information. The least invasive next step was to obtain additional history from his wife and other medical records to refine the differential diagnosis.

HISTORY Bizarre behavior
Mr. A allows staff to speak with his wife and obtain records from a psychiatric hospitaliza­tion 3 years earlier. Mrs. A reports significant and rapid changes in her husband’s behav­ior and personality over 3 months, but does not describe a recent alcohol relapse. Mr. A sleeps very little, remaining awake and active throughout the night. He frequently rear­ranges the furniture in their home for no clear reason. Once, he knocked on the door of a young female neighbor asking if she found him attractive.

Mr. A has a significant criminal history. Approximately 30 years ago, he was charged with attempted murder of his ex-wife and he had faced charges of attempted kidnapping and assaulting a police officer. However, he has no recent legal issues.

Mr. A has a history of episodes that are simi­lar to this presentation. Seven years ago, he impulsively purchased a $650,000 house after his fourth wife died. He then had a $90,000 heart-shaped pool installed. He also drove a tractor through his stepdaughter’s car for no apparent reason. Also, 3 years ago, he displayed symptoms similar to his current presentation, including insomnia, irritability, and grandios­ity. He engaged in strange behaviors, such as dressing up and imitating homeless people at his church.

During the hospitalization 3 years ago, cli­nicians gave Mr. A a diagnosis of bipolar dis­order, current episode manic, and delirium of an unclear cause. A medical workup, includ­ing brain MRI, did not uncover a basis for his delirium. Antipsychotics (risperidone and per­phenazine) and mood stabilizers (lithium and valproic acid), stabilized his condition; after 7 weeks, Mr. A was discharged, but he did not pursue outpatient psychiatric care.

What is the most likely DSM-5 diagnosis?
   a) major neurocognitive disorder (dementia)
   b) alcohol use disorder (eg, Wernicke- Korsakoff syndrome)
   c) delirium secondary to mania
   d) psychotic disorder

The authors’ observations
DSM-5¹ suggests a stepwise approach to diagnosis, with consideration of:
   • signs and symptoms
   • substance use
   • general medical condition
   • developmental conflict or stage
   • whether a mental disorder is present.

Mr. A’s age and severe cognitive impair­ment raise the possibility of dementia. Rapid onset, history of similar episodes, and apparent inter-episode recovery make dementia unlikely. The history of alcohol abuse and mildly elevated hepatic func­tion tests suggest a substance use disorder such as Wernicke-Korsakoff syndrome or a withdrawal syndrome. However, there is no evidence of excessive alcohol use over the past several months, toxicology studies were negative, and vital signs were stable. General medical causes for Mr. A’s presen­tation, such as hypoglycemia, head trauma, intracranial infection, and metabolic dis­turbance were considered, but physical examination and laboratory studies did not suggest any condition that would explain his condition.

Mr. A’s previous psychiatric hospitaliza­tion is critical in clarifying the more likely diagnosis. A similar presentation yielded the diagnosis of bipolar disorder, manic phase. Our working diagnosis, therefore, was bipolar disorder with features of delir­ious mania.

Delirious mania
Delirious mania was first described by Luther Bell in 1849 and is characterized by an acute and simultaneous onset of mania— severe insomnia, poor judgment, grandios­ity, excitement, emotional lability, bizarre hallucinations, and delusions—and delir­ium—altered consciousness, disorientation, and confusion.^2,3 Although there are no diag­nostic criteria, some authors suggest that delirious mania is characterized by inappro­priate toileting, denudation, profound lack of sleep, and episodic memory impairment that can last hours or days.⁴ Catatonia fre­quently is seen with delirious mania.⁵ Initial case descriptions described a high mortality rate, approaching 75% of patients.⁶ There is little published literature and no classifica­tion of delirious mania in DSM-5.1 Estimates are that delirium is concomitant in 20% to 33% of patients with mania.^7,8

Several theories try to clarify the underly­ing etiology of delirious mania. Jacobowski et al⁹ summarized the etiology and pro­posed that it is:
   • 1 of 3 types of mania, including: acute and delusional manias, as initially pro­posed by Kraeplin
   • a severe form of catatonia
   • a condition akin to, but distinct from, delirium with similar underlying medi­cal causes
   • a primary psychiatric disorder under­lying the cause of delirium.

EVALUATION Brain changes
For several days, Mr. A continues to engage in strange behavior. He tries to take patients’ belongings, is denudative, crawls on floors, licks walls, is unable to feed himself, and exhib­its odd motor movements with purposeless motor activity.

We consult our internal medicine team to iden­tify treatable, medical causes. Results of serum B12, thyroid-stimulating hormone, and rapid plasma reagin studies are within normal limits. Urinalysis is negative. A brain MRI reveals numerous white-matter T2-weighted and FLAIR hyperintensities, indicating small-vessel ischemic changes that are consistent with the findings of an MRI 3 years ago. A sleep-deprived EEG with temporal leads obtained on Day 4 of hospitalization demonstrates a diffusely slow and marginally to poorly organized background, believed to indicate global cerebral dysfunction that is most consistent with nonfocal global encephalopathy. There is no seizure activity. We do not perform a lumbar puncture because of Mr. A’s absence of focal neurologic deficits, lack of fever, and normal white blood cell count.

What is the most appropriate treatment?
   a) electroconvulsive therapy (ECT)
   b) high-dose benzodiazepine
   c) mood stabilizer
   d) antipsychotic

The authors’ observations
We strongly suspect that Mr. A has delirious mania. Symptoms and signs of mania include labile mood, excessive spending, grandios­ity, insomnia, and psychosis together with delirium (marked disorientation, confusion). We ascribed Mr. A’s odd motor behaviors to catatonia, a hallmark of delirious mania. The literature has little description of EEG find­ings in suspected cases of delirious mania; however, abnormal EEG tracings have been reported.¹⁰ We also speculated that Mr. A’s EEG reflected effects produced by his pre­scribed antipsychotic regimen.

Treatment
There is no clear consensus on treating deliri­ous mania. Because catatonia is a key feature of delirious mania—whether etiologically or as a prominent sign of the condition—ECT and benzodiazepines are proposed as pri­mary treatments. In a study of 16 patients with delirious mania, Karmacharya et al4 found ECT to be effective, with patients showing improvement after 1 to 4 treat­ments. Lee et al¹⁰ reported similar findings. Although a high-dose benzodiazepine is not as effective as ECT, a 1-time oral dose of 3 to 4 mg of lorazepam has been used to treat delirious mania.

The efficacy of antipsychotic and mood-stabilizing pharmacotherapy is not clear. Bond³ described 3 cases in which patients were treated effectively with a typical anti­psychotic (haloperidol or chlorpromazine) and lithium. Jung and Lee_¹¹demonstrated the efficacy of atypical antipsychotics, with a marked improvement in symptoms within 1 week. However, other studies do not sup­port these findings. Karmacharya et al⁴ found that typical antipsychotics 1) make the clinical picture worse by increasing extrapy­ramidal symptoms and 2) produce incon­sistent effects. Mood stabilizers sometimes proved beneficial.

Karmacharya et al⁴ further argued that the delay in improvement seen with any antipsychotics and mood stabilizers suggest they should not be considered a first-line treatment. These discordant findings are the result of a small number of studies and a lack of understanding of the exact nature of delirious mania.


TREATMENT Quick Response
Mr. A’s symptoms rapidly resolve with a com­bination of quetiapine, 800 mg/d, haloperidol, 10 mg/d, and lithium, 1,200 mg/d. His mood returns to euthymia and his psychotic symptoms abate. He is able to attend to all activities of daily living. Mental status clears and he is fully oriented and able to hold a logical conversation. He scores 28 out of 30 on a subsequent Montreal Cognitive Assessment, administered 11 days after the ini­tial assessment (Figure 2), indicating normal neurocognitive function. He returns to his baseline level of functioning and is discharged in psychiatrically stable condition. Mr. A has no recollection of the bizarre behaviors he dis­played earlier in his hospitalization.

The authors’ observations
We started Mr. A on antipsychotics because of his initial level of agitation. In reviewing pharmacotherapy options for Mr. A’s mania and delirium, we contemplated several options. Quetiapine and lithium were cho­sen after a review of outside hospital records demonstrated a combination of a mood sta­bilizer and an antipsychotic was effective in treating a previous similar episode, which led to remission of Mr. A’s symptoms. We chose quetiapine because of it highly sedat­ing properties, suspecting that it would help treat his insomnia. We thought that the risk that lithium would make delirium worse was mitigated by Mr. A’s previous therapeu­tic response to it. Haloperidol was added for treating delirium, given its more potent D2 antagonism. Mr. A responded quickly to these interventions.

We did not consider ECT at the begin­ning of Mr. A’s admission, and we avoided sedative-hypnotic agents because we were concerned that a benzodiazepine might make his delirium worse. In light of avail­able data suggesting that ECT and ben­zodiazepines are preferred treatments for delirious mania, it is noteworthy that Mr. A responded so robustly and rapidly to an antipsychotic and a mood stabilizer.

Bottom Line
Consider delirious mania in any patient who has a history of bipolar disorder presenting with co-occuring symptoms of mania and delirium. Collateral information is vital to establishing a diagnosis. With suspected delirium, rule out concomitant reversible medical problems. Electroconvulsive therapy, high-dose benzodiazepines, antipsychotics, and mood stabilizers have shown efficacy.

Related Resources
• Nunes AL, Cheniaux E. Delirium and mania with catatonic fea­tures in a Brazilian patient: response to ECT. J Neuropsychiatry Clin Neurosci. 2014;26(1):E1-E3.
• Danivas V, Behere RV, Varambally S, et al. Electroconvulsive ther­apy in the treatment of delirious mania: a report of 2 patients. J ECT. 2010;26(4):278-279.

Drug Brand Names
Chlorpromazine • Thorazine               Perphenazine • Trilafon
Haloperidol • Haldol                           Quetiapine • Seroquel
Lithium • Eskalith                              Risperidone • Risperdal
Lorazepam • Ativan                           Valproic acid • Depakene

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

CASE Alien thoughts
Mr. C, age 23, is admitted to an intermediate-security facility because of unmanageable aggression. He is not charged with a crime and his legal status is admission by guardian. He is taking haloperidol decanoate, 300 mg IM every 28 days, and divalproex sodium, 1500 mg/d, but he continues to experience auditory hallucina­tions and the delusion that he is an alien.

Mr. C is given a primary diagnosis of chronic undifferentiated schizophrenia. He is started on risperidone tablets, 3 mg/d, and then switched to risperidone orally disintegrating tablets, titrated to 8 mg/d, to ensure compliance. Later, he receives separate trials of high-dose que­tiapine (up to 1200 mg/d) and olanzapine orally disintegrating tablets (up to 30 mg/d). Lithium, 1200 mg/d, sertraline, 100 mg/d, and long-acting propranolol, 120 mg/d, were added at various periods of his treatment.

He continues to experience hallucinations and delusions, is intermittently aggressive, is not engaged in the treatment program, and needs prompting for basic hygiene. Several times, we discuss with Mr. C using clozap­ine, but he refuses, mainly because of weekly blood draws.

How would you proceed with Mr. C’s care?
a) consider electroconvulsive therapy
b) order aripiprazole and an omega-3 fish oil supplement
c) consider involuntary clozapine therapy and lab testing

The author’s observations
Schizophrenia remains a chronic and often refractory illness. Patients suffer from intru­sive hallucinations; social and self-care defi­cits; cognitive impairment; and increased risk of violence, suicide, and premature death from medical causes. Pharmacotherapy is the mainstay of treatment, supplemented by individual and group therapies, psycho­social rehabilitation, housing assistance, and income support. Antipsychotics are funda­mental and clozapine has been established as the most effective antipsychotic in the Clinical Antipsychotic Trials for Intervention Effectiveness (CATIE) study,¹ but it remains underutilized.²

In 2008, clozapine accounted for only 4.4% of antipsychotic prescriptions in the United States.³ In our state forensic facility, only 10% of patients on an antipsychotic received clozapine in 2011. Despite the CATIE trial, there were no significant increases in clo­zapine prescribing after the results were published⁴ and patients often experience a substantial delay before clozapine is ini­tiated.⁵ In the last several years, we have looked at methods to increase clozapine use in our hospital and have described some of our experiences. Despite enthusiasm for, and good experi­ence with, clozapine, barriers limit the use of this medication (Table 1). One signifi­cant barrier is patient acceptance. Although most of our patients taking an atypical anti­psychotic will accept a blood draws every 6 months for metabolic monitoring, many will reject clozapine because of the initial weekly blood draw. Other patients will reject a trial of clozapine because of fears of serious adverse reactions.

Drug Brand Names
Aripiprazole • Abilify                            
Polyethylene glycol • MiraLax
Clozapine • Clozaril, FazaClo                
ropranolol • Inderal LA
Desmopressin • DDAVP                     
Quetiapine • Seroquel
Divalproex sodium • Depakote             
Risperidone • Risperdal
Haloperidol • Haldol                            
Sertraline • Zoloft
Lithium • Eskalith, Lithobid   
Terazosin • Hytrin
Olanzapine • Zyprexa            
Topiramate • Topamax

CASE Alien thoughts
Mr. C, age 23, is admitted to an intermediate-security facility because of unmanageable aggression. He is not charged with a crime and his legal status is admission by guardian. He is taking haloperidol decanoate, 300 mg IM every 28 days, and divalproex sodium, 1500 mg/d, but he continues to experience auditory hallucina­tions and the delusion that he is an alien.

Mr. C is given a primary diagnosis of chronic undifferentiated schizophrenia. He is started on risperidone tablets, 3 mg/d, and then switched to risperidone orally disintegrating tablets, titrated to 8 mg/d, to ensure compliance. Later, he receives separate trials of high-dose que­tiapine (up to 1200 mg/d) and olanzapine orally disintegrating tablets (up to 30 mg/d). Lithium, 1200 mg/d, sertraline, 100 mg/d, and long-acting propranolol, 120 mg/d, were added at various periods of his treatment.

He continues to experience hallucinations and delusions, is intermittently aggressive, is not engaged in the treatment program, and needs prompting for basic hygiene. Several times, we discuss with Mr. C using clozap­ine, but he refuses, mainly because of weekly blood draws.

How would you proceed with Mr. C’s care?
a) consider electroconvulsive therapy
b) order aripiprazole and an omega-3 fish oil supplement
c) consider involuntary clozapine therapy and lab testing

The author’s observations
Schizophrenia remains a chronic and often refractory illness. Patients suffer from intru­sive hallucinations; social and self-care defi­cits; cognitive impairment; and increased risk of violence, suicide, and premature death from medical causes. Pharmacotherapy is the mainstay of treatment, supplemented by individual and group therapies, psycho­social rehabilitation, housing assistance, and income support. Antipsychotics are funda­mental and clozapine has been established as the most effective antipsychotic in the Clinical Antipsychotic Trials for Intervention Effectiveness (CATIE) study,¹ but it remains underutilized.²

In 2008, clozapine accounted for only 4.4% of antipsychotic prescriptions in the United States.³ In our state forensic facility, only 10% of patients on an antipsychotic received clozapine in 2011. Despite the CATIE trial, there were no significant increases in clo­zapine prescribing after the results were published⁴ and patients often experience a substantial delay before clozapine is ini­tiated.⁵ In the last several years, we have looked at methods to increase clozapine use in our hospital and have described some of our experiences. Despite enthusiasm for, and good experi­ence with, clozapine, barriers limit the use of this medication (Table 1). One signifi­cant barrier is patient acceptance. Although most of our patients taking an atypical anti­psychotic will accept a blood draws every 6 months for metabolic monitoring, many will reject clozapine because of the initial weekly blood draw. Other patients will reject a trial of clozapine because of fears of serious adverse reactions.

Drug Brand Names
Aripiprazole • Abilify                            
Polyethylene glycol • MiraLax
Clozapine • Clozaril, FazaClo                
ropranolol • Inderal LA
Desmopressin • DDAVP                     
Quetiapine • Seroquel
Divalproex sodium • Depakote             
Risperidone • Risperdal
Haloperidol • Haldol                            
Sertraline • Zoloft
Lithium • Eskalith, Lithobid   
Terazosin • Hytrin
Olanzapine • Zyprexa            
Topiramate • Topamax

CASE Alien thoughts
Mr. C, age 23, is admitted to an intermediate-security facility because of unmanageable aggression. He is not charged with a crime and his legal status is admission by guardian. He is taking haloperidol decanoate, 300 mg IM every 28 days, and divalproex sodium, 1500 mg/d, but he continues to experience auditory hallucina­tions and the delusion that he is an alien.

Mr. C is given a primary diagnosis of chronic undifferentiated schizophrenia. He is started on risperidone tablets, 3 mg/d, and then switched to risperidone orally disintegrating tablets, titrated to 8 mg/d, to ensure compliance. Later, he receives separate trials of high-dose que­tiapine (up to 1200 mg/d) and olanzapine orally disintegrating tablets (up to 30 mg/d). Lithium, 1200 mg/d, sertraline, 100 mg/d, and long-acting propranolol, 120 mg/d, were added at various periods of his treatment.

He continues to experience hallucinations and delusions, is intermittently aggressive, is not engaged in the treatment program, and needs prompting for basic hygiene. Several times, we discuss with Mr. C using clozap­ine, but he refuses, mainly because of weekly blood draws.

How would you proceed with Mr. C’s care?
a) consider electroconvulsive therapy
b) order aripiprazole and an omega-3 fish oil supplement
c) consider involuntary clozapine therapy and lab testing

The author’s observations
Schizophrenia remains a chronic and often refractory illness. Patients suffer from intru­sive hallucinations; social and self-care defi­cits; cognitive impairment; and increased risk of violence, suicide, and premature death from medical causes. Pharmacotherapy is the mainstay of treatment, supplemented by individual and group therapies, psycho­social rehabilitation, housing assistance, and income support. Antipsychotics are funda­mental and clozapine has been established as the most effective antipsychotic in the Clinical Antipsychotic Trials for Intervention Effectiveness (CATIE) study,¹ but it remains underutilized.²

In 2008, clozapine accounted for only 4.4% of antipsychotic prescriptions in the United States.³ In our state forensic facility, only 10% of patients on an antipsychotic received clozapine in 2011. Despite the CATIE trial, there were no significant increases in clo­zapine prescribing after the results were published⁴ and patients often experience a substantial delay before clozapine is ini­tiated.⁵ In the last several years, we have looked at methods to increase clozapine use in our hospital and have described some of our experiences. Despite enthusiasm for, and good experi­ence with, clozapine, barriers limit the use of this medication (Table 1). One signifi­cant barrier is patient acceptance. Although most of our patients taking an atypical anti­psychotic will accept a blood draws every 6 months for metabolic monitoring, many will reject clozapine because of the initial weekly blood draw. Other patients will reject a trial of clozapine because of fears of serious adverse reactions.

Drug Brand Names
Aripiprazole • Abilify                            
Polyethylene glycol • MiraLax
Clozapine • Clozaril, FazaClo                
ropranolol • Inderal LA
Desmopressin • DDAVP                     
Quetiapine • Seroquel
Divalproex sodium • Depakote             
Risperidone • Risperdal
Haloperidol • Haldol                            
Sertraline • Zoloft
Lithium • Eskalith, Lithobid   
Terazosin • Hytrin
Olanzapine • Zyprexa            
Topiramate • Topamax

From the Yale School of Medicine, New Haven, CT.

ABSTRACT

• Objective: To review management of papillary thyroid cancer.

• Methods: Review of the literature.

• Results: Papillary thyroid cancer is the most common endocrine malignancy. The standard treatment for papillary thyroid cancer is thyroidectomy. Adjuvant therapy includes lifelong thyroid-stimulating hormone suppression and radioiodine therapy. Local recurrence is common and is normally treated with surgery and/or radioiodine. Metastatic radioiodine-resistant disease is a more infrequent event.

• Conclusion: The incidence of papillary thyroid cancer is rapidly increasing. Surgery remains the cornerstone of treatment.

Papillary thyroid cancer is the most common endocrine malignancy and accounts for the majority of cancers of the thyroid. The incidence of papillary thyroid cancer is rapidly increasing [1]. Although increasing detection has been proposed as a possible factor [2], some studies reject this hypothesis, reporting increase in the incidence of larger tumors [3]. Papillary thyroid cancer is characterized by a low mortality but a high recurrence rate [1], posing challenges not only to the endocrinologist and oncologist but also to the general practitioner.

The most frequent presentation of papillary thyroid cancer is a palpable thyroid nodule, cervical lymphadenopathy, or incidental detection on imaging. Locally advanced disease can present with hoarseness or voice alteration. Common risks factors include history of radiation exposure during childhood (the most important risk factor), thyroid cancer in a first-degree relative, family history of a thyroid cancer syndrome (such as Werner syndrome, Cowden syndrome, Carney complex, or familial polyposis), and female sex (2.5:1). Thyroid nodules in the context of an autoimmune thyroiditis may have a higher risk of malignancy [4].

CASE STUDY

Initial Presentation

A 49-year-old man with no significant past medical history presents with a painless mass in the anterior part of his neck.

History, Physical Examination, and Initial Investigations

He has no other symptoms, no weight changes, no history of radiation exposure to the neck, and no family history of malignancy. Physical exam shows a mass in the left thyroid lobe. There is no evidence of cardiac arrhythmias, tremors, or ophthalmologic abnormalities. Thyroid-stimulating hormone (TSH) level is 2.8 mIU/L (normal range, 0.4–4.5 mIU/L) and free thyroxine (T4) level is 1.1 ng/dL (normal range, 0.8–1.5 ng/dL). An ultrasound scan of the neck shows enlargement of the left lobe of thyroid gland, containing multiple complex lesions, the largest measuring 2 x 3 cm, with calcification as well as 3 enlarged lymph nodes in the left level IV. Fine-needle aspiration of the thyroid mass is positive for papillary carcinoma.

• What is the approach to the initial evaluation of a thyroid nodule?

Initial diagnostic evaluation includes history, physical examination, and TSH measurement; nonfunctioning nodules, associated with normal or high values of TSH, carry a higher risk of malignancy [5]. Cervical ultrasound should be performed in all patients with nodules. Fine-needle aspiration (FNA) should be used to evaluate nonfunctioning nodules > 1 cm or subcentimeter nodules with suspicious ultrasound features or if the patient has major risk factors (history of ionizing radiation exposure, external beam radiation exposure, family or personal history of papillary thyroid cancer, or FDG-PET [fluorinated glucose positron emission tomography]–positive thyroid nodules). Scintigraphy can be used to evaluate the need for ultrasound and FNA in patients with low TSH values [6,7]; hyperfunctioning nodules are at low risk for malignancy and do not require biopsy.

• What is initial treatment of papillary thyroid cancer?

Surgery is the primary treatment for papillary thyroid cancer. Unlike for many cancers, surgical removal of the primary tumor is indicated even in the presence of metastatic disease [8]. Total or near-total thyroidectomy is used to treat patients with tumors > 1 cm or with tumors < 1 cm and associated risk factors (eg, contralateral nodules, affected lymph nodes, metastasis, history of radiation, first-degree family history of papillary thyroid cancer, or age > 45 years) [6]. There is a lower risk of recurrence in patients treated with total thyroidectomy versus lobectomy in papillary thyroid cancer [9,10]. Thyroid lobectomy may be used in small (< 1 cm) unifocal tumors without the presence of the associated risk factors listed above.

Patients with central or lateral neck lymph node involvement should also undergo central-compartment (level VI) neck dissection. Therapeutic lateral neck compartmental lymph node dissection is recommended in patients with biopsy-proven metastatic lateral cervical adenopathy [6,7]. The role of unilateral or bilateral prophylactic central-compartment nodal dissection (PCND), that is, lymph node dissection in the level VI compartment of neck in patients without evidence of lymphadenopathy, is controversial. The data for the possible benefit of PCND are inconclusive [11] although the ATA recommends the procedure for locally invasive T3 and T4 tumors [6].

The American Thyroid Association (ATA) and National Comprehensive Cancer Network (NCCN) guidelines [6,7] recommend a preoperative cervical ultrasound in patients with biopsy-proven papillary thyroid cancer to evaluate the presence of disease in the cervical lymph nodes, especially in the lateral and central compartments, and in the contralateral thyroid lobe. If suspicious lymph nodes are found, FNA confirmation is necessary only if this would change management. Systematic use of other preoperative imaging studies, such as CT or MRI, is not recommended [6,7].

Surgical Treatment

The patient underwent a total thyroidectomy with bilateral central neck dissection and selective supraclavicular left-sided lateral neck dissection. Lymph nodes on both sides of the neck (paratracheal nodes) as well as the left supraclavicular nodes were removed. Pathology showed multifocal papillary cancer with extracapsular extension to the paratracheal soft tissue, 14/14 lymph nodes affected, stage IVA T4N1_bM0.

• How is papillary thyroid cancer staged?

• How should this patient be treated after surgery? Is any adjuvant therapy indicated?

TSH Suppression

In an effort to reduce risk of recurrence, patients should receive lifelong suppression of TSH using supraphysiologic doses of levothyroxine after total thyroidectomy. This is based upon the hypothesis that TSH is a growth factor for thyroid cancer cells [12,13]. Although a meta-analysis [14] supports the efficacy of TSH suppression therapy, some authors have questioned its widespread use, especially in light of the adverse effects of its use over the long term [15]. Many support its use only in high-risk patients [16], arguing that there is no evidence of benefit for low-risk patients [17]. This view is reflected in the ATA guidelines, which recommend TSH suppression below 0.1 mU/L for high-risk and intermediate-risk patients, while normal or slightly below normal TSH levels are recommended for low-risk patients [6].

Adverse effects of TSH suppression therapy are derived from the induced mild thyrotoxicosis, including cardiovascular and skeletal manifestations. Notably, elderly patients have a higher risk of cardiovascular side effects [18] such as atrial fibrillation, diastolic dysfunction, tachyarrhythmias, increased heart rate or increased left ventricular mass. Likewise, postmenopausal women are most susceptible for skeletal effects such as decreased mineral bone density and fractures [19].

Radioiodine Ablative Therapy

Radioactive iodine (RAI or radioiodine) therapy is based on the capacity of thyroid tissue to take up and retain iodine, specifically, radioiodine. This capacity is present but reduced in papillary and follicular cancer cells.

Radioiodine remnant ablation is performed after surgery, acting as adjuvant therapy by destroying remnant pathological or normal thyroid tissue. The destruction of normal thyroid tissue is useful as it increases the reliability of thyroglobulin testing and radioiodine scanning in the detection of recurrent or metastatic disease. Moreover, remnant ablation has been shown to prevent new thyroid neoplasias in high-risk patients (ie, those with history of radiation exposure). Radioiodine ablative therapy has been shown to reduce recurrence and cause-specific mortality [20] in certain subgroups; however, patients with low mortality risk do not seem to benefit from this therapy [21,22]. Its use is recommended in patients with distant metastases, tumors > 4 cm, or with extrathyroidal extension. It is also recommended for selected patients with tumors 1–4 cm who have high-risk features (such as lymph node involvement, history of radiation, or others previously mentioned) when there is an intermediate to high risk of recurrence or death from thyroid cancer [6]. Lymph node involvement can occur in up to 50% of cases [39] and normally responds to radioiodine therapy.

Since TSH increases radioiodine uptake by normal or pathological thyroid cells, TSH stimulation is required for radioiodine therapy. This can be done by endogenous TSH elevation or by recombinant human TSH (rhTSH). The former can be achieved by either stopping thyroxine 2 to 3 weeks prior to the remnant ablation, or by withdrawing thyroxine and switching to liothyronine for 2 to 3 weeks followed by a discontinuation of liothyronine for 2 weeks. Both approaches seem to produce the same incidence of hypothyroid symptoms [23]. Thyroxine therapy can be resumed 2 to 3 days after radioiodine ablative therapy. Recombinant human TSH can be used with equal efficacy in place of thyroxine withdrawal [24], with the advantage of not producing transitory hypothyroidism. It is especially recommended for patients who are unable to tolerate hypothyroidism or who cannot achieve an adequate TSH level. Short-term recurrence rates are similar in patients treated with rhTSH or thyroxine withdrawal [25].

In addition, a low-iodine diet for 1 or 2 weeks is recommended for patients undergoing radioiodine remnant ablation. The rationale is that a high-iodine diet or iodine exposure (ie, amiodarone treatment or intravenous contrast) can decrease radioiodine uptake by papillary cancer cells due to further dilution of radioactive iodine in an expanded endogenous non-radioactive iodine pool. Patients with suspected high iodine levels can be screened using spot urinary levels [26].

Commonly, a diagnostic scan using low activities of iodine-131 is performed prior to radioablation to avoid the controversial “stunning effect” [27] from any exposure to sublethal radiation in a diagnostic dose. In stunning, the diagnostic RAI dose decreases uptake of a subsequent therapeutic dose. Alternatively, we use [I-123] radioiodine at very low dose (1.4 mCi) in pre-ablation patients. Uptake in the thyroid bed occurs in 75% to 100% of patients, commonly due to remnant normal thyroid tissue [28].

The typical activity used for RAI ablative therapy is 30–100 mCi. The administration of high activities (150–200 mCi) of [I-131] radioiodine has been used to treat recurrent or metastatic disease. This treatment can be very effective, especially in young patients [29].

Side Effects and Contraindications

Common side effects of radioiodine treatment include sialadenitis, radiation thyroiditis, tumor hemorrhage or edema, nausea, transient oligospermia or amenorrhea and nasolacrimal duct obstruction. Moreover, patients treated with radioiodine have a modest increased risk of developing other malignancies [30].

[I-131]Radioiodine must be avoided in pregnancy and in breastfeeding [31]. Indeed, breast tissue has a strong tendency to uptake iodine so breastfeeding should be stopped 5 to 8 weeks before radioiodine treatment, otherwise it can lead to a false-positive radioiodine scan in the chest [32], or worse, deliver radioiodine to the baby with detrimental effects and potential ablation to the baby’s thyroid gland.

Patients treated with radioiodine are advised to drink abundant water after the treatment in order to increase its renal elimination. If no stool elimination occurs in 14 to 24 hours, laxatives may be indicated to eliminate radioiodine from the gastrointestinal track. In addition, patients are advised to avoid sexual contact, avoid sharing bed, utensils, towels, toothbrushes, razors, and avoid public transportation and public places among other measures to avoid exposing the population to radiation [33]. The duration of this restriction depends on the dose administered.

Adjuvant Treatment in this Patient

As the patient was at high risk for recurrence, he received TSH suppression therapy to levels < 0.1 mIU/L. He was referred to nuclear medicine for I-131 treatment. However, at 3 months following thyroidectomy, thyroglobulin measurement showed an elevation (40.5 ng/mL). Ultrasound showed enlarged lymph nodes at level II at the right and at level II at the left. A FNA of left neck node was positive for papillary thyroid cancer.

• How should the patient be treated now?

Treatment of Locoregional Metastatic Disease

The best treatment for residual disease or local recurrences is surgery. ATA guidelines recommend compartmental lateral and/or central neck dissection for patients with persistent or recurrent disease confined to the neck [6]. Radioiodine can be an alternative when recurrent disease is not visible on imaging. Other treatments that can be used for local recurrences or isolated metastases when surgery is not possible are radiofrequency ablation [34], chemo-embolization [35], or ethanol ablation [36]. External beam radiotherapy, which is discussed later, could also be used in selected cases.

Further Treatment

The patient underwent a bilateral modified radical neck dissection followed by adjunctive radioiodine therapy. His initial radioiodine scan showed mild uptake in the neck at the site of his prior surgery. He received treatment with 215 mCi, then 6 months later he was treated with 250 mCi, as his scan showed continued mild uptake. Eleven months later his radioiodine scan showed no uptake and thyroglobulin levels remained stable at 14.4 ng/mL.

One year later, in a follow-up blood analysis he was found to have an elevated thyroglobulin level (90.4 ng/mL). A PET/CT scan showed multiple bone metastases. A neck ultrasound revealed enlarged lymph nodes in the right thyroid bed.

• How common is radioiodine-refractory thyroid cancer?

Radioiodine-refractory thyroid cancer in patients with progression of disease despite radioiodine therapy, or with non-radioiodine-avid lesions [37], is uncommon. It has a poor prognosis with a median survival of 3 to 6 years after diagnosis. It is more frequent in older patients. These lesions are often hypermetabolic and hence [F-18]FDG-avid [38], with a worse prognosis. In one study of patients with metastatic differentiated thyroid cancer, the 10-year overall survival rate was 56% in patients with radioiodine-avid lesions but only 10% in patients with non-radioiodine-avid lesions [38].

• Is the bone a common place for metastasis? Where else should we expect to find a lesion?

Metastatic Pattern

The most common sites for distant metastasis of papillary thyroid cancer are the lungs and the bone. The 10-year survival rate of papillary thyroid cancer patients with lung metastases is between 30% and 50% [38,39]; the prog-nosis is better in patients < 45 years and with radiodine uptake [40]; indeed, patients with pulmonary metastasis seen only in 131-I scans and not on CT or chest x-ray have a longer survival [41]. Pulmonary metastasis can be treated with radioiodine if they are radioiodine-avid. With this treatment complete remission is possible, although it is extremely difficult to achieve in macronodular metastasis.

Bones are the second most common place for distant metastases. Bone metastases seem to have a worse response to treatment with an unfavorable prognosis [42]. Pamidronate (a biphosphonate) and denosumab (a RANK ligand inhibitor) have been used to prevent skeletal related events, including pathologic fractures and cord compression, in bone metastases from other cancers such as breast and prostate, and may also be useful in thyroid cancer, although this has not yet been studied [43,44]. Moreover, surgical resection of isolated bone metastasis seems to improve survival [45].

Skin, liver, and brain metastasis, although uncommon, can also occur. There are also reported rare cases of metastasis in the breast, parotid, larynx, pharynx, adrenal glands, pituitary, kidney, liver, orbit, the sphenoid sinus, choroid plexus, pancreas, and skeletal muscles [46].

• Which treatments can we offer to a patient with metastatic disease refractory to radioiodine?

Chemotherapy and Treatment of Radioiodine-Resistant Disease

Therapeutic options for patients with metastatic papillary thyroid cancer resistant to radioiodine and TSH suppression are limited. Cytotoxic drugs do not play a major role in the treatment of refractory metastatic papillary thyroid cancer, and new research is mainly focused on tyrosine kinase inhibitors (TKIs) with a considerable number of clinical trials either completed or ongoing.

Tyrosine kinases are enzymes that transfer phosphate groups from adenosine triphosphate to proteins. In tumor cells their signaling paths promote proliferation, avoidance of apoptosis, invasion, angiogenesis, and metastasis. TKIs are small molecules that are able to inhibit tyrosine kinase function even at very low intracellullar concentrations. Some of them inhibit various tyrosine kinases and are known as multi-kinase inhibitors (MKIs).

Sorafenib

Sorafenib (400 mg twice daily) is an oral MKI that targets RAF, platelet-derived growth factor receptor, vascular endothelial growth factor receptors 2 and 3, RET and c-Kit [47]. It was approved in November 2013 for patients with radioiodine-refractory differentiated thyroid cancer [48]. Three phase II studies had previously evaluated sorafenib in papillary thyroid cancer, showing a partial response in 15% to 31% of patients and a progression-free survival up to 79 weeks [49–51]. Common adverse effects included weight loss, fatigue, rash, hypertension and the main dose-limiting toxicity—a hand-foot syndrome consisting of swelling, reddening, numbness, and desquamation on palms and soles [52].

Approval of the drug was based on the DECISION trial [52]. A total of 417 patients were randomized (207 to sorafenib and 210 to placebo), of which 57% had papillary thyroid cancer. The primary endpoint of progression-free survival (PFS) was significantly higher in the sorafenib arm, (median, 10.8 months) compared with placebo (median, 5.8 months) (hazard ratio [HR] 0.58, 95% confidence interval [CI] 0.45–0.75, P < 0.001). Median overall survival had not been reached in either arm [52]. The PFS of 5.8 months in the placebo arm confirmed that the group of patients in this study had a rapidly progressing disease, unlike the majority of patients with RAI-sensitive disease.

Selumetinib

Radioiodine re-sensitization was addressed in a study using selumitinib, an inhibitor of mitogen-activated protein kinase kinase (MAPK kinase or MEK). Preclinical models had shown that radioiodine-refractory tumors exposed to inhibitors of this enzyme were able to uptake radioiodine again. Twenty patients with radioiodine-refractory thyroid cancers were treated with selumetinib for 4 weeks and 12 showed increased radioiodine uptake following the treatment. Furthermore, 8 of these patients went on to show responses clinically to retreatment with radioiodine [53].Further studies with this agent will be needed to determine its place in treating patients with differentiated thyroid cancer.

External Beam Radiotherapy and Local Treatment for Metastases

The role of external beam radiotherapy in papillary thyroid cancer is mainly for symptom management. Local radiation can be used in patients with refractory metastatic disease or in lesions that do not uptake radioiodine. Examples include painful bone metastasis or brain metastasis that cannot be treated with surgery. In addition, radiofrequency ablation, chemo-embolization, or ethanol ablation can be used in certain patients.

Sequence of Treatments

In the setting of symptomatic metastatic, radioiodine-resistant disease, we prefer to use a TKI, normally sorafenib, as a first-line treatment. For second-line treatments, enrollment in a clinical trial is an option. Over 70% of patients with metastatic papillary thyroid cancer have mutations of the enzyme BRAF kinase. Vemurafenib is an inhibitor of this enzyme and appears to have some activity in patients with RAI-refractory thyroid cancer in early clinical trials [54–58]. Other TKIs such as sunitinib can also be used. Doxorubicin is only used in cases when a patient is not eligible for a trial and the off-label use of another TKI is contraindicated.

Further Treatment in this Patient

The patient received a trial of sorafenib. He showed disease stabilization that lasted 5 months. The treatment was stopped due to adverse effects (loss of weight and vomiting) and progression of the disease. He was then enrolled in a trial of vemurafenib. He stopped treatment because of adverse events related to the medication and currently has stable disease.

Summary

Papillary thyroid cancer is the most common endocrine malignancy. It is characterized by low mortality but high recurrence rate and can have a considerable impact on quality of life. Any anterior neck nodule, especially in a patient with a history of neck irradiation, should raise concern for this disease. Surgery remains the cornerstone of treatment. Adjuvant therapy includes lifelong TSH suppression and radioiodine therapy. Local recurrence is common and is normally treated with surgery and/or radioiodine. Metastatic radioiodine-resistant disease is a more infrequent event. Thyroid cancer has a tendency to metastasize to the bones and lungs. Metastatic radioiodine-resistant disease is often treated with TKIs such as sorafenib. Enrollment in clinical trials is recommended as second-line therapy in radioiodine-resistant metastatic disease.

Corresponding author: Hari A. Deshpande, MD, Yale Cancer Center, FMP 124, 333 Cedar St., New Haven, CT 06520, [email protected]

Financial disclosures: Dr. Deshpande reports that he is on the advisory board of Bayer/Onyx.

Author contributions: conception and design, PT, EHH, GGC, HAD; drafting of article, PT, EHH, GGC, HAD; critical revision of the article, EHH, GGC, HAD.

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From the Yale School of Medicine, New Haven, CT.

ABSTRACT

• Objective: To review management of papillary thyroid cancer.

• Methods: Review of the literature.

• Results: Papillary thyroid cancer is the most common endocrine malignancy. The standard treatment for papillary thyroid cancer is thyroidectomy. Adjuvant therapy includes lifelong thyroid-stimulating hormone suppression and radioiodine therapy. Local recurrence is common and is normally treated with surgery and/or radioiodine. Metastatic radioiodine-resistant disease is a more infrequent event.

• Conclusion: The incidence of papillary thyroid cancer is rapidly increasing. Surgery remains the cornerstone of treatment.

Papillary thyroid cancer is the most common endocrine malignancy and accounts for the majority of cancers of the thyroid. The incidence of papillary thyroid cancer is rapidly increasing [1]. Although increasing detection has been proposed as a possible factor [2], some studies reject this hypothesis, reporting increase in the incidence of larger tumors [3]. Papillary thyroid cancer is characterized by a low mortality but a high recurrence rate [1], posing challenges not only to the endocrinologist and oncologist but also to the general practitioner.

The most frequent presentation of papillary thyroid cancer is a palpable thyroid nodule, cervical lymphadenopathy, or incidental detection on imaging. Locally advanced disease can present with hoarseness or voice alteration. Common risks factors include history of radiation exposure during childhood (the most important risk factor), thyroid cancer in a first-degree relative, family history of a thyroid cancer syndrome (such as Werner syndrome, Cowden syndrome, Carney complex, or familial polyposis), and female sex (2.5:1). Thyroid nodules in the context of an autoimmune thyroiditis may have a higher risk of malignancy [4].

CASE STUDY

Initial Presentation

A 49-year-old man with no significant past medical history presents with a painless mass in the anterior part of his neck.

History, Physical Examination, and Initial Investigations

He has no other symptoms, no weight changes, no history of radiation exposure to the neck, and no family history of malignancy. Physical exam shows a mass in the left thyroid lobe. There is no evidence of cardiac arrhythmias, tremors, or ophthalmologic abnormalities. Thyroid-stimulating hormone (TSH) level is 2.8 mIU/L (normal range, 0.4–4.5 mIU/L) and free thyroxine (T4) level is 1.1 ng/dL (normal range, 0.8–1.5 ng/dL). An ultrasound scan of the neck shows enlargement of the left lobe of thyroid gland, containing multiple complex lesions, the largest measuring 2 x 3 cm, with calcification as well as 3 enlarged lymph nodes in the left level IV. Fine-needle aspiration of the thyroid mass is positive for papillary carcinoma.

• What is the approach to the initial evaluation of a thyroid nodule?

Initial diagnostic evaluation includes history, physical examination, and TSH measurement; nonfunctioning nodules, associated with normal or high values of TSH, carry a higher risk of malignancy [5]. Cervical ultrasound should be performed in all patients with nodules. Fine-needle aspiration (FNA) should be used to evaluate nonfunctioning nodules > 1 cm or subcentimeter nodules with suspicious ultrasound features or if the patient has major risk factors (history of ionizing radiation exposure, external beam radiation exposure, family or personal history of papillary thyroid cancer, or FDG-PET [fluorinated glucose positron emission tomography]–positive thyroid nodules). Scintigraphy can be used to evaluate the need for ultrasound and FNA in patients with low TSH values [6,7]; hyperfunctioning nodules are at low risk for malignancy and do not require biopsy.

• What is initial treatment of papillary thyroid cancer?

Surgery is the primary treatment for papillary thyroid cancer. Unlike for many cancers, surgical removal of the primary tumor is indicated even in the presence of metastatic disease [8]. Total or near-total thyroidectomy is used to treat patients with tumors > 1 cm or with tumors < 1 cm and associated risk factors (eg, contralateral nodules, affected lymph nodes, metastasis, history of radiation, first-degree family history of papillary thyroid cancer, or age > 45 years) [6]. There is a lower risk of recurrence in patients treated with total thyroidectomy versus lobectomy in papillary thyroid cancer [9,10]. Thyroid lobectomy may be used in small (< 1 cm) unifocal tumors without the presence of the associated risk factors listed above.

Patients with central or lateral neck lymph node involvement should also undergo central-compartment (level VI) neck dissection. Therapeutic lateral neck compartmental lymph node dissection is recommended in patients with biopsy-proven metastatic lateral cervical adenopathy [6,7]. The role of unilateral or bilateral prophylactic central-compartment nodal dissection (PCND), that is, lymph node dissection in the level VI compartment of neck in patients without evidence of lymphadenopathy, is controversial. The data for the possible benefit of PCND are inconclusive [11] although the ATA recommends the procedure for locally invasive T3 and T4 tumors [6].

The American Thyroid Association (ATA) and National Comprehensive Cancer Network (NCCN) guidelines [6,7] recommend a preoperative cervical ultrasound in patients with biopsy-proven papillary thyroid cancer to evaluate the presence of disease in the cervical lymph nodes, especially in the lateral and central compartments, and in the contralateral thyroid lobe. If suspicious lymph nodes are found, FNA confirmation is necessary only if this would change management. Systematic use of other preoperative imaging studies, such as CT or MRI, is not recommended [6,7].

Surgical Treatment

The patient underwent a total thyroidectomy with bilateral central neck dissection and selective supraclavicular left-sided lateral neck dissection. Lymph nodes on both sides of the neck (paratracheal nodes) as well as the left supraclavicular nodes were removed. Pathology showed multifocal papillary cancer with extracapsular extension to the paratracheal soft tissue, 14/14 lymph nodes affected, stage IVA T4N1_bM0.

• How is papillary thyroid cancer staged?

• How should this patient be treated after surgery? Is any adjuvant therapy indicated?

TSH Suppression

In an effort to reduce risk of recurrence, patients should receive lifelong suppression of TSH using supraphysiologic doses of levothyroxine after total thyroidectomy. This is based upon the hypothesis that TSH is a growth factor for thyroid cancer cells [12,13]. Although a meta-analysis [14] supports the efficacy of TSH suppression therapy, some authors have questioned its widespread use, especially in light of the adverse effects of its use over the long term [15]. Many support its use only in high-risk patients [16], arguing that there is no evidence of benefit for low-risk patients [17]. This view is reflected in the ATA guidelines, which recommend TSH suppression below 0.1 mU/L for high-risk and intermediate-risk patients, while normal or slightly below normal TSH levels are recommended for low-risk patients [6].

Adverse effects of TSH suppression therapy are derived from the induced mild thyrotoxicosis, including cardiovascular and skeletal manifestations. Notably, elderly patients have a higher risk of cardiovascular side effects [18] such as atrial fibrillation, diastolic dysfunction, tachyarrhythmias, increased heart rate or increased left ventricular mass. Likewise, postmenopausal women are most susceptible for skeletal effects such as decreased mineral bone density and fractures [19].

Radioiodine Ablative Therapy

Radioactive iodine (RAI or radioiodine) therapy is based on the capacity of thyroid tissue to take up and retain iodine, specifically, radioiodine. This capacity is present but reduced in papillary and follicular cancer cells.

Radioiodine remnant ablation is performed after surgery, acting as adjuvant therapy by destroying remnant pathological or normal thyroid tissue. The destruction of normal thyroid tissue is useful as it increases the reliability of thyroglobulin testing and radioiodine scanning in the detection of recurrent or metastatic disease. Moreover, remnant ablation has been shown to prevent new thyroid neoplasias in high-risk patients (ie, those with history of radiation exposure). Radioiodine ablative therapy has been shown to reduce recurrence and cause-specific mortality [20] in certain subgroups; however, patients with low mortality risk do not seem to benefit from this therapy [21,22]. Its use is recommended in patients with distant metastases, tumors > 4 cm, or with extrathyroidal extension. It is also recommended for selected patients with tumors 1–4 cm who have high-risk features (such as lymph node involvement, history of radiation, or others previously mentioned) when there is an intermediate to high risk of recurrence or death from thyroid cancer [6]. Lymph node involvement can occur in up to 50% of cases [39] and normally responds to radioiodine therapy.

Since TSH increases radioiodine uptake by normal or pathological thyroid cells, TSH stimulation is required for radioiodine therapy. This can be done by endogenous TSH elevation or by recombinant human TSH (rhTSH). The former can be achieved by either stopping thyroxine 2 to 3 weeks prior to the remnant ablation, or by withdrawing thyroxine and switching to liothyronine for 2 to 3 weeks followed by a discontinuation of liothyronine for 2 weeks. Both approaches seem to produce the same incidence of hypothyroid symptoms [23]. Thyroxine therapy can be resumed 2 to 3 days after radioiodine ablative therapy. Recombinant human TSH can be used with equal efficacy in place of thyroxine withdrawal [24], with the advantage of not producing transitory hypothyroidism. It is especially recommended for patients who are unable to tolerate hypothyroidism or who cannot achieve an adequate TSH level. Short-term recurrence rates are similar in patients treated with rhTSH or thyroxine withdrawal [25].

In addition, a low-iodine diet for 1 or 2 weeks is recommended for patients undergoing radioiodine remnant ablation. The rationale is that a high-iodine diet or iodine exposure (ie, amiodarone treatment or intravenous contrast) can decrease radioiodine uptake by papillary cancer cells due to further dilution of radioactive iodine in an expanded endogenous non-radioactive iodine pool. Patients with suspected high iodine levels can be screened using spot urinary levels [26].

Commonly, a diagnostic scan using low activities of iodine-131 is performed prior to radioablation to avoid the controversial “stunning effect” [27] from any exposure to sublethal radiation in a diagnostic dose. In stunning, the diagnostic RAI dose decreases uptake of a subsequent therapeutic dose. Alternatively, we use [I-123] radioiodine at very low dose (1.4 mCi) in pre-ablation patients. Uptake in the thyroid bed occurs in 75% to 100% of patients, commonly due to remnant normal thyroid tissue [28].

The typical activity used for RAI ablative therapy is 30–100 mCi. The administration of high activities (150–200 mCi) of [I-131] radioiodine has been used to treat recurrent or metastatic disease. This treatment can be very effective, especially in young patients [29].

Side Effects and Contraindications

Common side effects of radioiodine treatment include sialadenitis, radiation thyroiditis, tumor hemorrhage or edema, nausea, transient oligospermia or amenorrhea and nasolacrimal duct obstruction. Moreover, patients treated with radioiodine have a modest increased risk of developing other malignancies [30].

[I-131]Radioiodine must be avoided in pregnancy and in breastfeeding [31]. Indeed, breast tissue has a strong tendency to uptake iodine so breastfeeding should be stopped 5 to 8 weeks before radioiodine treatment, otherwise it can lead to a false-positive radioiodine scan in the chest [32], or worse, deliver radioiodine to the baby with detrimental effects and potential ablation to the baby’s thyroid gland.

Patients treated with radioiodine are advised to drink abundant water after the treatment in order to increase its renal elimination. If no stool elimination occurs in 14 to 24 hours, laxatives may be indicated to eliminate radioiodine from the gastrointestinal track. In addition, patients are advised to avoid sexual contact, avoid sharing bed, utensils, towels, toothbrushes, razors, and avoid public transportation and public places among other measures to avoid exposing the population to radiation [33]. The duration of this restriction depends on the dose administered.

Adjuvant Treatment in this Patient

As the patient was at high risk for recurrence, he received TSH suppression therapy to levels < 0.1 mIU/L. He was referred to nuclear medicine for I-131 treatment. However, at 3 months following thyroidectomy, thyroglobulin measurement showed an elevation (40.5 ng/mL). Ultrasound showed enlarged lymph nodes at level II at the right and at level II at the left. A FNA of left neck node was positive for papillary thyroid cancer.

• How should the patient be treated now?

Treatment of Locoregional Metastatic Disease

The best treatment for residual disease or local recurrences is surgery. ATA guidelines recommend compartmental lateral and/or central neck dissection for patients with persistent or recurrent disease confined to the neck [6]. Radioiodine can be an alternative when recurrent disease is not visible on imaging. Other treatments that can be used for local recurrences or isolated metastases when surgery is not possible are radiofrequency ablation [34], chemo-embolization [35], or ethanol ablation [36]. External beam radiotherapy, which is discussed later, could also be used in selected cases.

Further Treatment

The patient underwent a bilateral modified radical neck dissection followed by adjunctive radioiodine therapy. His initial radioiodine scan showed mild uptake in the neck at the site of his prior surgery. He received treatment with 215 mCi, then 6 months later he was treated with 250 mCi, as his scan showed continued mild uptake. Eleven months later his radioiodine scan showed no uptake and thyroglobulin levels remained stable at 14.4 ng/mL.

One year later, in a follow-up blood analysis he was found to have an elevated thyroglobulin level (90.4 ng/mL). A PET/CT scan showed multiple bone metastases. A neck ultrasound revealed enlarged lymph nodes in the right thyroid bed.

• How common is radioiodine-refractory thyroid cancer?

Radioiodine-refractory thyroid cancer in patients with progression of disease despite radioiodine therapy, or with non-radioiodine-avid lesions [37], is uncommon. It has a poor prognosis with a median survival of 3 to 6 years after diagnosis. It is more frequent in older patients. These lesions are often hypermetabolic and hence [F-18]FDG-avid [38], with a worse prognosis. In one study of patients with metastatic differentiated thyroid cancer, the 10-year overall survival rate was 56% in patients with radioiodine-avid lesions but only 10% in patients with non-radioiodine-avid lesions [38].

• Is the bone a common place for metastasis? Where else should we expect to find a lesion?

Metastatic Pattern

The most common sites for distant metastasis of papillary thyroid cancer are the lungs and the bone. The 10-year survival rate of papillary thyroid cancer patients with lung metastases is between 30% and 50% [38,39]; the prog-nosis is better in patients < 45 years and with radiodine uptake [40]; indeed, patients with pulmonary metastasis seen only in 131-I scans and not on CT or chest x-ray have a longer survival [41]. Pulmonary metastasis can be treated with radioiodine if they are radioiodine-avid. With this treatment complete remission is possible, although it is extremely difficult to achieve in macronodular metastasis.

Bones are the second most common place for distant metastases. Bone metastases seem to have a worse response to treatment with an unfavorable prognosis [42]. Pamidronate (a biphosphonate) and denosumab (a RANK ligand inhibitor) have been used to prevent skeletal related events, including pathologic fractures and cord compression, in bone metastases from other cancers such as breast and prostate, and may also be useful in thyroid cancer, although this has not yet been studied [43,44]. Moreover, surgical resection of isolated bone metastasis seems to improve survival [45].

Skin, liver, and brain metastasis, although uncommon, can also occur. There are also reported rare cases of metastasis in the breast, parotid, larynx, pharynx, adrenal glands, pituitary, kidney, liver, orbit, the sphenoid sinus, choroid plexus, pancreas, and skeletal muscles [46].

• Which treatments can we offer to a patient with metastatic disease refractory to radioiodine?

Chemotherapy and Treatment of Radioiodine-Resistant Disease

Therapeutic options for patients with metastatic papillary thyroid cancer resistant to radioiodine and TSH suppression are limited. Cytotoxic drugs do not play a major role in the treatment of refractory metastatic papillary thyroid cancer, and new research is mainly focused on tyrosine kinase inhibitors (TKIs) with a considerable number of clinical trials either completed or ongoing.

Tyrosine kinases are enzymes that transfer phosphate groups from adenosine triphosphate to proteins. In tumor cells their signaling paths promote proliferation, avoidance of apoptosis, invasion, angiogenesis, and metastasis. TKIs are small molecules that are able to inhibit tyrosine kinase function even at very low intracellullar concentrations. Some of them inhibit various tyrosine kinases and are known as multi-kinase inhibitors (MKIs).

Sorafenib

Sorafenib (400 mg twice daily) is an oral MKI that targets RAF, platelet-derived growth factor receptor, vascular endothelial growth factor receptors 2 and 3, RET and c-Kit [47]. It was approved in November 2013 for patients with radioiodine-refractory differentiated thyroid cancer [48]. Three phase II studies had previously evaluated sorafenib in papillary thyroid cancer, showing a partial response in 15% to 31% of patients and a progression-free survival up to 79 weeks [49–51]. Common adverse effects included weight loss, fatigue, rash, hypertension and the main dose-limiting toxicity—a hand-foot syndrome consisting of swelling, reddening, numbness, and desquamation on palms and soles [52].

Approval of the drug was based on the DECISION trial [52]. A total of 417 patients were randomized (207 to sorafenib and 210 to placebo), of which 57% had papillary thyroid cancer. The primary endpoint of progression-free survival (PFS) was significantly higher in the sorafenib arm, (median, 10.8 months) compared with placebo (median, 5.8 months) (hazard ratio [HR] 0.58, 95% confidence interval [CI] 0.45–0.75, P < 0.001). Median overall survival had not been reached in either arm [52]. The PFS of 5.8 months in the placebo arm confirmed that the group of patients in this study had a rapidly progressing disease, unlike the majority of patients with RAI-sensitive disease.

Selumetinib

Radioiodine re-sensitization was addressed in a study using selumitinib, an inhibitor of mitogen-activated protein kinase kinase (MAPK kinase or MEK). Preclinical models had shown that radioiodine-refractory tumors exposed to inhibitors of this enzyme were able to uptake radioiodine again. Twenty patients with radioiodine-refractory thyroid cancers were treated with selumetinib for 4 weeks and 12 showed increased radioiodine uptake following the treatment. Furthermore, 8 of these patients went on to show responses clinically to retreatment with radioiodine [53].Further studies with this agent will be needed to determine its place in treating patients with differentiated thyroid cancer.

External Beam Radiotherapy and Local Treatment for Metastases

The role of external beam radiotherapy in papillary thyroid cancer is mainly for symptom management. Local radiation can be used in patients with refractory metastatic disease or in lesions that do not uptake radioiodine. Examples include painful bone metastasis or brain metastasis that cannot be treated with surgery. In addition, radiofrequency ablation, chemo-embolization, or ethanol ablation can be used in certain patients.

Sequence of Treatments

In the setting of symptomatic metastatic, radioiodine-resistant disease, we prefer to use a TKI, normally sorafenib, as a first-line treatment. For second-line treatments, enrollment in a clinical trial is an option. Over 70% of patients with metastatic papillary thyroid cancer have mutations of the enzyme BRAF kinase. Vemurafenib is an inhibitor of this enzyme and appears to have some activity in patients with RAI-refractory thyroid cancer in early clinical trials [54–58]. Other TKIs such as sunitinib can also be used. Doxorubicin is only used in cases when a patient is not eligible for a trial and the off-label use of another TKI is contraindicated.

Further Treatment in this Patient

The patient received a trial of sorafenib. He showed disease stabilization that lasted 5 months. The treatment was stopped due to adverse effects (loss of weight and vomiting) and progression of the disease. He was then enrolled in a trial of vemurafenib. He stopped treatment because of adverse events related to the medication and currently has stable disease.

Summary

Papillary thyroid cancer is the most common endocrine malignancy. It is characterized by low mortality but high recurrence rate and can have a considerable impact on quality of life. Any anterior neck nodule, especially in a patient with a history of neck irradiation, should raise concern for this disease. Surgery remains the cornerstone of treatment. Adjuvant therapy includes lifelong TSH suppression and radioiodine therapy. Local recurrence is common and is normally treated with surgery and/or radioiodine. Metastatic radioiodine-resistant disease is a more infrequent event. Thyroid cancer has a tendency to metastasize to the bones and lungs. Metastatic radioiodine-resistant disease is often treated with TKIs such as sorafenib. Enrollment in clinical trials is recommended as second-line therapy in radioiodine-resistant metastatic disease.

Corresponding author: Hari A. Deshpande, MD, Yale Cancer Center, FMP 124, 333 Cedar St., New Haven, CT 06520, [email protected]

Financial disclosures: Dr. Deshpande reports that he is on the advisory board of Bayer/Onyx.

Author contributions: conception and design, PT, EHH, GGC, HAD; drafting of article, PT, EHH, GGC, HAD; critical revision of the article, EHH, GGC, HAD.

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From the Yale School of Medicine, New Haven, CT.

ABSTRACT

• Objective: To review management of papillary thyroid cancer.

• Methods: Review of the literature.

• Results: Papillary thyroid cancer is the most common endocrine malignancy. The standard treatment for papillary thyroid cancer is thyroidectomy. Adjuvant therapy includes lifelong thyroid-stimulating hormone suppression and radioiodine therapy. Local recurrence is common and is normally treated with surgery and/or radioiodine. Metastatic radioiodine-resistant disease is a more infrequent event.

• Conclusion: The incidence of papillary thyroid cancer is rapidly increasing. Surgery remains the cornerstone of treatment.

Papillary thyroid cancer is the most common endocrine malignancy and accounts for the majority of cancers of the thyroid. The incidence of papillary thyroid cancer is rapidly increasing [1]. Although increasing detection has been proposed as a possible factor [2], some studies reject this hypothesis, reporting increase in the incidence of larger tumors [3]. Papillary thyroid cancer is characterized by a low mortality but a high recurrence rate [1], posing challenges not only to the endocrinologist and oncologist but also to the general practitioner.

The most frequent presentation of papillary thyroid cancer is a palpable thyroid nodule, cervical lymphadenopathy, or incidental detection on imaging. Locally advanced disease can present with hoarseness or voice alteration. Common risks factors include history of radiation exposure during childhood (the most important risk factor), thyroid cancer in a first-degree relative, family history of a thyroid cancer syndrome (such as Werner syndrome, Cowden syndrome, Carney complex, or familial polyposis), and female sex (2.5:1). Thyroid nodules in the context of an autoimmune thyroiditis may have a higher risk of malignancy [4].

CASE STUDY

Initial Presentation

A 49-year-old man with no significant past medical history presents with a painless mass in the anterior part of his neck.

History, Physical Examination, and Initial Investigations

He has no other symptoms, no weight changes, no history of radiation exposure to the neck, and no family history of malignancy. Physical exam shows a mass in the left thyroid lobe. There is no evidence of cardiac arrhythmias, tremors, or ophthalmologic abnormalities. Thyroid-stimulating hormone (TSH) level is 2.8 mIU/L (normal range, 0.4–4.5 mIU/L) and free thyroxine (T4) level is 1.1 ng/dL (normal range, 0.8–1.5 ng/dL). An ultrasound scan of the neck shows enlargement of the left lobe of thyroid gland, containing multiple complex lesions, the largest measuring 2 x 3 cm, with calcification as well as 3 enlarged lymph nodes in the left level IV. Fine-needle aspiration of the thyroid mass is positive for papillary carcinoma.

• What is the approach to the initial evaluation of a thyroid nodule?

Initial diagnostic evaluation includes history, physical examination, and TSH measurement; nonfunctioning nodules, associated with normal or high values of TSH, carry a higher risk of malignancy [5]. Cervical ultrasound should be performed in all patients with nodules. Fine-needle aspiration (FNA) should be used to evaluate nonfunctioning nodules > 1 cm or subcentimeter nodules with suspicious ultrasound features or if the patient has major risk factors (history of ionizing radiation exposure, external beam radiation exposure, family or personal history of papillary thyroid cancer, or FDG-PET [fluorinated glucose positron emission tomography]–positive thyroid nodules). Scintigraphy can be used to evaluate the need for ultrasound and FNA in patients with low TSH values [6,7]; hyperfunctioning nodules are at low risk for malignancy and do not require biopsy.

• What is initial treatment of papillary thyroid cancer?

Surgery is the primary treatment for papillary thyroid cancer. Unlike for many cancers, surgical removal of the primary tumor is indicated even in the presence of metastatic disease [8]. Total or near-total thyroidectomy is used to treat patients with tumors > 1 cm or with tumors < 1 cm and associated risk factors (eg, contralateral nodules, affected lymph nodes, metastasis, history of radiation, first-degree family history of papillary thyroid cancer, or age > 45 years) [6]. There is a lower risk of recurrence in patients treated with total thyroidectomy versus lobectomy in papillary thyroid cancer [9,10]. Thyroid lobectomy may be used in small (< 1 cm) unifocal tumors without the presence of the associated risk factors listed above.

Patients with central or lateral neck lymph node involvement should also undergo central-compartment (level VI) neck dissection. Therapeutic lateral neck compartmental lymph node dissection is recommended in patients with biopsy-proven metastatic lateral cervical adenopathy [6,7]. The role of unilateral or bilateral prophylactic central-compartment nodal dissection (PCND), that is, lymph node dissection in the level VI compartment of neck in patients without evidence of lymphadenopathy, is controversial. The data for the possible benefit of PCND are inconclusive [11] although the ATA recommends the procedure for locally invasive T3 and T4 tumors [6].

The American Thyroid Association (ATA) and National Comprehensive Cancer Network (NCCN) guidelines [6,7] recommend a preoperative cervical ultrasound in patients with biopsy-proven papillary thyroid cancer to evaluate the presence of disease in the cervical lymph nodes, especially in the lateral and central compartments, and in the contralateral thyroid lobe. If suspicious lymph nodes are found, FNA confirmation is necessary only if this would change management. Systematic use of other preoperative imaging studies, such as CT or MRI, is not recommended [6,7].

Surgical Treatment

The patient underwent a total thyroidectomy with bilateral central neck dissection and selective supraclavicular left-sided lateral neck dissection. Lymph nodes on both sides of the neck (paratracheal nodes) as well as the left supraclavicular nodes were removed. Pathology showed multifocal papillary cancer with extracapsular extension to the paratracheal soft tissue, 14/14 lymph nodes affected, stage IVA T4N1_bM0.

• How is papillary thyroid cancer staged?

• How should this patient be treated after surgery? Is any adjuvant therapy indicated?

TSH Suppression

In an effort to reduce risk of recurrence, patients should receive lifelong suppression of TSH using supraphysiologic doses of levothyroxine after total thyroidectomy. This is based upon the hypothesis that TSH is a growth factor for thyroid cancer cells [12,13]. Although a meta-analysis [14] supports the efficacy of TSH suppression therapy, some authors have questioned its widespread use, especially in light of the adverse effects of its use over the long term [15]. Many support its use only in high-risk patients [16], arguing that there is no evidence of benefit for low-risk patients [17]. This view is reflected in the ATA guidelines, which recommend TSH suppression below 0.1 mU/L for high-risk and intermediate-risk patients, while normal or slightly below normal TSH levels are recommended for low-risk patients [6].

Adverse effects of TSH suppression therapy are derived from the induced mild thyrotoxicosis, including cardiovascular and skeletal manifestations. Notably, elderly patients have a higher risk of cardiovascular side effects [18] such as atrial fibrillation, diastolic dysfunction, tachyarrhythmias, increased heart rate or increased left ventricular mass. Likewise, postmenopausal women are most susceptible for skeletal effects such as decreased mineral bone density and fractures [19].

Radioiodine Ablative Therapy

Radioactive iodine (RAI or radioiodine) therapy is based on the capacity of thyroid tissue to take up and retain iodine, specifically, radioiodine. This capacity is present but reduced in papillary and follicular cancer cells.

Radioiodine remnant ablation is performed after surgery, acting as adjuvant therapy by destroying remnant pathological or normal thyroid tissue. The destruction of normal thyroid tissue is useful as it increases the reliability of thyroglobulin testing and radioiodine scanning in the detection of recurrent or metastatic disease. Moreover, remnant ablation has been shown to prevent new thyroid neoplasias in high-risk patients (ie, those with history of radiation exposure). Radioiodine ablative therapy has been shown to reduce recurrence and cause-specific mortality [20] in certain subgroups; however, patients with low mortality risk do not seem to benefit from this therapy [21,22]. Its use is recommended in patients with distant metastases, tumors > 4 cm, or with extrathyroidal extension. It is also recommended for selected patients with tumors 1–4 cm who have high-risk features (such as lymph node involvement, history of radiation, or others previously mentioned) when there is an intermediate to high risk of recurrence or death from thyroid cancer [6]. Lymph node involvement can occur in up to 50% of cases [39] and normally responds to radioiodine therapy.

Since TSH increases radioiodine uptake by normal or pathological thyroid cells, TSH stimulation is required for radioiodine therapy. This can be done by endogenous TSH elevation or by recombinant human TSH (rhTSH). The former can be achieved by either stopping thyroxine 2 to 3 weeks prior to the remnant ablation, or by withdrawing thyroxine and switching to liothyronine for 2 to 3 weeks followed by a discontinuation of liothyronine for 2 weeks. Both approaches seem to produce the same incidence of hypothyroid symptoms [23]. Thyroxine therapy can be resumed 2 to 3 days after radioiodine ablative therapy. Recombinant human TSH can be used with equal efficacy in place of thyroxine withdrawal [24], with the advantage of not producing transitory hypothyroidism. It is especially recommended for patients who are unable to tolerate hypothyroidism or who cannot achieve an adequate TSH level. Short-term recurrence rates are similar in patients treated with rhTSH or thyroxine withdrawal [25].

In addition, a low-iodine diet for 1 or 2 weeks is recommended for patients undergoing radioiodine remnant ablation. The rationale is that a high-iodine diet or iodine exposure (ie, amiodarone treatment or intravenous contrast) can decrease radioiodine uptake by papillary cancer cells due to further dilution of radioactive iodine in an expanded endogenous non-radioactive iodine pool. Patients with suspected high iodine levels can be screened using spot urinary levels [26].

Commonly, a diagnostic scan using low activities of iodine-131 is performed prior to radioablation to avoid the controversial “stunning effect” [27] from any exposure to sublethal radiation in a diagnostic dose. In stunning, the diagnostic RAI dose decreases uptake of a subsequent therapeutic dose. Alternatively, we use [I-123] radioiodine at very low dose (1.4 mCi) in pre-ablation patients. Uptake in the thyroid bed occurs in 75% to 100% of patients, commonly due to remnant normal thyroid tissue [28].

The typical activity used for RAI ablative therapy is 30–100 mCi. The administration of high activities (150–200 mCi) of [I-131] radioiodine has been used to treat recurrent or metastatic disease. This treatment can be very effective, especially in young patients [29].

Side Effects and Contraindications

Common side effects of radioiodine treatment include sialadenitis, radiation thyroiditis, tumor hemorrhage or edema, nausea, transient oligospermia or amenorrhea and nasolacrimal duct obstruction. Moreover, patients treated with radioiodine have a modest increased risk of developing other malignancies [30].

[I-131]Radioiodine must be avoided in pregnancy and in breastfeeding [31]. Indeed, breast tissue has a strong tendency to uptake iodine so breastfeeding should be stopped 5 to 8 weeks before radioiodine treatment, otherwise it can lead to a false-positive radioiodine scan in the chest [32], or worse, deliver radioiodine to the baby with detrimental effects and potential ablation to the baby’s thyroid gland.

Patients treated with radioiodine are advised to drink abundant water after the treatment in order to increase its renal elimination. If no stool elimination occurs in 14 to 24 hours, laxatives may be indicated to eliminate radioiodine from the gastrointestinal track. In addition, patients are advised to avoid sexual contact, avoid sharing bed, utensils, towels, toothbrushes, razors, and avoid public transportation and public places among other measures to avoid exposing the population to radiation [33]. The duration of this restriction depends on the dose administered.

Adjuvant Treatment in this Patient

As the patient was at high risk for recurrence, he received TSH suppression therapy to levels < 0.1 mIU/L. He was referred to nuclear medicine for I-131 treatment. However, at 3 months following thyroidectomy, thyroglobulin measurement showed an elevation (40.5 ng/mL). Ultrasound showed enlarged lymph nodes at level II at the right and at level II at the left. A FNA of left neck node was positive for papillary thyroid cancer.

• How should the patient be treated now?

Treatment of Locoregional Metastatic Disease

The best treatment for residual disease or local recurrences is surgery. ATA guidelines recommend compartmental lateral and/or central neck dissection for patients with persistent or recurrent disease confined to the neck [6]. Radioiodine can be an alternative when recurrent disease is not visible on imaging. Other treatments that can be used for local recurrences or isolated metastases when surgery is not possible are radiofrequency ablation [34], chemo-embolization [35], or ethanol ablation [36]. External beam radiotherapy, which is discussed later, could also be used in selected cases.

Further Treatment

The patient underwent a bilateral modified radical neck dissection followed by adjunctive radioiodine therapy. His initial radioiodine scan showed mild uptake in the neck at the site of his prior surgery. He received treatment with 215 mCi, then 6 months later he was treated with 250 mCi, as his scan showed continued mild uptake. Eleven months later his radioiodine scan showed no uptake and thyroglobulin levels remained stable at 14.4 ng/mL.

One year later, in a follow-up blood analysis he was found to have an elevated thyroglobulin level (90.4 ng/mL). A PET/CT scan showed multiple bone metastases. A neck ultrasound revealed enlarged lymph nodes in the right thyroid bed.

• How common is radioiodine-refractory thyroid cancer?

Radioiodine-refractory thyroid cancer in patients with progression of disease despite radioiodine therapy, or with non-radioiodine-avid lesions [37], is uncommon. It has a poor prognosis with a median survival of 3 to 6 years after diagnosis. It is more frequent in older patients. These lesions are often hypermetabolic and hence [F-18]FDG-avid [38], with a worse prognosis. In one study of patients with metastatic differentiated thyroid cancer, the 10-year overall survival rate was 56% in patients with radioiodine-avid lesions but only 10% in patients with non-radioiodine-avid lesions [38].

• Is the bone a common place for metastasis? Where else should we expect to find a lesion?

Metastatic Pattern

The most common sites for distant metastasis of papillary thyroid cancer are the lungs and the bone. The 10-year survival rate of papillary thyroid cancer patients with lung metastases is between 30% and 50% [38,39]; the prog-nosis is better in patients < 45 years and with radiodine uptake [40]; indeed, patients with pulmonary metastasis seen only in 131-I scans and not on CT or chest x-ray have a longer survival [41]. Pulmonary metastasis can be treated with radioiodine if they are radioiodine-avid. With this treatment complete remission is possible, although it is extremely difficult to achieve in macronodular metastasis.

Bones are the second most common place for distant metastases. Bone metastases seem to have a worse response to treatment with an unfavorable prognosis [42]. Pamidronate (a biphosphonate) and denosumab (a RANK ligand inhibitor) have been used to prevent skeletal related events, including pathologic fractures and cord compression, in bone metastases from other cancers such as breast and prostate, and may also be useful in thyroid cancer, although this has not yet been studied [43,44]. Moreover, surgical resection of isolated bone metastasis seems to improve survival [45].

Skin, liver, and brain metastasis, although uncommon, can also occur. There are also reported rare cases of metastasis in the breast, parotid, larynx, pharynx, adrenal glands, pituitary, kidney, liver, orbit, the sphenoid sinus, choroid plexus, pancreas, and skeletal muscles [46].

• Which treatments can we offer to a patient with metastatic disease refractory to radioiodine?

Chemotherapy and Treatment of Radioiodine-Resistant Disease

Therapeutic options for patients with metastatic papillary thyroid cancer resistant to radioiodine and TSH suppression are limited. Cytotoxic drugs do not play a major role in the treatment of refractory metastatic papillary thyroid cancer, and new research is mainly focused on tyrosine kinase inhibitors (TKIs) with a considerable number of clinical trials either completed or ongoing.

Tyrosine kinases are enzymes that transfer phosphate groups from adenosine triphosphate to proteins. In tumor cells their signaling paths promote proliferation, avoidance of apoptosis, invasion, angiogenesis, and metastasis. TKIs are small molecules that are able to inhibit tyrosine kinase function even at very low intracellullar concentrations. Some of them inhibit various tyrosine kinases and are known as multi-kinase inhibitors (MKIs).

Sorafenib

Sorafenib (400 mg twice daily) is an oral MKI that targets RAF, platelet-derived growth factor receptor, vascular endothelial growth factor receptors 2 and 3, RET and c-Kit [47]. It was approved in November 2013 for patients with radioiodine-refractory differentiated thyroid cancer [48]. Three phase II studies had previously evaluated sorafenib in papillary thyroid cancer, showing a partial response in 15% to 31% of patients and a progression-free survival up to 79 weeks [49–51]. Common adverse effects included weight loss, fatigue, rash, hypertension and the main dose-limiting toxicity—a hand-foot syndrome consisting of swelling, reddening, numbness, and desquamation on palms and soles [52].

Approval of the drug was based on the DECISION trial [52]. A total of 417 patients were randomized (207 to sorafenib and 210 to placebo), of which 57% had papillary thyroid cancer. The primary endpoint of progression-free survival (PFS) was significantly higher in the sorafenib arm, (median, 10.8 months) compared with placebo (median, 5.8 months) (hazard ratio [HR] 0.58, 95% confidence interval [CI] 0.45–0.75, P < 0.001). Median overall survival had not been reached in either arm [52]. The PFS of 5.8 months in the placebo arm confirmed that the group of patients in this study had a rapidly progressing disease, unlike the majority of patients with RAI-sensitive disease.

Selumetinib

Radioiodine re-sensitization was addressed in a study using selumitinib, an inhibitor of mitogen-activated protein kinase kinase (MAPK kinase or MEK). Preclinical models had shown that radioiodine-refractory tumors exposed to inhibitors of this enzyme were able to uptake radioiodine again. Twenty patients with radioiodine-refractory thyroid cancers were treated with selumetinib for 4 weeks and 12 showed increased radioiodine uptake following the treatment. Furthermore, 8 of these patients went on to show responses clinically to retreatment with radioiodine [53].Further studies with this agent will be needed to determine its place in treating patients with differentiated thyroid cancer.

External Beam Radiotherapy and Local Treatment for Metastases

The role of external beam radiotherapy in papillary thyroid cancer is mainly for symptom management. Local radiation can be used in patients with refractory metastatic disease or in lesions that do not uptake radioiodine. Examples include painful bone metastasis or brain metastasis that cannot be treated with surgery. In addition, radiofrequency ablation, chemo-embolization, or ethanol ablation can be used in certain patients.

Sequence of Treatments

In the setting of symptomatic metastatic, radioiodine-resistant disease, we prefer to use a TKI, normally sorafenib, as a first-line treatment. For second-line treatments, enrollment in a clinical trial is an option. Over 70% of patients with metastatic papillary thyroid cancer have mutations of the enzyme BRAF kinase. Vemurafenib is an inhibitor of this enzyme and appears to have some activity in patients with RAI-refractory thyroid cancer in early clinical trials [54–58]. Other TKIs such as sunitinib can also be used. Doxorubicin is only used in cases when a patient is not eligible for a trial and the off-label use of another TKI is contraindicated.

Further Treatment in this Patient

The patient received a trial of sorafenib. He showed disease stabilization that lasted 5 months. The treatment was stopped due to adverse effects (loss of weight and vomiting) and progression of the disease. He was then enrolled in a trial of vemurafenib. He stopped treatment because of adverse events related to the medication and currently has stable disease.

Summary

Papillary thyroid cancer is the most common endocrine malignancy. It is characterized by low mortality but high recurrence rate and can have a considerable impact on quality of life. Any anterior neck nodule, especially in a patient with a history of neck irradiation, should raise concern for this disease. Surgery remains the cornerstone of treatment. Adjuvant therapy includes lifelong TSH suppression and radioiodine therapy. Local recurrence is common and is normally treated with surgery and/or radioiodine. Metastatic radioiodine-resistant disease is a more infrequent event. Thyroid cancer has a tendency to metastasize to the bones and lungs. Metastatic radioiodine-resistant disease is often treated with TKIs such as sorafenib. Enrollment in clinical trials is recommended as second-line therapy in radioiodine-resistant metastatic disease.

Corresponding author: Hari A. Deshpande, MD, Yale Cancer Center, FMP 124, 333 Cedar St., New Haven, CT 06520, [email protected]

Financial disclosures: Dr. Deshpande reports that he is on the advisory board of Bayer/Onyx.

Author contributions: conception and design, PT, EHH, GGC, HAD; drafting of article, PT, EHH, GGC, HAD; critical revision of the article, EHH, GGC, HAD.

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