Use metrics for populations, not individuals

Dr. Kanofsky’s commentary on CD metrics is 100% correct. As an ethical question for physicians and society alike, I would ask, is applying metrics to physicians even moral?

As an ObGyn for most of 4 decades, my approach to obstetrics has not changed. In some years, my CD rate was very low, and in others my rate was average. Women must be treated as individuals. Although the industrial revolution increased quality and decreased costs in manufacturing, I do not believe that we can or should apply those principles to our patients.

Government regulators, insurance companies, and many physician leaders have lost sight of the Oath of Maimonides, which states, “May the love of my art actuate me at all times; may neither avarice nor miserliness…engage my mind,”¹ as well as Hippocrates’ ancient observation, “Whatsoever house I may enter, my visit shall be for the convenience and advantage of the patient.”² In addition, in the modern version of the Hippocratic Oath that most schools use today, physicians swear to “apply, for the benefit of the sick, all measures [that] are required...”³—not to the benefit of the government, the federal budget, or an accountable care organization (ACO).

Clearly, the informed consent of a 42-year-old who had in vitro fertilization and has a floating presentation with a low Bishop score and an estimated fetal weight of 4,000 at 40 6/7 weeks must include not only the risks of primary CD but also the risks of a long labor that may result in a CD, the occasional risk of shoulder dystocia, or third- or fourth-degree extension. Not having had a case of shoulder dystocia or a third- or fourth-degree in more than a decade clearly justifies my rationale.

The morbidity of a multiple repeat CD or even a primary CD in an obese woman is significantly more risky than a non-labored elective CD in a woman of normal weight who plans to have only 1 or 2 children. We must individualize our care. Metrics are for populations, not individuals.

Health economists who aggressively advocate lower cesarean rates accept stillbirths and babies with hypoxic ischemic encephalopathy, cerebral palsy, or Erb’s palsy as long as governmental expenditures are lowered. Do the parents of these children get a vote? The majority of practicing physicians like myself feel more aligned with the Hippocratic Oath and the Oath of Maimonides. We believe that we have a moral, ethical, and medical responsibility to the individual patient and not to an ACO or government bean counter.

I would suggest an overarching theme: choice—the freedom to make our own intelligent decisions based on reasonable data and interpretation of the medical literature.

One size does not fit all. So why do those pushing comparative metrics tell us there is only one way to practice obstetrics?

Howard C. Mandel, MD
Los Angeles, California
 

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Use metrics for populations, not individuals

Dr. Kanofsky’s commentary on CD metrics is 100% correct. As an ethical question for physicians and society alike, I would ask, is applying metrics to physicians even moral?

As an ObGyn for most of 4 decades, my approach to obstetrics has not changed. In some years, my CD rate was very low, and in others my rate was average. Women must be treated as individuals. Although the industrial revolution increased quality and decreased costs in manufacturing, I do not believe that we can or should apply those principles to our patients.

Government regulators, insurance companies, and many physician leaders have lost sight of the Oath of Maimonides, which states, “May the love of my art actuate me at all times; may neither avarice nor miserliness…engage my mind,”¹ as well as Hippocrates’ ancient observation, “Whatsoever house I may enter, my visit shall be for the convenience and advantage of the patient.”² In addition, in the modern version of the Hippocratic Oath that most schools use today, physicians swear to “apply, for the benefit of the sick, all measures [that] are required...”³—not to the benefit of the government, the federal budget, or an accountable care organization (ACO).

Clearly, the informed consent of a 42-year-old who had in vitro fertilization and has a floating presentation with a low Bishop score and an estimated fetal weight of 4,000 at 40 6/7 weeks must include not only the risks of primary CD but also the risks of a long labor that may result in a CD, the occasional risk of shoulder dystocia, or third- or fourth-degree extension. Not having had a case of shoulder dystocia or a third- or fourth-degree in more than a decade clearly justifies my rationale.

The morbidity of a multiple repeat CD or even a primary CD in an obese woman is significantly more risky than a non-labored elective CD in a woman of normal weight who plans to have only 1 or 2 children. We must individualize our care. Metrics are for populations, not individuals.

Health economists who aggressively advocate lower cesarean rates accept stillbirths and babies with hypoxic ischemic encephalopathy, cerebral palsy, or Erb’s palsy as long as governmental expenditures are lowered. Do the parents of these children get a vote? The majority of practicing physicians like myself feel more aligned with the Hippocratic Oath and the Oath of Maimonides. We believe that we have a moral, ethical, and medical responsibility to the individual patient and not to an ACO or government bean counter.

I would suggest an overarching theme: choice—the freedom to make our own intelligent decisions based on reasonable data and interpretation of the medical literature.

One size does not fit all. So why do those pushing comparative metrics tell us there is only one way to practice obstetrics?

Howard C. Mandel, MD
Los Angeles, California
 

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Use metrics for populations, not individuals

Dr. Kanofsky’s commentary on CD metrics is 100% correct. As an ethical question for physicians and society alike, I would ask, is applying metrics to physicians even moral?

As an ObGyn for most of 4 decades, my approach to obstetrics has not changed. In some years, my CD rate was very low, and in others my rate was average. Women must be treated as individuals. Although the industrial revolution increased quality and decreased costs in manufacturing, I do not believe that we can or should apply those principles to our patients.

Government regulators, insurance companies, and many physician leaders have lost sight of the Oath of Maimonides, which states, “May the love of my art actuate me at all times; may neither avarice nor miserliness…engage my mind,”¹ as well as Hippocrates’ ancient observation, “Whatsoever house I may enter, my visit shall be for the convenience and advantage of the patient.”² In addition, in the modern version of the Hippocratic Oath that most schools use today, physicians swear to “apply, for the benefit of the sick, all measures [that] are required...”³—not to the benefit of the government, the federal budget, or an accountable care organization (ACO).

Clearly, the informed consent of a 42-year-old who had in vitro fertilization and has a floating presentation with a low Bishop score and an estimated fetal weight of 4,000 at 40 6/7 weeks must include not only the risks of primary CD but also the risks of a long labor that may result in a CD, the occasional risk of shoulder dystocia, or third- or fourth-degree extension. Not having had a case of shoulder dystocia or a third- or fourth-degree in more than a decade clearly justifies my rationale.

The morbidity of a multiple repeat CD or even a primary CD in an obese woman is significantly more risky than a non-labored elective CD in a woman of normal weight who plans to have only 1 or 2 children. We must individualize our care. Metrics are for populations, not individuals.

Health economists who aggressively advocate lower cesarean rates accept stillbirths and babies with hypoxic ischemic encephalopathy, cerebral palsy, or Erb’s palsy as long as governmental expenditures are lowered. Do the parents of these children get a vote? The majority of practicing physicians like myself feel more aligned with the Hippocratic Oath and the Oath of Maimonides. We believe that we have a moral, ethical, and medical responsibility to the individual patient and not to an ACO or government bean counter.

I would suggest an overarching theme: choice—the freedom to make our own intelligent decisions based on reasonable data and interpretation of the medical literature.

One size does not fit all. So why do those pushing comparative metrics tell us there is only one way to practice obstetrics?

Howard C. Mandel, MD
Los Angeles, California
 

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Because of the high prevalence of obesity and diabetes, bariatric surgery has become very popular. In the United States alone, there were an estimated 228,000 weight loss surgical procedures performed in 2017.¹

But I must confess that for many years, I was skeptical about the value of surgery to treat obesity. Yes, everyone who had a bariatric procedure lost weight, but did the long-term benefits really outweigh the harms? I wondered if most people gradually gained back the weight they lost. And the harms can be significant, including dumping syndrome, hypoglycemia, and malabsorption—in addition to the potential for surgical complications and repeat surgery. And, I must confess that my views were likely affected by the death of a friend from complications of gastric bypass 25 years ago.

My skepticism, however, has changed to cautious optimism for carefully selected patients.

My skepticism, however, has changed to cautious optimism for carefully selected patients. I say this because we now have long-term follow-up studies demonstrating the value of bariatric procedures—especially for people with type 2 diabetes.

Most studies have been cohort studies that compare results to similar patients with obesity who did not have surgery, and the outcomes have been consistently better in patients who underwent surgery. Two recent meta-analyses summarized these results; one for all patients with obesity and the other for patients with type 2 diabetes.

Continue to: The first meta-analysis

The first meta-analysis included 11 randomized trials, 4 nonrandomized controlled trials, and 17 cohort studies and showed probable reductions in all-cause mortality and possible reductions in cancer and cardiovascular events.² The second demonstrated significant improvements in microvascular and macrovascular disease and reduced mortality.³ The data were limited, however, because of the lack of large randomized trials with long-term follow-up.

The Stampede trial is one of a few bariatric surgery randomized trials focusing on patients with diabetes.⁴ The 5-year follow-up results are impressive. Nearly 30% of patients who had gastric bypass and 23% who had sleeve gastrectomy had an A1C ≤6 at 5 years compared to only 5% of those treated medically. Some patients discontinued all medications for diabetes, hypertension, and hyperlipidemia.

There is now adequate research to show that bariatric surgery provides significant benefits to properly selected patients who understand the risks. I no longer hesitate to refer patients for bariatric surgery who have been unsuccessful with weight loss—despite their best efforts.

Where do you stand?

Because of the high prevalence of obesity and diabetes, bariatric surgery has become very popular. In the United States alone, there were an estimated 228,000 weight loss surgical procedures performed in 2017.¹

But I must confess that for many years, I was skeptical about the value of surgery to treat obesity. Yes, everyone who had a bariatric procedure lost weight, but did the long-term benefits really outweigh the harms? I wondered if most people gradually gained back the weight they lost. And the harms can be significant, including dumping syndrome, hypoglycemia, and malabsorption—in addition to the potential for surgical complications and repeat surgery. And, I must confess that my views were likely affected by the death of a friend from complications of gastric bypass 25 years ago.

My skepticism, however, has changed to cautious optimism for carefully selected patients.

My skepticism, however, has changed to cautious optimism for carefully selected patients. I say this because we now have long-term follow-up studies demonstrating the value of bariatric procedures—especially for people with type 2 diabetes.

Most studies have been cohort studies that compare results to similar patients with obesity who did not have surgery, and the outcomes have been consistently better in patients who underwent surgery. Two recent meta-analyses summarized these results; one for all patients with obesity and the other for patients with type 2 diabetes.

Continue to: The first meta-analysis

The first meta-analysis included 11 randomized trials, 4 nonrandomized controlled trials, and 17 cohort studies and showed probable reductions in all-cause mortality and possible reductions in cancer and cardiovascular events.² The second demonstrated significant improvements in microvascular and macrovascular disease and reduced mortality.³ The data were limited, however, because of the lack of large randomized trials with long-term follow-up.

The Stampede trial is one of a few bariatric surgery randomized trials focusing on patients with diabetes.⁴ The 5-year follow-up results are impressive. Nearly 30% of patients who had gastric bypass and 23% who had sleeve gastrectomy had an A1C ≤6 at 5 years compared to only 5% of those treated medically. Some patients discontinued all medications for diabetes, hypertension, and hyperlipidemia.

There is now adequate research to show that bariatric surgery provides significant benefits to properly selected patients who understand the risks. I no longer hesitate to refer patients for bariatric surgery who have been unsuccessful with weight loss—despite their best efforts.

Where do you stand?

Because of the high prevalence of obesity and diabetes, bariatric surgery has become very popular. In the United States alone, there were an estimated 228,000 weight loss surgical procedures performed in 2017.¹

But I must confess that for many years, I was skeptical about the value of surgery to treat obesity. Yes, everyone who had a bariatric procedure lost weight, but did the long-term benefits really outweigh the harms? I wondered if most people gradually gained back the weight they lost. And the harms can be significant, including dumping syndrome, hypoglycemia, and malabsorption—in addition to the potential for surgical complications and repeat surgery. And, I must confess that my views were likely affected by the death of a friend from complications of gastric bypass 25 years ago.

My skepticism, however, has changed to cautious optimism for carefully selected patients.

My skepticism, however, has changed to cautious optimism for carefully selected patients. I say this because we now have long-term follow-up studies demonstrating the value of bariatric procedures—especially for people with type 2 diabetes.

Most studies have been cohort studies that compare results to similar patients with obesity who did not have surgery, and the outcomes have been consistently better in patients who underwent surgery. Two recent meta-analyses summarized these results; one for all patients with obesity and the other for patients with type 2 diabetes.

Continue to: The first meta-analysis

The first meta-analysis included 11 randomized trials, 4 nonrandomized controlled trials, and 17 cohort studies and showed probable reductions in all-cause mortality and possible reductions in cancer and cardiovascular events.² The second demonstrated significant improvements in microvascular and macrovascular disease and reduced mortality.³ The data were limited, however, because of the lack of large randomized trials with long-term follow-up.

The Stampede trial is one of a few bariatric surgery randomized trials focusing on patients with diabetes.⁴ The 5-year follow-up results are impressive. Nearly 30% of patients who had gastric bypass and 23% who had sleeve gastrectomy had an A1C ≤6 at 5 years compared to only 5% of those treated medically. Some patients discontinued all medications for diabetes, hypertension, and hyperlipidemia.

There is now adequate research to show that bariatric surgery provides significant benefits to properly selected patients who understand the risks. I no longer hesitate to refer patients for bariatric surgery who have been unsuccessful with weight loss—despite their best efforts.

Where do you stand?

Laparoscopic suturing is an option 

Dr. Lum presented a nicely produced video demonstrating various strategies aimed at facilitating total laparoscopic hysterectomy (TLH) of the very large uterus. Her patient’s evaluation included magnetic resonance imaging. In the video, she demonstrates a variety of interventions, including the use of a preoperative gonadotropin–releasing hormone (GNRH) agonist and immediate perioperative radial artery–uterine artery embolization. Intraoperative techniques include use of ureteral stents and securing the uterine arteries at their origins.

Clearly, TLH of a huge uterus is a technical challenge. However, I’d like to suggest that a relatively basic and important skill would greatly assist in such procedures and likely obviate the need for a GNRH agonist and/or uterine artery embolization. The vessel-sealing devices shown in the video are generally not capable of sealing such large vessels adequately, and this is what leads to the massive hemorrhaging that often occurs.

Laparoscopic suturing with extracorporeal knot tying can  be used effectively to control the extremely large vessels associated with a huge uterus. The judicious placement of sutures can completely control such vessels and prevent bleeding from both proximal and distal ends when 2 sutures are placed and the vessels are transected between the stitches. Many laparoscopic surgeons have come to rely on bipolar energy or ultrasonic devices to coagulate vessels. But when dealing with huge vessels, a return to basics using laparoscopic suturing will greatly benefit the patient and the surgeon by reducing blood loss and operative time.

David L. Zisow, MD
Baltimore, Maryland

Dr. Lum responds

I thank Dr. Zisow for his thoughtful comments. I agree that laparoscopic suturing is an essential skill that can be utilized to suture ligate vessels. If we consider the basics of an open hysterectomy, the uterine artery is clamped first, then suture ligated. When approaching a very large vessel during TLH, I would be concerned that a simple suture around a large vessel might tear through and cause more bleeding. To mitigate this risk, the vessel can be clamped with a grasper first, similar to the approach in an open hysterectomy. However, once a vessel is compressed, a sealing device can usually work just as well as a suture. It becomes a matter of preference and cost.

During hysterectomy of a very large uterus, a big challenge is managing bleeding of the uterus itself during manipulation from above. Bleeding from the vascular sinuses of the myometrium can be brisk and obscure visualization, potentially leading to laparotomy conversion. A common misconception is that uterine artery embolization is equivalent to suturing the uterine arteries. In actuality, the goal of a uterine artery embolization is to embolize the distal branches of the uterine arteries, which can help with any potential bleeding from the uterus itself during hysterectomy.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Laparoscopic suturing is an option 

Dr. Lum presented a nicely produced video demonstrating various strategies aimed at facilitating total laparoscopic hysterectomy (TLH) of the very large uterus. Her patient’s evaluation included magnetic resonance imaging. In the video, she demonstrates a variety of interventions, including the use of a preoperative gonadotropin–releasing hormone (GNRH) agonist and immediate perioperative radial artery–uterine artery embolization. Intraoperative techniques include use of ureteral stents and securing the uterine arteries at their origins.

Clearly, TLH of a huge uterus is a technical challenge. However, I’d like to suggest that a relatively basic and important skill would greatly assist in such procedures and likely obviate the need for a GNRH agonist and/or uterine artery embolization. The vessel-sealing devices shown in the video are generally not capable of sealing such large vessels adequately, and this is what leads to the massive hemorrhaging that often occurs.

Laparoscopic suturing with extracorporeal knot tying can  be used effectively to control the extremely large vessels associated with a huge uterus. The judicious placement of sutures can completely control such vessels and prevent bleeding from both proximal and distal ends when 2 sutures are placed and the vessels are transected between the stitches. Many laparoscopic surgeons have come to rely on bipolar energy or ultrasonic devices to coagulate vessels. But when dealing with huge vessels, a return to basics using laparoscopic suturing will greatly benefit the patient and the surgeon by reducing blood loss and operative time.

David L. Zisow, MD
Baltimore, Maryland

Dr. Lum responds

I thank Dr. Zisow for his thoughtful comments. I agree that laparoscopic suturing is an essential skill that can be utilized to suture ligate vessels. If we consider the basics of an open hysterectomy, the uterine artery is clamped first, then suture ligated. When approaching a very large vessel during TLH, I would be concerned that a simple suture around a large vessel might tear through and cause more bleeding. To mitigate this risk, the vessel can be clamped with a grasper first, similar to the approach in an open hysterectomy. However, once a vessel is compressed, a sealing device can usually work just as well as a suture. It becomes a matter of preference and cost.

During hysterectomy of a very large uterus, a big challenge is managing bleeding of the uterus itself during manipulation from above. Bleeding from the vascular sinuses of the myometrium can be brisk and obscure visualization, potentially leading to laparotomy conversion. A common misconception is that uterine artery embolization is equivalent to suturing the uterine arteries. In actuality, the goal of a uterine artery embolization is to embolize the distal branches of the uterine arteries, which can help with any potential bleeding from the uterus itself during hysterectomy.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Laparoscopic suturing is an option 

Dr. Lum presented a nicely produced video demonstrating various strategies aimed at facilitating total laparoscopic hysterectomy (TLH) of the very large uterus. Her patient’s evaluation included magnetic resonance imaging. In the video, she demonstrates a variety of interventions, including the use of a preoperative gonadotropin–releasing hormone (GNRH) agonist and immediate perioperative radial artery–uterine artery embolization. Intraoperative techniques include use of ureteral stents and securing the uterine arteries at their origins.

Clearly, TLH of a huge uterus is a technical challenge. However, I’d like to suggest that a relatively basic and important skill would greatly assist in such procedures and likely obviate the need for a GNRH agonist and/or uterine artery embolization. The vessel-sealing devices shown in the video are generally not capable of sealing such large vessels adequately, and this is what leads to the massive hemorrhaging that often occurs.

Laparoscopic suturing with extracorporeal knot tying can  be used effectively to control the extremely large vessels associated with a huge uterus. The judicious placement of sutures can completely control such vessels and prevent bleeding from both proximal and distal ends when 2 sutures are placed and the vessels are transected between the stitches. Many laparoscopic surgeons have come to rely on bipolar energy or ultrasonic devices to coagulate vessels. But when dealing with huge vessels, a return to basics using laparoscopic suturing will greatly benefit the patient and the surgeon by reducing blood loss and operative time.

David L. Zisow, MD
Baltimore, Maryland

Dr. Lum responds

I thank Dr. Zisow for his thoughtful comments. I agree that laparoscopic suturing is an essential skill that can be utilized to suture ligate vessels. If we consider the basics of an open hysterectomy, the uterine artery is clamped first, then suture ligated. When approaching a very large vessel during TLH, I would be concerned that a simple suture around a large vessel might tear through and cause more bleeding. To mitigate this risk, the vessel can be clamped with a grasper first, similar to the approach in an open hysterectomy. However, once a vessel is compressed, a sealing device can usually work just as well as a suture. It becomes a matter of preference and cost.

During hysterectomy of a very large uterus, a big challenge is managing bleeding of the uterus itself during manipulation from above. Bleeding from the vascular sinuses of the myometrium can be brisk and obscure visualization, potentially leading to laparotomy conversion. A common misconception is that uterine artery embolization is equivalent to suturing the uterine arteries. In actuality, the goal of a uterine artery embolization is to embolize the distal branches of the uterine arteries, which can help with any potential bleeding from the uterus itself during hysterectomy.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

A 64-year-old woman with no significant medical history presented to the emergency department with worsening intermittent abdominal pain and chronic diarrhea, which had increased in frequency over the prior 3 months. She had taken loperamide, which yielded mild symptomatic relief. A complete metabolic panel revealed no significant abnormalities, with a normal inflammatory marker and erythrocyte sedimentation rate (ESR).

Physical examination revealed mild tenderness to palpation over the right hemiabdomen, but no rebound tenderness or guarding. An abdominal radiograph (FIGURE 1), computed tomography (CT) without contrast of the abdomen and pelvis (FIGURE 2), and a whole-body octreotide scan (FIGURE 3) were ordered.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Based on the patient’s symptoms and imaging studies, we suspected that she had a carcinoid tumor with mesenteric involvement. The CT showed a 2.6-cm mesenteric mass with a characteristic sunburst pattern and desmoplastic stranding, as well as numerous prominent retroperitoneal lymph nodes, suggestive of nodal involvement. The octreotide scan showed abnormal focal intense radiotracer uptake in the corresponding right lower quadrant mass, which confirmed our suspicion. There was no evidence of hepatic metastasis on the CT or octreotide scan.

Most common locations

Carcinoid tumors are the most common type of neuroendocrine tumors and are derived primarily from serotonin-producing enterochromaffin cells.¹ These slow-growing, well-differentiated tumors usually originate in the gastrointestinal and bronchopulmonary tracts (67.5% and 25.3%, respectively), with uncommon primary sites involving the mesentery, ovaries, and kidneys.² Generally, carcinoid tumors that arise in the mesentery are metastatic, often from an occult primary site. It has been reported that 40% to 80% of midgut carcinoid tumors spread to the mesentery.³

Carcinoid tumors are derived primarily from serotonin-producing cells in the gastrointestinal tract, which can lead to symptoms such as chronic diarrhea.

Carcinoid tumors are estimated to occur in 1.9 individuals per 100,000 annually.⁴ Traditionally, the appendix was cited as the most common location for these tumors. However, more recently, Modlin et al² conducted a comprehensive analysis of epidemiologic data from the 13,715 carcinoid tumors registered in the National Cancer Institute database. Over the more than 25-year study period (1973-1999), Modlin and colleagues found a significant change in the distribution of gastrointestinal carcinoid tumors, with the incidence rates of small bowel (41.8%) and rectal carcinoids (27.4%) increasing, while appendiceal carcinoids decreased (24.1%).²

Gastrointestinal complications can arise from metastasis

Small bowel carcinoid tumors often manifest with intermittent abdominal pain, which can be caused by fibrosis of the mesentery, intestinal obstruction, or kinking of the bowel. Less common is the constellation of diarrhea, cutaneous flushing, and asthma seen with carcinoid syndrome. The prevalence of this syndrome is mediated by various humoral factors, the most notable of which is serotonin.

Continue to: Patients with carcinoid syndrome...

Patients with carcinoid syndrome often have metastasis to the liver, where serotonin is normally metabolized. This metastasis allows serotonin and other vasoactive substances to bypass hepatic metabolic degradation, resulting in the aforementioned symptoms. Carcinoid syndrome can also occur without hepatic metastasis in the setting of nodal involvement, which enables direct hormone release into the systemic circulation.⁵

Carcinoid syndrome affects fewer than 10% of patients with carcinoid tumors.⁶ Therefore, although carcinoid tumor should be suspected in patients with suggestive symptoms, other diagnoses must be considered.

Other disorders to consider on work-up

Chronic diarrhea and colicky abdominal pain are nonspecific features also associated with conditions such as inflammatory bowel disease and celiac disease, necessitating further work-up to elucidate the diagnosis.

Inflammatory bowel disease often involves elevated inflammatory markers, such as increased ESR and C-reactive protein.

Ulcerative colitis can show thickened and inflamed bowel walls on CT, with cross-sectional target appearance due to transmural involvement.

Continue to: Crohn's disease

Crohn’s disease usually affects the terminal ileum. CT is useful for identifying complications such as strictures/fistulas and abscesses.

Celiac disease involves elevated endomysial antibody and human tissue transglutaminase antibody. On CT, a characteristic jejunoileal fold pattern reversal can be seen.

A 24-hour urine test + imaging studies

The most useful diagnostic test for carcinoid tumor is the 24-hour urinary test for 5-hydroxyindoleacetic acid (5-HIAA), the metabolic end-product of serotonin. The normal rate of 5-HIAA excretion ranges from 3 to 15 mg/d, whereas the rates of patients with carcinoid tumors may have elevated levels.⁷

What you’ll see. On CT scan, a carcinoid tumor affecting the mesentery appears as a soft tissue mass with calcification and desmoplastic stranding, which produces a “sunburst” appearance. Another diagnostic tool is the octreotide scan, which is considered the test of choice due to its high sensitivity for detection of the tumor and metastases.⁸ The increase in somatostatin receptors seen with carcinoid tumors allows not only imaging by octreotide scan but also therapy using octreotide with larger doses of therapeutic radioactive agents.

Continue to: If tumor is operable, surgery is curative

Surgery is the only curative therapy and is the mainstay of treatment for carcinoid tumors. Local segmental resection is generally adequate for tumors <2 cm without nodal involvement. However, tumors >2 cm with regional mesentery metastasis and nodal involvement require wide excision of the bowel and mesentery with lymph node dissection because of the associated higher incidence of metastasis.⁹ If the tumor has metastasized to the liver and is considered inoperable, radiolabeled octreotide or ¹³¹I-metaiodobenzylguanidine are potential treatment options for arresting tumor growth and improving survival rates.¹⁰

Our patient underwent an uncomplicated surgical resection of the mesenteric carcinoid tumor and adjacent small bowel, as well as lymph node dissection. Intraoperatively, there was no evidence of tumor elsewhere in the abdomen or pelvis, including the liver, ovaries, and other solid organs, suggesting probable metastasis from an occult primary site. The patient had an unremarkable postoperative course and was reported to be asymptomatic on follow-up.

CORRESPONDENCE
Don N. Nguyen, MD, MHA, Dept. of Diagnostic Radiology, 320 E. North Ave., Pittsburgh, PA 15212; [email protected]

A 64-year-old woman with no significant medical history presented to the emergency department with worsening intermittent abdominal pain and chronic diarrhea, which had increased in frequency over the prior 3 months. She had taken loperamide, which yielded mild symptomatic relief. A complete metabolic panel revealed no significant abnormalities, with a normal inflammatory marker and erythrocyte sedimentation rate (ESR).

Physical examination revealed mild tenderness to palpation over the right hemiabdomen, but no rebound tenderness or guarding. An abdominal radiograph (FIGURE 1), computed tomography (CT) without contrast of the abdomen and pelvis (FIGURE 2), and a whole-body octreotide scan (FIGURE 3) were ordered.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Based on the patient’s symptoms and imaging studies, we suspected that she had a carcinoid tumor with mesenteric involvement. The CT showed a 2.6-cm mesenteric mass with a characteristic sunburst pattern and desmoplastic stranding, as well as numerous prominent retroperitoneal lymph nodes, suggestive of nodal involvement. The octreotide scan showed abnormal focal intense radiotracer uptake in the corresponding right lower quadrant mass, which confirmed our suspicion. There was no evidence of hepatic metastasis on the CT or octreotide scan.

Most common locations

Carcinoid tumors are the most common type of neuroendocrine tumors and are derived primarily from serotonin-producing enterochromaffin cells.¹ These slow-growing, well-differentiated tumors usually originate in the gastrointestinal and bronchopulmonary tracts (67.5% and 25.3%, respectively), with uncommon primary sites involving the mesentery, ovaries, and kidneys.² Generally, carcinoid tumors that arise in the mesentery are metastatic, often from an occult primary site. It has been reported that 40% to 80% of midgut carcinoid tumors spread to the mesentery.³

Carcinoid tumors are derived primarily from serotonin-producing cells in the gastrointestinal tract, which can lead to symptoms such as chronic diarrhea.

Carcinoid tumors are estimated to occur in 1.9 individuals per 100,000 annually.⁴ Traditionally, the appendix was cited as the most common location for these tumors. However, more recently, Modlin et al² conducted a comprehensive analysis of epidemiologic data from the 13,715 carcinoid tumors registered in the National Cancer Institute database. Over the more than 25-year study period (1973-1999), Modlin and colleagues found a significant change in the distribution of gastrointestinal carcinoid tumors, with the incidence rates of small bowel (41.8%) and rectal carcinoids (27.4%) increasing, while appendiceal carcinoids decreased (24.1%).²

Gastrointestinal complications can arise from metastasis

Small bowel carcinoid tumors often manifest with intermittent abdominal pain, which can be caused by fibrosis of the mesentery, intestinal obstruction, or kinking of the bowel. Less common is the constellation of diarrhea, cutaneous flushing, and asthma seen with carcinoid syndrome. The prevalence of this syndrome is mediated by various humoral factors, the most notable of which is serotonin.

Continue to: Patients with carcinoid syndrome...

Patients with carcinoid syndrome often have metastasis to the liver, where serotonin is normally metabolized. This metastasis allows serotonin and other vasoactive substances to bypass hepatic metabolic degradation, resulting in the aforementioned symptoms. Carcinoid syndrome can also occur without hepatic metastasis in the setting of nodal involvement, which enables direct hormone release into the systemic circulation.⁵

Carcinoid syndrome affects fewer than 10% of patients with carcinoid tumors.⁶ Therefore, although carcinoid tumor should be suspected in patients with suggestive symptoms, other diagnoses must be considered.

Other disorders to consider on work-up

Chronic diarrhea and colicky abdominal pain are nonspecific features also associated with conditions such as inflammatory bowel disease and celiac disease, necessitating further work-up to elucidate the diagnosis.

Inflammatory bowel disease often involves elevated inflammatory markers, such as increased ESR and C-reactive protein.

Ulcerative colitis can show thickened and inflamed bowel walls on CT, with cross-sectional target appearance due to transmural involvement.

Continue to: Crohn's disease

Crohn’s disease usually affects the terminal ileum. CT is useful for identifying complications such as strictures/fistulas and abscesses.

Celiac disease involves elevated endomysial antibody and human tissue transglutaminase antibody. On CT, a characteristic jejunoileal fold pattern reversal can be seen.

A 24-hour urine test + imaging studies

The most useful diagnostic test for carcinoid tumor is the 24-hour urinary test for 5-hydroxyindoleacetic acid (5-HIAA), the metabolic end-product of serotonin. The normal rate of 5-HIAA excretion ranges from 3 to 15 mg/d, whereas the rates of patients with carcinoid tumors may have elevated levels.⁷

What you’ll see. On CT scan, a carcinoid tumor affecting the mesentery appears as a soft tissue mass with calcification and desmoplastic stranding, which produces a “sunburst” appearance. Another diagnostic tool is the octreotide scan, which is considered the test of choice due to its high sensitivity for detection of the tumor and metastases.⁸ The increase in somatostatin receptors seen with carcinoid tumors allows not only imaging by octreotide scan but also therapy using octreotide with larger doses of therapeutic radioactive agents.

Continue to: If tumor is operable, surgery is curative

Surgery is the only curative therapy and is the mainstay of treatment for carcinoid tumors. Local segmental resection is generally adequate for tumors <2 cm without nodal involvement. However, tumors >2 cm with regional mesentery metastasis and nodal involvement require wide excision of the bowel and mesentery with lymph node dissection because of the associated higher incidence of metastasis.⁹ If the tumor has metastasized to the liver and is considered inoperable, radiolabeled octreotide or ¹³¹I-metaiodobenzylguanidine are potential treatment options for arresting tumor growth and improving survival rates.¹⁰

Our patient underwent an uncomplicated surgical resection of the mesenteric carcinoid tumor and adjacent small bowel, as well as lymph node dissection. Intraoperatively, there was no evidence of tumor elsewhere in the abdomen or pelvis, including the liver, ovaries, and other solid organs, suggesting probable metastasis from an occult primary site. The patient had an unremarkable postoperative course and was reported to be asymptomatic on follow-up.

CORRESPONDENCE
Don N. Nguyen, MD, MHA, Dept. of Diagnostic Radiology, 320 E. North Ave., Pittsburgh, PA 15212; [email protected]

A 64-year-old woman with no significant medical history presented to the emergency department with worsening intermittent abdominal pain and chronic diarrhea, which had increased in frequency over the prior 3 months. She had taken loperamide, which yielded mild symptomatic relief. A complete metabolic panel revealed no significant abnormalities, with a normal inflammatory marker and erythrocyte sedimentation rate (ESR).

Physical examination revealed mild tenderness to palpation over the right hemiabdomen, but no rebound tenderness or guarding. An abdominal radiograph (FIGURE 1), computed tomography (CT) without contrast of the abdomen and pelvis (FIGURE 2), and a whole-body octreotide scan (FIGURE 3) were ordered.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Based on the patient’s symptoms and imaging studies, we suspected that she had a carcinoid tumor with mesenteric involvement. The CT showed a 2.6-cm mesenteric mass with a characteristic sunburst pattern and desmoplastic stranding, as well as numerous prominent retroperitoneal lymph nodes, suggestive of nodal involvement. The octreotide scan showed abnormal focal intense radiotracer uptake in the corresponding right lower quadrant mass, which confirmed our suspicion. There was no evidence of hepatic metastasis on the CT or octreotide scan.

Most common locations

Carcinoid tumors are the most common type of neuroendocrine tumors and are derived primarily from serotonin-producing enterochromaffin cells.¹ These slow-growing, well-differentiated tumors usually originate in the gastrointestinal and bronchopulmonary tracts (67.5% and 25.3%, respectively), with uncommon primary sites involving the mesentery, ovaries, and kidneys.² Generally, carcinoid tumors that arise in the mesentery are metastatic, often from an occult primary site. It has been reported that 40% to 80% of midgut carcinoid tumors spread to the mesentery.³

Carcinoid tumors are derived primarily from serotonin-producing cells in the gastrointestinal tract, which can lead to symptoms such as chronic diarrhea.

Carcinoid tumors are estimated to occur in 1.9 individuals per 100,000 annually.⁴ Traditionally, the appendix was cited as the most common location for these tumors. However, more recently, Modlin et al² conducted a comprehensive analysis of epidemiologic data from the 13,715 carcinoid tumors registered in the National Cancer Institute database. Over the more than 25-year study period (1973-1999), Modlin and colleagues found a significant change in the distribution of gastrointestinal carcinoid tumors, with the incidence rates of small bowel (41.8%) and rectal carcinoids (27.4%) increasing, while appendiceal carcinoids decreased (24.1%).²

Gastrointestinal complications can arise from metastasis

Small bowel carcinoid tumors often manifest with intermittent abdominal pain, which can be caused by fibrosis of the mesentery, intestinal obstruction, or kinking of the bowel. Less common is the constellation of diarrhea, cutaneous flushing, and asthma seen with carcinoid syndrome. The prevalence of this syndrome is mediated by various humoral factors, the most notable of which is serotonin.

Continue to: Patients with carcinoid syndrome...

Patients with carcinoid syndrome often have metastasis to the liver, where serotonin is normally metabolized. This metastasis allows serotonin and other vasoactive substances to bypass hepatic metabolic degradation, resulting in the aforementioned symptoms. Carcinoid syndrome can also occur without hepatic metastasis in the setting of nodal involvement, which enables direct hormone release into the systemic circulation.⁵

Carcinoid syndrome affects fewer than 10% of patients with carcinoid tumors.⁶ Therefore, although carcinoid tumor should be suspected in patients with suggestive symptoms, other diagnoses must be considered.

Other disorders to consider on work-up

Chronic diarrhea and colicky abdominal pain are nonspecific features also associated with conditions such as inflammatory bowel disease and celiac disease, necessitating further work-up to elucidate the diagnosis.

Inflammatory bowel disease often involves elevated inflammatory markers, such as increased ESR and C-reactive protein.

Ulcerative colitis can show thickened and inflamed bowel walls on CT, with cross-sectional target appearance due to transmural involvement.

Continue to: Crohn's disease

Crohn’s disease usually affects the terminal ileum. CT is useful for identifying complications such as strictures/fistulas and abscesses.

Celiac disease involves elevated endomysial antibody and human tissue transglutaminase antibody. On CT, a characteristic jejunoileal fold pattern reversal can be seen.

A 24-hour urine test + imaging studies

The most useful diagnostic test for carcinoid tumor is the 24-hour urinary test for 5-hydroxyindoleacetic acid (5-HIAA), the metabolic end-product of serotonin. The normal rate of 5-HIAA excretion ranges from 3 to 15 mg/d, whereas the rates of patients with carcinoid tumors may have elevated levels.⁷

What you’ll see. On CT scan, a carcinoid tumor affecting the mesentery appears as a soft tissue mass with calcification and desmoplastic stranding, which produces a “sunburst” appearance. Another diagnostic tool is the octreotide scan, which is considered the test of choice due to its high sensitivity for detection of the tumor and metastases.⁸ The increase in somatostatin receptors seen with carcinoid tumors allows not only imaging by octreotide scan but also therapy using octreotide with larger doses of therapeutic radioactive agents.

Continue to: If tumor is operable, surgery is curative

Surgery is the only curative therapy and is the mainstay of treatment for carcinoid tumors. Local segmental resection is generally adequate for tumors <2 cm without nodal involvement. However, tumors >2 cm with regional mesentery metastasis and nodal involvement require wide excision of the bowel and mesentery with lymph node dissection because of the associated higher incidence of metastasis.⁹ If the tumor has metastasized to the liver and is considered inoperable, radiolabeled octreotide or ¹³¹I-metaiodobenzylguanidine are potential treatment options for arresting tumor growth and improving survival rates.¹⁰

Our patient underwent an uncomplicated surgical resection of the mesenteric carcinoid tumor and adjacent small bowel, as well as lymph node dissection. Intraoperatively, there was no evidence of tumor elsewhere in the abdomen or pelvis, including the liver, ovaries, and other solid organs, suggesting probable metastasis from an occult primary site. The patient had an unremarkable postoperative course and was reported to be asymptomatic on follow-up.

CORRESPONDENCE
Don N. Nguyen, MD, MHA, Dept. of Diagnostic Radiology, 320 E. North Ave., Pittsburgh, PA 15212; [email protected]

THE CASE

A 57-year-old woman presented to a family physician with acute encephalopathy and complaints of recent gastritis. She reported a 2-month history of nausea, vomiting, decreased oral intake, and extreme sensitivity to smell. The patient had a history of hypertension, and a family member privately disclosed to the FP that she also had a history of alcohol abuse. The patient was taking lorazepam daily, as needed, for anxiety.

On initial assessment, the patient was alert, but not oriented to time or situation. She was ataxic and agitated but did not exhibit pupillary constriction or tremor. The FP sent her to the emergency department (ED).

After being assessed in the ED, the patient was admitted. Over the course of several days, she showed worsening mentation; she persistently believed she was in Chicago, her childhood home. On memory testing, she was unable to recall any of 3 objects after 5 minutes. She exhibited horizontal nystagmus and dysmetria bilaterally and continued to be ataxic, requiring 2-point assistance. Her agitation was managed nonpharmacologically.

A work-up was performed, which included laboratory testing, a urinalysis, and computed tomography (CT) of the head. A comprehensive metabolic panel, complete blood count, and thyroid stimulating hormone test were unremarkable except for electrolyte disturbances, with a sodium level of 158 mEq/L and a potassium level of 2.6 mEq/L (reference ranges: 135-145 mEq/L and 3.5-5 mEq/L, respectively).

Her blood alcohol level was zero, and not surprisingly given her use of lorazepam, a urine drug screen was positive for benzodiazepines. The urinalysis results were consistent with a urinary tract infection (UTI), for which she was treated with an antibiotic. A carbohydrate-deficient transferrin test may have been useful to establish chronic alcohol abuse, but was not ordered. The head CT was negative.

After a few days with fluids and electrolyte replacement, the patient’s electrolytes normalized.

THE DIAGNOSIS

The differential diagnosis included sepsis, metabolic encephalopathy, and alcoholic encephalopathy. Given that the patient’s urine drug screen was positive, benzodiazepine withdrawal was also considered a plausible explanation for her continued cognitive disturbances. (It was surmised that she had likely taken her last lorazepam several days prior.) However, the lack of other signs of withdrawal prompted further investigation.

Continue to: Since her encephalopathy...

Since her encephalopathy, ataxia, and nystagmus persisted, magnetic resonance imaging (MRI) of the brain was performed on Day 3 of hospitalization (FIGURE). A lumbar puncture and an electroencephalogram were also considered but were not performed because the MRI results revealed bilateral enhancement of the mammillary bodies and mild signal hyperintensity, thus confirming a diagnosis of Wernicke-Korsakoff syndrome (WKS).

DISCUSSION

WKS is the concurrence of Wernicke’s encephalopathy (an acute, life-threatening condition marked by ataxia, confusion, and ocular signs) and Korsakoff’s psychosis (a long-term, debilitating amnestic syndrome). WKS is a neuropsychiatric disorder in which patients experience profound short-term amnesia; it is precipitated by thiamine deficiency (defined as a whole blood thiamine level <0.7 ng/ml¹).The link to thiamine was confirmed during World War II, when thiamine treatment resolved symptoms in starving prisoners. If recognized early, treatment of thiamine deficiency can prevent long-term morbidity from WKS.

Etiology of thiamine deficiency

Procedures such as gastric bypass and dialysis can precipitate Wernicke-Korsakoff syndrome.

Our patient’s alcohol abuse placed her at risk for WKS, and her olfactory aversion to certain foods was a diagnostic clue. In this case, we inadvertently administered dextrose with antibiotics for the UTI prior to administering thiamine; this exacerbated the thiamine deficiency because glucose and thiamine compete for the same substrate.

Is alcohol abuse always to blame for WKS?

The quantity and type of alcohol that results in the development of WKS has not been well studied, but the Caine diagnostic criteria defines chronic alcoholism as the consumption of 80 g/d of ethanol (8 drinks/d).² While WKS is commonly associated with alcoholism, other causative conditions may be overlooked. Other associated illnesses include acquired immune deficiency syndrome (AIDS), cancer, hyperemesis gravidarum, prolonged total parenteral nutrition, and psychiatric illnesses such as eating disorders and schizophrenia. Procedures such as gastric bypass and dialysis can also precipitate WKS.³

Men and women are both at risk of developing WKS. A lack of consumption of thiamine-rich sources such as cereals, rice, and legumes puts patients at risk for WKS. The recommended dietary allowance of thiamine increases with age and may be higher for obese patients.⁴

Continue to: Suspect thiamine deficiency and obstain a thorough history

A high index of suspicion for thiamine deficiency is essential for diagnosis of WKS. History of alcohol use should be obtained, including quantity, frequency, pattern, duration, and time of last use. Physicians should assess nutrition and ask about vomiting and diarrhea. It is important to collaborate with the patient’s family and friends and inquire into other substance misuse.⁵

The clinical triad of mental status change, ophthalmoplegia, and gait ataxia is present in as few as 10% of cases of Wernicke-Korsakoff syndrome.

Since WKS targets the dorsomedial thalamus, which is responsible for olfactory processing, patients may complain of a distorted perception of smell.⁶ On physical examination, look for signs of protein-calorie malnutrition, including cheilitis, glossitis, and bleeding gums; signs of alcohol abuse, such as hepatomegaly; and evidence of injuries or poor self-care.⁵

Varied presentation leads to under- and misdiagnosis

Diagnosis of WKS can be difficult due to the varied presentation; there is a broad spectrum of clinical features. The clinical triad of mental status change, ophthalmoplegia, and gait ataxia is present in as few as 10% of cases.³ Mental status changes may include a global confusional state ranging from disorientation, apathy, anxiety, fear, and mild memory impairment to pronounced amnesia. Ophthalmoplegia can include nystagmus, ocular palsies, retinal hemorrhages, scotoma, or photophobia; and ataxia can range from a mild gait abnormality to an inability to stand.⁷ This varied presentation ultimately leads to underdiagnosis and misdiagnosis.

MRI findings are also varied in WKS. However, the mammillary bodies are involved in many cases, where atrophy of these structures have high specificity. The dorsomedial thalamus is associated with the reported impairment in memory and can be identified antemortem on MRI.³ There is no quantifiable evidence of how much thiamine should be used to prevent WKS. However, thiamine should be given before the administration of glucose whenever WKS is considered.

Our patient. Despite the administration of thiamine (100 mg parenterally for 5 d, followed by oral thiamine 300 mg/d indefinitely), our patient’s memory and cognition remained unchanged. She underwent intensive inpatient rehabilitation for 2 months and was eventually placed in long-term nursing care.

Continue to: THE TAKEAWAY

THE TAKEAWAY

A high index of suspicion is crucial to prevent possible long-term neurologic sequelae in WKS. Appropriate care starts at the beginning, with the patient’s story.

CORRESPONDENCE
Romith Naug, MD, 15 St. Andrew Street, Unit 601, Brockville, ON Canada K6V0B8; [email protected].

THE CASE

A 57-year-old woman presented to a family physician with acute encephalopathy and complaints of recent gastritis. She reported a 2-month history of nausea, vomiting, decreased oral intake, and extreme sensitivity to smell. The patient had a history of hypertension, and a family member privately disclosed to the FP that she also had a history of alcohol abuse. The patient was taking lorazepam daily, as needed, for anxiety.

On initial assessment, the patient was alert, but not oriented to time or situation. She was ataxic and agitated but did not exhibit pupillary constriction or tremor. The FP sent her to the emergency department (ED).

After being assessed in the ED, the patient was admitted. Over the course of several days, she showed worsening mentation; she persistently believed she was in Chicago, her childhood home. On memory testing, she was unable to recall any of 3 objects after 5 minutes. She exhibited horizontal nystagmus and dysmetria bilaterally and continued to be ataxic, requiring 2-point assistance. Her agitation was managed nonpharmacologically.

A work-up was performed, which included laboratory testing, a urinalysis, and computed tomography (CT) of the head. A comprehensive metabolic panel, complete blood count, and thyroid stimulating hormone test were unremarkable except for electrolyte disturbances, with a sodium level of 158 mEq/L and a potassium level of 2.6 mEq/L (reference ranges: 135-145 mEq/L and 3.5-5 mEq/L, respectively).

Her blood alcohol level was zero, and not surprisingly given her use of lorazepam, a urine drug screen was positive for benzodiazepines. The urinalysis results were consistent with a urinary tract infection (UTI), for which she was treated with an antibiotic. A carbohydrate-deficient transferrin test may have been useful to establish chronic alcohol abuse, but was not ordered. The head CT was negative.

After a few days with fluids and electrolyte replacement, the patient’s electrolytes normalized.

THE DIAGNOSIS

The differential diagnosis included sepsis, metabolic encephalopathy, and alcoholic encephalopathy. Given that the patient’s urine drug screen was positive, benzodiazepine withdrawal was also considered a plausible explanation for her continued cognitive disturbances. (It was surmised that she had likely taken her last lorazepam several days prior.) However, the lack of other signs of withdrawal prompted further investigation.

Continue to: Since her encephalopathy...

Since her encephalopathy, ataxia, and nystagmus persisted, magnetic resonance imaging (MRI) of the brain was performed on Day 3 of hospitalization (FIGURE). A lumbar puncture and an electroencephalogram were also considered but were not performed because the MRI results revealed bilateral enhancement of the mammillary bodies and mild signal hyperintensity, thus confirming a diagnosis of Wernicke-Korsakoff syndrome (WKS).

DISCUSSION

WKS is the concurrence of Wernicke’s encephalopathy (an acute, life-threatening condition marked by ataxia, confusion, and ocular signs) and Korsakoff’s psychosis (a long-term, debilitating amnestic syndrome). WKS is a neuropsychiatric disorder in which patients experience profound short-term amnesia; it is precipitated by thiamine deficiency (defined as a whole blood thiamine level <0.7 ng/ml¹).The link to thiamine was confirmed during World War II, when thiamine treatment resolved symptoms in starving prisoners. If recognized early, treatment of thiamine deficiency can prevent long-term morbidity from WKS.

Etiology of thiamine deficiency

Procedures such as gastric bypass and dialysis can precipitate Wernicke-Korsakoff syndrome.

Our patient’s alcohol abuse placed her at risk for WKS, and her olfactory aversion to certain foods was a diagnostic clue. In this case, we inadvertently administered dextrose with antibiotics for the UTI prior to administering thiamine; this exacerbated the thiamine deficiency because glucose and thiamine compete for the same substrate.

Is alcohol abuse always to blame for WKS?

The quantity and type of alcohol that results in the development of WKS has not been well studied, but the Caine diagnostic criteria defines chronic alcoholism as the consumption of 80 g/d of ethanol (8 drinks/d).² While WKS is commonly associated with alcoholism, other causative conditions may be overlooked. Other associated illnesses include acquired immune deficiency syndrome (AIDS), cancer, hyperemesis gravidarum, prolonged total parenteral nutrition, and psychiatric illnesses such as eating disorders and schizophrenia. Procedures such as gastric bypass and dialysis can also precipitate WKS.³

Men and women are both at risk of developing WKS. A lack of consumption of thiamine-rich sources such as cereals, rice, and legumes puts patients at risk for WKS. The recommended dietary allowance of thiamine increases with age and may be higher for obese patients.⁴

Continue to: Suspect thiamine deficiency and obstain a thorough history

A high index of suspicion for thiamine deficiency is essential for diagnosis of WKS. History of alcohol use should be obtained, including quantity, frequency, pattern, duration, and time of last use. Physicians should assess nutrition and ask about vomiting and diarrhea. It is important to collaborate with the patient’s family and friends and inquire into other substance misuse.⁵

The clinical triad of mental status change, ophthalmoplegia, and gait ataxia is present in as few as 10% of cases of Wernicke-Korsakoff syndrome.

Since WKS targets the dorsomedial thalamus, which is responsible for olfactory processing, patients may complain of a distorted perception of smell.⁶ On physical examination, look for signs of protein-calorie malnutrition, including cheilitis, glossitis, and bleeding gums; signs of alcohol abuse, such as hepatomegaly; and evidence of injuries or poor self-care.⁵

Varied presentation leads to under- and misdiagnosis

Diagnosis of WKS can be difficult due to the varied presentation; there is a broad spectrum of clinical features. The clinical triad of mental status change, ophthalmoplegia, and gait ataxia is present in as few as 10% of cases.³ Mental status changes may include a global confusional state ranging from disorientation, apathy, anxiety, fear, and mild memory impairment to pronounced amnesia. Ophthalmoplegia can include nystagmus, ocular palsies, retinal hemorrhages, scotoma, or photophobia; and ataxia can range from a mild gait abnormality to an inability to stand.⁷ This varied presentation ultimately leads to underdiagnosis and misdiagnosis.

MRI findings are also varied in WKS. However, the mammillary bodies are involved in many cases, where atrophy of these structures have high specificity. The dorsomedial thalamus is associated with the reported impairment in memory and can be identified antemortem on MRI.³ There is no quantifiable evidence of how much thiamine should be used to prevent WKS. However, thiamine should be given before the administration of glucose whenever WKS is considered.

Our patient. Despite the administration of thiamine (100 mg parenterally for 5 d, followed by oral thiamine 300 mg/d indefinitely), our patient’s memory and cognition remained unchanged. She underwent intensive inpatient rehabilitation for 2 months and was eventually placed in long-term nursing care.

Continue to: THE TAKEAWAY

THE TAKEAWAY

A high index of suspicion is crucial to prevent possible long-term neurologic sequelae in WKS. Appropriate care starts at the beginning, with the patient’s story.

CORRESPONDENCE
Romith Naug, MD, 15 St. Andrew Street, Unit 601, Brockville, ON Canada K6V0B8; [email protected].

THE CASE

A 57-year-old woman presented to a family physician with acute encephalopathy and complaints of recent gastritis. She reported a 2-month history of nausea, vomiting, decreased oral intake, and extreme sensitivity to smell. The patient had a history of hypertension, and a family member privately disclosed to the FP that she also had a history of alcohol abuse. The patient was taking lorazepam daily, as needed, for anxiety.

On initial assessment, the patient was alert, but not oriented to time or situation. She was ataxic and agitated but did not exhibit pupillary constriction or tremor. The FP sent her to the emergency department (ED).

After being assessed in the ED, the patient was admitted. Over the course of several days, she showed worsening mentation; she persistently believed she was in Chicago, her childhood home. On memory testing, she was unable to recall any of 3 objects after 5 minutes. She exhibited horizontal nystagmus and dysmetria bilaterally and continued to be ataxic, requiring 2-point assistance. Her agitation was managed nonpharmacologically.

A work-up was performed, which included laboratory testing, a urinalysis, and computed tomography (CT) of the head. A comprehensive metabolic panel, complete blood count, and thyroid stimulating hormone test were unremarkable except for electrolyte disturbances, with a sodium level of 158 mEq/L and a potassium level of 2.6 mEq/L (reference ranges: 135-145 mEq/L and 3.5-5 mEq/L, respectively).

Her blood alcohol level was zero, and not surprisingly given her use of lorazepam, a urine drug screen was positive for benzodiazepines. The urinalysis results were consistent with a urinary tract infection (UTI), for which she was treated with an antibiotic. A carbohydrate-deficient transferrin test may have been useful to establish chronic alcohol abuse, but was not ordered. The head CT was negative.

After a few days with fluids and electrolyte replacement, the patient’s electrolytes normalized.

THE DIAGNOSIS

The differential diagnosis included sepsis, metabolic encephalopathy, and alcoholic encephalopathy. Given that the patient’s urine drug screen was positive, benzodiazepine withdrawal was also considered a plausible explanation for her continued cognitive disturbances. (It was surmised that she had likely taken her last lorazepam several days prior.) However, the lack of other signs of withdrawal prompted further investigation.

Continue to: Since her encephalopathy...

Since her encephalopathy, ataxia, and nystagmus persisted, magnetic resonance imaging (MRI) of the brain was performed on Day 3 of hospitalization (FIGURE). A lumbar puncture and an electroencephalogram were also considered but were not performed because the MRI results revealed bilateral enhancement of the mammillary bodies and mild signal hyperintensity, thus confirming a diagnosis of Wernicke-Korsakoff syndrome (WKS).

DISCUSSION

WKS is the concurrence of Wernicke’s encephalopathy (an acute, life-threatening condition marked by ataxia, confusion, and ocular signs) and Korsakoff’s psychosis (a long-term, debilitating amnestic syndrome). WKS is a neuropsychiatric disorder in which patients experience profound short-term amnesia; it is precipitated by thiamine deficiency (defined as a whole blood thiamine level <0.7 ng/ml¹).The link to thiamine was confirmed during World War II, when thiamine treatment resolved symptoms in starving prisoners. If recognized early, treatment of thiamine deficiency can prevent long-term morbidity from WKS.

Etiology of thiamine deficiency

Procedures such as gastric bypass and dialysis can precipitate Wernicke-Korsakoff syndrome.

Our patient’s alcohol abuse placed her at risk for WKS, and her olfactory aversion to certain foods was a diagnostic clue. In this case, we inadvertently administered dextrose with antibiotics for the UTI prior to administering thiamine; this exacerbated the thiamine deficiency because glucose and thiamine compete for the same substrate.

Is alcohol abuse always to blame for WKS?

The quantity and type of alcohol that results in the development of WKS has not been well studied, but the Caine diagnostic criteria defines chronic alcoholism as the consumption of 80 g/d of ethanol (8 drinks/d).² While WKS is commonly associated with alcoholism, other causative conditions may be overlooked. Other associated illnesses include acquired immune deficiency syndrome (AIDS), cancer, hyperemesis gravidarum, prolonged total parenteral nutrition, and psychiatric illnesses such as eating disorders and schizophrenia. Procedures such as gastric bypass and dialysis can also precipitate WKS.³

Men and women are both at risk of developing WKS. A lack of consumption of thiamine-rich sources such as cereals, rice, and legumes puts patients at risk for WKS. The recommended dietary allowance of thiamine increases with age and may be higher for obese patients.⁴

Continue to: Suspect thiamine deficiency and obstain a thorough history

A high index of suspicion for thiamine deficiency is essential for diagnosis of WKS. History of alcohol use should be obtained, including quantity, frequency, pattern, duration, and time of last use. Physicians should assess nutrition and ask about vomiting and diarrhea. It is important to collaborate with the patient’s family and friends and inquire into other substance misuse.⁵

The clinical triad of mental status change, ophthalmoplegia, and gait ataxia is present in as few as 10% of cases of Wernicke-Korsakoff syndrome.

Since WKS targets the dorsomedial thalamus, which is responsible for olfactory processing, patients may complain of a distorted perception of smell.⁶ On physical examination, look for signs of protein-calorie malnutrition, including cheilitis, glossitis, and bleeding gums; signs of alcohol abuse, such as hepatomegaly; and evidence of injuries or poor self-care.⁵

Varied presentation leads to under- and misdiagnosis

Diagnosis of WKS can be difficult due to the varied presentation; there is a broad spectrum of clinical features. The clinical triad of mental status change, ophthalmoplegia, and gait ataxia is present in as few as 10% of cases.³ Mental status changes may include a global confusional state ranging from disorientation, apathy, anxiety, fear, and mild memory impairment to pronounced amnesia. Ophthalmoplegia can include nystagmus, ocular palsies, retinal hemorrhages, scotoma, or photophobia; and ataxia can range from a mild gait abnormality to an inability to stand.⁷ This varied presentation ultimately leads to underdiagnosis and misdiagnosis.

MRI findings are also varied in WKS. However, the mammillary bodies are involved in many cases, where atrophy of these structures have high specificity. The dorsomedial thalamus is associated with the reported impairment in memory and can be identified antemortem on MRI.³ There is no quantifiable evidence of how much thiamine should be used to prevent WKS. However, thiamine should be given before the administration of glucose whenever WKS is considered.

Our patient. Despite the administration of thiamine (100 mg parenterally for 5 d, followed by oral thiamine 300 mg/d indefinitely), our patient’s memory and cognition remained unchanged. She underwent intensive inpatient rehabilitation for 2 months and was eventually placed in long-term nursing care.

Continue to: THE TAKEAWAY

THE TAKEAWAY

A high index of suspicion is crucial to prevent possible long-term neurologic sequelae in WKS. Appropriate care starts at the beginning, with the patient’s story.

CORRESPONDENCE
Romith Naug, MD, 15 St. Andrew Street, Unit 601, Brockville, ON Canada K6V0B8; [email protected].

THE CASE

Al* is a 48-year-old patient whose wife, Vera, died of complications from chronic illness 14 months ago. Al thinks about Vera constantly and says he still has difficulty accepting that she is gone. He does not leave the house much anymore and continues to set a place for her at the kitchen table on special occasions. He says, “Some nights in bed, I swear I can hear her in the living room.”

How would you proceed with this patient?

* The names of the patient and his spouse have been changed to protect their identities.

After the loss of a loved one, grief is a natural response to the separation and stress that go along with the death. Most people, after suffering a loss, experience distress that varies in intensity and gradually decreases over time. Thus, the grieving individual does not act as they would normally if they were not bereaved. However, gains are generally made month by month, and most people adjust to the grief and adapt their lives after some time dealing with the absence of the loved one.¹

There’s grief, and then there’s complicated grief

For about 2% to 4% of the population who have experienced a significant loss, complicated grief is an issue.² As its hallmark, complicated grief exceeds the typical amount of time (6-12 months) that people need to recover from a loss. Prevalence has been estimated at 10% to 20% among grieving individuals for whom the death being grieved was that of a romantic partner or child.² At increased risk for this disorder are women older than 60 years, patients diagnosed with depression or substance abuse, individuals under financial strain, and those who have experienced a violent or sudden loss.³

The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) has conceptualized complicated grief with the name, persistent complex bereavement disorder (PCBD).⁴ While the guidelines for the definition are still in progress, several specified symptoms must have been present for at least 6 months to a year or more (TABLE 1⁴). For instance, the patient has been ruminating about the death, has been unable to accept the death, or has felt shocked or numb. They may also experience anger, have difficulty trusting others, and be preoccupied with the deceased (eg, sense they can hear their lost loved one, feel the loved one’s pain for them). Symptoms of PCBD may also include experiencing vivid reminders of the loss and avoiding situations that bring up thoughts about the death.⁴ (Of note: A grief diagnosis in ICD-10 is captured by the code F43.21; however, there is no specific code for complicated grief or PCBD.)

PCBD is a “condition for further study” in DSM-5; it was omitted from DSM-IV only after much debate. One reason for its omission was concern that clinicians might “pathologize” grief more than it needs to be.⁵ Grief is regarded as a natural process that might be stymied by a formal diagnosis leading to medical treatment.

Shifting the grief diagnosis paradigm

One new development is that recently bereaved patients can be diagnosed with depression if they meet the criteria for that diagnosis. In the past, someone who met criteria for major depression would be excluded from that diagnosis if the depression ensued from grief. DSM-5 no longer makes that distinction.⁴ Given this diagnostic shift, one might wonder about the difference between PCBD and depression, particularly if the patient is a grieving individual with a current diagnosis of depression.⁵

Continue to: Differences between PCBD and major depression

Differences between PCBD and major depression. While antidepressant medication is helpful for patients with moderate-to-severe depression, it has thus far been less helpful for those solely experiencing complicated grief.⁶ The same holds true for traditional psychotherapy. While family physicians can confidently refer people to psychotherapy for depression, it is not as efficacious as focused therapy designed for those with PCBD.⁶

Other differences between PCBD and major depression involve the constructs of guilt and yearning. Depressed patients typically feel guilty about a number of things, while those with complicated grief have specific death-focused guilt.⁷ Depressed people generally do not yearn, while those with grief yearn for their loved one. Finally, and most concerning to clinicians, some patients with PCBD have suicidal thoughts.⁸ While such thoughts in depression are often linked to hopelessness, suicidal thoughts for grieving individuals are generally driven by a desire to be reunited with the deceased loved one.

While suicidal thoughts in depression are generally linked to hopelessness, these thoughts for grieving individuals are generally driven by a desire to be reunited with the deceased loved one.

While these differences may help in making treatment decisions, there can be overlap between depression and complicated grief. As with many mental health diagnoses, major depression and PCBD are not mutually exclusive.⁴

The role of hospice. Another factor sometimes associated with complicated grief is any hindrance to the survivor’s ability to communicate or say goodbye to the loved one at the end of life.⁹ This may be avoided if the loved one is in hospice care and is not subjected to procedures that impair communication (ie, ventilator use, sedation). Medicare requires that certified hospice programs offer bereavement services for 1 year following patient death.¹⁰ Some hospice providers even offer bereavement services to those not enrolled in hospice. However, evidence indicates that only about 30% of bereaved caregivers take advantage of hospice bereavement services.¹¹ Family physicians may help patients during this process by providing an early referral to hospice services and recommending bereavement counseling. Referral to hospice care can also facilitate discussions that the patient may need to have with the physician or others regarding spirituality. Hospital chaplains can also be referred or get involved with patients and family upon request.

Assessment focal points and tools

As is the case with most mental health concerns, primary care is at the forefront of early assessment. Evaluation of grief is an ongoing process and is multifactorial. One focus is the intensity of the grief. Is the patient reacting to the loss in a way that is disproportionately severe when compared with others who grieve? Another factor is the time elapsed since the loss. If the loss was more than 6 months ago, the patient should have made some progress. Assess grieving patients at around 6 months post-loss to determine how they are handling grief. As mentioned, DSM-5 has criteria for PCBD that providers can use in determining a patient’s grief status. Also needed are assessments for the other DSM-5 issues often associated with loss: depression and post-traumatic stress disorder.

Continue to: While no clinical measure is perfect...

While no clinical measure is perfect, there are tools that can help in assessing patients for the possibility of complicated grief (TABLE 2). Also keep in mind that no measure can make a diagnosis of PCBD, as it is a clinical judgment, not a score on a scale. Furthermore, there is no measure that can accurately predict future complicated grief.⁶ In most busy practices, the Brief Grief Questionnaire (http://www.massgeneral.org/psychiatry/assets/Brief_Grief_Questionnaire.pdf ) would be the easiest tool to administer, but a case could be made for any of the measures.

Treatment hallmarks

The literature base emphasizes that PCBD treatment requires a different focus than that applied to uncomplicated grief. And while most people with major depression will respond to medication and psychotherapy, there are provisos to keep in mind when depression is associated with complicated grief.

Complicated grief treatment (CGT) has been studied extensively.⁶ This treatment combines some of the tenets of evidence-based PTSD treatments, interpersonal therapy for grief, and cognitive behavioral therapy. CGT is generally an individual treatment, although group therapy using some of its tenets can also be effective. According to complicated grief researchers, tasks to accomplish in CGT include establishing a “new normal” following the loss, promoting self-regulation in the grieving, building social connections, and setting aspirational goals for the future.⁶ Other goals are to revisit the world, tell stories of the past, and relive old memories in a more positive light. Common suggestions in CGT that run parallel to conventional thoughts on dealing with grief include increasing time outside the home, getting more involved interpersonally, and increasing mindfulness-based practices.

A second-line evidence-based treatment for PCBD is the use of selective serotonin-reuptake inhibitors (SSRIs).⁶ Some studies have found benefit from SSRI treatment, although the findings are preliminary and modest.¹² One observational study examined patients who had recently experienced loss and were receiving CGT with or without medication. Researchers found that CGT with medication (citalopram) led to a 61% positive response rate while CGT alone led to a 41% response rate.¹³ Thus, findings revealed some benefit to combining an antidepressant with CGT, indicating that SSRIs may be helpful as an adjunct treatment.

THE CASE

Al was treated for complicated grief by his family physician and a psychologist for approximately a year. He responded well to an SSRI and received psychotherapy that focused on the tenets of CGT. Prior to his last psychotherapy visit, he reported leaving the house regularly to dine at restaurants and meet up with co-workers after hours. He said, “I still miss Vera quite a bit, but I know that I feel better.”

CORRESPONDENCE
Scott A. Fields, PhD, 3200 MacCorkle Avenue Southeast, 5th Floor, Robert C. Byrd Clinical Teaching Center, Department of Family Medicine, Charleston, WV 25304; [email protected]

THE CASE

Al* is a 48-year-old patient whose wife, Vera, died of complications from chronic illness 14 months ago. Al thinks about Vera constantly and says he still has difficulty accepting that she is gone. He does not leave the house much anymore and continues to set a place for her at the kitchen table on special occasions. He says, “Some nights in bed, I swear I can hear her in the living room.”

How would you proceed with this patient?

* The names of the patient and his spouse have been changed to protect their identities.

After the loss of a loved one, grief is a natural response to the separation and stress that go along with the death. Most people, after suffering a loss, experience distress that varies in intensity and gradually decreases over time. Thus, the grieving individual does not act as they would normally if they were not bereaved. However, gains are generally made month by month, and most people adjust to the grief and adapt their lives after some time dealing with the absence of the loved one.¹

There’s grief, and then there’s complicated grief

For about 2% to 4% of the population who have experienced a significant loss, complicated grief is an issue.² As its hallmark, complicated grief exceeds the typical amount of time (6-12 months) that people need to recover from a loss. Prevalence has been estimated at 10% to 20% among grieving individuals for whom the death being grieved was that of a romantic partner or child.² At increased risk for this disorder are women older than 60 years, patients diagnosed with depression or substance abuse, individuals under financial strain, and those who have experienced a violent or sudden loss.³

The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) has conceptualized complicated grief with the name, persistent complex bereavement disorder (PCBD).⁴ While the guidelines for the definition are still in progress, several specified symptoms must have been present for at least 6 months to a year or more (TABLE 1⁴). For instance, the patient has been ruminating about the death, has been unable to accept the death, or has felt shocked or numb. They may also experience anger, have difficulty trusting others, and be preoccupied with the deceased (eg, sense they can hear their lost loved one, feel the loved one’s pain for them). Symptoms of PCBD may also include experiencing vivid reminders of the loss and avoiding situations that bring up thoughts about the death.⁴ (Of note: A grief diagnosis in ICD-10 is captured by the code F43.21; however, there is no specific code for complicated grief or PCBD.)

PCBD is a “condition for further study” in DSM-5; it was omitted from DSM-IV only after much debate. One reason for its omission was concern that clinicians might “pathologize” grief more than it needs to be.⁵ Grief is regarded as a natural process that might be stymied by a formal diagnosis leading to medical treatment.

Shifting the grief diagnosis paradigm

One new development is that recently bereaved patients can be diagnosed with depression if they meet the criteria for that diagnosis. In the past, someone who met criteria for major depression would be excluded from that diagnosis if the depression ensued from grief. DSM-5 no longer makes that distinction.⁴ Given this diagnostic shift, one might wonder about the difference between PCBD and depression, particularly if the patient is a grieving individual with a current diagnosis of depression.⁵

Continue to: Differences between PCBD and major depression

Differences between PCBD and major depression. While antidepressant medication is helpful for patients with moderate-to-severe depression, it has thus far been less helpful for those solely experiencing complicated grief.⁶ The same holds true for traditional psychotherapy. While family physicians can confidently refer people to psychotherapy for depression, it is not as efficacious as focused therapy designed for those with PCBD.⁶

Other differences between PCBD and major depression involve the constructs of guilt and yearning. Depressed patients typically feel guilty about a number of things, while those with complicated grief have specific death-focused guilt.⁷ Depressed people generally do not yearn, while those with grief yearn for their loved one. Finally, and most concerning to clinicians, some patients with PCBD have suicidal thoughts.⁸ While such thoughts in depression are often linked to hopelessness, suicidal thoughts for grieving individuals are generally driven by a desire to be reunited with the deceased loved one.

While suicidal thoughts in depression are generally linked to hopelessness, these thoughts for grieving individuals are generally driven by a desire to be reunited with the deceased loved one.

While these differences may help in making treatment decisions, there can be overlap between depression and complicated grief. As with many mental health diagnoses, major depression and PCBD are not mutually exclusive.⁴

The role of hospice. Another factor sometimes associated with complicated grief is any hindrance to the survivor’s ability to communicate or say goodbye to the loved one at the end of life.⁹ This may be avoided if the loved one is in hospice care and is not subjected to procedures that impair communication (ie, ventilator use, sedation). Medicare requires that certified hospice programs offer bereavement services for 1 year following patient death.¹⁰ Some hospice providers even offer bereavement services to those not enrolled in hospice. However, evidence indicates that only about 30% of bereaved caregivers take advantage of hospice bereavement services.¹¹ Family physicians may help patients during this process by providing an early referral to hospice services and recommending bereavement counseling. Referral to hospice care can also facilitate discussions that the patient may need to have with the physician or others regarding spirituality. Hospital chaplains can also be referred or get involved with patients and family upon request.

Assessment focal points and tools

As is the case with most mental health concerns, primary care is at the forefront of early assessment. Evaluation of grief is an ongoing process and is multifactorial. One focus is the intensity of the grief. Is the patient reacting to the loss in a way that is disproportionately severe when compared with others who grieve? Another factor is the time elapsed since the loss. If the loss was more than 6 months ago, the patient should have made some progress. Assess grieving patients at around 6 months post-loss to determine how they are handling grief. As mentioned, DSM-5 has criteria for PCBD that providers can use in determining a patient’s grief status. Also needed are assessments for the other DSM-5 issues often associated with loss: depression and post-traumatic stress disorder.

Continue to: While no clinical measure is perfect...

While no clinical measure is perfect, there are tools that can help in assessing patients for the possibility of complicated grief (TABLE 2). Also keep in mind that no measure can make a diagnosis of PCBD, as it is a clinical judgment, not a score on a scale. Furthermore, there is no measure that can accurately predict future complicated grief.⁶ In most busy practices, the Brief Grief Questionnaire (http://www.massgeneral.org/psychiatry/assets/Brief_Grief_Questionnaire.pdf ) would be the easiest tool to administer, but a case could be made for any of the measures.

Treatment hallmarks

The literature base emphasizes that PCBD treatment requires a different focus than that applied to uncomplicated grief. And while most people with major depression will respond to medication and psychotherapy, there are provisos to keep in mind when depression is associated with complicated grief.

Complicated grief treatment (CGT) has been studied extensively.⁶ This treatment combines some of the tenets of evidence-based PTSD treatments, interpersonal therapy for grief, and cognitive behavioral therapy. CGT is generally an individual treatment, although group therapy using some of its tenets can also be effective. According to complicated grief researchers, tasks to accomplish in CGT include establishing a “new normal” following the loss, promoting self-regulation in the grieving, building social connections, and setting aspirational goals for the future.⁶ Other goals are to revisit the world, tell stories of the past, and relive old memories in a more positive light. Common suggestions in CGT that run parallel to conventional thoughts on dealing with grief include increasing time outside the home, getting more involved interpersonally, and increasing mindfulness-based practices.

A second-line evidence-based treatment for PCBD is the use of selective serotonin-reuptake inhibitors (SSRIs).⁶ Some studies have found benefit from SSRI treatment, although the findings are preliminary and modest.¹² One observational study examined patients who had recently experienced loss and were receiving CGT with or without medication. Researchers found that CGT with medication (citalopram) led to a 61% positive response rate while CGT alone led to a 41% response rate.¹³ Thus, findings revealed some benefit to combining an antidepressant with CGT, indicating that SSRIs may be helpful as an adjunct treatment.

THE CASE

Al was treated for complicated grief by his family physician and a psychologist for approximately a year. He responded well to an SSRI and received psychotherapy that focused on the tenets of CGT. Prior to his last psychotherapy visit, he reported leaving the house regularly to dine at restaurants and meet up with co-workers after hours. He said, “I still miss Vera quite a bit, but I know that I feel better.”

CORRESPONDENCE
Scott A. Fields, PhD, 3200 MacCorkle Avenue Southeast, 5th Floor, Robert C. Byrd Clinical Teaching Center, Department of Family Medicine, Charleston, WV 25304; [email protected]

THE CASE

Al* is a 48-year-old patient whose wife, Vera, died of complications from chronic illness 14 months ago. Al thinks about Vera constantly and says he still has difficulty accepting that she is gone. He does not leave the house much anymore and continues to set a place for her at the kitchen table on special occasions. He says, “Some nights in bed, I swear I can hear her in the living room.”

How would you proceed with this patient?

* The names of the patient and his spouse have been changed to protect their identities.

After the loss of a loved one, grief is a natural response to the separation and stress that go along with the death. Most people, after suffering a loss, experience distress that varies in intensity and gradually decreases over time. Thus, the grieving individual does not act as they would normally if they were not bereaved. However, gains are generally made month by month, and most people adjust to the grief and adapt their lives after some time dealing with the absence of the loved one.¹

There’s grief, and then there’s complicated grief

For about 2% to 4% of the population who have experienced a significant loss, complicated grief is an issue.² As its hallmark, complicated grief exceeds the typical amount of time (6-12 months) that people need to recover from a loss. Prevalence has been estimated at 10% to 20% among grieving individuals for whom the death being grieved was that of a romantic partner or child.² At increased risk for this disorder are women older than 60 years, patients diagnosed with depression or substance abuse, individuals under financial strain, and those who have experienced a violent or sudden loss.³

The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) has conceptualized complicated grief with the name, persistent complex bereavement disorder (PCBD).⁴ While the guidelines for the definition are still in progress, several specified symptoms must have been present for at least 6 months to a year or more (TABLE 1⁴). For instance, the patient has been ruminating about the death, has been unable to accept the death, or has felt shocked or numb. They may also experience anger, have difficulty trusting others, and be preoccupied with the deceased (eg, sense they can hear their lost loved one, feel the loved one’s pain for them). Symptoms of PCBD may also include experiencing vivid reminders of the loss and avoiding situations that bring up thoughts about the death.⁴ (Of note: A grief diagnosis in ICD-10 is captured by the code F43.21; however, there is no specific code for complicated grief or PCBD.)

PCBD is a “condition for further study” in DSM-5; it was omitted from DSM-IV only after much debate. One reason for its omission was concern that clinicians might “pathologize” grief more than it needs to be.⁵ Grief is regarded as a natural process that might be stymied by a formal diagnosis leading to medical treatment.

Shifting the grief diagnosis paradigm

One new development is that recently bereaved patients can be diagnosed with depression if they meet the criteria for that diagnosis. In the past, someone who met criteria for major depression would be excluded from that diagnosis if the depression ensued from grief. DSM-5 no longer makes that distinction.⁴ Given this diagnostic shift, one might wonder about the difference between PCBD and depression, particularly if the patient is a grieving individual with a current diagnosis of depression.⁵

Continue to: Differences between PCBD and major depression

Differences between PCBD and major depression. While antidepressant medication is helpful for patients with moderate-to-severe depression, it has thus far been less helpful for those solely experiencing complicated grief.⁶ The same holds true for traditional psychotherapy. While family physicians can confidently refer people to psychotherapy for depression, it is not as efficacious as focused therapy designed for those with PCBD.⁶

Other differences between PCBD and major depression involve the constructs of guilt and yearning. Depressed patients typically feel guilty about a number of things, while those with complicated grief have specific death-focused guilt.⁷ Depressed people generally do not yearn, while those with grief yearn for their loved one. Finally, and most concerning to clinicians, some patients with PCBD have suicidal thoughts.⁸ While such thoughts in depression are often linked to hopelessness, suicidal thoughts for grieving individuals are generally driven by a desire to be reunited with the deceased loved one.

While suicidal thoughts in depression are generally linked to hopelessness, these thoughts for grieving individuals are generally driven by a desire to be reunited with the deceased loved one.

While these differences may help in making treatment decisions, there can be overlap between depression and complicated grief. As with many mental health diagnoses, major depression and PCBD are not mutually exclusive.⁴

The role of hospice. Another factor sometimes associated with complicated grief is any hindrance to the survivor’s ability to communicate or say goodbye to the loved one at the end of life.⁹ This may be avoided if the loved one is in hospice care and is not subjected to procedures that impair communication (ie, ventilator use, sedation). Medicare requires that certified hospice programs offer bereavement services for 1 year following patient death.¹⁰ Some hospice providers even offer bereavement services to those not enrolled in hospice. However, evidence indicates that only about 30% of bereaved caregivers take advantage of hospice bereavement services.¹¹ Family physicians may help patients during this process by providing an early referral to hospice services and recommending bereavement counseling. Referral to hospice care can also facilitate discussions that the patient may need to have with the physician or others regarding spirituality. Hospital chaplains can also be referred or get involved with patients and family upon request.

Assessment focal points and tools

As is the case with most mental health concerns, primary care is at the forefront of early assessment. Evaluation of grief is an ongoing process and is multifactorial. One focus is the intensity of the grief. Is the patient reacting to the loss in a way that is disproportionately severe when compared with others who grieve? Another factor is the time elapsed since the loss. If the loss was more than 6 months ago, the patient should have made some progress. Assess grieving patients at around 6 months post-loss to determine how they are handling grief. As mentioned, DSM-5 has criteria for PCBD that providers can use in determining a patient’s grief status. Also needed are assessments for the other DSM-5 issues often associated with loss: depression and post-traumatic stress disorder.

Continue to: While no clinical measure is perfect...

While no clinical measure is perfect, there are tools that can help in assessing patients for the possibility of complicated grief (TABLE 2). Also keep in mind that no measure can make a diagnosis of PCBD, as it is a clinical judgment, not a score on a scale. Furthermore, there is no measure that can accurately predict future complicated grief.⁶ In most busy practices, the Brief Grief Questionnaire (http://www.massgeneral.org/psychiatry/assets/Brief_Grief_Questionnaire.pdf ) would be the easiest tool to administer, but a case could be made for any of the measures.

Treatment hallmarks

The literature base emphasizes that PCBD treatment requires a different focus than that applied to uncomplicated grief. And while most people with major depression will respond to medication and psychotherapy, there are provisos to keep in mind when depression is associated with complicated grief.

Complicated grief treatment (CGT) has been studied extensively.⁶ This treatment combines some of the tenets of evidence-based PTSD treatments, interpersonal therapy for grief, and cognitive behavioral therapy. CGT is generally an individual treatment, although group therapy using some of its tenets can also be effective. According to complicated grief researchers, tasks to accomplish in CGT include establishing a “new normal” following the loss, promoting self-regulation in the grieving, building social connections, and setting aspirational goals for the future.⁶ Other goals are to revisit the world, tell stories of the past, and relive old memories in a more positive light. Common suggestions in CGT that run parallel to conventional thoughts on dealing with grief include increasing time outside the home, getting more involved interpersonally, and increasing mindfulness-based practices.

A second-line evidence-based treatment for PCBD is the use of selective serotonin-reuptake inhibitors (SSRIs).⁶ Some studies have found benefit from SSRI treatment, although the findings are preliminary and modest.¹² One observational study examined patients who had recently experienced loss and were receiving CGT with or without medication. Researchers found that CGT with medication (citalopram) led to a 61% positive response rate while CGT alone led to a 41% response rate.¹³ Thus, findings revealed some benefit to combining an antidepressant with CGT, indicating that SSRIs may be helpful as an adjunct treatment.

THE CASE

Al was treated for complicated grief by his family physician and a psychologist for approximately a year. He responded well to an SSRI and received psychotherapy that focused on the tenets of CGT. Prior to his last psychotherapy visit, he reported leaving the house regularly to dine at restaurants and meet up with co-workers after hours. He said, “I still miss Vera quite a bit, but I know that I feel better.”

CORRESPONDENCE
Scott A. Fields, PhD, 3200 MacCorkle Avenue Southeast, 5th Floor, Robert C. Byrd Clinical Teaching Center, Department of Family Medicine, Charleston, WV 25304; [email protected]

Women who use combined oral contraceptives (COC) without hormone-free or low-dose hormone intervals have a slightly elevated, but not statistically significant, risk of venous thromboembolism (VTE), compared with women who use cyclic COCs, according to research published in JAMA Internal Medicine.

areeya_ann/Thinkstock

Jie Li, PhD, from the Center for Drug Evaluation and Research, and colleagues performed a retrospective cohort study of 733,007 women aged 18-50 years in the Sentinel Distributed Database from 2007 to 2015 who received low-dose extended and continuous cycle (210,691 women; mean age, 30 years) COCs or cyclic COCs (522,316 women; mean age, 29 years). Continuous cycle COCs were defined as an 84/7 cycle or a 365/0 cycle, while cyclic COCs were 21/7 cycles.

The researchers noted some baseline differences between the two groups, with gynecologic conditions occurring in 40% of the noncyclic group, compared with 32% in the cyclic group; cardiovascular and metabolic conditions occurring in 7% of noncyclic women, compared with 5% of cyclic women; inflammatory disease occurring in 3% of noncyclic women, compared with 2% of cyclic women; and a slightly higher rate of health care services use in the noncyclic group, compared with the cyclic group.

Dr. Li and associates found 228 cases of VTE in the noncyclic group and 297 cases in the cyclic group, with an incidence rate of 1.54 (95% confidence interval, 1.34-1.74) per 1,000 person-years for noncyclic users and 0.83 (95% CI, 0.74-0.93) per 1,000 person-years for cyclic users (crude hazard ratio, 1.84; 95% CI, 1.53-2.21).

However, propensity score matching lowered the incidence rate to 1.44 (95% CI, 1.24-1.64) per 1,000 person-years for the noncyclic group and raised it to 1.09 (95% CI, 0.92-1.27) per 1,000 person-years for the cyclic group, for an adjusted hazard ratio of 1.32 (95% CI, 1.07-1.64), which does not show “strong evidence” of VTE risk based on a small absolute risk difference of 0.27 cases per 1,000 persons, the researchers said. They added that there might be residual or unmeasured confounding, perhaps for potential concurrent medication use or incompletely measured covariates.

“Accordingly, we do not recommend selective prescribing of COCs based on the cyclic and continuous/extended type,” Dr. Li and colleagues wrote. “Clinicians should prescribe COCs based on patients’ individual risk factors and preferences.”

The Sentinel Initiative is funded by a contract from the Department of Health and Human Services. The authors reported no relevant conflicts of interest.

SOURCE: Li J et al. JAMA Intern Med. 2018 Oct 1. doi: 10.1001/jamainternmed.2018.4251.

Women who use combined oral contraceptives (COC) without hormone-free or low-dose hormone intervals have a slightly elevated, but not statistically significant, risk of venous thromboembolism (VTE), compared with women who use cyclic COCs, according to research published in JAMA Internal Medicine.

areeya_ann/Thinkstock

Jie Li, PhD, from the Center for Drug Evaluation and Research, and colleagues performed a retrospective cohort study of 733,007 women aged 18-50 years in the Sentinel Distributed Database from 2007 to 2015 who received low-dose extended and continuous cycle (210,691 women; mean age, 30 years) COCs or cyclic COCs (522,316 women; mean age, 29 years). Continuous cycle COCs were defined as an 84/7 cycle or a 365/0 cycle, while cyclic COCs were 21/7 cycles.

The researchers noted some baseline differences between the two groups, with gynecologic conditions occurring in 40% of the noncyclic group, compared with 32% in the cyclic group; cardiovascular and metabolic conditions occurring in 7% of noncyclic women, compared with 5% of cyclic women; inflammatory disease occurring in 3% of noncyclic women, compared with 2% of cyclic women; and a slightly higher rate of health care services use in the noncyclic group, compared with the cyclic group.

Dr. Li and associates found 228 cases of VTE in the noncyclic group and 297 cases in the cyclic group, with an incidence rate of 1.54 (95% confidence interval, 1.34-1.74) per 1,000 person-years for noncyclic users and 0.83 (95% CI, 0.74-0.93) per 1,000 person-years for cyclic users (crude hazard ratio, 1.84; 95% CI, 1.53-2.21).

However, propensity score matching lowered the incidence rate to 1.44 (95% CI, 1.24-1.64) per 1,000 person-years for the noncyclic group and raised it to 1.09 (95% CI, 0.92-1.27) per 1,000 person-years for the cyclic group, for an adjusted hazard ratio of 1.32 (95% CI, 1.07-1.64), which does not show “strong evidence” of VTE risk based on a small absolute risk difference of 0.27 cases per 1,000 persons, the researchers said. They added that there might be residual or unmeasured confounding, perhaps for potential concurrent medication use or incompletely measured covariates.

“Accordingly, we do not recommend selective prescribing of COCs based on the cyclic and continuous/extended type,” Dr. Li and colleagues wrote. “Clinicians should prescribe COCs based on patients’ individual risk factors and preferences.”

The Sentinel Initiative is funded by a contract from the Department of Health and Human Services. The authors reported no relevant conflicts of interest.

SOURCE: Li J et al. JAMA Intern Med. 2018 Oct 1. doi: 10.1001/jamainternmed.2018.4251.

Women who use combined oral contraceptives (COC) without hormone-free or low-dose hormone intervals have a slightly elevated, but not statistically significant, risk of venous thromboembolism (VTE), compared with women who use cyclic COCs, according to research published in JAMA Internal Medicine.

areeya_ann/Thinkstock

Jie Li, PhD, from the Center for Drug Evaluation and Research, and colleagues performed a retrospective cohort study of 733,007 women aged 18-50 years in the Sentinel Distributed Database from 2007 to 2015 who received low-dose extended and continuous cycle (210,691 women; mean age, 30 years) COCs or cyclic COCs (522,316 women; mean age, 29 years). Continuous cycle COCs were defined as an 84/7 cycle or a 365/0 cycle, while cyclic COCs were 21/7 cycles.

The researchers noted some baseline differences between the two groups, with gynecologic conditions occurring in 40% of the noncyclic group, compared with 32% in the cyclic group; cardiovascular and metabolic conditions occurring in 7% of noncyclic women, compared with 5% of cyclic women; inflammatory disease occurring in 3% of noncyclic women, compared with 2% of cyclic women; and a slightly higher rate of health care services use in the noncyclic group, compared with the cyclic group.

Dr. Li and associates found 228 cases of VTE in the noncyclic group and 297 cases in the cyclic group, with an incidence rate of 1.54 (95% confidence interval, 1.34-1.74) per 1,000 person-years for noncyclic users and 0.83 (95% CI, 0.74-0.93) per 1,000 person-years for cyclic users (crude hazard ratio, 1.84; 95% CI, 1.53-2.21).

However, propensity score matching lowered the incidence rate to 1.44 (95% CI, 1.24-1.64) per 1,000 person-years for the noncyclic group and raised it to 1.09 (95% CI, 0.92-1.27) per 1,000 person-years for the cyclic group, for an adjusted hazard ratio of 1.32 (95% CI, 1.07-1.64), which does not show “strong evidence” of VTE risk based on a small absolute risk difference of 0.27 cases per 1,000 persons, the researchers said. They added that there might be residual or unmeasured confounding, perhaps for potential concurrent medication use or incompletely measured covariates.

“Accordingly, we do not recommend selective prescribing of COCs based on the cyclic and continuous/extended type,” Dr. Li and colleagues wrote. “Clinicians should prescribe COCs based on patients’ individual risk factors and preferences.”

The Sentinel Initiative is funded by a contract from the Department of Health and Human Services. The authors reported no relevant conflicts of interest.

SOURCE: Li J et al. JAMA Intern Med. 2018 Oct 1. doi: 10.1001/jamainternmed.2018.4251.

Unintentional transduction of a single leukemic B cell appears to have induced resistance to CTL019 (tisagenlecleucel, Kymriah) therapy, a recent case study suggests.

Courtesy Penn Medicine

A total of 9 months after receiving a seemingly successful CD19-targeted chimeric antigen receptor (CAR) T-cell (CTL019; tisagenlecleucel) infusion, a 20-year-old man with B-cell acute lymphoblastic leukemia (B-ALL) had a frank relapse, with more than 90% bone marrow infiltration of CAR-transduced B-cell leukemia cells. Further investigation showed that the CAR gene had unintentionally been added to a solitary leukemic B cell during the CAR T-cell manufacturing process, reported Marco Ruella, MD, of the University of Pennsylvania, Philadelphia.

“The transduction of a single leukemic cell with an anti-CD19 CAR lentivirus during CTL019 manufacturing is sufficient to mediate resistance through masking of the CD19 epitope. This is a rare event, as this is the only case out of 369 patients reported worldwide at the time of publication. ... These findings illustrate the need for improved manufacturing technologies that can purge residual contaminating tumor cells from engineered T cells,” the authors wrote in Nature Medicine.

The findings also confirm the cancer stem cell hypothesis in humans, “given that clonal analysis indicated that the relapse and subsequent death of the patient were attributed to the progeny of a single leukemic blast cell with extensive replicative capacity, both in culture and in vivo,” they wrote.

Initially, “the infused CTL019 cells displayed the typical pattern of in vivo engraftment and expansion by CAR19-specific flow cytometry, followed by decline to an undetectable level in the peripheral blood” of the affected patient, the authors wrote. “The expansion and contraction phases and long-term persistence of CAR T cells were confirmed via qPCR using CAR-specific primers.” The patient was in complete remission at day 28.

However, they added, routine peripheral blood monitoring with quantitative polymerase chain reaction for CAR-specific sequences identified “the emergence of a second expansion phase of CAR cells starting at day 252, which did not correlate with re-expansion of CAR + T cells by flow cytometry.” Frank relapse soon followed.

Analysis confirmed “that the lack of detection of CD19 by flow cytometry was due to CAR19 binding in cis to CD19 on the surface of leukemic blasts, thus masking the epitope from detection by standard flow cytometry,” the authors wrote.

Study funding was provided by Bristol-Myers Squibb, Novartis, the National Institutes of Health, and others. Dr. Ruella and several of his colleagues work under a research collaboration involving the University of Pennsylvania and the Novartis Institutes of Biomedical Research and are inventors of intellectual property licensed by the University of Pennsylvania to Novartis.

SOURCE: Ruella M et al. Nat Med. 2018 Oct 1. doi: 10.1038/s41591-018-0201-9.

Unintentional transduction of a single leukemic B cell appears to have induced resistance to CTL019 (tisagenlecleucel, Kymriah) therapy, a recent case study suggests.

Courtesy Penn Medicine

A total of 9 months after receiving a seemingly successful CD19-targeted chimeric antigen receptor (CAR) T-cell (CTL019; tisagenlecleucel) infusion, a 20-year-old man with B-cell acute lymphoblastic leukemia (B-ALL) had a frank relapse, with more than 90% bone marrow infiltration of CAR-transduced B-cell leukemia cells. Further investigation showed that the CAR gene had unintentionally been added to a solitary leukemic B cell during the CAR T-cell manufacturing process, reported Marco Ruella, MD, of the University of Pennsylvania, Philadelphia.

“The transduction of a single leukemic cell with an anti-CD19 CAR lentivirus during CTL019 manufacturing is sufficient to mediate resistance through masking of the CD19 epitope. This is a rare event, as this is the only case out of 369 patients reported worldwide at the time of publication. ... These findings illustrate the need for improved manufacturing technologies that can purge residual contaminating tumor cells from engineered T cells,” the authors wrote in Nature Medicine.

The findings also confirm the cancer stem cell hypothesis in humans, “given that clonal analysis indicated that the relapse and subsequent death of the patient were attributed to the progeny of a single leukemic blast cell with extensive replicative capacity, both in culture and in vivo,” they wrote.

Initially, “the infused CTL019 cells displayed the typical pattern of in vivo engraftment and expansion by CAR19-specific flow cytometry, followed by decline to an undetectable level in the peripheral blood” of the affected patient, the authors wrote. “The expansion and contraction phases and long-term persistence of CAR T cells were confirmed via qPCR using CAR-specific primers.” The patient was in complete remission at day 28.

However, they added, routine peripheral blood monitoring with quantitative polymerase chain reaction for CAR-specific sequences identified “the emergence of a second expansion phase of CAR cells starting at day 252, which did not correlate with re-expansion of CAR + T cells by flow cytometry.” Frank relapse soon followed.

Analysis confirmed “that the lack of detection of CD19 by flow cytometry was due to CAR19 binding in cis to CD19 on the surface of leukemic blasts, thus masking the epitope from detection by standard flow cytometry,” the authors wrote.

Study funding was provided by Bristol-Myers Squibb, Novartis, the National Institutes of Health, and others. Dr. Ruella and several of his colleagues work under a research collaboration involving the University of Pennsylvania and the Novartis Institutes of Biomedical Research and are inventors of intellectual property licensed by the University of Pennsylvania to Novartis.

SOURCE: Ruella M et al. Nat Med. 2018 Oct 1. doi: 10.1038/s41591-018-0201-9.

Unintentional transduction of a single leukemic B cell appears to have induced resistance to CTL019 (tisagenlecleucel, Kymriah) therapy, a recent case study suggests.

Courtesy Penn Medicine

A total of 9 months after receiving a seemingly successful CD19-targeted chimeric antigen receptor (CAR) T-cell (CTL019; tisagenlecleucel) infusion, a 20-year-old man with B-cell acute lymphoblastic leukemia (B-ALL) had a frank relapse, with more than 90% bone marrow infiltration of CAR-transduced B-cell leukemia cells. Further investigation showed that the CAR gene had unintentionally been added to a solitary leukemic B cell during the CAR T-cell manufacturing process, reported Marco Ruella, MD, of the University of Pennsylvania, Philadelphia.

“The transduction of a single leukemic cell with an anti-CD19 CAR lentivirus during CTL019 manufacturing is sufficient to mediate resistance through masking of the CD19 epitope. This is a rare event, as this is the only case out of 369 patients reported worldwide at the time of publication. ... These findings illustrate the need for improved manufacturing technologies that can purge residual contaminating tumor cells from engineered T cells,” the authors wrote in Nature Medicine.

The findings also confirm the cancer stem cell hypothesis in humans, “given that clonal analysis indicated that the relapse and subsequent death of the patient were attributed to the progeny of a single leukemic blast cell with extensive replicative capacity, both in culture and in vivo,” they wrote.

Initially, “the infused CTL019 cells displayed the typical pattern of in vivo engraftment and expansion by CAR19-specific flow cytometry, followed by decline to an undetectable level in the peripheral blood” of the affected patient, the authors wrote. “The expansion and contraction phases and long-term persistence of CAR T cells were confirmed via qPCR using CAR-specific primers.” The patient was in complete remission at day 28.

However, they added, routine peripheral blood monitoring with quantitative polymerase chain reaction for CAR-specific sequences identified “the emergence of a second expansion phase of CAR cells starting at day 252, which did not correlate with re-expansion of CAR + T cells by flow cytometry.” Frank relapse soon followed.

Analysis confirmed “that the lack of detection of CD19 by flow cytometry was due to CAR19 binding in cis to CD19 on the surface of leukemic blasts, thus masking the epitope from detection by standard flow cytometry,” the authors wrote.

Study funding was provided by Bristol-Myers Squibb, Novartis, the National Institutes of Health, and others. Dr. Ruella and several of his colleagues work under a research collaboration involving the University of Pennsylvania and the Novartis Institutes of Biomedical Research and are inventors of intellectual property licensed by the University of Pennsylvania to Novartis.

SOURCE: Ruella M et al. Nat Med. 2018 Oct 1. doi: 10.1038/s41591-018-0201-9.

Idiopathic myointimal hyperplasia of the mesenteric veins

Gross examination of the rectosigmoid colon resected from this patient demonstrated transmural fibrosis. The mucosa was necrotic and hemorrhagic with a granular and cobblestone pattern (Figure B). Histopathologic examination of the mucosa revealed veins with myointimal hyperplasia with sparing of arterial vasculature (Figure C; stain: elastin; original magnification, ×10). The combined findings via endoscopy and histopathology confirmed the diagnosis of idiopathic myointimal hyperplasia of the mesenteric veins (IMHMV).

IMHMV is a rare cause of proctosigmoiditis first described in a case series of 4 patients in 1991 by Genta and Haggitt.¹ Owing to its clinical presentation of lower quadrant abdominal pain, diarrhea, hematochezia, and mucous in the stools, the diagnosis is often mistaken for inflammatory bowel disease. However, the endoscopic and pathologic findings of IHMVH resemble ischemic colitis. IMHMV is refractory to medical treatment and its definitive diagnosis and curative management involves surgical resection of the involved segment (often the rectosigmoid colon). The precise pathophysiology of IMHMV is unclear. Histopathologic analysis of veins in the involved segment of colon can demonstrate changes similar to those of failed saphenous grafts from coronary artery bypass.² Myointimal hyperplasia of the mesenteric veins occurs (best identified with elastin stain on histopathology) with near total occlusion of the venous lumen and without any associated inflammatory infiltrate or arterial involvement.³

After colectomy, our patient’s abdominal symptoms resolved and follow-up colonoscopy at 6 months did not reveal recurrence of IMHMV, at which time, the patient underwent take-down of his colostomy. In the year after colostomy take-down, the patient showed no clinical or endoscopic signs of colitis while off of all medical therapies. Here, we present the first case of a successful take-down of a curative colostomy for an IMHMV patient, a treatment course not described previously in the literature. Prompt diagnosis and timely surgical intervention may allow for avoidance of permanent colostomy in patients with IMHMV.

References

1. Genta R.M., Haggitt, R.C. Idiopathic myointimal hyperplasia of mesenteric veins. Gastroenterology. 1991;101:533-9.

2. Abu-Alfa A.K., Ayer U., West A.B. Mucosal biopsy findings and venous abnormalities in idiopathic myointimal hyperplasia of the mesenteric veins. Am J Surg Pathol. 1996;20:1271-8.

3. Chiang C.K., Lee C.L., Huang C.S., et al. A rare cause of ischemic proctosigmoiditis: Idiopathic myointimal hyperplasia of mesenteric veins. Endoscopy. 2012;44:54-5.
 

[email protected]

Idiopathic myointimal hyperplasia of the mesenteric veins

Gross examination of the rectosigmoid colon resected from this patient demonstrated transmural fibrosis. The mucosa was necrotic and hemorrhagic with a granular and cobblestone pattern (Figure B). Histopathologic examination of the mucosa revealed veins with myointimal hyperplasia with sparing of arterial vasculature (Figure C; stain: elastin; original magnification, ×10). The combined findings via endoscopy and histopathology confirmed the diagnosis of idiopathic myointimal hyperplasia of the mesenteric veins (IMHMV).

IMHMV is a rare cause of proctosigmoiditis first described in a case series of 4 patients in 1991 by Genta and Haggitt.¹ Owing to its clinical presentation of lower quadrant abdominal pain, diarrhea, hematochezia, and mucous in the stools, the diagnosis is often mistaken for inflammatory bowel disease. However, the endoscopic and pathologic findings of IHMVH resemble ischemic colitis. IMHMV is refractory to medical treatment and its definitive diagnosis and curative management involves surgical resection of the involved segment (often the rectosigmoid colon). The precise pathophysiology of IMHMV is unclear. Histopathologic analysis of veins in the involved segment of colon can demonstrate changes similar to those of failed saphenous grafts from coronary artery bypass.² Myointimal hyperplasia of the mesenteric veins occurs (best identified with elastin stain on histopathology) with near total occlusion of the venous lumen and without any associated inflammatory infiltrate or arterial involvement.³

After colectomy, our patient’s abdominal symptoms resolved and follow-up colonoscopy at 6 months did not reveal recurrence of IMHMV, at which time, the patient underwent take-down of his colostomy. In the year after colostomy take-down, the patient showed no clinical or endoscopic signs of colitis while off of all medical therapies. Here, we present the first case of a successful take-down of a curative colostomy for an IMHMV patient, a treatment course not described previously in the literature. Prompt diagnosis and timely surgical intervention may allow for avoidance of permanent colostomy in patients with IMHMV.

References

1. Genta R.M., Haggitt, R.C. Idiopathic myointimal hyperplasia of mesenteric veins. Gastroenterology. 1991;101:533-9.

2. Abu-Alfa A.K., Ayer U., West A.B. Mucosal biopsy findings and venous abnormalities in idiopathic myointimal hyperplasia of the mesenteric veins. Am J Surg Pathol. 1996;20:1271-8.

3. Chiang C.K., Lee C.L., Huang C.S., et al. A rare cause of ischemic proctosigmoiditis: Idiopathic myointimal hyperplasia of mesenteric veins. Endoscopy. 2012;44:54-5.
 

[email protected]

Idiopathic myointimal hyperplasia of the mesenteric veins

Gross examination of the rectosigmoid colon resected from this patient demonstrated transmural fibrosis. The mucosa was necrotic and hemorrhagic with a granular and cobblestone pattern (Figure B). Histopathologic examination of the mucosa revealed veins with myointimal hyperplasia with sparing of arterial vasculature (Figure C; stain: elastin; original magnification, ×10). The combined findings via endoscopy and histopathology confirmed the diagnosis of idiopathic myointimal hyperplasia of the mesenteric veins (IMHMV).

IMHMV is a rare cause of proctosigmoiditis first described in a case series of 4 patients in 1991 by Genta and Haggitt.¹ Owing to its clinical presentation of lower quadrant abdominal pain, diarrhea, hematochezia, and mucous in the stools, the diagnosis is often mistaken for inflammatory bowel disease. However, the endoscopic and pathologic findings of IHMVH resemble ischemic colitis. IMHMV is refractory to medical treatment and its definitive diagnosis and curative management involves surgical resection of the involved segment (often the rectosigmoid colon). The precise pathophysiology of IMHMV is unclear. Histopathologic analysis of veins in the involved segment of colon can demonstrate changes similar to those of failed saphenous grafts from coronary artery bypass.² Myointimal hyperplasia of the mesenteric veins occurs (best identified with elastin stain on histopathology) with near total occlusion of the venous lumen and without any associated inflammatory infiltrate or arterial involvement.³

After colectomy, our patient’s abdominal symptoms resolved and follow-up colonoscopy at 6 months did not reveal recurrence of IMHMV, at which time, the patient underwent take-down of his colostomy. In the year after colostomy take-down, the patient showed no clinical or endoscopic signs of colitis while off of all medical therapies. Here, we present the first case of a successful take-down of a curative colostomy for an IMHMV patient, a treatment course not described previously in the literature. Prompt diagnosis and timely surgical intervention may allow for avoidance of permanent colostomy in patients with IMHMV.

References

1. Genta R.M., Haggitt, R.C. Idiopathic myointimal hyperplasia of mesenteric veins. Gastroenterology. 1991;101:533-9.

2. Abu-Alfa A.K., Ayer U., West A.B. Mucosal biopsy findings and venous abnormalities in idiopathic myointimal hyperplasia of the mesenteric veins. Am J Surg Pathol. 1996;20:1271-8.

3. Chiang C.K., Lee C.L., Huang C.S., et al. A rare cause of ischemic proctosigmoiditis: Idiopathic myointimal hyperplasia of mesenteric veins. Endoscopy. 2012;44:54-5.
 

[email protected]

Cancer survivors represent a rapidly increasing population. In 1971, there were 3 million cancer survivors; this number increased to 15.5 million in 2016 and will reach 20 million by 2026.¹TABLE 1¹ shows the percentage of survivors by type of cancer. Cancer survivors tend to be older,* comprising nearly 1 of every 5 people older than 65 years.²

The Institute of Medicine (IOM) identified 3 key characteristics of cancer survivors³:

• Trajectories of survivorship are variable; many cancer patients have periods of relative health between episodes of their disease.
• Survivors require careful cancer monitoring; in addition to the risk that their primary cancer will recur, they have an elevated risk for another, second cancer.
• Both cancer and its treatments increase the risk of other medical and psychiatric problems.

Family physicians (FPs) have optimal skills for navigating the chronic risks and health concerns of the well cancer survivor. This article reviews the primary care management of the functional cancer survivor, focusing on the management of chronic conditions and preventive care.

Survivorship follows any of 6 paths

Cancer survivorship is increasing in importance as treatment has steadily reduced mortality. Six trajectories of cancer survivors have been identified¹:

• living cancer-free after treatment with minimal effects
• living cancer-free but suffering serious treatment complications
• Suffering late recurrence
• Developing a second cancer
• Living with intermittent cancer recurrences
• Living with cancer continuously.

Only patients in the last 2 groups are likely to be managed primarily by oncologists.

Survivors look to their FPs for ongoing care

Cancer survivors routinely see their primary care physician after initial treatment. A study of 30,000 Canadian breast cancer survivors demonstrated that follow-up care was limited to an oncologist in only 2%; 84% saw a primary care provider and an oncologist; and 14% saw a primary care provider only.⁴ A study of colorectal cancer survivors showed that primary care visits increased in each of the 5 years after diagnosis, during which time oncology visits decreased steadily⁵; in that study, primary care physicians delivered more preventive care than oncologists did.⁵ Similar to what is done in other chronic conditions, the various effects of cancer are best managed as a whole.

The IOM recommends that cancer survivor care comprise 4 elements²:

1. coordination between oncologist and primary care physician
2. surveillance for recurrence or spread of existing cancer
3. screening for new cancer
4. intervention for the effects of cancer and treatment.

Continue to: The following discussion summarizes...

The following discussion summarizes evidence and recommendations for each element of the IOM recommendations for survivor care.

Implementing the 4 elements of cancer survivor care

1. Coordinate care through a unified survivorship care plan

The IOM has noted that the needs of cancer survivors are rarely met²; communication between oncology and primary care is often deficient during transition of care. The IOM has recommended that oncologists provide a survivorship care plan that details the cancer (ie, tumor characteristics), the type of treatment (ie, enrollment in a clinical trial; medical, surgical, or radiation), support services, and follow-up recommendations for the primary care provider. (Examples of elements of a survivorship care plan can be found at www.mskcc.org/hcp-education-training/survivorship/survivorship-care-plan⁶ and http://sma.org/southern-medical-journal/article/cancer-survivors-history-physical/⁷).

Regrettably, survivorship care plans have been rarely and poorly employed. Studies show that fewer than one-half of oncologists provide a plan, and that when they do, the plan often lacks recommended information.^8,9 Survivorship care plans may soon become common practice, however; the Commission on Cancer of the American College of Surgeons has required their use in all certified cancer centers since 2015.¹⁰

2. Provide surveillance of existing cancer

Cancer follow-up is challenging after the initial treatment phase. Although there are many conflicting guidelines for surveillance after cancer, guidelines of the National Comprehensive Cancer Network (NCCN) (summarized in TABLE 2¹¹ for the 10 most common cancers in survivors) are the ones generally accepted.^12,13

Although individual surveillance recommendations are based on limited evidence, studies confirm the importance of surveillance. A systematic review showed that surveillance mammography after breast cancer reduces breast cancer mortality by 36%.¹⁴ A study showed that bladder cancer recurrence diagnosed by surveillance instead of by symptoms led to a 35% increase in 5-year survival.¹⁵

Continue to: Yet adherence to cancer surveillance...

Yet adherence to cancer surveillance recommendations is poor. A study of patients with colon cancer demonstrated that only 12% met all recommended surveillance guidelines.¹⁶ A study of patients with bladder cancer after radical cystectomy showed that only 9% met recommended surveillance more than 2 years after diagnosis.¹⁷ Those dismal statistics may be the result of provider oversight—not patient reluctance.

In the colon cancer study, for example, compliance with follow-up colonoscopy was 80% but compliance with carcinoembryonic antigen testing was only 22%.¹⁶ In the bladder cancer study, follow-up urine cytology was obtained in only 23% of patients, although 75% completed recommended imaging.¹⁷

Although surveillance remains the oncologist’s responsibility, visits to the FP provide an opportunity to review surveillance and order needed laboratory testing and other studies, including imaging.

3. Screen for new cancers

The risk of a second cancer is elevated for cancer survivors compared with the risk of a primary cancer in the healthy general population; some survivors have a lifetime risk of a second cancer as high as 36%.¹⁸ Risk varies by cancer type (TABLE 3¹⁹). Some of this variation is due to the impact of smoking: Smoking-related cancers have the highest risk of second malignancy.¹⁹ Genetic predisposition to malignant transformation is also theorized to contribute to increased risk. Second malignancies are dangerous; 55% of patients die of the second cancer compared with only 13% of their initial cancer.¹⁹

A study of colorectal cancer survivors showed that primary care visits increased in each of the 5 years after diagnosis, during which time oncology visits decreased steadily.

Studies show that cancer survivors display varying adherence with recommended screening for second cancers. In a study of Latina cancer survivors, depressive symptoms were associated with lower screening compliance.²⁰ A study of survivors of hematologic cancer showed a low rate of cancer screening and high fear of cancer recurrence—suggesting avoidance due to fear.²¹ Other studies, however, show similar or increased compliance with screening in cancer survivors.^22,23 A meta-analysis of 19 studies determined that, overall, cancer survivors receive 25% to 38% more recommended screening than the general population.²⁴

Continue to: Few guidelines exist to guide FPs...

Few guidelines exist to guide FPs in adjusting screening for the cancer survivor. For women who received radiation therapy for a tumor in the chest, for example, the recommendation offered by several groups is to start breast cancer screening 8 to 10 years after treatment or by 30 years of age, and to consider combining magnetic resonance imaging and mammography.²⁵ Recommendations for breast cancer screening do not account for a history of other gynecologic cancers unless genetic markers are present.²⁵ On the other hand, the impact of a history of cancer on the risk of prostate cancer and on screening decisions has not been studied,²⁶ and cervical cancer screening guidelines, which recommend that screening continue after 65 years of age for patients who are immunocompromised, do not address a history of other cancer.²⁷

4. Manage the effects of both the cancer and the treatment

Medical issues faced by cancer survivors are familiar to FPs, but there are some specific recommendations regarding evaluation and treatment that stand in contrast to what would be considered for a healthy, or non-cancer, patient. For example, each chemotherapeutic agent has characteristic adverse effects; TABLE 4⁷ lists the principal adverse effects of common agents and recommendations for testing when these problems develop. Common long-term problems in cancer survivors include fatigue, chronic pain, cognitive dysfunction, psychiatric illness, and cardiovascular disease. Although these symptoms and manifestations are common, the physician must be careful: New or changing symptoms could signal the spread or recurrence of disease. Fear of recurrence can lead patients to exaggerate or minimize symptoms.

Fatigue is the most common symptom seen in cancer survivors during treatment and following remission.²⁸ More than 40% of cancer survivors report significant fatigue.²⁹ Although fatigue is concerning for cancer recurrence, other causes are common in cancer survivors. Both depression and anxiety commonly present with worsened fatigue.³⁰ Sleep disturbances are common, even without a psychiatric diagnosis.³¹ Effects of treatment, including nausea, anemia, heart failure, and medication adverse effects can cause or worsen fatigue. Pain is associated with fatigue, but to a lesser extent than are depression, anxiety, and nausea.³²

Pharmacotherapy of cancer-related fatigue is challenging. Psychostimulants have been most studied. A recent systematic review shows that methylphenidate produces mild or moderate improvement in fatigue, whereas modafanil has minimal effectiveness.³³ Antidepressants have not been shown to relieve fatigue.³³

A recent meta-analysis showed that nonpharmaceutical treatments for cancer-related fatigue are more effective than pharmacotherapy. In this review, both exercise and pharmacotherapy had a mild-to-moderate effect on fatigue.³⁵ Exercise is best studied in this regard, and has shown the most consistent results.³¹

Continue to: Chronic pain

Chronic pain. Pain is common in cancer survivors: As many as 40% experience pain for years after initial therapy.³⁶ Treatment of some cancers—eg, thoracotomy (80%), amputation (50%-80%), neck dissection (52%), and surgical management of breast cancer (63%)—increase the likelihood of chronic pain.³⁷ Reports of pain in cancer survivors that should be considered red flags that might signal recurrence of cancer include new or worsening pain; pain worse at night or when recumbent; new neurologic symptoms; and general symptoms of systemic illness³⁷ (TABLE 5³⁷).

Management of pain is best approached by its cause, with neurologic, rheumatologic (including myofascial pain and arthralgia), lymphatic, and genital causes most common.³⁷ Across all types of pain, complete relief is unlikely; functional goals provide a more effective target.

For neuropathic cancer pain, duloxetine is the only medication with evidence of benefit; anticonvulsant and topical medications are recommended on the basis of the findings of studies of noncancer pain.³⁸ There are few data on the value of treatments for cancer-related rheumatologic and lymphatic pain, although exercise has shown benefit in both types.³⁸ For dyspareunia and sexual dysfunction (common after gynecologic and nongynecologic cancers), vaginal lubricants and pelvic-floor physiotherapy have shown benefit.³⁹ There is significant overlap in psychiatric comorbidities, sleep, and pain, and addressing all of a patient’s problems can reduce pain and improve function.⁴⁰

Opioids are often prescribed for pain in cancer survivors. Cancer survivors have a higher rate of opioid prescribing compared with that of non-cancer patients, even 10 years after diagnosis.⁴¹ Guidelines of the Centers for Disease Control and Prevention for using opioids to manage chronic pain specifically exclude cancer patients.⁴² Regrettably, there is no evidence that opioids have long-term efficacy in chronic pain; in fact, evidence is accumulating that chronic opioid therapy exacerbates chronic pain.⁴³

Cognitive dysfunction is present in 17% to 75% of cancer survivors as memory disturbance, psychological disorder, sleep dysfunction, or impairment of executive functioning.⁴⁴ Cognitive deficits appear to be secondary to both cancer and treatment modalities⁴⁵; as many as one-third of patients have cognitive dysfunction prior to receiving chemotherapy.⁴⁶

Continue to: Chemotherapies that are more likely...

Chemotherapies that are more likely to cause cognitive symptoms include methotrexate, 5-fluorouracil, cyclophosphamide, and hormone antagonists.⁴⁷ More powerful regimens and repetitive chemotherapy regimens tend to cause more cognitive effects.⁴⁷

Cognitive training interventions show evidence of likely benefit,^44,48 leading to recommendations for self-treatment strategies, such as written lists, wordplay, crossword puzzles, jigsaw puzzles, playing a musical instrument, and new hobbies. Small studies suggest a benefit from cognitive behavioral therapy.^44,49 A study of breast cancer survivors showed that yoga led to improvement in patient-reported cognitive dysfunction.⁵⁰ Physical exercise yields cognitive benefit in healthy older adults and is supported by limited evidence in cancer survivors.⁵¹

There is no effective pharmacotherapy for cancer- and cancer chemotherapy-related cognitive dysfunction unless a treatable underlying cause is found.⁴⁴ Symptoms tend to subside with time after completion of chemotherapy, which might be reassuring to patients and families.⁴⁵

Psychiatric problems. The most common psychiatric issues in cancer survivors are anxiety and depression; the prevalence of anxiety is nearly double that of depression.⁵² Anxiety often presents as fear of a recurrence of cancer or a feeling of lack of control over present or future circumstances.⁵³ Screening for anxiety and depression is recommended at each visit, using standardized screening questionnaires.⁵⁴

A small study suggests that psychiatric treatment reduces the risk of early mortality.⁵⁵ Small studies also suggest that mindfulness-based therapy and cognitive behavioral therapy delivered by telehealth offer benefit.⁵⁶ A meta-analysis shows that exercise interventions improve depression and anxiety in breast cancer patients.⁵⁷

Continue to: There are few studies of pharmacotherapy...

There are few studies of pharmacotherapy of anxiety or depression in cancer survivors⁵⁶; it is known that cancer survivors are nearly twice as likely as the general population to be taking medical therapy for anxiety and depression.⁵⁸ A Cochrane systematic review of 7 small studies showed uncertain improvement in depressive symptoms in patients with cancer from antidepressant medication; however, an earlier systematic review did show benefit.^59,60

Second malignancies are dangerous; 55% of patients die of the second cancer, compared to only 13% of their initial cancer.

In a trial of patients without depression who were being treated for head and neck cancer, escitalopram, 20 mg/d, reduced the risk of subsequent depression compared with placebo.⁶¹ A study of 420 breast cancer survivors showed that 300 mg/d and 900 mg/d dosages of gabapentin were both superior to placebo, and nearly equivalent to each other, at reducing anxiety scores.⁶² In both studies, however, the evidence is nonetheless insufficient to make specific recommendations about these medications.

Cardiac risk. The risk of cardiovascular morbidity in cancer survivors is, in fact, higher than the risk of recurrence of cancer.⁶³ Cancer survivors have 5 times the risk of heart failure and 10 times the risk of coronary artery disease and cerebrovascular disease than patients without cancer.⁶³ Most of this risk is incurred because of the physiologic effects of chemotherapy and radiation.

Among chemotherapeutic agents, anthracyclines, such as doxorubicin, cause the most rapid and striking myocyte damage. This damage is dose-dependent and nearly irreversible, with 98% of injury occurring within the first year of chemotherapy.⁶⁴ More than one half of cancer patients taking an anthracycline have cardiac dysfunction on imaging; 5% will be in overt heart failure 10 to 20 years, or longer, after chemotherapy.⁶³ Following monitoring at 1 year post-therapy, regular cardiac imaging is not recommended in the absence of symptoms.⁶²

Because other cardiotoxic chemotherapeutic agents cause partially reversible damage, imaging is not recommended in the absence of symptoms in patients taking those agents.⁶⁴

Continue to: Radiation therapy to the chest leads...

Radiation therapy to the chest leads to many cardiac complications, including cardiomyopathy, valvular disease, pericardial disease, and arrhythmias. Development of cardiomyopathy can be delayed 20 to 30 years after radiation; screening echocardiography is therefore recommended every 5 to 10 years after radiation therapy.⁶⁵ Recent adjustments to the dosages and delivery of radiation therapy should reduce cardiac damage, but will require decades to validate.⁶³

Evidence is accumulating that chronic opioid therapy exacerbates chronic pain.

For patients at risk of cardiovascular disease prior to treatment of cancer, there is evidence to support preventive treatment with angiotensin II-receptor antagonists, beta-blockers, and statins to prevent cardiomyopathy.⁶³ Treatment of diagnosed cardiomyopathy and heart failure follows standard guidelines, with significant emphasis on aerobic exercise and smoking cessation.⁶³

Cancer survivorship care: Your critical role

Cancer survivors constitute a large population who frequent the practices of primary care physicians. Primary care visits provide an opportunity to monitor key elements of survivorship, including surveillance of the current cancer and screening for second cancers. Similar to what is seen with diabetes and coronary artery disease, cancer increases cardiac risk, which requires preventive care and chronic management. FPs are well placed to treat common issues in cancer survivors—issues that mirror concerns seen in the general population.

CORRESPONDENCE
Michael J. Arnold, MD, CDR, USN, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814; [email protected].

ACKNOWLEDGEMENT
Kristian Sanchack, MD, and James Higgins, DO, assisted with the editing of the manuscript.

Cancer survivors represent a rapidly increasing population. In 1971, there were 3 million cancer survivors; this number increased to 15.5 million in 2016 and will reach 20 million by 2026.¹TABLE 1¹ shows the percentage of survivors by type of cancer. Cancer survivors tend to be older,* comprising nearly 1 of every 5 people older than 65 years.²

The Institute of Medicine (IOM) identified 3 key characteristics of cancer survivors³:

• Trajectories of survivorship are variable; many cancer patients have periods of relative health between episodes of their disease.
• Survivors require careful cancer monitoring; in addition to the risk that their primary cancer will recur, they have an elevated risk for another, second cancer.
• Both cancer and its treatments increase the risk of other medical and psychiatric problems.

Family physicians (FPs) have optimal skills for navigating the chronic risks and health concerns of the well cancer survivor. This article reviews the primary care management of the functional cancer survivor, focusing on the management of chronic conditions and preventive care.

Survivorship follows any of 6 paths

Cancer survivorship is increasing in importance as treatment has steadily reduced mortality. Six trajectories of cancer survivors have been identified¹:

• living cancer-free after treatment with minimal effects
• living cancer-free but suffering serious treatment complications
• Suffering late recurrence
• Developing a second cancer
• Living with intermittent cancer recurrences
• Living with cancer continuously.

Only patients in the last 2 groups are likely to be managed primarily by oncologists.

Survivors look to their FPs for ongoing care

Cancer survivors routinely see their primary care physician after initial treatment. A study of 30,000 Canadian breast cancer survivors demonstrated that follow-up care was limited to an oncologist in only 2%; 84% saw a primary care provider and an oncologist; and 14% saw a primary care provider only.⁴ A study of colorectal cancer survivors showed that primary care visits increased in each of the 5 years after diagnosis, during which time oncology visits decreased steadily⁵; in that study, primary care physicians delivered more preventive care than oncologists did.⁵ Similar to what is done in other chronic conditions, the various effects of cancer are best managed as a whole.

The IOM recommends that cancer survivor care comprise 4 elements²:

1. coordination between oncologist and primary care physician
2. surveillance for recurrence or spread of existing cancer
3. screening for new cancer
4. intervention for the effects of cancer and treatment.

Continue to: The following discussion summarizes...

The following discussion summarizes evidence and recommendations for each element of the IOM recommendations for survivor care.

Implementing the 4 elements of cancer survivor care

1. Coordinate care through a unified survivorship care plan

The IOM has noted that the needs of cancer survivors are rarely met²; communication between oncology and primary care is often deficient during transition of care. The IOM has recommended that oncologists provide a survivorship care plan that details the cancer (ie, tumor characteristics), the type of treatment (ie, enrollment in a clinical trial; medical, surgical, or radiation), support services, and follow-up recommendations for the primary care provider. (Examples of elements of a survivorship care plan can be found at www.mskcc.org/hcp-education-training/survivorship/survivorship-care-plan⁶ and http://sma.org/southern-medical-journal/article/cancer-survivors-history-physical/⁷).

Regrettably, survivorship care plans have been rarely and poorly employed. Studies show that fewer than one-half of oncologists provide a plan, and that when they do, the plan often lacks recommended information.^8,9 Survivorship care plans may soon become common practice, however; the Commission on Cancer of the American College of Surgeons has required their use in all certified cancer centers since 2015.¹⁰

2. Provide surveillance of existing cancer

Cancer follow-up is challenging after the initial treatment phase. Although there are many conflicting guidelines for surveillance after cancer, guidelines of the National Comprehensive Cancer Network (NCCN) (summarized in TABLE 2¹¹ for the 10 most common cancers in survivors) are the ones generally accepted.^12,13

Although individual surveillance recommendations are based on limited evidence, studies confirm the importance of surveillance. A systematic review showed that surveillance mammography after breast cancer reduces breast cancer mortality by 36%.¹⁴ A study showed that bladder cancer recurrence diagnosed by surveillance instead of by symptoms led to a 35% increase in 5-year survival.¹⁵

Continue to: Yet adherence to cancer surveillance...

Yet adherence to cancer surveillance recommendations is poor. A study of patients with colon cancer demonstrated that only 12% met all recommended surveillance guidelines.¹⁶ A study of patients with bladder cancer after radical cystectomy showed that only 9% met recommended surveillance more than 2 years after diagnosis.¹⁷ Those dismal statistics may be the result of provider oversight—not patient reluctance.

In the colon cancer study, for example, compliance with follow-up colonoscopy was 80% but compliance with carcinoembryonic antigen testing was only 22%.¹⁶ In the bladder cancer study, follow-up urine cytology was obtained in only 23% of patients, although 75% completed recommended imaging.¹⁷

Although surveillance remains the oncologist’s responsibility, visits to the FP provide an opportunity to review surveillance and order needed laboratory testing and other studies, including imaging.

3. Screen for new cancers

The risk of a second cancer is elevated for cancer survivors compared with the risk of a primary cancer in the healthy general population; some survivors have a lifetime risk of a second cancer as high as 36%.¹⁸ Risk varies by cancer type (TABLE 3¹⁹). Some of this variation is due to the impact of smoking: Smoking-related cancers have the highest risk of second malignancy.¹⁹ Genetic predisposition to malignant transformation is also theorized to contribute to increased risk. Second malignancies are dangerous; 55% of patients die of the second cancer compared with only 13% of their initial cancer.¹⁹

A study of colorectal cancer survivors showed that primary care visits increased in each of the 5 years after diagnosis, during which time oncology visits decreased steadily.

Studies show that cancer survivors display varying adherence with recommended screening for second cancers. In a study of Latina cancer survivors, depressive symptoms were associated with lower screening compliance.²⁰ A study of survivors of hematologic cancer showed a low rate of cancer screening and high fear of cancer recurrence—suggesting avoidance due to fear.²¹ Other studies, however, show similar or increased compliance with screening in cancer survivors.^22,23 A meta-analysis of 19 studies determined that, overall, cancer survivors receive 25% to 38% more recommended screening than the general population.²⁴

Continue to: Few guidelines exist to guide FPs...

Few guidelines exist to guide FPs in adjusting screening for the cancer survivor. For women who received radiation therapy for a tumor in the chest, for example, the recommendation offered by several groups is to start breast cancer screening 8 to 10 years after treatment or by 30 years of age, and to consider combining magnetic resonance imaging and mammography.²⁵ Recommendations for breast cancer screening do not account for a history of other gynecologic cancers unless genetic markers are present.²⁵ On the other hand, the impact of a history of cancer on the risk of prostate cancer and on screening decisions has not been studied,²⁶ and cervical cancer screening guidelines, which recommend that screening continue after 65 years of age for patients who are immunocompromised, do not address a history of other cancer.²⁷

4. Manage the effects of both the cancer and the treatment

Medical issues faced by cancer survivors are familiar to FPs, but there are some specific recommendations regarding evaluation and treatment that stand in contrast to what would be considered for a healthy, or non-cancer, patient. For example, each chemotherapeutic agent has characteristic adverse effects; TABLE 4⁷ lists the principal adverse effects of common agents and recommendations for testing when these problems develop. Common long-term problems in cancer survivors include fatigue, chronic pain, cognitive dysfunction, psychiatric illness, and cardiovascular disease. Although these symptoms and manifestations are common, the physician must be careful: New or changing symptoms could signal the spread or recurrence of disease. Fear of recurrence can lead patients to exaggerate or minimize symptoms.

Fatigue is the most common symptom seen in cancer survivors during treatment and following remission.²⁸ More than 40% of cancer survivors report significant fatigue.²⁹ Although fatigue is concerning for cancer recurrence, other causes are common in cancer survivors. Both depression and anxiety commonly present with worsened fatigue.³⁰ Sleep disturbances are common, even without a psychiatric diagnosis.³¹ Effects of treatment, including nausea, anemia, heart failure, and medication adverse effects can cause or worsen fatigue. Pain is associated with fatigue, but to a lesser extent than are depression, anxiety, and nausea.³²

Pharmacotherapy of cancer-related fatigue is challenging. Psychostimulants have been most studied. A recent systematic review shows that methylphenidate produces mild or moderate improvement in fatigue, whereas modafanil has minimal effectiveness.³³ Antidepressants have not been shown to relieve fatigue.³³

A recent meta-analysis showed that nonpharmaceutical treatments for cancer-related fatigue are more effective than pharmacotherapy. In this review, both exercise and pharmacotherapy had a mild-to-moderate effect on fatigue.³⁵ Exercise is best studied in this regard, and has shown the most consistent results.³¹

Continue to: Chronic pain

Chronic pain. Pain is common in cancer survivors: As many as 40% experience pain for years after initial therapy.³⁶ Treatment of some cancers—eg, thoracotomy (80%), amputation (50%-80%), neck dissection (52%), and surgical management of breast cancer (63%)—increase the likelihood of chronic pain.³⁷ Reports of pain in cancer survivors that should be considered red flags that might signal recurrence of cancer include new or worsening pain; pain worse at night or when recumbent; new neurologic symptoms; and general symptoms of systemic illness³⁷ (TABLE 5³⁷).

Management of pain is best approached by its cause, with neurologic, rheumatologic (including myofascial pain and arthralgia), lymphatic, and genital causes most common.³⁷ Across all types of pain, complete relief is unlikely; functional goals provide a more effective target.

For neuropathic cancer pain, duloxetine is the only medication with evidence of benefit; anticonvulsant and topical medications are recommended on the basis of the findings of studies of noncancer pain.³⁸ There are few data on the value of treatments for cancer-related rheumatologic and lymphatic pain, although exercise has shown benefit in both types.³⁸ For dyspareunia and sexual dysfunction (common after gynecologic and nongynecologic cancers), vaginal lubricants and pelvic-floor physiotherapy have shown benefit.³⁹ There is significant overlap in psychiatric comorbidities, sleep, and pain, and addressing all of a patient’s problems can reduce pain and improve function.⁴⁰

Opioids are often prescribed for pain in cancer survivors. Cancer survivors have a higher rate of opioid prescribing compared with that of non-cancer patients, even 10 years after diagnosis.⁴¹ Guidelines of the Centers for Disease Control and Prevention for using opioids to manage chronic pain specifically exclude cancer patients.⁴² Regrettably, there is no evidence that opioids have long-term efficacy in chronic pain; in fact, evidence is accumulating that chronic opioid therapy exacerbates chronic pain.⁴³

Cognitive dysfunction is present in 17% to 75% of cancer survivors as memory disturbance, psychological disorder, sleep dysfunction, or impairment of executive functioning.⁴⁴ Cognitive deficits appear to be secondary to both cancer and treatment modalities⁴⁵; as many as one-third of patients have cognitive dysfunction prior to receiving chemotherapy.⁴⁶

Continue to: Chemotherapies that are more likely...

Chemotherapies that are more likely to cause cognitive symptoms include methotrexate, 5-fluorouracil, cyclophosphamide, and hormone antagonists.⁴⁷ More powerful regimens and repetitive chemotherapy regimens tend to cause more cognitive effects.⁴⁷

Cognitive training interventions show evidence of likely benefit,^44,48 leading to recommendations for self-treatment strategies, such as written lists, wordplay, crossword puzzles, jigsaw puzzles, playing a musical instrument, and new hobbies. Small studies suggest a benefit from cognitive behavioral therapy.^44,49 A study of breast cancer survivors showed that yoga led to improvement in patient-reported cognitive dysfunction.⁵⁰ Physical exercise yields cognitive benefit in healthy older adults and is supported by limited evidence in cancer survivors.⁵¹

There is no effective pharmacotherapy for cancer- and cancer chemotherapy-related cognitive dysfunction unless a treatable underlying cause is found.⁴⁴ Symptoms tend to subside with time after completion of chemotherapy, which might be reassuring to patients and families.⁴⁵

Psychiatric problems. The most common psychiatric issues in cancer survivors are anxiety and depression; the prevalence of anxiety is nearly double that of depression.⁵² Anxiety often presents as fear of a recurrence of cancer or a feeling of lack of control over present or future circumstances.⁵³ Screening for anxiety and depression is recommended at each visit, using standardized screening questionnaires.⁵⁴

A small study suggests that psychiatric treatment reduces the risk of early mortality.⁵⁵ Small studies also suggest that mindfulness-based therapy and cognitive behavioral therapy delivered by telehealth offer benefit.⁵⁶ A meta-analysis shows that exercise interventions improve depression and anxiety in breast cancer patients.⁵⁷

Continue to: There are few studies of pharmacotherapy...

There are few studies of pharmacotherapy of anxiety or depression in cancer survivors⁵⁶; it is known that cancer survivors are nearly twice as likely as the general population to be taking medical therapy for anxiety and depression.⁵⁸ A Cochrane systematic review of 7 small studies showed uncertain improvement in depressive symptoms in patients with cancer from antidepressant medication; however, an earlier systematic review did show benefit.^59,60

Second malignancies are dangerous; 55% of patients die of the second cancer, compared to only 13% of their initial cancer.

In a trial of patients without depression who were being treated for head and neck cancer, escitalopram, 20 mg/d, reduced the risk of subsequent depression compared with placebo.⁶¹ A study of 420 breast cancer survivors showed that 300 mg/d and 900 mg/d dosages of gabapentin were both superior to placebo, and nearly equivalent to each other, at reducing anxiety scores.⁶² In both studies, however, the evidence is nonetheless insufficient to make specific recommendations about these medications.

Cardiac risk. The risk of cardiovascular morbidity in cancer survivors is, in fact, higher than the risk of recurrence of cancer.⁶³ Cancer survivors have 5 times the risk of heart failure and 10 times the risk of coronary artery disease and cerebrovascular disease than patients without cancer.⁶³ Most of this risk is incurred because of the physiologic effects of chemotherapy and radiation.

Among chemotherapeutic agents, anthracyclines, such as doxorubicin, cause the most rapid and striking myocyte damage. This damage is dose-dependent and nearly irreversible, with 98% of injury occurring within the first year of chemotherapy.⁶⁴ More than one half of cancer patients taking an anthracycline have cardiac dysfunction on imaging; 5% will be in overt heart failure 10 to 20 years, or longer, after chemotherapy.⁶³ Following monitoring at 1 year post-therapy, regular cardiac imaging is not recommended in the absence of symptoms.⁶²

Because other cardiotoxic chemotherapeutic agents cause partially reversible damage, imaging is not recommended in the absence of symptoms in patients taking those agents.⁶⁴

Continue to: Radiation therapy to the chest leads...

Radiation therapy to the chest leads to many cardiac complications, including cardiomyopathy, valvular disease, pericardial disease, and arrhythmias. Development of cardiomyopathy can be delayed 20 to 30 years after radiation; screening echocardiography is therefore recommended every 5 to 10 years after radiation therapy.⁶⁵ Recent adjustments to the dosages and delivery of radiation therapy should reduce cardiac damage, but will require decades to validate.⁶³

Evidence is accumulating that chronic opioid therapy exacerbates chronic pain.

For patients at risk of cardiovascular disease prior to treatment of cancer, there is evidence to support preventive treatment with angiotensin II-receptor antagonists, beta-blockers, and statins to prevent cardiomyopathy.⁶³ Treatment of diagnosed cardiomyopathy and heart failure follows standard guidelines, with significant emphasis on aerobic exercise and smoking cessation.⁶³

Cancer survivorship care: Your critical role

Cancer survivors constitute a large population who frequent the practices of primary care physicians. Primary care visits provide an opportunity to monitor key elements of survivorship, including surveillance of the current cancer and screening for second cancers. Similar to what is seen with diabetes and coronary artery disease, cancer increases cardiac risk, which requires preventive care and chronic management. FPs are well placed to treat common issues in cancer survivors—issues that mirror concerns seen in the general population.

CORRESPONDENCE
Michael J. Arnold, MD, CDR, USN, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814; [email protected].

ACKNOWLEDGEMENT
Kristian Sanchack, MD, and James Higgins, DO, assisted with the editing of the manuscript.

Cancer survivors represent a rapidly increasing population. In 1971, there were 3 million cancer survivors; this number increased to 15.5 million in 2016 and will reach 20 million by 2026.¹TABLE 1¹ shows the percentage of survivors by type of cancer. Cancer survivors tend to be older,* comprising nearly 1 of every 5 people older than 65 years.²

The Institute of Medicine (IOM) identified 3 key characteristics of cancer survivors³:

• Trajectories of survivorship are variable; many cancer patients have periods of relative health between episodes of their disease.
• Survivors require careful cancer monitoring; in addition to the risk that their primary cancer will recur, they have an elevated risk for another, second cancer.
• Both cancer and its treatments increase the risk of other medical and psychiatric problems.

Family physicians (FPs) have optimal skills for navigating the chronic risks and health concerns of the well cancer survivor. This article reviews the primary care management of the functional cancer survivor, focusing on the management of chronic conditions and preventive care.

Survivorship follows any of 6 paths

Cancer survivorship is increasing in importance as treatment has steadily reduced mortality. Six trajectories of cancer survivors have been identified¹:

• living cancer-free after treatment with minimal effects
• living cancer-free but suffering serious treatment complications
• Suffering late recurrence
• Developing a second cancer
• Living with intermittent cancer recurrences
• Living with cancer continuously.

Only patients in the last 2 groups are likely to be managed primarily by oncologists.

Survivors look to their FPs for ongoing care

Cancer survivors routinely see their primary care physician after initial treatment. A study of 30,000 Canadian breast cancer survivors demonstrated that follow-up care was limited to an oncologist in only 2%; 84% saw a primary care provider and an oncologist; and 14% saw a primary care provider only.⁴ A study of colorectal cancer survivors showed that primary care visits increased in each of the 5 years after diagnosis, during which time oncology visits decreased steadily⁵; in that study, primary care physicians delivered more preventive care than oncologists did.⁵ Similar to what is done in other chronic conditions, the various effects of cancer are best managed as a whole.

The IOM recommends that cancer survivor care comprise 4 elements²:

1. coordination between oncologist and primary care physician
2. surveillance for recurrence or spread of existing cancer
3. screening for new cancer
4. intervention for the effects of cancer and treatment.

Continue to: The following discussion summarizes...

The following discussion summarizes evidence and recommendations for each element of the IOM recommendations for survivor care.

Implementing the 4 elements of cancer survivor care

1. Coordinate care through a unified survivorship care plan

The IOM has noted that the needs of cancer survivors are rarely met²; communication between oncology and primary care is often deficient during transition of care. The IOM has recommended that oncologists provide a survivorship care plan that details the cancer (ie, tumor characteristics), the type of treatment (ie, enrollment in a clinical trial; medical, surgical, or radiation), support services, and follow-up recommendations for the primary care provider. (Examples of elements of a survivorship care plan can be found at www.mskcc.org/hcp-education-training/survivorship/survivorship-care-plan⁶ and http://sma.org/southern-medical-journal/article/cancer-survivors-history-physical/⁷).

Regrettably, survivorship care plans have been rarely and poorly employed. Studies show that fewer than one-half of oncologists provide a plan, and that when they do, the plan often lacks recommended information.^8,9 Survivorship care plans may soon become common practice, however; the Commission on Cancer of the American College of Surgeons has required their use in all certified cancer centers since 2015.¹⁰

2. Provide surveillance of existing cancer

Cancer follow-up is challenging after the initial treatment phase. Although there are many conflicting guidelines for surveillance after cancer, guidelines of the National Comprehensive Cancer Network (NCCN) (summarized in TABLE 2¹¹ for the 10 most common cancers in survivors) are the ones generally accepted.^12,13

Although individual surveillance recommendations are based on limited evidence, studies confirm the importance of surveillance. A systematic review showed that surveillance mammography after breast cancer reduces breast cancer mortality by 36%.¹⁴ A study showed that bladder cancer recurrence diagnosed by surveillance instead of by symptoms led to a 35% increase in 5-year survival.¹⁵

Continue to: Yet adherence to cancer surveillance...

Yet adherence to cancer surveillance recommendations is poor. A study of patients with colon cancer demonstrated that only 12% met all recommended surveillance guidelines.¹⁶ A study of patients with bladder cancer after radical cystectomy showed that only 9% met recommended surveillance more than 2 years after diagnosis.¹⁷ Those dismal statistics may be the result of provider oversight—not patient reluctance.

In the colon cancer study, for example, compliance with follow-up colonoscopy was 80% but compliance with carcinoembryonic antigen testing was only 22%.¹⁶ In the bladder cancer study, follow-up urine cytology was obtained in only 23% of patients, although 75% completed recommended imaging.¹⁷

Although surveillance remains the oncologist’s responsibility, visits to the FP provide an opportunity to review surveillance and order needed laboratory testing and other studies, including imaging.

3. Screen for new cancers

The risk of a second cancer is elevated for cancer survivors compared with the risk of a primary cancer in the healthy general population; some survivors have a lifetime risk of a second cancer as high as 36%.¹⁸ Risk varies by cancer type (TABLE 3¹⁹). Some of this variation is due to the impact of smoking: Smoking-related cancers have the highest risk of second malignancy.¹⁹ Genetic predisposition to malignant transformation is also theorized to contribute to increased risk. Second malignancies are dangerous; 55% of patients die of the second cancer compared with only 13% of their initial cancer.¹⁹

A study of colorectal cancer survivors showed that primary care visits increased in each of the 5 years after diagnosis, during which time oncology visits decreased steadily.

Studies show that cancer survivors display varying adherence with recommended screening for second cancers. In a study of Latina cancer survivors, depressive symptoms were associated with lower screening compliance.²⁰ A study of survivors of hematologic cancer showed a low rate of cancer screening and high fear of cancer recurrence—suggesting avoidance due to fear.²¹ Other studies, however, show similar or increased compliance with screening in cancer survivors.^22,23 A meta-analysis of 19 studies determined that, overall, cancer survivors receive 25% to 38% more recommended screening than the general population.²⁴

Continue to: Few guidelines exist to guide FPs...

Few guidelines exist to guide FPs in adjusting screening for the cancer survivor. For women who received radiation therapy for a tumor in the chest, for example, the recommendation offered by several groups is to start breast cancer screening 8 to 10 years after treatment or by 30 years of age, and to consider combining magnetic resonance imaging and mammography.²⁵ Recommendations for breast cancer screening do not account for a history of other gynecologic cancers unless genetic markers are present.²⁵ On the other hand, the impact of a history of cancer on the risk of prostate cancer and on screening decisions has not been studied,²⁶ and cervical cancer screening guidelines, which recommend that screening continue after 65 years of age for patients who are immunocompromised, do not address a history of other cancer.²⁷

4. Manage the effects of both the cancer and the treatment

Medical issues faced by cancer survivors are familiar to FPs, but there are some specific recommendations regarding evaluation and treatment that stand in contrast to what would be considered for a healthy, or non-cancer, patient. For example, each chemotherapeutic agent has characteristic adverse effects; TABLE 4⁷ lists the principal adverse effects of common agents and recommendations for testing when these problems develop. Common long-term problems in cancer survivors include fatigue, chronic pain, cognitive dysfunction, psychiatric illness, and cardiovascular disease. Although these symptoms and manifestations are common, the physician must be careful: New or changing symptoms could signal the spread or recurrence of disease. Fear of recurrence can lead patients to exaggerate or minimize symptoms.

Fatigue is the most common symptom seen in cancer survivors during treatment and following remission.²⁸ More than 40% of cancer survivors report significant fatigue.²⁹ Although fatigue is concerning for cancer recurrence, other causes are common in cancer survivors. Both depression and anxiety commonly present with worsened fatigue.³⁰ Sleep disturbances are common, even without a psychiatric diagnosis.³¹ Effects of treatment, including nausea, anemia, heart failure, and medication adverse effects can cause or worsen fatigue. Pain is associated with fatigue, but to a lesser extent than are depression, anxiety, and nausea.³²

Pharmacotherapy of cancer-related fatigue is challenging. Psychostimulants have been most studied. A recent systematic review shows that methylphenidate produces mild or moderate improvement in fatigue, whereas modafanil has minimal effectiveness.³³ Antidepressants have not been shown to relieve fatigue.³³

A recent meta-analysis showed that nonpharmaceutical treatments for cancer-related fatigue are more effective than pharmacotherapy. In this review, both exercise and pharmacotherapy had a mild-to-moderate effect on fatigue.³⁵ Exercise is best studied in this regard, and has shown the most consistent results.³¹

Continue to: Chronic pain

Chronic pain. Pain is common in cancer survivors: As many as 40% experience pain for years after initial therapy.³⁶ Treatment of some cancers—eg, thoracotomy (80%), amputation (50%-80%), neck dissection (52%), and surgical management of breast cancer (63%)—increase the likelihood of chronic pain.³⁷ Reports of pain in cancer survivors that should be considered red flags that might signal recurrence of cancer include new or worsening pain; pain worse at night or when recumbent; new neurologic symptoms; and general symptoms of systemic illness³⁷ (TABLE 5³⁷).

Management of pain is best approached by its cause, with neurologic, rheumatologic (including myofascial pain and arthralgia), lymphatic, and genital causes most common.³⁷ Across all types of pain, complete relief is unlikely; functional goals provide a more effective target.

For neuropathic cancer pain, duloxetine is the only medication with evidence of benefit; anticonvulsant and topical medications are recommended on the basis of the findings of studies of noncancer pain.³⁸ There are few data on the value of treatments for cancer-related rheumatologic and lymphatic pain, although exercise has shown benefit in both types.³⁸ For dyspareunia and sexual dysfunction (common after gynecologic and nongynecologic cancers), vaginal lubricants and pelvic-floor physiotherapy have shown benefit.³⁹ There is significant overlap in psychiatric comorbidities, sleep, and pain, and addressing all of a patient’s problems can reduce pain and improve function.⁴⁰

Opioids are often prescribed for pain in cancer survivors. Cancer survivors have a higher rate of opioid prescribing compared with that of non-cancer patients, even 10 years after diagnosis.⁴¹ Guidelines of the Centers for Disease Control and Prevention for using opioids to manage chronic pain specifically exclude cancer patients.⁴² Regrettably, there is no evidence that opioids have long-term efficacy in chronic pain; in fact, evidence is accumulating that chronic opioid therapy exacerbates chronic pain.⁴³

Cognitive dysfunction is present in 17% to 75% of cancer survivors as memory disturbance, psychological disorder, sleep dysfunction, or impairment of executive functioning.⁴⁴ Cognitive deficits appear to be secondary to both cancer and treatment modalities⁴⁵; as many as one-third of patients have cognitive dysfunction prior to receiving chemotherapy.⁴⁶

Continue to: Chemotherapies that are more likely...

Chemotherapies that are more likely to cause cognitive symptoms include methotrexate, 5-fluorouracil, cyclophosphamide, and hormone antagonists.⁴⁷ More powerful regimens and repetitive chemotherapy regimens tend to cause more cognitive effects.⁴⁷

Cognitive training interventions show evidence of likely benefit,^44,48 leading to recommendations for self-treatment strategies, such as written lists, wordplay, crossword puzzles, jigsaw puzzles, playing a musical instrument, and new hobbies. Small studies suggest a benefit from cognitive behavioral therapy.^44,49 A study of breast cancer survivors showed that yoga led to improvement in patient-reported cognitive dysfunction.⁵⁰ Physical exercise yields cognitive benefit in healthy older adults and is supported by limited evidence in cancer survivors.⁵¹

There is no effective pharmacotherapy for cancer- and cancer chemotherapy-related cognitive dysfunction unless a treatable underlying cause is found.⁴⁴ Symptoms tend to subside with time after completion of chemotherapy, which might be reassuring to patients and families.⁴⁵

Psychiatric problems. The most common psychiatric issues in cancer survivors are anxiety and depression; the prevalence of anxiety is nearly double that of depression.⁵² Anxiety often presents as fear of a recurrence of cancer or a feeling of lack of control over present or future circumstances.⁵³ Screening for anxiety and depression is recommended at each visit, using standardized screening questionnaires.⁵⁴

A small study suggests that psychiatric treatment reduces the risk of early mortality.⁵⁵ Small studies also suggest that mindfulness-based therapy and cognitive behavioral therapy delivered by telehealth offer benefit.⁵⁶ A meta-analysis shows that exercise interventions improve depression and anxiety in breast cancer patients.⁵⁷

Continue to: There are few studies of pharmacotherapy...

There are few studies of pharmacotherapy of anxiety or depression in cancer survivors⁵⁶; it is known that cancer survivors are nearly twice as likely as the general population to be taking medical therapy for anxiety and depression.⁵⁸ A Cochrane systematic review of 7 small studies showed uncertain improvement in depressive symptoms in patients with cancer from antidepressant medication; however, an earlier systematic review did show benefit.^59,60

Second malignancies are dangerous; 55% of patients die of the second cancer, compared to only 13% of their initial cancer.

In a trial of patients without depression who were being treated for head and neck cancer, escitalopram, 20 mg/d, reduced the risk of subsequent depression compared with placebo.⁶¹ A study of 420 breast cancer survivors showed that 300 mg/d and 900 mg/d dosages of gabapentin were both superior to placebo, and nearly equivalent to each other, at reducing anxiety scores.⁶² In both studies, however, the evidence is nonetheless insufficient to make specific recommendations about these medications.

Cardiac risk. The risk of cardiovascular morbidity in cancer survivors is, in fact, higher than the risk of recurrence of cancer.⁶³ Cancer survivors have 5 times the risk of heart failure and 10 times the risk of coronary artery disease and cerebrovascular disease than patients without cancer.⁶³ Most of this risk is incurred because of the physiologic effects of chemotherapy and radiation.

Among chemotherapeutic agents, anthracyclines, such as doxorubicin, cause the most rapid and striking myocyte damage. This damage is dose-dependent and nearly irreversible, with 98% of injury occurring within the first year of chemotherapy.⁶⁴ More than one half of cancer patients taking an anthracycline have cardiac dysfunction on imaging; 5% will be in overt heart failure 10 to 20 years, or longer, after chemotherapy.⁶³ Following monitoring at 1 year post-therapy, regular cardiac imaging is not recommended in the absence of symptoms.⁶²

Because other cardiotoxic chemotherapeutic agents cause partially reversible damage, imaging is not recommended in the absence of symptoms in patients taking those agents.⁶⁴

Continue to: Radiation therapy to the chest leads...

Radiation therapy to the chest leads to many cardiac complications, including cardiomyopathy, valvular disease, pericardial disease, and arrhythmias. Development of cardiomyopathy can be delayed 20 to 30 years after radiation; screening echocardiography is therefore recommended every 5 to 10 years after radiation therapy.⁶⁵ Recent adjustments to the dosages and delivery of radiation therapy should reduce cardiac damage, but will require decades to validate.⁶³

Evidence is accumulating that chronic opioid therapy exacerbates chronic pain.

For patients at risk of cardiovascular disease prior to treatment of cancer, there is evidence to support preventive treatment with angiotensin II-receptor antagonists, beta-blockers, and statins to prevent cardiomyopathy.⁶³ Treatment of diagnosed cardiomyopathy and heart failure follows standard guidelines, with significant emphasis on aerobic exercise and smoking cessation.⁶³

Cancer survivorship care: Your critical role

Cancer survivors constitute a large population who frequent the practices of primary care physicians. Primary care visits provide an opportunity to monitor key elements of survivorship, including surveillance of the current cancer and screening for second cancers. Similar to what is seen with diabetes and coronary artery disease, cancer increases cardiac risk, which requires preventive care and chronic management. FPs are well placed to treat common issues in cancer survivors—issues that mirror concerns seen in the general population.

CORRESPONDENCE
Michael J. Arnold, MD, CDR, USN, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814; [email protected].

ACKNOWLEDGEMENT
Kristian Sanchack, MD, and James Higgins, DO, assisted with the editing of the manuscript.