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Stroke risk is highest right after COVID infection
, new research shows.
The study among Medicare beneficiaries with COVID-19 also showed that stroke risk is higher for relatively young older adults, those aged 65 to 74 years, and those without a history of stroke.
The study highlights the impact COVID-19 has on the cardiovascular system, said study author Quanhe Yang, PhD, senior scientist, Division for Heart Disease and Stroke Prevention, Centers for Disease Control and Prevention, Atlanta.
“Clinicians and patients should understand that stroke might be one of the very important clinical consequences of COVID-19.”
The study was presented during the hybrid International Stroke Conference held in New Orleans and online. The meeting was presented by the American Stroke Association, a division of the American Heart Association.
Stroke is the fifth leading cause of death in the U.S. As an increasing number of people become infected with COVID-19, “it’s important to determine if there’s a relationship between COVID and the risk of stroke,” said Dr. Yang.
Findings from prior research examining the link between stroke and COVID-19 have been inconsistent, he noted. Some studies found an association while others did not, and in still others, the association was not as strong as expected.
Many factors may contribute to these inconsistent findings, said Dr. Yang, including differences in study design, inclusion criteria, comparison groups, sample sizes, and countries where the research was carried out. Dr. Yang pointed out that many of these studies were done in the early stages of the pandemic or didn’t include older adults, the population most at risk for stroke.
The current study included 19,553 Medicare beneficiaries aged 65 years and older diagnosed with COVID-19 and hospitalized with acute ischemic stroke. The median age at diagnosis of COVID-19 was 80.5 years, 57.5% were women, and more than 75% were non-Hispanic Whites.
To ensure the stroke occurred after a COVID infection, researchers used a self-controlled case series study design, a “within person” comparison between the risk period and the control period.
They divided the study period (Jan. 1, 2019 to Feb. 28, 2021) into the exposure or stroke risk periods after the COVID diagnosis (0-3 days; 4-7 days; 8-15 days; and 15-28 days) and control periods.
Strokes that occurred 7 days before or 28 days after a COVID diagnosis served as a control period. “Any stroke that occurred outside the risk window is in the control period,” explained Dr. Yang.
He added that the control period provides a baseline. “Without COVID-19, this is what I would expect” in terms of the number of strokes.
To estimate the incidence rate ratio (IRR), investigators compared the incidence of acute ischemic stroke in the various risk periods with control periods.
The IRR was 10.97 (95% confidence interval, 10.30-11.68) at 0-3 days. The risk then quickly declined but stayed higher than the control period. The IRRs were: 1.59 (95% CI, 1.35-1.87) at 4-7 days; 1.23 (95% CI, 1.07-1.41) at 8-14 days; and 1.06 (95% CI, 0.95-1.18) at 15-28 days.
The temporary increase in stroke risk early after an infection isn’t novel; the pattern has been observed with influenza, respiratory infections, and shingles, said Dr. Yang. “But COVID-19 appears to be particularly risky.”
Although the mechanism driving the early increased stroke risk isn’t fully understood, it’s likely tied to an “exaggerated inflammatory response,” said Dr. Yang. This can trigger the cascade of events setting the stage for a stroke – a hypercoagulation state leading to the formation of blood clots that then block arteries to the brain, he said.
It’s also possible the infection directly affects endothelial cells, leading to rupture of plaque, again blocking arteries and raising stroke risks, added Dr. Yang.
The association was stronger among younger beneficiaries, aged 65 to 74 years, compared with those 85 years and older, a finding Dr. Yang said was somewhat surprising. But he noted other studies have found stroke patients with COVID are younger than stroke patients without COVID – by some 5 to 6 years.
“If COVID-19 disproportionately affects younger patients, that may explain the stronger association,” said Dr. Yang. “Stroke risk increases tremendously with age, so if you’re a younger age, your baseline stroke risk is lower.”
The association was also stronger among beneficiaries without a history of stroke. Again, this could be related to the stronger association among younger patients who are less likely to have suffered a stroke. The association was largely consistent across sex and race/ethnicities.
Dr. Yang stressed that the findings need to be confirmed with further studies.
The study was carried out before widespread use of vaccinations in the U.S. Once those data are available, Dr. Yang and his colleagues plan to determine if vaccinations modify the association between COVID-19 and stroke risk.
The new results contribute to the mounting evidence that a COVID-19 infection “can actually affect multiple human organs structurally or functionally in addition to the impact on [the] respiratory system,” said Dr. Yang.
Some dates of COVID-19 diagnoses may be incorrect due to limited test availability, particularly early in the pandemic. Another limitation of the study was possible misclassification from the use of Medicare real-time preliminary claims.
In a provided statement, Louise D. McCullough, MD, PhD, chair of the ISC 2022 and professor and chair of neurology, McGovern Medical School, University of Texas Health Science Center at Houston, noted that the study focused on older adults because it was examining Medicare beneficiaries.
“But everyone is likely at risk for stroke after COVID,” she said. “Any infection is linked to stroke risk, probably because any infection will cause inflammation, and inflammation can cause clots or thrombus, which is the cause of stroke.”
There was no outside funding for the study. No relevant conflicts of interest were disclosed.
A version of this article first appeared on Medscape.com.
, new research shows.
The study among Medicare beneficiaries with COVID-19 also showed that stroke risk is higher for relatively young older adults, those aged 65 to 74 years, and those without a history of stroke.
The study highlights the impact COVID-19 has on the cardiovascular system, said study author Quanhe Yang, PhD, senior scientist, Division for Heart Disease and Stroke Prevention, Centers for Disease Control and Prevention, Atlanta.
“Clinicians and patients should understand that stroke might be one of the very important clinical consequences of COVID-19.”
The study was presented during the hybrid International Stroke Conference held in New Orleans and online. The meeting was presented by the American Stroke Association, a division of the American Heart Association.
Stroke is the fifth leading cause of death in the U.S. As an increasing number of people become infected with COVID-19, “it’s important to determine if there’s a relationship between COVID and the risk of stroke,” said Dr. Yang.
Findings from prior research examining the link between stroke and COVID-19 have been inconsistent, he noted. Some studies found an association while others did not, and in still others, the association was not as strong as expected.
Many factors may contribute to these inconsistent findings, said Dr. Yang, including differences in study design, inclusion criteria, comparison groups, sample sizes, and countries where the research was carried out. Dr. Yang pointed out that many of these studies were done in the early stages of the pandemic or didn’t include older adults, the population most at risk for stroke.
The current study included 19,553 Medicare beneficiaries aged 65 years and older diagnosed with COVID-19 and hospitalized with acute ischemic stroke. The median age at diagnosis of COVID-19 was 80.5 years, 57.5% were women, and more than 75% were non-Hispanic Whites.
To ensure the stroke occurred after a COVID infection, researchers used a self-controlled case series study design, a “within person” comparison between the risk period and the control period.
They divided the study period (Jan. 1, 2019 to Feb. 28, 2021) into the exposure or stroke risk periods after the COVID diagnosis (0-3 days; 4-7 days; 8-15 days; and 15-28 days) and control periods.
Strokes that occurred 7 days before or 28 days after a COVID diagnosis served as a control period. “Any stroke that occurred outside the risk window is in the control period,” explained Dr. Yang.
He added that the control period provides a baseline. “Without COVID-19, this is what I would expect” in terms of the number of strokes.
To estimate the incidence rate ratio (IRR), investigators compared the incidence of acute ischemic stroke in the various risk periods with control periods.
The IRR was 10.97 (95% confidence interval, 10.30-11.68) at 0-3 days. The risk then quickly declined but stayed higher than the control period. The IRRs were: 1.59 (95% CI, 1.35-1.87) at 4-7 days; 1.23 (95% CI, 1.07-1.41) at 8-14 days; and 1.06 (95% CI, 0.95-1.18) at 15-28 days.
The temporary increase in stroke risk early after an infection isn’t novel; the pattern has been observed with influenza, respiratory infections, and shingles, said Dr. Yang. “But COVID-19 appears to be particularly risky.”
Although the mechanism driving the early increased stroke risk isn’t fully understood, it’s likely tied to an “exaggerated inflammatory response,” said Dr. Yang. This can trigger the cascade of events setting the stage for a stroke – a hypercoagulation state leading to the formation of blood clots that then block arteries to the brain, he said.
It’s also possible the infection directly affects endothelial cells, leading to rupture of plaque, again blocking arteries and raising stroke risks, added Dr. Yang.
The association was stronger among younger beneficiaries, aged 65 to 74 years, compared with those 85 years and older, a finding Dr. Yang said was somewhat surprising. But he noted other studies have found stroke patients with COVID are younger than stroke patients without COVID – by some 5 to 6 years.
“If COVID-19 disproportionately affects younger patients, that may explain the stronger association,” said Dr. Yang. “Stroke risk increases tremendously with age, so if you’re a younger age, your baseline stroke risk is lower.”
The association was also stronger among beneficiaries without a history of stroke. Again, this could be related to the stronger association among younger patients who are less likely to have suffered a stroke. The association was largely consistent across sex and race/ethnicities.
Dr. Yang stressed that the findings need to be confirmed with further studies.
The study was carried out before widespread use of vaccinations in the U.S. Once those data are available, Dr. Yang and his colleagues plan to determine if vaccinations modify the association between COVID-19 and stroke risk.
The new results contribute to the mounting evidence that a COVID-19 infection “can actually affect multiple human organs structurally or functionally in addition to the impact on [the] respiratory system,” said Dr. Yang.
Some dates of COVID-19 diagnoses may be incorrect due to limited test availability, particularly early in the pandemic. Another limitation of the study was possible misclassification from the use of Medicare real-time preliminary claims.
In a provided statement, Louise D. McCullough, MD, PhD, chair of the ISC 2022 and professor and chair of neurology, McGovern Medical School, University of Texas Health Science Center at Houston, noted that the study focused on older adults because it was examining Medicare beneficiaries.
“But everyone is likely at risk for stroke after COVID,” she said. “Any infection is linked to stroke risk, probably because any infection will cause inflammation, and inflammation can cause clots or thrombus, which is the cause of stroke.”
There was no outside funding for the study. No relevant conflicts of interest were disclosed.
A version of this article first appeared on Medscape.com.
, new research shows.
The study among Medicare beneficiaries with COVID-19 also showed that stroke risk is higher for relatively young older adults, those aged 65 to 74 years, and those without a history of stroke.
The study highlights the impact COVID-19 has on the cardiovascular system, said study author Quanhe Yang, PhD, senior scientist, Division for Heart Disease and Stroke Prevention, Centers for Disease Control and Prevention, Atlanta.
“Clinicians and patients should understand that stroke might be one of the very important clinical consequences of COVID-19.”
The study was presented during the hybrid International Stroke Conference held in New Orleans and online. The meeting was presented by the American Stroke Association, a division of the American Heart Association.
Stroke is the fifth leading cause of death in the U.S. As an increasing number of people become infected with COVID-19, “it’s important to determine if there’s a relationship between COVID and the risk of stroke,” said Dr. Yang.
Findings from prior research examining the link between stroke and COVID-19 have been inconsistent, he noted. Some studies found an association while others did not, and in still others, the association was not as strong as expected.
Many factors may contribute to these inconsistent findings, said Dr. Yang, including differences in study design, inclusion criteria, comparison groups, sample sizes, and countries where the research was carried out. Dr. Yang pointed out that many of these studies were done in the early stages of the pandemic or didn’t include older adults, the population most at risk for stroke.
The current study included 19,553 Medicare beneficiaries aged 65 years and older diagnosed with COVID-19 and hospitalized with acute ischemic stroke. The median age at diagnosis of COVID-19 was 80.5 years, 57.5% were women, and more than 75% were non-Hispanic Whites.
To ensure the stroke occurred after a COVID infection, researchers used a self-controlled case series study design, a “within person” comparison between the risk period and the control period.
They divided the study period (Jan. 1, 2019 to Feb. 28, 2021) into the exposure or stroke risk periods after the COVID diagnosis (0-3 days; 4-7 days; 8-15 days; and 15-28 days) and control periods.
Strokes that occurred 7 days before or 28 days after a COVID diagnosis served as a control period. “Any stroke that occurred outside the risk window is in the control period,” explained Dr. Yang.
He added that the control period provides a baseline. “Without COVID-19, this is what I would expect” in terms of the number of strokes.
To estimate the incidence rate ratio (IRR), investigators compared the incidence of acute ischemic stroke in the various risk periods with control periods.
The IRR was 10.97 (95% confidence interval, 10.30-11.68) at 0-3 days. The risk then quickly declined but stayed higher than the control period. The IRRs were: 1.59 (95% CI, 1.35-1.87) at 4-7 days; 1.23 (95% CI, 1.07-1.41) at 8-14 days; and 1.06 (95% CI, 0.95-1.18) at 15-28 days.
The temporary increase in stroke risk early after an infection isn’t novel; the pattern has been observed with influenza, respiratory infections, and shingles, said Dr. Yang. “But COVID-19 appears to be particularly risky.”
Although the mechanism driving the early increased stroke risk isn’t fully understood, it’s likely tied to an “exaggerated inflammatory response,” said Dr. Yang. This can trigger the cascade of events setting the stage for a stroke – a hypercoagulation state leading to the formation of blood clots that then block arteries to the brain, he said.
It’s also possible the infection directly affects endothelial cells, leading to rupture of plaque, again blocking arteries and raising stroke risks, added Dr. Yang.
The association was stronger among younger beneficiaries, aged 65 to 74 years, compared with those 85 years and older, a finding Dr. Yang said was somewhat surprising. But he noted other studies have found stroke patients with COVID are younger than stroke patients without COVID – by some 5 to 6 years.
“If COVID-19 disproportionately affects younger patients, that may explain the stronger association,” said Dr. Yang. “Stroke risk increases tremendously with age, so if you’re a younger age, your baseline stroke risk is lower.”
The association was also stronger among beneficiaries without a history of stroke. Again, this could be related to the stronger association among younger patients who are less likely to have suffered a stroke. The association was largely consistent across sex and race/ethnicities.
Dr. Yang stressed that the findings need to be confirmed with further studies.
The study was carried out before widespread use of vaccinations in the U.S. Once those data are available, Dr. Yang and his colleagues plan to determine if vaccinations modify the association between COVID-19 and stroke risk.
The new results contribute to the mounting evidence that a COVID-19 infection “can actually affect multiple human organs structurally or functionally in addition to the impact on [the] respiratory system,” said Dr. Yang.
Some dates of COVID-19 diagnoses may be incorrect due to limited test availability, particularly early in the pandemic. Another limitation of the study was possible misclassification from the use of Medicare real-time preliminary claims.
In a provided statement, Louise D. McCullough, MD, PhD, chair of the ISC 2022 and professor and chair of neurology, McGovern Medical School, University of Texas Health Science Center at Houston, noted that the study focused on older adults because it was examining Medicare beneficiaries.
“But everyone is likely at risk for stroke after COVID,” she said. “Any infection is linked to stroke risk, probably because any infection will cause inflammation, and inflammation can cause clots or thrombus, which is the cause of stroke.”
There was no outside funding for the study. No relevant conflicts of interest were disclosed.
A version of this article first appeared on Medscape.com.
FROM ISC 2022
Virtual exams for routine surveillance after ovarian cancer
Among patients with ovarian cancer who have achieved remission, routine surveillance with virtual appointments, along with tumor marker monitoring and imaging, may offer an alternative to the currently mandated frequent in-person visits.
The suggestion comes from Jacqueline Feinberg, MD, gynecologic oncology fellow at Memorial Sloan Kettering Cancer Center, New York, and colleagues, who conducted a retrospective study of 147 patients who experienced ovarian cancer recurrence within 2 years of their first clinical remission, and found that none of these recurrences were detected by physical examination alone.
About one third of these patients had a recurrence that was first detected by tumor marker, over half by imaging, and the rest by the presentation of new symptoms and biopsies taken during nononcologic surgery.
the team concluded. The study was published in the International Journal of Gynecologic Cancer.
The COVID-19 pandemic has accelerated the use of telemedicine, with new international guidelines recommending minimizing in-person contact, noted the authors.
They wondered how this would work in patients who have achieved remission from ovarian cancer.
At MSKCC, the usual surveillance protocol for the first 2 years after ovarian cancer remission includes an in-person physical examination every 3 months, along with CA-125 testing and imaging of the chest, abdomen, and pelvis. For year 3, the time between surveillance testing is extended to every 3-6 months, for the fourth and fifth year, to every 6 months. Beyond 5 years, physical examination and testing for the protein CA-125 are performed annually, and imaging is optional.
However, there is no strong evidence to support this current surveillance regimen, the authors pointed out. They sought to determine if it was possible to do virtual visits instead, along with tumor marker monitoring and imaging.
Evidence for virtual exams
To answer that question, Dr. Feinberg and colleagues conducted a retrospective study that included patients who were initially seen from January 2015 to December 2017, and who had achieved clinical remission and then experienced ovarian cancer recurrence with 2 years of remission.
A total of 147 patients were included in the final analysis. None of these patients had their recurrence detected on routine physical exam, including pelvic exam, as the primary method of detection. More than half of patients (n = 81; 55%) had their recurrence detected on radiographic scan, whereas for 46 patients (31%), it was by tumor marker. Among the remaining patients, 17 (12%) experienced new symptoms and for 3 (2%), it was by biopsy during a nononcologic surgery.
By the time treatment was initiated for recurrence, 111 patients (75%) had multiple positive findings; 48 (33%) had symptoms, 21 (14%) had physical exam findings, 106 (72%) had increases in their tumor markers, and 141 (96%) had changes on their imaging.
In addition, 131 (89%) had baseline increases in CA-125, and of 16 remaining patients, 12 experienced a CA-125 increase during recurrence.
There were 21 patients who had positive physical exam findings following their recurrence, which had already been detected. Within this subset, 19 had concurrent symptoms, and for 6 of them, symptom onset had been the primary method of detection. For the 2 patients without symptoms, recurrence was initially detected by a rise in CA-125 on routine check in one patient, by surveillance imaging in the other.
The authors are now planning a pilot virtual intensive surveillance program, where they will evaluate patient-reported outcomes
The study was funded in part through the National Institutes of Health/National Cancer Institute Cancer Center Support Grant P30 CA008748. Study author Dennis Chi, MD, reports personal fees from Bovie Medical (now Apyx Medical), Verthermia, C Surgeries, and Biom’Up, and is also a former stockholder of Intuitive Surgical and TransEnterix. The other authors disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Among patients with ovarian cancer who have achieved remission, routine surveillance with virtual appointments, along with tumor marker monitoring and imaging, may offer an alternative to the currently mandated frequent in-person visits.
The suggestion comes from Jacqueline Feinberg, MD, gynecologic oncology fellow at Memorial Sloan Kettering Cancer Center, New York, and colleagues, who conducted a retrospective study of 147 patients who experienced ovarian cancer recurrence within 2 years of their first clinical remission, and found that none of these recurrences were detected by physical examination alone.
About one third of these patients had a recurrence that was first detected by tumor marker, over half by imaging, and the rest by the presentation of new symptoms and biopsies taken during nononcologic surgery.
the team concluded. The study was published in the International Journal of Gynecologic Cancer.
The COVID-19 pandemic has accelerated the use of telemedicine, with new international guidelines recommending minimizing in-person contact, noted the authors.
They wondered how this would work in patients who have achieved remission from ovarian cancer.
At MSKCC, the usual surveillance protocol for the first 2 years after ovarian cancer remission includes an in-person physical examination every 3 months, along with CA-125 testing and imaging of the chest, abdomen, and pelvis. For year 3, the time between surveillance testing is extended to every 3-6 months, for the fourth and fifth year, to every 6 months. Beyond 5 years, physical examination and testing for the protein CA-125 are performed annually, and imaging is optional.
However, there is no strong evidence to support this current surveillance regimen, the authors pointed out. They sought to determine if it was possible to do virtual visits instead, along with tumor marker monitoring and imaging.
Evidence for virtual exams
To answer that question, Dr. Feinberg and colleagues conducted a retrospective study that included patients who were initially seen from January 2015 to December 2017, and who had achieved clinical remission and then experienced ovarian cancer recurrence with 2 years of remission.
A total of 147 patients were included in the final analysis. None of these patients had their recurrence detected on routine physical exam, including pelvic exam, as the primary method of detection. More than half of patients (n = 81; 55%) had their recurrence detected on radiographic scan, whereas for 46 patients (31%), it was by tumor marker. Among the remaining patients, 17 (12%) experienced new symptoms and for 3 (2%), it was by biopsy during a nononcologic surgery.
By the time treatment was initiated for recurrence, 111 patients (75%) had multiple positive findings; 48 (33%) had symptoms, 21 (14%) had physical exam findings, 106 (72%) had increases in their tumor markers, and 141 (96%) had changes on their imaging.
In addition, 131 (89%) had baseline increases in CA-125, and of 16 remaining patients, 12 experienced a CA-125 increase during recurrence.
There were 21 patients who had positive physical exam findings following their recurrence, which had already been detected. Within this subset, 19 had concurrent symptoms, and for 6 of them, symptom onset had been the primary method of detection. For the 2 patients without symptoms, recurrence was initially detected by a rise in CA-125 on routine check in one patient, by surveillance imaging in the other.
The authors are now planning a pilot virtual intensive surveillance program, where they will evaluate patient-reported outcomes
The study was funded in part through the National Institutes of Health/National Cancer Institute Cancer Center Support Grant P30 CA008748. Study author Dennis Chi, MD, reports personal fees from Bovie Medical (now Apyx Medical), Verthermia, C Surgeries, and Biom’Up, and is also a former stockholder of Intuitive Surgical and TransEnterix. The other authors disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Among patients with ovarian cancer who have achieved remission, routine surveillance with virtual appointments, along with tumor marker monitoring and imaging, may offer an alternative to the currently mandated frequent in-person visits.
The suggestion comes from Jacqueline Feinberg, MD, gynecologic oncology fellow at Memorial Sloan Kettering Cancer Center, New York, and colleagues, who conducted a retrospective study of 147 patients who experienced ovarian cancer recurrence within 2 years of their first clinical remission, and found that none of these recurrences were detected by physical examination alone.
About one third of these patients had a recurrence that was first detected by tumor marker, over half by imaging, and the rest by the presentation of new symptoms and biopsies taken during nononcologic surgery.
the team concluded. The study was published in the International Journal of Gynecologic Cancer.
The COVID-19 pandemic has accelerated the use of telemedicine, with new international guidelines recommending minimizing in-person contact, noted the authors.
They wondered how this would work in patients who have achieved remission from ovarian cancer.
At MSKCC, the usual surveillance protocol for the first 2 years after ovarian cancer remission includes an in-person physical examination every 3 months, along with CA-125 testing and imaging of the chest, abdomen, and pelvis. For year 3, the time between surveillance testing is extended to every 3-6 months, for the fourth and fifth year, to every 6 months. Beyond 5 years, physical examination and testing for the protein CA-125 are performed annually, and imaging is optional.
However, there is no strong evidence to support this current surveillance regimen, the authors pointed out. They sought to determine if it was possible to do virtual visits instead, along with tumor marker monitoring and imaging.
Evidence for virtual exams
To answer that question, Dr. Feinberg and colleagues conducted a retrospective study that included patients who were initially seen from January 2015 to December 2017, and who had achieved clinical remission and then experienced ovarian cancer recurrence with 2 years of remission.
A total of 147 patients were included in the final analysis. None of these patients had their recurrence detected on routine physical exam, including pelvic exam, as the primary method of detection. More than half of patients (n = 81; 55%) had their recurrence detected on radiographic scan, whereas for 46 patients (31%), it was by tumor marker. Among the remaining patients, 17 (12%) experienced new symptoms and for 3 (2%), it was by biopsy during a nononcologic surgery.
By the time treatment was initiated for recurrence, 111 patients (75%) had multiple positive findings; 48 (33%) had symptoms, 21 (14%) had physical exam findings, 106 (72%) had increases in their tumor markers, and 141 (96%) had changes on their imaging.
In addition, 131 (89%) had baseline increases in CA-125, and of 16 remaining patients, 12 experienced a CA-125 increase during recurrence.
There were 21 patients who had positive physical exam findings following their recurrence, which had already been detected. Within this subset, 19 had concurrent symptoms, and for 6 of them, symptom onset had been the primary method of detection. For the 2 patients without symptoms, recurrence was initially detected by a rise in CA-125 on routine check in one patient, by surveillance imaging in the other.
The authors are now planning a pilot virtual intensive surveillance program, where they will evaluate patient-reported outcomes
The study was funded in part through the National Institutes of Health/National Cancer Institute Cancer Center Support Grant P30 CA008748. Study author Dennis Chi, MD, reports personal fees from Bovie Medical (now Apyx Medical), Verthermia, C Surgeries, and Biom’Up, and is also a former stockholder of Intuitive Surgical and TransEnterix. The other authors disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM THE INTERNATIONAL JOURNAL OF GYNECOLOGIC CANCER
Innovative ‘chatbot’ reduces eating disorder risk
Results of a randomized trial show that at-risk women who interacted with the chatbot showed lower concern about their weight and body shape compared to a wait-list control group.
“Chatbots are widely used in industry and have begun to be used in medical settings, although few studies have examined their effectiveness for mental health issues and none address EDs or ED prevention,” senior investigator C. Barr Taylor, MD, a research faculty member at Palo Alto (Calif.) University, said in a press release.
“We found that the group with access to the chatbot had a greater reduction in weight and shape concerns, both right after using it at 3 months and at the 6-month follow-up. The effects had sustainability over time, and we also found indication that the chatbot may reduce ED onset more so than the control group, where there was a greater incidence of EDs,” Dr. Taylor told this news organization.
The study was published online Dec. 28, 2021, in the International Journal of Eating Disorders.
Deadly disorders
“EDs are a common problem with huge risk factors; and, given how widespread they are, we need scalable tools that can reach a lot of people at low cost, reduce risk factors for developing an ED – which is the second most deadly of all psychiatric illnesses – so prevention is of the utmost importance,” Dr. Taylor said.
The investigators developed a targeted Internet-based preventive program called StudentBodies that utilizes cognitive-behavioral therapy approaches. The program was successful in reducing weight/shape concerns in women at high risk for the onset of an ED, and it reduced ED onset in the highest-risk women.
However, it required trained moderators who spent over 45 minutes with participants. Given the large number of people at risk for an ED who might benefit, the researchers noted that it is unlikely that a human-moderated version would be widely disseminated.
A chatbot may represent a “possible solution to reducing delivery costs” because it mimics aspects of human moderation in simulating conversations, the investigators noted.
“We wanted to take the earlier program we developed into this century and program it for delivery in this new format that would allow for bite-size pieces of information for the chatbot to communicate to the user,” lead author Ellen Fitzsimmons-Craft, PhD, assistant professor of psychiatry, Washington University, St. Louis, told this news organization.
“Our ED prevention online version was more effective when there was guidance from a human moderator who could provide feedback on progress, encourage you to go on, and apply the skills in daily life. But that’s not the most scalable. So we thought that a chatbot, in addition to providing content in this perhaps more engaging format, could also provide some aspect of human moderation, although the person is chatting with a robot,” added Dr. Fitzsimmons-Craft, associate director of the Center for Healthy Weight and Wellness.
Tessa will speak to you now
Participants (n = 700 women; mean [SD] age, 21.08 [3.09] years; 84.6% White; 53.8% heterosexual; 31.08% bisexual), were randomized to an intervention group or a wait-list control group (n = 352 and 348, respectively). There were no significant differences between groups in age, race, ethnicity, education, or sexual orientation.
The StudentBodies program was adapted for delivery via a chatbot named Tessa “while retaining the core intervention principles” and referred to as “Body Positive.”
It consisted of several components programmed into the chatbot, which initiated each conversation in a predetermined order. Participants were encouraged to engage in two conversations weekly. The program included an introduction and eight sessions as well as a crisis module that provided users with a referral to a crisis hotline in case of emergency. Referral was triggered on the basis of “recognized keywords,” such as “hurting myself.”
The researchers used the Weight Concerns Scale questionnaire to assess weight and shape concerns and the Internalization: Thin/Low Body Fat subscale of the Sociocultural Attitudes Toward Appearance Questionnaire–4 to “assess the cognitive aspect of thin-ideal internalization.”
Secondary outcomes tested the hypothesis that the chatbot would be more likely to reduce clinical outcomes (ED psychopathology, depression, and anxiety) and prevent ED onset, compared to the control condition.
Ready for prime time
At 3- and 6-month follow-up, there was significantly greater reduction in the intervention group compared with the control group in weight/shape concerns (d = -.20, P = .03 and d = -.19, P = .04, respectively), although there were no differences in thin-ideal internalization change.
The chatbot intervention was associated with significantly greater reductions in overall ED psychopathology at 3 months (d = -.29, P = .003) compared to the control condition, but not at 6 months.
Notably, the intervention group had significantly higher odds than the control group of remaining nonclinical for EDs at 3- and 6-month follow-up (OR, 2.37 [95% confidence interval, 1.37-4.11] and OR, 2.13 [95% CI,1.26-3.59], respectively).
“We were very excited about the study, and frankly, I was surprised by the effectiveness [of the chatbot intervention] because I didn’t think it would have as much of an impact as it did,” said Dr. Taylor. “Prevention gets short shrift everywhere, and I think we succeeded very well.”
Dr. Fitzsimmons-Craft added that the National Eating Disorders Association (NEDA) has agreed to make the chatbot available on its website for people who screen positive for having an ED or for being at high risk, and so their group is working with their industry partner, a company called X2AI, which developed the chatbot, to make this happen.
“This is definitely the fastest research-to-practice translation I’ve ever seen, where we can so quickly show that it works and make it available to tens of thousands almost immediately.”
Dr. Fitzsimmons-Craft is optimistic that it will be available to launch the week of Feb. 21, which is National Eating Disorders Week.
Innovative, creative research
Commenting on the research, Evelyn Attia, MD, professor of psychiatry, Columbia University Medical Center, and director of the Columbia Center for Eating Disorders New York–Presbyterian Hospital, New York, described the study as “innovative and creative.”
Dr. Attia, a member of the Research Advisory Council of the NEDA, noted that the structure of the study is “very preliminary” and that the comparison to a wait-list control makes it hard to know whether this is an effective intervention compared with other types of interventions, rather than compared with no intervention.
“But I’m sure that when the researchers are set up and primed to study this more robustly, they will consider a more active control intervention to see whether this preliminary finding holds up,” she said.
Also commenting on the study, Deborah R. Glasofer, PhD, associate professor of clinical medical psychology (in psychiatry), Columbia Center for Eating Disorders, said, “Higher-than-average concern about appearance – body shape, size, or weight – and a tightly held belief that it is ideal to be thin are known risk factors for the development of an eating disorder.
“This study offers an indication that technology can be leveraged to fill a gap and help folks before unhelpful and sometimes misguided thoughts about food, eating, and appearance evolve into a full-blown eating disorder,” said Dr. Glasofer, who was not involved with the study.
The study was supported by the NEDA Feeding Hope Fund, the National Institute of Mental Health, the National Heart, Lung, and Blood Institute, and the Swedish Research Council. The authors and Dr. Glasofer have disclosed no relevant financial relationships. Dr. Attia is on the board and the Research Advisory Council of NEDA.
A version of this article first appeared on Medscape.com.
Results of a randomized trial show that at-risk women who interacted with the chatbot showed lower concern about their weight and body shape compared to a wait-list control group.
“Chatbots are widely used in industry and have begun to be used in medical settings, although few studies have examined their effectiveness for mental health issues and none address EDs or ED prevention,” senior investigator C. Barr Taylor, MD, a research faculty member at Palo Alto (Calif.) University, said in a press release.
“We found that the group with access to the chatbot had a greater reduction in weight and shape concerns, both right after using it at 3 months and at the 6-month follow-up. The effects had sustainability over time, and we also found indication that the chatbot may reduce ED onset more so than the control group, where there was a greater incidence of EDs,” Dr. Taylor told this news organization.
The study was published online Dec. 28, 2021, in the International Journal of Eating Disorders.
Deadly disorders
“EDs are a common problem with huge risk factors; and, given how widespread they are, we need scalable tools that can reach a lot of people at low cost, reduce risk factors for developing an ED – which is the second most deadly of all psychiatric illnesses – so prevention is of the utmost importance,” Dr. Taylor said.
The investigators developed a targeted Internet-based preventive program called StudentBodies that utilizes cognitive-behavioral therapy approaches. The program was successful in reducing weight/shape concerns in women at high risk for the onset of an ED, and it reduced ED onset in the highest-risk women.
However, it required trained moderators who spent over 45 minutes with participants. Given the large number of people at risk for an ED who might benefit, the researchers noted that it is unlikely that a human-moderated version would be widely disseminated.
A chatbot may represent a “possible solution to reducing delivery costs” because it mimics aspects of human moderation in simulating conversations, the investigators noted.
“We wanted to take the earlier program we developed into this century and program it for delivery in this new format that would allow for bite-size pieces of information for the chatbot to communicate to the user,” lead author Ellen Fitzsimmons-Craft, PhD, assistant professor of psychiatry, Washington University, St. Louis, told this news organization.
“Our ED prevention online version was more effective when there was guidance from a human moderator who could provide feedback on progress, encourage you to go on, and apply the skills in daily life. But that’s not the most scalable. So we thought that a chatbot, in addition to providing content in this perhaps more engaging format, could also provide some aspect of human moderation, although the person is chatting with a robot,” added Dr. Fitzsimmons-Craft, associate director of the Center for Healthy Weight and Wellness.
Tessa will speak to you now
Participants (n = 700 women; mean [SD] age, 21.08 [3.09] years; 84.6% White; 53.8% heterosexual; 31.08% bisexual), were randomized to an intervention group or a wait-list control group (n = 352 and 348, respectively). There were no significant differences between groups in age, race, ethnicity, education, or sexual orientation.
The StudentBodies program was adapted for delivery via a chatbot named Tessa “while retaining the core intervention principles” and referred to as “Body Positive.”
It consisted of several components programmed into the chatbot, which initiated each conversation in a predetermined order. Participants were encouraged to engage in two conversations weekly. The program included an introduction and eight sessions as well as a crisis module that provided users with a referral to a crisis hotline in case of emergency. Referral was triggered on the basis of “recognized keywords,” such as “hurting myself.”
The researchers used the Weight Concerns Scale questionnaire to assess weight and shape concerns and the Internalization: Thin/Low Body Fat subscale of the Sociocultural Attitudes Toward Appearance Questionnaire–4 to “assess the cognitive aspect of thin-ideal internalization.”
Secondary outcomes tested the hypothesis that the chatbot would be more likely to reduce clinical outcomes (ED psychopathology, depression, and anxiety) and prevent ED onset, compared to the control condition.
Ready for prime time
At 3- and 6-month follow-up, there was significantly greater reduction in the intervention group compared with the control group in weight/shape concerns (d = -.20, P = .03 and d = -.19, P = .04, respectively), although there were no differences in thin-ideal internalization change.
The chatbot intervention was associated with significantly greater reductions in overall ED psychopathology at 3 months (d = -.29, P = .003) compared to the control condition, but not at 6 months.
Notably, the intervention group had significantly higher odds than the control group of remaining nonclinical for EDs at 3- and 6-month follow-up (OR, 2.37 [95% confidence interval, 1.37-4.11] and OR, 2.13 [95% CI,1.26-3.59], respectively).
“We were very excited about the study, and frankly, I was surprised by the effectiveness [of the chatbot intervention] because I didn’t think it would have as much of an impact as it did,” said Dr. Taylor. “Prevention gets short shrift everywhere, and I think we succeeded very well.”
Dr. Fitzsimmons-Craft added that the National Eating Disorders Association (NEDA) has agreed to make the chatbot available on its website for people who screen positive for having an ED or for being at high risk, and so their group is working with their industry partner, a company called X2AI, which developed the chatbot, to make this happen.
“This is definitely the fastest research-to-practice translation I’ve ever seen, where we can so quickly show that it works and make it available to tens of thousands almost immediately.”
Dr. Fitzsimmons-Craft is optimistic that it will be available to launch the week of Feb. 21, which is National Eating Disorders Week.
Innovative, creative research
Commenting on the research, Evelyn Attia, MD, professor of psychiatry, Columbia University Medical Center, and director of the Columbia Center for Eating Disorders New York–Presbyterian Hospital, New York, described the study as “innovative and creative.”
Dr. Attia, a member of the Research Advisory Council of the NEDA, noted that the structure of the study is “very preliminary” and that the comparison to a wait-list control makes it hard to know whether this is an effective intervention compared with other types of interventions, rather than compared with no intervention.
“But I’m sure that when the researchers are set up and primed to study this more robustly, they will consider a more active control intervention to see whether this preliminary finding holds up,” she said.
Also commenting on the study, Deborah R. Glasofer, PhD, associate professor of clinical medical psychology (in psychiatry), Columbia Center for Eating Disorders, said, “Higher-than-average concern about appearance – body shape, size, or weight – and a tightly held belief that it is ideal to be thin are known risk factors for the development of an eating disorder.
“This study offers an indication that technology can be leveraged to fill a gap and help folks before unhelpful and sometimes misguided thoughts about food, eating, and appearance evolve into a full-blown eating disorder,” said Dr. Glasofer, who was not involved with the study.
The study was supported by the NEDA Feeding Hope Fund, the National Institute of Mental Health, the National Heart, Lung, and Blood Institute, and the Swedish Research Council. The authors and Dr. Glasofer have disclosed no relevant financial relationships. Dr. Attia is on the board and the Research Advisory Council of NEDA.
A version of this article first appeared on Medscape.com.
Results of a randomized trial show that at-risk women who interacted with the chatbot showed lower concern about their weight and body shape compared to a wait-list control group.
“Chatbots are widely used in industry and have begun to be used in medical settings, although few studies have examined their effectiveness for mental health issues and none address EDs or ED prevention,” senior investigator C. Barr Taylor, MD, a research faculty member at Palo Alto (Calif.) University, said in a press release.
“We found that the group with access to the chatbot had a greater reduction in weight and shape concerns, both right after using it at 3 months and at the 6-month follow-up. The effects had sustainability over time, and we also found indication that the chatbot may reduce ED onset more so than the control group, where there was a greater incidence of EDs,” Dr. Taylor told this news organization.
The study was published online Dec. 28, 2021, in the International Journal of Eating Disorders.
Deadly disorders
“EDs are a common problem with huge risk factors; and, given how widespread they are, we need scalable tools that can reach a lot of people at low cost, reduce risk factors for developing an ED – which is the second most deadly of all psychiatric illnesses – so prevention is of the utmost importance,” Dr. Taylor said.
The investigators developed a targeted Internet-based preventive program called StudentBodies that utilizes cognitive-behavioral therapy approaches. The program was successful in reducing weight/shape concerns in women at high risk for the onset of an ED, and it reduced ED onset in the highest-risk women.
However, it required trained moderators who spent over 45 minutes with participants. Given the large number of people at risk for an ED who might benefit, the researchers noted that it is unlikely that a human-moderated version would be widely disseminated.
A chatbot may represent a “possible solution to reducing delivery costs” because it mimics aspects of human moderation in simulating conversations, the investigators noted.
“We wanted to take the earlier program we developed into this century and program it for delivery in this new format that would allow for bite-size pieces of information for the chatbot to communicate to the user,” lead author Ellen Fitzsimmons-Craft, PhD, assistant professor of psychiatry, Washington University, St. Louis, told this news organization.
“Our ED prevention online version was more effective when there was guidance from a human moderator who could provide feedback on progress, encourage you to go on, and apply the skills in daily life. But that’s not the most scalable. So we thought that a chatbot, in addition to providing content in this perhaps more engaging format, could also provide some aspect of human moderation, although the person is chatting with a robot,” added Dr. Fitzsimmons-Craft, associate director of the Center for Healthy Weight and Wellness.
Tessa will speak to you now
Participants (n = 700 women; mean [SD] age, 21.08 [3.09] years; 84.6% White; 53.8% heterosexual; 31.08% bisexual), were randomized to an intervention group or a wait-list control group (n = 352 and 348, respectively). There were no significant differences between groups in age, race, ethnicity, education, or sexual orientation.
The StudentBodies program was adapted for delivery via a chatbot named Tessa “while retaining the core intervention principles” and referred to as “Body Positive.”
It consisted of several components programmed into the chatbot, which initiated each conversation in a predetermined order. Participants were encouraged to engage in two conversations weekly. The program included an introduction and eight sessions as well as a crisis module that provided users with a referral to a crisis hotline in case of emergency. Referral was triggered on the basis of “recognized keywords,” such as “hurting myself.”
The researchers used the Weight Concerns Scale questionnaire to assess weight and shape concerns and the Internalization: Thin/Low Body Fat subscale of the Sociocultural Attitudes Toward Appearance Questionnaire–4 to “assess the cognitive aspect of thin-ideal internalization.”
Secondary outcomes tested the hypothesis that the chatbot would be more likely to reduce clinical outcomes (ED psychopathology, depression, and anxiety) and prevent ED onset, compared to the control condition.
Ready for prime time
At 3- and 6-month follow-up, there was significantly greater reduction in the intervention group compared with the control group in weight/shape concerns (d = -.20, P = .03 and d = -.19, P = .04, respectively), although there were no differences in thin-ideal internalization change.
The chatbot intervention was associated with significantly greater reductions in overall ED psychopathology at 3 months (d = -.29, P = .003) compared to the control condition, but not at 6 months.
Notably, the intervention group had significantly higher odds than the control group of remaining nonclinical for EDs at 3- and 6-month follow-up (OR, 2.37 [95% confidence interval, 1.37-4.11] and OR, 2.13 [95% CI,1.26-3.59], respectively).
“We were very excited about the study, and frankly, I was surprised by the effectiveness [of the chatbot intervention] because I didn’t think it would have as much of an impact as it did,” said Dr. Taylor. “Prevention gets short shrift everywhere, and I think we succeeded very well.”
Dr. Fitzsimmons-Craft added that the National Eating Disorders Association (NEDA) has agreed to make the chatbot available on its website for people who screen positive for having an ED or for being at high risk, and so their group is working with their industry partner, a company called X2AI, which developed the chatbot, to make this happen.
“This is definitely the fastest research-to-practice translation I’ve ever seen, where we can so quickly show that it works and make it available to tens of thousands almost immediately.”
Dr. Fitzsimmons-Craft is optimistic that it will be available to launch the week of Feb. 21, which is National Eating Disorders Week.
Innovative, creative research
Commenting on the research, Evelyn Attia, MD, professor of psychiatry, Columbia University Medical Center, and director of the Columbia Center for Eating Disorders New York–Presbyterian Hospital, New York, described the study as “innovative and creative.”
Dr. Attia, a member of the Research Advisory Council of the NEDA, noted that the structure of the study is “very preliminary” and that the comparison to a wait-list control makes it hard to know whether this is an effective intervention compared with other types of interventions, rather than compared with no intervention.
“But I’m sure that when the researchers are set up and primed to study this more robustly, they will consider a more active control intervention to see whether this preliminary finding holds up,” she said.
Also commenting on the study, Deborah R. Glasofer, PhD, associate professor of clinical medical psychology (in psychiatry), Columbia Center for Eating Disorders, said, “Higher-than-average concern about appearance – body shape, size, or weight – and a tightly held belief that it is ideal to be thin are known risk factors for the development of an eating disorder.
“This study offers an indication that technology can be leveraged to fill a gap and help folks before unhelpful and sometimes misguided thoughts about food, eating, and appearance evolve into a full-blown eating disorder,” said Dr. Glasofer, who was not involved with the study.
The study was supported by the NEDA Feeding Hope Fund, the National Institute of Mental Health, the National Heart, Lung, and Blood Institute, and the Swedish Research Council. The authors and Dr. Glasofer have disclosed no relevant financial relationships. Dr. Attia is on the board and the Research Advisory Council of NEDA.
A version of this article first appeared on Medscape.com.
Recent onset of polyuria and polydipsia
The patient's clinical presentation and laboratory findings are consistent with a diagnosis of T2D.
The prevalence of T2D is increasing dramatically in children and adolescents. Like adult-onset T2D, obesity, family history, and sedentary lifestyle are major predisposing risk factors for T2D in children and adolescents. Significantly, the onset of diabetes at a younger age is associated with longer disease exposure and increased risk for chronic complications. Moreover, T2D in adolescents manifests as a severe progressive phenotype that often presents with complications, poor treatment response, and rapid progression of microvascular and macrovascular complications. Studies have shown that the risk for complications is greater in youth-onset T2D than it is in type 1 diabetes (T1D) and adult-onset T2D.
T2D has a variable presentation in children and adolescents. Approximately one third of patients are diagnosed without having typical diabetes signs or symptoms. In most cases, these patients are in their mid-adolescence are obese and were screened because of one or more positive risk factors or because glycosuria was detected on a random urine test. These patients typically have one or more of the typical characteristics of metabolic syndrome, such as hypertension and dyslipidemia.
Polyuria and polydipsia are seen in approximately 67% of youth with T2D at presentation. Recent weight loss may be present, but it is usually less severe in patients with T2D compared with T1D. Additionally, frequent fungal skin infections or severe vulvovaginitis because of Candida in adolescent girls can be the presenting complaint.
Diabetic ketoacidosis is present in less than 1 in 10 adolescents diagnosed with T2D. Most of these patients belong to ethnic minority groups, report polyuria, polydipsia, fatigue, and lethargy, and require hospital admission, rehydration, and insulin replacement therapy. Patients with symptoms such as vomiting can decline rapidly and need urgent evaluation and management.
Certain adolescent patients with obesity who present with diabetic ketoacidosis and are diagnosed with T2D at presentation can also have T1D and will require lifelong insulin treatment. Therefore, following a diagnosis of diabetes in an adolescent, it is critical to differentiate T2D from type 1 diabetes, as well as from other more rare diabetes types, to ensure proper long-term management. Given the substantial overlap between T2D and T1D symptoms, a combination of history clues, clinical characteristics, and laboratory studies must be used to reliably make the distinction. Important clues in the patient's history include:
• Age. Patients with T2D typically present after the onset of puberty, at a mean age of 13.5 years. Conversely, nearly one half of patients with T1D present before 10 years of age, regardless of race or ethnicity.
• Family history. Up to 90% of patients with T2D have an affected first- or second-degree relative; the corresponding percentage for patients with T1D is less than 10%.
• Ethnicity. T2D disproportionately affects youth of ethnic and racial minorities. Compared with White individuals, youth belonging to minority groups such as Native American, African American, Hispanic, and Pacific Islander have a much higher risk of developing T2D.
• Body weight. Most adolescents with T2D have obesity (BMI ≥ 95 percentile for age and sex), whereas those with T1D are usually of normal weight and may report a recent history of weight loss.
• Clinical findings. Adolescents with T2D usually present with features of insulin resistance and metabolic syndrome, such as acanthosis nigricans, hypertension, dyslipidemia, and polycystic ovary syndrome, whereas these findings are rare in youth with T1D. One study showed that up to 90% of youth diagnosed with T2D had acanthosis nigricans, in contrast to only 12% of those diagnosed with T1D.
Additionally, when the diagnosis of T2D is being considered in children and adolescents, a panel of pancreatic autoantibodies should be tested to exclude the possibility of autoimmune T1D. Because T2D is not immunologically mediated, the identification of one or more pancreatic (islet) cell antibodies in a diabetic adolescent with obesity supports the diagnosis of autoimmune diabetes. Antibodies that are usually measured include islet cell antibodies (against cytoplasmic proteins in the beta cell), anti-glutamic acid decarboxylase, and tyrosine phosphatase insulinoma-associated antigen 2, as well as anti-insulin antibodies if insulin replacement therapy has not been used for more than 2 weeks. In addition, a beta cell–specific autoantibody to zinc transporter 8 is frequently detected in children with T1D and can aid in the differential diagnosis. However, up to one third of children with T2D can have at least one detectable beta-cell autoantibody; therefore, total absence of diabetes autoimmune markers is not required for the diagnosis of T2D in children and adolescents.
When a diagnosis of T2D has been established, treatment should consist of lifestyle management, diabetes self-management education, and pharmacologic therapy. According to the 2022 American Diabetes Association Standards of Medical Care, the management of diabetes in children and adolescents cannot simply be drawn from the typical care provided to adults with diabetes. The epidemiology, pathophysiology, developmental considerations, and response to therapy in pediatric populations often vary from adult diabetes, and differences exist in recommended care for children and adolescents with T1D, T2D, and other forms of pediatric diabetes.
Because the diabetes type is often uncertain in the first few weeks of treatment, initial therapy should address the hyperglycemia and associated metabolic derangements regardless of the ultimate diabetes type; therapy should then be adjusted once metabolic compensation has been established and subsequent information, such as islet autoantibody results, becomes available.
Romesh K. Khardori, MD, PhD, Professor, Department of Internal Medicine, Division of Diabetes, Endocrine, and Metabolic Disorders, Eastern Virginia Medical School; EVMS Medical Group, Norfolk, Virginia
Romesh K. Khardori, MD, PhD, has disclosed no relevant financial relationships
The patient's clinical presentation and laboratory findings are consistent with a diagnosis of T2D.
The prevalence of T2D is increasing dramatically in children and adolescents. Like adult-onset T2D, obesity, family history, and sedentary lifestyle are major predisposing risk factors for T2D in children and adolescents. Significantly, the onset of diabetes at a younger age is associated with longer disease exposure and increased risk for chronic complications. Moreover, T2D in adolescents manifests as a severe progressive phenotype that often presents with complications, poor treatment response, and rapid progression of microvascular and macrovascular complications. Studies have shown that the risk for complications is greater in youth-onset T2D than it is in type 1 diabetes (T1D) and adult-onset T2D.
T2D has a variable presentation in children and adolescents. Approximately one third of patients are diagnosed without having typical diabetes signs or symptoms. In most cases, these patients are in their mid-adolescence are obese and were screened because of one or more positive risk factors or because glycosuria was detected on a random urine test. These patients typically have one or more of the typical characteristics of metabolic syndrome, such as hypertension and dyslipidemia.
Polyuria and polydipsia are seen in approximately 67% of youth with T2D at presentation. Recent weight loss may be present, but it is usually less severe in patients with T2D compared with T1D. Additionally, frequent fungal skin infections or severe vulvovaginitis because of Candida in adolescent girls can be the presenting complaint.
Diabetic ketoacidosis is present in less than 1 in 10 adolescents diagnosed with T2D. Most of these patients belong to ethnic minority groups, report polyuria, polydipsia, fatigue, and lethargy, and require hospital admission, rehydration, and insulin replacement therapy. Patients with symptoms such as vomiting can decline rapidly and need urgent evaluation and management.
Certain adolescent patients with obesity who present with diabetic ketoacidosis and are diagnosed with T2D at presentation can also have T1D and will require lifelong insulin treatment. Therefore, following a diagnosis of diabetes in an adolescent, it is critical to differentiate T2D from type 1 diabetes, as well as from other more rare diabetes types, to ensure proper long-term management. Given the substantial overlap between T2D and T1D symptoms, a combination of history clues, clinical characteristics, and laboratory studies must be used to reliably make the distinction. Important clues in the patient's history include:
• Age. Patients with T2D typically present after the onset of puberty, at a mean age of 13.5 years. Conversely, nearly one half of patients with T1D present before 10 years of age, regardless of race or ethnicity.
• Family history. Up to 90% of patients with T2D have an affected first- or second-degree relative; the corresponding percentage for patients with T1D is less than 10%.
• Ethnicity. T2D disproportionately affects youth of ethnic and racial minorities. Compared with White individuals, youth belonging to minority groups such as Native American, African American, Hispanic, and Pacific Islander have a much higher risk of developing T2D.
• Body weight. Most adolescents with T2D have obesity (BMI ≥ 95 percentile for age and sex), whereas those with T1D are usually of normal weight and may report a recent history of weight loss.
• Clinical findings. Adolescents with T2D usually present with features of insulin resistance and metabolic syndrome, such as acanthosis nigricans, hypertension, dyslipidemia, and polycystic ovary syndrome, whereas these findings are rare in youth with T1D. One study showed that up to 90% of youth diagnosed with T2D had acanthosis nigricans, in contrast to only 12% of those diagnosed with T1D.
Additionally, when the diagnosis of T2D is being considered in children and adolescents, a panel of pancreatic autoantibodies should be tested to exclude the possibility of autoimmune T1D. Because T2D is not immunologically mediated, the identification of one or more pancreatic (islet) cell antibodies in a diabetic adolescent with obesity supports the diagnosis of autoimmune diabetes. Antibodies that are usually measured include islet cell antibodies (against cytoplasmic proteins in the beta cell), anti-glutamic acid decarboxylase, and tyrosine phosphatase insulinoma-associated antigen 2, as well as anti-insulin antibodies if insulin replacement therapy has not been used for more than 2 weeks. In addition, a beta cell–specific autoantibody to zinc transporter 8 is frequently detected in children with T1D and can aid in the differential diagnosis. However, up to one third of children with T2D can have at least one detectable beta-cell autoantibody; therefore, total absence of diabetes autoimmune markers is not required for the diagnosis of T2D in children and adolescents.
When a diagnosis of T2D has been established, treatment should consist of lifestyle management, diabetes self-management education, and pharmacologic therapy. According to the 2022 American Diabetes Association Standards of Medical Care, the management of diabetes in children and adolescents cannot simply be drawn from the typical care provided to adults with diabetes. The epidemiology, pathophysiology, developmental considerations, and response to therapy in pediatric populations often vary from adult diabetes, and differences exist in recommended care for children and adolescents with T1D, T2D, and other forms of pediatric diabetes.
Because the diabetes type is often uncertain in the first few weeks of treatment, initial therapy should address the hyperglycemia and associated metabolic derangements regardless of the ultimate diabetes type; therapy should then be adjusted once metabolic compensation has been established and subsequent information, such as islet autoantibody results, becomes available.
Romesh K. Khardori, MD, PhD, Professor, Department of Internal Medicine, Division of Diabetes, Endocrine, and Metabolic Disorders, Eastern Virginia Medical School; EVMS Medical Group, Norfolk, Virginia
Romesh K. Khardori, MD, PhD, has disclosed no relevant financial relationships
The patient's clinical presentation and laboratory findings are consistent with a diagnosis of T2D.
The prevalence of T2D is increasing dramatically in children and adolescents. Like adult-onset T2D, obesity, family history, and sedentary lifestyle are major predisposing risk factors for T2D in children and adolescents. Significantly, the onset of diabetes at a younger age is associated with longer disease exposure and increased risk for chronic complications. Moreover, T2D in adolescents manifests as a severe progressive phenotype that often presents with complications, poor treatment response, and rapid progression of microvascular and macrovascular complications. Studies have shown that the risk for complications is greater in youth-onset T2D than it is in type 1 diabetes (T1D) and adult-onset T2D.
T2D has a variable presentation in children and adolescents. Approximately one third of patients are diagnosed without having typical diabetes signs or symptoms. In most cases, these patients are in their mid-adolescence are obese and were screened because of one or more positive risk factors or because glycosuria was detected on a random urine test. These patients typically have one or more of the typical characteristics of metabolic syndrome, such as hypertension and dyslipidemia.
Polyuria and polydipsia are seen in approximately 67% of youth with T2D at presentation. Recent weight loss may be present, but it is usually less severe in patients with T2D compared with T1D. Additionally, frequent fungal skin infections or severe vulvovaginitis because of Candida in adolescent girls can be the presenting complaint.
Diabetic ketoacidosis is present in less than 1 in 10 adolescents diagnosed with T2D. Most of these patients belong to ethnic minority groups, report polyuria, polydipsia, fatigue, and lethargy, and require hospital admission, rehydration, and insulin replacement therapy. Patients with symptoms such as vomiting can decline rapidly and need urgent evaluation and management.
Certain adolescent patients with obesity who present with diabetic ketoacidosis and are diagnosed with T2D at presentation can also have T1D and will require lifelong insulin treatment. Therefore, following a diagnosis of diabetes in an adolescent, it is critical to differentiate T2D from type 1 diabetes, as well as from other more rare diabetes types, to ensure proper long-term management. Given the substantial overlap between T2D and T1D symptoms, a combination of history clues, clinical characteristics, and laboratory studies must be used to reliably make the distinction. Important clues in the patient's history include:
• Age. Patients with T2D typically present after the onset of puberty, at a mean age of 13.5 years. Conversely, nearly one half of patients with T1D present before 10 years of age, regardless of race or ethnicity.
• Family history. Up to 90% of patients with T2D have an affected first- or second-degree relative; the corresponding percentage for patients with T1D is less than 10%.
• Ethnicity. T2D disproportionately affects youth of ethnic and racial minorities. Compared with White individuals, youth belonging to minority groups such as Native American, African American, Hispanic, and Pacific Islander have a much higher risk of developing T2D.
• Body weight. Most adolescents with T2D have obesity (BMI ≥ 95 percentile for age and sex), whereas those with T1D are usually of normal weight and may report a recent history of weight loss.
• Clinical findings. Adolescents with T2D usually present with features of insulin resistance and metabolic syndrome, such as acanthosis nigricans, hypertension, dyslipidemia, and polycystic ovary syndrome, whereas these findings are rare in youth with T1D. One study showed that up to 90% of youth diagnosed with T2D had acanthosis nigricans, in contrast to only 12% of those diagnosed with T1D.
Additionally, when the diagnosis of T2D is being considered in children and adolescents, a panel of pancreatic autoantibodies should be tested to exclude the possibility of autoimmune T1D. Because T2D is not immunologically mediated, the identification of one or more pancreatic (islet) cell antibodies in a diabetic adolescent with obesity supports the diagnosis of autoimmune diabetes. Antibodies that are usually measured include islet cell antibodies (against cytoplasmic proteins in the beta cell), anti-glutamic acid decarboxylase, and tyrosine phosphatase insulinoma-associated antigen 2, as well as anti-insulin antibodies if insulin replacement therapy has not been used for more than 2 weeks. In addition, a beta cell–specific autoantibody to zinc transporter 8 is frequently detected in children with T1D and can aid in the differential diagnosis. However, up to one third of children with T2D can have at least one detectable beta-cell autoantibody; therefore, total absence of diabetes autoimmune markers is not required for the diagnosis of T2D in children and adolescents.
When a diagnosis of T2D has been established, treatment should consist of lifestyle management, diabetes self-management education, and pharmacologic therapy. According to the 2022 American Diabetes Association Standards of Medical Care, the management of diabetes in children and adolescents cannot simply be drawn from the typical care provided to adults with diabetes. The epidemiology, pathophysiology, developmental considerations, and response to therapy in pediatric populations often vary from adult diabetes, and differences exist in recommended care for children and adolescents with T1D, T2D, and other forms of pediatric diabetes.
Because the diabetes type is often uncertain in the first few weeks of treatment, initial therapy should address the hyperglycemia and associated metabolic derangements regardless of the ultimate diabetes type; therapy should then be adjusted once metabolic compensation has been established and subsequent information, such as islet autoantibody results, becomes available.
Romesh K. Khardori, MD, PhD, Professor, Department of Internal Medicine, Division of Diabetes, Endocrine, and Metabolic Disorders, Eastern Virginia Medical School; EVMS Medical Group, Norfolk, Virginia
Romesh K. Khardori, MD, PhD, has disclosed no relevant financial relationships
A 14-year-old Black girl presents with complaints of increasing fatigue and recent onset of polyuria and polydipsia. According to the patient's chart, she has lost approximately 5 lb since her last examination 8 months ago. Physical examination revealed a blood pressure of 120/80 mm Hg, pulse of 79, and temperature of 100.4°F (38°C). Her weight is 165 lb (75 kg, 96th percentile), height is 62 in (157.5 cm, 32nd percentile), and BMI is 30.2 (97th percentile). Acanthosis nigricans is present. The patient is at Tanner stage 3 of sexual development. There is a positive first-degree family history of type 2 diabetes (T2D), hypertension, and obesity, as well as premature cardiac death in an uncle. Laboratory findings include an A1c value of 7.4%, HDL-C 220 mg/dL, LDL-C 144 mg/dL, and serum creatinine 1.1 mg/dL.
Increase in late-stage cancer diagnoses after pandemic
at Moores Cancer Center in La Jolla, Calif., according to a research letter in JAMA Network Open.
“The number of patients presenting at late, incurable stages is increasing,” say the authors, led by Jade Zifei Zhou, MD, PhD, a hematology/oncology fellow at the center, which is affiliated with the University of California, San Diego.
As the pandemic unfolded and much of routine medicine was put on hold, the postponement or delay in mammograms, colonoscopies, and other screenings led many cancer experts to warn of trouble ahead. In June 2020, for instance, the National Cancer Institute predicted tens of thousands of excess cancer deaths through 2030 because of missed screenings and delays in care.
The message now, Dr. Zhou and colleagues say, is that “patients who have delayed preventative care during the pandemic should be encouraged to resume treatment as soon as possible.”
The team compared the number of people presenting to their cancer center with stage I and IV disease, either for a new diagnosis or a second opinion, during 2019 and with the number during 2020, the first year of the pandemic. The review included over 500 patients, almost 90% of whom were women aged 58 years on average.
While 63.9% of patients with breast cancer presented with stage I disease in 2019, 51.3% did so in 2020. Conversely, while just 1.9% presented with stage IV breast cancer in 2019, the number went up to 6.2% in 2020.
The numbers were even worse from January through March 2021, with only 41.9% of women presenting with stage I and 8% presenting with stage IV breast cancer.
It was the same story for colon cancer, but because of smaller numbers, the findings were not statistically significant.
After the start of the pandemic, the number of patients presenting with stage I colon cancer fell from 17.8% (eight patients) to 14.6% (six patients), while stage IV presentations climbed from 6.7% (three) to 19.5% (eight).
Across all cancer types, stage I presentations fell from 31.9% in 2019 to 29% in 2020, while stage IV presentations rose from 26% to 26.4%.
One of the study limitations is that the patients who came in for a second opinion could have been newly diagnosed but might also have been referred for refractory disease, the authors comment.
No funding for this study was reported. Senior author Kathryn Ann Gold, MD, reported personal fees from AstraZeneca, Takeda, Rakuten, and Regeneron as well as grants from Pfizer and Pharmacyclics.
A version of this article first appeared on Medscape.com.
at Moores Cancer Center in La Jolla, Calif., according to a research letter in JAMA Network Open.
“The number of patients presenting at late, incurable stages is increasing,” say the authors, led by Jade Zifei Zhou, MD, PhD, a hematology/oncology fellow at the center, which is affiliated with the University of California, San Diego.
As the pandemic unfolded and much of routine medicine was put on hold, the postponement or delay in mammograms, colonoscopies, and other screenings led many cancer experts to warn of trouble ahead. In June 2020, for instance, the National Cancer Institute predicted tens of thousands of excess cancer deaths through 2030 because of missed screenings and delays in care.
The message now, Dr. Zhou and colleagues say, is that “patients who have delayed preventative care during the pandemic should be encouraged to resume treatment as soon as possible.”
The team compared the number of people presenting to their cancer center with stage I and IV disease, either for a new diagnosis or a second opinion, during 2019 and with the number during 2020, the first year of the pandemic. The review included over 500 patients, almost 90% of whom were women aged 58 years on average.
While 63.9% of patients with breast cancer presented with stage I disease in 2019, 51.3% did so in 2020. Conversely, while just 1.9% presented with stage IV breast cancer in 2019, the number went up to 6.2% in 2020.
The numbers were even worse from January through March 2021, with only 41.9% of women presenting with stage I and 8% presenting with stage IV breast cancer.
It was the same story for colon cancer, but because of smaller numbers, the findings were not statistically significant.
After the start of the pandemic, the number of patients presenting with stage I colon cancer fell from 17.8% (eight patients) to 14.6% (six patients), while stage IV presentations climbed from 6.7% (three) to 19.5% (eight).
Across all cancer types, stage I presentations fell from 31.9% in 2019 to 29% in 2020, while stage IV presentations rose from 26% to 26.4%.
One of the study limitations is that the patients who came in for a second opinion could have been newly diagnosed but might also have been referred for refractory disease, the authors comment.
No funding for this study was reported. Senior author Kathryn Ann Gold, MD, reported personal fees from AstraZeneca, Takeda, Rakuten, and Regeneron as well as grants from Pfizer and Pharmacyclics.
A version of this article first appeared on Medscape.com.
at Moores Cancer Center in La Jolla, Calif., according to a research letter in JAMA Network Open.
“The number of patients presenting at late, incurable stages is increasing,” say the authors, led by Jade Zifei Zhou, MD, PhD, a hematology/oncology fellow at the center, which is affiliated with the University of California, San Diego.
As the pandemic unfolded and much of routine medicine was put on hold, the postponement or delay in mammograms, colonoscopies, and other screenings led many cancer experts to warn of trouble ahead. In June 2020, for instance, the National Cancer Institute predicted tens of thousands of excess cancer deaths through 2030 because of missed screenings and delays in care.
The message now, Dr. Zhou and colleagues say, is that “patients who have delayed preventative care during the pandemic should be encouraged to resume treatment as soon as possible.”
The team compared the number of people presenting to their cancer center with stage I and IV disease, either for a new diagnosis or a second opinion, during 2019 and with the number during 2020, the first year of the pandemic. The review included over 500 patients, almost 90% of whom were women aged 58 years on average.
While 63.9% of patients with breast cancer presented with stage I disease in 2019, 51.3% did so in 2020. Conversely, while just 1.9% presented with stage IV breast cancer in 2019, the number went up to 6.2% in 2020.
The numbers were even worse from January through March 2021, with only 41.9% of women presenting with stage I and 8% presenting with stage IV breast cancer.
It was the same story for colon cancer, but because of smaller numbers, the findings were not statistically significant.
After the start of the pandemic, the number of patients presenting with stage I colon cancer fell from 17.8% (eight patients) to 14.6% (six patients), while stage IV presentations climbed from 6.7% (three) to 19.5% (eight).
Across all cancer types, stage I presentations fell from 31.9% in 2019 to 29% in 2020, while stage IV presentations rose from 26% to 26.4%.
One of the study limitations is that the patients who came in for a second opinion could have been newly diagnosed but might also have been referred for refractory disease, the authors comment.
No funding for this study was reported. Senior author Kathryn Ann Gold, MD, reported personal fees from AstraZeneca, Takeda, Rakuten, and Regeneron as well as grants from Pfizer and Pharmacyclics.
A version of this article first appeared on Medscape.com.
FROM JAMA NETWORK OPEN
Mild Grisel Syndrome: Expanding the Differential for Posttonsillectomy Adenoidectomy Symptoms
Tonsillectomy with or without adenoidectomy (T&A) is the second most common pediatric surgical procedure in the United States.1 It is most often performed during childhood between 5 and 8 years of age with a second peak observed between 17 and 21 years of age in the adolescent and young adult populations.2 While recurrent tonsillitis has been traditionally associated with tonsillectomy, sleep disordered breathing with obstructive sleep apnea is now the primary indication for the procedure.1
Up to 97% of T&As are performed as an outpatient same-day surgery not requiring inpatient admission.2 Although largely a safe and routinely performed surgery, several complications have been described. Due to the outpatient nature of the procedure, the complications are often encountered in the emergency department (ED) and sometimes in primary care settings. Common complications (outside of the perioperative time frame) include nausea, vomiting, otalgia, odynophagia, infection of the throat (broadly), and hemorrhage; uncommon complications include subcutaneous emphysema, taste disorders, and Eagle syndrome. Some complications are rarer still and carry significant morbidity and even mortality, including mediastinitis, cervical osteomyelitis, and Grisel syndrome.3 The following case encourages the clinician to expand the differential for a patient presenting after T&A.
Case Presentation
A child aged < 3 years was brought to the ED by their mother. She reported neck pain and stiffness 10 days after T&A with concurrent tympanostomy tube placement at an outside pediatric hospital. At triage, their heart rate was 94 bpm, temperature was 98.2 °F, respiratory rate, 22 breaths per minute, and oxygen saturation, 97% on room air. The mother of the patient (MOP) had been giving the prescribed oral liquid formulations of ibuprofen and acetaminophen with hydrocodone as directed. No drug allergies were reported, and immunizations were up to date for age. Other medical and surgical history included eczema and remote cutaneous hemangioma resection. The patient lived at home with 2 parents and was not exposed to smoke; their family history was noncontributory.
Since the surgery, the MOP had noticed constant and increasing neck stiffness, specifically with looking up and down but not side to side. She also had noticed swelling behind both ears. She reported no substantial decrease in intake by mouth or decrease in urine or bowel frequency. On review of systems, she reported no fever, vomiting, difficulty breathing, bleeding from the mouth or nose, eye or ear drainage, or rash.
On physical examination, the patient was alert and in no acute distress; active and playful on an electronic device but was notably not moving their head, which was held in a forward-looking position without any signs of trauma. When asked, the child would not flex or extend their neck but would rotate a few degrees from neutral to both sides. Even with moving the electronic device up and down in space, no active neck extension or flexion could be elicited. The examination of the head, eyes, ears, nose, and throat was otherwise only remarkable for palpable and mildly tender postauricular lymph nodes and diffuse erythema in the posterior pharynx. Cardiopulmonary, abdominal, skin, and extremity examinations were unremarkable.
With concern for an infectious process, the physician ordered blood chemistry and hematology tests along with neck radiography. While awaiting the results, the patient was given a weight-based bolus of normal saline, and the home pain regimen was administered. An attempt was made to passively flex and extend the neck as the child slept in their mother’s arms, but the patient immediately awoke and began to cry.
All values of the comprehensive metabolic panel were within normal limits except for a slight elevation in the blood urea nitrogen to 21 mg/dL and glucose to 159 mg/dL. The complete blood count was unrevealing. The computed tomography (CT) scan with contrast of the soft tissues of the neck was limited by motion artifact but showed a head held in axial rotation with soft tissue irregularity in the anterior aspect of the adenoids (Figure 1). There was what appeared to be normal lymphadenopathy in the hypopharynx, but the soft tissues were otherwise unremarkable.
The on-call pediatric otolaryngologist at the hospital where the procedure was performed was paged. On hearing the details of the case, the specialist was concerned for Grisel syndrome and requested to see the patient in their facility. No additional recommendations for care were provided; the mother was updated and agreed to transfer. The patient was comfortable and stable with repeat vitals as follows: heart rate, 86 beats per minute, blood pressure, 99/62, temperature, 98.3 °F, respiratory rate, 20 breaths per minute, and oxygen saturation, 99% on room air.
On arrival at the receiving facility, the emergency team performed a history and physical that revealed no significant changes from the initial evaluation. They then facilitated evaluation by the pediatric otolaryngologist who conducted a more directed physical examination. Decreased active and passive range of motion (ROM) of the neck without rotatory restriction was again noted. They also observed scant fibrinous exudate within the oropharynx and tonsillar fossa, which was normal in the setting of the recent surgery. They recommended additional analgesia with intramuscular ketorolac, weight-based dosing at 1 mg/kg.
With repeat examination after this additional analgesic, ROM of the neck first passive then active had improved. The patient was then discharged to follow up in the coming days with instructions to continue the pain and anti-inflammatory regimen. They were not started on an antibiotic at that time nor were they placed in a cervical collar. At the follow-up, the MOP reported persistence of neck stiffness for a few days initially but then observed slow improvement. By postoperative day 18, the stiffness had resolved. No other follow-up or referrals related to this issue were readily apparent in review of the patient’s health record.
Discussion
Grisel syndrome is the atraumatic rotary subluxation of the atlantoaxial joint, specifically, the atlas (C1 vertebra) rotates to a fixed, nonanatomic position while the axis (C2 vertebra) remains in normal alignment in relation to the remainder of the spinal column. The subluxation occurs in the absence of ligamentous injury but is associated with an increase in ligamentous laxity.4 The atlas is a ring-shaped vertebra with 2 lateral masses connected by anterior and posterior arches; it lacks a spinous process unlike other vertebrae. It articulates with the skull by means of the 2 articular facets on the superior aspect of the lateral masses. Articulation with the axis occurs at 3 sites: 2 articular facets on the inferior portion of the lateral masses of the atlas and a facet for the dens on the posterior portion of the anterior arch. The dens projects superiorly from the body of the axis and is bound posteriorly by the transverse ligament of the atlas.5
The degree of subluxation seen in Grisel syndrome correlates to the disease severity and is classified by the Fielding and Hawkins (FH) system (Table). This system accounts for the distance from the atlas to the dens (atlantodens interval) and the relative asymmetry of the atlantoaxial joint.6 In a normal adult, the upper limit of normal for the atlantodens interval is 3 mm, whereas this distance increases to 4.5 mm for the pediatric population.7 Type I (FH-I) involves rotary subluxation alone without any increase in the atlantodens interval; in FH-II, that interval has increased from normal but to no more than 5 mm. FH-I and FH-II are the most encountered and are not associated with neurologic impairment. In FH-III, neurologic deficits can be present, and the atlantodens interval is increased to > 5 mm. Different from FH-II and FH-III in which anterior dislocation of the atlas with reference to the dens is observed, FH-IV involves a rotary movement of the atlas with concurrent posterior displacement and often involves spinal cord compression.6
Subluxation and displacement without trauma are key components of Grisel syndrome. The 2-hit hypothesis is often used to explain how this can occur, ie, 2 anomalies must be present simultaneously for this condition to develop. First, the laxity of the transverse ligament, the posterior wall of the dens, and other atlantoaxial ligaments must be increased. Second, an asymmetric contraction of the deep erector muscles of the neck either abruptly or more insidiously rotate and dislocate the atlas.8 The pathophysiology is not exactly understood, but the most commonly held hypothesis describes contiguous spread of infection or inflammatory mediators from the pharynx to the ligaments and muscles described.6
Spread could occur via the venous system. The posterior superior pharyngeal region is drained by the periodontoidal venous plexus; the connections here with the pharyngovertebral veins allow for the embolization of infectious or other proinflammatory material to the prevertebral fascia. These emboli induce fasciitis and subsequent aberrant relaxation of the ligaments. In reaction to the inflammation or increased laxity, contiguous muscles of the deep neck contract and freeze the joint out of anatomic alignment.4
The abnormal alignment is apparent grossly as torticollis. Most broadly, torticollis describes an anomalous head posture due to involuntary muscle contractions of neck muscles and specifically describes chin deviation to the side. The antecollis and retrocollis subtypes of torticollis describe forward flexion and backward extension of the neck, respectively.7 Torticollis (broadly) is the most frequently reported condition of those found to have Grisel syndrome (90.7%); other common presenting conditions include neck pain (81.5%) and neck stiffness (31.5%). Fever is found in only 27.8% of cases. Pediatric patients (aged ≤ 12 years) are the most commonly affected, accounting for 87% of cases with an observed 4:1 male to female predominance.7,8 Symptoms begin most often within the first week from the inciting event in 85% of the cases.8 Head and neck surgery precedes up to 67% of cases, and infectious etiologies largely account for the remaining cases.7 Of the postsurgical cases, 55.6% had undergone T&A.8
Although anomalous head posture or neck stiffness following T&A would be of great clinic concern for Grisel syndrome, radiographic studies play a confirmatory role. CT scan is used to evaluate the bony structures, with 3D reconstruction of the cervical spine being most useful to determine the presence and degree of subluxation.8 Magnetic resonance imaging also aids in diagnosis to evaluate ligamentous structures in the area of concern as well as in the evaluation of spinal cord compression.6 Laboratory tests are largely unhelpful in making or excluding the diagnosis.8
If Grisel syndrome is suspected, both the original surgeon (if preceded by surgery) and the neurosurgical team should be consulted. Although no widely adopted guidelines exist for the management of this rare disease, general practice patterns have emerged with the degree of intervention predictably correlating to disease severity. FH-I is usually treated with nonsteroidal anti-inflammatory drugs and muscle relaxants with or without a soft cervical collar. For FH-II, closed reduction and immobilization in a stiff cervical collar is recommended. If no neurologic defect is present, FH-III is treated with bed rest, a period of inline cervical traction, and subsequent immobilization. FH-III with neurologic sequelae and all FH-IV necessitate emergent neurosurgical consultation.4 Surgical intervention is a last resort but is required in up to 24.1% of cases.8
Antibiotic therapy is not routinely given unless clear infectious etiology is identified. No standard antibiotic regimen exists, but coverage for typical upper respiratory pathogens likely suffices. Empiric antibiotic therapy is not recommended for all causes of Grisel syndrome, ie, when the underlying cause is not yet elucidated.6 One case of Grisel syndrome occurring in the setting of cervical osteomyelitis has been described, though, and required prolonged IV antibiotics.3 Physical therapy is recommended as adjunct with no limitations for range of motion save for that of the patient’s individual pain threshold.4
Possibly attributable to waxing and waning ligamentous laxity and strength of the neck muscle contraction, the atlantodens interval and the degree of subluxation can change, making Grisel syndrome dynamic. As such, the FH classification can change, necessitating more or less aggressive therapy. A neurologic evaluation is recommended at least every 2 weeks after the diagnosis is made. If initial identification or recognition of known disease progression is delayed, serious complications can develop. Acutely, spinal cord compression can lead to quadriplegia and death; more insidious complications include reduced neck mobility, dysphonia, and dysphagia.4 As serious, life-threatening complications can arise from Grisel syndrome while good functional outcomes can be achieved with timely and appropriate treatment, the clinician should be inspired to have a high clinical suspicion for this syndrome given the right context.
Conclusions
The patient experienced a desirable outcome with minimal, conservative treatment. As such, the pathology in this case was likely attributed to the mildest form of Grisel syndrome (FH-I). The follow-up was reassuring as well, revealing no worsening or progression of symptoms. The initial evaluation in this case was limited by the inadequacy of the CT scan. Motion artifact in the pharynx prevented the definite exclusion of deep space infection, while the rotation of the head in combination with motion artifact in the cranial-most portions of the vertebral column made determining alignment difficult. One clear axial image, though, does show rotation of the atlas (Figure 2). The uncertainty at the end of our workup prompted surgical consultation, not, admittedly, concern for Grisel syndrome. Awareness of this disease entity is nevertheless important and clinically relevant. Early identification and treatment is associated with decreased morbidity and improvement in long-term functional outcomes.6 Despite its rarity, the clinician should consider Grisel syndrome in any pediatric patient presenting with neck stiffness following the commonly performed T&A.
1. Ramos SD, Mukerji S, Pine HS. Tonsillectomy and adenoidectomy. Pediatr Clin North Am. 2013;60(4):793-807. doi:10.1016/j.pcl.2013.04.015
2. Stoner MJ, Dulaurier M. Pediatric ENT emergencies. Emerg Med Clin North Am. 2013;31(3):795-808. doi:10.1016/j.emc.2013.04.005
3. Leong SC, Karoos PD, Papouliakos SM, et al. Unusual complications of tonsillectomy: a systematic review. Am J Otolaryngol. 2007;28(6):419-422. doi:10.1016/j.amjoto.2006.10.016
4. Fath L, Cebula H, Santin MN, Cocab A, Debrya C, Proustb F. The Grisel’s syndrome: a non-traumatic subluxation of the atlantoaxial joint. Neurochirurgie. 2018;64(4):327-330. doi:10.1016/j.neuchi.2018.02.001
5. Moore K, Agur A, Dalley A. Essential Clinical Anatomy. 5th ed. Baltimore: Lippincott, Williams, and Wilkins; 2015:282-287.
6. Spennato P, Nicosia G, Rapanà A, et al. Grisel syndrome following adenoidectomy: surgical management in a case with delayed diagnosis. World Neurosurg. 2015;84(5):1494.e7-e12.
7. Anania P, Pavone P, Pacetti M, et al. Grisel syndrome in pediatric age: a single-center Italian experience and review of the literature. World Neurosurg. 2019;125:374-382. doi:10.1016/j.wneu.2019.02.035
8. Aldriweesh T, Altheyab F, Alenezi M, et al. Grisel’s syndrome post otolaryngology procedures: a systematic review. Int J Pediatr Otorhinolaryngol. 2020;137:110-125. doi:10.1016/j.ijporl.2020.110225
Tonsillectomy with or without adenoidectomy (T&A) is the second most common pediatric surgical procedure in the United States.1 It is most often performed during childhood between 5 and 8 years of age with a second peak observed between 17 and 21 years of age in the adolescent and young adult populations.2 While recurrent tonsillitis has been traditionally associated with tonsillectomy, sleep disordered breathing with obstructive sleep apnea is now the primary indication for the procedure.1
Up to 97% of T&As are performed as an outpatient same-day surgery not requiring inpatient admission.2 Although largely a safe and routinely performed surgery, several complications have been described. Due to the outpatient nature of the procedure, the complications are often encountered in the emergency department (ED) and sometimes in primary care settings. Common complications (outside of the perioperative time frame) include nausea, vomiting, otalgia, odynophagia, infection of the throat (broadly), and hemorrhage; uncommon complications include subcutaneous emphysema, taste disorders, and Eagle syndrome. Some complications are rarer still and carry significant morbidity and even mortality, including mediastinitis, cervical osteomyelitis, and Grisel syndrome.3 The following case encourages the clinician to expand the differential for a patient presenting after T&A.
Case Presentation
A child aged < 3 years was brought to the ED by their mother. She reported neck pain and stiffness 10 days after T&A with concurrent tympanostomy tube placement at an outside pediatric hospital. At triage, their heart rate was 94 bpm, temperature was 98.2 °F, respiratory rate, 22 breaths per minute, and oxygen saturation, 97% on room air. The mother of the patient (MOP) had been giving the prescribed oral liquid formulations of ibuprofen and acetaminophen with hydrocodone as directed. No drug allergies were reported, and immunizations were up to date for age. Other medical and surgical history included eczema and remote cutaneous hemangioma resection. The patient lived at home with 2 parents and was not exposed to smoke; their family history was noncontributory.
Since the surgery, the MOP had noticed constant and increasing neck stiffness, specifically with looking up and down but not side to side. She also had noticed swelling behind both ears. She reported no substantial decrease in intake by mouth or decrease in urine or bowel frequency. On review of systems, she reported no fever, vomiting, difficulty breathing, bleeding from the mouth or nose, eye or ear drainage, or rash.
On physical examination, the patient was alert and in no acute distress; active and playful on an electronic device but was notably not moving their head, which was held in a forward-looking position without any signs of trauma. When asked, the child would not flex or extend their neck but would rotate a few degrees from neutral to both sides. Even with moving the electronic device up and down in space, no active neck extension or flexion could be elicited. The examination of the head, eyes, ears, nose, and throat was otherwise only remarkable for palpable and mildly tender postauricular lymph nodes and diffuse erythema in the posterior pharynx. Cardiopulmonary, abdominal, skin, and extremity examinations were unremarkable.
With concern for an infectious process, the physician ordered blood chemistry and hematology tests along with neck radiography. While awaiting the results, the patient was given a weight-based bolus of normal saline, and the home pain regimen was administered. An attempt was made to passively flex and extend the neck as the child slept in their mother’s arms, but the patient immediately awoke and began to cry.
All values of the comprehensive metabolic panel were within normal limits except for a slight elevation in the blood urea nitrogen to 21 mg/dL and glucose to 159 mg/dL. The complete blood count was unrevealing. The computed tomography (CT) scan with contrast of the soft tissues of the neck was limited by motion artifact but showed a head held in axial rotation with soft tissue irregularity in the anterior aspect of the adenoids (Figure 1). There was what appeared to be normal lymphadenopathy in the hypopharynx, but the soft tissues were otherwise unremarkable.
The on-call pediatric otolaryngologist at the hospital where the procedure was performed was paged. On hearing the details of the case, the specialist was concerned for Grisel syndrome and requested to see the patient in their facility. No additional recommendations for care were provided; the mother was updated and agreed to transfer. The patient was comfortable and stable with repeat vitals as follows: heart rate, 86 beats per minute, blood pressure, 99/62, temperature, 98.3 °F, respiratory rate, 20 breaths per minute, and oxygen saturation, 99% on room air.
On arrival at the receiving facility, the emergency team performed a history and physical that revealed no significant changes from the initial evaluation. They then facilitated evaluation by the pediatric otolaryngologist who conducted a more directed physical examination. Decreased active and passive range of motion (ROM) of the neck without rotatory restriction was again noted. They also observed scant fibrinous exudate within the oropharynx and tonsillar fossa, which was normal in the setting of the recent surgery. They recommended additional analgesia with intramuscular ketorolac, weight-based dosing at 1 mg/kg.
With repeat examination after this additional analgesic, ROM of the neck first passive then active had improved. The patient was then discharged to follow up in the coming days with instructions to continue the pain and anti-inflammatory regimen. They were not started on an antibiotic at that time nor were they placed in a cervical collar. At the follow-up, the MOP reported persistence of neck stiffness for a few days initially but then observed slow improvement. By postoperative day 18, the stiffness had resolved. No other follow-up or referrals related to this issue were readily apparent in review of the patient’s health record.
Discussion
Grisel syndrome is the atraumatic rotary subluxation of the atlantoaxial joint, specifically, the atlas (C1 vertebra) rotates to a fixed, nonanatomic position while the axis (C2 vertebra) remains in normal alignment in relation to the remainder of the spinal column. The subluxation occurs in the absence of ligamentous injury but is associated with an increase in ligamentous laxity.4 The atlas is a ring-shaped vertebra with 2 lateral masses connected by anterior and posterior arches; it lacks a spinous process unlike other vertebrae. It articulates with the skull by means of the 2 articular facets on the superior aspect of the lateral masses. Articulation with the axis occurs at 3 sites: 2 articular facets on the inferior portion of the lateral masses of the atlas and a facet for the dens on the posterior portion of the anterior arch. The dens projects superiorly from the body of the axis and is bound posteriorly by the transverse ligament of the atlas.5
The degree of subluxation seen in Grisel syndrome correlates to the disease severity and is classified by the Fielding and Hawkins (FH) system (Table). This system accounts for the distance from the atlas to the dens (atlantodens interval) and the relative asymmetry of the atlantoaxial joint.6 In a normal adult, the upper limit of normal for the atlantodens interval is 3 mm, whereas this distance increases to 4.5 mm for the pediatric population.7 Type I (FH-I) involves rotary subluxation alone without any increase in the atlantodens interval; in FH-II, that interval has increased from normal but to no more than 5 mm. FH-I and FH-II are the most encountered and are not associated with neurologic impairment. In FH-III, neurologic deficits can be present, and the atlantodens interval is increased to > 5 mm. Different from FH-II and FH-III in which anterior dislocation of the atlas with reference to the dens is observed, FH-IV involves a rotary movement of the atlas with concurrent posterior displacement and often involves spinal cord compression.6
Subluxation and displacement without trauma are key components of Grisel syndrome. The 2-hit hypothesis is often used to explain how this can occur, ie, 2 anomalies must be present simultaneously for this condition to develop. First, the laxity of the transverse ligament, the posterior wall of the dens, and other atlantoaxial ligaments must be increased. Second, an asymmetric contraction of the deep erector muscles of the neck either abruptly or more insidiously rotate and dislocate the atlas.8 The pathophysiology is not exactly understood, but the most commonly held hypothesis describes contiguous spread of infection or inflammatory mediators from the pharynx to the ligaments and muscles described.6
Spread could occur via the venous system. The posterior superior pharyngeal region is drained by the periodontoidal venous plexus; the connections here with the pharyngovertebral veins allow for the embolization of infectious or other proinflammatory material to the prevertebral fascia. These emboli induce fasciitis and subsequent aberrant relaxation of the ligaments. In reaction to the inflammation or increased laxity, contiguous muscles of the deep neck contract and freeze the joint out of anatomic alignment.4
The abnormal alignment is apparent grossly as torticollis. Most broadly, torticollis describes an anomalous head posture due to involuntary muscle contractions of neck muscles and specifically describes chin deviation to the side. The antecollis and retrocollis subtypes of torticollis describe forward flexion and backward extension of the neck, respectively.7 Torticollis (broadly) is the most frequently reported condition of those found to have Grisel syndrome (90.7%); other common presenting conditions include neck pain (81.5%) and neck stiffness (31.5%). Fever is found in only 27.8% of cases. Pediatric patients (aged ≤ 12 years) are the most commonly affected, accounting for 87% of cases with an observed 4:1 male to female predominance.7,8 Symptoms begin most often within the first week from the inciting event in 85% of the cases.8 Head and neck surgery precedes up to 67% of cases, and infectious etiologies largely account for the remaining cases.7 Of the postsurgical cases, 55.6% had undergone T&A.8
Although anomalous head posture or neck stiffness following T&A would be of great clinic concern for Grisel syndrome, radiographic studies play a confirmatory role. CT scan is used to evaluate the bony structures, with 3D reconstruction of the cervical spine being most useful to determine the presence and degree of subluxation.8 Magnetic resonance imaging also aids in diagnosis to evaluate ligamentous structures in the area of concern as well as in the evaluation of spinal cord compression.6 Laboratory tests are largely unhelpful in making or excluding the diagnosis.8
If Grisel syndrome is suspected, both the original surgeon (if preceded by surgery) and the neurosurgical team should be consulted. Although no widely adopted guidelines exist for the management of this rare disease, general practice patterns have emerged with the degree of intervention predictably correlating to disease severity. FH-I is usually treated with nonsteroidal anti-inflammatory drugs and muscle relaxants with or without a soft cervical collar. For FH-II, closed reduction and immobilization in a stiff cervical collar is recommended. If no neurologic defect is present, FH-III is treated with bed rest, a period of inline cervical traction, and subsequent immobilization. FH-III with neurologic sequelae and all FH-IV necessitate emergent neurosurgical consultation.4 Surgical intervention is a last resort but is required in up to 24.1% of cases.8
Antibiotic therapy is not routinely given unless clear infectious etiology is identified. No standard antibiotic regimen exists, but coverage for typical upper respiratory pathogens likely suffices. Empiric antibiotic therapy is not recommended for all causes of Grisel syndrome, ie, when the underlying cause is not yet elucidated.6 One case of Grisel syndrome occurring in the setting of cervical osteomyelitis has been described, though, and required prolonged IV antibiotics.3 Physical therapy is recommended as adjunct with no limitations for range of motion save for that of the patient’s individual pain threshold.4
Possibly attributable to waxing and waning ligamentous laxity and strength of the neck muscle contraction, the atlantodens interval and the degree of subluxation can change, making Grisel syndrome dynamic. As such, the FH classification can change, necessitating more or less aggressive therapy. A neurologic evaluation is recommended at least every 2 weeks after the diagnosis is made. If initial identification or recognition of known disease progression is delayed, serious complications can develop. Acutely, spinal cord compression can lead to quadriplegia and death; more insidious complications include reduced neck mobility, dysphonia, and dysphagia.4 As serious, life-threatening complications can arise from Grisel syndrome while good functional outcomes can be achieved with timely and appropriate treatment, the clinician should be inspired to have a high clinical suspicion for this syndrome given the right context.
Conclusions
The patient experienced a desirable outcome with minimal, conservative treatment. As such, the pathology in this case was likely attributed to the mildest form of Grisel syndrome (FH-I). The follow-up was reassuring as well, revealing no worsening or progression of symptoms. The initial evaluation in this case was limited by the inadequacy of the CT scan. Motion artifact in the pharynx prevented the definite exclusion of deep space infection, while the rotation of the head in combination with motion artifact in the cranial-most portions of the vertebral column made determining alignment difficult. One clear axial image, though, does show rotation of the atlas (Figure 2). The uncertainty at the end of our workup prompted surgical consultation, not, admittedly, concern for Grisel syndrome. Awareness of this disease entity is nevertheless important and clinically relevant. Early identification and treatment is associated with decreased morbidity and improvement in long-term functional outcomes.6 Despite its rarity, the clinician should consider Grisel syndrome in any pediatric patient presenting with neck stiffness following the commonly performed T&A.
Tonsillectomy with or without adenoidectomy (T&A) is the second most common pediatric surgical procedure in the United States.1 It is most often performed during childhood between 5 and 8 years of age with a second peak observed between 17 and 21 years of age in the adolescent and young adult populations.2 While recurrent tonsillitis has been traditionally associated with tonsillectomy, sleep disordered breathing with obstructive sleep apnea is now the primary indication for the procedure.1
Up to 97% of T&As are performed as an outpatient same-day surgery not requiring inpatient admission.2 Although largely a safe and routinely performed surgery, several complications have been described. Due to the outpatient nature of the procedure, the complications are often encountered in the emergency department (ED) and sometimes in primary care settings. Common complications (outside of the perioperative time frame) include nausea, vomiting, otalgia, odynophagia, infection of the throat (broadly), and hemorrhage; uncommon complications include subcutaneous emphysema, taste disorders, and Eagle syndrome. Some complications are rarer still and carry significant morbidity and even mortality, including mediastinitis, cervical osteomyelitis, and Grisel syndrome.3 The following case encourages the clinician to expand the differential for a patient presenting after T&A.
Case Presentation
A child aged < 3 years was brought to the ED by their mother. She reported neck pain and stiffness 10 days after T&A with concurrent tympanostomy tube placement at an outside pediatric hospital. At triage, their heart rate was 94 bpm, temperature was 98.2 °F, respiratory rate, 22 breaths per minute, and oxygen saturation, 97% on room air. The mother of the patient (MOP) had been giving the prescribed oral liquid formulations of ibuprofen and acetaminophen with hydrocodone as directed. No drug allergies were reported, and immunizations were up to date for age. Other medical and surgical history included eczema and remote cutaneous hemangioma resection. The patient lived at home with 2 parents and was not exposed to smoke; their family history was noncontributory.
Since the surgery, the MOP had noticed constant and increasing neck stiffness, specifically with looking up and down but not side to side. She also had noticed swelling behind both ears. She reported no substantial decrease in intake by mouth or decrease in urine or bowel frequency. On review of systems, she reported no fever, vomiting, difficulty breathing, bleeding from the mouth or nose, eye or ear drainage, or rash.
On physical examination, the patient was alert and in no acute distress; active and playful on an electronic device but was notably not moving their head, which was held in a forward-looking position without any signs of trauma. When asked, the child would not flex or extend their neck but would rotate a few degrees from neutral to both sides. Even with moving the electronic device up and down in space, no active neck extension or flexion could be elicited. The examination of the head, eyes, ears, nose, and throat was otherwise only remarkable for palpable and mildly tender postauricular lymph nodes and diffuse erythema in the posterior pharynx. Cardiopulmonary, abdominal, skin, and extremity examinations were unremarkable.
With concern for an infectious process, the physician ordered blood chemistry and hematology tests along with neck radiography. While awaiting the results, the patient was given a weight-based bolus of normal saline, and the home pain regimen was administered. An attempt was made to passively flex and extend the neck as the child slept in their mother’s arms, but the patient immediately awoke and began to cry.
All values of the comprehensive metabolic panel were within normal limits except for a slight elevation in the blood urea nitrogen to 21 mg/dL and glucose to 159 mg/dL. The complete blood count was unrevealing. The computed tomography (CT) scan with contrast of the soft tissues of the neck was limited by motion artifact but showed a head held in axial rotation with soft tissue irregularity in the anterior aspect of the adenoids (Figure 1). There was what appeared to be normal lymphadenopathy in the hypopharynx, but the soft tissues were otherwise unremarkable.
The on-call pediatric otolaryngologist at the hospital where the procedure was performed was paged. On hearing the details of the case, the specialist was concerned for Grisel syndrome and requested to see the patient in their facility. No additional recommendations for care were provided; the mother was updated and agreed to transfer. The patient was comfortable and stable with repeat vitals as follows: heart rate, 86 beats per minute, blood pressure, 99/62, temperature, 98.3 °F, respiratory rate, 20 breaths per minute, and oxygen saturation, 99% on room air.
On arrival at the receiving facility, the emergency team performed a history and physical that revealed no significant changes from the initial evaluation. They then facilitated evaluation by the pediatric otolaryngologist who conducted a more directed physical examination. Decreased active and passive range of motion (ROM) of the neck without rotatory restriction was again noted. They also observed scant fibrinous exudate within the oropharynx and tonsillar fossa, which was normal in the setting of the recent surgery. They recommended additional analgesia with intramuscular ketorolac, weight-based dosing at 1 mg/kg.
With repeat examination after this additional analgesic, ROM of the neck first passive then active had improved. The patient was then discharged to follow up in the coming days with instructions to continue the pain and anti-inflammatory regimen. They were not started on an antibiotic at that time nor were they placed in a cervical collar. At the follow-up, the MOP reported persistence of neck stiffness for a few days initially but then observed slow improvement. By postoperative day 18, the stiffness had resolved. No other follow-up or referrals related to this issue were readily apparent in review of the patient’s health record.
Discussion
Grisel syndrome is the atraumatic rotary subluxation of the atlantoaxial joint, specifically, the atlas (C1 vertebra) rotates to a fixed, nonanatomic position while the axis (C2 vertebra) remains in normal alignment in relation to the remainder of the spinal column. The subluxation occurs in the absence of ligamentous injury but is associated with an increase in ligamentous laxity.4 The atlas is a ring-shaped vertebra with 2 lateral masses connected by anterior and posterior arches; it lacks a spinous process unlike other vertebrae. It articulates with the skull by means of the 2 articular facets on the superior aspect of the lateral masses. Articulation with the axis occurs at 3 sites: 2 articular facets on the inferior portion of the lateral masses of the atlas and a facet for the dens on the posterior portion of the anterior arch. The dens projects superiorly from the body of the axis and is bound posteriorly by the transverse ligament of the atlas.5
The degree of subluxation seen in Grisel syndrome correlates to the disease severity and is classified by the Fielding and Hawkins (FH) system (Table). This system accounts for the distance from the atlas to the dens (atlantodens interval) and the relative asymmetry of the atlantoaxial joint.6 In a normal adult, the upper limit of normal for the atlantodens interval is 3 mm, whereas this distance increases to 4.5 mm for the pediatric population.7 Type I (FH-I) involves rotary subluxation alone without any increase in the atlantodens interval; in FH-II, that interval has increased from normal but to no more than 5 mm. FH-I and FH-II are the most encountered and are not associated with neurologic impairment. In FH-III, neurologic deficits can be present, and the atlantodens interval is increased to > 5 mm. Different from FH-II and FH-III in which anterior dislocation of the atlas with reference to the dens is observed, FH-IV involves a rotary movement of the atlas with concurrent posterior displacement and often involves spinal cord compression.6
Subluxation and displacement without trauma are key components of Grisel syndrome. The 2-hit hypothesis is often used to explain how this can occur, ie, 2 anomalies must be present simultaneously for this condition to develop. First, the laxity of the transverse ligament, the posterior wall of the dens, and other atlantoaxial ligaments must be increased. Second, an asymmetric contraction of the deep erector muscles of the neck either abruptly or more insidiously rotate and dislocate the atlas.8 The pathophysiology is not exactly understood, but the most commonly held hypothesis describes contiguous spread of infection or inflammatory mediators from the pharynx to the ligaments and muscles described.6
Spread could occur via the venous system. The posterior superior pharyngeal region is drained by the periodontoidal venous plexus; the connections here with the pharyngovertebral veins allow for the embolization of infectious or other proinflammatory material to the prevertebral fascia. These emboli induce fasciitis and subsequent aberrant relaxation of the ligaments. In reaction to the inflammation or increased laxity, contiguous muscles of the deep neck contract and freeze the joint out of anatomic alignment.4
The abnormal alignment is apparent grossly as torticollis. Most broadly, torticollis describes an anomalous head posture due to involuntary muscle contractions of neck muscles and specifically describes chin deviation to the side. The antecollis and retrocollis subtypes of torticollis describe forward flexion and backward extension of the neck, respectively.7 Torticollis (broadly) is the most frequently reported condition of those found to have Grisel syndrome (90.7%); other common presenting conditions include neck pain (81.5%) and neck stiffness (31.5%). Fever is found in only 27.8% of cases. Pediatric patients (aged ≤ 12 years) are the most commonly affected, accounting for 87% of cases with an observed 4:1 male to female predominance.7,8 Symptoms begin most often within the first week from the inciting event in 85% of the cases.8 Head and neck surgery precedes up to 67% of cases, and infectious etiologies largely account for the remaining cases.7 Of the postsurgical cases, 55.6% had undergone T&A.8
Although anomalous head posture or neck stiffness following T&A would be of great clinic concern for Grisel syndrome, radiographic studies play a confirmatory role. CT scan is used to evaluate the bony structures, with 3D reconstruction of the cervical spine being most useful to determine the presence and degree of subluxation.8 Magnetic resonance imaging also aids in diagnosis to evaluate ligamentous structures in the area of concern as well as in the evaluation of spinal cord compression.6 Laboratory tests are largely unhelpful in making or excluding the diagnosis.8
If Grisel syndrome is suspected, both the original surgeon (if preceded by surgery) and the neurosurgical team should be consulted. Although no widely adopted guidelines exist for the management of this rare disease, general practice patterns have emerged with the degree of intervention predictably correlating to disease severity. FH-I is usually treated with nonsteroidal anti-inflammatory drugs and muscle relaxants with or without a soft cervical collar. For FH-II, closed reduction and immobilization in a stiff cervical collar is recommended. If no neurologic defect is present, FH-III is treated with bed rest, a period of inline cervical traction, and subsequent immobilization. FH-III with neurologic sequelae and all FH-IV necessitate emergent neurosurgical consultation.4 Surgical intervention is a last resort but is required in up to 24.1% of cases.8
Antibiotic therapy is not routinely given unless clear infectious etiology is identified. No standard antibiotic regimen exists, but coverage for typical upper respiratory pathogens likely suffices. Empiric antibiotic therapy is not recommended for all causes of Grisel syndrome, ie, when the underlying cause is not yet elucidated.6 One case of Grisel syndrome occurring in the setting of cervical osteomyelitis has been described, though, and required prolonged IV antibiotics.3 Physical therapy is recommended as adjunct with no limitations for range of motion save for that of the patient’s individual pain threshold.4
Possibly attributable to waxing and waning ligamentous laxity and strength of the neck muscle contraction, the atlantodens interval and the degree of subluxation can change, making Grisel syndrome dynamic. As such, the FH classification can change, necessitating more or less aggressive therapy. A neurologic evaluation is recommended at least every 2 weeks after the diagnosis is made. If initial identification or recognition of known disease progression is delayed, serious complications can develop. Acutely, spinal cord compression can lead to quadriplegia and death; more insidious complications include reduced neck mobility, dysphonia, and dysphagia.4 As serious, life-threatening complications can arise from Grisel syndrome while good functional outcomes can be achieved with timely and appropriate treatment, the clinician should be inspired to have a high clinical suspicion for this syndrome given the right context.
Conclusions
The patient experienced a desirable outcome with minimal, conservative treatment. As such, the pathology in this case was likely attributed to the mildest form of Grisel syndrome (FH-I). The follow-up was reassuring as well, revealing no worsening or progression of symptoms. The initial evaluation in this case was limited by the inadequacy of the CT scan. Motion artifact in the pharynx prevented the definite exclusion of deep space infection, while the rotation of the head in combination with motion artifact in the cranial-most portions of the vertebral column made determining alignment difficult. One clear axial image, though, does show rotation of the atlas (Figure 2). The uncertainty at the end of our workup prompted surgical consultation, not, admittedly, concern for Grisel syndrome. Awareness of this disease entity is nevertheless important and clinically relevant. Early identification and treatment is associated with decreased morbidity and improvement in long-term functional outcomes.6 Despite its rarity, the clinician should consider Grisel syndrome in any pediatric patient presenting with neck stiffness following the commonly performed T&A.
1. Ramos SD, Mukerji S, Pine HS. Tonsillectomy and adenoidectomy. Pediatr Clin North Am. 2013;60(4):793-807. doi:10.1016/j.pcl.2013.04.015
2. Stoner MJ, Dulaurier M. Pediatric ENT emergencies. Emerg Med Clin North Am. 2013;31(3):795-808. doi:10.1016/j.emc.2013.04.005
3. Leong SC, Karoos PD, Papouliakos SM, et al. Unusual complications of tonsillectomy: a systematic review. Am J Otolaryngol. 2007;28(6):419-422. doi:10.1016/j.amjoto.2006.10.016
4. Fath L, Cebula H, Santin MN, Cocab A, Debrya C, Proustb F. The Grisel’s syndrome: a non-traumatic subluxation of the atlantoaxial joint. Neurochirurgie. 2018;64(4):327-330. doi:10.1016/j.neuchi.2018.02.001
5. Moore K, Agur A, Dalley A. Essential Clinical Anatomy. 5th ed. Baltimore: Lippincott, Williams, and Wilkins; 2015:282-287.
6. Spennato P, Nicosia G, Rapanà A, et al. Grisel syndrome following adenoidectomy: surgical management in a case with delayed diagnosis. World Neurosurg. 2015;84(5):1494.e7-e12.
7. Anania P, Pavone P, Pacetti M, et al. Grisel syndrome in pediatric age: a single-center Italian experience and review of the literature. World Neurosurg. 2019;125:374-382. doi:10.1016/j.wneu.2019.02.035
8. Aldriweesh T, Altheyab F, Alenezi M, et al. Grisel’s syndrome post otolaryngology procedures: a systematic review. Int J Pediatr Otorhinolaryngol. 2020;137:110-125. doi:10.1016/j.ijporl.2020.110225
1. Ramos SD, Mukerji S, Pine HS. Tonsillectomy and adenoidectomy. Pediatr Clin North Am. 2013;60(4):793-807. doi:10.1016/j.pcl.2013.04.015
2. Stoner MJ, Dulaurier M. Pediatric ENT emergencies. Emerg Med Clin North Am. 2013;31(3):795-808. doi:10.1016/j.emc.2013.04.005
3. Leong SC, Karoos PD, Papouliakos SM, et al. Unusual complications of tonsillectomy: a systematic review. Am J Otolaryngol. 2007;28(6):419-422. doi:10.1016/j.amjoto.2006.10.016
4. Fath L, Cebula H, Santin MN, Cocab A, Debrya C, Proustb F. The Grisel’s syndrome: a non-traumatic subluxation of the atlantoaxial joint. Neurochirurgie. 2018;64(4):327-330. doi:10.1016/j.neuchi.2018.02.001
5. Moore K, Agur A, Dalley A. Essential Clinical Anatomy. 5th ed. Baltimore: Lippincott, Williams, and Wilkins; 2015:282-287.
6. Spennato P, Nicosia G, Rapanà A, et al. Grisel syndrome following adenoidectomy: surgical management in a case with delayed diagnosis. World Neurosurg. 2015;84(5):1494.e7-e12.
7. Anania P, Pavone P, Pacetti M, et al. Grisel syndrome in pediatric age: a single-center Italian experience and review of the literature. World Neurosurg. 2019;125:374-382. doi:10.1016/j.wneu.2019.02.035
8. Aldriweesh T, Altheyab F, Alenezi M, et al. Grisel’s syndrome post otolaryngology procedures: a systematic review. Int J Pediatr Otorhinolaryngol. 2020;137:110-125. doi:10.1016/j.ijporl.2020.110225
Repeat Laparoscopic Cholecystectomy for Duplicated Gallbladder After 16-Year Interval
Gallbladder duplication is a congenital abnormality of the hepatobiliary system and often is not considered in the evaluation of a patient with right upper quadrant pain. Accuracy of the most commonly used imaging study to assess for biliary disease, abdominal ultrasound, is highly dependent on the skills of the ultrasonographer, and given its relative rarity, this condition is often not considered prior to planned cholecystectomy.1 Small case reviews found that < 50% of gallbladder duplications are diagnosed preoperatively despite use of ultrasound or computed tomography (CT) scan.2-4 Failure to recognize duplicate gallbladder anatomy in symptomatic patients may result in incomplete surgical management, an increase in perioperative complications, and years of morbidity due to unresolved symptoms. Once a patient has had a cholecystectomy, symptoms are presumed to be due to a nonbiliary etiology and an extensive, often repetitive, workup is pursued before “repeat cholecystectomy” is considered.5
Case Presentation
A 63-year-old man was referred to gastroenterology for recurrent episodic right upper quadrant pain. He reported intermittent both right and left upper abdominal pain that was variable in quality. At times it was associated with an empty stomach prior to meals; at other times, onset was 30 to 60 minutes after meals. The patient also reported significant flatulence and bloating and intermittent loose stools. Sixteen years before, he underwent a laparoscopic cholecystectomy. He reported that the pain he experienced before the cholecystectomy never resolved after surgery but occurred less frequently. For the next 16 years, the patient did not seek evaluation of his ongoing but infrequent symptoms until his pain became a daily occurrence. The patient’s surgical history included a remote open vagotomy and antrectomy for peptic ulcer disease, laparoscopic appendectomy, and a laparoscopic cholecystectomy for reported biliary colic.
The gastroenterology evaluation included a colonoscopy and esophagogastroduodenoscopy (EGD); both were benign and without findings specific to identify the etiology for the patient’s pain. The patient was given a course of rifaximin 1200 mg daily for 7 days for possible bacterial overgrowth and placed on a proton pump inhibitor twice daily. Neither of these interventions helped resolve the patient’s symptoms. Further workup was pursued by gastroenterology to include a right upper quadrant ultrasound that showed a structure most consistent with a small gallbladder containing a small polyp vs stone. Magnetic resonance cholangiopancreatography (MRCP) also was performed and showed the presence of a small gallbladder with a small 2-mm filling defect and an otherwise benign biliary tree. MRCP images and EGD documented a Billroth 1 reconstruction at the time of his remote antrectomy and vagotomy (Figure 1).
The patient was referred to general surgery for consideration of a repeat cholecystectomy. He confirmed the history of intermittent upper abdominal pain for the past 16 years, which was similar to the symptoms he had experienced before his original laparoscopic cholecystectomy. On examination, the patient had a body mass index of 38, had a large upper midline incision from his prior antrectomy and vagotomy procedure, and several scars presumed to be port incision scars to the right lateral abdominal wall. Hospital records were obtained from the patient’s prior workup for biliary colic and cholecystectomy 16 years before. The preoperative abdominal ultrasound examination showed a mildly distended gallbladder but was notably described as “quite limited due to patient’s body habitus and liver is not well seen.” No additional imaging was documented in his presurgical evaluation notes and imaging records.
The operative report described a gallbladder that was densely adherent to adjacent fat and omental tissue with significant adhesions secondary to the prior vagotomy and antrectomy procedure. The cystic duct and artery were dissected free at the level of their junction with the gallbladder infundibulum. The cystic artery was divided with a harmonic scalpel. Following this the gallbladder body was dissected free from the liver bed in top-down fashion. A 0 Vicryl Endoloop suture was placed over the gallbladder and secured just past the origin of the cystic duct on the gallbladder infundibulum and the cystic duct divided above this suture. No surgical clips were used, which corresponded with the lack of surgical clips seen in imaging in his recent gastroenterology workup. No documentation of an intraoperative cholangiogram existed or was considered in the operative report.
The pathology report from this first cholecystectomy procedure noted the removed specimen to be an unopened 6-cm gallbladder containing 2 small yellow stones that otherwise were benign. At the time of this patient’s re-presentation to general surgery, there was suspicion that the patient’s prior surgical procedure had not been a cholecystectomy but rather a subtotal cholecystectomy. However, after appropriate workup and review of prior records, the patient had, indeed, previously undergone cholecystectomy and represented a rare case of gallbladder duplication resulting in abdominal pain for 16 years after his index operation.
The patient was consented for repeat cholecystectomy and underwent a laparoscopic lysis of adhesions, cholecystectomy, and intraoperative cholangiogram. Significant scarring was found at the liver undersurface that would have been exposed during the original laparoscopic resection of the gallbladder from its liver bed. Deeper to this, a small saccular structure was identified as the duplicate gallbladder (Figure 2). Though the visualized gallbladder was small with a deep intrahepatic lie, the critical view of safety was achieved and was without additional variation. An intraoperative cholangiogram was performed to determine whether residual ductal stumps or other additional evidence of the previously removed gallbladder could be identified. The cholangiogram showed clear visualization of the cystic duct, common bile duct, right and left hepatic ducts, and contrast into the duodenum without abnormal variants. There was no visualized accessory or secondary cystic duct stump seen on the cholangiogram (Figure 3). Pathology of the repeat cholecystectomy specimen confirmed a 3-cm gallbladder with a distinct duct leading out of the gallbladder and the presence of several gallstones. The patient had an uneventful recovery after the repeat laparoscopic cholecystectomy with complete resolution of his upper abdominal pain.
Discussion
The first reported human case of gallbladder duplication was noted in a sacrificial victim of Emperor Augustus in 31 BCE. Sherren reported the first documented case of double accessory gallbladder in a living human in 1911.1,6 Though the exact incidence of gallbladder duplication is not fully known due to primary documentation from case reports, incidence is approximately 1 in 4000 to 5000 people. It was first formally classified by Boyden in 1926.7 Further anatomic classification based on morphology and embryogenesis was delineated by Harlaftis and colleagues in 1977, establishing type 1 and 2 structures of a duplicated gallbladder.8 Type 1 duplicated gallbladder anatomy shares a single cystic duct, whereas in type 2 each gallbladder has its own cystic duct. Later reports and studies identified triple gallbladders as well as trabecular variants with the most common classification used currently being the modified Harlaftis classification.9,10
The case presented here most likely represents either a Y-shaped type 1 primordial gallbladder or a type 2 accessory gallbladder based on historical data and intraoperative cholangiogram findings at the time of repeat cholecystectomy. Gallbladder duplication is clinically indistinguishable from regular gallbladder pathology preoperatively and can only be identified on imaging or intraoperatively.11 Prior case reports and studies have found that it is frequently missed on preoperative abdominal ultrasonography and CT in up to 50% of cases.12-14
The differential diagnosis of gallbladder duplication seen on preoperative imaging includes a gallbladder diverticulum, choledochal cyst, focal adenonomyomatosis, Phrygian cap, or folded gallbladder.1,2 Historically, the most definitive test for gallbladder duplication has been either intraoperative cholangiography, which can also clarify biliary anatomy, or endoscopic retrograde cholangiopancreatography with cholangiography.1,3 The debate over routine use of intraoperative cholangiography has been ongoing for the past several decades.15 Though intraoperative cholangiogram remains one of the most definitive tests for gallbladder duplication, given the overall low incidence of this variant, recommendation for routine intraoperative cholangiography solely to rule out gallbladder duplication cannot be definitively recommended based on our review of the literature. Currently, preoperative MRCP is the study of choice when there is concern from historical facts or from other imaging of gallbladder duplication as it is noninvasive and has a high degree of detail, particularly with 3D reconstructions.14,16 At the time of surgery, the most critical step to avoid inadvertent ductal injury is clear visualization of ductal anatomy and obtaining the critical view of safety.17 Though this will also assist in identifying some cases of gallbladder duplication, given the great variation of duplication, it will not prevent missing some variants. In our case, extensive local scarring from the patient’s prior antrectomy and vagotomy along with lack of the use of intraoperative cholangiography likely contributed to missing his duplication at the time of his index cholecystectomy.
Undiagnosed gallbladder duplication can lead to additional morbidity related to common entities associated with gallbladder pathology, such as biliary colic, cholecystitis, cholangitis, and pancreatitis. Additionally, case reports in the literature have documented more rare associations, such as empyema, carcinoma, cholecystoenteric fistula, and torsion, all associated with a duplicated gallbladder.18-21 Once identified pre- or intraoperatively, it is generally recommended that all gallbladders be removed in symptomatic patients and that intraoperative cholangiography be done to assure complete resection of the duplicated gallbladders and to avoid injury to the biliary trees.22-25
Conclusions
Gallbladder duplication and other congenital biliary anatomic variations should be considered before a biliary operation and included in the differential diagnosis when evaluating patients who have clinical symptoms consistent with biliary pathology. In addition, intraoperative cholangiogram should be performed during cholecystectomy if the inferior liver edge cannot be visualized well, as in the case of this patient where a prior foregut operation resulted in extensive adhesive disease. Intraoperative cholangiogram also should be considered in patients whose preoperative imaging does not visualize the right upper quadrant well due to patient habitus. Doing so may identify gallbladder duplication and allow for complete cholecystectomy as well as proper identification and management of cystic duct variants. Awareness and consideration of duplicated biliary variants can help prevent intraoperative complications related to biliary anomalies and avoid the morbidity related to recurrent biliary disease and the need for repeat operative procedures.
Acknowledgments
We extend our thanks to Veterans Affairs Puget Sound Healthcare System and the Departments of Surgery and Radiology for their support of this case report, and Lorrie Langdale, MD, and Roger Tatum, MD, for their mentorship of this project
1. Vezakis A, Pantiora E, Giannoulopoulos D, et al. A duplicated gallbladder in a patient presenting with acute cholangitis. A case study and a literature review. Ann Hepatol. 2019;18(1):240-245. doi:10.5604/01.3001.0012.7932
2. Barut Í, Tarhan ÖR, Dog^ru U, Bülbül M. Gallbladder duplication: diagnosed and treated by laparoscopy. Eur J Gen Med. 2006;3(3):142-145. doi:10.29333/ejgm/82396 3. Cozacov Y, Subhas G, Jacobs M, Parikh J. Total laparoscopic removal of accessory gallbladder: a case report and review of literature. World J Gastrointest Surg. 2015;7(12):398-402. doi:10.4240/wjgs.v7.i12.398
4. Musleh MG, Burnett H, Rajashanker B, Ammori BJ. Laparoscopic double cholecystectomy for duplicated gallbladder: a case report. Int J Surg Case Rep. 2017;41:502-504. Published 2017 Nov 27. doi:10.1016/j.ijscr.2017.11.046
5. Walbolt TD, Lalezarzadeh F. Laparoscopic management of a duplicated gallbladder: a case study and anatomic history. Surg Laparosc Endosc Percutan Tech. 2011;21(3):e156-e158. doi:10.1097/SLE.0b013e31821d47ce
6. Sherren J. A double gall-bladder removed by operation. Ann Surg. 1911;54(2):204-205. doi:10.1097/00000658-191108000-00009
7. Boyden EA. The accessory gall-bladder—an embryological and comparative study of aberrant biliary vesicles occurring in man and the domestic mammals. Am J Anat. 1926; 38(2):177-231. doi:10.1002/aja.1000380202
8. Harlaftis N, Gray SW, Skandalakis JE. Multiple gallbladders. Surg Gynecol Obstet. 1977;145(6):928-934.
9. Kim RD, Zendejas I, Velopulos C, et al. Duplicate gallbladder arising from the left hepatic duct: report of a case. Surg Today. 2009;39(6):536-539. doi:10.1007/s00595-008-3878-4
10. Causey MW, Miller S, Fernelius CA, Burgess JR, Brown TA, Newton C. Gallbladder duplication: evaluation, treatment, and classification. J Pediatr Surg. 2010;45(2):443-446. doi:10.1016/j.jpedsurg.2009.12.015
11. Apolo Romero EX, Gálvez Salazar PF, Estrada Chandi JA, et al. Gallbladder duplication and cholecystitis. J Surg Case Rep. 2018;2018(7):rjy158. Published 2018 Jul 3. doi:10.1093/jscr/rjy158
12. Gorecki PJ, Andrei VE, Musacchio T, Schein M. Double gallbladder originating from left hepatic duct: a case report and review of literature. JSLS. 1998;2(4):337-339.
13. Cueto García J, Weber A, Serrano Berry F, Tanur Tatz B. Double gallbladder treated successfully by laparoscopy. J Laparoendosc Surg. 1993;3(2):153-155. doi:10.1089/lps.1993.3.153
14. Fazio V, Damiano G, Palumbo VD, et al. An unexpected surprise at the end of a “quiet” cholecystectomy. A case report and review of the literature. Ann Ital Chir. 2012;83(3):265-267.
15. Flum DR, Dellinger EP, Cheadle A, Chan L, Koepsell T. Intraoperative cholangiography and risk of common bile duct injury during cholecystectomy. JAMA. 2003;289(13):1639-1644. doi:10.1001/jama.289.13.1639
16. Botsford A, McKay K, Hartery A, Hapgood C. MRCP imaging of duplicate gallbladder: a case report and review of the literature. Surg Radiol Anat. 2015;37(5):425-429. doi:10.1007/s00276-015-1456-1
17. Strasberg SM, Hertl M, Soper NJ. An analysis of the problem of biliary injury during laparoscopic cholecystectomy. J Am Coll Surg. 1995;180(1):101-125.
18. Raymond SW, Thrift CB. Carcinoma of a duplicated gall bladder. Ill Med J. 1956;110(5):239-240.
19. Cunningham JJ. Empyema of a duplicated gallbladder: echographic findings. J Clin Ultrasound. 1980;8(6):511-512. doi:10.1002/jcu.1870080612
20. Recht W. Torsion of a double gallbladder; a report of a case and a review of the literature. Br J Surg. 1952;39(156):342-344. doi:10.1002/bjs.18003915616
21. Ritchie AW, Crucioli V. Double gallbladder with cholecystocolic fistula: a case report. Br J Surg. 1980;67(2):145-146. doi:10.1002/bjs.1800670226
22. Shapiro T, Rennie W. Duplicate gallbladder cholecystitis after open cholecystectomy. Ann Emerg Med. 1999;33(5):584-587. doi:10.1016/s0196-0644(99)70348-3
23. Hobbs MS, Mai Q, Knuiman MW, Fletcher DR, Ridout SC. Surgeon experience and trends in intraoperative complications in laparoscopic cholecystectomy. Br J Surg. 2006;93(7):844-853. doi:10.1002/bjs.5333
24. Davidoff AM, Pappas TN, Murray EA, et al. Mechanisms of major biliary injury during laparoscopic cholecystectomy. Ann Surg. 1992;215(3):196-202. doi:10.1097/00000658-199203000-00002
25. Flowers JL, Zucker KA, Graham SM, Scovill WA, Imbembo AL, Bailey RW. Laparoscopic cholangiography. Results and indications. Ann Surg. 1992;215(3):209-216. doi:10.1097/00000658-199203000-00004
Gallbladder duplication is a congenital abnormality of the hepatobiliary system and often is not considered in the evaluation of a patient with right upper quadrant pain. Accuracy of the most commonly used imaging study to assess for biliary disease, abdominal ultrasound, is highly dependent on the skills of the ultrasonographer, and given its relative rarity, this condition is often not considered prior to planned cholecystectomy.1 Small case reviews found that < 50% of gallbladder duplications are diagnosed preoperatively despite use of ultrasound or computed tomography (CT) scan.2-4 Failure to recognize duplicate gallbladder anatomy in symptomatic patients may result in incomplete surgical management, an increase in perioperative complications, and years of morbidity due to unresolved symptoms. Once a patient has had a cholecystectomy, symptoms are presumed to be due to a nonbiliary etiology and an extensive, often repetitive, workup is pursued before “repeat cholecystectomy” is considered.5
Case Presentation
A 63-year-old man was referred to gastroenterology for recurrent episodic right upper quadrant pain. He reported intermittent both right and left upper abdominal pain that was variable in quality. At times it was associated with an empty stomach prior to meals; at other times, onset was 30 to 60 minutes after meals. The patient also reported significant flatulence and bloating and intermittent loose stools. Sixteen years before, he underwent a laparoscopic cholecystectomy. He reported that the pain he experienced before the cholecystectomy never resolved after surgery but occurred less frequently. For the next 16 years, the patient did not seek evaluation of his ongoing but infrequent symptoms until his pain became a daily occurrence. The patient’s surgical history included a remote open vagotomy and antrectomy for peptic ulcer disease, laparoscopic appendectomy, and a laparoscopic cholecystectomy for reported biliary colic.
The gastroenterology evaluation included a colonoscopy and esophagogastroduodenoscopy (EGD); both were benign and without findings specific to identify the etiology for the patient’s pain. The patient was given a course of rifaximin 1200 mg daily for 7 days for possible bacterial overgrowth and placed on a proton pump inhibitor twice daily. Neither of these interventions helped resolve the patient’s symptoms. Further workup was pursued by gastroenterology to include a right upper quadrant ultrasound that showed a structure most consistent with a small gallbladder containing a small polyp vs stone. Magnetic resonance cholangiopancreatography (MRCP) also was performed and showed the presence of a small gallbladder with a small 2-mm filling defect and an otherwise benign biliary tree. MRCP images and EGD documented a Billroth 1 reconstruction at the time of his remote antrectomy and vagotomy (Figure 1).
The patient was referred to general surgery for consideration of a repeat cholecystectomy. He confirmed the history of intermittent upper abdominal pain for the past 16 years, which was similar to the symptoms he had experienced before his original laparoscopic cholecystectomy. On examination, the patient had a body mass index of 38, had a large upper midline incision from his prior antrectomy and vagotomy procedure, and several scars presumed to be port incision scars to the right lateral abdominal wall. Hospital records were obtained from the patient’s prior workup for biliary colic and cholecystectomy 16 years before. The preoperative abdominal ultrasound examination showed a mildly distended gallbladder but was notably described as “quite limited due to patient’s body habitus and liver is not well seen.” No additional imaging was documented in his presurgical evaluation notes and imaging records.
The operative report described a gallbladder that was densely adherent to adjacent fat and omental tissue with significant adhesions secondary to the prior vagotomy and antrectomy procedure. The cystic duct and artery were dissected free at the level of their junction with the gallbladder infundibulum. The cystic artery was divided with a harmonic scalpel. Following this the gallbladder body was dissected free from the liver bed in top-down fashion. A 0 Vicryl Endoloop suture was placed over the gallbladder and secured just past the origin of the cystic duct on the gallbladder infundibulum and the cystic duct divided above this suture. No surgical clips were used, which corresponded with the lack of surgical clips seen in imaging in his recent gastroenterology workup. No documentation of an intraoperative cholangiogram existed or was considered in the operative report.
The pathology report from this first cholecystectomy procedure noted the removed specimen to be an unopened 6-cm gallbladder containing 2 small yellow stones that otherwise were benign. At the time of this patient’s re-presentation to general surgery, there was suspicion that the patient’s prior surgical procedure had not been a cholecystectomy but rather a subtotal cholecystectomy. However, after appropriate workup and review of prior records, the patient had, indeed, previously undergone cholecystectomy and represented a rare case of gallbladder duplication resulting in abdominal pain for 16 years after his index operation.
The patient was consented for repeat cholecystectomy and underwent a laparoscopic lysis of adhesions, cholecystectomy, and intraoperative cholangiogram. Significant scarring was found at the liver undersurface that would have been exposed during the original laparoscopic resection of the gallbladder from its liver bed. Deeper to this, a small saccular structure was identified as the duplicate gallbladder (Figure 2). Though the visualized gallbladder was small with a deep intrahepatic lie, the critical view of safety was achieved and was without additional variation. An intraoperative cholangiogram was performed to determine whether residual ductal stumps or other additional evidence of the previously removed gallbladder could be identified. The cholangiogram showed clear visualization of the cystic duct, common bile duct, right and left hepatic ducts, and contrast into the duodenum without abnormal variants. There was no visualized accessory or secondary cystic duct stump seen on the cholangiogram (Figure 3). Pathology of the repeat cholecystectomy specimen confirmed a 3-cm gallbladder with a distinct duct leading out of the gallbladder and the presence of several gallstones. The patient had an uneventful recovery after the repeat laparoscopic cholecystectomy with complete resolution of his upper abdominal pain.
Discussion
The first reported human case of gallbladder duplication was noted in a sacrificial victim of Emperor Augustus in 31 BCE. Sherren reported the first documented case of double accessory gallbladder in a living human in 1911.1,6 Though the exact incidence of gallbladder duplication is not fully known due to primary documentation from case reports, incidence is approximately 1 in 4000 to 5000 people. It was first formally classified by Boyden in 1926.7 Further anatomic classification based on morphology and embryogenesis was delineated by Harlaftis and colleagues in 1977, establishing type 1 and 2 structures of a duplicated gallbladder.8 Type 1 duplicated gallbladder anatomy shares a single cystic duct, whereas in type 2 each gallbladder has its own cystic duct. Later reports and studies identified triple gallbladders as well as trabecular variants with the most common classification used currently being the modified Harlaftis classification.9,10
The case presented here most likely represents either a Y-shaped type 1 primordial gallbladder or a type 2 accessory gallbladder based on historical data and intraoperative cholangiogram findings at the time of repeat cholecystectomy. Gallbladder duplication is clinically indistinguishable from regular gallbladder pathology preoperatively and can only be identified on imaging or intraoperatively.11 Prior case reports and studies have found that it is frequently missed on preoperative abdominal ultrasonography and CT in up to 50% of cases.12-14
The differential diagnosis of gallbladder duplication seen on preoperative imaging includes a gallbladder diverticulum, choledochal cyst, focal adenonomyomatosis, Phrygian cap, or folded gallbladder.1,2 Historically, the most definitive test for gallbladder duplication has been either intraoperative cholangiography, which can also clarify biliary anatomy, or endoscopic retrograde cholangiopancreatography with cholangiography.1,3 The debate over routine use of intraoperative cholangiography has been ongoing for the past several decades.15 Though intraoperative cholangiogram remains one of the most definitive tests for gallbladder duplication, given the overall low incidence of this variant, recommendation for routine intraoperative cholangiography solely to rule out gallbladder duplication cannot be definitively recommended based on our review of the literature. Currently, preoperative MRCP is the study of choice when there is concern from historical facts or from other imaging of gallbladder duplication as it is noninvasive and has a high degree of detail, particularly with 3D reconstructions.14,16 At the time of surgery, the most critical step to avoid inadvertent ductal injury is clear visualization of ductal anatomy and obtaining the critical view of safety.17 Though this will also assist in identifying some cases of gallbladder duplication, given the great variation of duplication, it will not prevent missing some variants. In our case, extensive local scarring from the patient’s prior antrectomy and vagotomy along with lack of the use of intraoperative cholangiography likely contributed to missing his duplication at the time of his index cholecystectomy.
Undiagnosed gallbladder duplication can lead to additional morbidity related to common entities associated with gallbladder pathology, such as biliary colic, cholecystitis, cholangitis, and pancreatitis. Additionally, case reports in the literature have documented more rare associations, such as empyema, carcinoma, cholecystoenteric fistula, and torsion, all associated with a duplicated gallbladder.18-21 Once identified pre- or intraoperatively, it is generally recommended that all gallbladders be removed in symptomatic patients and that intraoperative cholangiography be done to assure complete resection of the duplicated gallbladders and to avoid injury to the biliary trees.22-25
Conclusions
Gallbladder duplication and other congenital biliary anatomic variations should be considered before a biliary operation and included in the differential diagnosis when evaluating patients who have clinical symptoms consistent with biliary pathology. In addition, intraoperative cholangiogram should be performed during cholecystectomy if the inferior liver edge cannot be visualized well, as in the case of this patient where a prior foregut operation resulted in extensive adhesive disease. Intraoperative cholangiogram also should be considered in patients whose preoperative imaging does not visualize the right upper quadrant well due to patient habitus. Doing so may identify gallbladder duplication and allow for complete cholecystectomy as well as proper identification and management of cystic duct variants. Awareness and consideration of duplicated biliary variants can help prevent intraoperative complications related to biliary anomalies and avoid the morbidity related to recurrent biliary disease and the need for repeat operative procedures.
Acknowledgments
We extend our thanks to Veterans Affairs Puget Sound Healthcare System and the Departments of Surgery and Radiology for their support of this case report, and Lorrie Langdale, MD, and Roger Tatum, MD, for their mentorship of this project
Gallbladder duplication is a congenital abnormality of the hepatobiliary system and often is not considered in the evaluation of a patient with right upper quadrant pain. Accuracy of the most commonly used imaging study to assess for biliary disease, abdominal ultrasound, is highly dependent on the skills of the ultrasonographer, and given its relative rarity, this condition is often not considered prior to planned cholecystectomy.1 Small case reviews found that < 50% of gallbladder duplications are diagnosed preoperatively despite use of ultrasound or computed tomography (CT) scan.2-4 Failure to recognize duplicate gallbladder anatomy in symptomatic patients may result in incomplete surgical management, an increase in perioperative complications, and years of morbidity due to unresolved symptoms. Once a patient has had a cholecystectomy, symptoms are presumed to be due to a nonbiliary etiology and an extensive, often repetitive, workup is pursued before “repeat cholecystectomy” is considered.5
Case Presentation
A 63-year-old man was referred to gastroenterology for recurrent episodic right upper quadrant pain. He reported intermittent both right and left upper abdominal pain that was variable in quality. At times it was associated with an empty stomach prior to meals; at other times, onset was 30 to 60 minutes after meals. The patient also reported significant flatulence and bloating and intermittent loose stools. Sixteen years before, he underwent a laparoscopic cholecystectomy. He reported that the pain he experienced before the cholecystectomy never resolved after surgery but occurred less frequently. For the next 16 years, the patient did not seek evaluation of his ongoing but infrequent symptoms until his pain became a daily occurrence. The patient’s surgical history included a remote open vagotomy and antrectomy for peptic ulcer disease, laparoscopic appendectomy, and a laparoscopic cholecystectomy for reported biliary colic.
The gastroenterology evaluation included a colonoscopy and esophagogastroduodenoscopy (EGD); both were benign and without findings specific to identify the etiology for the patient’s pain. The patient was given a course of rifaximin 1200 mg daily for 7 days for possible bacterial overgrowth and placed on a proton pump inhibitor twice daily. Neither of these interventions helped resolve the patient’s symptoms. Further workup was pursued by gastroenterology to include a right upper quadrant ultrasound that showed a structure most consistent with a small gallbladder containing a small polyp vs stone. Magnetic resonance cholangiopancreatography (MRCP) also was performed and showed the presence of a small gallbladder with a small 2-mm filling defect and an otherwise benign biliary tree. MRCP images and EGD documented a Billroth 1 reconstruction at the time of his remote antrectomy and vagotomy (Figure 1).
The patient was referred to general surgery for consideration of a repeat cholecystectomy. He confirmed the history of intermittent upper abdominal pain for the past 16 years, which was similar to the symptoms he had experienced before his original laparoscopic cholecystectomy. On examination, the patient had a body mass index of 38, had a large upper midline incision from his prior antrectomy and vagotomy procedure, and several scars presumed to be port incision scars to the right lateral abdominal wall. Hospital records were obtained from the patient’s prior workup for biliary colic and cholecystectomy 16 years before. The preoperative abdominal ultrasound examination showed a mildly distended gallbladder but was notably described as “quite limited due to patient’s body habitus and liver is not well seen.” No additional imaging was documented in his presurgical evaluation notes and imaging records.
The operative report described a gallbladder that was densely adherent to adjacent fat and omental tissue with significant adhesions secondary to the prior vagotomy and antrectomy procedure. The cystic duct and artery were dissected free at the level of their junction with the gallbladder infundibulum. The cystic artery was divided with a harmonic scalpel. Following this the gallbladder body was dissected free from the liver bed in top-down fashion. A 0 Vicryl Endoloop suture was placed over the gallbladder and secured just past the origin of the cystic duct on the gallbladder infundibulum and the cystic duct divided above this suture. No surgical clips were used, which corresponded with the lack of surgical clips seen in imaging in his recent gastroenterology workup. No documentation of an intraoperative cholangiogram existed or was considered in the operative report.
The pathology report from this first cholecystectomy procedure noted the removed specimen to be an unopened 6-cm gallbladder containing 2 small yellow stones that otherwise were benign. At the time of this patient’s re-presentation to general surgery, there was suspicion that the patient’s prior surgical procedure had not been a cholecystectomy but rather a subtotal cholecystectomy. However, after appropriate workup and review of prior records, the patient had, indeed, previously undergone cholecystectomy and represented a rare case of gallbladder duplication resulting in abdominal pain for 16 years after his index operation.
The patient was consented for repeat cholecystectomy and underwent a laparoscopic lysis of adhesions, cholecystectomy, and intraoperative cholangiogram. Significant scarring was found at the liver undersurface that would have been exposed during the original laparoscopic resection of the gallbladder from its liver bed. Deeper to this, a small saccular structure was identified as the duplicate gallbladder (Figure 2). Though the visualized gallbladder was small with a deep intrahepatic lie, the critical view of safety was achieved and was without additional variation. An intraoperative cholangiogram was performed to determine whether residual ductal stumps or other additional evidence of the previously removed gallbladder could be identified. The cholangiogram showed clear visualization of the cystic duct, common bile duct, right and left hepatic ducts, and contrast into the duodenum without abnormal variants. There was no visualized accessory or secondary cystic duct stump seen on the cholangiogram (Figure 3). Pathology of the repeat cholecystectomy specimen confirmed a 3-cm gallbladder with a distinct duct leading out of the gallbladder and the presence of several gallstones. The patient had an uneventful recovery after the repeat laparoscopic cholecystectomy with complete resolution of his upper abdominal pain.
Discussion
The first reported human case of gallbladder duplication was noted in a sacrificial victim of Emperor Augustus in 31 BCE. Sherren reported the first documented case of double accessory gallbladder in a living human in 1911.1,6 Though the exact incidence of gallbladder duplication is not fully known due to primary documentation from case reports, incidence is approximately 1 in 4000 to 5000 people. It was first formally classified by Boyden in 1926.7 Further anatomic classification based on morphology and embryogenesis was delineated by Harlaftis and colleagues in 1977, establishing type 1 and 2 structures of a duplicated gallbladder.8 Type 1 duplicated gallbladder anatomy shares a single cystic duct, whereas in type 2 each gallbladder has its own cystic duct. Later reports and studies identified triple gallbladders as well as trabecular variants with the most common classification used currently being the modified Harlaftis classification.9,10
The case presented here most likely represents either a Y-shaped type 1 primordial gallbladder or a type 2 accessory gallbladder based on historical data and intraoperative cholangiogram findings at the time of repeat cholecystectomy. Gallbladder duplication is clinically indistinguishable from regular gallbladder pathology preoperatively and can only be identified on imaging or intraoperatively.11 Prior case reports and studies have found that it is frequently missed on preoperative abdominal ultrasonography and CT in up to 50% of cases.12-14
The differential diagnosis of gallbladder duplication seen on preoperative imaging includes a gallbladder diverticulum, choledochal cyst, focal adenonomyomatosis, Phrygian cap, or folded gallbladder.1,2 Historically, the most definitive test for gallbladder duplication has been either intraoperative cholangiography, which can also clarify biliary anatomy, or endoscopic retrograde cholangiopancreatography with cholangiography.1,3 The debate over routine use of intraoperative cholangiography has been ongoing for the past several decades.15 Though intraoperative cholangiogram remains one of the most definitive tests for gallbladder duplication, given the overall low incidence of this variant, recommendation for routine intraoperative cholangiography solely to rule out gallbladder duplication cannot be definitively recommended based on our review of the literature. Currently, preoperative MRCP is the study of choice when there is concern from historical facts or from other imaging of gallbladder duplication as it is noninvasive and has a high degree of detail, particularly with 3D reconstructions.14,16 At the time of surgery, the most critical step to avoid inadvertent ductal injury is clear visualization of ductal anatomy and obtaining the critical view of safety.17 Though this will also assist in identifying some cases of gallbladder duplication, given the great variation of duplication, it will not prevent missing some variants. In our case, extensive local scarring from the patient’s prior antrectomy and vagotomy along with lack of the use of intraoperative cholangiography likely contributed to missing his duplication at the time of his index cholecystectomy.
Undiagnosed gallbladder duplication can lead to additional morbidity related to common entities associated with gallbladder pathology, such as biliary colic, cholecystitis, cholangitis, and pancreatitis. Additionally, case reports in the literature have documented more rare associations, such as empyema, carcinoma, cholecystoenteric fistula, and torsion, all associated with a duplicated gallbladder.18-21 Once identified pre- or intraoperatively, it is generally recommended that all gallbladders be removed in symptomatic patients and that intraoperative cholangiography be done to assure complete resection of the duplicated gallbladders and to avoid injury to the biliary trees.22-25
Conclusions
Gallbladder duplication and other congenital biliary anatomic variations should be considered before a biliary operation and included in the differential diagnosis when evaluating patients who have clinical symptoms consistent with biliary pathology. In addition, intraoperative cholangiogram should be performed during cholecystectomy if the inferior liver edge cannot be visualized well, as in the case of this patient where a prior foregut operation resulted in extensive adhesive disease. Intraoperative cholangiogram also should be considered in patients whose preoperative imaging does not visualize the right upper quadrant well due to patient habitus. Doing so may identify gallbladder duplication and allow for complete cholecystectomy as well as proper identification and management of cystic duct variants. Awareness and consideration of duplicated biliary variants can help prevent intraoperative complications related to biliary anomalies and avoid the morbidity related to recurrent biliary disease and the need for repeat operative procedures.
Acknowledgments
We extend our thanks to Veterans Affairs Puget Sound Healthcare System and the Departments of Surgery and Radiology for their support of this case report, and Lorrie Langdale, MD, and Roger Tatum, MD, for their mentorship of this project
1. Vezakis A, Pantiora E, Giannoulopoulos D, et al. A duplicated gallbladder in a patient presenting with acute cholangitis. A case study and a literature review. Ann Hepatol. 2019;18(1):240-245. doi:10.5604/01.3001.0012.7932
2. Barut Í, Tarhan ÖR, Dog^ru U, Bülbül M. Gallbladder duplication: diagnosed and treated by laparoscopy. Eur J Gen Med. 2006;3(3):142-145. doi:10.29333/ejgm/82396 3. Cozacov Y, Subhas G, Jacobs M, Parikh J. Total laparoscopic removal of accessory gallbladder: a case report and review of literature. World J Gastrointest Surg. 2015;7(12):398-402. doi:10.4240/wjgs.v7.i12.398
4. Musleh MG, Burnett H, Rajashanker B, Ammori BJ. Laparoscopic double cholecystectomy for duplicated gallbladder: a case report. Int J Surg Case Rep. 2017;41:502-504. Published 2017 Nov 27. doi:10.1016/j.ijscr.2017.11.046
5. Walbolt TD, Lalezarzadeh F. Laparoscopic management of a duplicated gallbladder: a case study and anatomic history. Surg Laparosc Endosc Percutan Tech. 2011;21(3):e156-e158. doi:10.1097/SLE.0b013e31821d47ce
6. Sherren J. A double gall-bladder removed by operation. Ann Surg. 1911;54(2):204-205. doi:10.1097/00000658-191108000-00009
7. Boyden EA. The accessory gall-bladder—an embryological and comparative study of aberrant biliary vesicles occurring in man and the domestic mammals. Am J Anat. 1926; 38(2):177-231. doi:10.1002/aja.1000380202
8. Harlaftis N, Gray SW, Skandalakis JE. Multiple gallbladders. Surg Gynecol Obstet. 1977;145(6):928-934.
9. Kim RD, Zendejas I, Velopulos C, et al. Duplicate gallbladder arising from the left hepatic duct: report of a case. Surg Today. 2009;39(6):536-539. doi:10.1007/s00595-008-3878-4
10. Causey MW, Miller S, Fernelius CA, Burgess JR, Brown TA, Newton C. Gallbladder duplication: evaluation, treatment, and classification. J Pediatr Surg. 2010;45(2):443-446. doi:10.1016/j.jpedsurg.2009.12.015
11. Apolo Romero EX, Gálvez Salazar PF, Estrada Chandi JA, et al. Gallbladder duplication and cholecystitis. J Surg Case Rep. 2018;2018(7):rjy158. Published 2018 Jul 3. doi:10.1093/jscr/rjy158
12. Gorecki PJ, Andrei VE, Musacchio T, Schein M. Double gallbladder originating from left hepatic duct: a case report and review of literature. JSLS. 1998;2(4):337-339.
13. Cueto García J, Weber A, Serrano Berry F, Tanur Tatz B. Double gallbladder treated successfully by laparoscopy. J Laparoendosc Surg. 1993;3(2):153-155. doi:10.1089/lps.1993.3.153
14. Fazio V, Damiano G, Palumbo VD, et al. An unexpected surprise at the end of a “quiet” cholecystectomy. A case report and review of the literature. Ann Ital Chir. 2012;83(3):265-267.
15. Flum DR, Dellinger EP, Cheadle A, Chan L, Koepsell T. Intraoperative cholangiography and risk of common bile duct injury during cholecystectomy. JAMA. 2003;289(13):1639-1644. doi:10.1001/jama.289.13.1639
16. Botsford A, McKay K, Hartery A, Hapgood C. MRCP imaging of duplicate gallbladder: a case report and review of the literature. Surg Radiol Anat. 2015;37(5):425-429. doi:10.1007/s00276-015-1456-1
17. Strasberg SM, Hertl M, Soper NJ. An analysis of the problem of biliary injury during laparoscopic cholecystectomy. J Am Coll Surg. 1995;180(1):101-125.
18. Raymond SW, Thrift CB. Carcinoma of a duplicated gall bladder. Ill Med J. 1956;110(5):239-240.
19. Cunningham JJ. Empyema of a duplicated gallbladder: echographic findings. J Clin Ultrasound. 1980;8(6):511-512. doi:10.1002/jcu.1870080612
20. Recht W. Torsion of a double gallbladder; a report of a case and a review of the literature. Br J Surg. 1952;39(156):342-344. doi:10.1002/bjs.18003915616
21. Ritchie AW, Crucioli V. Double gallbladder with cholecystocolic fistula: a case report. Br J Surg. 1980;67(2):145-146. doi:10.1002/bjs.1800670226
22. Shapiro T, Rennie W. Duplicate gallbladder cholecystitis after open cholecystectomy. Ann Emerg Med. 1999;33(5):584-587. doi:10.1016/s0196-0644(99)70348-3
23. Hobbs MS, Mai Q, Knuiman MW, Fletcher DR, Ridout SC. Surgeon experience and trends in intraoperative complications in laparoscopic cholecystectomy. Br J Surg. 2006;93(7):844-853. doi:10.1002/bjs.5333
24. Davidoff AM, Pappas TN, Murray EA, et al. Mechanisms of major biliary injury during laparoscopic cholecystectomy. Ann Surg. 1992;215(3):196-202. doi:10.1097/00000658-199203000-00002
25. Flowers JL, Zucker KA, Graham SM, Scovill WA, Imbembo AL, Bailey RW. Laparoscopic cholangiography. Results and indications. Ann Surg. 1992;215(3):209-216. doi:10.1097/00000658-199203000-00004
1. Vezakis A, Pantiora E, Giannoulopoulos D, et al. A duplicated gallbladder in a patient presenting with acute cholangitis. A case study and a literature review. Ann Hepatol. 2019;18(1):240-245. doi:10.5604/01.3001.0012.7932
2. Barut Í, Tarhan ÖR, Dog^ru U, Bülbül M. Gallbladder duplication: diagnosed and treated by laparoscopy. Eur J Gen Med. 2006;3(3):142-145. doi:10.29333/ejgm/82396 3. Cozacov Y, Subhas G, Jacobs M, Parikh J. Total laparoscopic removal of accessory gallbladder: a case report and review of literature. World J Gastrointest Surg. 2015;7(12):398-402. doi:10.4240/wjgs.v7.i12.398
4. Musleh MG, Burnett H, Rajashanker B, Ammori BJ. Laparoscopic double cholecystectomy for duplicated gallbladder: a case report. Int J Surg Case Rep. 2017;41:502-504. Published 2017 Nov 27. doi:10.1016/j.ijscr.2017.11.046
5. Walbolt TD, Lalezarzadeh F. Laparoscopic management of a duplicated gallbladder: a case study and anatomic history. Surg Laparosc Endosc Percutan Tech. 2011;21(3):e156-e158. doi:10.1097/SLE.0b013e31821d47ce
6. Sherren J. A double gall-bladder removed by operation. Ann Surg. 1911;54(2):204-205. doi:10.1097/00000658-191108000-00009
7. Boyden EA. The accessory gall-bladder—an embryological and comparative study of aberrant biliary vesicles occurring in man and the domestic mammals. Am J Anat. 1926; 38(2):177-231. doi:10.1002/aja.1000380202
8. Harlaftis N, Gray SW, Skandalakis JE. Multiple gallbladders. Surg Gynecol Obstet. 1977;145(6):928-934.
9. Kim RD, Zendejas I, Velopulos C, et al. Duplicate gallbladder arising from the left hepatic duct: report of a case. Surg Today. 2009;39(6):536-539. doi:10.1007/s00595-008-3878-4
10. Causey MW, Miller S, Fernelius CA, Burgess JR, Brown TA, Newton C. Gallbladder duplication: evaluation, treatment, and classification. J Pediatr Surg. 2010;45(2):443-446. doi:10.1016/j.jpedsurg.2009.12.015
11. Apolo Romero EX, Gálvez Salazar PF, Estrada Chandi JA, et al. Gallbladder duplication and cholecystitis. J Surg Case Rep. 2018;2018(7):rjy158. Published 2018 Jul 3. doi:10.1093/jscr/rjy158
12. Gorecki PJ, Andrei VE, Musacchio T, Schein M. Double gallbladder originating from left hepatic duct: a case report and review of literature. JSLS. 1998;2(4):337-339.
13. Cueto García J, Weber A, Serrano Berry F, Tanur Tatz B. Double gallbladder treated successfully by laparoscopy. J Laparoendosc Surg. 1993;3(2):153-155. doi:10.1089/lps.1993.3.153
14. Fazio V, Damiano G, Palumbo VD, et al. An unexpected surprise at the end of a “quiet” cholecystectomy. A case report and review of the literature. Ann Ital Chir. 2012;83(3):265-267.
15. Flum DR, Dellinger EP, Cheadle A, Chan L, Koepsell T. Intraoperative cholangiography and risk of common bile duct injury during cholecystectomy. JAMA. 2003;289(13):1639-1644. doi:10.1001/jama.289.13.1639
16. Botsford A, McKay K, Hartery A, Hapgood C. MRCP imaging of duplicate gallbladder: a case report and review of the literature. Surg Radiol Anat. 2015;37(5):425-429. doi:10.1007/s00276-015-1456-1
17. Strasberg SM, Hertl M, Soper NJ. An analysis of the problem of biliary injury during laparoscopic cholecystectomy. J Am Coll Surg. 1995;180(1):101-125.
18. Raymond SW, Thrift CB. Carcinoma of a duplicated gall bladder. Ill Med J. 1956;110(5):239-240.
19. Cunningham JJ. Empyema of a duplicated gallbladder: echographic findings. J Clin Ultrasound. 1980;8(6):511-512. doi:10.1002/jcu.1870080612
20. Recht W. Torsion of a double gallbladder; a report of a case and a review of the literature. Br J Surg. 1952;39(156):342-344. doi:10.1002/bjs.18003915616
21. Ritchie AW, Crucioli V. Double gallbladder with cholecystocolic fistula: a case report. Br J Surg. 1980;67(2):145-146. doi:10.1002/bjs.1800670226
22. Shapiro T, Rennie W. Duplicate gallbladder cholecystitis after open cholecystectomy. Ann Emerg Med. 1999;33(5):584-587. doi:10.1016/s0196-0644(99)70348-3
23. Hobbs MS, Mai Q, Knuiman MW, Fletcher DR, Ridout SC. Surgeon experience and trends in intraoperative complications in laparoscopic cholecystectomy. Br J Surg. 2006;93(7):844-853. doi:10.1002/bjs.5333
24. Davidoff AM, Pappas TN, Murray EA, et al. Mechanisms of major biliary injury during laparoscopic cholecystectomy. Ann Surg. 1992;215(3):196-202. doi:10.1097/00000658-199203000-00002
25. Flowers JL, Zucker KA, Graham SM, Scovill WA, Imbembo AL, Bailey RW. Laparoscopic cholangiography. Results and indications. Ann Surg. 1992;215(3):209-216. doi:10.1097/00000658-199203000-00004
FDA hints at deadlines to meet accelerated approval requirements
The FDA launched its accelerated approval program in 1992 in response to the AIDS crisis, but the bulk of approvals since then have been for cancer drugs, wrote the authors who included Gautam U. Mehta, MD, a clinical reviewer with the FDA’s Center for Drug Evaluation and Research; R. Angelo de Claro, MD, associate director of the FDA’s Global Clinical Sciences division within the Oncology Center of Excellence; and Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence.
Accelerated approvals are typically granted in oncology based on overall response rate with a requirement that companies confirm that there’s actually a clinical benefit in postmarketing studies.
The system has inspired European nations and Australia to launch their own programs, but with a key difference: Conditional approvals expire within 1 year or 2.
To be reinstated and remain on the market, companies have to submit a timeline for when they’ll meet their outstanding obligations and demonstrate that the benefit of leaving their product on the market outweighs the risk.
The approach puts “the onus of timely completion of confirmatory trials and verification of benefit” on the drug maker. In the meantime, the system limits “public exposure to stale claims of effectiveness that cannot be expeditiously substantiated,” Dr. Mehta and colleagues wrote.
There aren’t any deadlines in the United States, however, so the FDA has “to initiate a resource-intensive withdrawal process” when proof of clinical benefit is not forthcoming, they said.
In the United States, only 14 of 167 oncology indications granted accelerated approval since 1992 were withdrawn voluntarily and one was withdrawn by FDA request, and one was forced by the agency. The median time from accelerated approval to withdrawal was 8.8 years.
The actual withdrawal process itself took 11 months when bevacizumab’s breast cancer indication was canceled in 2011.
The authors didn’t call for change outright, but they did say that “future discussions of the accelerated approval program in the U.S.” will seek “to coordinate regulatory processes” with other countries, with an eye towards building “harmony between” agencies.
Among other targets for possible harmonization, they noted that only new molecular entities are eligible for accelerated approval in Europe, whereas supplemental indications are also eligible in the United States
Europe also requires a risk-benefit assessment for conditional approvals, which “has led to relatively few approvals based on single-arm clinical trial data,” the authors said.
Dr. Mehta, Dr. de Claro, and Dr. Pazdur had no conflicts of interest.
The FDA launched its accelerated approval program in 1992 in response to the AIDS crisis, but the bulk of approvals since then have been for cancer drugs, wrote the authors who included Gautam U. Mehta, MD, a clinical reviewer with the FDA’s Center for Drug Evaluation and Research; R. Angelo de Claro, MD, associate director of the FDA’s Global Clinical Sciences division within the Oncology Center of Excellence; and Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence.
Accelerated approvals are typically granted in oncology based on overall response rate with a requirement that companies confirm that there’s actually a clinical benefit in postmarketing studies.
The system has inspired European nations and Australia to launch their own programs, but with a key difference: Conditional approvals expire within 1 year or 2.
To be reinstated and remain on the market, companies have to submit a timeline for when they’ll meet their outstanding obligations and demonstrate that the benefit of leaving their product on the market outweighs the risk.
The approach puts “the onus of timely completion of confirmatory trials and verification of benefit” on the drug maker. In the meantime, the system limits “public exposure to stale claims of effectiveness that cannot be expeditiously substantiated,” Dr. Mehta and colleagues wrote.
There aren’t any deadlines in the United States, however, so the FDA has “to initiate a resource-intensive withdrawal process” when proof of clinical benefit is not forthcoming, they said.
In the United States, only 14 of 167 oncology indications granted accelerated approval since 1992 were withdrawn voluntarily and one was withdrawn by FDA request, and one was forced by the agency. The median time from accelerated approval to withdrawal was 8.8 years.
The actual withdrawal process itself took 11 months when bevacizumab’s breast cancer indication was canceled in 2011.
The authors didn’t call for change outright, but they did say that “future discussions of the accelerated approval program in the U.S.” will seek “to coordinate regulatory processes” with other countries, with an eye towards building “harmony between” agencies.
Among other targets for possible harmonization, they noted that only new molecular entities are eligible for accelerated approval in Europe, whereas supplemental indications are also eligible in the United States
Europe also requires a risk-benefit assessment for conditional approvals, which “has led to relatively few approvals based on single-arm clinical trial data,” the authors said.
Dr. Mehta, Dr. de Claro, and Dr. Pazdur had no conflicts of interest.
The FDA launched its accelerated approval program in 1992 in response to the AIDS crisis, but the bulk of approvals since then have been for cancer drugs, wrote the authors who included Gautam U. Mehta, MD, a clinical reviewer with the FDA’s Center for Drug Evaluation and Research; R. Angelo de Claro, MD, associate director of the FDA’s Global Clinical Sciences division within the Oncology Center of Excellence; and Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence.
Accelerated approvals are typically granted in oncology based on overall response rate with a requirement that companies confirm that there’s actually a clinical benefit in postmarketing studies.
The system has inspired European nations and Australia to launch their own programs, but with a key difference: Conditional approvals expire within 1 year or 2.
To be reinstated and remain on the market, companies have to submit a timeline for when they’ll meet their outstanding obligations and demonstrate that the benefit of leaving their product on the market outweighs the risk.
The approach puts “the onus of timely completion of confirmatory trials and verification of benefit” on the drug maker. In the meantime, the system limits “public exposure to stale claims of effectiveness that cannot be expeditiously substantiated,” Dr. Mehta and colleagues wrote.
There aren’t any deadlines in the United States, however, so the FDA has “to initiate a resource-intensive withdrawal process” when proof of clinical benefit is not forthcoming, they said.
In the United States, only 14 of 167 oncology indications granted accelerated approval since 1992 were withdrawn voluntarily and one was withdrawn by FDA request, and one was forced by the agency. The median time from accelerated approval to withdrawal was 8.8 years.
The actual withdrawal process itself took 11 months when bevacizumab’s breast cancer indication was canceled in 2011.
The authors didn’t call for change outright, but they did say that “future discussions of the accelerated approval program in the U.S.” will seek “to coordinate regulatory processes” with other countries, with an eye towards building “harmony between” agencies.
Among other targets for possible harmonization, they noted that only new molecular entities are eligible for accelerated approval in Europe, whereas supplemental indications are also eligible in the United States
Europe also requires a risk-benefit assessment for conditional approvals, which “has led to relatively few approvals based on single-arm clinical trial data,” the authors said.
Dr. Mehta, Dr. de Claro, and Dr. Pazdur had no conflicts of interest.
FROM JAMA ONCOLOGY
The battle of egos behind the life-saving discovery of insulin
Leonard Thompson’s father was so desperate to save his 14-year-old child from certain death due to diabetes that, on Jan. 11, 1922, he took him to Toronto General Hospital to receive what is arguably the first dose of insulin given to a human. From an anticipated life expectancy of weeks – months at best – Thompson lived for an astonishing further 13 years, eventually dying from pneumonia unrelated to diabetes.
By all accounts, the story is a centenary celebration of a remarkable discovery. Insulin has changed what was once a death sentence to a near-normal life expectancy for the millions of people with type 1 diabetes over the past 100 years.
But behind the life-changing success of the discovery – and the Nobel Prize that went with it – lies a tale blighted by disputed claims, twisted truths, and likely injustices between the scientists involved, as they each vied for an honored place in medical history.
Kersten Hall, PhD, honorary fellow, religion and history of science, at the University of Leeds, England, has scoured archives and personal records held at the University of Toronto to uncover the personal stories behind insulin’s discovery.
Despite the wranglings, Dr. Hall asserts: “There’s a distinction between the science and the scientists. Scientists are wonderfully flawed and complex human beings with all their glorious virtues and vices, as we all are. It’s no surprise that they get greedy, jealous, and insecure.”
At death’s door: Diabetes before the 1920s
Prior to insulin’s discovery in 1921, a diagnosis of type 1 diabetes placed someone at death’s door, with nothing but starvation – albeit a slightly slower death – to mitigate a fast-approaching departure from this world. At that time, most diabetes cases would have been type 1 diabetes because, with less obesogenic diets and shorter lifespans, people were much less likely to develop type 2 diabetes.
Nowadays, it is widely recognized that the prevalence of type 2 diabetes is on a steep upward curve, but so too is type 1 diabetes. In the United States alone, there are 1.5 million people diagnosed with type 1 diabetes, a number expected to rise to around 5 million by 2050, according to JDRF, the type 1 diabetes advocacy organization.
Interestingly, 100 years since the first treated patient, life-long insulin remains the only real effective therapy for patients with type 1 diabetes. Once pancreatic beta cells have ceased to function and insulin production has stopped, insulin replacement is the only way to keep blood glucose levels within the recommended range (A1c ≤ 48 mmol/mol [6.5%]), according to the UK National Institute for Health and Care Excellence (NICE), as well as numerous diabetes organizations, including the American Diabetes Association (ADA).
Preliminary clinical trials have looked at stem cell transplantation, prematurely dubbed as a “cure” for type 1 diabetes, as an alternative to insulin therapy. The procedure involves transplanting stem cell–derived cells, which become functional beta cells when infused into humans, but requires immunosuppression, as reported by this news organization.
Today, the life expectancy of people with type 1 diabetes treated with insulin is close to those without the disease, although this is dependent on how tightly blood glucose is controlled. Some studies show life expectancy of those with type 1 diabetes is around 8-12 years lower than the general population but varies depending on where a person lives.
In some lower-income countries, many with type 1 diabetes still die prematurely either because they are undiagnosed or cannot access insulin. The high cost of insulin in the United States is well publicized, as featured in numerous articles by this news organization, and numerous patients in the United States have died because they cannot afford insulin.
Without insulin, young Leonard Thompson would have been lucky to have reached his 15th birthday.
“Such patients were cachectic and thin and would have weighed around 40-50 pounds (18-23 kg), which is very low for an older child. Survival was short and lasted weeks or months usually,” said Elizabeth Stephens, MD, an endocrinologist in Portland, Ore.
“The discovery of insulin was really a miracle because without it diabetes patients were facing certain death. Even nowadays, if people don’t get their insulin because they can’t afford it or for whatever reason, they can still die,” Dr. Stephens stressed.
Antidiabetic effects of pancreatic extract limited
Back in 1869, Paul Langerhans, MD, discovered pancreatic islet cells, or islets of Langerhans, as a medical student. Researchers tried to produce extracts that lowered blood glucose but they were too toxic for patient use.
In 1908, as detailed in his recent book, Insulin – the Crooked Timber, Dr. Hall also refers to the fact that a German researcher, Georg Zuelzer, MD, demonstrated in six patients that pancreatic extracts could reduce urinary levels of glucose and ketones, and that in one case, the treatment woke the patient from a coma. Dr. Zuelzer had purified the extract with alcohol but patients still experienced convulsions and coma; in fact, they were experiencing hypoglycemic shock, but Dr. Zuelzer had not identified it as such.
“He thought his preparation was full of impurities – and that’s the irony. He had in his hands an insulin prep that was so clean and so potent that it sent the test animals into hypoglycemic shock,” Dr. Hall pointed out.
By 1921, two young researchers, Frederick G. Banting, MD, a practicing medical doctor in Toronto, together with a final year physiology student at the University of Toronto, Charles H. Best, MD, DSc, collaborated on the instruction of Dr. Best’s superior, John James Rickard Macleod, MBChB, professor of physiology at the University of Toronto, to make pancreatic extracts, first from dogs and then from cattle.
Over the months prior to treating Thompson, working together in the laboratory, Dr. Banting and Dr. Best prepared the pancreatic extract from cattle and tested it on dogs with diabetes.
Then, in what amounted to a phase 1 trial of its day, with an “n of one,” a frail and close-to-death Thompson was given 15 cc of pancreatic extract at Toronto General Hospital in January 1922. His blood glucose level dropped by 25%, but unfortunately, his body still produced ketones, indicating the antidiabetic effect was limited. He also experienced an adverse reaction at the injection site with an accumulation of abscesses.
So despite success with isolating the extract and administering it to Thompson, the product remained tainted with impurities.
At this point, colleague James Collip, MD, PhD, came to the rescue. He used his skills as a biochemist to purify the pancreatic extract enough to eliminate impurities.
When Thompson was treated 2 weeks later with the purified extract, he experienced a more positive outcome. Gone was the injection site reaction, gone were the high blood glucose levels, and Thompson “became brighter, more active, looked better, and said he felt stronger,” according to a publication describing the treatment.
Dr. Collip also determined that by over-purifying the product, the animals he experimented on could overreact and experience convulsions, coma, and death due to hypoglycemia from too much insulin.
Fighting talk
Recalling an excerpt from Dr. Banting’s diary, Dr. Hall said that Dr. Banting had a mercurial temper and testified to his loss of patience with Dr. Collip when the chemist refused to share his formula of purification. His diary reads: “I grabbed him in one hand by the overcoat ... and almost lifting him I sat him down hard on the chair ... I remember telling him that it was a good job he was so much smaller – otherwise I would ‘knock hell out of him.’ ”
According to Dr. Hall, in 1923, when Dr. Banting and Dr. Macleod were jointly awarded the Nobel Prize for Medicine, Dr. Best resented being excluded, and despite Dr. Banting’s sharing half his prize money with Dr. Best, animosity prevailed.
At one point, before leaving on a plane for a wartime mission to the United Kingdom, Dr. Banting noted that if he didn’t make it back alive, “and they give my [professorial] chair to that son-of-a-bitch Best, I’ll never rest in my grave.” In a cruel twist of fate, Dr. Banting’s plane crashed and all aboard died.
The Nobel Prize had also been a source of rivalry between Dr. Banting and his boss, Dr. Macleod. In late 1921, while presenting the findings from animal models at the American Physiological Society conference, Dr. Banting’s nerves got the better of him and Dr. Macleod took over at the podium to finish the talk. Dr. Banting perceived this as his boss stealing the limelight.
Only a few months later, at the Association of American Physicians annual conference, Dr. Macleod played to an audience for a second time by making the first formal announcement of the discovery to the scientific community. Notably, Dr. Banting was absent.
The Nobel Prize or a poisoned chalice?
Awarded annually for physics, chemistry, medicine/physiology, literature, peace, and economics, Nobel Prizes are usually considered the holy grail of achievement. In 1895, funds for the prizes were bequeathed by Alfred Nobel in his last will and testament, with each prize worth around $40,000 at the time (approximately $1,000,000 in today’s value).
Writing in 2001 in the journal Diabetes Voice, Professor Sir George Alberti, DPhil, BM BCh, former president of the UK Royal College of Physicians, summarized the burden that accompanies the Nobel Prize: “I personally believe that such prizes and awards do more harm than good and should be abolished. Many a scientist has gone to their grave feeling deeply aggrieved because they were not awarded a Nobel Prize.”
Such high stakes surround the prize that, in the case of insulin, the course of its discovery meant courtesies and truth were swept aside in hot pursuit of fame. After Dr. Macleod died in 1935 and Dr. Banting died in 1941, Dr. Best took the opportunity to try to revise history. There was the small obstacle of Dr. Collip, but Dr. Best managed to play down Dr. Collip’s contribution by focusing on the eureka moment as being the first insulin dose administered, despite the fact that a more complete recovery without side effects was later achieved only with Dr. Collip’s help.
Despite exclusion from the Nobel Prize, Dr. Best nevertheless became recognized as the “go-to-guy” for the discovery of insulin, said Dr. Hall. When Dr. Best spoke about the discovery of insulin at the New York Diabetes Association meeting in 1946, he was introduced as a speaker whose reputation was already so great that he did “not require much of an introduction.”
“And when a new research institute was opened in Toronto in 1953, it was named in his honor. The opening address, by Sir Henry Dale of the UK Medical Research Council, sang Best’s praises to the rafters, much to the disgruntlement of Best’s former colleague, James Collip, who was sitting in the audience,” Dr. Hall pointed out.
Both Dr. Hall and Dr. Stephens live with type 1 diabetes and have benefited from the efforts of Dr. Banting, Dr. Best, Dr. Collip, Dr. Zuelzer, and Dr. Macleod.
“The discovery of insulin was a miracle, it has allowed people to survive,” said Dr. Stephens. “Few medicines can reverse a death sentence like insulin can. It’s easy to forget how it was when insulin wasn’t there – and it wasn’t that long ago.”
Dr. Hall reflects that scientific progress and discovery are often portrayed as being the result of towering geniuses standing on each other’s shoulders.
“But I think that when German philosopher Immanuel Kant remarked that ‘Out of the crooked timber of humanity, no straight thing can ever be made,’ he offered us a much more accurate picture of how science works. And I think that there’s perhaps no more powerful example of this than the story of insulin,” he said.
A version of this article first appeared on Medscape.com.
Leonard Thompson’s father was so desperate to save his 14-year-old child from certain death due to diabetes that, on Jan. 11, 1922, he took him to Toronto General Hospital to receive what is arguably the first dose of insulin given to a human. From an anticipated life expectancy of weeks – months at best – Thompson lived for an astonishing further 13 years, eventually dying from pneumonia unrelated to diabetes.
By all accounts, the story is a centenary celebration of a remarkable discovery. Insulin has changed what was once a death sentence to a near-normal life expectancy for the millions of people with type 1 diabetes over the past 100 years.
But behind the life-changing success of the discovery – and the Nobel Prize that went with it – lies a tale blighted by disputed claims, twisted truths, and likely injustices between the scientists involved, as they each vied for an honored place in medical history.
Kersten Hall, PhD, honorary fellow, religion and history of science, at the University of Leeds, England, has scoured archives and personal records held at the University of Toronto to uncover the personal stories behind insulin’s discovery.
Despite the wranglings, Dr. Hall asserts: “There’s a distinction between the science and the scientists. Scientists are wonderfully flawed and complex human beings with all their glorious virtues and vices, as we all are. It’s no surprise that they get greedy, jealous, and insecure.”
At death’s door: Diabetes before the 1920s
Prior to insulin’s discovery in 1921, a diagnosis of type 1 diabetes placed someone at death’s door, with nothing but starvation – albeit a slightly slower death – to mitigate a fast-approaching departure from this world. At that time, most diabetes cases would have been type 1 diabetes because, with less obesogenic diets and shorter lifespans, people were much less likely to develop type 2 diabetes.
Nowadays, it is widely recognized that the prevalence of type 2 diabetes is on a steep upward curve, but so too is type 1 diabetes. In the United States alone, there are 1.5 million people diagnosed with type 1 diabetes, a number expected to rise to around 5 million by 2050, according to JDRF, the type 1 diabetes advocacy organization.
Interestingly, 100 years since the first treated patient, life-long insulin remains the only real effective therapy for patients with type 1 diabetes. Once pancreatic beta cells have ceased to function and insulin production has stopped, insulin replacement is the only way to keep blood glucose levels within the recommended range (A1c ≤ 48 mmol/mol [6.5%]), according to the UK National Institute for Health and Care Excellence (NICE), as well as numerous diabetes organizations, including the American Diabetes Association (ADA).
Preliminary clinical trials have looked at stem cell transplantation, prematurely dubbed as a “cure” for type 1 diabetes, as an alternative to insulin therapy. The procedure involves transplanting stem cell–derived cells, which become functional beta cells when infused into humans, but requires immunosuppression, as reported by this news organization.
Today, the life expectancy of people with type 1 diabetes treated with insulin is close to those without the disease, although this is dependent on how tightly blood glucose is controlled. Some studies show life expectancy of those with type 1 diabetes is around 8-12 years lower than the general population but varies depending on where a person lives.
In some lower-income countries, many with type 1 diabetes still die prematurely either because they are undiagnosed or cannot access insulin. The high cost of insulin in the United States is well publicized, as featured in numerous articles by this news organization, and numerous patients in the United States have died because they cannot afford insulin.
Without insulin, young Leonard Thompson would have been lucky to have reached his 15th birthday.
“Such patients were cachectic and thin and would have weighed around 40-50 pounds (18-23 kg), which is very low for an older child. Survival was short and lasted weeks or months usually,” said Elizabeth Stephens, MD, an endocrinologist in Portland, Ore.
“The discovery of insulin was really a miracle because without it diabetes patients were facing certain death. Even nowadays, if people don’t get their insulin because they can’t afford it or for whatever reason, they can still die,” Dr. Stephens stressed.
Antidiabetic effects of pancreatic extract limited
Back in 1869, Paul Langerhans, MD, discovered pancreatic islet cells, or islets of Langerhans, as a medical student. Researchers tried to produce extracts that lowered blood glucose but they were too toxic for patient use.
In 1908, as detailed in his recent book, Insulin – the Crooked Timber, Dr. Hall also refers to the fact that a German researcher, Georg Zuelzer, MD, demonstrated in six patients that pancreatic extracts could reduce urinary levels of glucose and ketones, and that in one case, the treatment woke the patient from a coma. Dr. Zuelzer had purified the extract with alcohol but patients still experienced convulsions and coma; in fact, they were experiencing hypoglycemic shock, but Dr. Zuelzer had not identified it as such.
“He thought his preparation was full of impurities – and that’s the irony. He had in his hands an insulin prep that was so clean and so potent that it sent the test animals into hypoglycemic shock,” Dr. Hall pointed out.
By 1921, two young researchers, Frederick G. Banting, MD, a practicing medical doctor in Toronto, together with a final year physiology student at the University of Toronto, Charles H. Best, MD, DSc, collaborated on the instruction of Dr. Best’s superior, John James Rickard Macleod, MBChB, professor of physiology at the University of Toronto, to make pancreatic extracts, first from dogs and then from cattle.
Over the months prior to treating Thompson, working together in the laboratory, Dr. Banting and Dr. Best prepared the pancreatic extract from cattle and tested it on dogs with diabetes.
Then, in what amounted to a phase 1 trial of its day, with an “n of one,” a frail and close-to-death Thompson was given 15 cc of pancreatic extract at Toronto General Hospital in January 1922. His blood glucose level dropped by 25%, but unfortunately, his body still produced ketones, indicating the antidiabetic effect was limited. He also experienced an adverse reaction at the injection site with an accumulation of abscesses.
So despite success with isolating the extract and administering it to Thompson, the product remained tainted with impurities.
At this point, colleague James Collip, MD, PhD, came to the rescue. He used his skills as a biochemist to purify the pancreatic extract enough to eliminate impurities.
When Thompson was treated 2 weeks later with the purified extract, he experienced a more positive outcome. Gone was the injection site reaction, gone were the high blood glucose levels, and Thompson “became brighter, more active, looked better, and said he felt stronger,” according to a publication describing the treatment.
Dr. Collip also determined that by over-purifying the product, the animals he experimented on could overreact and experience convulsions, coma, and death due to hypoglycemia from too much insulin.
Fighting talk
Recalling an excerpt from Dr. Banting’s diary, Dr. Hall said that Dr. Banting had a mercurial temper and testified to his loss of patience with Dr. Collip when the chemist refused to share his formula of purification. His diary reads: “I grabbed him in one hand by the overcoat ... and almost lifting him I sat him down hard on the chair ... I remember telling him that it was a good job he was so much smaller – otherwise I would ‘knock hell out of him.’ ”
According to Dr. Hall, in 1923, when Dr. Banting and Dr. Macleod were jointly awarded the Nobel Prize for Medicine, Dr. Best resented being excluded, and despite Dr. Banting’s sharing half his prize money with Dr. Best, animosity prevailed.
At one point, before leaving on a plane for a wartime mission to the United Kingdom, Dr. Banting noted that if he didn’t make it back alive, “and they give my [professorial] chair to that son-of-a-bitch Best, I’ll never rest in my grave.” In a cruel twist of fate, Dr. Banting’s plane crashed and all aboard died.
The Nobel Prize had also been a source of rivalry between Dr. Banting and his boss, Dr. Macleod. In late 1921, while presenting the findings from animal models at the American Physiological Society conference, Dr. Banting’s nerves got the better of him and Dr. Macleod took over at the podium to finish the talk. Dr. Banting perceived this as his boss stealing the limelight.
Only a few months later, at the Association of American Physicians annual conference, Dr. Macleod played to an audience for a second time by making the first formal announcement of the discovery to the scientific community. Notably, Dr. Banting was absent.
The Nobel Prize or a poisoned chalice?
Awarded annually for physics, chemistry, medicine/physiology, literature, peace, and economics, Nobel Prizes are usually considered the holy grail of achievement. In 1895, funds for the prizes were bequeathed by Alfred Nobel in his last will and testament, with each prize worth around $40,000 at the time (approximately $1,000,000 in today’s value).
Writing in 2001 in the journal Diabetes Voice, Professor Sir George Alberti, DPhil, BM BCh, former president of the UK Royal College of Physicians, summarized the burden that accompanies the Nobel Prize: “I personally believe that such prizes and awards do more harm than good and should be abolished. Many a scientist has gone to their grave feeling deeply aggrieved because they were not awarded a Nobel Prize.”
Such high stakes surround the prize that, in the case of insulin, the course of its discovery meant courtesies and truth were swept aside in hot pursuit of fame. After Dr. Macleod died in 1935 and Dr. Banting died in 1941, Dr. Best took the opportunity to try to revise history. There was the small obstacle of Dr. Collip, but Dr. Best managed to play down Dr. Collip’s contribution by focusing on the eureka moment as being the first insulin dose administered, despite the fact that a more complete recovery without side effects was later achieved only with Dr. Collip’s help.
Despite exclusion from the Nobel Prize, Dr. Best nevertheless became recognized as the “go-to-guy” for the discovery of insulin, said Dr. Hall. When Dr. Best spoke about the discovery of insulin at the New York Diabetes Association meeting in 1946, he was introduced as a speaker whose reputation was already so great that he did “not require much of an introduction.”
“And when a new research institute was opened in Toronto in 1953, it was named in his honor. The opening address, by Sir Henry Dale of the UK Medical Research Council, sang Best’s praises to the rafters, much to the disgruntlement of Best’s former colleague, James Collip, who was sitting in the audience,” Dr. Hall pointed out.
Both Dr. Hall and Dr. Stephens live with type 1 diabetes and have benefited from the efforts of Dr. Banting, Dr. Best, Dr. Collip, Dr. Zuelzer, and Dr. Macleod.
“The discovery of insulin was a miracle, it has allowed people to survive,” said Dr. Stephens. “Few medicines can reverse a death sentence like insulin can. It’s easy to forget how it was when insulin wasn’t there – and it wasn’t that long ago.”
Dr. Hall reflects that scientific progress and discovery are often portrayed as being the result of towering geniuses standing on each other’s shoulders.
“But I think that when German philosopher Immanuel Kant remarked that ‘Out of the crooked timber of humanity, no straight thing can ever be made,’ he offered us a much more accurate picture of how science works. And I think that there’s perhaps no more powerful example of this than the story of insulin,” he said.
A version of this article first appeared on Medscape.com.
Leonard Thompson’s father was so desperate to save his 14-year-old child from certain death due to diabetes that, on Jan. 11, 1922, he took him to Toronto General Hospital to receive what is arguably the first dose of insulin given to a human. From an anticipated life expectancy of weeks – months at best – Thompson lived for an astonishing further 13 years, eventually dying from pneumonia unrelated to diabetes.
By all accounts, the story is a centenary celebration of a remarkable discovery. Insulin has changed what was once a death sentence to a near-normal life expectancy for the millions of people with type 1 diabetes over the past 100 years.
But behind the life-changing success of the discovery – and the Nobel Prize that went with it – lies a tale blighted by disputed claims, twisted truths, and likely injustices between the scientists involved, as they each vied for an honored place in medical history.
Kersten Hall, PhD, honorary fellow, religion and history of science, at the University of Leeds, England, has scoured archives and personal records held at the University of Toronto to uncover the personal stories behind insulin’s discovery.
Despite the wranglings, Dr. Hall asserts: “There’s a distinction between the science and the scientists. Scientists are wonderfully flawed and complex human beings with all their glorious virtues and vices, as we all are. It’s no surprise that they get greedy, jealous, and insecure.”
At death’s door: Diabetes before the 1920s
Prior to insulin’s discovery in 1921, a diagnosis of type 1 diabetes placed someone at death’s door, with nothing but starvation – albeit a slightly slower death – to mitigate a fast-approaching departure from this world. At that time, most diabetes cases would have been type 1 diabetes because, with less obesogenic diets and shorter lifespans, people were much less likely to develop type 2 diabetes.
Nowadays, it is widely recognized that the prevalence of type 2 diabetes is on a steep upward curve, but so too is type 1 diabetes. In the United States alone, there are 1.5 million people diagnosed with type 1 diabetes, a number expected to rise to around 5 million by 2050, according to JDRF, the type 1 diabetes advocacy organization.
Interestingly, 100 years since the first treated patient, life-long insulin remains the only real effective therapy for patients with type 1 diabetes. Once pancreatic beta cells have ceased to function and insulin production has stopped, insulin replacement is the only way to keep blood glucose levels within the recommended range (A1c ≤ 48 mmol/mol [6.5%]), according to the UK National Institute for Health and Care Excellence (NICE), as well as numerous diabetes organizations, including the American Diabetes Association (ADA).
Preliminary clinical trials have looked at stem cell transplantation, prematurely dubbed as a “cure” for type 1 diabetes, as an alternative to insulin therapy. The procedure involves transplanting stem cell–derived cells, which become functional beta cells when infused into humans, but requires immunosuppression, as reported by this news organization.
Today, the life expectancy of people with type 1 diabetes treated with insulin is close to those without the disease, although this is dependent on how tightly blood glucose is controlled. Some studies show life expectancy of those with type 1 diabetes is around 8-12 years lower than the general population but varies depending on where a person lives.
In some lower-income countries, many with type 1 diabetes still die prematurely either because they are undiagnosed or cannot access insulin. The high cost of insulin in the United States is well publicized, as featured in numerous articles by this news organization, and numerous patients in the United States have died because they cannot afford insulin.
Without insulin, young Leonard Thompson would have been lucky to have reached his 15th birthday.
“Such patients were cachectic and thin and would have weighed around 40-50 pounds (18-23 kg), which is very low for an older child. Survival was short and lasted weeks or months usually,” said Elizabeth Stephens, MD, an endocrinologist in Portland, Ore.
“The discovery of insulin was really a miracle because without it diabetes patients were facing certain death. Even nowadays, if people don’t get their insulin because they can’t afford it or for whatever reason, they can still die,” Dr. Stephens stressed.
Antidiabetic effects of pancreatic extract limited
Back in 1869, Paul Langerhans, MD, discovered pancreatic islet cells, or islets of Langerhans, as a medical student. Researchers tried to produce extracts that lowered blood glucose but they were too toxic for patient use.
In 1908, as detailed in his recent book, Insulin – the Crooked Timber, Dr. Hall also refers to the fact that a German researcher, Georg Zuelzer, MD, demonstrated in six patients that pancreatic extracts could reduce urinary levels of glucose and ketones, and that in one case, the treatment woke the patient from a coma. Dr. Zuelzer had purified the extract with alcohol but patients still experienced convulsions and coma; in fact, they were experiencing hypoglycemic shock, but Dr. Zuelzer had not identified it as such.
“He thought his preparation was full of impurities – and that’s the irony. He had in his hands an insulin prep that was so clean and so potent that it sent the test animals into hypoglycemic shock,” Dr. Hall pointed out.
By 1921, two young researchers, Frederick G. Banting, MD, a practicing medical doctor in Toronto, together with a final year physiology student at the University of Toronto, Charles H. Best, MD, DSc, collaborated on the instruction of Dr. Best’s superior, John James Rickard Macleod, MBChB, professor of physiology at the University of Toronto, to make pancreatic extracts, first from dogs and then from cattle.
Over the months prior to treating Thompson, working together in the laboratory, Dr. Banting and Dr. Best prepared the pancreatic extract from cattle and tested it on dogs with diabetes.
Then, in what amounted to a phase 1 trial of its day, with an “n of one,” a frail and close-to-death Thompson was given 15 cc of pancreatic extract at Toronto General Hospital in January 1922. His blood glucose level dropped by 25%, but unfortunately, his body still produced ketones, indicating the antidiabetic effect was limited. He also experienced an adverse reaction at the injection site with an accumulation of abscesses.
So despite success with isolating the extract and administering it to Thompson, the product remained tainted with impurities.
At this point, colleague James Collip, MD, PhD, came to the rescue. He used his skills as a biochemist to purify the pancreatic extract enough to eliminate impurities.
When Thompson was treated 2 weeks later with the purified extract, he experienced a more positive outcome. Gone was the injection site reaction, gone were the high blood glucose levels, and Thompson “became brighter, more active, looked better, and said he felt stronger,” according to a publication describing the treatment.
Dr. Collip also determined that by over-purifying the product, the animals he experimented on could overreact and experience convulsions, coma, and death due to hypoglycemia from too much insulin.
Fighting talk
Recalling an excerpt from Dr. Banting’s diary, Dr. Hall said that Dr. Banting had a mercurial temper and testified to his loss of patience with Dr. Collip when the chemist refused to share his formula of purification. His diary reads: “I grabbed him in one hand by the overcoat ... and almost lifting him I sat him down hard on the chair ... I remember telling him that it was a good job he was so much smaller – otherwise I would ‘knock hell out of him.’ ”
According to Dr. Hall, in 1923, when Dr. Banting and Dr. Macleod were jointly awarded the Nobel Prize for Medicine, Dr. Best resented being excluded, and despite Dr. Banting’s sharing half his prize money with Dr. Best, animosity prevailed.
At one point, before leaving on a plane for a wartime mission to the United Kingdom, Dr. Banting noted that if he didn’t make it back alive, “and they give my [professorial] chair to that son-of-a-bitch Best, I’ll never rest in my grave.” In a cruel twist of fate, Dr. Banting’s plane crashed and all aboard died.
The Nobel Prize had also been a source of rivalry between Dr. Banting and his boss, Dr. Macleod. In late 1921, while presenting the findings from animal models at the American Physiological Society conference, Dr. Banting’s nerves got the better of him and Dr. Macleod took over at the podium to finish the talk. Dr. Banting perceived this as his boss stealing the limelight.
Only a few months later, at the Association of American Physicians annual conference, Dr. Macleod played to an audience for a second time by making the first formal announcement of the discovery to the scientific community. Notably, Dr. Banting was absent.
The Nobel Prize or a poisoned chalice?
Awarded annually for physics, chemistry, medicine/physiology, literature, peace, and economics, Nobel Prizes are usually considered the holy grail of achievement. In 1895, funds for the prizes were bequeathed by Alfred Nobel in his last will and testament, with each prize worth around $40,000 at the time (approximately $1,000,000 in today’s value).
Writing in 2001 in the journal Diabetes Voice, Professor Sir George Alberti, DPhil, BM BCh, former president of the UK Royal College of Physicians, summarized the burden that accompanies the Nobel Prize: “I personally believe that such prizes and awards do more harm than good and should be abolished. Many a scientist has gone to their grave feeling deeply aggrieved because they were not awarded a Nobel Prize.”
Such high stakes surround the prize that, in the case of insulin, the course of its discovery meant courtesies and truth were swept aside in hot pursuit of fame. After Dr. Macleod died in 1935 and Dr. Banting died in 1941, Dr. Best took the opportunity to try to revise history. There was the small obstacle of Dr. Collip, but Dr. Best managed to play down Dr. Collip’s contribution by focusing on the eureka moment as being the first insulin dose administered, despite the fact that a more complete recovery without side effects was later achieved only with Dr. Collip’s help.
Despite exclusion from the Nobel Prize, Dr. Best nevertheless became recognized as the “go-to-guy” for the discovery of insulin, said Dr. Hall. When Dr. Best spoke about the discovery of insulin at the New York Diabetes Association meeting in 1946, he was introduced as a speaker whose reputation was already so great that he did “not require much of an introduction.”
“And when a new research institute was opened in Toronto in 1953, it was named in his honor. The opening address, by Sir Henry Dale of the UK Medical Research Council, sang Best’s praises to the rafters, much to the disgruntlement of Best’s former colleague, James Collip, who was sitting in the audience,” Dr. Hall pointed out.
Both Dr. Hall and Dr. Stephens live with type 1 diabetes and have benefited from the efforts of Dr. Banting, Dr. Best, Dr. Collip, Dr. Zuelzer, and Dr. Macleod.
“The discovery of insulin was a miracle, it has allowed people to survive,” said Dr. Stephens. “Few medicines can reverse a death sentence like insulin can. It’s easy to forget how it was when insulin wasn’t there – and it wasn’t that long ago.”
Dr. Hall reflects that scientific progress and discovery are often portrayed as being the result of towering geniuses standing on each other’s shoulders.
“But I think that when German philosopher Immanuel Kant remarked that ‘Out of the crooked timber of humanity, no straight thing can ever be made,’ he offered us a much more accurate picture of how science works. And I think that there’s perhaps no more powerful example of this than the story of insulin,” he said.
A version of this article first appeared on Medscape.com.
Combination antidepressant treatment outperforms monotherapy in meta-analysis
Clinicians should consider this approach as a viable first-line treatment for severe depression and for nonresponders, a team of German researchers concluded.
The findings were published online Feb. 16 in JAMA Psychiatry.
Combining antidepressants is often the next step if a patient with acute depression fails to respond to a monotherapy. In a previous meta-analysis, first author Jonathan Henssler, MD, and colleagues reported on the merits of combining monoamine reuptake inhibitors (selective serotonin reuptake inhibitor, serotonin-norepinephrine reuptake inhibitor [SNRI], or tricyclic antidepressant) and antagonists of presynaptic alpha2-autoreceptors (mianserin, mirtazapine, trazodone).
Studies that followed yielded mixed results. One randomized controlled trial (RCT) showed signs of substantial superiority when antidepressants were combined; another report from Japan only demonstrated a modest effect, said Christopher Baethge, MD, senior author of the meta-analysis, in an interview. Another recent trial showed better efficacy with monotherapy.
“In our view, this diverse field of trials suggested a reassessment. Specifically, we wanted to find out whether certain combinations are effective whereas others are not,” said Dr. Baethge, a professor of psychiatry at the University of Cologne (Germany).
Combing through Embase, PsycINFO, and the Cochrane Central Register of Controlled Trials, the investigators selected RCTs that compared combinations versus monotherapy antidepressants in adult patients with acute depression. The meta-analysis did not include studies on bipolar depression or maintenance therapy. It also didn’t include comorbid medical conditions and concomitant diagnoses of other psychiatric disorders as exclusion criteria.
Separate investigations of combinations using presynaptic alpha2-autoreceptor antagonists or bupropion also took place.
Treatment efficacy measured as standardized mean difference (SMD) between combination and monotherapy was the primary outcome. Other outcomes included the percent of patients in remission after either treatment course or the percentage of patients stopping drug therapy.
Combination treatments yield better outcomes
Among 39 trials and 6,751 patients included in the analysis, 38 of the trials provided data on the primary outcome.
Combination treatments yielded more superior outcomes, compared with monotherapy (SMD, 0.31; 95% confidence interval, 0.19-0.44). Greater efficacy in the combination approach was indicated in 82% of the studies. This finding also held up when the analysis was restricted to low risk of bias trials, applied as a first-line treatment, and among nonresponders.
Potential advantages of presynaptic alpha2-autoreceptors
In the separate analysis, presynaptic alpha2-autoreceptors did a better job than monotherapy as a first-line treatment and when applied to nonresponder populations. In comparison, bupropion combinations did not outperform monotherapy.
It’s possible that in combinations, “alpha2-autoreceptors effectively counteract, through sedation, the restlessness and agitation that many patients find troublesome when taking monoamine-reuptake inhibitors. Similarly, they may help against sexual dysfunction associated with reuptake inhibitors,” Dr. Baethge suggested.
Presynaptic alpha2-autoreceptors might also boost monoaminergic neurotransmission “by interrupting the inhibition feedback loop initiated when reuptake inhibitors increase neurotransmitter concentrations in the synaptic cleft,” he added.
Whether or not bupropion combinations help patients with treatment-resistant depression is inconclusive, noted Dr. Baethge. “More studies will likely help us get a clearer picture. So far, we can only say that we have not enough evidence to positively recommend bupropion combinations to that group of patients.”
Combining treatments did not yield more dropouts or adverse events than monotherapy. “It may thus be a safe treatment alternative when compared with other second-step strategies in treatment-resistant depression, such as augmenting monotherapy with lithium or atypical psychotic,” the investigators concluded.
Looking at this study’s limitations, the multiple clinical trials examined in a meta-analysis often have different designs, definitions of response and control groups, and use different rating scales, noted Henry A. Nasrallah, MD, professor of psychiatry, neurology, and neuroscience at the University of Cincinnati, who was not involved in the study.
Some publication bias was found but overall the results kept their integrity across secondary outcomes and subgroup and sensitivity analyses.
Guidance for choosing more effective therapies
The hope is these results will help clinicians choose more promising combinations, such as presynaptic alpha2-autoreceptor antagonists with SSRIs or SNRIs, as opposed to combinations that are less helpful or haven’t gone through an RCT, said Dr. Baethge.
The findings on tolerability may also encourage some clinicians to consider these combinations, especially if they’ve favored less evidence-based approaches such as switching drugs or increasing the dose, he said.
Polypharmacy is often viewed as undesirable or leading to more side effects, noted Dr. Nasrallah. However, “the combination of a reuptake inhibitor plus an alpha2–presynaptic receptor antagonist like mirtazapine, can actually improve tolerability compared to monotherapy antidepressant because their mechanisms of action offset the side effects while increasing efficacy,” he said.
“Finally, although sedation is a side effect of both mirtazapine and trazodone, that can be helpful for patients with difficulty falling asleep, which is common in major depression,” added Dr. Nasrallah.
Dr. Baethge and Dr. Nasrallah had no disclosures. Dr. Henssler received a research grant from the German Federal Ministry of Education and Research.
Clinicians should consider this approach as a viable first-line treatment for severe depression and for nonresponders, a team of German researchers concluded.
The findings were published online Feb. 16 in JAMA Psychiatry.
Combining antidepressants is often the next step if a patient with acute depression fails to respond to a monotherapy. In a previous meta-analysis, first author Jonathan Henssler, MD, and colleagues reported on the merits of combining monoamine reuptake inhibitors (selective serotonin reuptake inhibitor, serotonin-norepinephrine reuptake inhibitor [SNRI], or tricyclic antidepressant) and antagonists of presynaptic alpha2-autoreceptors (mianserin, mirtazapine, trazodone).
Studies that followed yielded mixed results. One randomized controlled trial (RCT) showed signs of substantial superiority when antidepressants were combined; another report from Japan only demonstrated a modest effect, said Christopher Baethge, MD, senior author of the meta-analysis, in an interview. Another recent trial showed better efficacy with monotherapy.
“In our view, this diverse field of trials suggested a reassessment. Specifically, we wanted to find out whether certain combinations are effective whereas others are not,” said Dr. Baethge, a professor of psychiatry at the University of Cologne (Germany).
Combing through Embase, PsycINFO, and the Cochrane Central Register of Controlled Trials, the investigators selected RCTs that compared combinations versus monotherapy antidepressants in adult patients with acute depression. The meta-analysis did not include studies on bipolar depression or maintenance therapy. It also didn’t include comorbid medical conditions and concomitant diagnoses of other psychiatric disorders as exclusion criteria.
Separate investigations of combinations using presynaptic alpha2-autoreceptor antagonists or bupropion also took place.
Treatment efficacy measured as standardized mean difference (SMD) between combination and monotherapy was the primary outcome. Other outcomes included the percent of patients in remission after either treatment course or the percentage of patients stopping drug therapy.
Combination treatments yield better outcomes
Among 39 trials and 6,751 patients included in the analysis, 38 of the trials provided data on the primary outcome.
Combination treatments yielded more superior outcomes, compared with monotherapy (SMD, 0.31; 95% confidence interval, 0.19-0.44). Greater efficacy in the combination approach was indicated in 82% of the studies. This finding also held up when the analysis was restricted to low risk of bias trials, applied as a first-line treatment, and among nonresponders.
Potential advantages of presynaptic alpha2-autoreceptors
In the separate analysis, presynaptic alpha2-autoreceptors did a better job than monotherapy as a first-line treatment and when applied to nonresponder populations. In comparison, bupropion combinations did not outperform monotherapy.
It’s possible that in combinations, “alpha2-autoreceptors effectively counteract, through sedation, the restlessness and agitation that many patients find troublesome when taking monoamine-reuptake inhibitors. Similarly, they may help against sexual dysfunction associated with reuptake inhibitors,” Dr. Baethge suggested.
Presynaptic alpha2-autoreceptors might also boost monoaminergic neurotransmission “by interrupting the inhibition feedback loop initiated when reuptake inhibitors increase neurotransmitter concentrations in the synaptic cleft,” he added.
Whether or not bupropion combinations help patients with treatment-resistant depression is inconclusive, noted Dr. Baethge. “More studies will likely help us get a clearer picture. So far, we can only say that we have not enough evidence to positively recommend bupropion combinations to that group of patients.”
Combining treatments did not yield more dropouts or adverse events than monotherapy. “It may thus be a safe treatment alternative when compared with other second-step strategies in treatment-resistant depression, such as augmenting monotherapy with lithium or atypical psychotic,” the investigators concluded.
Looking at this study’s limitations, the multiple clinical trials examined in a meta-analysis often have different designs, definitions of response and control groups, and use different rating scales, noted Henry A. Nasrallah, MD, professor of psychiatry, neurology, and neuroscience at the University of Cincinnati, who was not involved in the study.
Some publication bias was found but overall the results kept their integrity across secondary outcomes and subgroup and sensitivity analyses.
Guidance for choosing more effective therapies
The hope is these results will help clinicians choose more promising combinations, such as presynaptic alpha2-autoreceptor antagonists with SSRIs or SNRIs, as opposed to combinations that are less helpful or haven’t gone through an RCT, said Dr. Baethge.
The findings on tolerability may also encourage some clinicians to consider these combinations, especially if they’ve favored less evidence-based approaches such as switching drugs or increasing the dose, he said.
Polypharmacy is often viewed as undesirable or leading to more side effects, noted Dr. Nasrallah. However, “the combination of a reuptake inhibitor plus an alpha2–presynaptic receptor antagonist like mirtazapine, can actually improve tolerability compared to monotherapy antidepressant because their mechanisms of action offset the side effects while increasing efficacy,” he said.
“Finally, although sedation is a side effect of both mirtazapine and trazodone, that can be helpful for patients with difficulty falling asleep, which is common in major depression,” added Dr. Nasrallah.
Dr. Baethge and Dr. Nasrallah had no disclosures. Dr. Henssler received a research grant from the German Federal Ministry of Education and Research.
Clinicians should consider this approach as a viable first-line treatment for severe depression and for nonresponders, a team of German researchers concluded.
The findings were published online Feb. 16 in JAMA Psychiatry.
Combining antidepressants is often the next step if a patient with acute depression fails to respond to a monotherapy. In a previous meta-analysis, first author Jonathan Henssler, MD, and colleagues reported on the merits of combining monoamine reuptake inhibitors (selective serotonin reuptake inhibitor, serotonin-norepinephrine reuptake inhibitor [SNRI], or tricyclic antidepressant) and antagonists of presynaptic alpha2-autoreceptors (mianserin, mirtazapine, trazodone).
Studies that followed yielded mixed results. One randomized controlled trial (RCT) showed signs of substantial superiority when antidepressants were combined; another report from Japan only demonstrated a modest effect, said Christopher Baethge, MD, senior author of the meta-analysis, in an interview. Another recent trial showed better efficacy with monotherapy.
“In our view, this diverse field of trials suggested a reassessment. Specifically, we wanted to find out whether certain combinations are effective whereas others are not,” said Dr. Baethge, a professor of psychiatry at the University of Cologne (Germany).
Combing through Embase, PsycINFO, and the Cochrane Central Register of Controlled Trials, the investigators selected RCTs that compared combinations versus monotherapy antidepressants in adult patients with acute depression. The meta-analysis did not include studies on bipolar depression or maintenance therapy. It also didn’t include comorbid medical conditions and concomitant diagnoses of other psychiatric disorders as exclusion criteria.
Separate investigations of combinations using presynaptic alpha2-autoreceptor antagonists or bupropion also took place.
Treatment efficacy measured as standardized mean difference (SMD) between combination and monotherapy was the primary outcome. Other outcomes included the percent of patients in remission after either treatment course or the percentage of patients stopping drug therapy.
Combination treatments yield better outcomes
Among 39 trials and 6,751 patients included in the analysis, 38 of the trials provided data on the primary outcome.
Combination treatments yielded more superior outcomes, compared with monotherapy (SMD, 0.31; 95% confidence interval, 0.19-0.44). Greater efficacy in the combination approach was indicated in 82% of the studies. This finding also held up when the analysis was restricted to low risk of bias trials, applied as a first-line treatment, and among nonresponders.
Potential advantages of presynaptic alpha2-autoreceptors
In the separate analysis, presynaptic alpha2-autoreceptors did a better job than monotherapy as a first-line treatment and when applied to nonresponder populations. In comparison, bupropion combinations did not outperform monotherapy.
It’s possible that in combinations, “alpha2-autoreceptors effectively counteract, through sedation, the restlessness and agitation that many patients find troublesome when taking monoamine-reuptake inhibitors. Similarly, they may help against sexual dysfunction associated with reuptake inhibitors,” Dr. Baethge suggested.
Presynaptic alpha2-autoreceptors might also boost monoaminergic neurotransmission “by interrupting the inhibition feedback loop initiated when reuptake inhibitors increase neurotransmitter concentrations in the synaptic cleft,” he added.
Whether or not bupropion combinations help patients with treatment-resistant depression is inconclusive, noted Dr. Baethge. “More studies will likely help us get a clearer picture. So far, we can only say that we have not enough evidence to positively recommend bupropion combinations to that group of patients.”
Combining treatments did not yield more dropouts or adverse events than monotherapy. “It may thus be a safe treatment alternative when compared with other second-step strategies in treatment-resistant depression, such as augmenting monotherapy with lithium or atypical psychotic,” the investigators concluded.
Looking at this study’s limitations, the multiple clinical trials examined in a meta-analysis often have different designs, definitions of response and control groups, and use different rating scales, noted Henry A. Nasrallah, MD, professor of psychiatry, neurology, and neuroscience at the University of Cincinnati, who was not involved in the study.
Some publication bias was found but overall the results kept their integrity across secondary outcomes and subgroup and sensitivity analyses.
Guidance for choosing more effective therapies
The hope is these results will help clinicians choose more promising combinations, such as presynaptic alpha2-autoreceptor antagonists with SSRIs or SNRIs, as opposed to combinations that are less helpful or haven’t gone through an RCT, said Dr. Baethge.
The findings on tolerability may also encourage some clinicians to consider these combinations, especially if they’ve favored less evidence-based approaches such as switching drugs or increasing the dose, he said.
Polypharmacy is often viewed as undesirable or leading to more side effects, noted Dr. Nasrallah. However, “the combination of a reuptake inhibitor plus an alpha2–presynaptic receptor antagonist like mirtazapine, can actually improve tolerability compared to monotherapy antidepressant because their mechanisms of action offset the side effects while increasing efficacy,” he said.
“Finally, although sedation is a side effect of both mirtazapine and trazodone, that can be helpful for patients with difficulty falling asleep, which is common in major depression,” added Dr. Nasrallah.
Dr. Baethge and Dr. Nasrallah had no disclosures. Dr. Henssler received a research grant from the German Federal Ministry of Education and Research.
FROM JAMA PSYCHIATRY