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 drop-off in cancer screening during the first year of the COVID-19 pandemic has led to a marked increase in people presenting with advanced breast and colon cancer 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.

A drop-off in cancer screening during the first year of the COVID-19 pandemic has led to a marked increase in people presenting with advanced breast and colon cancer 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.

A drop-off in cancer screening during the first year of the COVID-19 pandemic has led to a marked increase in people presenting with advanced breast and colon cancer 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.

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.

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.

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.

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.

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).

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).

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).

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

Three physicians with the Food and Drug Administration suggest in a recent JAMA Oncology viewpoint article that it might be time to give drug companies a deadline to meet accelerated approval requirements, as is done in other countries.

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.

Three physicians with the Food and Drug Administration suggest in a recent JAMA Oncology viewpoint article that it might be time to give drug companies a deadline to meet accelerated approval requirements, as is done in other countries.

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.

Three physicians with the Food and Drug Administration suggest in a recent JAMA Oncology viewpoint article that it might be time to give drug companies a deadline to meet accelerated approval requirements, as is done in other countries.

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.

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.

National Museum of American History/CC BY-NC-ND 2.0

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.

University of Toronto/public domain

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.

University of Toronto/public domain

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.

National Museum of American History/CC BY-NC-ND 2.0

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.

University of Toronto/public domain

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.

University of Toronto/public domain

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.

National Museum of American History/CC BY-NC-ND 2.0

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.

University of Toronto/public domain

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.

University of Toronto/public domain

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.

In clinical management of depression, combining a reuptake inhibitor with presynaptic alpha2-autoreceptors significantly improves treatment outcomes, compared with monotherapy, a meta-analysis found. 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.

In clinical management of depression, combining a reuptake inhibitor with presynaptic alpha2-autoreceptors significantly improves treatment outcomes, compared with monotherapy, a meta-analysis found. 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.

In clinical management of depression, combining a reuptake inhibitor with presynaptic alpha2-autoreceptors significantly improves treatment outcomes, compared with monotherapy, a meta-analysis found. 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.

Tennessee’s Board of Medical Examiners unanimously adopted in September 2021 a statement that said doctors spreading COVID misinformation – such as suggesting that vaccines contain microchips – could jeopardize their license to practice.

“I’m very glad that we’re taking this step,” Dr. Stephen Loyd, MD, the panel’s vice president, said at the time. “If you’re spreading this willful misinformation, for me it’s going to be really hard to do anything other than put you on probation or take your license for a year. There has to be a message sent for this. It’s not okay.”

The board’s statement was posted on a government website.

But before any physicians could be reprimanded for spreading falsehoods about COVID-19 vaccines or treatments, Republican lawmakers threatened to disband the medical board.

The growing tension in Tennessee between conservative lawmakers and the state’s medical board may be the most prominent example in the country. But the Federation of State Medical Boards, which created the language adopted by at least 15 state boards, is tracking legislation introduced by Republicans in at least 14 states that would restrict a medical board’s authority to discipline doctors for their advice on COVID.

Humayun Chaudhry, DO, the federation’s CEO, called it “an unwelcome trend.” The nonprofit association, based in Euless, Tex., said the statement is merely a COVID-specific restatement of an existing rule: that doctors who engage in behavior that puts patients at risk could face disciplinary action.

Although doctors have leeway to decide which treatments to provide, the medical boards that oversee them have broad authority over licensing. Often, doctors are investigated for violating guidelines on prescribing high-powered drugs. But physicians are sometimes punished for other “unprofessional conduct.” In 2013, Tennessee’s board fined U.S. Rep. Scott DesJarlais for separately having sexual relations with two female patients more than a decade earlier.

Still, stopping doctors from sharing unsound medical advice has proved challenging. Even defining misinformation has been difficult. And during the pandemic, resistance from some state legislatures is complicating the effort.

A relatively small group of physicians peddle COVID misinformation, but many of them associate with America’s Frontline Doctors. Its founder, Simone Gold, MD, has claimed patients are dying from COVID treatments, not the virus itself. Sherri Tenpenny, DO, said in a legislative hearing in Ohio that the COVID vaccine could magnetize patients. Stella Immanuel, MD, has pushed hydroxychloroquine as a COVID cure in Texas, although clinical trials showed that it had no benefit. None of them agreed to requests for comment.

The Texas Medical Board fined Dr. Immanuel $500 for not informing a patient of the risks associated with using hydroxychloroquine as an off-label COVID treatment.

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation. This story is part of a partnership that includes Nashville Public Radio, NPR, and KHN.

Tennessee’s Board of Medical Examiners unanimously adopted in September 2021 a statement that said doctors spreading COVID misinformation – such as suggesting that vaccines contain microchips – could jeopardize their license to practice.

“I’m very glad that we’re taking this step,” Dr. Stephen Loyd, MD, the panel’s vice president, said at the time. “If you’re spreading this willful misinformation, for me it’s going to be really hard to do anything other than put you on probation or take your license for a year. There has to be a message sent for this. It’s not okay.”

The board’s statement was posted on a government website.

But before any physicians could be reprimanded for spreading falsehoods about COVID-19 vaccines or treatments, Republican lawmakers threatened to disband the medical board.

The growing tension in Tennessee between conservative lawmakers and the state’s medical board may be the most prominent example in the country. But the Federation of State Medical Boards, which created the language adopted by at least 15 state boards, is tracking legislation introduced by Republicans in at least 14 states that would restrict a medical board’s authority to discipline doctors for their advice on COVID.

Humayun Chaudhry, DO, the federation’s CEO, called it “an unwelcome trend.” The nonprofit association, based in Euless, Tex., said the statement is merely a COVID-specific restatement of an existing rule: that doctors who engage in behavior that puts patients at risk could face disciplinary action.

Although doctors have leeway to decide which treatments to provide, the medical boards that oversee them have broad authority over licensing. Often, doctors are investigated for violating guidelines on prescribing high-powered drugs. But physicians are sometimes punished for other “unprofessional conduct.” In 2013, Tennessee’s board fined U.S. Rep. Scott DesJarlais for separately having sexual relations with two female patients more than a decade earlier.

Still, stopping doctors from sharing unsound medical advice has proved challenging. Even defining misinformation has been difficult. And during the pandemic, resistance from some state legislatures is complicating the effort.

A relatively small group of physicians peddle COVID misinformation, but many of them associate with America’s Frontline Doctors. Its founder, Simone Gold, MD, has claimed patients are dying from COVID treatments, not the virus itself. Sherri Tenpenny, DO, said in a legislative hearing in Ohio that the COVID vaccine could magnetize patients. Stella Immanuel, MD, has pushed hydroxychloroquine as a COVID cure in Texas, although clinical trials showed that it had no benefit. None of them agreed to requests for comment.

The Texas Medical Board fined Dr. Immanuel $500 for not informing a patient of the risks associated with using hydroxychloroquine as an off-label COVID treatment.

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation. This story is part of a partnership that includes Nashville Public Radio, NPR, and KHN.

Tennessee’s Board of Medical Examiners unanimously adopted in September 2021 a statement that said doctors spreading COVID misinformation – such as suggesting that vaccines contain microchips – could jeopardize their license to practice.

“I’m very glad that we’re taking this step,” Dr. Stephen Loyd, MD, the panel’s vice president, said at the time. “If you’re spreading this willful misinformation, for me it’s going to be really hard to do anything other than put you on probation or take your license for a year. There has to be a message sent for this. It’s not okay.”

The board’s statement was posted on a government website.

But before any physicians could be reprimanded for spreading falsehoods about COVID-19 vaccines or treatments, Republican lawmakers threatened to disband the medical board.

The growing tension in Tennessee between conservative lawmakers and the state’s medical board may be the most prominent example in the country. But the Federation of State Medical Boards, which created the language adopted by at least 15 state boards, is tracking legislation introduced by Republicans in at least 14 states that would restrict a medical board’s authority to discipline doctors for their advice on COVID.

Humayun Chaudhry, DO, the federation’s CEO, called it “an unwelcome trend.” The nonprofit association, based in Euless, Tex., said the statement is merely a COVID-specific restatement of an existing rule: that doctors who engage in behavior that puts patients at risk could face disciplinary action.

Although doctors have leeway to decide which treatments to provide, the medical boards that oversee them have broad authority over licensing. Often, doctors are investigated for violating guidelines on prescribing high-powered drugs. But physicians are sometimes punished for other “unprofessional conduct.” In 2013, Tennessee’s board fined U.S. Rep. Scott DesJarlais for separately having sexual relations with two female patients more than a decade earlier.

Still, stopping doctors from sharing unsound medical advice has proved challenging. Even defining misinformation has been difficult. And during the pandemic, resistance from some state legislatures is complicating the effort.

A relatively small group of physicians peddle COVID misinformation, but many of them associate with America’s Frontline Doctors. Its founder, Simone Gold, MD, has claimed patients are dying from COVID treatments, not the virus itself. Sherri Tenpenny, DO, said in a legislative hearing in Ohio that the COVID vaccine could magnetize patients. Stella Immanuel, MD, has pushed hydroxychloroquine as a COVID cure in Texas, although clinical trials showed that it had no benefit. None of them agreed to requests for comment.

The Texas Medical Board fined Dr. Immanuel $500 for not informing a patient of the risks associated with using hydroxychloroquine as an off-label COVID treatment.

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation. This story is part of a partnership that includes Nashville Public Radio, NPR, and KHN.

Hours after their births, 34 infants began a three-drug combination HIV treatment. Now, 2 years later, a third of those toddlers have tested negative for HIV antibodies and have no detectable HIV DNA in their blood. The children aren’t cured of HIV, but as many as 16 of them may be candidates to stop treatment and see if they are in fact in HIV remission.

If one or more are, it would be the first time since the Mississippi baby in 2013 that scientists have induced childhood HIV remission by beginning HIV treatment very early.    

At the Conference on Retroviruses and Opportunistic Infections, Deborah Persaud, MD, interim director of pediatric infectious diseases and professor of pediatrics at Johns Hopkins University School of Medicine, Baltimore, Md., told this news organization that the evidence suggests that more U.S. clinicians should start infants at high risk for HIV on presumptive treatment – not only to potentially prevent transmission but also to set the child up for the lowest possible viral reservoir, the first step to HIV remission.

The three-drug preemptive treatment is “not uniformly practiced,” Dr. Persaud said in an interview. “We’re at a point now where we don’t have to wait to see if we have remission” to act on these findings, she said. “The question is, should this now become standard of care for in-utero infected infants?” 

Every year, about 150 infants are born with HIV in the United States, according to the Elizabeth Glaser Pediatric AIDS Foundation. Current U.S. perinatal treatment guidelines already suggest either treatment with one or more HIV drugs at birth to attempt preventing transmission or initiating three-drug regimens for infants at high risk for perinatally acquired HIV. In this case “high risk” is defined as infants born to:

• people who haven’t received any HIV treatment before delivery or during delivery,
• people who did receive treatment but failed to achieve undetectable viral loads, or
• people who acquire HIV during pregnancy, or who otherwise weren’t diagnosed until after birth.

Trying to replicate the Mississippi baby

The Mississippi baby did eventually relapse. But ever since Dr. Persaud reported the case of that 2-year-old who went into treatment-free remission in 2013, she has been trying to figure out how to duplicate that initial success. There were several factors in that remission, but one piece researchers could control was starting treatment very early – before HIV blood tests even come back positive. So, in this trial, researchers enrolled 440 infants in Africa and Asia at high risk for in utero HIV transmission.

All 440 of those infants received their first doses of the three-drug preemptive treatment within 24 hours of birth. Of those 440 infants, 34 tested positive for HIV and remained in the trial.*

Meanwhile, in North America, South America, and African countries, another 20 infants enrolled in the trial – not as part of the protocol but because their clinicians had been influenced by the news of the Mississippi baby, Dr. Persaud said, and decided on their own to start high-risk infants on three-drug regimens preemptively.

“We wanted to take advantage of those real-world situations of infants being treated outside the clinical trials,” Dr. Persaud said.

Now there were 54 infants trying this very early treatment. In Cohort One, they started their first drug cocktail 7 hours after delivery. In Cohort Two, their first antiretroviral combination treatment was at 32.8 hours of life, and they enrolled in the trial at 8 days. Then researchers followed the infants closely, adding on lopinavir and ritonavir when age-appropriate.
 

Meeting milestones

To continue in the trial and be considered for treatment interruption, infants had to meet certain milestones. At 24 weeks, HIV RNA needed to be below 200 copies per milliliter. Then their HIV RNA needed to stay below 200 copies consistently until week 48. At week 48, they had to have an HIV RNA that was even lower – below 20 or 40 copies – with “target not detected” in the test in HIV RNA. That’s a sign that there weren’t even any trace levels of viral nucleic acid RNA in the blood to indicate HIV. Then, from week 48 on, they had to maintain that level of viral suppression until age 2.

At that point, not only did they need to maintain that level of viral suppression, they also needed to have a negative HIV antibody test and a PCR test for total HIV DNA, which had to be undetectable down to the limit of 4 copies per 106 – that is, there were fewer than 4 copies of the virus out of 1 million cells tested. Only then would they be considered for treatment interruption.

“After week 28 there was no leeway,” Dr. Persaud said. Then “they had to have nothing detectable from the first year of age. We thought the best shot at remission were cases that achieved very good and strict virologic control.”

 

Criteria for consideration

Of the 34 infants in Cohort One, 24 infants made it past the first hurdle at 24 weeks and 6 had PCR tests that found no cell-associated HIV DNA. In Cohort Two, 15 made it past the week-24 hurdle and 4 had no detectable HIV DNA via PCR test.

Now, more than 2 years out from study initiation, Dr. Persaud and colleagues are evaluating each child to see if any still meet the requirements for treatment interruption. The COVID-19 pandemic has delayed their evaluations, and it’s possible that fewer children now meet the requirements. But Dr. Persaud said there are still candidates left. An analysis suggests that up to 30% of the children, or 16, were candidates at 2 years.

“We have kids who are eligible for [antiretroviral therapy] cessation years out from this, which I think is really important,” she said in an interview. “It’s not game over.”

And although 30% is not an overwhelming victory, Dr. Persaud said the team’s goal was “to identify an N of 1 to replicate the Mississippi baby.” The study team, led by Ellen Chadwick, MD, of Northwestern University’s Feinberg School of Medicine, Chicago, and a member of the board that creates HIV perinatal treatment guidelines, is starting a new trial, using more modern, integrase inhibitor-based, three-drug regimens for infants and pairing them with broadly neutralizing antibodies. The combination used in this trial included zidovudine, or AZT.

If one of the children is able to go off treatment, it would be the first step toward creating a functional cure for HIV, starting with the youngest people affected by the virus.  

“This trial convinces me that very early treatment was the key strategy that led to remission in the Mississippi baby,” Dr. Persaud said in an interview. “We’re confirming here that the first step toward remission and cure is reducing reservoirs. We’ve got that here. Whether we need more on top of that – therapeutic vaccines, immunotherapies, or a better regimen to start out with – needs to be determined.”

The presentation was met with excitement and questions. For instance, if very early treatment works, why does it work for just 30% of the children?

Were some of the children able to control HIV on their own because they were rare post-treatment controllers? And was 30% really a victory? Others were convinced of it.

“Amazing outcome to have 30% so well suppressed after 2 years with CA-DNA not detected,” commented Hermione Lyall, MBChB, a pediatric infectious disease doctor at Imperial College Healthcare NHS Trust in the United Kingdom, in the virtual chat.

As for whether the study should change practice, Elaine Abrams, MD, professor of epidemiology and pediatrics at Columbia University Medical Center, New York, and CROI cochair, said that this study proves that the three-drug regimen is at the very least safe to start immediately.

Whether it should become standard of care everywhere is still up for discussion, she told this news organization.

“It very much depends on what you’re trying to achieve,” she said. “Postnatal prophylaxis is provided to reduce the risk of acquiring infection. That’s a different objective than early treatment. If you have 1,000 high-risk babies, how many are likely to turn out to have HIV infection? And how many of those will you be treating with three drugs and actually making this impact by doing so? And how many babies are going to be getting possibly extra treatment that they don’t need?”

Regardless, what’s clear is that treatment is essential – for mother and infant, said Carl Dieffenbach, PhD, director of the division of AIDS at the National Institute of Allergy and Infectious Diseases. It needs to start, he said, by making sure all mothers know their HIV status and have access early in pregnancy to the treatment that can prevent transmission.

“So much of what’s wrong in the world is about implementation of health care,” he said in an interview. Still, “if you could demonstrate that early treatment to the mother plus early treatment to the babies [is efficacious], we could really talk about an HIV-free generation of kids.”

The study was funded by the National Institutes of Health. Dr. Persaud, Dr. Dieffenbach, Dr. Abrams, and Dr. Lyall all report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Correction, 2/16/22: An earlier version of this article misstated the number that tested positive for HIV and remained in the trial.

This article was updated 2/16/22.

Hours after their births, 34 infants began a three-drug combination HIV treatment. Now, 2 years later, a third of those toddlers have tested negative for HIV antibodies and have no detectable HIV DNA in their blood. The children aren’t cured of HIV, but as many as 16 of them may be candidates to stop treatment and see if they are in fact in HIV remission.

If one or more are, it would be the first time since the Mississippi baby in 2013 that scientists have induced childhood HIV remission by beginning HIV treatment very early.    

At the Conference on Retroviruses and Opportunistic Infections, Deborah Persaud, MD, interim director of pediatric infectious diseases and professor of pediatrics at Johns Hopkins University School of Medicine, Baltimore, Md., told this news organization that the evidence suggests that more U.S. clinicians should start infants at high risk for HIV on presumptive treatment – not only to potentially prevent transmission but also to set the child up for the lowest possible viral reservoir, the first step to HIV remission.

The three-drug preemptive treatment is “not uniformly practiced,” Dr. Persaud said in an interview. “We’re at a point now where we don’t have to wait to see if we have remission” to act on these findings, she said. “The question is, should this now become standard of care for in-utero infected infants?” 

Every year, about 150 infants are born with HIV in the United States, according to the Elizabeth Glaser Pediatric AIDS Foundation. Current U.S. perinatal treatment guidelines already suggest either treatment with one or more HIV drugs at birth to attempt preventing transmission or initiating three-drug regimens for infants at high risk for perinatally acquired HIV. In this case “high risk” is defined as infants born to:

• people who haven’t received any HIV treatment before delivery or during delivery,
• people who did receive treatment but failed to achieve undetectable viral loads, or
• people who acquire HIV during pregnancy, or who otherwise weren’t diagnosed until after birth.

Trying to replicate the Mississippi baby

The Mississippi baby did eventually relapse. But ever since Dr. Persaud reported the case of that 2-year-old who went into treatment-free remission in 2013, she has been trying to figure out how to duplicate that initial success. There were several factors in that remission, but one piece researchers could control was starting treatment very early – before HIV blood tests even come back positive. So, in this trial, researchers enrolled 440 infants in Africa and Asia at high risk for in utero HIV transmission.

All 440 of those infants received their first doses of the three-drug preemptive treatment within 24 hours of birth. Of those 440 infants, 34 tested positive for HIV and remained in the trial.*

Meanwhile, in North America, South America, and African countries, another 20 infants enrolled in the trial – not as part of the protocol but because their clinicians had been influenced by the news of the Mississippi baby, Dr. Persaud said, and decided on their own to start high-risk infants on three-drug regimens preemptively.

“We wanted to take advantage of those real-world situations of infants being treated outside the clinical trials,” Dr. Persaud said.

Now there were 54 infants trying this very early treatment. In Cohort One, they started their first drug cocktail 7 hours after delivery. In Cohort Two, their first antiretroviral combination treatment was at 32.8 hours of life, and they enrolled in the trial at 8 days. Then researchers followed the infants closely, adding on lopinavir and ritonavir when age-appropriate.
 

Meeting milestones

To continue in the trial and be considered for treatment interruption, infants had to meet certain milestones. At 24 weeks, HIV RNA needed to be below 200 copies per milliliter. Then their HIV RNA needed to stay below 200 copies consistently until week 48. At week 48, they had to have an HIV RNA that was even lower – below 20 or 40 copies – with “target not detected” in the test in HIV RNA. That’s a sign that there weren’t even any trace levels of viral nucleic acid RNA in the blood to indicate HIV. Then, from week 48 on, they had to maintain that level of viral suppression until age 2.

At that point, not only did they need to maintain that level of viral suppression, they also needed to have a negative HIV antibody test and a PCR test for total HIV DNA, which had to be undetectable down to the limit of 4 copies per 106 – that is, there were fewer than 4 copies of the virus out of 1 million cells tested. Only then would they be considered for treatment interruption.

“After week 28 there was no leeway,” Dr. Persaud said. Then “they had to have nothing detectable from the first year of age. We thought the best shot at remission were cases that achieved very good and strict virologic control.”

 

Criteria for consideration

Of the 34 infants in Cohort One, 24 infants made it past the first hurdle at 24 weeks and 6 had PCR tests that found no cell-associated HIV DNA. In Cohort Two, 15 made it past the week-24 hurdle and 4 had no detectable HIV DNA via PCR test.

Now, more than 2 years out from study initiation, Dr. Persaud and colleagues are evaluating each child to see if any still meet the requirements for treatment interruption. The COVID-19 pandemic has delayed their evaluations, and it’s possible that fewer children now meet the requirements. But Dr. Persaud said there are still candidates left. An analysis suggests that up to 30% of the children, or 16, were candidates at 2 years.

“We have kids who are eligible for [antiretroviral therapy] cessation years out from this, which I think is really important,” she said in an interview. “It’s not game over.”

And although 30% is not an overwhelming victory, Dr. Persaud said the team’s goal was “to identify an N of 1 to replicate the Mississippi baby.” The study team, led by Ellen Chadwick, MD, of Northwestern University’s Feinberg School of Medicine, Chicago, and a member of the board that creates HIV perinatal treatment guidelines, is starting a new trial, using more modern, integrase inhibitor-based, three-drug regimens for infants and pairing them with broadly neutralizing antibodies. The combination used in this trial included zidovudine, or AZT.

If one of the children is able to go off treatment, it would be the first step toward creating a functional cure for HIV, starting with the youngest people affected by the virus.  

“This trial convinces me that very early treatment was the key strategy that led to remission in the Mississippi baby,” Dr. Persaud said in an interview. “We’re confirming here that the first step toward remission and cure is reducing reservoirs. We’ve got that here. Whether we need more on top of that – therapeutic vaccines, immunotherapies, or a better regimen to start out with – needs to be determined.”

The presentation was met with excitement and questions. For instance, if very early treatment works, why does it work for just 30% of the children?

Were some of the children able to control HIV on their own because they were rare post-treatment controllers? And was 30% really a victory? Others were convinced of it.

“Amazing outcome to have 30% so well suppressed after 2 years with CA-DNA not detected,” commented Hermione Lyall, MBChB, a pediatric infectious disease doctor at Imperial College Healthcare NHS Trust in the United Kingdom, in the virtual chat.

As for whether the study should change practice, Elaine Abrams, MD, professor of epidemiology and pediatrics at Columbia University Medical Center, New York, and CROI cochair, said that this study proves that the three-drug regimen is at the very least safe to start immediately.

Whether it should become standard of care everywhere is still up for discussion, she told this news organization.

“It very much depends on what you’re trying to achieve,” she said. “Postnatal prophylaxis is provided to reduce the risk of acquiring infection. That’s a different objective than early treatment. If you have 1,000 high-risk babies, how many are likely to turn out to have HIV infection? And how many of those will you be treating with three drugs and actually making this impact by doing so? And how many babies are going to be getting possibly extra treatment that they don’t need?”

Regardless, what’s clear is that treatment is essential – for mother and infant, said Carl Dieffenbach, PhD, director of the division of AIDS at the National Institute of Allergy and Infectious Diseases. It needs to start, he said, by making sure all mothers know their HIV status and have access early in pregnancy to the treatment that can prevent transmission.

“So much of what’s wrong in the world is about implementation of health care,” he said in an interview. Still, “if you could demonstrate that early treatment to the mother plus early treatment to the babies [is efficacious], we could really talk about an HIV-free generation of kids.”

The study was funded by the National Institutes of Health. Dr. Persaud, Dr. Dieffenbach, Dr. Abrams, and Dr. Lyall all report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Correction, 2/16/22: An earlier version of this article misstated the number that tested positive for HIV and remained in the trial.

This article was updated 2/16/22.

Hours after their births, 34 infants began a three-drug combination HIV treatment. Now, 2 years later, a third of those toddlers have tested negative for HIV antibodies and have no detectable HIV DNA in their blood. The children aren’t cured of HIV, but as many as 16 of them may be candidates to stop treatment and see if they are in fact in HIV remission.

If one or more are, it would be the first time since the Mississippi baby in 2013 that scientists have induced childhood HIV remission by beginning HIV treatment very early.    

At the Conference on Retroviruses and Opportunistic Infections, Deborah Persaud, MD, interim director of pediatric infectious diseases and professor of pediatrics at Johns Hopkins University School of Medicine, Baltimore, Md., told this news organization that the evidence suggests that more U.S. clinicians should start infants at high risk for HIV on presumptive treatment – not only to potentially prevent transmission but also to set the child up for the lowest possible viral reservoir, the first step to HIV remission.

The three-drug preemptive treatment is “not uniformly practiced,” Dr. Persaud said in an interview. “We’re at a point now where we don’t have to wait to see if we have remission” to act on these findings, she said. “The question is, should this now become standard of care for in-utero infected infants?” 

Every year, about 150 infants are born with HIV in the United States, according to the Elizabeth Glaser Pediatric AIDS Foundation. Current U.S. perinatal treatment guidelines already suggest either treatment with one or more HIV drugs at birth to attempt preventing transmission or initiating three-drug regimens for infants at high risk for perinatally acquired HIV. In this case “high risk” is defined as infants born to:

• people who haven’t received any HIV treatment before delivery or during delivery,
• people who did receive treatment but failed to achieve undetectable viral loads, or
• people who acquire HIV during pregnancy, or who otherwise weren’t diagnosed until after birth.

Trying to replicate the Mississippi baby

The Mississippi baby did eventually relapse. But ever since Dr. Persaud reported the case of that 2-year-old who went into treatment-free remission in 2013, she has been trying to figure out how to duplicate that initial success. There were several factors in that remission, but one piece researchers could control was starting treatment very early – before HIV blood tests even come back positive. So, in this trial, researchers enrolled 440 infants in Africa and Asia at high risk for in utero HIV transmission.

All 440 of those infants received their first doses of the three-drug preemptive treatment within 24 hours of birth. Of those 440 infants, 34 tested positive for HIV and remained in the trial.*

Meanwhile, in North America, South America, and African countries, another 20 infants enrolled in the trial – not as part of the protocol but because their clinicians had been influenced by the news of the Mississippi baby, Dr. Persaud said, and decided on their own to start high-risk infants on three-drug regimens preemptively.

“We wanted to take advantage of those real-world situations of infants being treated outside the clinical trials,” Dr. Persaud said.

Now there were 54 infants trying this very early treatment. In Cohort One, they started their first drug cocktail 7 hours after delivery. In Cohort Two, their first antiretroviral combination treatment was at 32.8 hours of life, and they enrolled in the trial at 8 days. Then researchers followed the infants closely, adding on lopinavir and ritonavir when age-appropriate.
 

Meeting milestones

To continue in the trial and be considered for treatment interruption, infants had to meet certain milestones. At 24 weeks, HIV RNA needed to be below 200 copies per milliliter. Then their HIV RNA needed to stay below 200 copies consistently until week 48. At week 48, they had to have an HIV RNA that was even lower – below 20 or 40 copies – with “target not detected” in the test in HIV RNA. That’s a sign that there weren’t even any trace levels of viral nucleic acid RNA in the blood to indicate HIV. Then, from week 48 on, they had to maintain that level of viral suppression until age 2.

At that point, not only did they need to maintain that level of viral suppression, they also needed to have a negative HIV antibody test and a PCR test for total HIV DNA, which had to be undetectable down to the limit of 4 copies per 106 – that is, there were fewer than 4 copies of the virus out of 1 million cells tested. Only then would they be considered for treatment interruption.

“After week 28 there was no leeway,” Dr. Persaud said. Then “they had to have nothing detectable from the first year of age. We thought the best shot at remission were cases that achieved very good and strict virologic control.”

 

Criteria for consideration

Of the 34 infants in Cohort One, 24 infants made it past the first hurdle at 24 weeks and 6 had PCR tests that found no cell-associated HIV DNA. In Cohort Two, 15 made it past the week-24 hurdle and 4 had no detectable HIV DNA via PCR test.

Now, more than 2 years out from study initiation, Dr. Persaud and colleagues are evaluating each child to see if any still meet the requirements for treatment interruption. The COVID-19 pandemic has delayed their evaluations, and it’s possible that fewer children now meet the requirements. But Dr. Persaud said there are still candidates left. An analysis suggests that up to 30% of the children, or 16, were candidates at 2 years.

“We have kids who are eligible for [antiretroviral therapy] cessation years out from this, which I think is really important,” she said in an interview. “It’s not game over.”

And although 30% is not an overwhelming victory, Dr. Persaud said the team’s goal was “to identify an N of 1 to replicate the Mississippi baby.” The study team, led by Ellen Chadwick, MD, of Northwestern University’s Feinberg School of Medicine, Chicago, and a member of the board that creates HIV perinatal treatment guidelines, is starting a new trial, using more modern, integrase inhibitor-based, three-drug regimens for infants and pairing them with broadly neutralizing antibodies. The combination used in this trial included zidovudine, or AZT.

If one of the children is able to go off treatment, it would be the first step toward creating a functional cure for HIV, starting with the youngest people affected by the virus.  

“This trial convinces me that very early treatment was the key strategy that led to remission in the Mississippi baby,” Dr. Persaud said in an interview. “We’re confirming here that the first step toward remission and cure is reducing reservoirs. We’ve got that here. Whether we need more on top of that – therapeutic vaccines, immunotherapies, or a better regimen to start out with – needs to be determined.”

The presentation was met with excitement and questions. For instance, if very early treatment works, why does it work for just 30% of the children?

Were some of the children able to control HIV on their own because they were rare post-treatment controllers? And was 30% really a victory? Others were convinced of it.

“Amazing outcome to have 30% so well suppressed after 2 years with CA-DNA not detected,” commented Hermione Lyall, MBChB, a pediatric infectious disease doctor at Imperial College Healthcare NHS Trust in the United Kingdom, in the virtual chat.

As for whether the study should change practice, Elaine Abrams, MD, professor of epidemiology and pediatrics at Columbia University Medical Center, New York, and CROI cochair, said that this study proves that the three-drug regimen is at the very least safe to start immediately.

Whether it should become standard of care everywhere is still up for discussion, she told this news organization.

“It very much depends on what you’re trying to achieve,” she said. “Postnatal prophylaxis is provided to reduce the risk of acquiring infection. That’s a different objective than early treatment. If you have 1,000 high-risk babies, how many are likely to turn out to have HIV infection? And how many of those will you be treating with three drugs and actually making this impact by doing so? And how many babies are going to be getting possibly extra treatment that they don’t need?”

Regardless, what’s clear is that treatment is essential – for mother and infant, said Carl Dieffenbach, PhD, director of the division of AIDS at the National Institute of Allergy and Infectious Diseases. It needs to start, he said, by making sure all mothers know their HIV status and have access early in pregnancy to the treatment that can prevent transmission.

“So much of what’s wrong in the world is about implementation of health care,” he said in an interview. Still, “if you could demonstrate that early treatment to the mother plus early treatment to the babies [is efficacious], we could really talk about an HIV-free generation of kids.”

The study was funded by the National Institutes of Health. Dr. Persaud, Dr. Dieffenbach, Dr. Abrams, and Dr. Lyall all report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Correction, 2/16/22: An earlier version of this article misstated the number that tested positive for HIV and remained in the trial.

This article was updated 2/16/22.

Medicinal and recreational marijuana use has become common across the country, warranting greater awareness among clinicians about any potential adverse effects of marijuana on brain health, a new American Heart Association scientific statement concludes.

The existing evidence base of preclinical and clinical research suggests that marijuana use may have a harmful effect on the brain, although the specific adverse effects have not been well defined, the statement authors said.

Smithore

Fernando D. Testai, MD, PhD, professor of neurology and rehabilitation at the University of Illinois at Chicago, led the writing panel for the statement, published online Feb. 10, 2022, in Stroke.

Numerous research studies challenge the idea that marijuana use is harmless, and instead demonstrate that cannabis, especially tetrahydrocannabinol (THC), has adverse effects on brain health, Dr. Testai and colleagues noted.

“Social media tends to overemphasize the beneficial effects of marijuana. However, its ultimate effect on brain health is still to be established. Physicians should provide periodic and unbiased education to their patients about the known and unknown ramifications of consuming cannabinoids,” Dr. Testai said.

Findings collected from animal studies demonstrate that THC interferes with normal development of signaling pathways and hinders synaptic plasticity. The authors also pointed out that these studies show connections between neurons are affected in the short term, whereas in the long haul, this contributes to changes in how neuronal networks work.

“Personally, the most striking point is the epidemiological data that indicate that the use of marijuana is widespread in the general population, and this starts early in life, particularly during adolescence,” Dr. Testai told this news organization.

Dr. Testai also noted that pregnant women are using cannabis for nausea and vomiting. Other data on prenatal exposure to cannabis show that THC hinders the signaling mechanism of the endocannabinoid system during development and ontogenesis, which ultimately leads to abnormal neurotransmission.

“Prenatal THC affects neuroanatomic areas associated with cognition and emotional regulation, including the prefrontal cortex, limbic system, and ventral tegmentum of the midbrain,” the researchers added.

The writing panel also found that marijuana use had effects on human cognition:
 

• Acute marijuana use affects impulsivity, memory, and behavioral disinhibition, they noted, that “can affect performance in real-world activities,” such as driving. The long-term effects of cannabis on cognition are “less well established.”
• Neuroimaging research has highlighted structural changes in the brain, but these data are inconsistent.
• Functional MRI studies show cannabis users may experience functional changes in regions of the brain that play a role in cognition, particularly with prolonged use.

The statement also addresses studies assessing the effects of marijuana use on cerebrovascular risk and disease, which show:

• A relation between cannabis use and increased risk for stroke.
• Frequency and other trends of cannabis use may raise stroke risk.
• Cannabis users often smoke cigarettes, which is an important factor in the association between cannabis use and stroke risk.

Looking ahead, public health initiatives are needed to increase awareness among the public about the negative effects of marijuana use. Other efforts may include setting standards regarding the concentrations of biologically active ingredients and warning notices on available formulations, the group concluded.

The document was prepared on behalf of the AHA Stroke Brain Health Science Subcommittee of the Stroke Council; Council on Arteriosclerosis, Thrombosis, and Vascular Biology; Council on Cardiovascular and Stroke Nursing; Council on Lifestyle and Cardiometabolic Health; and Council on Peripheral Vascular Disease.

The American Academy of Neurology “affirms the value of this statement as an educational tool for neurologists,” the document notes.

Dr. Testai reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Medicinal and recreational marijuana use has become common across the country, warranting greater awareness among clinicians about any potential adverse effects of marijuana on brain health, a new American Heart Association scientific statement concludes.

The existing evidence base of preclinical and clinical research suggests that marijuana use may have a harmful effect on the brain, although the specific adverse effects have not been well defined, the statement authors said.

Smithore

Fernando D. Testai, MD, PhD, professor of neurology and rehabilitation at the University of Illinois at Chicago, led the writing panel for the statement, published online Feb. 10, 2022, in Stroke.

Numerous research studies challenge the idea that marijuana use is harmless, and instead demonstrate that cannabis, especially tetrahydrocannabinol (THC), has adverse effects on brain health, Dr. Testai and colleagues noted.

“Social media tends to overemphasize the beneficial effects of marijuana. However, its ultimate effect on brain health is still to be established. Physicians should provide periodic and unbiased education to their patients about the known and unknown ramifications of consuming cannabinoids,” Dr. Testai said.

Findings collected from animal studies demonstrate that THC interferes with normal development of signaling pathways and hinders synaptic plasticity. The authors also pointed out that these studies show connections between neurons are affected in the short term, whereas in the long haul, this contributes to changes in how neuronal networks work.

“Personally, the most striking point is the epidemiological data that indicate that the use of marijuana is widespread in the general population, and this starts early in life, particularly during adolescence,” Dr. Testai told this news organization.

Dr. Testai also noted that pregnant women are using cannabis for nausea and vomiting. Other data on prenatal exposure to cannabis show that THC hinders the signaling mechanism of the endocannabinoid system during development and ontogenesis, which ultimately leads to abnormal neurotransmission.

“Prenatal THC affects neuroanatomic areas associated with cognition and emotional regulation, including the prefrontal cortex, limbic system, and ventral tegmentum of the midbrain,” the researchers added.

The writing panel also found that marijuana use had effects on human cognition:
 

• Acute marijuana use affects impulsivity, memory, and behavioral disinhibition, they noted, that “can affect performance in real-world activities,” such as driving. The long-term effects of cannabis on cognition are “less well established.”
• Neuroimaging research has highlighted structural changes in the brain, but these data are inconsistent.
• Functional MRI studies show cannabis users may experience functional changes in regions of the brain that play a role in cognition, particularly with prolonged use.

The statement also addresses studies assessing the effects of marijuana use on cerebrovascular risk and disease, which show:

• A relation between cannabis use and increased risk for stroke.
• Frequency and other trends of cannabis use may raise stroke risk.
• Cannabis users often smoke cigarettes, which is an important factor in the association between cannabis use and stroke risk.

Looking ahead, public health initiatives are needed to increase awareness among the public about the negative effects of marijuana use. Other efforts may include setting standards regarding the concentrations of biologically active ingredients and warning notices on available formulations, the group concluded.

The document was prepared on behalf of the AHA Stroke Brain Health Science Subcommittee of the Stroke Council; Council on Arteriosclerosis, Thrombosis, and Vascular Biology; Council on Cardiovascular and Stroke Nursing; Council on Lifestyle and Cardiometabolic Health; and Council on Peripheral Vascular Disease.

The American Academy of Neurology “affirms the value of this statement as an educational tool for neurologists,” the document notes.

Dr. Testai reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Medicinal and recreational marijuana use has become common across the country, warranting greater awareness among clinicians about any potential adverse effects of marijuana on brain health, a new American Heart Association scientific statement concludes.

The existing evidence base of preclinical and clinical research suggests that marijuana use may have a harmful effect on the brain, although the specific adverse effects have not been well defined, the statement authors said.

Smithore

Fernando D. Testai, MD, PhD, professor of neurology and rehabilitation at the University of Illinois at Chicago, led the writing panel for the statement, published online Feb. 10, 2022, in Stroke.

Numerous research studies challenge the idea that marijuana use is harmless, and instead demonstrate that cannabis, especially tetrahydrocannabinol (THC), has adverse effects on brain health, Dr. Testai and colleagues noted.

“Social media tends to overemphasize the beneficial effects of marijuana. However, its ultimate effect on brain health is still to be established. Physicians should provide periodic and unbiased education to their patients about the known and unknown ramifications of consuming cannabinoids,” Dr. Testai said.

Findings collected from animal studies demonstrate that THC interferes with normal development of signaling pathways and hinders synaptic plasticity. The authors also pointed out that these studies show connections between neurons are affected in the short term, whereas in the long haul, this contributes to changes in how neuronal networks work.

“Personally, the most striking point is the epidemiological data that indicate that the use of marijuana is widespread in the general population, and this starts early in life, particularly during adolescence,” Dr. Testai told this news organization.

Dr. Testai also noted that pregnant women are using cannabis for nausea and vomiting. Other data on prenatal exposure to cannabis show that THC hinders the signaling mechanism of the endocannabinoid system during development and ontogenesis, which ultimately leads to abnormal neurotransmission.

“Prenatal THC affects neuroanatomic areas associated with cognition and emotional regulation, including the prefrontal cortex, limbic system, and ventral tegmentum of the midbrain,” the researchers added.

The writing panel also found that marijuana use had effects on human cognition:
 

• Acute marijuana use affects impulsivity, memory, and behavioral disinhibition, they noted, that “can affect performance in real-world activities,” such as driving. The long-term effects of cannabis on cognition are “less well established.”
• Neuroimaging research has highlighted structural changes in the brain, but these data are inconsistent.
• Functional MRI studies show cannabis users may experience functional changes in regions of the brain that play a role in cognition, particularly with prolonged use.

The statement also addresses studies assessing the effects of marijuana use on cerebrovascular risk and disease, which show:

• A relation between cannabis use and increased risk for stroke.
• Frequency and other trends of cannabis use may raise stroke risk.
• Cannabis users often smoke cigarettes, which is an important factor in the association between cannabis use and stroke risk.

Looking ahead, public health initiatives are needed to increase awareness among the public about the negative effects of marijuana use. Other efforts may include setting standards regarding the concentrations of biologically active ingredients and warning notices on available formulations, the group concluded.

The document was prepared on behalf of the AHA Stroke Brain Health Science Subcommittee of the Stroke Council; Council on Arteriosclerosis, Thrombosis, and Vascular Biology; Council on Cardiovascular and Stroke Nursing; Council on Lifestyle and Cardiometabolic Health; and Council on Peripheral Vascular Disease.

The American Academy of Neurology “affirms the value of this statement as an educational tool for neurologists,” the document notes.

Dr. Testai reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.