Case

A 28-year-old woman was brought to the ED by emergency medical services for evaluation of injuries sustained from a high-speed, rollover motor vehicle collision (MVC), during which she was partially ejected from the passenger front seat. The patient did not experience any loss of consciousness following the MVC. At presentation, she was oriented to place and time, and actively complained of bilateral clavicular pain (which she noted was worse on her right side) as well as right forearm pain.

The patient’s vital signs upon arrival were: heart rate, 94 beats/min; respiratory rate, 24 breaths/min; blood pressure, 107/84 mm Hg; and temperature, 98°F. Oxygen saturation was 98% on room air. Examination revealed a contusion over the right breast, normal lung and heart sounds, and equal pulses bilaterally. The patient had an open deformity of the right forearm; otherwise, her motor and sensory faculties were intact.

The focused assessment with sonography for trauma examination was negative. In addition to the bilateral clavicular and right forearm pain, the patient also had tenderness bilaterally over the sternoclavicular joints (SCJ) and the right midclavicle, though there were no obvious deformities. Laboratory studies were within normal limits, with the exception of an elevated white blood cell count of 21 x 10⁹/L.

Initial plain radiographs showed a normal chest X-ray (CXR) and right forearm fracture.

Discussion

Sternoclavicular joint dislocation is a rare traumatic injury, accounting for less than 3% of shoulder girdle injuries.^1-4 Dislocations of the SCJ, which may be anterior or posterior, superior or inferior, are typically due to an MVC or athletic injury involving great force.⁵

Although an injury involving mediastinal compression such as a posterior SCJ dislocation can be fatal if not treated early, these dislocations are typically not detected in a multitrauma patient until the secondary survey.⁶ A missed diagnosis of posterior SCJ dislocation carries a mortality rate of 3% to 4% due to the potential for retrosternal injuries.^4,6 Unfortunately, SCJ dislocations can be an easily overlooked injury in the multitrauma patient, as plain radiographs are difficult to interpret and physical examination findings other than tenderness may not always be present.^5-7

Anatomy

The SCJ is comprised of the manubrium’s clavicular notch, the medial end of the clavicle, and the cartilage of the first rib.³ The capsular ligaments cover the anterior and posterior parts of the joint and offer stability along with the costoclavicular and interclavicular ligaments. Since the surrounding ligaments provide strong support to the joint, an incredible amount of force is needed for a dislocation to occur.

The clavicle is the first long bone in the body to ossify, and it does so in utero; however, the epiphysis of the medial clavicle is the last to ossify, and it does not fuse with the body of the clavicle until the early-to-mid-third decade of life. Since younger patients are therefore more prone to physeal fracture than joint dislocation, it is imperative to keep this as part of the differential in patients younger than age 25 years.^1,3,8-10

Primary Survey

The emergency physician (EP) should approach the multitrauma patient in the usual fashion, ie, by first performing the primary survey. However, there may be some signs present in this early examination to indicate a posterior SCJ dislocation, including painful range of motion at the joint, inability to move the shoulder joint, hoarseness, dyspnea, dysphagia, neurovascular compromise of the arm, or frank hemodynamic instability.^6-8 After the first survey is completed, if the EP has a high level of suspicion for SCJ dislocation, it is essential to perform a thorough secondary survey to confirm the diagnosis.

Secondary Survey

Anterior SCJ dislocations might be easier to detect clinically during the secondary survey, as the patient might have a deformity of the clavicle and swelling.⁸ However, posterior and superior SCJ dislocations might be more subtle during examination, and may only exhibit tenderness and limited range of motion.

Imaging Studies

Computed Tomography. Since overlying structures often make it difficult to interpret simple radiographs, advanced imaging studies such as CT are often needed for diagnosis. A CT angiogram (CTA) may be considered if there is concern for vascular injury and compromise of the limb, as this modality is more accurate in evaluating vasculature such as the subclavian artery.^4,10

Special Radiographic Views. If advanced imaging is not immediately available or if the patient is not in a suitable condition to leave the ED, an alternative is to obtain a serendipity view X-ray. Described in 2009 by Wirth and Rockwood,¹¹ the serendipity view is obtained with the patient in the supine position and the X-ray beam tilted to a 40-degree cephalic angle centered through the manubrium. This view permits comparison of both clavicles without overlying structures. The usefulness of serendipity view X-ray, however, is limited, as it does not allow for differentiation of sprains.

Other plain radiographic views, such as the Hobbs, Heinig, and Kattan views, have also been described to evaluate for SCJ dislocation, but these views are often not feasible or easily obtained in an emergency setting with an acutely injured patient.^6,9,12

Magnetic Resonance Imaging. Though CT is typically the advanced initial imaging modality of choice for assessing the presence of an SCJ dislocation, additional studies using MRI are indicated for patients in whom there is a concern of physeal injury.¹Ultrasound. Point-of-care ultrasound has become an important tool in the EP’s armamentarium, and can easily be employed to diagnose a posterior SCJ dislocation, as well as confirm the reduction. The method described by Bengtzen and Petering¹³ involves placing a linear array probe in the long axis to the clavicle and scanning until the clavicle and sternum are identified by finding the hyperechoic areas. The hypoechoic area in between the clavicle and sternum is the SCJ space. An ultrasound of the unaffected side can be useful for comparison purposes.^6,13

Management

Posterior SCJ dislocations are considered a true emergency because of the potential structures associated with this type of injury. Concomitant injuries requiring immediate intervention include mediastinal compression, pneumothorax, laceration of the superior vena cava, tracheal erosion, esophageal injury, and brachial plexus compression and injury. Moreover, an unstable patient with an SCJ dislocation may have a lacerated thoracic vessel and need immediate thoracotomy.⁶

Anterior Reduction. Prior to any attempts at reduction, it is imperative to consult with orthopedic and cardiothoracic surgery services. However, if the patient’s dislocation is causing limb or life compromise, then the EP should attempt closed reduction in the ED.^1,3 One reduction technique is to place the patient in the supine position with a towel rolled up between his or her shoulders. The EP then extends and abducts the affected arm using a traction-countertraction approach.

Another technique is to have an assistant either pushing posteriorly or pulling anteriorly on the medial clavicle, while the EP performs lateral traction. An audible “snap” sound might be heard with successful reduction. If the assistant is unable to grasp the medial clavicle, then a towel clip should be used percutaneously to grasp it. If the joint remains reduced, the limb is immobilized with a figure-of-8 bandage^1,8

Further treatment options for complete SCJ dislocation include operative and nonoperative management. Posterior Reduction. While anterior dislocations are often managed conservatively with closed reduction and nonoperative treatment, posterior dislocations can often be reduced using either an open or closed approach.^1-3,8,9,14 If a posterior SCJ dislocation is reduced using a closed approach, it is more likely to be stable after reduction when compared to anterior SCJ dislocation reduction.

An attempt of closed reduction of posterior SCJ dislocation is often recommended before open approach is attempted, if it occurred within 48 hours and there are no signs of mediastinal compression.⁹ Some authors however, prefer immediate surgical approach and treatment of all complete dislocations due to better visualization of other structures such as the meniscus and potentially damaged fibrocartilage, which if untreated can result in decreased mobility and pain.^14,15

Conclusion

Although rare, posterior SCJ dislocations can be fatal when they are not diagnosed early. The EP must keep the possibility of an SCJ dislocation in mind based on the mechanism of injury—usually direct force to the joint such as occurs in an MVC or a lateral compression of the shoulder. There are clues during the primary survey that might point in the direction of an SCJ dislocation.

If the patient is hemodynamically unstable, immediate reduction is warranted and the possibility of a thoracotomy must be considered. Thirty percent of all posterior SCJ dislocations will have concomitant life-threatening injuries involving structures such as the esophagus, great vessels, and trachea.

Since sternoclavicular dislocation is often difficult to detect on CXR, the gold standard for diagnosis is CT or MRI. While the serendipity view X-ray can facilitate the evaluation of the SCJ, its value is limited. Other available plain radiographs are the Hobbs, Heinig, and Kattan views, but bedside ultrasound is often more useful and allows for faster evaluation and without ionizing radiation. Orthopedic services should be immediately consulted, and cardiothoracic surgery should readily available.

Case

A 28-year-old woman was brought to the ED by emergency medical services for evaluation of injuries sustained from a high-speed, rollover motor vehicle collision (MVC), during which she was partially ejected from the passenger front seat. The patient did not experience any loss of consciousness following the MVC. At presentation, she was oriented to place and time, and actively complained of bilateral clavicular pain (which she noted was worse on her right side) as well as right forearm pain.

The patient’s vital signs upon arrival were: heart rate, 94 beats/min; respiratory rate, 24 breaths/min; blood pressure, 107/84 mm Hg; and temperature, 98°F. Oxygen saturation was 98% on room air. Examination revealed a contusion over the right breast, normal lung and heart sounds, and equal pulses bilaterally. The patient had an open deformity of the right forearm; otherwise, her motor and sensory faculties were intact.

The focused assessment with sonography for trauma examination was negative. In addition to the bilateral clavicular and right forearm pain, the patient also had tenderness bilaterally over the sternoclavicular joints (SCJ) and the right midclavicle, though there were no obvious deformities. Laboratory studies were within normal limits, with the exception of an elevated white blood cell count of 21 x 10⁹/L.

Initial plain radiographs showed a normal chest X-ray (CXR) and right forearm fracture.

Discussion

Sternoclavicular joint dislocation is a rare traumatic injury, accounting for less than 3% of shoulder girdle injuries.^1-4 Dislocations of the SCJ, which may be anterior or posterior, superior or inferior, are typically due to an MVC or athletic injury involving great force.⁵

Although an injury involving mediastinal compression such as a posterior SCJ dislocation can be fatal if not treated early, these dislocations are typically not detected in a multitrauma patient until the secondary survey.⁶ A missed diagnosis of posterior SCJ dislocation carries a mortality rate of 3% to 4% due to the potential for retrosternal injuries.^4,6 Unfortunately, SCJ dislocations can be an easily overlooked injury in the multitrauma patient, as plain radiographs are difficult to interpret and physical examination findings other than tenderness may not always be present.^5-7

Anatomy

The SCJ is comprised of the manubrium’s clavicular notch, the medial end of the clavicle, and the cartilage of the first rib.³ The capsular ligaments cover the anterior and posterior parts of the joint and offer stability along with the costoclavicular and interclavicular ligaments. Since the surrounding ligaments provide strong support to the joint, an incredible amount of force is needed for a dislocation to occur.

The clavicle is the first long bone in the body to ossify, and it does so in utero; however, the epiphysis of the medial clavicle is the last to ossify, and it does not fuse with the body of the clavicle until the early-to-mid-third decade of life. Since younger patients are therefore more prone to physeal fracture than joint dislocation, it is imperative to keep this as part of the differential in patients younger than age 25 years.^1,3,8-10

Primary Survey

The emergency physician (EP) should approach the multitrauma patient in the usual fashion, ie, by first performing the primary survey. However, there may be some signs present in this early examination to indicate a posterior SCJ dislocation, including painful range of motion at the joint, inability to move the shoulder joint, hoarseness, dyspnea, dysphagia, neurovascular compromise of the arm, or frank hemodynamic instability.^6-8 After the first survey is completed, if the EP has a high level of suspicion for SCJ dislocation, it is essential to perform a thorough secondary survey to confirm the diagnosis.

Secondary Survey

Anterior SCJ dislocations might be easier to detect clinically during the secondary survey, as the patient might have a deformity of the clavicle and swelling.⁸ However, posterior and superior SCJ dislocations might be more subtle during examination, and may only exhibit tenderness and limited range of motion.

Imaging Studies

Computed Tomography. Since overlying structures often make it difficult to interpret simple radiographs, advanced imaging studies such as CT are often needed for diagnosis. A CT angiogram (CTA) may be considered if there is concern for vascular injury and compromise of the limb, as this modality is more accurate in evaluating vasculature such as the subclavian artery.^4,10

Special Radiographic Views. If advanced imaging is not immediately available or if the patient is not in a suitable condition to leave the ED, an alternative is to obtain a serendipity view X-ray. Described in 2009 by Wirth and Rockwood,¹¹ the serendipity view is obtained with the patient in the supine position and the X-ray beam tilted to a 40-degree cephalic angle centered through the manubrium. This view permits comparison of both clavicles without overlying structures. The usefulness of serendipity view X-ray, however, is limited, as it does not allow for differentiation of sprains.

Other plain radiographic views, such as the Hobbs, Heinig, and Kattan views, have also been described to evaluate for SCJ dislocation, but these views are often not feasible or easily obtained in an emergency setting with an acutely injured patient.^6,9,12

Magnetic Resonance Imaging. Though CT is typically the advanced initial imaging modality of choice for assessing the presence of an SCJ dislocation, additional studies using MRI are indicated for patients in whom there is a concern of physeal injury.¹Ultrasound. Point-of-care ultrasound has become an important tool in the EP’s armamentarium, and can easily be employed to diagnose a posterior SCJ dislocation, as well as confirm the reduction. The method described by Bengtzen and Petering¹³ involves placing a linear array probe in the long axis to the clavicle and scanning until the clavicle and sternum are identified by finding the hyperechoic areas. The hypoechoic area in between the clavicle and sternum is the SCJ space. An ultrasound of the unaffected side can be useful for comparison purposes.^6,13

Management

Posterior SCJ dislocations are considered a true emergency because of the potential structures associated with this type of injury. Concomitant injuries requiring immediate intervention include mediastinal compression, pneumothorax, laceration of the superior vena cava, tracheal erosion, esophageal injury, and brachial plexus compression and injury. Moreover, an unstable patient with an SCJ dislocation may have a lacerated thoracic vessel and need immediate thoracotomy.⁶

Anterior Reduction. Prior to any attempts at reduction, it is imperative to consult with orthopedic and cardiothoracic surgery services. However, if the patient’s dislocation is causing limb or life compromise, then the EP should attempt closed reduction in the ED.^1,3 One reduction technique is to place the patient in the supine position with a towel rolled up between his or her shoulders. The EP then extends and abducts the affected arm using a traction-countertraction approach.

Another technique is to have an assistant either pushing posteriorly or pulling anteriorly on the medial clavicle, while the EP performs lateral traction. An audible “snap” sound might be heard with successful reduction. If the assistant is unable to grasp the medial clavicle, then a towel clip should be used percutaneously to grasp it. If the joint remains reduced, the limb is immobilized with a figure-of-8 bandage^1,8

Further treatment options for complete SCJ dislocation include operative and nonoperative management. Posterior Reduction. While anterior dislocations are often managed conservatively with closed reduction and nonoperative treatment, posterior dislocations can often be reduced using either an open or closed approach.^1-3,8,9,14 If a posterior SCJ dislocation is reduced using a closed approach, it is more likely to be stable after reduction when compared to anterior SCJ dislocation reduction.

An attempt of closed reduction of posterior SCJ dislocation is often recommended before open approach is attempted, if it occurred within 48 hours and there are no signs of mediastinal compression.⁹ Some authors however, prefer immediate surgical approach and treatment of all complete dislocations due to better visualization of other structures such as the meniscus and potentially damaged fibrocartilage, which if untreated can result in decreased mobility and pain.^14,15

Conclusion

Although rare, posterior SCJ dislocations can be fatal when they are not diagnosed early. The EP must keep the possibility of an SCJ dislocation in mind based on the mechanism of injury—usually direct force to the joint such as occurs in an MVC or a lateral compression of the shoulder. There are clues during the primary survey that might point in the direction of an SCJ dislocation.

If the patient is hemodynamically unstable, immediate reduction is warranted and the possibility of a thoracotomy must be considered. Thirty percent of all posterior SCJ dislocations will have concomitant life-threatening injuries involving structures such as the esophagus, great vessels, and trachea.

Since sternoclavicular dislocation is often difficult to detect on CXR, the gold standard for diagnosis is CT or MRI. While the serendipity view X-ray can facilitate the evaluation of the SCJ, its value is limited. Other available plain radiographs are the Hobbs, Heinig, and Kattan views, but bedside ultrasound is often more useful and allows for faster evaluation and without ionizing radiation. Orthopedic services should be immediately consulted, and cardiothoracic surgery should readily available.

Case

A 28-year-old woman was brought to the ED by emergency medical services for evaluation of injuries sustained from a high-speed, rollover motor vehicle collision (MVC), during which she was partially ejected from the passenger front seat. The patient did not experience any loss of consciousness following the MVC. At presentation, she was oriented to place and time, and actively complained of bilateral clavicular pain (which she noted was worse on her right side) as well as right forearm pain.

The patient’s vital signs upon arrival were: heart rate, 94 beats/min; respiratory rate, 24 breaths/min; blood pressure, 107/84 mm Hg; and temperature, 98°F. Oxygen saturation was 98% on room air. Examination revealed a contusion over the right breast, normal lung and heart sounds, and equal pulses bilaterally. The patient had an open deformity of the right forearm; otherwise, her motor and sensory faculties were intact.

The focused assessment with sonography for trauma examination was negative. In addition to the bilateral clavicular and right forearm pain, the patient also had tenderness bilaterally over the sternoclavicular joints (SCJ) and the right midclavicle, though there were no obvious deformities. Laboratory studies were within normal limits, with the exception of an elevated white blood cell count of 21 x 10⁹/L.

Initial plain radiographs showed a normal chest X-ray (CXR) and right forearm fracture.

Discussion

Sternoclavicular joint dislocation is a rare traumatic injury, accounting for less than 3% of shoulder girdle injuries.^1-4 Dislocations of the SCJ, which may be anterior or posterior, superior or inferior, are typically due to an MVC or athletic injury involving great force.⁵

Although an injury involving mediastinal compression such as a posterior SCJ dislocation can be fatal if not treated early, these dislocations are typically not detected in a multitrauma patient until the secondary survey.⁶ A missed diagnosis of posterior SCJ dislocation carries a mortality rate of 3% to 4% due to the potential for retrosternal injuries.^4,6 Unfortunately, SCJ dislocations can be an easily overlooked injury in the multitrauma patient, as plain radiographs are difficult to interpret and physical examination findings other than tenderness may not always be present.^5-7

Anatomy

The SCJ is comprised of the manubrium’s clavicular notch, the medial end of the clavicle, and the cartilage of the first rib.³ The capsular ligaments cover the anterior and posterior parts of the joint and offer stability along with the costoclavicular and interclavicular ligaments. Since the surrounding ligaments provide strong support to the joint, an incredible amount of force is needed for a dislocation to occur.

The clavicle is the first long bone in the body to ossify, and it does so in utero; however, the epiphysis of the medial clavicle is the last to ossify, and it does not fuse with the body of the clavicle until the early-to-mid-third decade of life. Since younger patients are therefore more prone to physeal fracture than joint dislocation, it is imperative to keep this as part of the differential in patients younger than age 25 years.^1,3,8-10

Primary Survey

The emergency physician (EP) should approach the multitrauma patient in the usual fashion, ie, by first performing the primary survey. However, there may be some signs present in this early examination to indicate a posterior SCJ dislocation, including painful range of motion at the joint, inability to move the shoulder joint, hoarseness, dyspnea, dysphagia, neurovascular compromise of the arm, or frank hemodynamic instability.^6-8 After the first survey is completed, if the EP has a high level of suspicion for SCJ dislocation, it is essential to perform a thorough secondary survey to confirm the diagnosis.

Secondary Survey

Anterior SCJ dislocations might be easier to detect clinically during the secondary survey, as the patient might have a deformity of the clavicle and swelling.⁸ However, posterior and superior SCJ dislocations might be more subtle during examination, and may only exhibit tenderness and limited range of motion.

Imaging Studies

Computed Tomography. Since overlying structures often make it difficult to interpret simple radiographs, advanced imaging studies such as CT are often needed for diagnosis. A CT angiogram (CTA) may be considered if there is concern for vascular injury and compromise of the limb, as this modality is more accurate in evaluating vasculature such as the subclavian artery.^4,10

Special Radiographic Views. If advanced imaging is not immediately available or if the patient is not in a suitable condition to leave the ED, an alternative is to obtain a serendipity view X-ray. Described in 2009 by Wirth and Rockwood,¹¹ the serendipity view is obtained with the patient in the supine position and the X-ray beam tilted to a 40-degree cephalic angle centered through the manubrium. This view permits comparison of both clavicles without overlying structures. The usefulness of serendipity view X-ray, however, is limited, as it does not allow for differentiation of sprains.

Other plain radiographic views, such as the Hobbs, Heinig, and Kattan views, have also been described to evaluate for SCJ dislocation, but these views are often not feasible or easily obtained in an emergency setting with an acutely injured patient.^6,9,12

Magnetic Resonance Imaging. Though CT is typically the advanced initial imaging modality of choice for assessing the presence of an SCJ dislocation, additional studies using MRI are indicated for patients in whom there is a concern of physeal injury.¹Ultrasound. Point-of-care ultrasound has become an important tool in the EP’s armamentarium, and can easily be employed to diagnose a posterior SCJ dislocation, as well as confirm the reduction. The method described by Bengtzen and Petering¹³ involves placing a linear array probe in the long axis to the clavicle and scanning until the clavicle and sternum are identified by finding the hyperechoic areas. The hypoechoic area in between the clavicle and sternum is the SCJ space. An ultrasound of the unaffected side can be useful for comparison purposes.^6,13

Management

Posterior SCJ dislocations are considered a true emergency because of the potential structures associated with this type of injury. Concomitant injuries requiring immediate intervention include mediastinal compression, pneumothorax, laceration of the superior vena cava, tracheal erosion, esophageal injury, and brachial plexus compression and injury. Moreover, an unstable patient with an SCJ dislocation may have a lacerated thoracic vessel and need immediate thoracotomy.⁶

Anterior Reduction. Prior to any attempts at reduction, it is imperative to consult with orthopedic and cardiothoracic surgery services. However, if the patient’s dislocation is causing limb or life compromise, then the EP should attempt closed reduction in the ED.^1,3 One reduction technique is to place the patient in the supine position with a towel rolled up between his or her shoulders. The EP then extends and abducts the affected arm using a traction-countertraction approach.

Another technique is to have an assistant either pushing posteriorly or pulling anteriorly on the medial clavicle, while the EP performs lateral traction. An audible “snap” sound might be heard with successful reduction. If the assistant is unable to grasp the medial clavicle, then a towel clip should be used percutaneously to grasp it. If the joint remains reduced, the limb is immobilized with a figure-of-8 bandage^1,8

Further treatment options for complete SCJ dislocation include operative and nonoperative management. Posterior Reduction. While anterior dislocations are often managed conservatively with closed reduction and nonoperative treatment, posterior dislocations can often be reduced using either an open or closed approach.^1-3,8,9,14 If a posterior SCJ dislocation is reduced using a closed approach, it is more likely to be stable after reduction when compared to anterior SCJ dislocation reduction.

An attempt of closed reduction of posterior SCJ dislocation is often recommended before open approach is attempted, if it occurred within 48 hours and there are no signs of mediastinal compression.⁹ Some authors however, prefer immediate surgical approach and treatment of all complete dislocations due to better visualization of other structures such as the meniscus and potentially damaged fibrocartilage, which if untreated can result in decreased mobility and pain.^14,15

Conclusion

Although rare, posterior SCJ dislocations can be fatal when they are not diagnosed early. The EP must keep the possibility of an SCJ dislocation in mind based on the mechanism of injury—usually direct force to the joint such as occurs in an MVC or a lateral compression of the shoulder. There are clues during the primary survey that might point in the direction of an SCJ dislocation.

If the patient is hemodynamically unstable, immediate reduction is warranted and the possibility of a thoracotomy must be considered. Thirty percent of all posterior SCJ dislocations will have concomitant life-threatening injuries involving structures such as the esophagus, great vessels, and trachea.

Since sternoclavicular dislocation is often difficult to detect on CXR, the gold standard for diagnosis is CT or MRI. While the serendipity view X-ray can facilitate the evaluation of the SCJ, its value is limited. Other available plain radiographs are the Hobbs, Heinig, and Kattan views, but bedside ultrasound is often more useful and allows for faster evaluation and without ionizing radiation. Orthopedic services should be immediately consulted, and cardiothoracic surgery should readily available.

Case

A 21-year-old woman presented to the ED for evaluation of severe chest pain radiating to her left arm, and associated shortness of breath, nausea, and vomiting. She stated that the pain started 2 hours earlier while she was resting and had become progressively worse. She denied any history of similar symptoms. The patient denied fever, chills, or cough. She stated that she was otherwise in good health and did not take any medication on a regular basis. Regarding her social history, she admitted to smoking one pack of cigarettes a day and drinking alcohol on occasion.

On physical examination, the patient appeared uncomfortable. Her vital signs were: blood pressure, 136/86 mm Hg; heart rate, 102 beats/min; respiratory rate, 22 breaths/min; and temperature, 98.6⁰F. Oxygen saturation was 97% on room air. The head, eyes, ears, nose, and throat examination was unremarkable. Auscultation of the lungs revealed clear breath sounds bilaterally. The heart examination revealed tachycardia, but with regular rhythm and without murmurs, rubs, or gallops. The abdomen was soft and nontender. No lower extremity examination was documented.

The patient was seen by a physician assistant (PA) in the ED. An electrocardiogram (ECG), complete blood count (CBC), basic metabolic profile (BMP), troponin level, chest X-ray (CXR), and urine pregnancy test were ordered. The patient was given intravenous (IV) fluids and prochlorperazine 10 mg IV. The ECG and CXR were interpreted as normal. The urine pregnancy test was negative, and the remaining blood test results were within normal limits.

The PA believed the patient suffered from gastroenteritis, coupled with anxiety. He discharged the patient home with instructions to drink clear liquids for 24 hours, and take the prescribed prochlorperazine tablets as needed for continued nausea and vomiting.

At home, the patient continued to experience increasingly severe chest pain, shortness of breath, and vomiting. The next morning, she could no longer tolerate the pain and returned to the same ED via emergency medical services.

The patient’s history and physical examination remained unchanged from her presentation 16 hours earlier. At this ED visit, the patient was seen by an emergency physician (EP) who, concerned the patient had suffered an ischemic coronary event, ordered repeat ECG, CBC, BMP, and troponin evaluation. The EP also contacted cardiology services, but the cardiologist did not see the patient for several hours. When the cardiologist evaluated the patient and interpreted the ECG, he was concerned for an ST-segment elevation myocardial infarction (STEMI), and activated the catheterization lab.

Unfortunately, the patient had significant myocardial damage, with a resulting ejection fraction of only 10%. She was judged to be a candidate for heart transplantation, and received a left ventricular assist device (LVAD) as a bridge until a suitable donor heart could be identified. One month after implantation of the LVAD, the patient experienced an ischemic stroke that resulted in dense left-side weakness, leaving her confined to bed.

The patient sued the PA, the EP, the hospital, and the cardiologist for failing to identify and treat the acute STEMI in a timely manner. The plaintiff claimed the STEMI began at her first presentation to the ED, and that it should have been diagnosed and treated at that time. The plaintiff further argued that she should at least have been monitored and undergone repeat testing (ie, ECG and troponin level evaluation) at the first visit, stating that if she had received proper treatment, she would not have required an LVAD and therefore would not have had a stroke. The patient also alleged that at the second ED visit, there was a significant time delay before she was taken to the catheterization lab, which resulted in additional myocardial injury.

The defendants argued the patient was appropriately evaluated and treated at the first presentation, and that there was no evidence to suggest an MI. The EP argued that the delay in the patient’s care at the second visit was not his fault. All of the parties involved negotiated a settlement in the amount of $6 million in favor of the plaintiff.

Discussion

Myocardial infarction in adults younger than age 45 years is relatively rare, comprising only 2% to 10% of all MIs.^1,2 The percentage of MI in patients younger than age 25 years must be even smaller, but no good data are available. In fact, age 40 years and younger is usually an exclusion criteria in many of the multicenter studies involving MI. Women are relatively spared from coronary artery disease (CAD) before menopause, thanks to the cardioprotective effects of estrogen. Young women who do experience an MI usually will have cardiovascular risk factors, especially smoking.

Risk Factors for MI in Young Patients

Cigarette Smoking. When examining common risk factors in young patients who had an MI (defined as patients younger than age 45 years), cigarette smoking is the most common risk factor.^1,2 Between 76% and 91% of young patients with an MI are smokers, compared to only 40% incidence in older patients.¹ It is thought that cigarette smoking produces endothelial dysfunction and can precipitate coronary spasm.¹

Nonatherosclerotic Etiology. Interestingly, several studies of MI in young patients found a higher incidence of nonatherosclerotic causes of MI in women compared to men.² One explanation for this finding is that women experience vasospastic syndromes and hypercoagulable states, secondary to oral contraceptive use or hereditary coagulation disorders.² It has also been shown that young women have more active platelets following an MI and experience plaque erosions, rather than the plaque ruptures that occur in men and older women.^2,3

Hyperlipidemia. Hyperlipidemia is an additional risk factor for MI in the younger adult patient population. In one study of young patients who had an MI, hyperlipidemia was the most important risk factor, in the absence of other obvious risk factors.^1,4 In fact, some researchers think hyperlipidemia may be a more reliable predictor of MI in patients aged 30 to 39 years than in older patients.^1,5 Unfortunately, many of these young adults are not aware that they have hyperlipidemia until they experience a complication such as an acute coronary syndrome. With respect to the patient in this case, it is not clear from the published report whether or not she had hyperlipidemia.

Family History. Another risk factor for MI in younger patients is a positive family history of CAD in a first-degree relative younger than age 55 years.¹ Siblings of a young patient who experienced an MI have up to a 10-fold increase for developing CAD.¹ It is currently not known why a positive family history increases the risk of MI in younger patients, but it may be related to inherited disorders of lipid metabolism, blood coagulation, or other genetic factors.¹

Drug Abuse. Finally, drug abuse must be considered in young patients presenting with an MI. The use of cocaine, methamphetamine, marijuana, and K2 (synthetic marijuana) have all been associated with MI, especially in young patients,^6-9 who typically do not have cardiac risk factors and do not show evidence of atherosclerotic disease on cardiac catheterization. As for the patient in this case, we do not know if she used any illicit drugs prior to presentation.

Summary

This case underscores the importance of not excluding MI in the differential diagnosis based simply on age or sex. While MI is uncommon in a 21-year-old woman, it can and does occur. In young patients presenting with chest pain, it is important to obtain a thorough history, including smoking, family history of MI, hyperlipidemia, and illicit drug use. While MI may be low on the differential diagnosis, it still needs to be considered.

Case

A 21-year-old woman presented to the ED for evaluation of severe chest pain radiating to her left arm, and associated shortness of breath, nausea, and vomiting. She stated that the pain started 2 hours earlier while she was resting and had become progressively worse. She denied any history of similar symptoms. The patient denied fever, chills, or cough. She stated that she was otherwise in good health and did not take any medication on a regular basis. Regarding her social history, she admitted to smoking one pack of cigarettes a day and drinking alcohol on occasion.

On physical examination, the patient appeared uncomfortable. Her vital signs were: blood pressure, 136/86 mm Hg; heart rate, 102 beats/min; respiratory rate, 22 breaths/min; and temperature, 98.6⁰F. Oxygen saturation was 97% on room air. The head, eyes, ears, nose, and throat examination was unremarkable. Auscultation of the lungs revealed clear breath sounds bilaterally. The heart examination revealed tachycardia, but with regular rhythm and without murmurs, rubs, or gallops. The abdomen was soft and nontender. No lower extremity examination was documented.

The patient was seen by a physician assistant (PA) in the ED. An electrocardiogram (ECG), complete blood count (CBC), basic metabolic profile (BMP), troponin level, chest X-ray (CXR), and urine pregnancy test were ordered. The patient was given intravenous (IV) fluids and prochlorperazine 10 mg IV. The ECG and CXR were interpreted as normal. The urine pregnancy test was negative, and the remaining blood test results were within normal limits.

The PA believed the patient suffered from gastroenteritis, coupled with anxiety. He discharged the patient home with instructions to drink clear liquids for 24 hours, and take the prescribed prochlorperazine tablets as needed for continued nausea and vomiting.

At home, the patient continued to experience increasingly severe chest pain, shortness of breath, and vomiting. The next morning, she could no longer tolerate the pain and returned to the same ED via emergency medical services.

The patient’s history and physical examination remained unchanged from her presentation 16 hours earlier. At this ED visit, the patient was seen by an emergency physician (EP) who, concerned the patient had suffered an ischemic coronary event, ordered repeat ECG, CBC, BMP, and troponin evaluation. The EP also contacted cardiology services, but the cardiologist did not see the patient for several hours. When the cardiologist evaluated the patient and interpreted the ECG, he was concerned for an ST-segment elevation myocardial infarction (STEMI), and activated the catheterization lab.

Unfortunately, the patient had significant myocardial damage, with a resulting ejection fraction of only 10%. She was judged to be a candidate for heart transplantation, and received a left ventricular assist device (LVAD) as a bridge until a suitable donor heart could be identified. One month after implantation of the LVAD, the patient experienced an ischemic stroke that resulted in dense left-side weakness, leaving her confined to bed.

The patient sued the PA, the EP, the hospital, and the cardiologist for failing to identify and treat the acute STEMI in a timely manner. The plaintiff claimed the STEMI began at her first presentation to the ED, and that it should have been diagnosed and treated at that time. The plaintiff further argued that she should at least have been monitored and undergone repeat testing (ie, ECG and troponin level evaluation) at the first visit, stating that if she had received proper treatment, she would not have required an LVAD and therefore would not have had a stroke. The patient also alleged that at the second ED visit, there was a significant time delay before she was taken to the catheterization lab, which resulted in additional myocardial injury.

The defendants argued the patient was appropriately evaluated and treated at the first presentation, and that there was no evidence to suggest an MI. The EP argued that the delay in the patient’s care at the second visit was not his fault. All of the parties involved negotiated a settlement in the amount of $6 million in favor of the plaintiff.

Discussion

Myocardial infarction in adults younger than age 45 years is relatively rare, comprising only 2% to 10% of all MIs.^1,2 The percentage of MI in patients younger than age 25 years must be even smaller, but no good data are available. In fact, age 40 years and younger is usually an exclusion criteria in many of the multicenter studies involving MI. Women are relatively spared from coronary artery disease (CAD) before menopause, thanks to the cardioprotective effects of estrogen. Young women who do experience an MI usually will have cardiovascular risk factors, especially smoking.

Risk Factors for MI in Young Patients

Cigarette Smoking. When examining common risk factors in young patients who had an MI (defined as patients younger than age 45 years), cigarette smoking is the most common risk factor.^1,2 Between 76% and 91% of young patients with an MI are smokers, compared to only 40% incidence in older patients.¹ It is thought that cigarette smoking produces endothelial dysfunction and can precipitate coronary spasm.¹

Nonatherosclerotic Etiology. Interestingly, several studies of MI in young patients found a higher incidence of nonatherosclerotic causes of MI in women compared to men.² One explanation for this finding is that women experience vasospastic syndromes and hypercoagulable states, secondary to oral contraceptive use or hereditary coagulation disorders.² It has also been shown that young women have more active platelets following an MI and experience plaque erosions, rather than the plaque ruptures that occur in men and older women.^2,3

Hyperlipidemia. Hyperlipidemia is an additional risk factor for MI in the younger adult patient population. In one study of young patients who had an MI, hyperlipidemia was the most important risk factor, in the absence of other obvious risk factors.^1,4 In fact, some researchers think hyperlipidemia may be a more reliable predictor of MI in patients aged 30 to 39 years than in older patients.^1,5 Unfortunately, many of these young adults are not aware that they have hyperlipidemia until they experience a complication such as an acute coronary syndrome. With respect to the patient in this case, it is not clear from the published report whether or not she had hyperlipidemia.

Family History. Another risk factor for MI in younger patients is a positive family history of CAD in a first-degree relative younger than age 55 years.¹ Siblings of a young patient who experienced an MI have up to a 10-fold increase for developing CAD.¹ It is currently not known why a positive family history increases the risk of MI in younger patients, but it may be related to inherited disorders of lipid metabolism, blood coagulation, or other genetic factors.¹

Drug Abuse. Finally, drug abuse must be considered in young patients presenting with an MI. The use of cocaine, methamphetamine, marijuana, and K2 (synthetic marijuana) have all been associated with MI, especially in young patients,^6-9 who typically do not have cardiac risk factors and do not show evidence of atherosclerotic disease on cardiac catheterization. As for the patient in this case, we do not know if she used any illicit drugs prior to presentation.

Summary

This case underscores the importance of not excluding MI in the differential diagnosis based simply on age or sex. While MI is uncommon in a 21-year-old woman, it can and does occur. In young patients presenting with chest pain, it is important to obtain a thorough history, including smoking, family history of MI, hyperlipidemia, and illicit drug use. While MI may be low on the differential diagnosis, it still needs to be considered.

Case

A 21-year-old woman presented to the ED for evaluation of severe chest pain radiating to her left arm, and associated shortness of breath, nausea, and vomiting. She stated that the pain started 2 hours earlier while she was resting and had become progressively worse. She denied any history of similar symptoms. The patient denied fever, chills, or cough. She stated that she was otherwise in good health and did not take any medication on a regular basis. Regarding her social history, she admitted to smoking one pack of cigarettes a day and drinking alcohol on occasion.

On physical examination, the patient appeared uncomfortable. Her vital signs were: blood pressure, 136/86 mm Hg; heart rate, 102 beats/min; respiratory rate, 22 breaths/min; and temperature, 98.6⁰F. Oxygen saturation was 97% on room air. The head, eyes, ears, nose, and throat examination was unremarkable. Auscultation of the lungs revealed clear breath sounds bilaterally. The heart examination revealed tachycardia, but with regular rhythm and without murmurs, rubs, or gallops. The abdomen was soft and nontender. No lower extremity examination was documented.

The patient was seen by a physician assistant (PA) in the ED. An electrocardiogram (ECG), complete blood count (CBC), basic metabolic profile (BMP), troponin level, chest X-ray (CXR), and urine pregnancy test were ordered. The patient was given intravenous (IV) fluids and prochlorperazine 10 mg IV. The ECG and CXR were interpreted as normal. The urine pregnancy test was negative, and the remaining blood test results were within normal limits.

The PA believed the patient suffered from gastroenteritis, coupled with anxiety. He discharged the patient home with instructions to drink clear liquids for 24 hours, and take the prescribed prochlorperazine tablets as needed for continued nausea and vomiting.

At home, the patient continued to experience increasingly severe chest pain, shortness of breath, and vomiting. The next morning, she could no longer tolerate the pain and returned to the same ED via emergency medical services.

The patient’s history and physical examination remained unchanged from her presentation 16 hours earlier. At this ED visit, the patient was seen by an emergency physician (EP) who, concerned the patient had suffered an ischemic coronary event, ordered repeat ECG, CBC, BMP, and troponin evaluation. The EP also contacted cardiology services, but the cardiologist did not see the patient for several hours. When the cardiologist evaluated the patient and interpreted the ECG, he was concerned for an ST-segment elevation myocardial infarction (STEMI), and activated the catheterization lab.

Unfortunately, the patient had significant myocardial damage, with a resulting ejection fraction of only 10%. She was judged to be a candidate for heart transplantation, and received a left ventricular assist device (LVAD) as a bridge until a suitable donor heart could be identified. One month after implantation of the LVAD, the patient experienced an ischemic stroke that resulted in dense left-side weakness, leaving her confined to bed.

The patient sued the PA, the EP, the hospital, and the cardiologist for failing to identify and treat the acute STEMI in a timely manner. The plaintiff claimed the STEMI began at her first presentation to the ED, and that it should have been diagnosed and treated at that time. The plaintiff further argued that she should at least have been monitored and undergone repeat testing (ie, ECG and troponin level evaluation) at the first visit, stating that if she had received proper treatment, she would not have required an LVAD and therefore would not have had a stroke. The patient also alleged that at the second ED visit, there was a significant time delay before she was taken to the catheterization lab, which resulted in additional myocardial injury.

The defendants argued the patient was appropriately evaluated and treated at the first presentation, and that there was no evidence to suggest an MI. The EP argued that the delay in the patient’s care at the second visit was not his fault. All of the parties involved negotiated a settlement in the amount of $6 million in favor of the plaintiff.

Discussion

Myocardial infarction in adults younger than age 45 years is relatively rare, comprising only 2% to 10% of all MIs.^1,2 The percentage of MI in patients younger than age 25 years must be even smaller, but no good data are available. In fact, age 40 years and younger is usually an exclusion criteria in many of the multicenter studies involving MI. Women are relatively spared from coronary artery disease (CAD) before menopause, thanks to the cardioprotective effects of estrogen. Young women who do experience an MI usually will have cardiovascular risk factors, especially smoking.

Risk Factors for MI in Young Patients

Cigarette Smoking. When examining common risk factors in young patients who had an MI (defined as patients younger than age 45 years), cigarette smoking is the most common risk factor.^1,2 Between 76% and 91% of young patients with an MI are smokers, compared to only 40% incidence in older patients.¹ It is thought that cigarette smoking produces endothelial dysfunction and can precipitate coronary spasm.¹

Nonatherosclerotic Etiology. Interestingly, several studies of MI in young patients found a higher incidence of nonatherosclerotic causes of MI in women compared to men.² One explanation for this finding is that women experience vasospastic syndromes and hypercoagulable states, secondary to oral contraceptive use or hereditary coagulation disorders.² It has also been shown that young women have more active platelets following an MI and experience plaque erosions, rather than the plaque ruptures that occur in men and older women.^2,3

Hyperlipidemia. Hyperlipidemia is an additional risk factor for MI in the younger adult patient population. In one study of young patients who had an MI, hyperlipidemia was the most important risk factor, in the absence of other obvious risk factors.^1,4 In fact, some researchers think hyperlipidemia may be a more reliable predictor of MI in patients aged 30 to 39 years than in older patients.^1,5 Unfortunately, many of these young adults are not aware that they have hyperlipidemia until they experience a complication such as an acute coronary syndrome. With respect to the patient in this case, it is not clear from the published report whether or not she had hyperlipidemia.

Family History. Another risk factor for MI in younger patients is a positive family history of CAD in a first-degree relative younger than age 55 years.¹ Siblings of a young patient who experienced an MI have up to a 10-fold increase for developing CAD.¹ It is currently not known why a positive family history increases the risk of MI in younger patients, but it may be related to inherited disorders of lipid metabolism, blood coagulation, or other genetic factors.¹

Drug Abuse. Finally, drug abuse must be considered in young patients presenting with an MI. The use of cocaine, methamphetamine, marijuana, and K2 (synthetic marijuana) have all been associated with MI, especially in young patients,^6-9 who typically do not have cardiac risk factors and do not show evidence of atherosclerotic disease on cardiac catheterization. As for the patient in this case, we do not know if she used any illicit drugs prior to presentation.

Summary

This case underscores the importance of not excluding MI in the differential diagnosis based simply on age or sex. While MI is uncommon in a 21-year-old woman, it can and does occur. In young patients presenting with chest pain, it is important to obtain a thorough history, including smoking, family history of MI, hyperlipidemia, and illicit drug use. While MI may be low on the differential diagnosis, it still needs to be considered.

A 32-year-old man presented to the ED with acute onset of left testicular swelling and pain. He described the pain as severe, radiating to his lower back and lower abdomen. Regarding his medical history, the patient stated he had experienced similar episodes of significant testicular swelling in the past, for which he was treated with antibiotics.

Physical examination revealed mild enlargement of the left testis with tenderness to palpation. The right testis was normal in appearance and nontender. An ultrasound study of the testicles was ordered; representative images are shown (Figures 1a-1c).

What is the diagnosis?

The transverse image of both testes demonstrated an enlarged left testicle compared to the right testicle (Figure 2a). On color-flow Doppler ultrasound, spots of color within the testicle were noted within the right testicle only. The lack of blood flow was confirmed on the sagittal image of the left testicle, which also revealed a small hydrocele (white arrows, Figure 2b). A sagittal color Doppler image of the normal right testicle showed color flow (white arrows, Figure 2c) and normal vascular waveforms (red arrow, Figure 2c) within the testis, but no hydrocele, confirming the diagnosis of left testicular torsion. The Doppler ultrasound of the right testicle (white arrows, Figure 2c) further confirmed a normal right testicle but no evidence of flow in the left testicle. These findings were further consistent with the presence of left testicular torsion.

Answer

Testicular Torsion

Testicular torsion is a urological emergency that results from a twisting of the spermatic cord, cutting off arterial flow to, and venous drainage from, the affected testis. There are two types of testicular torsion depending on which side of the tunica vaginalis (the serous membrane pouch covering the testes) the torsion occurs: extra vaginal, seen mainly in newborns; and intravaginal, which can occur at any age, but is more common in adolescents.

“Bell clapper deformity” is a predisposing congenital condition resulting from intravaginal torsion of the testis in which the tunica vaginalis joins high on the spermatic cord, leaving the testis free to rotate.¹ Testicular torsion most commonly occurs in young males, with an estimated incidence of 4.5 cases per 100,000 patients between ages 1 and 25 years.²

Clinical Presentation

Patients with testicular torsion typically experience a sudden onset of severe unilateral pain often accompanied by nausea and vomiting, which can occur spontaneously or after vigorous physical activity or trauma. Associated complaints may include urinary symptoms and/or fever.³ The affected testis may lie transversely in the scrotum and be retracted, although physical examination is often nonspecific and unreliable. Since an absence of the cremasteric reflex is neither sensitive nor specific in determining the need for surgical intervention, further diagnostic testing is required.⁴

Doppler Ultrasound

Ultrasound utilizing color and spectral Doppler techniques is the imaging test of choice to evaluate for testicular torsion, and has a reported sensitivity of 82% to 89%, and a specificity of 98% to 100%.^5,6 Ultrasound findings include enlargement and decreased echogenicity of the affected testicle due to edema. Scrotal wall thickening and a small hydrocele also may be seen. Doppler imaging also typically demonstrates absence of flow, though hyperemia and increased flow may be present early in the disease process.

It is important to note that torsion may be intermittent; therefore, imaging studies can appear normal during periods of intermittent perfusion. If there is incomplete torsion and some arterial flow persists in the affected testis, comparison of the two testes using transverse views is very useful in making the diagnosis.⁷

With respect to the differential diagnoses, ultrasound imaging studies are also useful in diagnosing other conditions associated with testicular pain, including torsion of the appendix testis, epididymitis, orchitis, trauma, varicocele, and tumors.

Treatment

Rapid diagnosis of testicular torsion is important, as delay in diagnosis may lead to irreversible damage and loss of the testicle. Infertility can result even with a normal contralateral testis.⁸ When surgical intervention is performed within 6 hours from onset of torsion, salvage of the testicle has been reported to be 90% to 100%, but only 50% and 10% at 12 and 24 hours, respectively.³ The patient in this case was taken immediately for emergent surgical detorsion, and the left testicle was salvaged.

A 32-year-old man presented to the ED with acute onset of left testicular swelling and pain. He described the pain as severe, radiating to his lower back and lower abdomen. Regarding his medical history, the patient stated he had experienced similar episodes of significant testicular swelling in the past, for which he was treated with antibiotics.

Physical examination revealed mild enlargement of the left testis with tenderness to palpation. The right testis was normal in appearance and nontender. An ultrasound study of the testicles was ordered; representative images are shown (Figures 1a-1c).

What is the diagnosis?

The transverse image of both testes demonstrated an enlarged left testicle compared to the right testicle (Figure 2a). On color-flow Doppler ultrasound, spots of color within the testicle were noted within the right testicle only. The lack of blood flow was confirmed on the sagittal image of the left testicle, which also revealed a small hydrocele (white arrows, Figure 2b). A sagittal color Doppler image of the normal right testicle showed color flow (white arrows, Figure 2c) and normal vascular waveforms (red arrow, Figure 2c) within the testis, but no hydrocele, confirming the diagnosis of left testicular torsion. The Doppler ultrasound of the right testicle (white arrows, Figure 2c) further confirmed a normal right testicle but no evidence of flow in the left testicle. These findings were further consistent with the presence of left testicular torsion.

Answer

Testicular Torsion

Testicular torsion is a urological emergency that results from a twisting of the spermatic cord, cutting off arterial flow to, and venous drainage from, the affected testis. There are two types of testicular torsion depending on which side of the tunica vaginalis (the serous membrane pouch covering the testes) the torsion occurs: extra vaginal, seen mainly in newborns; and intravaginal, which can occur at any age, but is more common in adolescents.

“Bell clapper deformity” is a predisposing congenital condition resulting from intravaginal torsion of the testis in which the tunica vaginalis joins high on the spermatic cord, leaving the testis free to rotate.¹ Testicular torsion most commonly occurs in young males, with an estimated incidence of 4.5 cases per 100,000 patients between ages 1 and 25 years.²

Clinical Presentation

Patients with testicular torsion typically experience a sudden onset of severe unilateral pain often accompanied by nausea and vomiting, which can occur spontaneously or after vigorous physical activity or trauma. Associated complaints may include urinary symptoms and/or fever.³ The affected testis may lie transversely in the scrotum and be retracted, although physical examination is often nonspecific and unreliable. Since an absence of the cremasteric reflex is neither sensitive nor specific in determining the need for surgical intervention, further diagnostic testing is required.⁴

Doppler Ultrasound

Ultrasound utilizing color and spectral Doppler techniques is the imaging test of choice to evaluate for testicular torsion, and has a reported sensitivity of 82% to 89%, and a specificity of 98% to 100%.^5,6 Ultrasound findings include enlargement and decreased echogenicity of the affected testicle due to edema. Scrotal wall thickening and a small hydrocele also may be seen. Doppler imaging also typically demonstrates absence of flow, though hyperemia and increased flow may be present early in the disease process.

It is important to note that torsion may be intermittent; therefore, imaging studies can appear normal during periods of intermittent perfusion. If there is incomplete torsion and some arterial flow persists in the affected testis, comparison of the two testes using transverse views is very useful in making the diagnosis.⁷

With respect to the differential diagnoses, ultrasound imaging studies are also useful in diagnosing other conditions associated with testicular pain, including torsion of the appendix testis, epididymitis, orchitis, trauma, varicocele, and tumors.

Treatment

Rapid diagnosis of testicular torsion is important, as delay in diagnosis may lead to irreversible damage and loss of the testicle. Infertility can result even with a normal contralateral testis.⁸ When surgical intervention is performed within 6 hours from onset of torsion, salvage of the testicle has been reported to be 90% to 100%, but only 50% and 10% at 12 and 24 hours, respectively.³ The patient in this case was taken immediately for emergent surgical detorsion, and the left testicle was salvaged.

A 32-year-old man presented to the ED with acute onset of left testicular swelling and pain. He described the pain as severe, radiating to his lower back and lower abdomen. Regarding his medical history, the patient stated he had experienced similar episodes of significant testicular swelling in the past, for which he was treated with antibiotics.

Physical examination revealed mild enlargement of the left testis with tenderness to palpation. The right testis was normal in appearance and nontender. An ultrasound study of the testicles was ordered; representative images are shown (Figures 1a-1c).

What is the diagnosis?

The transverse image of both testes demonstrated an enlarged left testicle compared to the right testicle (Figure 2a). On color-flow Doppler ultrasound, spots of color within the testicle were noted within the right testicle only. The lack of blood flow was confirmed on the sagittal image of the left testicle, which also revealed a small hydrocele (white arrows, Figure 2b). A sagittal color Doppler image of the normal right testicle showed color flow (white arrows, Figure 2c) and normal vascular waveforms (red arrow, Figure 2c) within the testis, but no hydrocele, confirming the diagnosis of left testicular torsion. The Doppler ultrasound of the right testicle (white arrows, Figure 2c) further confirmed a normal right testicle but no evidence of flow in the left testicle. These findings were further consistent with the presence of left testicular torsion.

Answer

Testicular Torsion

Testicular torsion is a urological emergency that results from a twisting of the spermatic cord, cutting off arterial flow to, and venous drainage from, the affected testis. There are two types of testicular torsion depending on which side of the tunica vaginalis (the serous membrane pouch covering the testes) the torsion occurs: extra vaginal, seen mainly in newborns; and intravaginal, which can occur at any age, but is more common in adolescents.

“Bell clapper deformity” is a predisposing congenital condition resulting from intravaginal torsion of the testis in which the tunica vaginalis joins high on the spermatic cord, leaving the testis free to rotate.¹ Testicular torsion most commonly occurs in young males, with an estimated incidence of 4.5 cases per 100,000 patients between ages 1 and 25 years.²

Clinical Presentation

Patients with testicular torsion typically experience a sudden onset of severe unilateral pain often accompanied by nausea and vomiting, which can occur spontaneously or after vigorous physical activity or trauma. Associated complaints may include urinary symptoms and/or fever.³ The affected testis may lie transversely in the scrotum and be retracted, although physical examination is often nonspecific and unreliable. Since an absence of the cremasteric reflex is neither sensitive nor specific in determining the need for surgical intervention, further diagnostic testing is required.⁴

Doppler Ultrasound

Ultrasound utilizing color and spectral Doppler techniques is the imaging test of choice to evaluate for testicular torsion, and has a reported sensitivity of 82% to 89%, and a specificity of 98% to 100%.^5,6 Ultrasound findings include enlargement and decreased echogenicity of the affected testicle due to edema. Scrotal wall thickening and a small hydrocele also may be seen. Doppler imaging also typically demonstrates absence of flow, though hyperemia and increased flow may be present early in the disease process.

It is important to note that torsion may be intermittent; therefore, imaging studies can appear normal during periods of intermittent perfusion. If there is incomplete torsion and some arterial flow persists in the affected testis, comparison of the two testes using transverse views is very useful in making the diagnosis.⁷

With respect to the differential diagnoses, ultrasound imaging studies are also useful in diagnosing other conditions associated with testicular pain, including torsion of the appendix testis, epididymitis, orchitis, trauma, varicocele, and tumors.

Treatment

Rapid diagnosis of testicular torsion is important, as delay in diagnosis may lead to irreversible damage and loss of the testicle. Infertility can result even with a normal contralateral testis.⁸ When surgical intervention is performed within 6 hours from onset of torsion, salvage of the testicle has been reported to be 90% to 100%, but only 50% and 10% at 12 and 24 hours, respectively.³ The patient in this case was taken immediately for emergent surgical detorsion, and the left testicle was salvaged.

Education and service have always been important for Harry Cho, MD, who recently joined the editorial advisory board of The Hospitalist.

From joining AmeriCorps as a fresh faced college graduate, to his ongoing work as assistant professor of medicine and director of quality, safety, and value for the division of hospital medicine at Mount Sinai in New York, and as senior fellow at the Lown Institute, Dr. Cho has found a passion in helping others learn.

Q: Why did you choose medicine as a career?

A: Right after I finished undergrad at Cornell, I spent the summer and the following year doing AmeriCorps, which is service learning work, and I worked in the inner city of Philadelphia. I worked on after-school programs and weekend programs for inner city youth and I loved it. I was organizing and developing these programs, and I thought it was fantastic. The one thing that I thought was lacking, and I think what really drove me to get into medicine, was that at the end of the day, although I felt really connected with all the kids, I felt like I was a role model, like I was a mentor, and we had a really good connection, but I wanted something a little bit more concrete on improving outcomes. I knew we made connections, but I really wanted to know more – such as, did we reduce the dropout rate in high school for these students? I think that’s why medicine was really interesting.
 

Q: How did you end up in hospital medicine?

A: I think it’s a lot of things. I love the acuity, I love playing the quarterback in a place where a lot of things are going back and forth and you have to coordinate with others. You have to make sure you see the patient from top to bottom, the whole picture, and I love that part. I also love the action and the communication and the teamwork aspect of it.
 

Q: What part of being a hospitalist do you like the most?

A: I love the education on a daily basis: the morning rounds where you walk around for an hour or two with your team, and you teach them at the bedside, and these little pearls come up along the way. My career is positioned more within quality, value improvement, and safety, so I think that participating in the education process is really helpful. I think hospital medicine has taken over that spirit in the hospital setting, and I love that.
 

Q: Which part do you like the least?

A: I think we’re in a unique time right now. Burnout is getting a little tougher to beat. People are getting a bit more tired, and I don’t think we have a good solution to solve this. With quality improvement and the electronic medical record system, a lot of us are expected to do more. I still get queries from clinical documentation saying, “I need you to document this for billing purposes” or “I need you to document this for increasing the expected length of stay,” and doctors are not quite at the point where they can balance these requirements in an effective way. There tends to be an emphasis on “one more click,” one more thing to document, just one more thing to do on the checklist. It’s getting more complex.
 

Q: What is the most rewarding part of your work?

A: Larger scale accomplishments. When you give a talk, or teach a group of residents during morning rounds, and they look at you with wonder because you have this teaching pearl they’ve never heard before, and they think you’re a great attending – that’s very instant gratification, but there's more to be done beyond that. I’ve been co-directing in the Right Care educator program, and we have a High Value Care curriculum that we’ve been implementing across the country, and we’ve just finished our second year. There are around 60 programs involved, and it’s a great feeling. You’re not seeing actual people face to face after they’ve been taught, and you’re not getting that instant gratification. But just knowing what one of those chief residents who has implemented the program is feeling, and extrapolating across the number of programs this year alone, that makes me feel good.
 

Q: Outside of hospital work, what else are you interested in?

A: High-value care is my central aim right now. I want to expand it, and I want to do things on a national scale. We formed a High Value Care committee and I’m hoping to create new guidelines to reduce overuse, overtesting, and Choosing Wisely. Outside of medicine, I like photography. Nothing professional, but I love taking pictures, especially nature and travel. Back in the day, I used to do a lot of running and martial arts too.
 

Q: Where do you see yourself in 10 years?

A: I’m not sure if I will go the chief medical officer or chief quality officer route. That’s probably where I see myself. I definitely want to continue making bigger changes on a national scale, like implementing the overuse educator program across the country.
 

Q: What do you see as the future of hospital medicine?

A: Value-based health care is always going to get bigger as the cost of health care and the cost of overuse rises, and we start to see a lot of harms outlined in research. We’re going to be on top of it much more, because the hospital setting is complex and continues to change.

Education and service have always been important for Harry Cho, MD, who recently joined the editorial advisory board of The Hospitalist.

From joining AmeriCorps as a fresh faced college graduate, to his ongoing work as assistant professor of medicine and director of quality, safety, and value for the division of hospital medicine at Mount Sinai in New York, and as senior fellow at the Lown Institute, Dr. Cho has found a passion in helping others learn.

Q: Why did you choose medicine as a career?

A: Right after I finished undergrad at Cornell, I spent the summer and the following year doing AmeriCorps, which is service learning work, and I worked in the inner city of Philadelphia. I worked on after-school programs and weekend programs for inner city youth and I loved it. I was organizing and developing these programs, and I thought it was fantastic. The one thing that I thought was lacking, and I think what really drove me to get into medicine, was that at the end of the day, although I felt really connected with all the kids, I felt like I was a role model, like I was a mentor, and we had a really good connection, but I wanted something a little bit more concrete on improving outcomes. I knew we made connections, but I really wanted to know more – such as, did we reduce the dropout rate in high school for these students? I think that’s why medicine was really interesting.
 

Q: How did you end up in hospital medicine?

A: I think it’s a lot of things. I love the acuity, I love playing the quarterback in a place where a lot of things are going back and forth and you have to coordinate with others. You have to make sure you see the patient from top to bottom, the whole picture, and I love that part. I also love the action and the communication and the teamwork aspect of it.
 

Q: What part of being a hospitalist do you like the most?

A: I love the education on a daily basis: the morning rounds where you walk around for an hour or two with your team, and you teach them at the bedside, and these little pearls come up along the way. My career is positioned more within quality, value improvement, and safety, so I think that participating in the education process is really helpful. I think hospital medicine has taken over that spirit in the hospital setting, and I love that.
 

Q: Which part do you like the least?

A: I think we’re in a unique time right now. Burnout is getting a little tougher to beat. People are getting a bit more tired, and I don’t think we have a good solution to solve this. With quality improvement and the electronic medical record system, a lot of us are expected to do more. I still get queries from clinical documentation saying, “I need you to document this for billing purposes” or “I need you to document this for increasing the expected length of stay,” and doctors are not quite at the point where they can balance these requirements in an effective way. There tends to be an emphasis on “one more click,” one more thing to document, just one more thing to do on the checklist. It’s getting more complex.
 

Q: What is the most rewarding part of your work?

A: Larger scale accomplishments. When you give a talk, or teach a group of residents during morning rounds, and they look at you with wonder because you have this teaching pearl they’ve never heard before, and they think you’re a great attending – that’s very instant gratification, but there's more to be done beyond that. I’ve been co-directing in the Right Care educator program, and we have a High Value Care curriculum that we’ve been implementing across the country, and we’ve just finished our second year. There are around 60 programs involved, and it’s a great feeling. You’re not seeing actual people face to face after they’ve been taught, and you’re not getting that instant gratification. But just knowing what one of those chief residents who has implemented the program is feeling, and extrapolating across the number of programs this year alone, that makes me feel good.
 

Q: Outside of hospital work, what else are you interested in?

A: High-value care is my central aim right now. I want to expand it, and I want to do things on a national scale. We formed a High Value Care committee and I’m hoping to create new guidelines to reduce overuse, overtesting, and Choosing Wisely. Outside of medicine, I like photography. Nothing professional, but I love taking pictures, especially nature and travel. Back in the day, I used to do a lot of running and martial arts too.
 

Q: Where do you see yourself in 10 years?

A: I’m not sure if I will go the chief medical officer or chief quality officer route. That’s probably where I see myself. I definitely want to continue making bigger changes on a national scale, like implementing the overuse educator program across the country.
 

Q: What do you see as the future of hospital medicine?

A: Value-based health care is always going to get bigger as the cost of health care and the cost of overuse rises, and we start to see a lot of harms outlined in research. We’re going to be on top of it much more, because the hospital setting is complex and continues to change.

Education and service have always been important for Harry Cho, MD, who recently joined the editorial advisory board of The Hospitalist.

From joining AmeriCorps as a fresh faced college graduate, to his ongoing work as assistant professor of medicine and director of quality, safety, and value for the division of hospital medicine at Mount Sinai in New York, and as senior fellow at the Lown Institute, Dr. Cho has found a passion in helping others learn.

Q: Why did you choose medicine as a career?

A: Right after I finished undergrad at Cornell, I spent the summer and the following year doing AmeriCorps, which is service learning work, and I worked in the inner city of Philadelphia. I worked on after-school programs and weekend programs for inner city youth and I loved it. I was organizing and developing these programs, and I thought it was fantastic. The one thing that I thought was lacking, and I think what really drove me to get into medicine, was that at the end of the day, although I felt really connected with all the kids, I felt like I was a role model, like I was a mentor, and we had a really good connection, but I wanted something a little bit more concrete on improving outcomes. I knew we made connections, but I really wanted to know more – such as, did we reduce the dropout rate in high school for these students? I think that’s why medicine was really interesting.
 

Q: How did you end up in hospital medicine?

A: I think it’s a lot of things. I love the acuity, I love playing the quarterback in a place where a lot of things are going back and forth and you have to coordinate with others. You have to make sure you see the patient from top to bottom, the whole picture, and I love that part. I also love the action and the communication and the teamwork aspect of it.
 

Q: What part of being a hospitalist do you like the most?

A: I love the education on a daily basis: the morning rounds where you walk around for an hour or two with your team, and you teach them at the bedside, and these little pearls come up along the way. My career is positioned more within quality, value improvement, and safety, so I think that participating in the education process is really helpful. I think hospital medicine has taken over that spirit in the hospital setting, and I love that.
 

Q: Which part do you like the least?

A: I think we’re in a unique time right now. Burnout is getting a little tougher to beat. People are getting a bit more tired, and I don’t think we have a good solution to solve this. With quality improvement and the electronic medical record system, a lot of us are expected to do more. I still get queries from clinical documentation saying, “I need you to document this for billing purposes” or “I need you to document this for increasing the expected length of stay,” and doctors are not quite at the point where they can balance these requirements in an effective way. There tends to be an emphasis on “one more click,” one more thing to document, just one more thing to do on the checklist. It’s getting more complex.
 

Q: What is the most rewarding part of your work?

A: Larger scale accomplishments. When you give a talk, or teach a group of residents during morning rounds, and they look at you with wonder because you have this teaching pearl they’ve never heard before, and they think you’re a great attending – that’s very instant gratification, but there's more to be done beyond that. I’ve been co-directing in the Right Care educator program, and we have a High Value Care curriculum that we’ve been implementing across the country, and we’ve just finished our second year. There are around 60 programs involved, and it’s a great feeling. You’re not seeing actual people face to face after they’ve been taught, and you’re not getting that instant gratification. But just knowing what one of those chief residents who has implemented the program is feeling, and extrapolating across the number of programs this year alone, that makes me feel good.
 

Q: Outside of hospital work, what else are you interested in?

A: High-value care is my central aim right now. I want to expand it, and I want to do things on a national scale. We formed a High Value Care committee and I’m hoping to create new guidelines to reduce overuse, overtesting, and Choosing Wisely. Outside of medicine, I like photography. Nothing professional, but I love taking pictures, especially nature and travel. Back in the day, I used to do a lot of running and martial arts too.
 

Q: Where do you see yourself in 10 years?

A: I’m not sure if I will go the chief medical officer or chief quality officer route. That’s probably where I see myself. I definitely want to continue making bigger changes on a national scale, like implementing the overuse educator program across the country.
 

Q: What do you see as the future of hospital medicine?

A: Value-based health care is always going to get bigger as the cost of health care and the cost of overuse rises, and we start to see a lot of harms outlined in research. We’re going to be on top of it much more, because the hospital setting is complex and continues to change.

Vitamin C (ascorbic acid) deficiency is known to affect brain function and is associated with parkinsonism.¹ In 1752, James Lind, MD, described emotional and behavioral changes that herald the onset of scurvy and precede hemorrhagic findings.² The World Health Organization (WHO) today refers to this stage as latent scurvy.³ The 2 case studies that follow present examples of patients with vitamin C deficiencies whose parkinsonism responded robustly to vitamin C replacement. These cases suggest that vitamin C deficiency may be a treatable cause of parkinsonism.

Case 1

Mr. A, a 60-year-old white male, was admitted to the Medicine Service for alcohol detoxification. The patient had a history of alcohol dependence, alcohol withdrawal seizures, tobacco dependence, and hyperlipidemia. He took no medications as an outpatient. On admission Mr. A’s body mass index (BMI) was 27.2. An initial examination revealed a marked resting tremor of the patient’s right hand with cogwheeling, which had not been present in examinations conducted in the previous 3 years. Mr. A had no prior history of a tremor. He had no cerebellar findings and no evidence of asterixis or of tremulousness associated with high-output cardiac states, such as de Musset sign.

Mr. A reported he had experienced the tremor for a month and that it had been worsening. He also was having difficulty using his dominant right hand, for routine daily activities. Mr. A was oriented, and his short-term memory was intact. He was ill-appearing, irritable with psychomotor slowing, and did not wish to rise from his bed. He had no gingival or periungual bleeding and did not bruise easily. He had no corkscrew hairs. The patient was started on no medications known to cause extrapyramidal symptoms (EPS).

In the hospital, the tremor persisted unabated for 2 days. On the third day, Mr. A was started on 1,000 mg vitamin C IV twice daily. He received a total of 2,000 mg IV that day, but the IV fell out, and he refused its replacement. Several hours later, Mr. A stated that he felt much better, got out of bed, and asked to go outside to smoke. The author noted complete resolution of the right hand tremor and cogwheeling 20 hours after starting the vitamin C IV. Mr. A refused a repeat serum vitamin C assay.

Laboratory studies initially revealed that Mr. A had hyponatremia with a serum sodium of 121 mmol/L (normal range: 133 to 145 mmol/L) as well as hypokalemia with a serum potassium of 3.2 mmol/L (normal range: 3.5 to 5.0 mmol/L). He was hypoosmolar, with a serum osmolality of 276 mOsm/kg (normal range: 278 to 305 mOsm/kg). His vitamin C level was low at 0.2 mg/dL (normal range: 0.4 to 2.0 mg/dL). Mr. A also had a serum vitamin C level drawn 2 years prior that showed no symptoms of EPS, and at that time, the reading was 0.7 mg/dL. At admission to Medicine Services, Mr. A had a serum alcohol level of 211 mg/dL. Neuroimaging revealed diffuse cerebral and cerebellar volume loss.

Normal laboratory results included serum levels of vitamin B12, red cell folate, homocysteine, methylmalonic acid, free and total carnitine, alkaline phosphatase, manganese, and zinc. A urine drug screen was negative.

Case 2

Mr. B, a 69-year-old black male, was admitted to the hospital for depression complicated by alcohol dependence. He also had tobacco dependence, type 2 diabetes mellitus, hypertension, and gout. The patient’s BMI at admission was 16.1. Mr. B appeared ill, was worried about his health, and remained recumbent unless asked to move. He reported that his right hand had begun to shake at rest in the month prior to admission. The tremor made it difficult for him to drink. He pointed out stains on his hospital gurney from an attempt to drink orange juice prior to being assessed.

A physical examination revealed a distinct resting tremor with cogwheeling of the right hand; there was no other evidence of EPS, nor was there evidence of cognitive, cerebellar, or skin abnormalities, such as hemorrhages or corkscrew hairs. Asterixis was absent as was evidence of a high-output cardiac state that might produce a tremor, such as de Musset sign. A serum vitamin C level was obtained and returned at 0.0 mg/dL. A head computed tomography scan obtained the next day revealed mild cerebellar volume loss. A serum alkaline phosphatase level was elevated slightly at 136 U/L (normal range: 42 to 113 U/L). Normal serum values were returned for zinc, vitamins B12 and folate, rapid plasma reagin, sodium, and serum osmolality. A urine drug screen was negative, and serum alcohol level was < 5.0 mg/dL.

Mr. B took no medications expected to cause EPS. He received no micronutrient replacement until the day after admission when he began receiving oral vitamin C 1,000 mg twice a day. After receiving 3 doses, Mr. B’s resting tremor and cogwheeling completely resolved. He noticed he had stopped shaking and could now drink without spilling fluids. He also got out of bed and began interacting with others. Mr. B said he felt he was “doing well.” A repeat serum vitamin C level was 0.2 mg/dL on that day. The improvement was sustained over 3 days, and Mr. B was discharged to home.

Discussion

Both Mr. A and Mr. B presented with a typical picture of latent scurvy and the additional finding of parkinsonism. These cases are important for 2 reasons. First, the swift and full response of these patients’ parkinsonism to vitamin C replacement underscores the importance of considering a vitamin C deficiency when confronted with EPS. And second, both patients lacked signs of bleeding or of impaired collagen synthesis. This differs from the classic presentation of scurvy as a disorder primarily of collagen metabolism.⁴

Lind described the onset of scurvy as one in which striking emotional and behavior changes developed and later were followed by abnormal bleeding and even death.² These early changes also were recognized by Shapter in 1847.⁵ Furthermore, the evidence that exists about the time-course of scurvy’s development suggests that neuropsychiatric findings precede the hemorrhagic.⁶ Indeed, classic skin findings, such as petechiae or corkscrew hairs, may develop years after the onset of neuropsychiatric changes.^7,8

Despite WHO characterizing it as latent scurvy, the distinct syndromal presentation of hypovitaminosis C with parkinsonism along with the rapid response to vitamin C replacement argues for its recognition as a distinct clinical entity and not just a prelude to the hemorrhagic state. To assist in recognizing neuropsychiatric scurvy, the author suggests the operationalized approach described in Table 1.⁹

Pathophysiology

Vitamin C has an intimate role in the normal functioning of the basal ganglia. It is involved in the synthesis of catechecholamines, the regulation of the release and postsynaptic activities of various neurotransmitters, and managing the oxyradical toxicity of aerobic metabolism. Table 2 outlines some of the normal brain functions of vitamin C and the potential consequences of inadequate central vitamin C.^9,10 Risk factors for vitamin C deficiency include those affecting the uptake, response to, and elimination of this vitamin (Table 3).^11-14

The potential role of alcohol use by both patients also warrants mention. Current data suggest a nonlinear relationship between alcohol use and neurotoxicity. Epidemiologic data show that moderate alcohol consumption protects against the development of such neurodegenerative processes as Parkinson disease and Alzheimer disease.^15,16 But the cases here reflect excessive use of alcohol. In this situation, a variety of progressive insults, such as those caused by oxyradical toxicity as well as malnutrition may foster the development of basal ganglia dysfunction.¹⁷

Measuring Deficiency

A deficiency of vitamin C may be determined in several ways. The most frequently used laboratory measure of vitamin C status is the serum vitamin C level. This level is included in the WHO’s recommendations for diagnosis.³ However, this assay is limited because when facing total body depletion, the kidneys may restrict the elimination of vitamin C and tend to maintain serum vitamin C levels even as target tissue levels fall. An interesting example of this is the 0.2 mg/dL value that each patient registered. In Mr. A’s case, this reflected a systemic deficit of vitamin C, while in Mr. B’s case it correlated with the onset of effective repletion of body’s stores.

A fall in urinary output of vitamin C is another marker of hypovitaminosis C. When available, this laboratory test can be used with the serum level to assess total body stores of vitamin C. Lymphocytes, neutrophils, and platelets also store vitamin C. These target tissues tend to saturate when the oral intake ranges between 100 mg to 200 mg a day. This is the same point at which serum vitamin C levels peak and level off in normal, healthy adults.^18,19 Once again, the limited availability of target-tissue assays puts these studies out of reach for most clinicians.

No evaluation is complete without some assurance of what the disease is not. Deficiencies of biotin, zinc, folate, and B12 all may affect the function of the basal ganglia.²⁰ The biotin deficiencies literature is particularly robust. Biotin deficiencies affecting basal ganglia function are best known as inherited disorders of metabolism.²¹ Manganese intoxication also may present as a movement disorder.²²

Treatment

Treatment of neuropsychiatric scurvy has relied on IV administration of vitamin C. Although the bioavailability of oral vitamin C among healthy adult volunteers is nearly complete up to about 200 mg a day, a patient with neuropsychiatric scurvy may need substantially more than that amount to accommodate total body deficiencies and increased demands.²³ The IV route allows serum vitamin C levels up to 100 times higher than by the oral route.²⁴ Mr. B is, in fact, the first person reported in the literature with neuropsychiatric scurvy to respond to oral vitamin C replacement alone. Once repletion of vitamin C is complete, it is useful to consider a maintenance replacement dose based on a patient’s risk factors and needs.

A healthy adult should ingest about 120 mg of vitamin C daily. Smokers and pregnant women may require more, but this recommendation was intended to address their needs as well.²⁵ Many commercial multivitamins use the old recommended daily allowance of 60 mg, so it may be safest to recommend specifically a vitamin C tablet with at least 120 mg when ordering vitamin C replacement.

Tight control of the serum vitamin C concentration means that little additional vitamin C will be taken up by the gut beyond 200 mg orally a day, which helps minimize any concerns about long-term toxicity. It takes several weeks to deplete vitamin C from the human body when vitamin C is removed from the diet, so a patient with a previously treated deficiency of vitamin C should wait a month before a repeat serum vitamin C level measurement.

The half life of vitamin C is normally ≤ 2 hours. When renal function is intact, vitamin C in excess of immediate need is lost through renal filtration. Toxicity is rare under these conditions.²⁶ When vitamin C toxicity has been reported, it has occurred in the setting of prolonged supplementation, usually when a patient already experienced a renal injury. The main toxicities attributed to vitamin C are oxalate crystal formation with subsequent renal injury and exacerbation of glucose 6-phosphate dehydrogenase deficiency (G6PD).²⁴

Oxalate formation due to vitamin C replacement is uncommon, but patients with preexisting calcium oxalate stones may be at risk for further stone formation when they receive additional vitamin C.²⁷ This is most likely to occur when treatment with parenteral vitamin C is prolonged, which is not typical for patients with neuropsychiatric scurvy who tend to respond rapidly to vitamin C replenishment. Reports of acute hemolytic episodes among patient with G6PD deficiency receiving vitamin C exist, although these cases are rare.²⁸ Furthermore, some authors advocate for the use of ascorbic acid to treat methemoglobinemia associated with G6PD deficiency, when methylene blue is not available.²⁹ It may be reasonable to begin treatment with oral vitamin C for patients with NPS and G6PD deficiency. This is equivalent to a low-dose form of vitamin C replacement and may help avoid the theoretically pro-oxidant effects of larger, IV doses of vitamin C.³⁰

Conclusion

The recent discovery of movement disorders in scurvy has enlarged the picture of vitamin C deficiency. The cases here demonstrate how hypovitaminosis C with central nervous system manifestations may be identified and treated. This relationship fits well within the established basic science and clinical framework for scurvy, and the clinical implications for scurvy remain in many ways unchanged. First, malnutrition must be considered even when a patient’s habitus suggests he is well fed. Also, it is more likely to see scurvy without all of the classic findings than an end-stage case of the disease.³¹ In the right clinical setting, it is reasonable to think of a vitamin C deficiency before the patient develops bleeding gums and corkscrew hairs. And as is typical of vitamin deficiencies, the treatment of a vitamin C deficiency usually results in swift improvement. Finally, for those who treat movement disorders or who prescribe agents such as antipsychotics that may cause movement disorders, it is important to recognize vitamin C deficiency as another potential explanation for EPS.

Vitamin C (ascorbic acid) deficiency is known to affect brain function and is associated with parkinsonism.¹ In 1752, James Lind, MD, described emotional and behavioral changes that herald the onset of scurvy and precede hemorrhagic findings.² The World Health Organization (WHO) today refers to this stage as latent scurvy.³ The 2 case studies that follow present examples of patients with vitamin C deficiencies whose parkinsonism responded robustly to vitamin C replacement. These cases suggest that vitamin C deficiency may be a treatable cause of parkinsonism.

Case 1

Mr. A, a 60-year-old white male, was admitted to the Medicine Service for alcohol detoxification. The patient had a history of alcohol dependence, alcohol withdrawal seizures, tobacco dependence, and hyperlipidemia. He took no medications as an outpatient. On admission Mr. A’s body mass index (BMI) was 27.2. An initial examination revealed a marked resting tremor of the patient’s right hand with cogwheeling, which had not been present in examinations conducted in the previous 3 years. Mr. A had no prior history of a tremor. He had no cerebellar findings and no evidence of asterixis or of tremulousness associated with high-output cardiac states, such as de Musset sign.

Mr. A reported he had experienced the tremor for a month and that it had been worsening. He also was having difficulty using his dominant right hand, for routine daily activities. Mr. A was oriented, and his short-term memory was intact. He was ill-appearing, irritable with psychomotor slowing, and did not wish to rise from his bed. He had no gingival or periungual bleeding and did not bruise easily. He had no corkscrew hairs. The patient was started on no medications known to cause extrapyramidal symptoms (EPS).

In the hospital, the tremor persisted unabated for 2 days. On the third day, Mr. A was started on 1,000 mg vitamin C IV twice daily. He received a total of 2,000 mg IV that day, but the IV fell out, and he refused its replacement. Several hours later, Mr. A stated that he felt much better, got out of bed, and asked to go outside to smoke. The author noted complete resolution of the right hand tremor and cogwheeling 20 hours after starting the vitamin C IV. Mr. A refused a repeat serum vitamin C assay.

Laboratory studies initially revealed that Mr. A had hyponatremia with a serum sodium of 121 mmol/L (normal range: 133 to 145 mmol/L) as well as hypokalemia with a serum potassium of 3.2 mmol/L (normal range: 3.5 to 5.0 mmol/L). He was hypoosmolar, with a serum osmolality of 276 mOsm/kg (normal range: 278 to 305 mOsm/kg). His vitamin C level was low at 0.2 mg/dL (normal range: 0.4 to 2.0 mg/dL). Mr. A also had a serum vitamin C level drawn 2 years prior that showed no symptoms of EPS, and at that time, the reading was 0.7 mg/dL. At admission to Medicine Services, Mr. A had a serum alcohol level of 211 mg/dL. Neuroimaging revealed diffuse cerebral and cerebellar volume loss.

Normal laboratory results included serum levels of vitamin B12, red cell folate, homocysteine, methylmalonic acid, free and total carnitine, alkaline phosphatase, manganese, and zinc. A urine drug screen was negative.

Case 2

Mr. B, a 69-year-old black male, was admitted to the hospital for depression complicated by alcohol dependence. He also had tobacco dependence, type 2 diabetes mellitus, hypertension, and gout. The patient’s BMI at admission was 16.1. Mr. B appeared ill, was worried about his health, and remained recumbent unless asked to move. He reported that his right hand had begun to shake at rest in the month prior to admission. The tremor made it difficult for him to drink. He pointed out stains on his hospital gurney from an attempt to drink orange juice prior to being assessed.

A physical examination revealed a distinct resting tremor with cogwheeling of the right hand; there was no other evidence of EPS, nor was there evidence of cognitive, cerebellar, or skin abnormalities, such as hemorrhages or corkscrew hairs. Asterixis was absent as was evidence of a high-output cardiac state that might produce a tremor, such as de Musset sign. A serum vitamin C level was obtained and returned at 0.0 mg/dL. A head computed tomography scan obtained the next day revealed mild cerebellar volume loss. A serum alkaline phosphatase level was elevated slightly at 136 U/L (normal range: 42 to 113 U/L). Normal serum values were returned for zinc, vitamins B12 and folate, rapid plasma reagin, sodium, and serum osmolality. A urine drug screen was negative, and serum alcohol level was < 5.0 mg/dL.

Mr. B took no medications expected to cause EPS. He received no micronutrient replacement until the day after admission when he began receiving oral vitamin C 1,000 mg twice a day. After receiving 3 doses, Mr. B’s resting tremor and cogwheeling completely resolved. He noticed he had stopped shaking and could now drink without spilling fluids. He also got out of bed and began interacting with others. Mr. B said he felt he was “doing well.” A repeat serum vitamin C level was 0.2 mg/dL on that day. The improvement was sustained over 3 days, and Mr. B was discharged to home.

Discussion

Both Mr. A and Mr. B presented with a typical picture of latent scurvy and the additional finding of parkinsonism. These cases are important for 2 reasons. First, the swift and full response of these patients’ parkinsonism to vitamin C replacement underscores the importance of considering a vitamin C deficiency when confronted with EPS. And second, both patients lacked signs of bleeding or of impaired collagen synthesis. This differs from the classic presentation of scurvy as a disorder primarily of collagen metabolism.⁴

Lind described the onset of scurvy as one in which striking emotional and behavior changes developed and later were followed by abnormal bleeding and even death.² These early changes also were recognized by Shapter in 1847.⁵ Furthermore, the evidence that exists about the time-course of scurvy’s development suggests that neuropsychiatric findings precede the hemorrhagic.⁶ Indeed, classic skin findings, such as petechiae or corkscrew hairs, may develop years after the onset of neuropsychiatric changes.^7,8

Despite WHO characterizing it as latent scurvy, the distinct syndromal presentation of hypovitaminosis C with parkinsonism along with the rapid response to vitamin C replacement argues for its recognition as a distinct clinical entity and not just a prelude to the hemorrhagic state. To assist in recognizing neuropsychiatric scurvy, the author suggests the operationalized approach described in Table 1.⁹

Pathophysiology

Vitamin C has an intimate role in the normal functioning of the basal ganglia. It is involved in the synthesis of catechecholamines, the regulation of the release and postsynaptic activities of various neurotransmitters, and managing the oxyradical toxicity of aerobic metabolism. Table 2 outlines some of the normal brain functions of vitamin C and the potential consequences of inadequate central vitamin C.^9,10 Risk factors for vitamin C deficiency include those affecting the uptake, response to, and elimination of this vitamin (Table 3).^11-14

The potential role of alcohol use by both patients also warrants mention. Current data suggest a nonlinear relationship between alcohol use and neurotoxicity. Epidemiologic data show that moderate alcohol consumption protects against the development of such neurodegenerative processes as Parkinson disease and Alzheimer disease.^15,16 But the cases here reflect excessive use of alcohol. In this situation, a variety of progressive insults, such as those caused by oxyradical toxicity as well as malnutrition may foster the development of basal ganglia dysfunction.¹⁷

Measuring Deficiency

A deficiency of vitamin C may be determined in several ways. The most frequently used laboratory measure of vitamin C status is the serum vitamin C level. This level is included in the WHO’s recommendations for diagnosis.³ However, this assay is limited because when facing total body depletion, the kidneys may restrict the elimination of vitamin C and tend to maintain serum vitamin C levels even as target tissue levels fall. An interesting example of this is the 0.2 mg/dL value that each patient registered. In Mr. A’s case, this reflected a systemic deficit of vitamin C, while in Mr. B’s case it correlated with the onset of effective repletion of body’s stores.

A fall in urinary output of vitamin C is another marker of hypovitaminosis C. When available, this laboratory test can be used with the serum level to assess total body stores of vitamin C. Lymphocytes, neutrophils, and platelets also store vitamin C. These target tissues tend to saturate when the oral intake ranges between 100 mg to 200 mg a day. This is the same point at which serum vitamin C levels peak and level off in normal, healthy adults.^18,19 Once again, the limited availability of target-tissue assays puts these studies out of reach for most clinicians.

No evaluation is complete without some assurance of what the disease is not. Deficiencies of biotin, zinc, folate, and B12 all may affect the function of the basal ganglia.²⁰ The biotin deficiencies literature is particularly robust. Biotin deficiencies affecting basal ganglia function are best known as inherited disorders of metabolism.²¹ Manganese intoxication also may present as a movement disorder.²²

Treatment

Treatment of neuropsychiatric scurvy has relied on IV administration of vitamin C. Although the bioavailability of oral vitamin C among healthy adult volunteers is nearly complete up to about 200 mg a day, a patient with neuropsychiatric scurvy may need substantially more than that amount to accommodate total body deficiencies and increased demands.²³ The IV route allows serum vitamin C levels up to 100 times higher than by the oral route.²⁴ Mr. B is, in fact, the first person reported in the literature with neuropsychiatric scurvy to respond to oral vitamin C replacement alone. Once repletion of vitamin C is complete, it is useful to consider a maintenance replacement dose based on a patient’s risk factors and needs.

A healthy adult should ingest about 120 mg of vitamin C daily. Smokers and pregnant women may require more, but this recommendation was intended to address their needs as well.²⁵ Many commercial multivitamins use the old recommended daily allowance of 60 mg, so it may be safest to recommend specifically a vitamin C tablet with at least 120 mg when ordering vitamin C replacement.

Tight control of the serum vitamin C concentration means that little additional vitamin C will be taken up by the gut beyond 200 mg orally a day, which helps minimize any concerns about long-term toxicity. It takes several weeks to deplete vitamin C from the human body when vitamin C is removed from the diet, so a patient with a previously treated deficiency of vitamin C should wait a month before a repeat serum vitamin C level measurement.

The half life of vitamin C is normally ≤ 2 hours. When renal function is intact, vitamin C in excess of immediate need is lost through renal filtration. Toxicity is rare under these conditions.²⁶ When vitamin C toxicity has been reported, it has occurred in the setting of prolonged supplementation, usually when a patient already experienced a renal injury. The main toxicities attributed to vitamin C are oxalate crystal formation with subsequent renal injury and exacerbation of glucose 6-phosphate dehydrogenase deficiency (G6PD).²⁴

Oxalate formation due to vitamin C replacement is uncommon, but patients with preexisting calcium oxalate stones may be at risk for further stone formation when they receive additional vitamin C.²⁷ This is most likely to occur when treatment with parenteral vitamin C is prolonged, which is not typical for patients with neuropsychiatric scurvy who tend to respond rapidly to vitamin C replenishment. Reports of acute hemolytic episodes among patient with G6PD deficiency receiving vitamin C exist, although these cases are rare.²⁸ Furthermore, some authors advocate for the use of ascorbic acid to treat methemoglobinemia associated with G6PD deficiency, when methylene blue is not available.²⁹ It may be reasonable to begin treatment with oral vitamin C for patients with NPS and G6PD deficiency. This is equivalent to a low-dose form of vitamin C replacement and may help avoid the theoretically pro-oxidant effects of larger, IV doses of vitamin C.³⁰

Conclusion

The recent discovery of movement disorders in scurvy has enlarged the picture of vitamin C deficiency. The cases here demonstrate how hypovitaminosis C with central nervous system manifestations may be identified and treated. This relationship fits well within the established basic science and clinical framework for scurvy, and the clinical implications for scurvy remain in many ways unchanged. First, malnutrition must be considered even when a patient’s habitus suggests he is well fed. Also, it is more likely to see scurvy without all of the classic findings than an end-stage case of the disease.³¹ In the right clinical setting, it is reasonable to think of a vitamin C deficiency before the patient develops bleeding gums and corkscrew hairs. And as is typical of vitamin deficiencies, the treatment of a vitamin C deficiency usually results in swift improvement. Finally, for those who treat movement disorders or who prescribe agents such as antipsychotics that may cause movement disorders, it is important to recognize vitamin C deficiency as another potential explanation for EPS.

Vitamin C (ascorbic acid) deficiency is known to affect brain function and is associated with parkinsonism.¹ In 1752, James Lind, MD, described emotional and behavioral changes that herald the onset of scurvy and precede hemorrhagic findings.² The World Health Organization (WHO) today refers to this stage as latent scurvy.³ The 2 case studies that follow present examples of patients with vitamin C deficiencies whose parkinsonism responded robustly to vitamin C replacement. These cases suggest that vitamin C deficiency may be a treatable cause of parkinsonism.

Case 1

Mr. A, a 60-year-old white male, was admitted to the Medicine Service for alcohol detoxification. The patient had a history of alcohol dependence, alcohol withdrawal seizures, tobacco dependence, and hyperlipidemia. He took no medications as an outpatient. On admission Mr. A’s body mass index (BMI) was 27.2. An initial examination revealed a marked resting tremor of the patient’s right hand with cogwheeling, which had not been present in examinations conducted in the previous 3 years. Mr. A had no prior history of a tremor. He had no cerebellar findings and no evidence of asterixis or of tremulousness associated with high-output cardiac states, such as de Musset sign.

Mr. A reported he had experienced the tremor for a month and that it had been worsening. He also was having difficulty using his dominant right hand, for routine daily activities. Mr. A was oriented, and his short-term memory was intact. He was ill-appearing, irritable with psychomotor slowing, and did not wish to rise from his bed. He had no gingival or periungual bleeding and did not bruise easily. He had no corkscrew hairs. The patient was started on no medications known to cause extrapyramidal symptoms (EPS).

In the hospital, the tremor persisted unabated for 2 days. On the third day, Mr. A was started on 1,000 mg vitamin C IV twice daily. He received a total of 2,000 mg IV that day, but the IV fell out, and he refused its replacement. Several hours later, Mr. A stated that he felt much better, got out of bed, and asked to go outside to smoke. The author noted complete resolution of the right hand tremor and cogwheeling 20 hours after starting the vitamin C IV. Mr. A refused a repeat serum vitamin C assay.

Laboratory studies initially revealed that Mr. A had hyponatremia with a serum sodium of 121 mmol/L (normal range: 133 to 145 mmol/L) as well as hypokalemia with a serum potassium of 3.2 mmol/L (normal range: 3.5 to 5.0 mmol/L). He was hypoosmolar, with a serum osmolality of 276 mOsm/kg (normal range: 278 to 305 mOsm/kg). His vitamin C level was low at 0.2 mg/dL (normal range: 0.4 to 2.0 mg/dL). Mr. A also had a serum vitamin C level drawn 2 years prior that showed no symptoms of EPS, and at that time, the reading was 0.7 mg/dL. At admission to Medicine Services, Mr. A had a serum alcohol level of 211 mg/dL. Neuroimaging revealed diffuse cerebral and cerebellar volume loss.

Normal laboratory results included serum levels of vitamin B12, red cell folate, homocysteine, methylmalonic acid, free and total carnitine, alkaline phosphatase, manganese, and zinc. A urine drug screen was negative.

Case 2

Mr. B, a 69-year-old black male, was admitted to the hospital for depression complicated by alcohol dependence. He also had tobacco dependence, type 2 diabetes mellitus, hypertension, and gout. The patient’s BMI at admission was 16.1. Mr. B appeared ill, was worried about his health, and remained recumbent unless asked to move. He reported that his right hand had begun to shake at rest in the month prior to admission. The tremor made it difficult for him to drink. He pointed out stains on his hospital gurney from an attempt to drink orange juice prior to being assessed.

A physical examination revealed a distinct resting tremor with cogwheeling of the right hand; there was no other evidence of EPS, nor was there evidence of cognitive, cerebellar, or skin abnormalities, such as hemorrhages or corkscrew hairs. Asterixis was absent as was evidence of a high-output cardiac state that might produce a tremor, such as de Musset sign. A serum vitamin C level was obtained and returned at 0.0 mg/dL. A head computed tomography scan obtained the next day revealed mild cerebellar volume loss. A serum alkaline phosphatase level was elevated slightly at 136 U/L (normal range: 42 to 113 U/L). Normal serum values were returned for zinc, vitamins B12 and folate, rapid plasma reagin, sodium, and serum osmolality. A urine drug screen was negative, and serum alcohol level was < 5.0 mg/dL.

Mr. B took no medications expected to cause EPS. He received no micronutrient replacement until the day after admission when he began receiving oral vitamin C 1,000 mg twice a day. After receiving 3 doses, Mr. B’s resting tremor and cogwheeling completely resolved. He noticed he had stopped shaking and could now drink without spilling fluids. He also got out of bed and began interacting with others. Mr. B said he felt he was “doing well.” A repeat serum vitamin C level was 0.2 mg/dL on that day. The improvement was sustained over 3 days, and Mr. B was discharged to home.

Discussion

Both Mr. A and Mr. B presented with a typical picture of latent scurvy and the additional finding of parkinsonism. These cases are important for 2 reasons. First, the swift and full response of these patients’ parkinsonism to vitamin C replacement underscores the importance of considering a vitamin C deficiency when confronted with EPS. And second, both patients lacked signs of bleeding or of impaired collagen synthesis. This differs from the classic presentation of scurvy as a disorder primarily of collagen metabolism.⁴

Lind described the onset of scurvy as one in which striking emotional and behavior changes developed and later were followed by abnormal bleeding and even death.² These early changes also were recognized by Shapter in 1847.⁵ Furthermore, the evidence that exists about the time-course of scurvy’s development suggests that neuropsychiatric findings precede the hemorrhagic.⁶ Indeed, classic skin findings, such as petechiae or corkscrew hairs, may develop years after the onset of neuropsychiatric changes.^7,8

Despite WHO characterizing it as latent scurvy, the distinct syndromal presentation of hypovitaminosis C with parkinsonism along with the rapid response to vitamin C replacement argues for its recognition as a distinct clinical entity and not just a prelude to the hemorrhagic state. To assist in recognizing neuropsychiatric scurvy, the author suggests the operationalized approach described in Table 1.⁹

Pathophysiology

Vitamin C has an intimate role in the normal functioning of the basal ganglia. It is involved in the synthesis of catechecholamines, the regulation of the release and postsynaptic activities of various neurotransmitters, and managing the oxyradical toxicity of aerobic metabolism. Table 2 outlines some of the normal brain functions of vitamin C and the potential consequences of inadequate central vitamin C.^9,10 Risk factors for vitamin C deficiency include those affecting the uptake, response to, and elimination of this vitamin (Table 3).^11-14

The potential role of alcohol use by both patients also warrants mention. Current data suggest a nonlinear relationship between alcohol use and neurotoxicity. Epidemiologic data show that moderate alcohol consumption protects against the development of such neurodegenerative processes as Parkinson disease and Alzheimer disease.^15,16 But the cases here reflect excessive use of alcohol. In this situation, a variety of progressive insults, such as those caused by oxyradical toxicity as well as malnutrition may foster the development of basal ganglia dysfunction.¹⁷

Measuring Deficiency

A deficiency of vitamin C may be determined in several ways. The most frequently used laboratory measure of vitamin C status is the serum vitamin C level. This level is included in the WHO’s recommendations for diagnosis.³ However, this assay is limited because when facing total body depletion, the kidneys may restrict the elimination of vitamin C and tend to maintain serum vitamin C levels even as target tissue levels fall. An interesting example of this is the 0.2 mg/dL value that each patient registered. In Mr. A’s case, this reflected a systemic deficit of vitamin C, while in Mr. B’s case it correlated with the onset of effective repletion of body’s stores.

A fall in urinary output of vitamin C is another marker of hypovitaminosis C. When available, this laboratory test can be used with the serum level to assess total body stores of vitamin C. Lymphocytes, neutrophils, and platelets also store vitamin C. These target tissues tend to saturate when the oral intake ranges between 100 mg to 200 mg a day. This is the same point at which serum vitamin C levels peak and level off in normal, healthy adults.^18,19 Once again, the limited availability of target-tissue assays puts these studies out of reach for most clinicians.

No evaluation is complete without some assurance of what the disease is not. Deficiencies of biotin, zinc, folate, and B12 all may affect the function of the basal ganglia.²⁰ The biotin deficiencies literature is particularly robust. Biotin deficiencies affecting basal ganglia function are best known as inherited disorders of metabolism.²¹ Manganese intoxication also may present as a movement disorder.²²

Treatment

Treatment of neuropsychiatric scurvy has relied on IV administration of vitamin C. Although the bioavailability of oral vitamin C among healthy adult volunteers is nearly complete up to about 200 mg a day, a patient with neuropsychiatric scurvy may need substantially more than that amount to accommodate total body deficiencies and increased demands.²³ The IV route allows serum vitamin C levels up to 100 times higher than by the oral route.²⁴ Mr. B is, in fact, the first person reported in the literature with neuropsychiatric scurvy to respond to oral vitamin C replacement alone. Once repletion of vitamin C is complete, it is useful to consider a maintenance replacement dose based on a patient’s risk factors and needs.

A healthy adult should ingest about 120 mg of vitamin C daily. Smokers and pregnant women may require more, but this recommendation was intended to address their needs as well.²⁵ Many commercial multivitamins use the old recommended daily allowance of 60 mg, so it may be safest to recommend specifically a vitamin C tablet with at least 120 mg when ordering vitamin C replacement.

Tight control of the serum vitamin C concentration means that little additional vitamin C will be taken up by the gut beyond 200 mg orally a day, which helps minimize any concerns about long-term toxicity. It takes several weeks to deplete vitamin C from the human body when vitamin C is removed from the diet, so a patient with a previously treated deficiency of vitamin C should wait a month before a repeat serum vitamin C level measurement.

The half life of vitamin C is normally ≤ 2 hours. When renal function is intact, vitamin C in excess of immediate need is lost through renal filtration. Toxicity is rare under these conditions.²⁶ When vitamin C toxicity has been reported, it has occurred in the setting of prolonged supplementation, usually when a patient already experienced a renal injury. The main toxicities attributed to vitamin C are oxalate crystal formation with subsequent renal injury and exacerbation of glucose 6-phosphate dehydrogenase deficiency (G6PD).²⁴

Oxalate formation due to vitamin C replacement is uncommon, but patients with preexisting calcium oxalate stones may be at risk for further stone formation when they receive additional vitamin C.²⁷ This is most likely to occur when treatment with parenteral vitamin C is prolonged, which is not typical for patients with neuropsychiatric scurvy who tend to respond rapidly to vitamin C replenishment. Reports of acute hemolytic episodes among patient with G6PD deficiency receiving vitamin C exist, although these cases are rare.²⁸ Furthermore, some authors advocate for the use of ascorbic acid to treat methemoglobinemia associated with G6PD deficiency, when methylene blue is not available.²⁹ It may be reasonable to begin treatment with oral vitamin C for patients with NPS and G6PD deficiency. This is equivalent to a low-dose form of vitamin C replacement and may help avoid the theoretically pro-oxidant effects of larger, IV doses of vitamin C.³⁰

Conclusion

The recent discovery of movement disorders in scurvy has enlarged the picture of vitamin C deficiency. The cases here demonstrate how hypovitaminosis C with central nervous system manifestations may be identified and treated. This relationship fits well within the established basic science and clinical framework for scurvy, and the clinical implications for scurvy remain in many ways unchanged. First, malnutrition must be considered even when a patient’s habitus suggests he is well fed. Also, it is more likely to see scurvy without all of the classic findings than an end-stage case of the disease.³¹ In the right clinical setting, it is reasonable to think of a vitamin C deficiency before the patient develops bleeding gums and corkscrew hairs. And as is typical of vitamin deficiencies, the treatment of a vitamin C deficiency usually results in swift improvement. Finally, for those who treat movement disorders or who prescribe agents such as antipsychotics that may cause movement disorders, it is important to recognize vitamin C deficiency as another potential explanation for EPS.

What’s the right duration of dual antiplatelet therapy (DAPT) for patients who have had drug-eluting stents implanted? According to researchers from Sungkyunkwan University in Seoul, Korea, long-term clinical outcomes are similar whether patients receive therapy for less than or longer than 12 months.

The researchers conducted a retrospective study of 512 patients who had undergone percutaneous coronary intervention (PCI) for coronary chronic total occlusion (CTO) and were event free at 12 months. They separated the patients into 2 groups: 199 received aspirin and clopidogrel for ≤ 12 months, and 313 for > 12 months. The primary outcome was major adverse cardiac and cerebrovascular event (MACCE) during follow-up. Median follow-up was 64 months.

Related: Statins for the Physically Fit: Do They Help or Hurt?

No significant differences were seen between the groups in the incidence of MACCE: 21.6% of the patients in the ≤ 12-month group and 17.6% of the patients in the > 12-month group developed MACCE. After propensity matching, moderate or severe bleeding rates were also similar (1.6% in the shorter duration group and 2.2% in the longer duration group).

The researchers note that previously published data showed that longer duration DAPT was not associated with improved clinical outcomes in patients with CTO, although other subsets of complex PCI, such as longer stent length, bifurcation stenting, or multiple stents showed better clinical outcomes. To the best of their knowledge, the researchers add, theirs is the first study to directly compare DAPT durations in patients with CTO-PCI.

Related: A Heart Failure Management Program Using Shared Medical Appointments

Source:
Lee SH, Yang JH, Choi SH, et al. PLoS One. 2017;12(5):e0176737.
doi: 10.1371/journal.pone.0176737.

What’s the right duration of dual antiplatelet therapy (DAPT) for patients who have had drug-eluting stents implanted? According to researchers from Sungkyunkwan University in Seoul, Korea, long-term clinical outcomes are similar whether patients receive therapy for less than or longer than 12 months.

The researchers conducted a retrospective study of 512 patients who had undergone percutaneous coronary intervention (PCI) for coronary chronic total occlusion (CTO) and were event free at 12 months. They separated the patients into 2 groups: 199 received aspirin and clopidogrel for ≤ 12 months, and 313 for > 12 months. The primary outcome was major adverse cardiac and cerebrovascular event (MACCE) during follow-up. Median follow-up was 64 months.

Related: Statins for the Physically Fit: Do They Help or Hurt?

No significant differences were seen between the groups in the incidence of MACCE: 21.6% of the patients in the ≤ 12-month group and 17.6% of the patients in the > 12-month group developed MACCE. After propensity matching, moderate or severe bleeding rates were also similar (1.6% in the shorter duration group and 2.2% in the longer duration group).

The researchers note that previously published data showed that longer duration DAPT was not associated with improved clinical outcomes in patients with CTO, although other subsets of complex PCI, such as longer stent length, bifurcation stenting, or multiple stents showed better clinical outcomes. To the best of their knowledge, the researchers add, theirs is the first study to directly compare DAPT durations in patients with CTO-PCI.

Related: A Heart Failure Management Program Using Shared Medical Appointments

Source:
Lee SH, Yang JH, Choi SH, et al. PLoS One. 2017;12(5):e0176737.
doi: 10.1371/journal.pone.0176737.

What’s the right duration of dual antiplatelet therapy (DAPT) for patients who have had drug-eluting stents implanted? According to researchers from Sungkyunkwan University in Seoul, Korea, long-term clinical outcomes are similar whether patients receive therapy for less than or longer than 12 months.

The researchers conducted a retrospective study of 512 patients who had undergone percutaneous coronary intervention (PCI) for coronary chronic total occlusion (CTO) and were event free at 12 months. They separated the patients into 2 groups: 199 received aspirin and clopidogrel for ≤ 12 months, and 313 for > 12 months. The primary outcome was major adverse cardiac and cerebrovascular event (MACCE) during follow-up. Median follow-up was 64 months.

Related: Statins for the Physically Fit: Do They Help or Hurt?

No significant differences were seen between the groups in the incidence of MACCE: 21.6% of the patients in the ≤ 12-month group and 17.6% of the patients in the > 12-month group developed MACCE. After propensity matching, moderate or severe bleeding rates were also similar (1.6% in the shorter duration group and 2.2% in the longer duration group).

The researchers note that previously published data showed that longer duration DAPT was not associated with improved clinical outcomes in patients with CTO, although other subsets of complex PCI, such as longer stent length, bifurcation stenting, or multiple stents showed better clinical outcomes. To the best of their knowledge, the researchers add, theirs is the first study to directly compare DAPT durations in patients with CTO-PCI.

Related: A Heart Failure Management Program Using Shared Medical Appointments

Source:
Lee SH, Yang JH, Choi SH, et al. PLoS One. 2017;12(5):e0176737.
doi: 10.1371/journal.pone.0176737.

Male veterans who reported mild-to-moderate psychological distress in the previous year had 61% higher odds of experiencing sleep apnea, according to a California State University study. Those with serious psychological distress had 138% higher odds. The average prevalence of sleep apnea was 5.9%, but the proportions rose from 3.7% in 2005 to 8.1% in 2014.

The researchers analyzed data from the 2005-2014 National Survey on Drug Use and Health. They cite other research that found the age-adjusted prevalence of sleep apnea among U.S. veterans increased almost 6-fold from 2000 to 2010. They also point to an evaluation of veterans of Operation Enduring Freedom, Operation Iraqi Freedom, and Operation New Dawn that found that 69.2% of 159 veterans screened were at high risk for obstructive sleep apnea.

An even stronger risk factor was asthma. Veterans with a past-year diagnosis of asthma had 256% higher odds of experiencing sleep apnea than among those without asthma. The researchers note that men and women may be asymptomatic when they are recruited but develop asthma due to environmental factors during deployment. The researchers urge more and better screening regardless of whether the service member had asthma symptoms during recruitment.  

Their study is unique, the researchers say, in that it demonstrates a putative relationship between sleep apnea and mental illness. They suggest multidisciplinary interventions, including peer-support strategies to improve veterans’ mental health and community-based resources to help improve access to health care. Above all, the researchers urge more rigorous screening of sleep apnea and better sleep apnea treatment for veterans. 

Male veterans who reported mild-to-moderate psychological distress in the previous year had 61% higher odds of experiencing sleep apnea, according to a California State University study. Those with serious psychological distress had 138% higher odds. The average prevalence of sleep apnea was 5.9%, but the proportions rose from 3.7% in 2005 to 8.1% in 2014.

The researchers analyzed data from the 2005-2014 National Survey on Drug Use and Health. They cite other research that found the age-adjusted prevalence of sleep apnea among U.S. veterans increased almost 6-fold from 2000 to 2010. They also point to an evaluation of veterans of Operation Enduring Freedom, Operation Iraqi Freedom, and Operation New Dawn that found that 69.2% of 159 veterans screened were at high risk for obstructive sleep apnea.

An even stronger risk factor was asthma. Veterans with a past-year diagnosis of asthma had 256% higher odds of experiencing sleep apnea than among those without asthma. The researchers note that men and women may be asymptomatic when they are recruited but develop asthma due to environmental factors during deployment. The researchers urge more and better screening regardless of whether the service member had asthma symptoms during recruitment.  

Their study is unique, the researchers say, in that it demonstrates a putative relationship between sleep apnea and mental illness. They suggest multidisciplinary interventions, including peer-support strategies to improve veterans’ mental health and community-based resources to help improve access to health care. Above all, the researchers urge more rigorous screening of sleep apnea and better sleep apnea treatment for veterans. 

Male veterans who reported mild-to-moderate psychological distress in the previous year had 61% higher odds of experiencing sleep apnea, according to a California State University study. Those with serious psychological distress had 138% higher odds. The average prevalence of sleep apnea was 5.9%, but the proportions rose from 3.7% in 2005 to 8.1% in 2014.

The researchers analyzed data from the 2005-2014 National Survey on Drug Use and Health. They cite other research that found the age-adjusted prevalence of sleep apnea among U.S. veterans increased almost 6-fold from 2000 to 2010. They also point to an evaluation of veterans of Operation Enduring Freedom, Operation Iraqi Freedom, and Operation New Dawn that found that 69.2% of 159 veterans screened were at high risk for obstructive sleep apnea.

An even stronger risk factor was asthma. Veterans with a past-year diagnosis of asthma had 256% higher odds of experiencing sleep apnea than among those without asthma. The researchers note that men and women may be asymptomatic when they are recruited but develop asthma due to environmental factors during deployment. The researchers urge more and better screening regardless of whether the service member had asthma symptoms during recruitment.  

Their study is unique, the researchers say, in that it demonstrates a putative relationship between sleep apnea and mental illness. They suggest multidisciplinary interventions, including peer-support strategies to improve veterans’ mental health and community-based resources to help improve access to health care. Above all, the researchers urge more rigorous screening of sleep apnea and better sleep apnea treatment for veterans. 

Image from Graham Beards

New research published in Cell Reports suggests platelets are highly reliant on their ability to metabolize glucose.

Researchers studied mice lacking proteins that platelets use to import glucose—glucose transporter (GLUT) 1 and GLUT3.

These mice had lower platelet counts and their platelets had shorter life spans than platelets in wild-type mice.

“We found that glucose metabolism is very critical across the entire life cycle of platelets—from production, to what they do in the body, to how they get cleared from the body,” said E. Dale Abel, MBBS, PhD, of the University of Iowa in Iowa City.

For this study, Dr Abel and his colleagues studied genetically engineered mouse models that were missing GLUT1 and GLUT3 or GLUT3 alone and observed how platelet formation, function, and clearance were affected.

Mice missing glucose transporter proteins did produce platelets, and the platelets’ mitochondria metabolized other substances in place of glucose. However, the mice had platelet counts that were lower than normal.

The researchers were able to pinpoint 2 causes for the low platelet count in mice lacking GLUT1 and GLUT3—fewer platelets being produced and increased clearance of platelets.

The team tested megakaryocytes’ ability to generate new platelets by depleting the blood of platelets and observing the subsequent recovery, which was lower than normal.

They also tested the megakaryocytes in culture, stimulating them to create new platelets, and found the generation of new platelets was defective.

“Clearly, we show that there’s an obligate need for glucose to bud platelets off from the bone marrow,” Dr Abel said.

In addition, the team observed that young platelets functioned normally, even in the absence of glucose. But as they aged, the platelets were cleared from the circulation earlier than normal because they were being destroyed.

“We identified a new mechanism of necrosis by which the absence of glucose leads to the cleavage of a protein called calpain, which marks them for this necrotic pathway,” Dr Abel said. “If we treated the animals with a calpain inhibitor, we could reduce the increased platelet clearance.”

The team also sought to determine whether platelets could exist and function when mitochondria metabolism is halted.

They injected the mice with oligomycin, which inhibits mitochondrial metabolism. In the mice deficient in GLUT1 and GLUT3, platelet counts dropped to 0 within about 30 minutes. The same effect did not occur in wild-type mice.

“This work defined a very important role for metabolism in how platelets leave the bone marrow, how they come into circulation, and how they stay in circulation,” Dr Abel said. “It could even have implications for why platelets have to be used within a certain period of time when they’re donated at the blood bank—the fresher the better.”

Image from Graham Beards

New research published in Cell Reports suggests platelets are highly reliant on their ability to metabolize glucose.

Researchers studied mice lacking proteins that platelets use to import glucose—glucose transporter (GLUT) 1 and GLUT3.

These mice had lower platelet counts and their platelets had shorter life spans than platelets in wild-type mice.

“We found that glucose metabolism is very critical across the entire life cycle of platelets—from production, to what they do in the body, to how they get cleared from the body,” said E. Dale Abel, MBBS, PhD, of the University of Iowa in Iowa City.

For this study, Dr Abel and his colleagues studied genetically engineered mouse models that were missing GLUT1 and GLUT3 or GLUT3 alone and observed how platelet formation, function, and clearance were affected.

Mice missing glucose transporter proteins did produce platelets, and the platelets’ mitochondria metabolized other substances in place of glucose. However, the mice had platelet counts that were lower than normal.

The researchers were able to pinpoint 2 causes for the low platelet count in mice lacking GLUT1 and GLUT3—fewer platelets being produced and increased clearance of platelets.

The team tested megakaryocytes’ ability to generate new platelets by depleting the blood of platelets and observing the subsequent recovery, which was lower than normal.

They also tested the megakaryocytes in culture, stimulating them to create new platelets, and found the generation of new platelets was defective.

“Clearly, we show that there’s an obligate need for glucose to bud platelets off from the bone marrow,” Dr Abel said.

In addition, the team observed that young platelets functioned normally, even in the absence of glucose. But as they aged, the platelets were cleared from the circulation earlier than normal because they were being destroyed.

“We identified a new mechanism of necrosis by which the absence of glucose leads to the cleavage of a protein called calpain, which marks them for this necrotic pathway,” Dr Abel said. “If we treated the animals with a calpain inhibitor, we could reduce the increased platelet clearance.”

The team also sought to determine whether platelets could exist and function when mitochondria metabolism is halted.

They injected the mice with oligomycin, which inhibits mitochondrial metabolism. In the mice deficient in GLUT1 and GLUT3, platelet counts dropped to 0 within about 30 minutes. The same effect did not occur in wild-type mice.

“This work defined a very important role for metabolism in how platelets leave the bone marrow, how they come into circulation, and how they stay in circulation,” Dr Abel said. “It could even have implications for why platelets have to be used within a certain period of time when they’re donated at the blood bank—the fresher the better.”

Image from Graham Beards

New research published in Cell Reports suggests platelets are highly reliant on their ability to metabolize glucose.

Researchers studied mice lacking proteins that platelets use to import glucose—glucose transporter (GLUT) 1 and GLUT3.

These mice had lower platelet counts and their platelets had shorter life spans than platelets in wild-type mice.

“We found that glucose metabolism is very critical across the entire life cycle of platelets—from production, to what they do in the body, to how they get cleared from the body,” said E. Dale Abel, MBBS, PhD, of the University of Iowa in Iowa City.

For this study, Dr Abel and his colleagues studied genetically engineered mouse models that were missing GLUT1 and GLUT3 or GLUT3 alone and observed how platelet formation, function, and clearance were affected.

Mice missing glucose transporter proteins did produce platelets, and the platelets’ mitochondria metabolized other substances in place of glucose. However, the mice had platelet counts that were lower than normal.

The researchers were able to pinpoint 2 causes for the low platelet count in mice lacking GLUT1 and GLUT3—fewer platelets being produced and increased clearance of platelets.

The team tested megakaryocytes’ ability to generate new platelets by depleting the blood of platelets and observing the subsequent recovery, which was lower than normal.

They also tested the megakaryocytes in culture, stimulating them to create new platelets, and found the generation of new platelets was defective.

“Clearly, we show that there’s an obligate need for glucose to bud platelets off from the bone marrow,” Dr Abel said.

In addition, the team observed that young platelets functioned normally, even in the absence of glucose. But as they aged, the platelets were cleared from the circulation earlier than normal because they were being destroyed.

“We identified a new mechanism of necrosis by which the absence of glucose leads to the cleavage of a protein called calpain, which marks them for this necrotic pathway,” Dr Abel said. “If we treated the animals with a calpain inhibitor, we could reduce the increased platelet clearance.”

The team also sought to determine whether platelets could exist and function when mitochondria metabolism is halted.

They injected the mice with oligomycin, which inhibits mitochondrial metabolism. In the mice deficient in GLUT1 and GLUT3, platelet counts dropped to 0 within about 30 minutes. The same effect did not occur in wild-type mice.

“This work defined a very important role for metabolism in how platelets leave the bone marrow, how they come into circulation, and how they stay in circulation,” Dr Abel said. “It could even have implications for why platelets have to be used within a certain period of time when they’re donated at the blood bank—the fresher the better.”

Photo by Bill Branson

Neuroscientists say they have uncovered genetic differences between radiation-induced meningiomas (RIMs) and sporadic meningiomas (SMs).

Their work suggests RIMs have a different “mutational landscape” from SMs, a finding that may have “significant therapeutic implications” for childhood cancer survivors who undergo cranial radiation.

Gelareh Zadeh, MD, PhD, of the University of Toronto in Ontario, Canada, and her colleagues reported these findings in Nature Communications.

“Radiation-induced meningiomas appear the same [as SMs] on MRI and pathology, feel the same during surgery, and look the same under the operating microscope,” Dr Zadeh said.

“What’s different is they are more aggressive, tend to recur in multiples, and invade the brain, causing significant morbidity and limitations (or impairments) for individuals who survive following childhood radiation. By understanding the biology, the goal is to identify a therapeutic strategy that could be implemented early on after childhood radiation to prevent the formation of these tumors in the first place.”

To better understand the biology, Dr Zadeh and her colleagues analyzed 31 RIMs. This included 18 tumors from 16 patients with childhood cancers, 9 with leukemia.

The researchers found NF2 gene rearrangements in 12 of the RIMs and noted that such rearrangements have not been observed in SMs.

On the other hand, recurrent mutations characteristic of SMs—AKT1, KLF4, TRAF7, and SMO—were not found in the RIMs.

The researchers also noted that, overall, chromosomal aberrations in RIMs were more complex than those observed in SMs. And combined loss of chromosomes 1p and 22q was common in RIMs (16/18).

“Our research identified a specific rearrangement involving the NF2 gene that causes radiation-induced meningiomas,” said Kenneth Aldape, MD, of University Health Network in Toronto.

“But there are likely other genetic rearrangements that are occurring as a result of that radiation-induced DNA damage. So one of the next steps is to identify what the radiation is doing to the DNA of the meninges.”

“In addition, identifying the subset of childhood cancer patients who are at highest risk to develop meningioma is critical so that they could be followed closely for early detection and management.”

Photo by Bill Branson

Neuroscientists say they have uncovered genetic differences between radiation-induced meningiomas (RIMs) and sporadic meningiomas (SMs).

Their work suggests RIMs have a different “mutational landscape” from SMs, a finding that may have “significant therapeutic implications” for childhood cancer survivors who undergo cranial radiation.

Gelareh Zadeh, MD, PhD, of the University of Toronto in Ontario, Canada, and her colleagues reported these findings in Nature Communications.

“Radiation-induced meningiomas appear the same [as SMs] on MRI and pathology, feel the same during surgery, and look the same under the operating microscope,” Dr Zadeh said.

“What’s different is they are more aggressive, tend to recur in multiples, and invade the brain, causing significant morbidity and limitations (or impairments) for individuals who survive following childhood radiation. By understanding the biology, the goal is to identify a therapeutic strategy that could be implemented early on after childhood radiation to prevent the formation of these tumors in the first place.”

To better understand the biology, Dr Zadeh and her colleagues analyzed 31 RIMs. This included 18 tumors from 16 patients with childhood cancers, 9 with leukemia.

The researchers found NF2 gene rearrangements in 12 of the RIMs and noted that such rearrangements have not been observed in SMs.

On the other hand, recurrent mutations characteristic of SMs—AKT1, KLF4, TRAF7, and SMO—were not found in the RIMs.

The researchers also noted that, overall, chromosomal aberrations in RIMs were more complex than those observed in SMs. And combined loss of chromosomes 1p and 22q was common in RIMs (16/18).

“Our research identified a specific rearrangement involving the NF2 gene that causes radiation-induced meningiomas,” said Kenneth Aldape, MD, of University Health Network in Toronto.

“But there are likely other genetic rearrangements that are occurring as a result of that radiation-induced DNA damage. So one of the next steps is to identify what the radiation is doing to the DNA of the meninges.”

“In addition, identifying the subset of childhood cancer patients who are at highest risk to develop meningioma is critical so that they could be followed closely for early detection and management.”

Photo by Bill Branson

Neuroscientists say they have uncovered genetic differences between radiation-induced meningiomas (RIMs) and sporadic meningiomas (SMs).

Their work suggests RIMs have a different “mutational landscape” from SMs, a finding that may have “significant therapeutic implications” for childhood cancer survivors who undergo cranial radiation.

Gelareh Zadeh, MD, PhD, of the University of Toronto in Ontario, Canada, and her colleagues reported these findings in Nature Communications.

“Radiation-induced meningiomas appear the same [as SMs] on MRI and pathology, feel the same during surgery, and look the same under the operating microscope,” Dr Zadeh said.

“What’s different is they are more aggressive, tend to recur in multiples, and invade the brain, causing significant morbidity and limitations (or impairments) for individuals who survive following childhood radiation. By understanding the biology, the goal is to identify a therapeutic strategy that could be implemented early on after childhood radiation to prevent the formation of these tumors in the first place.”

To better understand the biology, Dr Zadeh and her colleagues analyzed 31 RIMs. This included 18 tumors from 16 patients with childhood cancers, 9 with leukemia.

The researchers found NF2 gene rearrangements in 12 of the RIMs and noted that such rearrangements have not been observed in SMs.

On the other hand, recurrent mutations characteristic of SMs—AKT1, KLF4, TRAF7, and SMO—were not found in the RIMs.

The researchers also noted that, overall, chromosomal aberrations in RIMs were more complex than those observed in SMs. And combined loss of chromosomes 1p and 22q was common in RIMs (16/18).

“Our research identified a specific rearrangement involving the NF2 gene that causes radiation-induced meningiomas,” said Kenneth Aldape, MD, of University Health Network in Toronto.

“But there are likely other genetic rearrangements that are occurring as a result of that radiation-induced DNA damage. So one of the next steps is to identify what the radiation is doing to the DNA of the meninges.”

“In addition, identifying the subset of childhood cancer patients who are at highest risk to develop meningioma is critical so that they could be followed closely for early detection and management.”

Image from Wikimedia

The US Food and Drug Administration (FDA) has granted priority review and breakthrough therapy designation to vemurafenib (Zelboraf®) as a treatment for Erdheim-Chester disease (ECD) with BRAF V600 mutation.

Vemurafenib is a kinase inhibitor designed to inhibit some mutated forms of BRAF.

The drug is already FDA-approved to treat patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test.

The FDA is expected to make a decision on the approval of vemurafenib in ECD by December 7, 2017.

The supplemental new drug application for vemurafenib in this indication is supported by data from the phase 2 VE-BASKET study.

VE-BASKET was designed to investigate the use of vemurafenib in patients with BRAF V600 mutation-positive diseases, including ECD.

Final results for the 22 people with ECD showed a best overall response rate of 54.5%. The median duration of response, progression-free survival, and overall survival were not reached at a median follow-up of 26.6 months.

The most common adverse events were joint pain, rash, hair loss, change in heart rhythm, fatigue, skin tags, diarrhea, and thickening of the skin. The most common grade 3 or higher adverse events were new skin cancers, high blood pressure, rash, and joint pain.

Initial results from this study were published in NEJM in August 2015.

About priority review

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

About breakthrough designation

The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.

The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as a rolling submission and priority review.

To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.

Image from Wikimedia

The US Food and Drug Administration (FDA) has granted priority review and breakthrough therapy designation to vemurafenib (Zelboraf®) as a treatment for Erdheim-Chester disease (ECD) with BRAF V600 mutation.

Vemurafenib is a kinase inhibitor designed to inhibit some mutated forms of BRAF.

The drug is already FDA-approved to treat patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test.

The FDA is expected to make a decision on the approval of vemurafenib in ECD by December 7, 2017.

The supplemental new drug application for vemurafenib in this indication is supported by data from the phase 2 VE-BASKET study.

VE-BASKET was designed to investigate the use of vemurafenib in patients with BRAF V600 mutation-positive diseases, including ECD.

Final results for the 22 people with ECD showed a best overall response rate of 54.5%. The median duration of response, progression-free survival, and overall survival were not reached at a median follow-up of 26.6 months.

The most common adverse events were joint pain, rash, hair loss, change in heart rhythm, fatigue, skin tags, diarrhea, and thickening of the skin. The most common grade 3 or higher adverse events were new skin cancers, high blood pressure, rash, and joint pain.

Initial results from this study were published in NEJM in August 2015.

About priority review

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

About breakthrough designation

The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.

The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as a rolling submission and priority review.

To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.

Image from Wikimedia

The US Food and Drug Administration (FDA) has granted priority review and breakthrough therapy designation to vemurafenib (Zelboraf®) as a treatment for Erdheim-Chester disease (ECD) with BRAF V600 mutation.

Vemurafenib is a kinase inhibitor designed to inhibit some mutated forms of BRAF.

The drug is already FDA-approved to treat patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test.

The FDA is expected to make a decision on the approval of vemurafenib in ECD by December 7, 2017.

The supplemental new drug application for vemurafenib in this indication is supported by data from the phase 2 VE-BASKET study.

VE-BASKET was designed to investigate the use of vemurafenib in patients with BRAF V600 mutation-positive diseases, including ECD.

Final results for the 22 people with ECD showed a best overall response rate of 54.5%. The median duration of response, progression-free survival, and overall survival were not reached at a median follow-up of 26.6 months.

The most common adverse events were joint pain, rash, hair loss, change in heart rhythm, fatigue, skin tags, diarrhea, and thickening of the skin. The most common grade 3 or higher adverse events were new skin cancers, high blood pressure, rash, and joint pain.

Initial results from this study were published in NEJM in August 2015.

About priority review

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

About breakthrough designation

The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.

The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as a rolling submission and priority review.

To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.