Case Reports

According to the United Nations Office on Drugs and Crime, the last decade saw an alarming rise in the use of recreational substances.¹ There was an escalation not only in the use of the more well-known street drugs (cannabis, stimulants, opiates, and hallucinogens), but also an exponential increase in the abuse of novel psychoactive substances. Although most health care providers (HCPs) are at least relatively familiar with some of these designer drugs—often synthesized analogues of common street drugs—region-specific herbal products with psychoactive properties are now entering the market worldwide. Certainly, the cause of this increased use is multifactorial: Ease of access to these drugs and ambiguous legality are believed to be among the largest contributors. Infrastructure established through globalization promotes easy drug transportation and distribution across borders, and widespread Internet use makes knowledge of and accessibility to such substances exceedingly simple.^2,3

In particular, widespread online access has permanently altered the acquisition of knowledge in all realms—including drug use. Although Erowid Center remains one of the oldest and best-known of the “dark Internet” websites and bills itself as providing “harm reduction,” others have cropped up online and disseminate information about many forms of potentially psychoactive substances. Despite these websites’ purported raison d’être, recent studies have demonstrated these sites’ efficacy in promoting drug use under the guise of safety, particularly among adolescents and young adults. Among these is a qualitative study by Boyer and colleagues of 12 drug users admitted to a pediatric psychiatry unit. Through extensive questioning about the patient’s digital habits, the researchers demonstrated that the majority of subjects used these websites and as a result either increased their drug use or learned about (and tried) new substances!⁴

One drug that has benefited from globalization and the Internet is kratom (Mitragyna speciosa korth). This formerly regionally confined herbal psychoactive substance is native to Southeast Asia, where it has been used (and abused) for centuries as a mild stimulant, to prevent opiate withdrawal, and for recreational purposes. In recent years, kratom has been marketed as a psychotropic drug and is increasingly popular in the U.S. and in the United Kingdom.^2,5,6 In the U.S., this poses a problem for HCPs who often are unaware of this plant’s existence, much less its abuse potential or health effects.² Also known as ketum, kakuam, thang, thom, or biak, kratom is marketed in stores and online as a cheap, safe alternative to opioids.

Although considered a “substance of concern” without any approved medical use by the U.S. Drug Enforcement Agency (DEA), kratom is not a regulated or controlled substance in the U.S.³ In the past few months, out of concern for public safety, the DEA placed a temporary ban on kratom. The agency’s move was followed by a substantial negative reaction from kratom supporters and was quickly rescinded. As of September 2016, the DEA does not have a timetable for banning or scheduling the drug.

To that end, users consider kratom a legal high, and it is easily purchased online. A 2010 study in the United Kingdom examined websites where kratom and many other quasilegal substances (including Salvia divinorum and legal precursors to LSD) could be purchased for an average of £10 (about U.S. $13).⁵ This study’s authors also noted a significant lack of product information on these marketplaces. As these products are not overseen by any regulatory body, the risk of overdose or adulteration is extremely high.^2,3,6-8 In fact, Krypton, a product sold online, was found to be adulterated with O-desmethyltramadol—the active metabolite of the synthetic opiate tramadol—and implicated in at least 9 deaths.⁷

This article presents a case of kratom abuse and will outline a brief history, the pharmacologic characteristics, clinical presentation of kratom abuse, and conclude with an overview of the treatment of kratom-related illness and evaluation of potential toxic sequelae. In light of the rapid proliferation of kratom in the U.S., a basic working knowledge of the drug is quickly becoming a must for federal HCPs.

Case Presentation

At his employer’s request, a 33-year-old married man presented to his family physician for a worsening of his uncontrolled back pain from a herniated lumbar disc resulting from a motor vehicle collision 3 months before. At his physician’s office he stated, “I don’t care if I live or die, I’m tired of the pain,” and “I’m going to go off on somebody if I can’t get this pain under control.” He also endorsed having auditory hallucinations for several years and a history of violence and homicide. The problem arose precipitously after he thought that he was abusing his opiate medication, and it was discontinued. The patient was transferred to the local hospital and admitted to the psychiatric service for his suicidal ideations and risk of harming self and others.

On admission to the psychiatric service, the patient complained of body aches, chills, rhinorrhea, and significantly worsened irritability from his baseline. Initial point-of-care admission drug testing had been negative as had expanded urine tests looking for synthetic opioids, cannabinoids, and cathinones. The patient reported no opioid use but was unable to explain his current symptom patterns, which were worsening his chronic pain and hampering any attempt to build rapport. On hospital day 3, the patient’s additional sequelae had passed, and psychiatric treatment was able to progress fully. On hospital day 4, the inpatient treatment team received a message from the patient’s primary care manager stating that a friend of the patient had found a bottle of herbal pills in the patient’s car. This was later revealed to be a kratom formulation that he had purchased online.

Background

Kratom is the colloquial name of a tree that is native to Thailand, Malaysia, and other countries in Southeast Asia. These trees, which can grow to 50 feet high and 15 feet wide, have long been the source of herbal remedies in Southeast Asia (eFigure).^2,3 The leaves contain psychoactive substances that have a variety of effects when consumed. At low doses, kratom causes a stimulant effect (akin to the leaves of the coca plant in South America); laborers and farmers often use it to help boost their energy. At higher doses, kratom causes an opioid-l

In the United Kingdom, kratom is currently the second most common drug that is considered a legal high, only behind salvia (Salvia divinorum), a hallucinogenic herb that is better known as a result of its use by young celebrities over the past decade.^5,8 Presently, kratom’s legal status in the U.S. continues to be nebulous: It has not been officially scheduled by the DEA, and it is easily obtained.

Kratom can be taken in a variety of ways: Crushed leaves often are placed in gel caps and swallowed; it can be drunk as a tea, juice, or boiled syrup; and it can be smoked or insufflated.^2,3,5,6

Pharmacology and Clinical Presentation

More than 20 psychoactive compounds have been isolated from kratom. Although a discussion of all these compounds is beyond the scope of this review, the 2 major compounds are mitragynine and 7-hydroxymitragynine.

Mitragynine

Mitragynine, the most abundant psychoactive compound found in kratom, is an indole alkaloid (Figure 1). Extraction and analysis of this compound has demonstrated numerous effects on multiple receptors, including μ, δ, and κ opioid receptors, leading to its opioid-like ef

7-Hydroxymitragynine

7-hydroxymitragynine, despite being far less concentrated in kratom preparations, is about 13 times more potent than morphine and 46 times more potent than mitragynine. It is thought that its hydroxyl side chain added to C7 (Figure 2) adds to its lipophilicity and ability to cross the blood-brain barrier at a far more rapid rate than that of mitragynine.²

Mitragynine and 7-hydroxymitragynine remain the best-studied psychoactive components of kratom at this time. Other compounds that have been isolated, such as speciociliatine, paynantheine, and speciogynine, may play a role in kratom’s analgesic and psychoactive effects. Animal studies have demonstrated antimuscarinic properties in these compounds, but the properties do not seem to have any demonstrable effect at the opioid receptors.²

Intoxication and Withdrawal

Due to its increasing worldwide popularity, it is now imperative for HCPs to be aware of the clinical presentation of kratom abuse as well as the management of withdrawal in light of its dependence potential. However, large-scale studies have not been performed, and much of the evidence comes not from the medical literature but from prodrug websites like Erowid or SageWisdom.^2,5-9 To that end, such information will be discussed along with the limited research and expert consensuses available in peer-reviewed medical literature.

Kratom seems to have dose-dependent effects. At low doses (1 g-5 g of raw crushed leaves), kratom abusers often report a mild energizing effect, thought to be secondary to the stimulant properties of kratom’s multiple alkaloids. Users have reported mild euphoria and highs similar to those of the abuse of methylphenidate or modafinil.^2,9,10 Also similar to abuse of those substances, users have reported anxiety, irritability, and aggressiveness as a result of the stimulant-like effects.

At moderate-to-high doses (5 g-15 g of raw crushed leaves), it is believed that the μ opiate receptor agonism overtakes the stimulant effects, leading to the euphoria, relaxation, and analgesia seen with conventional opioid use and abuse.^2,10 In light of the drug’s substantial binding and agonism of all opioid receptors, constipation and itching also are seen.² As such, if an individual is intoxicated, he or she should be managed symptomatically with judicious use of benzodiazepines and continuous monitoring of heart rate, blood pressure, respiratory rate, and oxygen saturation.^2,10 Kratom intoxication can precipitate psychotic episodes similar to those caused by opiate intoxication, so monitoring for agitation or psychotic behaviors is also indicated.^9,10

The medical management of an acute kratom overdose (typically requiring ingestion of > 15 g of crushed leaves) begins with addressing airway blockage, breathing, and circulation along with continuous vital sign monitoring and laboratory testing, including point-of-care glucose, complete blood count, electrolytes, lactate, venous blood gas, and measurable drug levels (ethanol, acetaminophen, tricyclic antidepressants, etc).¹¹ If it is determined that kratom was the intoxicant, the greatest concern of death is similar to that of opioid overdose: respiratory depression. Although there are no large-scale human studies demonstrating efficacy, multiple authors suggest the use of naloxone in kratom-related hypoventilation.^9,10

The development of dependence on kratom and its subsequent withdrawal phenomena are thought to be similar to that of opioids, in light of its strong μ agonism.^2,5,9,10 Indeed, kratom has a long history of being used by opioid-dependent patients as an attempt to quit drug abuse or stave off debilitating withdrawal symptoms when they are unable to acquire their substance of choice.^2,5-10 As such, withdrawal and the treatment thereof will also mimic that of opioid detoxification.

The kratom-dependent individual will often present with rhinorrhea, lacrimation, dry mouth, hostility, aggression, and emotional lability similar to the case study described earlier.^2,9,10 Kratom withdrawal, much like intoxication, also may precipitate or worsen psychotic symptoms, and monitoring is necessary throughout the detoxification process.^2,5,10 Withdrawal management should proceed along ambulatory clinic or hospital opioid withdrawal protocols that include step-down administration of opioids or with nonopioid medications for symptomatic relief, including muscle relaxants, α-2 agonists, and antidiarrheal agents.^5,9,10

Kratom Toxicity

A review of the available medical literature has demonstrated a number of toxic effects with kratom abuse, either as the sole agent or in concert with prescribed medications, recreational coingestants, or as a result of manufacturer’s adulteration with other chemicals or drugs. Of particular interest to HCPs are manic or psychotic episode precipitation, seizure, hypothyroidism, intrahepatic cholestatic injury, and even sudden cardiac death.^2,3,5-10 In addition to the basic history, physical, and laboratory examination, the workup of patients identified as kratom users should include the following:

• Fastidious medication reconciliation with drug-interaction check;
• Exhaustive substance abuse history;
• Identification of the brand name and source of kratom purchased, to determine whether there are advertised coingestants or reports of adulteration;
• Electrocardiogram;
• Thyroid function testing;
• Hepatic function testing; and
• Comprehensive neurologic and mental status exams.

In chronic users of kratom, a number of effects have been seen whose etiologies have not yet been determined. These effects include depression, anxiety, tremulousness, weight loss, and permanent psychosis.^3-7 Additionally, a 2008 study by Kittirattanapaiboon and colleagues correlated drug use by those with concurrent mental health disorders (in particular, kratom, which was used in 59% of the ≥ 14,000 individuals included in the study sample) with statistically significant higher suicide risk.¹²

Detection

Because kratom is a relatively new compound in the U.S., medical and forensic laboratories are only now implementing kratom detection protocols. Many laboratories now use high-performance liquid chromatography to analyze for mitragynine, 7-hydroxymitragynine, and 2 metabolites of mitragynine in urine.⁷ Le and colleagues were able to detect mitragynine in the urine in levels as low as 1 ng/mL, which is clinically useful as mitragynine has a half-life determined in animal studies to be 3.85 hours.¹³ Similar detection limits for mitragynine and 7-hydroxymitragynine are used only at Naval Medical Center Portsmouth in Virginia; however, kratom was not detected in the study patient’s urine because a urine test was not done until hospital day 5.

Conclusion

When gently confronted about the kratom found in his car, the case study patient admitted that he had purchased kratom online after he was “cut off” from prescription opioids for his pain. He admitted that although it was beneficial for his pain, he did notice worsening in his aggression toward his spouse and coworkers. This progressed to an exacerbation of his psychotic symptoms of hallucinations and persecutory delusions. These symptoms remained well hidden in this highly intelligent individual—but were present for years prior to his presentation at the hospital. The patient was discharged from the inpatient psychiatric unit on hospital day 16 with a diagnosis of schizoaffective disorder, depressive type in addition to opioid use disorder. The patient agreed to seek a pain management specialist and discontinue kratom use.

Kratom is an emerging drug of abuse in the Western World. Although significant research is being conducted on its possible medical uses, little is known about kratom beyond the “trip reports” of kratom users posted online. Because of its technically legal status in the U.S. and multiple other Western countries, kratom is easily accessible and is difficult to detect. Health care providers need to be aware of kratom, and during their evaluations, question patients about kratom and other legal highs.

According to the United Nations Office on Drugs and Crime, the last decade saw an alarming rise in the use of recreational substances.¹ There was an escalation not only in the use of the more well-known street drugs (cannabis, stimulants, opiates, and hallucinogens), but also an exponential increase in the abuse of novel psychoactive substances. Although most health care providers (HCPs) are at least relatively familiar with some of these designer drugs—often synthesized analogues of common street drugs—region-specific herbal products with psychoactive properties are now entering the market worldwide. Certainly, the cause of this increased use is multifactorial: Ease of access to these drugs and ambiguous legality are believed to be among the largest contributors. Infrastructure established through globalization promotes easy drug transportation and distribution across borders, and widespread Internet use makes knowledge of and accessibility to such substances exceedingly simple.^2,3

In particular, widespread online access has permanently altered the acquisition of knowledge in all realms—including drug use. Although Erowid Center remains one of the oldest and best-known of the “dark Internet” websites and bills itself as providing “harm reduction,” others have cropped up online and disseminate information about many forms of potentially psychoactive substances. Despite these websites’ purported raison d’être, recent studies have demonstrated these sites’ efficacy in promoting drug use under the guise of safety, particularly among adolescents and young adults. Among these is a qualitative study by Boyer and colleagues of 12 drug users admitted to a pediatric psychiatry unit. Through extensive questioning about the patient’s digital habits, the researchers demonstrated that the majority of subjects used these websites and as a result either increased their drug use or learned about (and tried) new substances!⁴

One drug that has benefited from globalization and the Internet is kratom (Mitragyna speciosa korth). This formerly regionally confined herbal psychoactive substance is native to Southeast Asia, where it has been used (and abused) for centuries as a mild stimulant, to prevent opiate withdrawal, and for recreational purposes. In recent years, kratom has been marketed as a psychotropic drug and is increasingly popular in the U.S. and in the United Kingdom.^2,5,6 In the U.S., this poses a problem for HCPs who often are unaware of this plant’s existence, much less its abuse potential or health effects.² Also known as ketum, kakuam, thang, thom, or biak, kratom is marketed in stores and online as a cheap, safe alternative to opioids.

Although considered a “substance of concern” without any approved medical use by the U.S. Drug Enforcement Agency (DEA), kratom is not a regulated or controlled substance in the U.S.³ In the past few months, out of concern for public safety, the DEA placed a temporary ban on kratom. The agency’s move was followed by a substantial negative reaction from kratom supporters and was quickly rescinded. As of September 2016, the DEA does not have a timetable for banning or scheduling the drug.

To that end, users consider kratom a legal high, and it is easily purchased online. A 2010 study in the United Kingdom examined websites where kratom and many other quasilegal substances (including Salvia divinorum and legal precursors to LSD) could be purchased for an average of £10 (about U.S. $13).⁵ This study’s authors also noted a significant lack of product information on these marketplaces. As these products are not overseen by any regulatory body, the risk of overdose or adulteration is extremely high.^2,3,6-8 In fact, Krypton, a product sold online, was found to be adulterated with O-desmethyltramadol—the active metabolite of the synthetic opiate tramadol—and implicated in at least 9 deaths.⁷

This article presents a case of kratom abuse and will outline a brief history, the pharmacologic characteristics, clinical presentation of kratom abuse, and conclude with an overview of the treatment of kratom-related illness and evaluation of potential toxic sequelae. In light of the rapid proliferation of kratom in the U.S., a basic working knowledge of the drug is quickly becoming a must for federal HCPs.

Case Presentation

At his employer’s request, a 33-year-old married man presented to his family physician for a worsening of his uncontrolled back pain from a herniated lumbar disc resulting from a motor vehicle collision 3 months before. At his physician’s office he stated, “I don’t care if I live or die, I’m tired of the pain,” and “I’m going to go off on somebody if I can’t get this pain under control.” He also endorsed having auditory hallucinations for several years and a history of violence and homicide. The problem arose precipitously after he thought that he was abusing his opiate medication, and it was discontinued. The patient was transferred to the local hospital and admitted to the psychiatric service for his suicidal ideations and risk of harming self and others.

On admission to the psychiatric service, the patient complained of body aches, chills, rhinorrhea, and significantly worsened irritability from his baseline. Initial point-of-care admission drug testing had been negative as had expanded urine tests looking for synthetic opioids, cannabinoids, and cathinones. The patient reported no opioid use but was unable to explain his current symptom patterns, which were worsening his chronic pain and hampering any attempt to build rapport. On hospital day 3, the patient’s additional sequelae had passed, and psychiatric treatment was able to progress fully. On hospital day 4, the inpatient treatment team received a message from the patient’s primary care manager stating that a friend of the patient had found a bottle of herbal pills in the patient’s car. This was later revealed to be a kratom formulation that he had purchased online.

Background

Kratom is the colloquial name of a tree that is native to Thailand, Malaysia, and other countries in Southeast Asia. These trees, which can grow to 50 feet high and 15 feet wide, have long been the source of herbal remedies in Southeast Asia (eFigure).^2,3 The leaves contain psychoactive substances that have a variety of effects when consumed. At low doses, kratom causes a stimulant effect (akin to the leaves of the coca plant in South America); laborers and farmers often use it to help boost their energy. At higher doses, kratom causes an opioid-l

In the United Kingdom, kratom is currently the second most common drug that is considered a legal high, only behind salvia (Salvia divinorum), a hallucinogenic herb that is better known as a result of its use by young celebrities over the past decade.^5,8 Presently, kratom’s legal status in the U.S. continues to be nebulous: It has not been officially scheduled by the DEA, and it is easily obtained.

Kratom can be taken in a variety of ways: Crushed leaves often are placed in gel caps and swallowed; it can be drunk as a tea, juice, or boiled syrup; and it can be smoked or insufflated.^2,3,5,6

Pharmacology and Clinical Presentation

More than 20 psychoactive compounds have been isolated from kratom. Although a discussion of all these compounds is beyond the scope of this review, the 2 major compounds are mitragynine and 7-hydroxymitragynine.

Mitragynine

Mitragynine, the most abundant psychoactive compound found in kratom, is an indole alkaloid (Figure 1). Extraction and analysis of this compound has demonstrated numerous effects on multiple receptors, including μ, δ, and κ opioid receptors, leading to its opioid-like ef

7-Hydroxymitragynine

7-hydroxymitragynine, despite being far less concentrated in kratom preparations, is about 13 times more potent than morphine and 46 times more potent than mitragynine. It is thought that its hydroxyl side chain added to C7 (Figure 2) adds to its lipophilicity and ability to cross the blood-brain barrier at a far more rapid rate than that of mitragynine.²

Mitragynine and 7-hydroxymitragynine remain the best-studied psychoactive components of kratom at this time. Other compounds that have been isolated, such as speciociliatine, paynantheine, and speciogynine, may play a role in kratom’s analgesic and psychoactive effects. Animal studies have demonstrated antimuscarinic properties in these compounds, but the properties do not seem to have any demonstrable effect at the opioid receptors.²

Intoxication and Withdrawal

Due to its increasing worldwide popularity, it is now imperative for HCPs to be aware of the clinical presentation of kratom abuse as well as the management of withdrawal in light of its dependence potential. However, large-scale studies have not been performed, and much of the evidence comes not from the medical literature but from prodrug websites like Erowid or SageWisdom.^2,5-9 To that end, such information will be discussed along with the limited research and expert consensuses available in peer-reviewed medical literature.

Kratom seems to have dose-dependent effects. At low doses (1 g-5 g of raw crushed leaves), kratom abusers often report a mild energizing effect, thought to be secondary to the stimulant properties of kratom’s multiple alkaloids. Users have reported mild euphoria and highs similar to those of the abuse of methylphenidate or modafinil.^2,9,10 Also similar to abuse of those substances, users have reported anxiety, irritability, and aggressiveness as a result of the stimulant-like effects.

At moderate-to-high doses (5 g-15 g of raw crushed leaves), it is believed that the μ opiate receptor agonism overtakes the stimulant effects, leading to the euphoria, relaxation, and analgesia seen with conventional opioid use and abuse.^2,10 In light of the drug’s substantial binding and agonism of all opioid receptors, constipation and itching also are seen.² As such, if an individual is intoxicated, he or she should be managed symptomatically with judicious use of benzodiazepines and continuous monitoring of heart rate, blood pressure, respiratory rate, and oxygen saturation.^2,10 Kratom intoxication can precipitate psychotic episodes similar to those caused by opiate intoxication, so monitoring for agitation or psychotic behaviors is also indicated.^9,10

The medical management of an acute kratom overdose (typically requiring ingestion of > 15 g of crushed leaves) begins with addressing airway blockage, breathing, and circulation along with continuous vital sign monitoring and laboratory testing, including point-of-care glucose, complete blood count, electrolytes, lactate, venous blood gas, and measurable drug levels (ethanol, acetaminophen, tricyclic antidepressants, etc).¹¹ If it is determined that kratom was the intoxicant, the greatest concern of death is similar to that of opioid overdose: respiratory depression. Although there are no large-scale human studies demonstrating efficacy, multiple authors suggest the use of naloxone in kratom-related hypoventilation.^9,10

The development of dependence on kratom and its subsequent withdrawal phenomena are thought to be similar to that of opioids, in light of its strong μ agonism.^2,5,9,10 Indeed, kratom has a long history of being used by opioid-dependent patients as an attempt to quit drug abuse or stave off debilitating withdrawal symptoms when they are unable to acquire their substance of choice.^2,5-10 As such, withdrawal and the treatment thereof will also mimic that of opioid detoxification.

The kratom-dependent individual will often present with rhinorrhea, lacrimation, dry mouth, hostility, aggression, and emotional lability similar to the case study described earlier.^2,9,10 Kratom withdrawal, much like intoxication, also may precipitate or worsen psychotic symptoms, and monitoring is necessary throughout the detoxification process.^2,5,10 Withdrawal management should proceed along ambulatory clinic or hospital opioid withdrawal protocols that include step-down administration of opioids or with nonopioid medications for symptomatic relief, including muscle relaxants, α-2 agonists, and antidiarrheal agents.^5,9,10

Kratom Toxicity

A review of the available medical literature has demonstrated a number of toxic effects with kratom abuse, either as the sole agent or in concert with prescribed medications, recreational coingestants, or as a result of manufacturer’s adulteration with other chemicals or drugs. Of particular interest to HCPs are manic or psychotic episode precipitation, seizure, hypothyroidism, intrahepatic cholestatic injury, and even sudden cardiac death.^2,3,5-10 In addition to the basic history, physical, and laboratory examination, the workup of patients identified as kratom users should include the following:

• Fastidious medication reconciliation with drug-interaction check;
• Exhaustive substance abuse history;
• Identification of the brand name and source of kratom purchased, to determine whether there are advertised coingestants or reports of adulteration;
• Electrocardiogram;
• Thyroid function testing;
• Hepatic function testing; and
• Comprehensive neurologic and mental status exams.

In chronic users of kratom, a number of effects have been seen whose etiologies have not yet been determined. These effects include depression, anxiety, tremulousness, weight loss, and permanent psychosis.^3-7 Additionally, a 2008 study by Kittirattanapaiboon and colleagues correlated drug use by those with concurrent mental health disorders (in particular, kratom, which was used in 59% of the ≥ 14,000 individuals included in the study sample) with statistically significant higher suicide risk.¹²

Detection

Because kratom is a relatively new compound in the U.S., medical and forensic laboratories are only now implementing kratom detection protocols. Many laboratories now use high-performance liquid chromatography to analyze for mitragynine, 7-hydroxymitragynine, and 2 metabolites of mitragynine in urine.⁷ Le and colleagues were able to detect mitragynine in the urine in levels as low as 1 ng/mL, which is clinically useful as mitragynine has a half-life determined in animal studies to be 3.85 hours.¹³ Similar detection limits for mitragynine and 7-hydroxymitragynine are used only at Naval Medical Center Portsmouth in Virginia; however, kratom was not detected in the study patient’s urine because a urine test was not done until hospital day 5.

Conclusion

When gently confronted about the kratom found in his car, the case study patient admitted that he had purchased kratom online after he was “cut off” from prescription opioids for his pain. He admitted that although it was beneficial for his pain, he did notice worsening in his aggression toward his spouse and coworkers. This progressed to an exacerbation of his psychotic symptoms of hallucinations and persecutory delusions. These symptoms remained well hidden in this highly intelligent individual—but were present for years prior to his presentation at the hospital. The patient was discharged from the inpatient psychiatric unit on hospital day 16 with a diagnosis of schizoaffective disorder, depressive type in addition to opioid use disorder. The patient agreed to seek a pain management specialist and discontinue kratom use.

Kratom is an emerging drug of abuse in the Western World. Although significant research is being conducted on its possible medical uses, little is known about kratom beyond the “trip reports” of kratom users posted online. Because of its technically legal status in the U.S. and multiple other Western countries, kratom is easily accessible and is difficult to detect. Health care providers need to be aware of kratom, and during their evaluations, question patients about kratom and other legal highs.

According to the United Nations Office on Drugs and Crime, the last decade saw an alarming rise in the use of recreational substances.¹ There was an escalation not only in the use of the more well-known street drugs (cannabis, stimulants, opiates, and hallucinogens), but also an exponential increase in the abuse of novel psychoactive substances. Although most health care providers (HCPs) are at least relatively familiar with some of these designer drugs—often synthesized analogues of common street drugs—region-specific herbal products with psychoactive properties are now entering the market worldwide. Certainly, the cause of this increased use is multifactorial: Ease of access to these drugs and ambiguous legality are believed to be among the largest contributors. Infrastructure established through globalization promotes easy drug transportation and distribution across borders, and widespread Internet use makes knowledge of and accessibility to such substances exceedingly simple.^2,3

In particular, widespread online access has permanently altered the acquisition of knowledge in all realms—including drug use. Although Erowid Center remains one of the oldest and best-known of the “dark Internet” websites and bills itself as providing “harm reduction,” others have cropped up online and disseminate information about many forms of potentially psychoactive substances. Despite these websites’ purported raison d’être, recent studies have demonstrated these sites’ efficacy in promoting drug use under the guise of safety, particularly among adolescents and young adults. Among these is a qualitative study by Boyer and colleagues of 12 drug users admitted to a pediatric psychiatry unit. Through extensive questioning about the patient’s digital habits, the researchers demonstrated that the majority of subjects used these websites and as a result either increased their drug use or learned about (and tried) new substances!⁴

One drug that has benefited from globalization and the Internet is kratom (Mitragyna speciosa korth). This formerly regionally confined herbal psychoactive substance is native to Southeast Asia, where it has been used (and abused) for centuries as a mild stimulant, to prevent opiate withdrawal, and for recreational purposes. In recent years, kratom has been marketed as a psychotropic drug and is increasingly popular in the U.S. and in the United Kingdom.^2,5,6 In the U.S., this poses a problem for HCPs who often are unaware of this plant’s existence, much less its abuse potential or health effects.² Also known as ketum, kakuam, thang, thom, or biak, kratom is marketed in stores and online as a cheap, safe alternative to opioids.

Although considered a “substance of concern” without any approved medical use by the U.S. Drug Enforcement Agency (DEA), kratom is not a regulated or controlled substance in the U.S.³ In the past few months, out of concern for public safety, the DEA placed a temporary ban on kratom. The agency’s move was followed by a substantial negative reaction from kratom supporters and was quickly rescinded. As of September 2016, the DEA does not have a timetable for banning or scheduling the drug.

To that end, users consider kratom a legal high, and it is easily purchased online. A 2010 study in the United Kingdom examined websites where kratom and many other quasilegal substances (including Salvia divinorum and legal precursors to LSD) could be purchased for an average of £10 (about U.S. $13).⁵ This study’s authors also noted a significant lack of product information on these marketplaces. As these products are not overseen by any regulatory body, the risk of overdose or adulteration is extremely high.^2,3,6-8 In fact, Krypton, a product sold online, was found to be adulterated with O-desmethyltramadol—the active metabolite of the synthetic opiate tramadol—and implicated in at least 9 deaths.⁷

This article presents a case of kratom abuse and will outline a brief history, the pharmacologic characteristics, clinical presentation of kratom abuse, and conclude with an overview of the treatment of kratom-related illness and evaluation of potential toxic sequelae. In light of the rapid proliferation of kratom in the U.S., a basic working knowledge of the drug is quickly becoming a must for federal HCPs.

Case Presentation

At his employer’s request, a 33-year-old married man presented to his family physician for a worsening of his uncontrolled back pain from a herniated lumbar disc resulting from a motor vehicle collision 3 months before. At his physician’s office he stated, “I don’t care if I live or die, I’m tired of the pain,” and “I’m going to go off on somebody if I can’t get this pain under control.” He also endorsed having auditory hallucinations for several years and a history of violence and homicide. The problem arose precipitously after he thought that he was abusing his opiate medication, and it was discontinued. The patient was transferred to the local hospital and admitted to the psychiatric service for his suicidal ideations and risk of harming self and others.

On admission to the psychiatric service, the patient complained of body aches, chills, rhinorrhea, and significantly worsened irritability from his baseline. Initial point-of-care admission drug testing had been negative as had expanded urine tests looking for synthetic opioids, cannabinoids, and cathinones. The patient reported no opioid use but was unable to explain his current symptom patterns, which were worsening his chronic pain and hampering any attempt to build rapport. On hospital day 3, the patient’s additional sequelae had passed, and psychiatric treatment was able to progress fully. On hospital day 4, the inpatient treatment team received a message from the patient’s primary care manager stating that a friend of the patient had found a bottle of herbal pills in the patient’s car. This was later revealed to be a kratom formulation that he had purchased online.

Background

Kratom is the colloquial name of a tree that is native to Thailand, Malaysia, and other countries in Southeast Asia. These trees, which can grow to 50 feet high and 15 feet wide, have long been the source of herbal remedies in Southeast Asia (eFigure).^2,3 The leaves contain psychoactive substances that have a variety of effects when consumed. At low doses, kratom causes a stimulant effect (akin to the leaves of the coca plant in South America); laborers and farmers often use it to help boost their energy. At higher doses, kratom causes an opioid-l

In the United Kingdom, kratom is currently the second most common drug that is considered a legal high, only behind salvia (Salvia divinorum), a hallucinogenic herb that is better known as a result of its use by young celebrities over the past decade.^5,8 Presently, kratom’s legal status in the U.S. continues to be nebulous: It has not been officially scheduled by the DEA, and it is easily obtained.

Kratom can be taken in a variety of ways: Crushed leaves often are placed in gel caps and swallowed; it can be drunk as a tea, juice, or boiled syrup; and it can be smoked or insufflated.^2,3,5,6

Pharmacology and Clinical Presentation

More than 20 psychoactive compounds have been isolated from kratom. Although a discussion of all these compounds is beyond the scope of this review, the 2 major compounds are mitragynine and 7-hydroxymitragynine.

Mitragynine

Mitragynine, the most abundant psychoactive compound found in kratom, is an indole alkaloid (Figure 1). Extraction and analysis of this compound has demonstrated numerous effects on multiple receptors, including μ, δ, and κ opioid receptors, leading to its opioid-like ef

7-Hydroxymitragynine

7-hydroxymitragynine, despite being far less concentrated in kratom preparations, is about 13 times more potent than morphine and 46 times more potent than mitragynine. It is thought that its hydroxyl side chain added to C7 (Figure 2) adds to its lipophilicity and ability to cross the blood-brain barrier at a far more rapid rate than that of mitragynine.²

Mitragynine and 7-hydroxymitragynine remain the best-studied psychoactive components of kratom at this time. Other compounds that have been isolated, such as speciociliatine, paynantheine, and speciogynine, may play a role in kratom’s analgesic and psychoactive effects. Animal studies have demonstrated antimuscarinic properties in these compounds, but the properties do not seem to have any demonstrable effect at the opioid receptors.²

Intoxication and Withdrawal

Due to its increasing worldwide popularity, it is now imperative for HCPs to be aware of the clinical presentation of kratom abuse as well as the management of withdrawal in light of its dependence potential. However, large-scale studies have not been performed, and much of the evidence comes not from the medical literature but from prodrug websites like Erowid or SageWisdom.^2,5-9 To that end, such information will be discussed along with the limited research and expert consensuses available in peer-reviewed medical literature.

Kratom seems to have dose-dependent effects. At low doses (1 g-5 g of raw crushed leaves), kratom abusers often report a mild energizing effect, thought to be secondary to the stimulant properties of kratom’s multiple alkaloids. Users have reported mild euphoria and highs similar to those of the abuse of methylphenidate or modafinil.^2,9,10 Also similar to abuse of those substances, users have reported anxiety, irritability, and aggressiveness as a result of the stimulant-like effects.

At moderate-to-high doses (5 g-15 g of raw crushed leaves), it is believed that the μ opiate receptor agonism overtakes the stimulant effects, leading to the euphoria, relaxation, and analgesia seen with conventional opioid use and abuse.^2,10 In light of the drug’s substantial binding and agonism of all opioid receptors, constipation and itching also are seen.² As such, if an individual is intoxicated, he or she should be managed symptomatically with judicious use of benzodiazepines and continuous monitoring of heart rate, blood pressure, respiratory rate, and oxygen saturation.^2,10 Kratom intoxication can precipitate psychotic episodes similar to those caused by opiate intoxication, so monitoring for agitation or psychotic behaviors is also indicated.^9,10

The medical management of an acute kratom overdose (typically requiring ingestion of > 15 g of crushed leaves) begins with addressing airway blockage, breathing, and circulation along with continuous vital sign monitoring and laboratory testing, including point-of-care glucose, complete blood count, electrolytes, lactate, venous blood gas, and measurable drug levels (ethanol, acetaminophen, tricyclic antidepressants, etc).¹¹ If it is determined that kratom was the intoxicant, the greatest concern of death is similar to that of opioid overdose: respiratory depression. Although there are no large-scale human studies demonstrating efficacy, multiple authors suggest the use of naloxone in kratom-related hypoventilation.^9,10

The development of dependence on kratom and its subsequent withdrawal phenomena are thought to be similar to that of opioids, in light of its strong μ agonism.^2,5,9,10 Indeed, kratom has a long history of being used by opioid-dependent patients as an attempt to quit drug abuse or stave off debilitating withdrawal symptoms when they are unable to acquire their substance of choice.^2,5-10 As such, withdrawal and the treatment thereof will also mimic that of opioid detoxification.

The kratom-dependent individual will often present with rhinorrhea, lacrimation, dry mouth, hostility, aggression, and emotional lability similar to the case study described earlier.^2,9,10 Kratom withdrawal, much like intoxication, also may precipitate or worsen psychotic symptoms, and monitoring is necessary throughout the detoxification process.^2,5,10 Withdrawal management should proceed along ambulatory clinic or hospital opioid withdrawal protocols that include step-down administration of opioids or with nonopioid medications for symptomatic relief, including muscle relaxants, α-2 agonists, and antidiarrheal agents.^5,9,10

Kratom Toxicity

A review of the available medical literature has demonstrated a number of toxic effects with kratom abuse, either as the sole agent or in concert with prescribed medications, recreational coingestants, or as a result of manufacturer’s adulteration with other chemicals or drugs. Of particular interest to HCPs are manic or psychotic episode precipitation, seizure, hypothyroidism, intrahepatic cholestatic injury, and even sudden cardiac death.^2,3,5-10 In addition to the basic history, physical, and laboratory examination, the workup of patients identified as kratom users should include the following:

• Fastidious medication reconciliation with drug-interaction check;
• Exhaustive substance abuse history;
• Identification of the brand name and source of kratom purchased, to determine whether there are advertised coingestants or reports of adulteration;
• Electrocardiogram;
• Thyroid function testing;
• Hepatic function testing; and
• Comprehensive neurologic and mental status exams.

In chronic users of kratom, a number of effects have been seen whose etiologies have not yet been determined. These effects include depression, anxiety, tremulousness, weight loss, and permanent psychosis.^3-7 Additionally, a 2008 study by Kittirattanapaiboon and colleagues correlated drug use by those with concurrent mental health disorders (in particular, kratom, which was used in 59% of the ≥ 14,000 individuals included in the study sample) with statistically significant higher suicide risk.¹²

Detection

Because kratom is a relatively new compound in the U.S., medical and forensic laboratories are only now implementing kratom detection protocols. Many laboratories now use high-performance liquid chromatography to analyze for mitragynine, 7-hydroxymitragynine, and 2 metabolites of mitragynine in urine.⁷ Le and colleagues were able to detect mitragynine in the urine in levels as low as 1 ng/mL, which is clinically useful as mitragynine has a half-life determined in animal studies to be 3.85 hours.¹³ Similar detection limits for mitragynine and 7-hydroxymitragynine are used only at Naval Medical Center Portsmouth in Virginia; however, kratom was not detected in the study patient’s urine because a urine test was not done until hospital day 5.

Conclusion

When gently confronted about the kratom found in his car, the case study patient admitted that he had purchased kratom online after he was “cut off” from prescription opioids for his pain. He admitted that although it was beneficial for his pain, he did notice worsening in his aggression toward his spouse and coworkers. This progressed to an exacerbation of his psychotic symptoms of hallucinations and persecutory delusions. These symptoms remained well hidden in this highly intelligent individual—but were present for years prior to his presentation at the hospital. The patient was discharged from the inpatient psychiatric unit on hospital day 16 with a diagnosis of schizoaffective disorder, depressive type in addition to opioid use disorder. The patient agreed to seek a pain management specialist and discontinue kratom use.

Kratom is an emerging drug of abuse in the Western World. Although significant research is being conducted on its possible medical uses, little is known about kratom beyond the “trip reports” of kratom users posted online. Because of its technically legal status in the U.S. and multiple other Western countries, kratom is easily accessible and is difficult to detect. Health care providers need to be aware of kratom, and during their evaluations, question patients about kratom and other legal highs.

Patients with head and neck squamous cell carcinoma typically present with dysphagia, odynophagia, and weight loss. Treatment of the disease with surgery or concurrent chemoradiation often results in local inflammation and limits further oral intake. Percutaneous endoscopic gastrostomy has been a common and effective means of nutritional support in these patients.

Click on the PDF icon at the top of this introduction to read the full article.

Patients with head and neck squamous cell carcinoma typically present with dysphagia, odynophagia, and weight loss. Treatment of the disease with surgery or concurrent chemoradiation often results in local inflammation and limits further oral intake. Percutaneous endoscopic gastrostomy has been a common and effective means of nutritional support in these patients.

Click on the PDF icon at the top of this introduction to read the full article.

Patients with head and neck squamous cell carcinoma typically present with dysphagia, odynophagia, and weight loss. Treatment of the disease with surgery or concurrent chemoradiation often results in local inflammation and limits further oral intake. Percutaneous endoscopic gastrostomy has been a common and effective means of nutritional support in these patients.

Click on the PDF icon at the top of this introduction to read the full article.

Acute myeloid leukemia (AML) is characterized by clonal proliferation of myeloid precursors with a reduced capacity to differentiate into mature cellular components.¹ Acute promyeloctic leukemia (APL; previously called AML-M3), a subtype of AML, is further characterized by a balanced translocation t(15;17) (q24.1;q21.1). It is an interesting model in cancer research because it responds to the differentiation and apoptosis induction therapy using arsenic trioxide (ATO) and all-trans retinoic acid (ATRA).²

Click on the PDF icon at the top of this introduction to read the full article.

Acute myeloid leukemia (AML) is characterized by clonal proliferation of myeloid precursors with a reduced capacity to differentiate into mature cellular components.¹ Acute promyeloctic leukemia (APL; previously called AML-M3), a subtype of AML, is further characterized by a balanced translocation t(15;17) (q24.1;q21.1). It is an interesting model in cancer research because it responds to the differentiation and apoptosis induction therapy using arsenic trioxide (ATO) and all-trans retinoic acid (ATRA).²

Click on the PDF icon at the top of this introduction to read the full article.

Acute myeloid leukemia (AML) is characterized by clonal proliferation of myeloid precursors with a reduced capacity to differentiate into mature cellular components.¹ Acute promyeloctic leukemia (APL; previously called AML-M3), a subtype of AML, is further characterized by a balanced translocation t(15;17) (q24.1;q21.1). It is an interesting model in cancer research because it responds to the differentiation and apoptosis induction therapy using arsenic trioxide (ATO) and all-trans retinoic acid (ATRA).²

Click on the PDF icon at the top of this introduction to read the full article.

A fracture occurring after anterior cruciate ligament (ACL) reconstruction is rare, and rarer still when it involves the harvest site of a bone—patellar tendon—bone (BPTB) autograft. The vast majority of fractures described in the literature are patellar, with the weak point along the patellar bone cut. A number of fractures generally also occur through the bone tunnels in both hamstring and BPTB grafts. However, only 2 cases of tibial tubercle fracture after BPTB graft have been published, and we expound on them in this case report.^1,2 The patient provided written informed consent for print and electronic publication of this case report.

Case Report

Eight years after undergoing successful left ACL reconstruction with ipsilateral BPTB graft, a 45-year-old man developed a graft rupture and demonstrated recurrent instability. He requested revision reconstruction, again with a BPTB construct. In the operating room, he was prepared and draped in the usual sterile fashion, and left ACL reconstruction was performed with right-knee central-third BPTB graft.

During surgery, the left knee was arthroscopically examined, and residual ACL graft from the initial reconstruction was removed. Notchplasty was performed, and the residual femoral interference screw was removed from the 12:30 position. A transtibial approach was used, with a 10-mm reamer brought through the proximal tibia, the posterior tibial ACL footprint, and the 2:00 distal femoral position, with 30 mm of femoral condyle drilled, leaving 1 mm of posterior femoral cortex.

After the right leg was exsanguinated, a central-third patellar tendon graft was harvested through a longitudinal incision with a 22-mm × 10-mm patellar plug, a 10-mm patellar graft, and a 22-mm × 11-mm tibial plug. The graft was prepared, the left tibia was overreamed, and the graft was passed. The graft was fixed with a 7-mm × 23-mm biointerference screw in the femur, trialed, and fixed with an 8-mm × 23-mm interference screw in the tibia. Excess bone graft was packed in the patellar defect in the right knee. The rent in the patellar tendon was closed. The rest of the incision was closed, and the patient was placed in an immobilizer and a cold therapy device (Polar Care; Breg, Inc).

At 2-week follow-up, the patient reported having slipped on ice and flexed the right knee, causing a pop, pain, and limitation in range of motion (ROM; 0°-70°).

Discussion

Cases of tibial tubercle fracture after BPTB autograft harvest are extremely rare in the published literature. PubMed and Cochrane Review searches revealed only 2—1 in the ipsilateral knee as ACL fixation¹ and 1 in the contralateral knee.² The middle third of the patellar tendon has been used for ACL reconstruction for more than 50 years, which supports the extreme rarity of this complication.³ Tibial tubercle fractures are so rare that they are not even mentioned in reviews of ACL complications.⁴ These fractures are universally treated with ORIF.^1,2

Far more common but still rare, fracture-type complications involve the extensor mechanism and the tibial plateau. Patellar fractures have been documented as occurring in 0.2% to 2.3% of cases.^5-7 One paper reported a fracture in 1.3% of cases at a mean of 57 days, with roughly half caused by trauma and the other half having atraumatic causes.⁸ Lee and colleagues⁹ found a 0.2% complication rate for all BPTB grafts in 1725 consecutive patients. Although some patients were treated nonoperatively, others underwent operative fixation. Time to clinical and radiographic healing was 7 and 10 weeks, respectively.

Tibial plateau fracture after BPTB harvest is a rare complication, with 11 cases reported in the literature.¹⁰ In 4 of those cases, the proposed mechanism of fracture was a stress riser resulting from the synergistic weakness of the tibial harvest site combined with the tibial tunnel reducing proximal tibial bone strength.^11-14 The mechanism of injury varied from traumatic to insufficiency fracture, with fixation varying with fracture displacement.

Tibial tubercle fracture after BPTB harvest is extremely rare, with the present case being only the third published in the literature. Like most reported post-ACL reconstruction extensor mechanism disruptions, our case resulted from a traumatic event at an interval after surgery. All other tibial tubercle fracture post-ACL reconstruction disruptions occurred within 2 weeks after surgery.^1,2 Sudden tension on the extensor mechanism secondary to hyperflexion caused a fracture through a weakened tibial tubercle with avulsion of the remaining tendon in 2 of the 3 cases, with the third being a lower stress popping noise that occurred during a pivot to stand.¹

The residual defect after tibial bone block harvest could represent a weakening of the tubercle by loss of structural bone and by development of stress risers. The previous reports of tibial tubercle fracture after BPTB harvest documented a similar methodology: Use a bone saw and osteotomes to harvest a trapezoidal tibial bone plug 10 mm to 11 mm wide and 22 cm to 35 cm long. As previously documented, we suggest taking care with saw cuts and osteotomes so as not to weaken the proximal tibia or distal patella more than is necessary.^1,2 Before surgery, patients should be warned about the possibility of extensor mechanism injuries with use of BPTB grafts.

Conclusion

Tibial tubercle fracture after BPTB harvest for ACL reconstruction is an extremely rare complication. Treatment is ORIF of the tubercle fragment, with a delay in ACL rehabilitation in cases involving the ipsilateral knee.

Am J Orthop. 2016;45(7):E469-E471. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

A fracture occurring after anterior cruciate ligament (ACL) reconstruction is rare, and rarer still when it involves the harvest site of a bone—patellar tendon—bone (BPTB) autograft. The vast majority of fractures described in the literature are patellar, with the weak point along the patellar bone cut. A number of fractures generally also occur through the bone tunnels in both hamstring and BPTB grafts. However, only 2 cases of tibial tubercle fracture after BPTB graft have been published, and we expound on them in this case report.^1,2 The patient provided written informed consent for print and electronic publication of this case report.

Case Report

Eight years after undergoing successful left ACL reconstruction with ipsilateral BPTB graft, a 45-year-old man developed a graft rupture and demonstrated recurrent instability. He requested revision reconstruction, again with a BPTB construct. In the operating room, he was prepared and draped in the usual sterile fashion, and left ACL reconstruction was performed with right-knee central-third BPTB graft.

During surgery, the left knee was arthroscopically examined, and residual ACL graft from the initial reconstruction was removed. Notchplasty was performed, and the residual femoral interference screw was removed from the 12:30 position. A transtibial approach was used, with a 10-mm reamer brought through the proximal tibia, the posterior tibial ACL footprint, and the 2:00 distal femoral position, with 30 mm of femoral condyle drilled, leaving 1 mm of posterior femoral cortex.

After the right leg was exsanguinated, a central-third patellar tendon graft was harvested through a longitudinal incision with a 22-mm × 10-mm patellar plug, a 10-mm patellar graft, and a 22-mm × 11-mm tibial plug. The graft was prepared, the left tibia was overreamed, and the graft was passed. The graft was fixed with a 7-mm × 23-mm biointerference screw in the femur, trialed, and fixed with an 8-mm × 23-mm interference screw in the tibia. Excess bone graft was packed in the patellar defect in the right knee. The rent in the patellar tendon was closed. The rest of the incision was closed, and the patient was placed in an immobilizer and a cold therapy device (Polar Care; Breg, Inc).

At 2-week follow-up, the patient reported having slipped on ice and flexed the right knee, causing a pop, pain, and limitation in range of motion (ROM; 0°-70°).

Discussion

Cases of tibial tubercle fracture after BPTB autograft harvest are extremely rare in the published literature. PubMed and Cochrane Review searches revealed only 2—1 in the ipsilateral knee as ACL fixation¹ and 1 in the contralateral knee.² The middle third of the patellar tendon has been used for ACL reconstruction for more than 50 years, which supports the extreme rarity of this complication.³ Tibial tubercle fractures are so rare that they are not even mentioned in reviews of ACL complications.⁴ These fractures are universally treated with ORIF.^1,2

Far more common but still rare, fracture-type complications involve the extensor mechanism and the tibial plateau. Patellar fractures have been documented as occurring in 0.2% to 2.3% of cases.^5-7 One paper reported a fracture in 1.3% of cases at a mean of 57 days, with roughly half caused by trauma and the other half having atraumatic causes.⁸ Lee and colleagues⁹ found a 0.2% complication rate for all BPTB grafts in 1725 consecutive patients. Although some patients were treated nonoperatively, others underwent operative fixation. Time to clinical and radiographic healing was 7 and 10 weeks, respectively.

Tibial plateau fracture after BPTB harvest is a rare complication, with 11 cases reported in the literature.¹⁰ In 4 of those cases, the proposed mechanism of fracture was a stress riser resulting from the synergistic weakness of the tibial harvest site combined with the tibial tunnel reducing proximal tibial bone strength.^11-14 The mechanism of injury varied from traumatic to insufficiency fracture, with fixation varying with fracture displacement.

Tibial tubercle fracture after BPTB harvest is extremely rare, with the present case being only the third published in the literature. Like most reported post-ACL reconstruction extensor mechanism disruptions, our case resulted from a traumatic event at an interval after surgery. All other tibial tubercle fracture post-ACL reconstruction disruptions occurred within 2 weeks after surgery.^1,2 Sudden tension on the extensor mechanism secondary to hyperflexion caused a fracture through a weakened tibial tubercle with avulsion of the remaining tendon in 2 of the 3 cases, with the third being a lower stress popping noise that occurred during a pivot to stand.¹

The residual defect after tibial bone block harvest could represent a weakening of the tubercle by loss of structural bone and by development of stress risers. The previous reports of tibial tubercle fracture after BPTB harvest documented a similar methodology: Use a bone saw and osteotomes to harvest a trapezoidal tibial bone plug 10 mm to 11 mm wide and 22 cm to 35 cm long. As previously documented, we suggest taking care with saw cuts and osteotomes so as not to weaken the proximal tibia or distal patella more than is necessary.^1,2 Before surgery, patients should be warned about the possibility of extensor mechanism injuries with use of BPTB grafts.

Conclusion

Tibial tubercle fracture after BPTB harvest for ACL reconstruction is an extremely rare complication. Treatment is ORIF of the tubercle fragment, with a delay in ACL rehabilitation in cases involving the ipsilateral knee.

Am J Orthop. 2016;45(7):E469-E471. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

A fracture occurring after anterior cruciate ligament (ACL) reconstruction is rare, and rarer still when it involves the harvest site of a bone—patellar tendon—bone (BPTB) autograft. The vast majority of fractures described in the literature are patellar, with the weak point along the patellar bone cut. A number of fractures generally also occur through the bone tunnels in both hamstring and BPTB grafts. However, only 2 cases of tibial tubercle fracture after BPTB graft have been published, and we expound on them in this case report.^1,2 The patient provided written informed consent for print and electronic publication of this case report.

Case Report

Eight years after undergoing successful left ACL reconstruction with ipsilateral BPTB graft, a 45-year-old man developed a graft rupture and demonstrated recurrent instability. He requested revision reconstruction, again with a BPTB construct. In the operating room, he was prepared and draped in the usual sterile fashion, and left ACL reconstruction was performed with right-knee central-third BPTB graft.

During surgery, the left knee was arthroscopically examined, and residual ACL graft from the initial reconstruction was removed. Notchplasty was performed, and the residual femoral interference screw was removed from the 12:30 position. A transtibial approach was used, with a 10-mm reamer brought through the proximal tibia, the posterior tibial ACL footprint, and the 2:00 distal femoral position, with 30 mm of femoral condyle drilled, leaving 1 mm of posterior femoral cortex.

After the right leg was exsanguinated, a central-third patellar tendon graft was harvested through a longitudinal incision with a 22-mm × 10-mm patellar plug, a 10-mm patellar graft, and a 22-mm × 11-mm tibial plug. The graft was prepared, the left tibia was overreamed, and the graft was passed. The graft was fixed with a 7-mm × 23-mm biointerference screw in the femur, trialed, and fixed with an 8-mm × 23-mm interference screw in the tibia. Excess bone graft was packed in the patellar defect in the right knee. The rent in the patellar tendon was closed. The rest of the incision was closed, and the patient was placed in an immobilizer and a cold therapy device (Polar Care; Breg, Inc).

At 2-week follow-up, the patient reported having slipped on ice and flexed the right knee, causing a pop, pain, and limitation in range of motion (ROM; 0°-70°).

Discussion

Cases of tibial tubercle fracture after BPTB autograft harvest are extremely rare in the published literature. PubMed and Cochrane Review searches revealed only 2—1 in the ipsilateral knee as ACL fixation¹ and 1 in the contralateral knee.² The middle third of the patellar tendon has been used for ACL reconstruction for more than 50 years, which supports the extreme rarity of this complication.³ Tibial tubercle fractures are so rare that they are not even mentioned in reviews of ACL complications.⁴ These fractures are universally treated with ORIF.^1,2

Far more common but still rare, fracture-type complications involve the extensor mechanism and the tibial plateau. Patellar fractures have been documented as occurring in 0.2% to 2.3% of cases.^5-7 One paper reported a fracture in 1.3% of cases at a mean of 57 days, with roughly half caused by trauma and the other half having atraumatic causes.⁸ Lee and colleagues⁹ found a 0.2% complication rate for all BPTB grafts in 1725 consecutive patients. Although some patients were treated nonoperatively, others underwent operative fixation. Time to clinical and radiographic healing was 7 and 10 weeks, respectively.

Tibial plateau fracture after BPTB harvest is a rare complication, with 11 cases reported in the literature.¹⁰ In 4 of those cases, the proposed mechanism of fracture was a stress riser resulting from the synergistic weakness of the tibial harvest site combined with the tibial tunnel reducing proximal tibial bone strength.^11-14 The mechanism of injury varied from traumatic to insufficiency fracture, with fixation varying with fracture displacement.

Tibial tubercle fracture after BPTB harvest is extremely rare, with the present case being only the third published in the literature. Like most reported post-ACL reconstruction extensor mechanism disruptions, our case resulted from a traumatic event at an interval after surgery. All other tibial tubercle fracture post-ACL reconstruction disruptions occurred within 2 weeks after surgery.^1,2 Sudden tension on the extensor mechanism secondary to hyperflexion caused a fracture through a weakened tibial tubercle with avulsion of the remaining tendon in 2 of the 3 cases, with the third being a lower stress popping noise that occurred during a pivot to stand.¹

The residual defect after tibial bone block harvest could represent a weakening of the tubercle by loss of structural bone and by development of stress risers. The previous reports of tibial tubercle fracture after BPTB harvest documented a similar methodology: Use a bone saw and osteotomes to harvest a trapezoidal tibial bone plug 10 mm to 11 mm wide and 22 cm to 35 cm long. As previously documented, we suggest taking care with saw cuts and osteotomes so as not to weaken the proximal tibia or distal patella more than is necessary.^1,2 Before surgery, patients should be warned about the possibility of extensor mechanism injuries with use of BPTB grafts.

Conclusion

Tibial tubercle fracture after BPTB harvest for ACL reconstruction is an extremely rare complication. Treatment is ORIF of the tubercle fragment, with a delay in ACL rehabilitation in cases involving the ipsilateral knee.

Am J Orthop. 2016;45(7):E469-E471. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

Primary chest-wall leiomyosarcoma (LMS) is an uncommon, malignant, soft-tissue tumor that most often affects the extremities. Malignant LMS originates from mesenchymal cells with smooth muscle differentiation. It is rare in adults, forming only 7% of all soft-tissue sarcomas (STS), but it is the most common STS. In adults, this type of tumor is usually found in the retroperitoneum and extremities.¹ Chest-wall LMS is rare and most often occurs in men aged 50-70 years.² When LMS is associated with rib destruction, it may mimic a primary bone tumor or metastasis. We present here the case of histologically proven chest-wall sarcoma with associated rib destruction that was initially mistaken on imaging for either a metastasis or primary bone tumor.

Case presentation and summary
A 69-year-old man presented to the emergency department complaining of pain over the right side of the chest. The pain, which was pleuritic in nature, had worsened over the previous 6 months and was severe at presentation. The patient had no fever, shortness of breath, or loss of weight. He had no history of chest trauma or chest wall radiation, and nothing noteworthy was discovered in his medical history. Subsequent test results for hemoglobin, white blood cell count, lymphocyte count, and cardiac enzymes were normal.

A frontal chest radiograph showed an osteolytic destructive lesion involving the posterior right 6th rib (Figure 1). A contrast-enhanced computedtomography (CE-CT) scan of the chest showed a heterogeneously enhancing, ovoid, soft-tissue mass of 5.6 x 3.6 cm (2.2 x 1.2 in) centered on the postero- lateral right 6th rib, with associated rib erosion. There was another 2.0-cm (0.8-in) subpleural nodule in the left upper lobe (Figure 2).

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Primary chest-wall leiomyosarcoma (LMS) is an uncommon, malignant, soft-tissue tumor that most often affects the extremities. Malignant LMS originates from mesenchymal cells with smooth muscle differentiation. It is rare in adults, forming only 7% of all soft-tissue sarcomas (STS), but it is the most common STS. In adults, this type of tumor is usually found in the retroperitoneum and extremities.¹ Chest-wall LMS is rare and most often occurs in men aged 50-70 years.² When LMS is associated with rib destruction, it may mimic a primary bone tumor or metastasis. We present here the case of histologically proven chest-wall sarcoma with associated rib destruction that was initially mistaken on imaging for either a metastasis or primary bone tumor.

Case presentation and summary
A 69-year-old man presented to the emergency department complaining of pain over the right side of the chest. The pain, which was pleuritic in nature, had worsened over the previous 6 months and was severe at presentation. The patient had no fever, shortness of breath, or loss of weight. He had no history of chest trauma or chest wall radiation, and nothing noteworthy was discovered in his medical history. Subsequent test results for hemoglobin, white blood cell count, lymphocyte count, and cardiac enzymes were normal.

A frontal chest radiograph showed an osteolytic destructive lesion involving the posterior right 6th rib (Figure 1). A contrast-enhanced computedtomography (CE-CT) scan of the chest showed a heterogeneously enhancing, ovoid, soft-tissue mass of 5.6 x 3.6 cm (2.2 x 1.2 in) centered on the postero- lateral right 6th rib, with associated rib erosion. There was another 2.0-cm (0.8-in) subpleural nodule in the left upper lobe (Figure 2).

Click on the PDF icon below to read the full article.
 

Primary chest-wall leiomyosarcoma (LMS) is an uncommon, malignant, soft-tissue tumor that most often affects the extremities. Malignant LMS originates from mesenchymal cells with smooth muscle differentiation. It is rare in adults, forming only 7% of all soft-tissue sarcomas (STS), but it is the most common STS. In adults, this type of tumor is usually found in the retroperitoneum and extremities.¹ Chest-wall LMS is rare and most often occurs in men aged 50-70 years.² When LMS is associated with rib destruction, it may mimic a primary bone tumor or metastasis. We present here the case of histologically proven chest-wall sarcoma with associated rib destruction that was initially mistaken on imaging for either a metastasis or primary bone tumor.

Case presentation and summary
A 69-year-old man presented to the emergency department complaining of pain over the right side of the chest. The pain, which was pleuritic in nature, had worsened over the previous 6 months and was severe at presentation. The patient had no fever, shortness of breath, or loss of weight. He had no history of chest trauma or chest wall radiation, and nothing noteworthy was discovered in his medical history. Subsequent test results for hemoglobin, white blood cell count, lymphocyte count, and cardiac enzymes were normal.

A frontal chest radiograph showed an osteolytic destructive lesion involving the posterior right 6th rib (Figure 1). A contrast-enhanced computedtomography (CE-CT) scan of the chest showed a heterogeneously enhancing, ovoid, soft-tissue mass of 5.6 x 3.6 cm (2.2 x 1.2 in) centered on the postero- lateral right 6th rib, with associated rib erosion. There was another 2.0-cm (0.8-in) subpleural nodule in the left upper lobe (Figure 2).

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Multiple myeloma accounts for about 1% of all cancers and for 10% of hematologic malignancies in the United States. This report describes the cases of 2 patients with multiple myeloma who developed CNS involvement after autologous stem cell transplant in the context of extramedullary disease.

Click on the PDF icon at the top of this introduction to read the full article.

Multiple myeloma accounts for about 1% of all cancers and for 10% of hematologic malignancies in the United States. This report describes the cases of 2 patients with multiple myeloma who developed CNS involvement after autologous stem cell transplant in the context of extramedullary disease.

Click on the PDF icon at the top of this introduction to read the full article.

Multiple myeloma accounts for about 1% of all cancers and for 10% of hematologic malignancies in the United States. This report describes the cases of 2 patients with multiple myeloma who developed CNS involvement after autologous stem cell transplant in the context of extramedullary disease.

Click on the PDF icon at the top of this introduction to read the full article.

Strangulated hernias are a medical emergency that can lead to small bowel obstruction (SBO), bowel necrosis, and death. Practitioners look for signs of strangulation on examination to guide the urgency of management. If the hernia is soft and reducible without overlying skin changes or signs of obstruction, patients may be monitored for years.¹ However, there is increasing evidence that even asymptomatic hernias should be repaired rather than monitored to avoid the need for emergent surgical intervention.¹

We present a case of a patient with a chronic umbilical hernia who experienced acute worsening of pain at the site of her hernia but with few additional objective signs of strangulation. Prior to this presentation, she had been recently evaluated at our ED for the “same” pain, which included a computed tomography (CT) scan that was negative for an acute surgical emergency. The patient’s second ED visit led to a diagnostic dilemma: Practitioners are encouraged to avoid “unnecessary” radiation—especially in cases of chronic pain—and to rely on history, physical examination findings, and prior recent imaging studies, as appropriate. In this case, repeat imaging ultimately revealed a surgical emergency with an unusual underlying pathology likely related to the chronicity of the patient’s hernia, and explained her repeat presentation to the ED.

Case

A 45-year-old obese woman (body mass index, 46 kg/m²) with a medical history of an umbilical hernia, tubal ligation, and chronic pelvic pain presented a second time to our ED with pain at the site of her hernia, which she stated began 5 hours prior to presentation. Although the pain was associated with nausea and vomiting, the patient said her bowel movements were normal. She first noticed the hernia more than 5 years ago, but experienced her first episode of acute pain related to the hernia with associated nausea and vomiting 3 weeks earlier, which prompted her initial presentation. During this first ED visit, a CT scan of the abdomen/pelvis was obtained as part of her evaluation and was significant for umbilical herniation of bowel without evidence of strangulation. Bedside reduction was successful, and the patient was discharged home and informed of the need to follow-up with a surgeon for an elective repair. She returned to the ED prior to her scheduled operation due to recurrent pain of similar character, but increased severity.

On physical examination, the patient was hemodynamically stable and afebrile. Her vital signs were: heart rate, 84 beats/min; blood pressure, 113/68 mm Hg; and respiratory rate, 20 breaths/min. Oxygen saturation was 100% on room air.

The abdomen was soft with tenderness to palpation over a 13-cm x 8-cm soft hernia to the left of the umbilicus without overlying skin changes. The patient’s pain was controlled with 1 mg of intravenous hydromorphone, after which bedside reduction was attempted. During reduction attempts, there was palpable bowel within the hernia sac, and a periumbilical defect was appreciated. Although the defect in the abdominal wall was estimated to be large enough to allow reduction, the hernia reduced only partially. Because imaging studies from the patient’s previous ED visit showed no visualized strangulation or obstruction, we deliberated over the need for a repeat CT scan prior to further attempts at reduction by general surgery services. Ultimately, we ordered a repeat CT scan, which was significant for a “mechanical small bowel obstruction with focal transition zone located within the hernia sac itself, not the neck of the umbilical hernia.”

Discussion

Abdominal wall hernias are a common pathology, with more than 700,000 repairs performed every year in the United States.² Patients most commonly present to the ED with abdominal pain, nausea, and vomiting. Less frequently, they present with obstruction, incarceration, strangulation, or rupture.³ Umbilical hernias are caused by increasing intra-abdominal pressure. As the incidence of obesity in the United States has continued to increase, the proportion of hernias that are umbilical or periumbilical has also increased.^2,4 Unfortunately, even though umbilical hernias are becoming more common, they are often given less attention than other types of hernias.⁵ The practice of solely monitoring umbilical hernias can lead to serious outcomes. For example, in a case presentation from Spain, a morbidly obese patient died due to a strangulated umbilical hernia that had progressed over a 15-year period without treatment.⁶

Compared to elective surgery, emergent operative repair is associated with a higher rate of postoperative complications,¹ and a growing body of evidence suggests that patients with symptomatic hernias should be encouraged to undergo operative repair.^1,6However, the timing and urgency of this repair is often difficult to determine when strangulation is not the obvious diagnosis. Recent literature has shown that, even in nonincarcerated hernias, conservative management is a significant contributing factor in the delay of treatment, ultimately leading to complications, including SBO.¹ Our patient had her umbilical hernia for over 5 years, during which time she had a tubal ligation and chronic pelvic pain, both of which could have led to intra-abdominal inflammation and the formation of adhesions. In her case, these adhesions led to an SBO, necessitating urgent surgery. This case supports the need to strongly consider ordering imaging studies to evaluate hernias when they cannot easily be reduced to avoid potential complications from attempting to reduce obstructed bowel, and to help determine surgical urgency, even when examination is otherwise benign. Additionally, while our patient had a good clinical outcome, the urgency of her procedure may further support surgical repair over conservative management of asymptomatic hernias.

Conclusion

Umbilical hernias have become more common with increasing rates of obesity. These hernias have the potential to lead to serious medical emergencies, and the common practice of monitoring chronic hernias may increase the patient’s risk of serious complications. Emergency physicians use the physical examination to help determine the urgency of repair; however, imaging should be considered to assess hernias that cannot easily be reduced to evaluate for obstructed, strangulated, or incarcerated bowel and to help determine the urgency of surgical repair.

Strangulated hernias are a medical emergency that can lead to small bowel obstruction (SBO), bowel necrosis, and death. Practitioners look for signs of strangulation on examination to guide the urgency of management. If the hernia is soft and reducible without overlying skin changes or signs of obstruction, patients may be monitored for years.¹ However, there is increasing evidence that even asymptomatic hernias should be repaired rather than monitored to avoid the need for emergent surgical intervention.¹

We present a case of a patient with a chronic umbilical hernia who experienced acute worsening of pain at the site of her hernia but with few additional objective signs of strangulation. Prior to this presentation, she had been recently evaluated at our ED for the “same” pain, which included a computed tomography (CT) scan that was negative for an acute surgical emergency. The patient’s second ED visit led to a diagnostic dilemma: Practitioners are encouraged to avoid “unnecessary” radiation—especially in cases of chronic pain—and to rely on history, physical examination findings, and prior recent imaging studies, as appropriate. In this case, repeat imaging ultimately revealed a surgical emergency with an unusual underlying pathology likely related to the chronicity of the patient’s hernia, and explained her repeat presentation to the ED.

Case

A 45-year-old obese woman (body mass index, 46 kg/m²) with a medical history of an umbilical hernia, tubal ligation, and chronic pelvic pain presented a second time to our ED with pain at the site of her hernia, which she stated began 5 hours prior to presentation. Although the pain was associated with nausea and vomiting, the patient said her bowel movements were normal. She first noticed the hernia more than 5 years ago, but experienced her first episode of acute pain related to the hernia with associated nausea and vomiting 3 weeks earlier, which prompted her initial presentation. During this first ED visit, a CT scan of the abdomen/pelvis was obtained as part of her evaluation and was significant for umbilical herniation of bowel without evidence of strangulation. Bedside reduction was successful, and the patient was discharged home and informed of the need to follow-up with a surgeon for an elective repair. She returned to the ED prior to her scheduled operation due to recurrent pain of similar character, but increased severity.

On physical examination, the patient was hemodynamically stable and afebrile. Her vital signs were: heart rate, 84 beats/min; blood pressure, 113/68 mm Hg; and respiratory rate, 20 breaths/min. Oxygen saturation was 100% on room air.

The abdomen was soft with tenderness to palpation over a 13-cm x 8-cm soft hernia to the left of the umbilicus without overlying skin changes. The patient’s pain was controlled with 1 mg of intravenous hydromorphone, after which bedside reduction was attempted. During reduction attempts, there was palpable bowel within the hernia sac, and a periumbilical defect was appreciated. Although the defect in the abdominal wall was estimated to be large enough to allow reduction, the hernia reduced only partially. Because imaging studies from the patient’s previous ED visit showed no visualized strangulation or obstruction, we deliberated over the need for a repeat CT scan prior to further attempts at reduction by general surgery services. Ultimately, we ordered a repeat CT scan, which was significant for a “mechanical small bowel obstruction with focal transition zone located within the hernia sac itself, not the neck of the umbilical hernia.”

Discussion

Abdominal wall hernias are a common pathology, with more than 700,000 repairs performed every year in the United States.² Patients most commonly present to the ED with abdominal pain, nausea, and vomiting. Less frequently, they present with obstruction, incarceration, strangulation, or rupture.³ Umbilical hernias are caused by increasing intra-abdominal pressure. As the incidence of obesity in the United States has continued to increase, the proportion of hernias that are umbilical or periumbilical has also increased.^2,4 Unfortunately, even though umbilical hernias are becoming more common, they are often given less attention than other types of hernias.⁵ The practice of solely monitoring umbilical hernias can lead to serious outcomes. For example, in a case presentation from Spain, a morbidly obese patient died due to a strangulated umbilical hernia that had progressed over a 15-year period without treatment.⁶

Compared to elective surgery, emergent operative repair is associated with a higher rate of postoperative complications,¹ and a growing body of evidence suggests that patients with symptomatic hernias should be encouraged to undergo operative repair.^1,6However, the timing and urgency of this repair is often difficult to determine when strangulation is not the obvious diagnosis. Recent literature has shown that, even in nonincarcerated hernias, conservative management is a significant contributing factor in the delay of treatment, ultimately leading to complications, including SBO.¹ Our patient had her umbilical hernia for over 5 years, during which time she had a tubal ligation and chronic pelvic pain, both of which could have led to intra-abdominal inflammation and the formation of adhesions. In her case, these adhesions led to an SBO, necessitating urgent surgery. This case supports the need to strongly consider ordering imaging studies to evaluate hernias when they cannot easily be reduced to avoid potential complications from attempting to reduce obstructed bowel, and to help determine surgical urgency, even when examination is otherwise benign. Additionally, while our patient had a good clinical outcome, the urgency of her procedure may further support surgical repair over conservative management of asymptomatic hernias.

Conclusion

Umbilical hernias have become more common with increasing rates of obesity. These hernias have the potential to lead to serious medical emergencies, and the common practice of monitoring chronic hernias may increase the patient’s risk of serious complications. Emergency physicians use the physical examination to help determine the urgency of repair; however, imaging should be considered to assess hernias that cannot easily be reduced to evaluate for obstructed, strangulated, or incarcerated bowel and to help determine the urgency of surgical repair.

Strangulated hernias are a medical emergency that can lead to small bowel obstruction (SBO), bowel necrosis, and death. Practitioners look for signs of strangulation on examination to guide the urgency of management. If the hernia is soft and reducible without overlying skin changes or signs of obstruction, patients may be monitored for years.¹ However, there is increasing evidence that even asymptomatic hernias should be repaired rather than monitored to avoid the need for emergent surgical intervention.¹

We present a case of a patient with a chronic umbilical hernia who experienced acute worsening of pain at the site of her hernia but with few additional objective signs of strangulation. Prior to this presentation, she had been recently evaluated at our ED for the “same” pain, which included a computed tomography (CT) scan that was negative for an acute surgical emergency. The patient’s second ED visit led to a diagnostic dilemma: Practitioners are encouraged to avoid “unnecessary” radiation—especially in cases of chronic pain—and to rely on history, physical examination findings, and prior recent imaging studies, as appropriate. In this case, repeat imaging ultimately revealed a surgical emergency with an unusual underlying pathology likely related to the chronicity of the patient’s hernia, and explained her repeat presentation to the ED.

Case

A 45-year-old obese woman (body mass index, 46 kg/m²) with a medical history of an umbilical hernia, tubal ligation, and chronic pelvic pain presented a second time to our ED with pain at the site of her hernia, which she stated began 5 hours prior to presentation. Although the pain was associated with nausea and vomiting, the patient said her bowel movements were normal. She first noticed the hernia more than 5 years ago, but experienced her first episode of acute pain related to the hernia with associated nausea and vomiting 3 weeks earlier, which prompted her initial presentation. During this first ED visit, a CT scan of the abdomen/pelvis was obtained as part of her evaluation and was significant for umbilical herniation of bowel without evidence of strangulation. Bedside reduction was successful, and the patient was discharged home and informed of the need to follow-up with a surgeon for an elective repair. She returned to the ED prior to her scheduled operation due to recurrent pain of similar character, but increased severity.

On physical examination, the patient was hemodynamically stable and afebrile. Her vital signs were: heart rate, 84 beats/min; blood pressure, 113/68 mm Hg; and respiratory rate, 20 breaths/min. Oxygen saturation was 100% on room air.

The abdomen was soft with tenderness to palpation over a 13-cm x 8-cm soft hernia to the left of the umbilicus without overlying skin changes. The patient’s pain was controlled with 1 mg of intravenous hydromorphone, after which bedside reduction was attempted. During reduction attempts, there was palpable bowel within the hernia sac, and a periumbilical defect was appreciated. Although the defect in the abdominal wall was estimated to be large enough to allow reduction, the hernia reduced only partially. Because imaging studies from the patient’s previous ED visit showed no visualized strangulation or obstruction, we deliberated over the need for a repeat CT scan prior to further attempts at reduction by general surgery services. Ultimately, we ordered a repeat CT scan, which was significant for a “mechanical small bowel obstruction with focal transition zone located within the hernia sac itself, not the neck of the umbilical hernia.”

Discussion

Abdominal wall hernias are a common pathology, with more than 700,000 repairs performed every year in the United States.² Patients most commonly present to the ED with abdominal pain, nausea, and vomiting. Less frequently, they present with obstruction, incarceration, strangulation, or rupture.³ Umbilical hernias are caused by increasing intra-abdominal pressure. As the incidence of obesity in the United States has continued to increase, the proportion of hernias that are umbilical or periumbilical has also increased.^2,4 Unfortunately, even though umbilical hernias are becoming more common, they are often given less attention than other types of hernias.⁵ The practice of solely monitoring umbilical hernias can lead to serious outcomes. For example, in a case presentation from Spain, a morbidly obese patient died due to a strangulated umbilical hernia that had progressed over a 15-year period without treatment.⁶

Compared to elective surgery, emergent operative repair is associated with a higher rate of postoperative complications,¹ and a growing body of evidence suggests that patients with symptomatic hernias should be encouraged to undergo operative repair.^1,6However, the timing and urgency of this repair is often difficult to determine when strangulation is not the obvious diagnosis. Recent literature has shown that, even in nonincarcerated hernias, conservative management is a significant contributing factor in the delay of treatment, ultimately leading to complications, including SBO.¹ Our patient had her umbilical hernia for over 5 years, during which time she had a tubal ligation and chronic pelvic pain, both of which could have led to intra-abdominal inflammation and the formation of adhesions. In her case, these adhesions led to an SBO, necessitating urgent surgery. This case supports the need to strongly consider ordering imaging studies to evaluate hernias when they cannot easily be reduced to avoid potential complications from attempting to reduce obstructed bowel, and to help determine surgical urgency, even when examination is otherwise benign. Additionally, while our patient had a good clinical outcome, the urgency of her procedure may further support surgical repair over conservative management of asymptomatic hernias.

Conclusion

Umbilical hernias have become more common with increasing rates of obesity. These hernias have the potential to lead to serious medical emergencies, and the common practice of monitoring chronic hernias may increase the patient’s risk of serious complications. Emergency physicians use the physical examination to help determine the urgency of repair; however, imaging should be considered to assess hernias that cannot easily be reduced to evaluate for obstructed, strangulated, or incarcerated bowel and to help determine the urgency of surgical repair.

Case

A 14-year-old girl with no known medical history presented to the ED via emergency medical services (EMS) approximately 1.5 hours after intentionally ingesting what she described as “a handful or two” of her mother’s lupus prescription medication in a suicide attempt. Initial vital signs and physical examination were normal, and her only complaint was nausea.

Thirty minutes after presentation, the patient suffered acute cardiovascular (CV) collapse: blood pressure, 57/39 mm Hg; heart rate, 90 beats/min. An initial electrocardiogram (ECG) revealed QRS duration of 123 milliseconds and QTc duration of 510 milliseconds, along with nonspecific T-wave abnormalities. A 150-mEq intravenous (IV) bolus of sodium bicarbonate and a 40-mEq potassium chloride IV infusion were administered, and both epinephrine and norepinephrine IV infusions were also initiated. A basic metabolic panel obtained prior to medication administration showed a potassium concentration of 1.9 mmol/L.

What is the differential diagnosis of toxicological hypokalemia?

Hypokalemia may be reflective of diminished whole body potassium stores or a transient alteration of intravascular potassium concentrations. In acute ingestions and overdose, the etiology of the hypokalemia is often electrolyte redistribution through either blockade of constitutive outward potassium leakage (eg, barium, insulin, quinine) or through increased activity of the Na⁺/K⁺-ATPase pump (eg, catecholamines, insulin, methylxanthines). This activity has little effect on whole body potassium stores, but can result in a profound fall in the serum potassium. While mild hypokalemia is generally well tolerated, more severe potassium abnormalities can cause muscular weakness, areflexic paralysis, respiratory failure, and life-threatening dysrhythmias. Common ECG findings include decreased T-wave amplitudes, ST-segment depression, and the presence or amplification of U waves.

Case Continuation

While the emergency physicians were stabilizing the patient, her mother provided additional information. Approximately 30 minutes after the exposure, the patient had become nauseated and told her mother what she had done. Her mother called EMS, and the patient was transported to the hospital, where she rapidly became symptomatic. Despite CV decompensation, she remained neurologically intact. On further questioning, the patient admitted to ingesting 6 g of her mother’s prescription of hydroxychloroquine (HCQ) in a suicide attempt but denied taking any other medications. She was stabilized on vasopressors and admitted to the intensive care unit.

What characterizes hydroxychloroquine toxicity?

Hydroxychloroquine is an aminoquinoline antibiotic that is classically used as an antimalarial to treat infection with Plasmodium vivax, P ovale, P malariae, and susceptible strains of P falciparum. In the United States, it is more commonly used to manage both rheumatoid arthritis and systemic lupus erythematosus (SLE), debilitating diseases which are estimated to affect anywhere from 161,000 to 322,000 Americans.¹ Hydroxychloroquine is considered first-line therapy for SLE, but its mechanism of action in treating SLE-associated arthralgias is unclear.

Hydroxychloroquine is structurally similar to quinine and chloroquine (CQ), and not surprisingly exerts quinidine-like effects on the CV system with resultant negative inotropy and vasodilation. Its toxicity is characterized by rapid onset of clinical effects including central nervous system depression, seizures, apnea, hypotension, and arrhythmia. After large overdoses, cardiac arrest and death can occur within hours.

Hypokalemia is another hallmark of HCQ toxicity. It is thought to develop secondary to potassium channel blockade, which slows the constitutive release of potassium from the myocytes.² As noted, the hypokalemia is transient and does not reflect whole-body depletion. With CQ, which is considered more toxic, there appears to be a correlation between the quantity of CQ ingested and both the degree of hypokalemia and the severity of the outcome. It is reasonable to assume the same for HCQ. There are little data to support that hypokalemia itself causes cardiotoxicity in patients with CQ or HCQ overdose.

Although lethal doses are not well established, animal studies suggest that HCQ is much less toxic than CQ, for which the clinical toxicity is better understood due to its more widespread use in overdose abroad.³ In children, the reported therapeutic dose is 10 mg/kg, but the minimum reported lethal dose was a single 300-mg tablet (30 mg/kg in a toddler). In adults, the toxic dose is reported as 20 mg/kg with lethal doses suggested to be as low as 30 mg/kg.

What are the treatment modalities for patients with hydroxychloroquine toxicity?

By analogy with the treatment of CQ poisoning, the mainstay of HCQ therapy is supportive care, including early intubation and ventilation to minimize metabolic demand. Direct-acting inotropes and vasopressors should be administered after saline to treat hypotension. Because of its large volume of distribution, extracorporeal removal has not proved to be of clinical value.^4,5 Though data are sparse to determine its efficacy, there may be a role for giving activated charcoal, particularly following large overdoses—if it is given early after exposure and the patient has normal consciousness. If the patient is intubated and aspiration risk is minimized, gastric lavage may also be beneficial—especially when performed within an hour of the overdose. Syrup of ipecac should not be used.

High-dose diazepam is typically recommended, again by analogy with CQ, although there is no clear mechanism of action and its use remains controversial. Its protective effect in patients with CQ overdose is based on swine and rat models that demonstrated dose dependent relationships between diazepam and survival.^6,7 A prospective study of CQ toxicity in humans reported improved survival rates when high-dose diazepam was given in combination with epinephrine.⁸ However, this study is limited by its comparison of prospectively studied patients with a retrospective control. A subsequent prospective study of moderately CQ-intoxicated patients did not find a benefit from treatment with diazepam.⁹ Furthermore, it remains unclear if the proposed benefit from high-dose diazepam in CQ toxicity may be extrapolated to HCQ, and cases of even massive HCQ ingestions report good outcomes without the use of high-dose diazepam.¹⁰

How aggressively should hypokalemia in hydroxychloroquine toxicity be treated?

As noted earlier, hypokalemia resulting from HCQ toxicity is transient, and aggressive repletion may result in rebound hyperkalemia once toxicity resolves. However, these dangers should be balanced with risks of hypokalemia-induced ventricular arrhythmias. Additionally, hypokalemia may be worsened by sodium bicarbonate that is administered to correct QRS prolongations, increasing the risk of dysrhythmia. Correction of hypokalemia in these cases is necessary but should be done with care and monitoring of serum potassium concentrations to minimize risk of hyperkalemia-induced ventricular arrhythmia.¹¹

Case Conclusion

Throughout treatment, the patient remained neurologically intact. She did not receive benzodiazepines. The epinephrine and norepinephrine infusions were weaned, and she was discharged on hospital day 3 with no neurological or cardiac sequelae. She received an inpatient psychiatric evaluation and was referred to outpatient services for ongoing care.  

Case

A 14-year-old girl with no known medical history presented to the ED via emergency medical services (EMS) approximately 1.5 hours after intentionally ingesting what she described as “a handful or two” of her mother’s lupus prescription medication in a suicide attempt. Initial vital signs and physical examination were normal, and her only complaint was nausea.

Thirty minutes after presentation, the patient suffered acute cardiovascular (CV) collapse: blood pressure, 57/39 mm Hg; heart rate, 90 beats/min. An initial electrocardiogram (ECG) revealed QRS duration of 123 milliseconds and QTc duration of 510 milliseconds, along with nonspecific T-wave abnormalities. A 150-mEq intravenous (IV) bolus of sodium bicarbonate and a 40-mEq potassium chloride IV infusion were administered, and both epinephrine and norepinephrine IV infusions were also initiated. A basic metabolic panel obtained prior to medication administration showed a potassium concentration of 1.9 mmol/L.

What is the differential diagnosis of toxicological hypokalemia?

Hypokalemia may be reflective of diminished whole body potassium stores or a transient alteration of intravascular potassium concentrations. In acute ingestions and overdose, the etiology of the hypokalemia is often electrolyte redistribution through either blockade of constitutive outward potassium leakage (eg, barium, insulin, quinine) or through increased activity of the Na⁺/K⁺-ATPase pump (eg, catecholamines, insulin, methylxanthines). This activity has little effect on whole body potassium stores, but can result in a profound fall in the serum potassium. While mild hypokalemia is generally well tolerated, more severe potassium abnormalities can cause muscular weakness, areflexic paralysis, respiratory failure, and life-threatening dysrhythmias. Common ECG findings include decreased T-wave amplitudes, ST-segment depression, and the presence or amplification of U waves.

Case Continuation

While the emergency physicians were stabilizing the patient, her mother provided additional information. Approximately 30 minutes after the exposure, the patient had become nauseated and told her mother what she had done. Her mother called EMS, and the patient was transported to the hospital, where she rapidly became symptomatic. Despite CV decompensation, she remained neurologically intact. On further questioning, the patient admitted to ingesting 6 g of her mother’s prescription of hydroxychloroquine (HCQ) in a suicide attempt but denied taking any other medications. She was stabilized on vasopressors and admitted to the intensive care unit.

What characterizes hydroxychloroquine toxicity?

Hydroxychloroquine is an aminoquinoline antibiotic that is classically used as an antimalarial to treat infection with Plasmodium vivax, P ovale, P malariae, and susceptible strains of P falciparum. In the United States, it is more commonly used to manage both rheumatoid arthritis and systemic lupus erythematosus (SLE), debilitating diseases which are estimated to affect anywhere from 161,000 to 322,000 Americans.¹ Hydroxychloroquine is considered first-line therapy for SLE, but its mechanism of action in treating SLE-associated arthralgias is unclear.

Hydroxychloroquine is structurally similar to quinine and chloroquine (CQ), and not surprisingly exerts quinidine-like effects on the CV system with resultant negative inotropy and vasodilation. Its toxicity is characterized by rapid onset of clinical effects including central nervous system depression, seizures, apnea, hypotension, and arrhythmia. After large overdoses, cardiac arrest and death can occur within hours.

Hypokalemia is another hallmark of HCQ toxicity. It is thought to develop secondary to potassium channel blockade, which slows the constitutive release of potassium from the myocytes.² As noted, the hypokalemia is transient and does not reflect whole-body depletion. With CQ, which is considered more toxic, there appears to be a correlation between the quantity of CQ ingested and both the degree of hypokalemia and the severity of the outcome. It is reasonable to assume the same for HCQ. There are little data to support that hypokalemia itself causes cardiotoxicity in patients with CQ or HCQ overdose.

Although lethal doses are not well established, animal studies suggest that HCQ is much less toxic than CQ, for which the clinical toxicity is better understood due to its more widespread use in overdose abroad.³ In children, the reported therapeutic dose is 10 mg/kg, but the minimum reported lethal dose was a single 300-mg tablet (30 mg/kg in a toddler). In adults, the toxic dose is reported as 20 mg/kg with lethal doses suggested to be as low as 30 mg/kg.

What are the treatment modalities for patients with hydroxychloroquine toxicity?

By analogy with the treatment of CQ poisoning, the mainstay of HCQ therapy is supportive care, including early intubation and ventilation to minimize metabolic demand. Direct-acting inotropes and vasopressors should be administered after saline to treat hypotension. Because of its large volume of distribution, extracorporeal removal has not proved to be of clinical value.^4,5 Though data are sparse to determine its efficacy, there may be a role for giving activated charcoal, particularly following large overdoses—if it is given early after exposure and the patient has normal consciousness. If the patient is intubated and aspiration risk is minimized, gastric lavage may also be beneficial—especially when performed within an hour of the overdose. Syrup of ipecac should not be used.

High-dose diazepam is typically recommended, again by analogy with CQ, although there is no clear mechanism of action and its use remains controversial. Its protective effect in patients with CQ overdose is based on swine and rat models that demonstrated dose dependent relationships between diazepam and survival.^6,7 A prospective study of CQ toxicity in humans reported improved survival rates when high-dose diazepam was given in combination with epinephrine.⁸ However, this study is limited by its comparison of prospectively studied patients with a retrospective control. A subsequent prospective study of moderately CQ-intoxicated patients did not find a benefit from treatment with diazepam.⁹ Furthermore, it remains unclear if the proposed benefit from high-dose diazepam in CQ toxicity may be extrapolated to HCQ, and cases of even massive HCQ ingestions report good outcomes without the use of high-dose diazepam.¹⁰

How aggressively should hypokalemia in hydroxychloroquine toxicity be treated?

As noted earlier, hypokalemia resulting from HCQ toxicity is transient, and aggressive repletion may result in rebound hyperkalemia once toxicity resolves. However, these dangers should be balanced with risks of hypokalemia-induced ventricular arrhythmias. Additionally, hypokalemia may be worsened by sodium bicarbonate that is administered to correct QRS prolongations, increasing the risk of dysrhythmia. Correction of hypokalemia in these cases is necessary but should be done with care and monitoring of serum potassium concentrations to minimize risk of hyperkalemia-induced ventricular arrhythmia.¹¹

Case Conclusion

Throughout treatment, the patient remained neurologically intact. She did not receive benzodiazepines. The epinephrine and norepinephrine infusions were weaned, and she was discharged on hospital day 3 with no neurological or cardiac sequelae. She received an inpatient psychiatric evaluation and was referred to outpatient services for ongoing care.  

Case

A 14-year-old girl with no known medical history presented to the ED via emergency medical services (EMS) approximately 1.5 hours after intentionally ingesting what she described as “a handful or two” of her mother’s lupus prescription medication in a suicide attempt. Initial vital signs and physical examination were normal, and her only complaint was nausea.

Thirty minutes after presentation, the patient suffered acute cardiovascular (CV) collapse: blood pressure, 57/39 mm Hg; heart rate, 90 beats/min. An initial electrocardiogram (ECG) revealed QRS duration of 123 milliseconds and QTc duration of 510 milliseconds, along with nonspecific T-wave abnormalities. A 150-mEq intravenous (IV) bolus of sodium bicarbonate and a 40-mEq potassium chloride IV infusion were administered, and both epinephrine and norepinephrine IV infusions were also initiated. A basic metabolic panel obtained prior to medication administration showed a potassium concentration of 1.9 mmol/L.

What is the differential diagnosis of toxicological hypokalemia?

Hypokalemia may be reflective of diminished whole body potassium stores or a transient alteration of intravascular potassium concentrations. In acute ingestions and overdose, the etiology of the hypokalemia is often electrolyte redistribution through either blockade of constitutive outward potassium leakage (eg, barium, insulin, quinine) or through increased activity of the Na⁺/K⁺-ATPase pump (eg, catecholamines, insulin, methylxanthines). This activity has little effect on whole body potassium stores, but can result in a profound fall in the serum potassium. While mild hypokalemia is generally well tolerated, more severe potassium abnormalities can cause muscular weakness, areflexic paralysis, respiratory failure, and life-threatening dysrhythmias. Common ECG findings include decreased T-wave amplitudes, ST-segment depression, and the presence or amplification of U waves.

Case Continuation

While the emergency physicians were stabilizing the patient, her mother provided additional information. Approximately 30 minutes after the exposure, the patient had become nauseated and told her mother what she had done. Her mother called EMS, and the patient was transported to the hospital, where she rapidly became symptomatic. Despite CV decompensation, she remained neurologically intact. On further questioning, the patient admitted to ingesting 6 g of her mother’s prescription of hydroxychloroquine (HCQ) in a suicide attempt but denied taking any other medications. She was stabilized on vasopressors and admitted to the intensive care unit.

What characterizes hydroxychloroquine toxicity?

Hydroxychloroquine is an aminoquinoline antibiotic that is classically used as an antimalarial to treat infection with Plasmodium vivax, P ovale, P malariae, and susceptible strains of P falciparum. In the United States, it is more commonly used to manage both rheumatoid arthritis and systemic lupus erythematosus (SLE), debilitating diseases which are estimated to affect anywhere from 161,000 to 322,000 Americans.¹ Hydroxychloroquine is considered first-line therapy for SLE, but its mechanism of action in treating SLE-associated arthralgias is unclear.

Hydroxychloroquine is structurally similar to quinine and chloroquine (CQ), and not surprisingly exerts quinidine-like effects on the CV system with resultant negative inotropy and vasodilation. Its toxicity is characterized by rapid onset of clinical effects including central nervous system depression, seizures, apnea, hypotension, and arrhythmia. After large overdoses, cardiac arrest and death can occur within hours.

Hypokalemia is another hallmark of HCQ toxicity. It is thought to develop secondary to potassium channel blockade, which slows the constitutive release of potassium from the myocytes.² As noted, the hypokalemia is transient and does not reflect whole-body depletion. With CQ, which is considered more toxic, there appears to be a correlation between the quantity of CQ ingested and both the degree of hypokalemia and the severity of the outcome. It is reasonable to assume the same for HCQ. There are little data to support that hypokalemia itself causes cardiotoxicity in patients with CQ or HCQ overdose.

Although lethal doses are not well established, animal studies suggest that HCQ is much less toxic than CQ, for which the clinical toxicity is better understood due to its more widespread use in overdose abroad.³ In children, the reported therapeutic dose is 10 mg/kg, but the minimum reported lethal dose was a single 300-mg tablet (30 mg/kg in a toddler). In adults, the toxic dose is reported as 20 mg/kg with lethal doses suggested to be as low as 30 mg/kg.

What are the treatment modalities for patients with hydroxychloroquine toxicity?

By analogy with the treatment of CQ poisoning, the mainstay of HCQ therapy is supportive care, including early intubation and ventilation to minimize metabolic demand. Direct-acting inotropes and vasopressors should be administered after saline to treat hypotension. Because of its large volume of distribution, extracorporeal removal has not proved to be of clinical value.^4,5 Though data are sparse to determine its efficacy, there may be a role for giving activated charcoal, particularly following large overdoses—if it is given early after exposure and the patient has normal consciousness. If the patient is intubated and aspiration risk is minimized, gastric lavage may also be beneficial—especially when performed within an hour of the overdose. Syrup of ipecac should not be used.

High-dose diazepam is typically recommended, again by analogy with CQ, although there is no clear mechanism of action and its use remains controversial. Its protective effect in patients with CQ overdose is based on swine and rat models that demonstrated dose dependent relationships between diazepam and survival.^6,7 A prospective study of CQ toxicity in humans reported improved survival rates when high-dose diazepam was given in combination with epinephrine.⁸ However, this study is limited by its comparison of prospectively studied patients with a retrospective control. A subsequent prospective study of moderately CQ-intoxicated patients did not find a benefit from treatment with diazepam.⁹ Furthermore, it remains unclear if the proposed benefit from high-dose diazepam in CQ toxicity may be extrapolated to HCQ, and cases of even massive HCQ ingestions report good outcomes without the use of high-dose diazepam.¹⁰

How aggressively should hypokalemia in hydroxychloroquine toxicity be treated?

As noted earlier, hypokalemia resulting from HCQ toxicity is transient, and aggressive repletion may result in rebound hyperkalemia once toxicity resolves. However, these dangers should be balanced with risks of hypokalemia-induced ventricular arrhythmias. Additionally, hypokalemia may be worsened by sodium bicarbonate that is administered to correct QRS prolongations, increasing the risk of dysrhythmia. Correction of hypokalemia in these cases is necessary but should be done with care and monitoring of serum potassium concentrations to minimize risk of hyperkalemia-induced ventricular arrhythmia.¹¹

Case Conclusion

Throughout treatment, the patient remained neurologically intact. She did not receive benzodiazepines. The epinephrine and norepinephrine infusions were weaned, and she was discharged on hospital day 3 with no neurological or cardiac sequelae. She received an inpatient psychiatric evaluation and was referred to outpatient services for ongoing care.  

Sneddon syndrome (SS) was first described in 1965 in patients with persistent livedo racemosa and neurological events.¹ Because the other manifestations of SS are nonspecific (eg, hypertension, cardiac valvulopathy, arterial and venous occlusion), the diagnosis often is delayed. Many patients who experience prodromal neurologic symptoms such as headaches, depression, anxiety, dizziness, and neuropathy often present to a physician prior to developing ischemic brain manifestations² but seldom receive the correct diagnosis. Onset of cerebral occlusive events typically occurs in patients younger than 45 years and may present as a transient ischemic attack, stroke, or intracranial hemorrhage.³ The disease is more prevalent in females than males (2:1 ratio). The exact pathogenesis of SS is still unknown, and although it has been thought of as a separate entity from systemic lupus erythematosus and other antiphospholipid disorders, it has been postulated that an immunological dysfunction damages vessel walls leading to thrombosis.

Cutaneous findings associated with SS involve small- to medium-sized dermal-subdermal arteries. Histopathology in some patients demonstrates proliferation of the endothelium and fibrin deposits with subsequent obliteration of involved arteries.⁴ In many patients including our patient, histopathologic examination of involved skin fails to show specific abnormalities.¹ Zelger et al⁵ reported the sequence of histopathologic skin events in a series of antiphospholipid-negative SS patients. The authors reported that only small arteries at the dermis-subcutis junction were involved and a progression of endothelial dysfunction was observed. The authors believed there were several nonspecific stages prior to fibrin occlusion of involved arteries.⁵ Stage I involved loosening of endothelial cells with nonspecific perivascular lymphocytic infiltration with perivascular inflammation and lymphocytic infiltration representing the prime mover of the disease.^5,6 This stage is thought to be short lived, thus the reason why it has gone undetected for many years in SS patients. Stages II to IV progress through fibrin deposition and occlusion.⁵ Histological features of stages I to II have not been reported because of late diagnosis of SS. Stage I patients typically present with an average duration of symptoms of 6 months with few neurologic symptoms, the most common being paresthesia of the legs.⁵

Case Report

A 37-year-old woman with epigastric tenderness on the left side and splenomegaly seen on computed tomography was referred by a hematologist for evaluation of a reticular rash on the left side of the flank of 9 months’ duration with a presumed diagnosis of focal melanoderma. Her medical history was remarkable for a congenital ventricular septal defect and coarctation of the aorta, as well as endometriosis, myalgia, and joint stiffness that had all developed over the last year. Her medical history also was remarkable for nephrolithiasis, irritable bowel syndrome, and chronic sinusitis, as well as psychiatric depression and anxiety disorders. She recently had been diagnosed with moderate hypertension and had experienced difficulty getting pregnant for the last several years with 3 consecutive miscarriages in the first trimester. Neurologic symptoms included neuropathy involving the feet, intermittent paresthesia of the legs, and a history of chronic migraine headaches for several months.

Dermatologic examination revealed a slightly overweight woman with a 25×30-cm dusky, erythematous, irregular, netlike pattern on the left side of the upper and lower trunk (Figure 1). Extensive livedo racemosa was not altered by changes in temperature and had been unchanged for more than 9 months. There were no signs of pruritus or ulcerations, and areas of livedo racemosa were slightly tender to palpation.

We performed 2 sets of three 4-mm biopsies. The first set targeted areas within the violaceous pattern, while the second set targeted areas of normal tissue between the mottled areas. All 6 specimens demonstrated superficial perivascular lymphocytic infiltrate with no evidence of vasculitis or connective tissue disease. The vessels showed no microthrombi or surrounding fibrosis. No eosinophils were identified within the epidermis. There was no evidence of increased dermal mucin. Both the superficial and deep vascular plexuses were unremarkable and showed no evidence of damage to the walls (Figure 2).

To rule out other possible causes of livedo racemosa, complete blood cell count, comprehensive metabolic panel, coagulation profile, lipase test, urinalysis, serologic testing, and immunologic workup were performed. Lipase was within reference range. The complete blood cell count revealed mild anemia, while the rest of the values were within reference range. An immunologic workup included Sjögren syndrome antigen A, Sjögren syndrome antigen B, anticardiolipin antibodies, and antinuclear antibody, which were all negative. Family history was remarkable for first-degree relatives with systemic lupus erythematosus and Crohn disease.

Computed tomography revealed enlargement of the spleen, as well as periaortic, portacaval, and porta hepatis lymphadenopathy. Based on the laboratory findings and clinical presentation as well as the patient’s medical history, the diagnosis of exclusion was idiopathic livedo racemosa with unknown progression to full-blown SS. The patient did not meet the current diagnostic criteria for SS, and her immunologic studies failed to confirm any present antibodies, but involvement of the reticuloendothelial system pointed to production of antibodies that were not yet detectable on laboratory testing.

Comment

More than 50 years after the first case of SS was diagnosed, better laboratory workup is available and more information is known about the pathophysiology. Sneddon syndrome is a rare disorder, affecting only approximately 4 patients per million each year worldwide. Seronegative antiphospholipid antibody syndrome (SNAPS) describes patients with clinical presentations of antiphospholipid syndrome (APS) without detectable serological markers.⁷ Antiphospholipid-negative SS, which was seen in our patient, would be categorized under SNAPS. A PubMed search of articles indexed for MEDLINE using the terms livedo racemosa, Sneddon syndrome, and SNAPS and splenomegaly revealed there currently are no known cases of SNAPS that have been reported with splenomegaly and lymphadenopathy. Our patient presented with the following clinical features of SS: livedo racemosa, history of miscarriage, psychiatric disturbances, and hypertension. Surprisingly, biopsies from affected skin did not show any fibrin deposition or microthrombi but did reveal perivascular lymphocytic infiltrations. Magnetic resonance imaging did not show any pathological lesions or vascular changes.

Sneddon syndrome and APS share a common pathway to occlusive arteriolopathy for which 4 stages have been described by Zelger et al.⁵ Stage I involves a nonspecific Langerhans cell infiltrate with polymorphonuclear leukocytes. The tunica media and elastic lamina usually are unaltered at this early stage, while the surrounding connective tissue may appear edematous.⁵ This early stage of histopathology has not been evaluated in SS patients, primarily because of delay of diagnosis. Late stages III and IV will show fibrin deposition and shrinkage of affected vessels.⁷

A PubMed search using the terms Sneddon syndrome, lymphadenopathy and livedo racemosa, and Sneddon syndrome and lymphadenopathy revealed that splenomegaly and lymphadenopathy have not been reported in patients with SS. In patients with antiphospholipid-negative SS, one can assume that antibodies to other phospholipids not tested must exist because of striking similarities between APS and antiphospholipid-negative SS.⁸ Although our patient did not test positive for any of these antibodies, she did present with lymphadenopathy and splenic enlargement, leading us to believe that involvement of the reticuloendothelial system may be a feature of SS that has not been previously reported. Further studies are required to name specific antigens responsible for clinical manifestations in SS.

Currently, no single diagnostic test for SS exists, thus delaying both diagnosis and initiation of treatment. Histopathologic examination may be helpful, but in many cases it is nonspecific, as are serologic markers. Neuroradiological confirmation of involvement usually is the confirmatory feature in many patients with late-stage diagnosis.² A diagnostic schematic for SS, which was first described by Daoud et al,² illustrates classification of symptoms and aids in diagnosis. A working diagnosis of idiopathic livedo racemosa is made after ruling out other causes of SS in a patient with nonspecific biopsy findings and negative magnetic resonance imaging results with prodromal symptoms. The prognosis for such patients progressing to full SS is unknown with or without management using anticoagulant therapy.

Conclusion

Early diagnosis of livedo racemosa and SS is essential, as prevention of cerebrovascular accidents, myocardial infarction, and other thromboembolic diseases can be minimized by attacking risk factors such as smoking, taking oral contraceptive pills, becoming pregnant,⁹ and by initiating either antiplatelet or anticoagulation treatments. These treatments have been shown to delay the development of neurovascular damage and early-onset dementia. We present this case to demonstrate the variability of early-presenting symptoms in idiopathic livedo racemosa. Recognizing some of the early manifestations can lead to early diagnosis and initiation of treatment.

Sneddon syndrome (SS) was first described in 1965 in patients with persistent livedo racemosa and neurological events.¹ Because the other manifestations of SS are nonspecific (eg, hypertension, cardiac valvulopathy, arterial and venous occlusion), the diagnosis often is delayed. Many patients who experience prodromal neurologic symptoms such as headaches, depression, anxiety, dizziness, and neuropathy often present to a physician prior to developing ischemic brain manifestations² but seldom receive the correct diagnosis. Onset of cerebral occlusive events typically occurs in patients younger than 45 years and may present as a transient ischemic attack, stroke, or intracranial hemorrhage.³ The disease is more prevalent in females than males (2:1 ratio). The exact pathogenesis of SS is still unknown, and although it has been thought of as a separate entity from systemic lupus erythematosus and other antiphospholipid disorders, it has been postulated that an immunological dysfunction damages vessel walls leading to thrombosis.

Cutaneous findings associated with SS involve small- to medium-sized dermal-subdermal arteries. Histopathology in some patients demonstrates proliferation of the endothelium and fibrin deposits with subsequent obliteration of involved arteries.⁴ In many patients including our patient, histopathologic examination of involved skin fails to show specific abnormalities.¹ Zelger et al⁵ reported the sequence of histopathologic skin events in a series of antiphospholipid-negative SS patients. The authors reported that only small arteries at the dermis-subcutis junction were involved and a progression of endothelial dysfunction was observed. The authors believed there were several nonspecific stages prior to fibrin occlusion of involved arteries.⁵ Stage I involved loosening of endothelial cells with nonspecific perivascular lymphocytic infiltration with perivascular inflammation and lymphocytic infiltration representing the prime mover of the disease.^5,6 This stage is thought to be short lived, thus the reason why it has gone undetected for many years in SS patients. Stages II to IV progress through fibrin deposition and occlusion.⁵ Histological features of stages I to II have not been reported because of late diagnosis of SS. Stage I patients typically present with an average duration of symptoms of 6 months with few neurologic symptoms, the most common being paresthesia of the legs.⁵

Case Report

A 37-year-old woman with epigastric tenderness on the left side and splenomegaly seen on computed tomography was referred by a hematologist for evaluation of a reticular rash on the left side of the flank of 9 months’ duration with a presumed diagnosis of focal melanoderma. Her medical history was remarkable for a congenital ventricular septal defect and coarctation of the aorta, as well as endometriosis, myalgia, and joint stiffness that had all developed over the last year. Her medical history also was remarkable for nephrolithiasis, irritable bowel syndrome, and chronic sinusitis, as well as psychiatric depression and anxiety disorders. She recently had been diagnosed with moderate hypertension and had experienced difficulty getting pregnant for the last several years with 3 consecutive miscarriages in the first trimester. Neurologic symptoms included neuropathy involving the feet, intermittent paresthesia of the legs, and a history of chronic migraine headaches for several months.

Dermatologic examination revealed a slightly overweight woman with a 25×30-cm dusky, erythematous, irregular, netlike pattern on the left side of the upper and lower trunk (Figure 1). Extensive livedo racemosa was not altered by changes in temperature and had been unchanged for more than 9 months. There were no signs of pruritus or ulcerations, and areas of livedo racemosa were slightly tender to palpation.

We performed 2 sets of three 4-mm biopsies. The first set targeted areas within the violaceous pattern, while the second set targeted areas of normal tissue between the mottled areas. All 6 specimens demonstrated superficial perivascular lymphocytic infiltrate with no evidence of vasculitis or connective tissue disease. The vessels showed no microthrombi or surrounding fibrosis. No eosinophils were identified within the epidermis. There was no evidence of increased dermal mucin. Both the superficial and deep vascular plexuses were unremarkable and showed no evidence of damage to the walls (Figure 2).

To rule out other possible causes of livedo racemosa, complete blood cell count, comprehensive metabolic panel, coagulation profile, lipase test, urinalysis, serologic testing, and immunologic workup were performed. Lipase was within reference range. The complete blood cell count revealed mild anemia, while the rest of the values were within reference range. An immunologic workup included Sjögren syndrome antigen A, Sjögren syndrome antigen B, anticardiolipin antibodies, and antinuclear antibody, which were all negative. Family history was remarkable for first-degree relatives with systemic lupus erythematosus and Crohn disease.

Computed tomography revealed enlargement of the spleen, as well as periaortic, portacaval, and porta hepatis lymphadenopathy. Based on the laboratory findings and clinical presentation as well as the patient’s medical history, the diagnosis of exclusion was idiopathic livedo racemosa with unknown progression to full-blown SS. The patient did not meet the current diagnostic criteria for SS, and her immunologic studies failed to confirm any present antibodies, but involvement of the reticuloendothelial system pointed to production of antibodies that were not yet detectable on laboratory testing.

Comment

More than 50 years after the first case of SS was diagnosed, better laboratory workup is available and more information is known about the pathophysiology. Sneddon syndrome is a rare disorder, affecting only approximately 4 patients per million each year worldwide. Seronegative antiphospholipid antibody syndrome (SNAPS) describes patients with clinical presentations of antiphospholipid syndrome (APS) without detectable serological markers.⁷ Antiphospholipid-negative SS, which was seen in our patient, would be categorized under SNAPS. A PubMed search of articles indexed for MEDLINE using the terms livedo racemosa, Sneddon syndrome, and SNAPS and splenomegaly revealed there currently are no known cases of SNAPS that have been reported with splenomegaly and lymphadenopathy. Our patient presented with the following clinical features of SS: livedo racemosa, history of miscarriage, psychiatric disturbances, and hypertension. Surprisingly, biopsies from affected skin did not show any fibrin deposition or microthrombi but did reveal perivascular lymphocytic infiltrations. Magnetic resonance imaging did not show any pathological lesions or vascular changes.

Sneddon syndrome and APS share a common pathway to occlusive arteriolopathy for which 4 stages have been described by Zelger et al.⁵ Stage I involves a nonspecific Langerhans cell infiltrate with polymorphonuclear leukocytes. The tunica media and elastic lamina usually are unaltered at this early stage, while the surrounding connective tissue may appear edematous.⁵ This early stage of histopathology has not been evaluated in SS patients, primarily because of delay of diagnosis. Late stages III and IV will show fibrin deposition and shrinkage of affected vessels.⁷

A PubMed search using the terms Sneddon syndrome, lymphadenopathy and livedo racemosa, and Sneddon syndrome and lymphadenopathy revealed that splenomegaly and lymphadenopathy have not been reported in patients with SS. In patients with antiphospholipid-negative SS, one can assume that antibodies to other phospholipids not tested must exist because of striking similarities between APS and antiphospholipid-negative SS.⁸ Although our patient did not test positive for any of these antibodies, she did present with lymphadenopathy and splenic enlargement, leading us to believe that involvement of the reticuloendothelial system may be a feature of SS that has not been previously reported. Further studies are required to name specific antigens responsible for clinical manifestations in SS.

Currently, no single diagnostic test for SS exists, thus delaying both diagnosis and initiation of treatment. Histopathologic examination may be helpful, but in many cases it is nonspecific, as are serologic markers. Neuroradiological confirmation of involvement usually is the confirmatory feature in many patients with late-stage diagnosis.² A diagnostic schematic for SS, which was first described by Daoud et al,² illustrates classification of symptoms and aids in diagnosis. A working diagnosis of idiopathic livedo racemosa is made after ruling out other causes of SS in a patient with nonspecific biopsy findings and negative magnetic resonance imaging results with prodromal symptoms. The prognosis for such patients progressing to full SS is unknown with or without management using anticoagulant therapy.

Conclusion

Early diagnosis of livedo racemosa and SS is essential, as prevention of cerebrovascular accidents, myocardial infarction, and other thromboembolic diseases can be minimized by attacking risk factors such as smoking, taking oral contraceptive pills, becoming pregnant,⁹ and by initiating either antiplatelet or anticoagulation treatments. These treatments have been shown to delay the development of neurovascular damage and early-onset dementia. We present this case to demonstrate the variability of early-presenting symptoms in idiopathic livedo racemosa. Recognizing some of the early manifestations can lead to early diagnosis and initiation of treatment.

Sneddon syndrome (SS) was first described in 1965 in patients with persistent livedo racemosa and neurological events.¹ Because the other manifestations of SS are nonspecific (eg, hypertension, cardiac valvulopathy, arterial and venous occlusion), the diagnosis often is delayed. Many patients who experience prodromal neurologic symptoms such as headaches, depression, anxiety, dizziness, and neuropathy often present to a physician prior to developing ischemic brain manifestations² but seldom receive the correct diagnosis. Onset of cerebral occlusive events typically occurs in patients younger than 45 years and may present as a transient ischemic attack, stroke, or intracranial hemorrhage.³ The disease is more prevalent in females than males (2:1 ratio). The exact pathogenesis of SS is still unknown, and although it has been thought of as a separate entity from systemic lupus erythematosus and other antiphospholipid disorders, it has been postulated that an immunological dysfunction damages vessel walls leading to thrombosis.

Cutaneous findings associated with SS involve small- to medium-sized dermal-subdermal arteries. Histopathology in some patients demonstrates proliferation of the endothelium and fibrin deposits with subsequent obliteration of involved arteries.⁴ In many patients including our patient, histopathologic examination of involved skin fails to show specific abnormalities.¹ Zelger et al⁵ reported the sequence of histopathologic skin events in a series of antiphospholipid-negative SS patients. The authors reported that only small arteries at the dermis-subcutis junction were involved and a progression of endothelial dysfunction was observed. The authors believed there were several nonspecific stages prior to fibrin occlusion of involved arteries.⁵ Stage I involved loosening of endothelial cells with nonspecific perivascular lymphocytic infiltration with perivascular inflammation and lymphocytic infiltration representing the prime mover of the disease.^5,6 This stage is thought to be short lived, thus the reason why it has gone undetected for many years in SS patients. Stages II to IV progress through fibrin deposition and occlusion.⁵ Histological features of stages I to II have not been reported because of late diagnosis of SS. Stage I patients typically present with an average duration of symptoms of 6 months with few neurologic symptoms, the most common being paresthesia of the legs.⁵

Case Report

A 37-year-old woman with epigastric tenderness on the left side and splenomegaly seen on computed tomography was referred by a hematologist for evaluation of a reticular rash on the left side of the flank of 9 months’ duration with a presumed diagnosis of focal melanoderma. Her medical history was remarkable for a congenital ventricular septal defect and coarctation of the aorta, as well as endometriosis, myalgia, and joint stiffness that had all developed over the last year. Her medical history also was remarkable for nephrolithiasis, irritable bowel syndrome, and chronic sinusitis, as well as psychiatric depression and anxiety disorders. She recently had been diagnosed with moderate hypertension and had experienced difficulty getting pregnant for the last several years with 3 consecutive miscarriages in the first trimester. Neurologic symptoms included neuropathy involving the feet, intermittent paresthesia of the legs, and a history of chronic migraine headaches for several months.

Dermatologic examination revealed a slightly overweight woman with a 25×30-cm dusky, erythematous, irregular, netlike pattern on the left side of the upper and lower trunk (Figure 1). Extensive livedo racemosa was not altered by changes in temperature and had been unchanged for more than 9 months. There were no signs of pruritus or ulcerations, and areas of livedo racemosa were slightly tender to palpation.

We performed 2 sets of three 4-mm biopsies. The first set targeted areas within the violaceous pattern, while the second set targeted areas of normal tissue between the mottled areas. All 6 specimens demonstrated superficial perivascular lymphocytic infiltrate with no evidence of vasculitis or connective tissue disease. The vessels showed no microthrombi or surrounding fibrosis. No eosinophils were identified within the epidermis. There was no evidence of increased dermal mucin. Both the superficial and deep vascular plexuses were unremarkable and showed no evidence of damage to the walls (Figure 2).

To rule out other possible causes of livedo racemosa, complete blood cell count, comprehensive metabolic panel, coagulation profile, lipase test, urinalysis, serologic testing, and immunologic workup were performed. Lipase was within reference range. The complete blood cell count revealed mild anemia, while the rest of the values were within reference range. An immunologic workup included Sjögren syndrome antigen A, Sjögren syndrome antigen B, anticardiolipin antibodies, and antinuclear antibody, which were all negative. Family history was remarkable for first-degree relatives with systemic lupus erythematosus and Crohn disease.

Computed tomography revealed enlargement of the spleen, as well as periaortic, portacaval, and porta hepatis lymphadenopathy. Based on the laboratory findings and clinical presentation as well as the patient’s medical history, the diagnosis of exclusion was idiopathic livedo racemosa with unknown progression to full-blown SS. The patient did not meet the current diagnostic criteria for SS, and her immunologic studies failed to confirm any present antibodies, but involvement of the reticuloendothelial system pointed to production of antibodies that were not yet detectable on laboratory testing.

Comment

More than 50 years after the first case of SS was diagnosed, better laboratory workup is available and more information is known about the pathophysiology. Sneddon syndrome is a rare disorder, affecting only approximately 4 patients per million each year worldwide. Seronegative antiphospholipid antibody syndrome (SNAPS) describes patients with clinical presentations of antiphospholipid syndrome (APS) without detectable serological markers.⁷ Antiphospholipid-negative SS, which was seen in our patient, would be categorized under SNAPS. A PubMed search of articles indexed for MEDLINE using the terms livedo racemosa, Sneddon syndrome, and SNAPS and splenomegaly revealed there currently are no known cases of SNAPS that have been reported with splenomegaly and lymphadenopathy. Our patient presented with the following clinical features of SS: livedo racemosa, history of miscarriage, psychiatric disturbances, and hypertension. Surprisingly, biopsies from affected skin did not show any fibrin deposition or microthrombi but did reveal perivascular lymphocytic infiltrations. Magnetic resonance imaging did not show any pathological lesions or vascular changes.

Sneddon syndrome and APS share a common pathway to occlusive arteriolopathy for which 4 stages have been described by Zelger et al.⁵ Stage I involves a nonspecific Langerhans cell infiltrate with polymorphonuclear leukocytes. The tunica media and elastic lamina usually are unaltered at this early stage, while the surrounding connective tissue may appear edematous.⁵ This early stage of histopathology has not been evaluated in SS patients, primarily because of delay of diagnosis. Late stages III and IV will show fibrin deposition and shrinkage of affected vessels.⁷

A PubMed search using the terms Sneddon syndrome, lymphadenopathy and livedo racemosa, and Sneddon syndrome and lymphadenopathy revealed that splenomegaly and lymphadenopathy have not been reported in patients with SS. In patients with antiphospholipid-negative SS, one can assume that antibodies to other phospholipids not tested must exist because of striking similarities between APS and antiphospholipid-negative SS.⁸ Although our patient did not test positive for any of these antibodies, she did present with lymphadenopathy and splenic enlargement, leading us to believe that involvement of the reticuloendothelial system may be a feature of SS that has not been previously reported. Further studies are required to name specific antigens responsible for clinical manifestations in SS.

Currently, no single diagnostic test for SS exists, thus delaying both diagnosis and initiation of treatment. Histopathologic examination may be helpful, but in many cases it is nonspecific, as are serologic markers. Neuroradiological confirmation of involvement usually is the confirmatory feature in many patients with late-stage diagnosis.² A diagnostic schematic for SS, which was first described by Daoud et al,² illustrates classification of symptoms and aids in diagnosis. A working diagnosis of idiopathic livedo racemosa is made after ruling out other causes of SS in a patient with nonspecific biopsy findings and negative magnetic resonance imaging results with prodromal symptoms. The prognosis for such patients progressing to full SS is unknown with or without management using anticoagulant therapy.

Conclusion

Early diagnosis of livedo racemosa and SS is essential, as prevention of cerebrovascular accidents, myocardial infarction, and other thromboembolic diseases can be minimized by attacking risk factors such as smoking, taking oral contraceptive pills, becoming pregnant,⁹ and by initiating either antiplatelet or anticoagulation treatments. These treatments have been shown to delay the development of neurovascular damage and early-onset dementia. We present this case to demonstrate the variability of early-presenting symptoms in idiopathic livedo racemosa. Recognizing some of the early manifestations can lead to early diagnosis and initiation of treatment.