CE/CME No: CR-1702

PROGRAM OVERVIEW
Earn credit by reading this article and successfully completing the posttest and evaluation. Successful completion is defined as a cumulative score of at least 70% correct.

EDUCATIONAL OBJECTIVES
• Define bipolar disorder according to the DSM-5 criteria.
• Recognize how patients with bipolar disorder can present to their primary care provider.
• Discuss how to perform a clinical and psychiatric evaluation on patients with suspected bipolar disorder.
• Describe the therapeutic options for a patient with bipolar disease in a primary care setting.

FACULTY
Jean Covino is a clinical professor at Pace University-Lenox Hill Hospital in New York City, and she practices at the Medemerge Family Practice Center in Green Brook, New Jersey. Jennifer Hofmann is an Associate Clinical Professor at Pace University-Lenox Hill Hospital in New York City.

The authors have no financial relationships to disclose.

ACCREDITATION STATEMENT

This program has been reviewed and is approved for a maximum of 1.0 hour of American Academy of Physician Assistants (AAPA) Category 1 CME credit by the Physician Assistant Review Panel. [NPs: Both ANCC and the AANP Certification Program recognize AAPA as an approved provider of Category 1 credit.] Approval is valid for one year from the issue date of February 2017.

Article begins on next page >>

Primary care clinicians are often the first point of contact for persons with bipolar disorder. Unfortunately, delays in diagnosis are common, as many of these patients are misdiagnosed with unipolar depression on initial presentation. Since an early and accurate diagnosis may reduce the burden of bipolar disorder and improve outcomes, clinicians should be able to recognize its symptoms and initiate treatment of this deceptive disorder.

Bipolar disorder is a chronic mental illness characterized by fluctuations in mood and energy that manifests as recurrent episodes of manic or depressive symptoms. It is estimated that between 10% and 38% of patients with bipolar disorder receive all their mental health care in a primary care setting.¹ Although patients with bipolar disorder often initially pre­sent to their primary care provider, they frequently go undiagnosed because of the complexity of the disorder’s symptomatology and a low index of suspicion among primary care providers.² Comorbid medical conditions and psychiatric issues can also lead to misdiagnoses.

Because primary care providers are often the first point of contact for patients with bipolar disorder, they are well positioned to recognize bipolar symptoms early in the course of the illness. The pure subtypes of bipolar disorder include bipolar I and bipolar II. Clinicians who work in a primary care or emergency department setting should be able to recognize and initiate treatment for these two subtypes while the patient is waiting for a psychiatric evaluation. Accurate early diagnosis of this disabling disorder can reduce morbidity and improve outcomes by allowing for appropriate referral, pharmacotherapy, and psychotherapy.

DEFINITION

According to the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM-5), bipolar disorder is a mood disorder defined by episodes of mania, hypomania, and major depression.³ Patients with bipolar I disorder experience manic episodes and almost always experience major depressive and hypomanic episodes. Bipolar II disorder is marked by at least one hypomanic episode, at least one major depressive episode (MDE), and the absence of manic episodes.³ A manic episode is at least one week of abnormally and continually elevated, expansive, or irritable mood and increased activity or energy accompanied by at least three of the following symptoms (or four if mood is only irritable): inflated self-esteem, decreased need for sleep, increased talkativeness, flight of ideas or racing thoughts, marked distractibility, increased goal-directed activity or agitation, and excessive involvement in dangerous or high-risk activities (eg, reckless spending or increased sexuality). To be considered a manic episode, the mood disturbance must cause marked impairment in social or occupational functioning, result in hospitalization, or involve psychotic features, and the symptoms cannot be attributable to the effects of drugs or medications or another medical condition.³

In a hypomanic episode, the period of elevated or irritable mood lasts for a shorter duration (at least four days); is associated with a clear, uncharacteristic change in functioning; and is observable by others but does not cause marked impairment, need for hospitalization, or psychosis. MDE is defined by the presence of at least five of nine symptoms for a minimum duration of two weeks and a change from previous functioning: depressed mood, markedly decreased interest or pleasure in activities, significant change in weight or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or excessive guilt, decreased ability to think or concentrate or indecisiveness, and recurrent thoughts of death or suicidality (at least one symptom must be depressed mood or loss of interest or pleasure).³

EPIDEMIOLOGY

Bipolar disorder affects men and women equally. It can occur at any age but is seen most commonly in persons younger than 25.⁴ The mean age at the first manic/hypomanic or major depressive episode was determined to be 18.2 in bipolar I and 20.3 in bipolar II.⁵ The lifetime prevalence of bipolar disorder in the United States is around 4%, with one study finding prevalence estimates of 1.0% for bipolar I disorder and 1.1% for bipolar II disorder.⁵

Bipolar disorder is common among primary care patients with depression. Two studies that explored the risk for bipolar disorder among depressed outpatients in primary care settings found that between 20% and 30% of these patients screened positive for bipolar disorder on the Mood Disorders Questionnaire (MDQ), indicating that a more thorough evaluation for bipolar disorder was needed.^6,7 A systematic review of the literature found similar rates of positive results on the MDQ screening measure among primary care patients with depression, a trauma exposure, medically unexplained symptoms, or a psychiatric complaint; bipolar disorder was diagnosed with a structured clinical interview in 3% to 9% of these patients.⁸ Children of parents with bipolar disorder have a 4% to 15% risk for also being affected.⁴

CLINICAL PRESENTATION IN PRIMARY CARE

Bipolar patients are often depressed or euthymic for a majority of their lives but can also present in a manic or hypomanic state. In primary care settings, these patients often present with depression (including postpartum depression), which can obscure the diagnosis. Misdiagnosis of bipolar disorder as recurrent unipolar depression occurs in 60% of patients seeking treatment for depression.⁹

Patients with bipolar disorder who pre­sent to primary care usually demonstrate a wide range of mood symptomatology other than depression, including mood swings, anxiety, fatigue, sleep disturbances, and the inability to focus or concentrate. Patients can also present in mixed states. These are characterized by elements of irritability, increased energy, and sleeplessness with depressive features.

Several clues that can assist in detecting bipolar disorder relate to age at onset, family history, mood shifts, seasonality, and atypical depressive symptoms  (eg, sleep dysregulation and appetite changes). Although the diagnosis of bipolar disorder is commonly delayed by many years, patients often report significant mood symptoms in their early 20s. In a study that used a self-administered questionnaire to assess the experience of persons living with bipolar disorder, 33% of the respondents were younger than 15 when their symptoms first started, 27% were between 15 and 19, and 39% were 20 or older.⁹ Parental and family history of bipolar disorder increases risk for the disorder in offspring, so a thorough family history is essential when the disorder is suspected.

Aside from the classic presentation defined by the DSM-5 criteria, patients with bipolar disorder can also exhibit other effects of their illness, such as alcohol-related problems and sexually transmitted or drug-related infections. In patients with bipolar disorder, rates of alcohol use range from 21.4% in adults to 54.5% in adolescents and young adults.¹⁰ Social history may reveal relationship and marital issues, financial problems, difficulties keeping a job, and legal problems.^9,11 Suicide attempts and completed suicides are significantly more common among persons with bipolar disorder than among the general population.^12,13

Comorbidity with at least one other disorder is common in bipolar disorder.⁵ The most common comorbid personality disorder associated with bipolar disorder is borderline personality disorder, which is characterized by ongoing instability in moods and behavior. Persons with this disorder can experience intense episodes of anger, depression, and anxiety that may last from hours to days. The high prevalence of persistent symptoms despite treatment in bipolar disorder and the unstable and partly remitting course of borderline personality make it difficult to distinguish between the two disorders.¹⁴ The frequent mood changes that occur with borderline personality disorder may appear to overlap with the mood swings characterizing bipolar disorder, but the mood episodes in borderline personality disorder are of shorter duration than those in bipolar disorder. Other common comorbid disorders seen in patients with bipolar disorder include substance abuse disorders, anxiety disorders (especially panic disorder, generalized anxiety disorder, and obsessive-compulsive disorder), and attention-deficit/hyperactivity disorder.⁵

Primary care providers should be aware of other common comorbidities that may be present in patients with bipolar disorder. These patients commonly experience medical problems such as diabetes, obesity, and metabolic syndrome, which all lead to increased cardiovascular risk.^15-17

CLINICAL EVALUATION

The initial clinical evaluation of the patient should include a thorough medical, social, family, and psychiatric history. Medical conditions that may mimic bipolar disorder include neurologic conditions (eg, partial seizures, neoplasm, strokes, dementia, delirium) and endocrine disorders (eg, Cushing disease, hyperthyroidism/hypothyroidism), as well as vitamin deficiencies (B₁₂, folate, niacin, thiamine) and drug and substance use/misuse (alcohol, drugs including antidepressants and stimulants).⁴ All patients should have a baseline complete physical examination, including neurologic and mental status examinations. Diagnostic tests to assess for potential differential diagnoses and evaluate baseline levels include the following:

• Basic metabolic panel, including fasting glucose, to evaluate electrolytes and risk for diabetes or Cushing disease, and to assess baseline renal function
• Thyroid function tests
• Complete blood count to assess status prior to anticonvulsant treatment (eg, carbamazepine)
• Pregnancy test if applicable (prior to use of medications)
• Liver function tests to assess baseline measurements prior to use of medications
• Electrocardiography in patients older than 40 to establish baseline and assess QTc interval, especially with use of antipsychotics and carbamazepine
• Urine toxicology screen (to rule out substance abuse).

PSYCHIATRIC EVALUATION

Psychiatric evaluation should focus on age at onset of symptoms, the presence of hypomanic or manic symptoms, prior response to antidepressants, course of the disease including history and duration of depression or manic/hypomanic episodes, and sleep disturbances (increased during depressive episodes and significantly decreased during manic episodes). It is important to assess for a history of self-harm, suicidal ideation, suicide attempts, hospitalizations, legal issues, multiple career shifts, marriage and relationship issues, and smoking and alcohol/substance misuse. Patients with severe manic or depressive episodes may experience psychotic features such as grandiose or paranoid delusions and hallucinations. A history of symptoms from close family members or friends can assist in the diagnosis of bipolar patients.

The use of DSM-5 criteria, as summarized earlier, improves the accuracy of bipolar diagnosis.³ In addition, validated tools are available to help clinicians screen for bipolar disorder, although it is important to remember that a positive screening result is not sufficient to establish a bipolar disorder diagnosis. A widely used instrument that has been validated for screening for bipolar disorder is the MDQ (available at www.dbsalliance.org/pdfs/MDQ.pdf). This self-report questionnaire consists of 15 questions that assess hypomanic or manic symptoms and functional impairment. The first 13 questions of the MDQ screen for a lifetime history of DSM-based hypomanic or manic symptoms. The last two questions ask whether these symptoms occurred at the same time and whether they caused dysfunction in various domains, such as work and family life. The MDQ is considered positive if a patient endorses at least seven of the symptom items, indicates that symptoms have occurred at the same time, and rates their dysfunction in life domains as “moderate” or “serious.” As a screening tool, the MDQ has a reported sensitivity of 73% and a specificity of 90% for bipolar disorder.¹¹ This questionnaire can and should be used by primary care providers to help determine if their patient is at risk and requires a comprehensive evaluation for bipolar disorder.

Notably, even after a clinician has properly diagnosed bipolar disorder, patients and family members are often reluctant to commence treatment due to the stigma associated with mental health disorders.¹⁸ To help offset the effects of stigma, patients should be referred for psychologic counseling, including family counseling.

MANAGEMENT

Management of bipolar disorder in the primary care setting includes psychiatric and psychologic counseling referrals. Primary care providers must know the medications used to treat bipolar disorder and their related adverse effects, toxicities, warnings, and drug interactions, as they may treat bipolar patients for other medical conditions. Early diagnosis and treatment/referral can improve prognosis and reduce the risk for relapse and subsequent disability.¹⁹ Inpatient management is generally recommended for severe manic episodes, psychotic episodes, patients who present a danger to themselves or others, and patients with suicidal or homicidal ideations/actions.

Medications are the primary treatment for all stages of bipolar disorder, and choice of medications is based on stage, previous response, and adverse effect profiles (see Table 1).^2,4,20 Generally, antidepressants (serotonin and norepinephrine reuptake inhibitors [SNRIs] and selective serotonin reuptake inhibitors [SSRIs]) should be avoided or should be used with an effective antimanic/mood stabilizer. Many patients with severe bipolar symptoms require more than two medications, and it is imperative that all primary care providers understand that often one drug alone is not sufficient treatment for patients with bipolar disorder. For less severe manic or hypomanic states, monotherapy with antipsychotics may be effective.

Medications for severe acute manic episodes generally include the mood stabilizers lithium, valproate, or carbamazepine in conjunction with an antipsychotic, such as haloperidol, or an atypical antipsychotic, such as asenapine, aripiprazole, olanza­pine, quetiapine, or risperidone.² The goal of initial therapy in patients with acute mania is rapid resolution of symptoms and restoration of adequate sleep. Lithium has a slower onset of action than valproate and carbamazepine and requires titration and monitoring. Valproate and carbamazepine have a faster onset of action but are less effective than lithium.² Atypical antipsychotics have a more rapid onset of action than mood stabilizers and are effective in controlling acute manic symptoms, psychosis, and sleep disturbances. Patients with severe acute mania may require hospital admission for stabilization, for their safety and the safety of others.

Acute bipolar depressive episodes can be treated with several different medication options, including combination olanzapine and fluoxetine; the atypical antipsychotic quetiapine; and recently lurasidone, alone or in combination with lithium or valproate. Lamotrigine is more effective for maintenance and prevention of depressive episodes than for treatment of acute episodes, and it is also indicated for treatment of bipolar II. Valproate is more effective than lithium for mixed states and can be titrated more rapidly for faster antimanic effects.⁴

Generally, due to the high rate of recurrence, maintenance medications should be continued indefinitely. Maintenance medications include the mood stabilizers, lamotrigine, and many of the antipsychotics, including olanzapine.⁴ Adherence to medications is essential in management of bipolar disorder and can decrease the risk for relapses and destabilization. Poor adherence to medications is common, however, with rates reported at approximately 50%.²¹ Patient and family education, as well as psychotherapy, can improve adherence rates.² Primary care providers should educate patients and family members about medication options and adverse effects and must stress the need for adherence to prevent relapse. Providers should also understand the safety profile of mood stabilizers and antipsychotics and the required monitoring of laboratory tests for patients on these medications.

Psychosocial treatments are an elemental component of management. Patients should be referred early for psychologic treatments including, but not limited to, family therapy, group therapy, cognitive-behavioral therapy, and psychotherapy, which have been shown to improve daily functioning, recognition of recurrences, and medication adherence.² The rate of relapse is significantly lower in patients receiving combination psychotherapy and pharmacotherapy.²²

Clinical pearls that every primary care provider should know about bipolar disorder are summarized in Table 2.

CONCLUSION

Given the substantial impact of bipolar disorder on patients and the community, primary care clinicians must maintain a high index of suspicion for this disorder. An early and accurate diagnosis may reduce the burden of bipolar disorder and improve outcomes. However, diagnosing and treating patients with bipolar disorder is challenging for primary care and specialty clinicians alike. In particular, establishing a diagnosis can be difficult, even for the most seasoned clinician, due to the diversity of symptoms. Nonetheless, diagnosing bipolar disorder, initiating treatment, and monitoring and referring patients when necessary are certainly within the purview of the primary care provider.

CE/CME No: CR-1702

PROGRAM OVERVIEW
Earn credit by reading this article and successfully completing the posttest and evaluation. Successful completion is defined as a cumulative score of at least 70% correct.

EDUCATIONAL OBJECTIVES
• Define bipolar disorder according to the DSM-5 criteria.
• Recognize how patients with bipolar disorder can present to their primary care provider.
• Discuss how to perform a clinical and psychiatric evaluation on patients with suspected bipolar disorder.
• Describe the therapeutic options for a patient with bipolar disease in a primary care setting.

FACULTY
Jean Covino is a clinical professor at Pace University-Lenox Hill Hospital in New York City, and she practices at the Medemerge Family Practice Center in Green Brook, New Jersey. Jennifer Hofmann is an Associate Clinical Professor at Pace University-Lenox Hill Hospital in New York City.

The authors have no financial relationships to disclose.

ACCREDITATION STATEMENT

This program has been reviewed and is approved for a maximum of 1.0 hour of American Academy of Physician Assistants (AAPA) Category 1 CME credit by the Physician Assistant Review Panel. [NPs: Both ANCC and the AANP Certification Program recognize AAPA as an approved provider of Category 1 credit.] Approval is valid for one year from the issue date of February 2017.

Article begins on next page >>

Primary care clinicians are often the first point of contact for persons with bipolar disorder. Unfortunately, delays in diagnosis are common, as many of these patients are misdiagnosed with unipolar depression on initial presentation. Since an early and accurate diagnosis may reduce the burden of bipolar disorder and improve outcomes, clinicians should be able to recognize its symptoms and initiate treatment of this deceptive disorder.

Bipolar disorder is a chronic mental illness characterized by fluctuations in mood and energy that manifests as recurrent episodes of manic or depressive symptoms. It is estimated that between 10% and 38% of patients with bipolar disorder receive all their mental health care in a primary care setting.¹ Although patients with bipolar disorder often initially pre­sent to their primary care provider, they frequently go undiagnosed because of the complexity of the disorder’s symptomatology and a low index of suspicion among primary care providers.² Comorbid medical conditions and psychiatric issues can also lead to misdiagnoses.

Because primary care providers are often the first point of contact for patients with bipolar disorder, they are well positioned to recognize bipolar symptoms early in the course of the illness. The pure subtypes of bipolar disorder include bipolar I and bipolar II. Clinicians who work in a primary care or emergency department setting should be able to recognize and initiate treatment for these two subtypes while the patient is waiting for a psychiatric evaluation. Accurate early diagnosis of this disabling disorder can reduce morbidity and improve outcomes by allowing for appropriate referral, pharmacotherapy, and psychotherapy.

DEFINITION

According to the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM-5), bipolar disorder is a mood disorder defined by episodes of mania, hypomania, and major depression.³ Patients with bipolar I disorder experience manic episodes and almost always experience major depressive and hypomanic episodes. Bipolar II disorder is marked by at least one hypomanic episode, at least one major depressive episode (MDE), and the absence of manic episodes.³ A manic episode is at least one week of abnormally and continually elevated, expansive, or irritable mood and increased activity or energy accompanied by at least three of the following symptoms (or four if mood is only irritable): inflated self-esteem, decreased need for sleep, increased talkativeness, flight of ideas or racing thoughts, marked distractibility, increased goal-directed activity or agitation, and excessive involvement in dangerous or high-risk activities (eg, reckless spending or increased sexuality). To be considered a manic episode, the mood disturbance must cause marked impairment in social or occupational functioning, result in hospitalization, or involve psychotic features, and the symptoms cannot be attributable to the effects of drugs or medications or another medical condition.³

In a hypomanic episode, the period of elevated or irritable mood lasts for a shorter duration (at least four days); is associated with a clear, uncharacteristic change in functioning; and is observable by others but does not cause marked impairment, need for hospitalization, or psychosis. MDE is defined by the presence of at least five of nine symptoms for a minimum duration of two weeks and a change from previous functioning: depressed mood, markedly decreased interest or pleasure in activities, significant change in weight or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or excessive guilt, decreased ability to think or concentrate or indecisiveness, and recurrent thoughts of death or suicidality (at least one symptom must be depressed mood or loss of interest or pleasure).³

EPIDEMIOLOGY

Bipolar disorder affects men and women equally. It can occur at any age but is seen most commonly in persons younger than 25.⁴ The mean age at the first manic/hypomanic or major depressive episode was determined to be 18.2 in bipolar I and 20.3 in bipolar II.⁵ The lifetime prevalence of bipolar disorder in the United States is around 4%, with one study finding prevalence estimates of 1.0% for bipolar I disorder and 1.1% for bipolar II disorder.⁵

Bipolar disorder is common among primary care patients with depression. Two studies that explored the risk for bipolar disorder among depressed outpatients in primary care settings found that between 20% and 30% of these patients screened positive for bipolar disorder on the Mood Disorders Questionnaire (MDQ), indicating that a more thorough evaluation for bipolar disorder was needed.^6,7 A systematic review of the literature found similar rates of positive results on the MDQ screening measure among primary care patients with depression, a trauma exposure, medically unexplained symptoms, or a psychiatric complaint; bipolar disorder was diagnosed with a structured clinical interview in 3% to 9% of these patients.⁸ Children of parents with bipolar disorder have a 4% to 15% risk for also being affected.⁴

CLINICAL PRESENTATION IN PRIMARY CARE

Bipolar patients are often depressed or euthymic for a majority of their lives but can also present in a manic or hypomanic state. In primary care settings, these patients often present with depression (including postpartum depression), which can obscure the diagnosis. Misdiagnosis of bipolar disorder as recurrent unipolar depression occurs in 60% of patients seeking treatment for depression.⁹

Patients with bipolar disorder who pre­sent to primary care usually demonstrate a wide range of mood symptomatology other than depression, including mood swings, anxiety, fatigue, sleep disturbances, and the inability to focus or concentrate. Patients can also present in mixed states. These are characterized by elements of irritability, increased energy, and sleeplessness with depressive features.

Several clues that can assist in detecting bipolar disorder relate to age at onset, family history, mood shifts, seasonality, and atypical depressive symptoms  (eg, sleep dysregulation and appetite changes). Although the diagnosis of bipolar disorder is commonly delayed by many years, patients often report significant mood symptoms in their early 20s. In a study that used a self-administered questionnaire to assess the experience of persons living with bipolar disorder, 33% of the respondents were younger than 15 when their symptoms first started, 27% were between 15 and 19, and 39% were 20 or older.⁹ Parental and family history of bipolar disorder increases risk for the disorder in offspring, so a thorough family history is essential when the disorder is suspected.

Aside from the classic presentation defined by the DSM-5 criteria, patients with bipolar disorder can also exhibit other effects of their illness, such as alcohol-related problems and sexually transmitted or drug-related infections. In patients with bipolar disorder, rates of alcohol use range from 21.4% in adults to 54.5% in adolescents and young adults.¹⁰ Social history may reveal relationship and marital issues, financial problems, difficulties keeping a job, and legal problems.^9,11 Suicide attempts and completed suicides are significantly more common among persons with bipolar disorder than among the general population.^12,13

Comorbidity with at least one other disorder is common in bipolar disorder.⁵ The most common comorbid personality disorder associated with bipolar disorder is borderline personality disorder, which is characterized by ongoing instability in moods and behavior. Persons with this disorder can experience intense episodes of anger, depression, and anxiety that may last from hours to days. The high prevalence of persistent symptoms despite treatment in bipolar disorder and the unstable and partly remitting course of borderline personality make it difficult to distinguish between the two disorders.¹⁴ The frequent mood changes that occur with borderline personality disorder may appear to overlap with the mood swings characterizing bipolar disorder, but the mood episodes in borderline personality disorder are of shorter duration than those in bipolar disorder. Other common comorbid disorders seen in patients with bipolar disorder include substance abuse disorders, anxiety disorders (especially panic disorder, generalized anxiety disorder, and obsessive-compulsive disorder), and attention-deficit/hyperactivity disorder.⁵

Primary care providers should be aware of other common comorbidities that may be present in patients with bipolar disorder. These patients commonly experience medical problems such as diabetes, obesity, and metabolic syndrome, which all lead to increased cardiovascular risk.^15-17

CLINICAL EVALUATION

The initial clinical evaluation of the patient should include a thorough medical, social, family, and psychiatric history. Medical conditions that may mimic bipolar disorder include neurologic conditions (eg, partial seizures, neoplasm, strokes, dementia, delirium) and endocrine disorders (eg, Cushing disease, hyperthyroidism/hypothyroidism), as well as vitamin deficiencies (B₁₂, folate, niacin, thiamine) and drug and substance use/misuse (alcohol, drugs including antidepressants and stimulants).⁴ All patients should have a baseline complete physical examination, including neurologic and mental status examinations. Diagnostic tests to assess for potential differential diagnoses and evaluate baseline levels include the following:

• Basic metabolic panel, including fasting glucose, to evaluate electrolytes and risk for diabetes or Cushing disease, and to assess baseline renal function
• Thyroid function tests
• Complete blood count to assess status prior to anticonvulsant treatment (eg, carbamazepine)
• Pregnancy test if applicable (prior to use of medications)
• Liver function tests to assess baseline measurements prior to use of medications
• Electrocardiography in patients older than 40 to establish baseline and assess QTc interval, especially with use of antipsychotics and carbamazepine
• Urine toxicology screen (to rule out substance abuse).

PSYCHIATRIC EVALUATION

Psychiatric evaluation should focus on age at onset of symptoms, the presence of hypomanic or manic symptoms, prior response to antidepressants, course of the disease including history and duration of depression or manic/hypomanic episodes, and sleep disturbances (increased during depressive episodes and significantly decreased during manic episodes). It is important to assess for a history of self-harm, suicidal ideation, suicide attempts, hospitalizations, legal issues, multiple career shifts, marriage and relationship issues, and smoking and alcohol/substance misuse. Patients with severe manic or depressive episodes may experience psychotic features such as grandiose or paranoid delusions and hallucinations. A history of symptoms from close family members or friends can assist in the diagnosis of bipolar patients.

The use of DSM-5 criteria, as summarized earlier, improves the accuracy of bipolar diagnosis.³ In addition, validated tools are available to help clinicians screen for bipolar disorder, although it is important to remember that a positive screening result is not sufficient to establish a bipolar disorder diagnosis. A widely used instrument that has been validated for screening for bipolar disorder is the MDQ (available at www.dbsalliance.org/pdfs/MDQ.pdf). This self-report questionnaire consists of 15 questions that assess hypomanic or manic symptoms and functional impairment. The first 13 questions of the MDQ screen for a lifetime history of DSM-based hypomanic or manic symptoms. The last two questions ask whether these symptoms occurred at the same time and whether they caused dysfunction in various domains, such as work and family life. The MDQ is considered positive if a patient endorses at least seven of the symptom items, indicates that symptoms have occurred at the same time, and rates their dysfunction in life domains as “moderate” or “serious.” As a screening tool, the MDQ has a reported sensitivity of 73% and a specificity of 90% for bipolar disorder.¹¹ This questionnaire can and should be used by primary care providers to help determine if their patient is at risk and requires a comprehensive evaluation for bipolar disorder.

Notably, even after a clinician has properly diagnosed bipolar disorder, patients and family members are often reluctant to commence treatment due to the stigma associated with mental health disorders.¹⁸ To help offset the effects of stigma, patients should be referred for psychologic counseling, including family counseling.

MANAGEMENT

Management of bipolar disorder in the primary care setting includes psychiatric and psychologic counseling referrals. Primary care providers must know the medications used to treat bipolar disorder and their related adverse effects, toxicities, warnings, and drug interactions, as they may treat bipolar patients for other medical conditions. Early diagnosis and treatment/referral can improve prognosis and reduce the risk for relapse and subsequent disability.¹⁹ Inpatient management is generally recommended for severe manic episodes, psychotic episodes, patients who present a danger to themselves or others, and patients with suicidal or homicidal ideations/actions.

Medications are the primary treatment for all stages of bipolar disorder, and choice of medications is based on stage, previous response, and adverse effect profiles (see Table 1).^2,4,20 Generally, antidepressants (serotonin and norepinephrine reuptake inhibitors [SNRIs] and selective serotonin reuptake inhibitors [SSRIs]) should be avoided or should be used with an effective antimanic/mood stabilizer. Many patients with severe bipolar symptoms require more than two medications, and it is imperative that all primary care providers understand that often one drug alone is not sufficient treatment for patients with bipolar disorder. For less severe manic or hypomanic states, monotherapy with antipsychotics may be effective.

Medications for severe acute manic episodes generally include the mood stabilizers lithium, valproate, or carbamazepine in conjunction with an antipsychotic, such as haloperidol, or an atypical antipsychotic, such as asenapine, aripiprazole, olanza­pine, quetiapine, or risperidone.² The goal of initial therapy in patients with acute mania is rapid resolution of symptoms and restoration of adequate sleep. Lithium has a slower onset of action than valproate and carbamazepine and requires titration and monitoring. Valproate and carbamazepine have a faster onset of action but are less effective than lithium.² Atypical antipsychotics have a more rapid onset of action than mood stabilizers and are effective in controlling acute manic symptoms, psychosis, and sleep disturbances. Patients with severe acute mania may require hospital admission for stabilization, for their safety and the safety of others.

Acute bipolar depressive episodes can be treated with several different medication options, including combination olanzapine and fluoxetine; the atypical antipsychotic quetiapine; and recently lurasidone, alone or in combination with lithium or valproate. Lamotrigine is more effective for maintenance and prevention of depressive episodes than for treatment of acute episodes, and it is also indicated for treatment of bipolar II. Valproate is more effective than lithium for mixed states and can be titrated more rapidly for faster antimanic effects.⁴

Generally, due to the high rate of recurrence, maintenance medications should be continued indefinitely. Maintenance medications include the mood stabilizers, lamotrigine, and many of the antipsychotics, including olanzapine.⁴ Adherence to medications is essential in management of bipolar disorder and can decrease the risk for relapses and destabilization. Poor adherence to medications is common, however, with rates reported at approximately 50%.²¹ Patient and family education, as well as psychotherapy, can improve adherence rates.² Primary care providers should educate patients and family members about medication options and adverse effects and must stress the need for adherence to prevent relapse. Providers should also understand the safety profile of mood stabilizers and antipsychotics and the required monitoring of laboratory tests for patients on these medications.

Psychosocial treatments are an elemental component of management. Patients should be referred early for psychologic treatments including, but not limited to, family therapy, group therapy, cognitive-behavioral therapy, and psychotherapy, which have been shown to improve daily functioning, recognition of recurrences, and medication adherence.² The rate of relapse is significantly lower in patients receiving combination psychotherapy and pharmacotherapy.²²

Clinical pearls that every primary care provider should know about bipolar disorder are summarized in Table 2.

CONCLUSION

Given the substantial impact of bipolar disorder on patients and the community, primary care clinicians must maintain a high index of suspicion for this disorder. An early and accurate diagnosis may reduce the burden of bipolar disorder and improve outcomes. However, diagnosing and treating patients with bipolar disorder is challenging for primary care and specialty clinicians alike. In particular, establishing a diagnosis can be difficult, even for the most seasoned clinician, due to the diversity of symptoms. Nonetheless, diagnosing bipolar disorder, initiating treatment, and monitoring and referring patients when necessary are certainly within the purview of the primary care provider.

CE/CME No: CR-1702

PROGRAM OVERVIEW
Earn credit by reading this article and successfully completing the posttest and evaluation. Successful completion is defined as a cumulative score of at least 70% correct.

EDUCATIONAL OBJECTIVES
• Define bipolar disorder according to the DSM-5 criteria.
• Recognize how patients with bipolar disorder can present to their primary care provider.
• Discuss how to perform a clinical and psychiatric evaluation on patients with suspected bipolar disorder.
• Describe the therapeutic options for a patient with bipolar disease in a primary care setting.

FACULTY
Jean Covino is a clinical professor at Pace University-Lenox Hill Hospital in New York City, and she practices at the Medemerge Family Practice Center in Green Brook, New Jersey. Jennifer Hofmann is an Associate Clinical Professor at Pace University-Lenox Hill Hospital in New York City.

The authors have no financial relationships to disclose.

ACCREDITATION STATEMENT

This program has been reviewed and is approved for a maximum of 1.0 hour of American Academy of Physician Assistants (AAPA) Category 1 CME credit by the Physician Assistant Review Panel. [NPs: Both ANCC and the AANP Certification Program recognize AAPA as an approved provider of Category 1 credit.] Approval is valid for one year from the issue date of February 2017.

Article begins on next page >>

Primary care clinicians are often the first point of contact for persons with bipolar disorder. Unfortunately, delays in diagnosis are common, as many of these patients are misdiagnosed with unipolar depression on initial presentation. Since an early and accurate diagnosis may reduce the burden of bipolar disorder and improve outcomes, clinicians should be able to recognize its symptoms and initiate treatment of this deceptive disorder.

Bipolar disorder is a chronic mental illness characterized by fluctuations in mood and energy that manifests as recurrent episodes of manic or depressive symptoms. It is estimated that between 10% and 38% of patients with bipolar disorder receive all their mental health care in a primary care setting.¹ Although patients with bipolar disorder often initially pre­sent to their primary care provider, they frequently go undiagnosed because of the complexity of the disorder’s symptomatology and a low index of suspicion among primary care providers.² Comorbid medical conditions and psychiatric issues can also lead to misdiagnoses.

Because primary care providers are often the first point of contact for patients with bipolar disorder, they are well positioned to recognize bipolar symptoms early in the course of the illness. The pure subtypes of bipolar disorder include bipolar I and bipolar II. Clinicians who work in a primary care or emergency department setting should be able to recognize and initiate treatment for these two subtypes while the patient is waiting for a psychiatric evaluation. Accurate early diagnosis of this disabling disorder can reduce morbidity and improve outcomes by allowing for appropriate referral, pharmacotherapy, and psychotherapy.

DEFINITION

According to the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM-5), bipolar disorder is a mood disorder defined by episodes of mania, hypomania, and major depression.³ Patients with bipolar I disorder experience manic episodes and almost always experience major depressive and hypomanic episodes. Bipolar II disorder is marked by at least one hypomanic episode, at least one major depressive episode (MDE), and the absence of manic episodes.³ A manic episode is at least one week of abnormally and continually elevated, expansive, or irritable mood and increased activity or energy accompanied by at least three of the following symptoms (or four if mood is only irritable): inflated self-esteem, decreased need for sleep, increased talkativeness, flight of ideas or racing thoughts, marked distractibility, increased goal-directed activity or agitation, and excessive involvement in dangerous or high-risk activities (eg, reckless spending or increased sexuality). To be considered a manic episode, the mood disturbance must cause marked impairment in social or occupational functioning, result in hospitalization, or involve psychotic features, and the symptoms cannot be attributable to the effects of drugs or medications or another medical condition.³

In a hypomanic episode, the period of elevated or irritable mood lasts for a shorter duration (at least four days); is associated with a clear, uncharacteristic change in functioning; and is observable by others but does not cause marked impairment, need for hospitalization, or psychosis. MDE is defined by the presence of at least five of nine symptoms for a minimum duration of two weeks and a change from previous functioning: depressed mood, markedly decreased interest or pleasure in activities, significant change in weight or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or excessive guilt, decreased ability to think or concentrate or indecisiveness, and recurrent thoughts of death or suicidality (at least one symptom must be depressed mood or loss of interest or pleasure).³

EPIDEMIOLOGY

Bipolar disorder affects men and women equally. It can occur at any age but is seen most commonly in persons younger than 25.⁴ The mean age at the first manic/hypomanic or major depressive episode was determined to be 18.2 in bipolar I and 20.3 in bipolar II.⁵ The lifetime prevalence of bipolar disorder in the United States is around 4%, with one study finding prevalence estimates of 1.0% for bipolar I disorder and 1.1% for bipolar II disorder.⁵

Bipolar disorder is common among primary care patients with depression. Two studies that explored the risk for bipolar disorder among depressed outpatients in primary care settings found that between 20% and 30% of these patients screened positive for bipolar disorder on the Mood Disorders Questionnaire (MDQ), indicating that a more thorough evaluation for bipolar disorder was needed.^6,7 A systematic review of the literature found similar rates of positive results on the MDQ screening measure among primary care patients with depression, a trauma exposure, medically unexplained symptoms, or a psychiatric complaint; bipolar disorder was diagnosed with a structured clinical interview in 3% to 9% of these patients.⁸ Children of parents with bipolar disorder have a 4% to 15% risk for also being affected.⁴

CLINICAL PRESENTATION IN PRIMARY CARE

Bipolar patients are often depressed or euthymic for a majority of their lives but can also present in a manic or hypomanic state. In primary care settings, these patients often present with depression (including postpartum depression), which can obscure the diagnosis. Misdiagnosis of bipolar disorder as recurrent unipolar depression occurs in 60% of patients seeking treatment for depression.⁹

Patients with bipolar disorder who pre­sent to primary care usually demonstrate a wide range of mood symptomatology other than depression, including mood swings, anxiety, fatigue, sleep disturbances, and the inability to focus or concentrate. Patients can also present in mixed states. These are characterized by elements of irritability, increased energy, and sleeplessness with depressive features.

Several clues that can assist in detecting bipolar disorder relate to age at onset, family history, mood shifts, seasonality, and atypical depressive symptoms  (eg, sleep dysregulation and appetite changes). Although the diagnosis of bipolar disorder is commonly delayed by many years, patients often report significant mood symptoms in their early 20s. In a study that used a self-administered questionnaire to assess the experience of persons living with bipolar disorder, 33% of the respondents were younger than 15 when their symptoms first started, 27% were between 15 and 19, and 39% were 20 or older.⁹ Parental and family history of bipolar disorder increases risk for the disorder in offspring, so a thorough family history is essential when the disorder is suspected.

Aside from the classic presentation defined by the DSM-5 criteria, patients with bipolar disorder can also exhibit other effects of their illness, such as alcohol-related problems and sexually transmitted or drug-related infections. In patients with bipolar disorder, rates of alcohol use range from 21.4% in adults to 54.5% in adolescents and young adults.¹⁰ Social history may reveal relationship and marital issues, financial problems, difficulties keeping a job, and legal problems.^9,11 Suicide attempts and completed suicides are significantly more common among persons with bipolar disorder than among the general population.^12,13

Comorbidity with at least one other disorder is common in bipolar disorder.⁵ The most common comorbid personality disorder associated with bipolar disorder is borderline personality disorder, which is characterized by ongoing instability in moods and behavior. Persons with this disorder can experience intense episodes of anger, depression, and anxiety that may last from hours to days. The high prevalence of persistent symptoms despite treatment in bipolar disorder and the unstable and partly remitting course of borderline personality make it difficult to distinguish between the two disorders.¹⁴ The frequent mood changes that occur with borderline personality disorder may appear to overlap with the mood swings characterizing bipolar disorder, but the mood episodes in borderline personality disorder are of shorter duration than those in bipolar disorder. Other common comorbid disorders seen in patients with bipolar disorder include substance abuse disorders, anxiety disorders (especially panic disorder, generalized anxiety disorder, and obsessive-compulsive disorder), and attention-deficit/hyperactivity disorder.⁵

Primary care providers should be aware of other common comorbidities that may be present in patients with bipolar disorder. These patients commonly experience medical problems such as diabetes, obesity, and metabolic syndrome, which all lead to increased cardiovascular risk.^15-17

CLINICAL EVALUATION

The initial clinical evaluation of the patient should include a thorough medical, social, family, and psychiatric history. Medical conditions that may mimic bipolar disorder include neurologic conditions (eg, partial seizures, neoplasm, strokes, dementia, delirium) and endocrine disorders (eg, Cushing disease, hyperthyroidism/hypothyroidism), as well as vitamin deficiencies (B₁₂, folate, niacin, thiamine) and drug and substance use/misuse (alcohol, drugs including antidepressants and stimulants).⁴ All patients should have a baseline complete physical examination, including neurologic and mental status examinations. Diagnostic tests to assess for potential differential diagnoses and evaluate baseline levels include the following:

• Basic metabolic panel, including fasting glucose, to evaluate electrolytes and risk for diabetes or Cushing disease, and to assess baseline renal function
• Thyroid function tests
• Complete blood count to assess status prior to anticonvulsant treatment (eg, carbamazepine)
• Pregnancy test if applicable (prior to use of medications)
• Liver function tests to assess baseline measurements prior to use of medications
• Electrocardiography in patients older than 40 to establish baseline and assess QTc interval, especially with use of antipsychotics and carbamazepine
• Urine toxicology screen (to rule out substance abuse).

PSYCHIATRIC EVALUATION

Psychiatric evaluation should focus on age at onset of symptoms, the presence of hypomanic or manic symptoms, prior response to antidepressants, course of the disease including history and duration of depression or manic/hypomanic episodes, and sleep disturbances (increased during depressive episodes and significantly decreased during manic episodes). It is important to assess for a history of self-harm, suicidal ideation, suicide attempts, hospitalizations, legal issues, multiple career shifts, marriage and relationship issues, and smoking and alcohol/substance misuse. Patients with severe manic or depressive episodes may experience psychotic features such as grandiose or paranoid delusions and hallucinations. A history of symptoms from close family members or friends can assist in the diagnosis of bipolar patients.

The use of DSM-5 criteria, as summarized earlier, improves the accuracy of bipolar diagnosis.³ In addition, validated tools are available to help clinicians screen for bipolar disorder, although it is important to remember that a positive screening result is not sufficient to establish a bipolar disorder diagnosis. A widely used instrument that has been validated for screening for bipolar disorder is the MDQ (available at www.dbsalliance.org/pdfs/MDQ.pdf). This self-report questionnaire consists of 15 questions that assess hypomanic or manic symptoms and functional impairment. The first 13 questions of the MDQ screen for a lifetime history of DSM-based hypomanic or manic symptoms. The last two questions ask whether these symptoms occurred at the same time and whether they caused dysfunction in various domains, such as work and family life. The MDQ is considered positive if a patient endorses at least seven of the symptom items, indicates that symptoms have occurred at the same time, and rates their dysfunction in life domains as “moderate” or “serious.” As a screening tool, the MDQ has a reported sensitivity of 73% and a specificity of 90% for bipolar disorder.¹¹ This questionnaire can and should be used by primary care providers to help determine if their patient is at risk and requires a comprehensive evaluation for bipolar disorder.

Notably, even after a clinician has properly diagnosed bipolar disorder, patients and family members are often reluctant to commence treatment due to the stigma associated with mental health disorders.¹⁸ To help offset the effects of stigma, patients should be referred for psychologic counseling, including family counseling.

MANAGEMENT

Management of bipolar disorder in the primary care setting includes psychiatric and psychologic counseling referrals. Primary care providers must know the medications used to treat bipolar disorder and their related adverse effects, toxicities, warnings, and drug interactions, as they may treat bipolar patients for other medical conditions. Early diagnosis and treatment/referral can improve prognosis and reduce the risk for relapse and subsequent disability.¹⁹ Inpatient management is generally recommended for severe manic episodes, psychotic episodes, patients who present a danger to themselves or others, and patients with suicidal or homicidal ideations/actions.

Medications are the primary treatment for all stages of bipolar disorder, and choice of medications is based on stage, previous response, and adverse effect profiles (see Table 1).^2,4,20 Generally, antidepressants (serotonin and norepinephrine reuptake inhibitors [SNRIs] and selective serotonin reuptake inhibitors [SSRIs]) should be avoided or should be used with an effective antimanic/mood stabilizer. Many patients with severe bipolar symptoms require more than two medications, and it is imperative that all primary care providers understand that often one drug alone is not sufficient treatment for patients with bipolar disorder. For less severe manic or hypomanic states, monotherapy with antipsychotics may be effective.

Medications for severe acute manic episodes generally include the mood stabilizers lithium, valproate, or carbamazepine in conjunction with an antipsychotic, such as haloperidol, or an atypical antipsychotic, such as asenapine, aripiprazole, olanza­pine, quetiapine, or risperidone.² The goal of initial therapy in patients with acute mania is rapid resolution of symptoms and restoration of adequate sleep. Lithium has a slower onset of action than valproate and carbamazepine and requires titration and monitoring. Valproate and carbamazepine have a faster onset of action but are less effective than lithium.² Atypical antipsychotics have a more rapid onset of action than mood stabilizers and are effective in controlling acute manic symptoms, psychosis, and sleep disturbances. Patients with severe acute mania may require hospital admission for stabilization, for their safety and the safety of others.

Acute bipolar depressive episodes can be treated with several different medication options, including combination olanzapine and fluoxetine; the atypical antipsychotic quetiapine; and recently lurasidone, alone or in combination with lithium or valproate. Lamotrigine is more effective for maintenance and prevention of depressive episodes than for treatment of acute episodes, and it is also indicated for treatment of bipolar II. Valproate is more effective than lithium for mixed states and can be titrated more rapidly for faster antimanic effects.⁴

Generally, due to the high rate of recurrence, maintenance medications should be continued indefinitely. Maintenance medications include the mood stabilizers, lamotrigine, and many of the antipsychotics, including olanzapine.⁴ Adherence to medications is essential in management of bipolar disorder and can decrease the risk for relapses and destabilization. Poor adherence to medications is common, however, with rates reported at approximately 50%.²¹ Patient and family education, as well as psychotherapy, can improve adherence rates.² Primary care providers should educate patients and family members about medication options and adverse effects and must stress the need for adherence to prevent relapse. Providers should also understand the safety profile of mood stabilizers and antipsychotics and the required monitoring of laboratory tests for patients on these medications.

Psychosocial treatments are an elemental component of management. Patients should be referred early for psychologic treatments including, but not limited to, family therapy, group therapy, cognitive-behavioral therapy, and psychotherapy, which have been shown to improve daily functioning, recognition of recurrences, and medication adherence.² The rate of relapse is significantly lower in patients receiving combination psychotherapy and pharmacotherapy.²²

Clinical pearls that every primary care provider should know about bipolar disorder are summarized in Table 2.

CONCLUSION

Given the substantial impact of bipolar disorder on patients and the community, primary care clinicians must maintain a high index of suspicion for this disorder. An early and accurate diagnosis may reduce the burden of bipolar disorder and improve outcomes. However, diagnosing and treating patients with bipolar disorder is challenging for primary care and specialty clinicians alike. In particular, establishing a diagnosis can be difficult, even for the most seasoned clinician, due to the diversity of symptoms. Nonetheless, diagnosing bipolar disorder, initiating treatment, and monitoring and referring patients when necessary are certainly within the purview of the primary care provider.

ILLUSTRATIVE CASE

A 21-year-old G1P0 at 35 weeks, 2 days of gestation presents to labor and delivery reporting a “gush of clear fluid.” On exam, you confirm she has preterm rupture of membranes. She is contracting every 3 minutes and has a cervix dilated to 3 cm. Is there any neonatal benefit to providing corticosteroids in this late preterm period?

Approximately 12% of all births in the United States are the result of preterm labor,² and 8% are born in the late preterm period, defined as 34 to 36 weeks’ gestation.³ To reduce the risk of neonatal death and respiratory complications, both the American College of Obstetricians and Gynecologists and the National Institutes of Health recommend a course of corticosteroids between 24 and 34 weeks’ gestation for women at increased risk of preterm delivery.^2,4 Due to a lack of evidence from randomized controlled trials (RCTs) on the benefit of corticosteroids in late preterm labor, there have not been recommendations to extend this period.⁵ However, multiple studies have shown that babies born during the late preterm period have more neonatal complications than term newborns.^6-8

A retrospective chart review of more than 130,000 live births found newborns delivered between 34 and 36 weeks had higher rates of respiratory distress than those delivered at 39 weeks (ventilator use dropped from 3.3% at 34 weeks to 0.3% at 39 weeks and transient tachypnea decreased from 2.4% at 34 weeks to 0.4% at 39 weeks).⁶ Another retrospective review of more than 230,000 newborns, of which 19,000 were born in the late preterm period, revealed that more neonates born between 34 and 36 weeks’ gestation had respiratory distress syndrome than neonates delivered at 39 weeks (10.5% at 34 weeks, 6% at 35 weeks, 2.8% at 36 weeks vs 0.3% at 39 weeks; P<.001 for the trend).⁸

STUDY SUMMARY

Late preterm newborns breathe better with antenatal betamethasone

This randomized placebo-controlled trial examined the effectiveness of betamethasone in preventing neonatal respiratory complications for 2831 women at high probability of preterm delivery between 34 weeks and 36 weeks, 6 days of gestation. “High probability of preterm delivery” was defined as preterm labor with intact membranes and at least 3 cm dilation or 75% cervical effacement; spontaneous rupture of membranes; or anticipated preterm delivery for any other indication either through induction or cesarean section between 24 hours and 7 days after the planned randomization.

Patients were randomly assigned to receive either 2 intramuscular injections (12 mg each) of betamethasone or placebo, 24 hours apart. The 2 doses were successfully given in 60% of the betamethasone group and 59% of the placebo group. In 95% of the cases where the second dose was not given, it was because delivery occurred within 24 hours of the first dose.

The primary outcome was the need for respiratory support within 72 hours of birth, which was defined as one or more of the following: the use of continuous positive airway pressure (CPAP) or high-flow nasal cannula for at least 2 consecutive hours, supplemental oxygen for at least 4 continuous hours, extracorporeal membrane oxygenation (ECMO), or mechanical ventilation.

This study demonstrated clear benefit in neonatal respiratory outcomes when betamethasone vs placebo was used in the late preterm period.

The median time to delivery from enrollment was 31 to 33 hours, and 31.4% underwent cesarean delivery. In the intention-to-treat analysis, the primary outcome was significantly lower in the betamethasone group than in the placebo group (11.6% vs 14.4%; relative risk [RR]=0.80; 95% CI, 0.66-0.97; P=.02; number needed to treat [NNT]=35). Secondary outcomes (severe complications, representing a composite of the use of CPAP or high-flow nasal cannula for at least 12 continuous hours, supplemental oxygen for at least 24 continuous hours, ECMO, mechanical ventilation, stillbirth, or neonatal death within 72 hours after delivery) were also lower in the betamethasone group (8.1% vs 12.1%; RR=0.67; 95% CI, 0.53-0.84; P<.001; NNT=25). The betamethasone group also had a lower risk of transient tachypnea of the newborn (6.7% vs 9.9%; RR=0.68; 95% CI, 0.53-0.87; P=.002).

There were no significant differences in the occurrence of maternal chorioamnionitis (about 2%) or endometritis (about 1%) between the groups. Hypoglycemia in the newborn occurred more in the betamethasone group (24% vs 15%; RR=1.6; 95% CI, 1.37-1.87; P<.001; number needed to harm [NNH]=11). The betamethasone group had 2 neonatal deaths: one from septic shock and the other from a structural cardiac anomaly and arrhythmia.

WHAT’S NEW

Betamethasone makes a difference even in the late, late preterm period

This study demonstrated clear benefit in neonatal respiratory outcomes when betamethasone vs placebo was used in the late preterm period. The findings were similar to those from the Antenatal Steroids for Term Elective Caesarean Section Research Team.⁹ Their trial showed a reduction in respiratory complications in term neonates delivered via elective cesarean section to mothers who received antenatal betamethasone (NNT=37 to prevent admission to a special care nursery with respiratory distress). The findings were also consistent with those of a recent meta-analysis (including this trial) evaluating the occurrence of respiratory complications with the use of antenatal betamethasone in women expected to deliver in the late preterm period or with a planned cesarean delivery at ≥37 weeks’ gestation.¹⁰

CAVEATS

Neonates may develop hypoglycemia

The authors of the study reported an increased risk of hypoglycemia in the neonates receiving antenatal betamethasone. The long-term implications of this are unclear, however, given that there was a reduction in intermediate care nursery and neonatal intensive care unit stays that were 3 days or longer in the betamethasone group. Also, there was no difference in hospital length of stay between the 2 groups. In addition, it’s not clear if there are any long-term neonatal complications of betamethasone use in the late preterm period.

CHALLENGES TO IMPLEMENTATION

Challenges are negligible since betamethasone is readily available

There are minimal challenges to implementing this strategy, as betamethasone is routinely used for preterm labor and is readily available on labor and delivery units.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 21-year-old G1P0 at 35 weeks, 2 days of gestation presents to labor and delivery reporting a “gush of clear fluid.” On exam, you confirm she has preterm rupture of membranes. She is contracting every 3 minutes and has a cervix dilated to 3 cm. Is there any neonatal benefit to providing corticosteroids in this late preterm period?

Approximately 12% of all births in the United States are the result of preterm labor,² and 8% are born in the late preterm period, defined as 34 to 36 weeks’ gestation.³ To reduce the risk of neonatal death and respiratory complications, both the American College of Obstetricians and Gynecologists and the National Institutes of Health recommend a course of corticosteroids between 24 and 34 weeks’ gestation for women at increased risk of preterm delivery.^2,4 Due to a lack of evidence from randomized controlled trials (RCTs) on the benefit of corticosteroids in late preterm labor, there have not been recommendations to extend this period.⁵ However, multiple studies have shown that babies born during the late preterm period have more neonatal complications than term newborns.^6-8

A retrospective chart review of more than 130,000 live births found newborns delivered between 34 and 36 weeks had higher rates of respiratory distress than those delivered at 39 weeks (ventilator use dropped from 3.3% at 34 weeks to 0.3% at 39 weeks and transient tachypnea decreased from 2.4% at 34 weeks to 0.4% at 39 weeks).⁶ Another retrospective review of more than 230,000 newborns, of which 19,000 were born in the late preterm period, revealed that more neonates born between 34 and 36 weeks’ gestation had respiratory distress syndrome than neonates delivered at 39 weeks (10.5% at 34 weeks, 6% at 35 weeks, 2.8% at 36 weeks vs 0.3% at 39 weeks; P<.001 for the trend).⁸

STUDY SUMMARY

Late preterm newborns breathe better with antenatal betamethasone

This randomized placebo-controlled trial examined the effectiveness of betamethasone in preventing neonatal respiratory complications for 2831 women at high probability of preterm delivery between 34 weeks and 36 weeks, 6 days of gestation. “High probability of preterm delivery” was defined as preterm labor with intact membranes and at least 3 cm dilation or 75% cervical effacement; spontaneous rupture of membranes; or anticipated preterm delivery for any other indication either through induction or cesarean section between 24 hours and 7 days after the planned randomization.

Patients were randomly assigned to receive either 2 intramuscular injections (12 mg each) of betamethasone or placebo, 24 hours apart. The 2 doses were successfully given in 60% of the betamethasone group and 59% of the placebo group. In 95% of the cases where the second dose was not given, it was because delivery occurred within 24 hours of the first dose.

The primary outcome was the need for respiratory support within 72 hours of birth, which was defined as one or more of the following: the use of continuous positive airway pressure (CPAP) or high-flow nasal cannula for at least 2 consecutive hours, supplemental oxygen for at least 4 continuous hours, extracorporeal membrane oxygenation (ECMO), or mechanical ventilation.

This study demonstrated clear benefit in neonatal respiratory outcomes when betamethasone vs placebo was used in the late preterm period.

The median time to delivery from enrollment was 31 to 33 hours, and 31.4% underwent cesarean delivery. In the intention-to-treat analysis, the primary outcome was significantly lower in the betamethasone group than in the placebo group (11.6% vs 14.4%; relative risk [RR]=0.80; 95% CI, 0.66-0.97; P=.02; number needed to treat [NNT]=35). Secondary outcomes (severe complications, representing a composite of the use of CPAP or high-flow nasal cannula for at least 12 continuous hours, supplemental oxygen for at least 24 continuous hours, ECMO, mechanical ventilation, stillbirth, or neonatal death within 72 hours after delivery) were also lower in the betamethasone group (8.1% vs 12.1%; RR=0.67; 95% CI, 0.53-0.84; P<.001; NNT=25). The betamethasone group also had a lower risk of transient tachypnea of the newborn (6.7% vs 9.9%; RR=0.68; 95% CI, 0.53-0.87; P=.002).

There were no significant differences in the occurrence of maternal chorioamnionitis (about 2%) or endometritis (about 1%) between the groups. Hypoglycemia in the newborn occurred more in the betamethasone group (24% vs 15%; RR=1.6; 95% CI, 1.37-1.87; P<.001; number needed to harm [NNH]=11). The betamethasone group had 2 neonatal deaths: one from septic shock and the other from a structural cardiac anomaly and arrhythmia.

WHAT’S NEW

Betamethasone makes a difference even in the late, late preterm period

This study demonstrated clear benefit in neonatal respiratory outcomes when betamethasone vs placebo was used in the late preterm period. The findings were similar to those from the Antenatal Steroids for Term Elective Caesarean Section Research Team.⁹ Their trial showed a reduction in respiratory complications in term neonates delivered via elective cesarean section to mothers who received antenatal betamethasone (NNT=37 to prevent admission to a special care nursery with respiratory distress). The findings were also consistent with those of a recent meta-analysis (including this trial) evaluating the occurrence of respiratory complications with the use of antenatal betamethasone in women expected to deliver in the late preterm period or with a planned cesarean delivery at ≥37 weeks’ gestation.¹⁰

CAVEATS

Neonates may develop hypoglycemia

The authors of the study reported an increased risk of hypoglycemia in the neonates receiving antenatal betamethasone. The long-term implications of this are unclear, however, given that there was a reduction in intermediate care nursery and neonatal intensive care unit stays that were 3 days or longer in the betamethasone group. Also, there was no difference in hospital length of stay between the 2 groups. In addition, it’s not clear if there are any long-term neonatal complications of betamethasone use in the late preterm period.

CHALLENGES TO IMPLEMENTATION

Challenges are negligible since betamethasone is readily available

There are minimal challenges to implementing this strategy, as betamethasone is routinely used for preterm labor and is readily available on labor and delivery units.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 21-year-old G1P0 at 35 weeks, 2 days of gestation presents to labor and delivery reporting a “gush of clear fluid.” On exam, you confirm she has preterm rupture of membranes. She is contracting every 3 minutes and has a cervix dilated to 3 cm. Is there any neonatal benefit to providing corticosteroids in this late preterm period?

Approximately 12% of all births in the United States are the result of preterm labor,² and 8% are born in the late preterm period, defined as 34 to 36 weeks’ gestation.³ To reduce the risk of neonatal death and respiratory complications, both the American College of Obstetricians and Gynecologists and the National Institutes of Health recommend a course of corticosteroids between 24 and 34 weeks’ gestation for women at increased risk of preterm delivery.^2,4 Due to a lack of evidence from randomized controlled trials (RCTs) on the benefit of corticosteroids in late preterm labor, there have not been recommendations to extend this period.⁵ However, multiple studies have shown that babies born during the late preterm period have more neonatal complications than term newborns.^6-8

A retrospective chart review of more than 130,000 live births found newborns delivered between 34 and 36 weeks had higher rates of respiratory distress than those delivered at 39 weeks (ventilator use dropped from 3.3% at 34 weeks to 0.3% at 39 weeks and transient tachypnea decreased from 2.4% at 34 weeks to 0.4% at 39 weeks).⁶ Another retrospective review of more than 230,000 newborns, of which 19,000 were born in the late preterm period, revealed that more neonates born between 34 and 36 weeks’ gestation had respiratory distress syndrome than neonates delivered at 39 weeks (10.5% at 34 weeks, 6% at 35 weeks, 2.8% at 36 weeks vs 0.3% at 39 weeks; P<.001 for the trend).⁸

STUDY SUMMARY

Late preterm newborns breathe better with antenatal betamethasone

This randomized placebo-controlled trial examined the effectiveness of betamethasone in preventing neonatal respiratory complications for 2831 women at high probability of preterm delivery between 34 weeks and 36 weeks, 6 days of gestation. “High probability of preterm delivery” was defined as preterm labor with intact membranes and at least 3 cm dilation or 75% cervical effacement; spontaneous rupture of membranes; or anticipated preterm delivery for any other indication either through induction or cesarean section between 24 hours and 7 days after the planned randomization.

Patients were randomly assigned to receive either 2 intramuscular injections (12 mg each) of betamethasone or placebo, 24 hours apart. The 2 doses were successfully given in 60% of the betamethasone group and 59% of the placebo group. In 95% of the cases where the second dose was not given, it was because delivery occurred within 24 hours of the first dose.

The primary outcome was the need for respiratory support within 72 hours of birth, which was defined as one or more of the following: the use of continuous positive airway pressure (CPAP) or high-flow nasal cannula for at least 2 consecutive hours, supplemental oxygen for at least 4 continuous hours, extracorporeal membrane oxygenation (ECMO), or mechanical ventilation.

This study demonstrated clear benefit in neonatal respiratory outcomes when betamethasone vs placebo was used in the late preterm period.

The median time to delivery from enrollment was 31 to 33 hours, and 31.4% underwent cesarean delivery. In the intention-to-treat analysis, the primary outcome was significantly lower in the betamethasone group than in the placebo group (11.6% vs 14.4%; relative risk [RR]=0.80; 95% CI, 0.66-0.97; P=.02; number needed to treat [NNT]=35). Secondary outcomes (severe complications, representing a composite of the use of CPAP or high-flow nasal cannula for at least 12 continuous hours, supplemental oxygen for at least 24 continuous hours, ECMO, mechanical ventilation, stillbirth, or neonatal death within 72 hours after delivery) were also lower in the betamethasone group (8.1% vs 12.1%; RR=0.67; 95% CI, 0.53-0.84; P<.001; NNT=25). The betamethasone group also had a lower risk of transient tachypnea of the newborn (6.7% vs 9.9%; RR=0.68; 95% CI, 0.53-0.87; P=.002).

There were no significant differences in the occurrence of maternal chorioamnionitis (about 2%) or endometritis (about 1%) between the groups. Hypoglycemia in the newborn occurred more in the betamethasone group (24% vs 15%; RR=1.6; 95% CI, 1.37-1.87; P<.001; number needed to harm [NNH]=11). The betamethasone group had 2 neonatal deaths: one from septic shock and the other from a structural cardiac anomaly and arrhythmia.

WHAT’S NEW

Betamethasone makes a difference even in the late, late preterm period

This study demonstrated clear benefit in neonatal respiratory outcomes when betamethasone vs placebo was used in the late preterm period. The findings were similar to those from the Antenatal Steroids for Term Elective Caesarean Section Research Team.⁹ Their trial showed a reduction in respiratory complications in term neonates delivered via elective cesarean section to mothers who received antenatal betamethasone (NNT=37 to prevent admission to a special care nursery with respiratory distress). The findings were also consistent with those of a recent meta-analysis (including this trial) evaluating the occurrence of respiratory complications with the use of antenatal betamethasone in women expected to deliver in the late preterm period or with a planned cesarean delivery at ≥37 weeks’ gestation.¹⁰

CAVEATS

Neonates may develop hypoglycemia

The authors of the study reported an increased risk of hypoglycemia in the neonates receiving antenatal betamethasone. The long-term implications of this are unclear, however, given that there was a reduction in intermediate care nursery and neonatal intensive care unit stays that were 3 days or longer in the betamethasone group. Also, there was no difference in hospital length of stay between the 2 groups. In addition, it’s not clear if there are any long-term neonatal complications of betamethasone use in the late preterm period.

CHALLENGES TO IMPLEMENTATION

Challenges are negligible since betamethasone is readily available

There are minimal challenges to implementing this strategy, as betamethasone is routinely used for preterm labor and is readily available on labor and delivery units.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

THE CASE

A 22-year-old woman presented to the emergency department (ED) with a 24-hour history of nausea, vomiting, diarrhea, generalized abdominal pain, and mild headache. She denied shortness of breath, chest pain, or anxiety, and didn’t have a history of cardiac problems. The physical examination revealed tachycardia (heart rate, 135 beats/min) and a respiratory rate of 24 breaths per minute. The patient was diagnosed with dehydration and was given 3 liters of intravenous (IV) fluids. After fluid administration, her heart rate decreased to 94 beats/min and she was discharged home.

The patient returned to the ED later that same day with recurrent nausea, vomiting, and a mild fever. This time she reported a several week history of palpitations, heat intolerance, agitation, mild cognitive impairment, and difficulty sleeping. Her mother accompanied her to this visit and added that the patient had unintentionally lost 13 pounds over the past 2 weeks. The patient denied pain or enlargement in her neck, obstructive symptoms, hives, pruritus, or changes in vision. Reexamination revealed tachycardia (132 beats/min) with no murmurs, rubs, or gallops; increased respiratory rate (26 breaths/min); and diffuse thyromegaly without distinct nodules. The thyroid was nontender to palpation. The patient was also found to have a fine resting tremor, hyperactive deep tendon reflexes, and clonus in her lower extremities. Bibasilar crackles were noted on lung exam.

THE DIAGNOSIS

An electrocardiogram (EKG) revealed sinus tachycardia with some sinus arrhythmia. A chest radiograph revealed prominent pulmonary vasculature and the presence of Kerley B lines consistent with marked pulmonary edema. Laboratory testing revealed an elevated N-terminal pro b-type natriuretic peptide level of 2420 pg/mL (normal range: <100 pg/mL). Evaluation of thyroid function revealed overt hyperthyroidism with an elevated free thyroxine of 4.6 ng/dL (normal range: 0.8-1.8 ng/dL), a total triiodothyronine of 199 ng/dL (normal range: 60-181 ng/dL), and a suppressed thyroid-stimulating hormone level of <0.02 mcU/mL (normal range: 0.35-5 mcU/mL). A subsequent thyroid ultrasound showed a diffusely enlarged thyroid gland with a thickened isthmus, but no nodules.

The patient’s results were discussed with the on-call endocrinology provider at the time of her revisit to the ED. The patient was started on antithyroid medications (methimazole 20 mg/d) and a beta-blocker (atenolol 25 mg/d). Arrangements were made for an outpatient endocrine consultation within 3 days of her visit to the ED.

Upon evaluation in the outpatient endocrinology clinic, a thyrotropin receptor antibody test was positive, confirming Graves’ disease. The patient was given a diagnosis of thyrotoxicosis secondary to hyperthyroidism due to Graves’ disease. Her marked pulmonary edema was secondary to thyrotoxicosis and aggressive hydration with IV fluids.

DISCUSSION

Hyperthyroidism is a common metabolic disorder with prominent cardiovascular manifestations.¹ Classically, patients with hyperthyroidism develop irritability, heat intolerance, emotional lability, muscle weakness, menstrual abnormalities, and weight loss (despite an increased appetite). Cardiovascular manifestations include palpitations in up to 85% of patients, and dyspnea on exertion and fatigue in approximately 50% of patients.² Hyperthyroidism has also been shown to produce changes in cardiac contractility, myocardial oxygen consumption, cardiac output, blood pressure, and systemic vascular resistance.^3,4 Hyperthyroidism may complicate preexisting cardiac disease or may cause cardiac complications in individuals without structural abnormalities. (Our patient had no known structural abnormalities.)

Hyperthyroidism has been shown to produce changes in cardiac contractility, myocardial oxygen consumption, cardiac output, blood pressure, and systemic vascular resistance.In a small subset of patients with severe hyperthyroidism and exaggerated sinus tachycardia or atrial fibrillation, rate-related left ventricular dysfunction may cause heart failure.⁵ The assessment of thyrotoxic manifestations, especially potential cardiovascular complications, is essential to formulating an appropriate treatment plan.⁶ Cardiac evaluation may require an echocardiogram, EKG, Holter monitor, or myocardial perfusion studies.

Beta-blockers, diuretics among treatment options

Treatment with beta-blockers to reduce heart rate should be first-line therapy.⁷ In patients with overt heart failure involving pulmonary congestion, the use of diuretics may be appropriate.⁸

Our patient continued to take the medications prescribed during her ED visit: methimazole 20 mg/d and atenolol 25 mg/d for her Graves’ disease. A chest radiograph one month later revealed resolution of her pulmonary edema.

THE TAKEAWAY

The cardiovascular manifestations of hyperthyroidism remain some of the most common signs and symptoms of thyroid disease. Pulmonary edema and congestive heart failure, however, are uncommon. Physicians need to be aware of this rare—but important—clinical presentation of a common condition.

THE CASE

A 22-year-old woman presented to the emergency department (ED) with a 24-hour history of nausea, vomiting, diarrhea, generalized abdominal pain, and mild headache. She denied shortness of breath, chest pain, or anxiety, and didn’t have a history of cardiac problems. The physical examination revealed tachycardia (heart rate, 135 beats/min) and a respiratory rate of 24 breaths per minute. The patient was diagnosed with dehydration and was given 3 liters of intravenous (IV) fluids. After fluid administration, her heart rate decreased to 94 beats/min and she was discharged home.

The patient returned to the ED later that same day with recurrent nausea, vomiting, and a mild fever. This time she reported a several week history of palpitations, heat intolerance, agitation, mild cognitive impairment, and difficulty sleeping. Her mother accompanied her to this visit and added that the patient had unintentionally lost 13 pounds over the past 2 weeks. The patient denied pain or enlargement in her neck, obstructive symptoms, hives, pruritus, or changes in vision. Reexamination revealed tachycardia (132 beats/min) with no murmurs, rubs, or gallops; increased respiratory rate (26 breaths/min); and diffuse thyromegaly without distinct nodules. The thyroid was nontender to palpation. The patient was also found to have a fine resting tremor, hyperactive deep tendon reflexes, and clonus in her lower extremities. Bibasilar crackles were noted on lung exam.

THE DIAGNOSIS

An electrocardiogram (EKG) revealed sinus tachycardia with some sinus arrhythmia. A chest radiograph revealed prominent pulmonary vasculature and the presence of Kerley B lines consistent with marked pulmonary edema. Laboratory testing revealed an elevated N-terminal pro b-type natriuretic peptide level of 2420 pg/mL (normal range: <100 pg/mL). Evaluation of thyroid function revealed overt hyperthyroidism with an elevated free thyroxine of 4.6 ng/dL (normal range: 0.8-1.8 ng/dL), a total triiodothyronine of 199 ng/dL (normal range: 60-181 ng/dL), and a suppressed thyroid-stimulating hormone level of <0.02 mcU/mL (normal range: 0.35-5 mcU/mL). A subsequent thyroid ultrasound showed a diffusely enlarged thyroid gland with a thickened isthmus, but no nodules.

The patient’s results were discussed with the on-call endocrinology provider at the time of her revisit to the ED. The patient was started on antithyroid medications (methimazole 20 mg/d) and a beta-blocker (atenolol 25 mg/d). Arrangements were made for an outpatient endocrine consultation within 3 days of her visit to the ED.

Upon evaluation in the outpatient endocrinology clinic, a thyrotropin receptor antibody test was positive, confirming Graves’ disease. The patient was given a diagnosis of thyrotoxicosis secondary to hyperthyroidism due to Graves’ disease. Her marked pulmonary edema was secondary to thyrotoxicosis and aggressive hydration with IV fluids.

DISCUSSION

Hyperthyroidism is a common metabolic disorder with prominent cardiovascular manifestations.¹ Classically, patients with hyperthyroidism develop irritability, heat intolerance, emotional lability, muscle weakness, menstrual abnormalities, and weight loss (despite an increased appetite). Cardiovascular manifestations include palpitations in up to 85% of patients, and dyspnea on exertion and fatigue in approximately 50% of patients.² Hyperthyroidism has also been shown to produce changes in cardiac contractility, myocardial oxygen consumption, cardiac output, blood pressure, and systemic vascular resistance.^3,4 Hyperthyroidism may complicate preexisting cardiac disease or may cause cardiac complications in individuals without structural abnormalities. (Our patient had no known structural abnormalities.)

Hyperthyroidism has been shown to produce changes in cardiac contractility, myocardial oxygen consumption, cardiac output, blood pressure, and systemic vascular resistance.In a small subset of patients with severe hyperthyroidism and exaggerated sinus tachycardia or atrial fibrillation, rate-related left ventricular dysfunction may cause heart failure.⁵ The assessment of thyrotoxic manifestations, especially potential cardiovascular complications, is essential to formulating an appropriate treatment plan.⁶ Cardiac evaluation may require an echocardiogram, EKG, Holter monitor, or myocardial perfusion studies.

Beta-blockers, diuretics among treatment options

Treatment with beta-blockers to reduce heart rate should be first-line therapy.⁷ In patients with overt heart failure involving pulmonary congestion, the use of diuretics may be appropriate.⁸

Our patient continued to take the medications prescribed during her ED visit: methimazole 20 mg/d and atenolol 25 mg/d for her Graves’ disease. A chest radiograph one month later revealed resolution of her pulmonary edema.

THE TAKEAWAY

The cardiovascular manifestations of hyperthyroidism remain some of the most common signs and symptoms of thyroid disease. Pulmonary edema and congestive heart failure, however, are uncommon. Physicians need to be aware of this rare—but important—clinical presentation of a common condition.

THE CASE

A 22-year-old woman presented to the emergency department (ED) with a 24-hour history of nausea, vomiting, diarrhea, generalized abdominal pain, and mild headache. She denied shortness of breath, chest pain, or anxiety, and didn’t have a history of cardiac problems. The physical examination revealed tachycardia (heart rate, 135 beats/min) and a respiratory rate of 24 breaths per minute. The patient was diagnosed with dehydration and was given 3 liters of intravenous (IV) fluids. After fluid administration, her heart rate decreased to 94 beats/min and she was discharged home.

The patient returned to the ED later that same day with recurrent nausea, vomiting, and a mild fever. This time she reported a several week history of palpitations, heat intolerance, agitation, mild cognitive impairment, and difficulty sleeping. Her mother accompanied her to this visit and added that the patient had unintentionally lost 13 pounds over the past 2 weeks. The patient denied pain or enlargement in her neck, obstructive symptoms, hives, pruritus, or changes in vision. Reexamination revealed tachycardia (132 beats/min) with no murmurs, rubs, or gallops; increased respiratory rate (26 breaths/min); and diffuse thyromegaly without distinct nodules. The thyroid was nontender to palpation. The patient was also found to have a fine resting tremor, hyperactive deep tendon reflexes, and clonus in her lower extremities. Bibasilar crackles were noted on lung exam.

THE DIAGNOSIS

An electrocardiogram (EKG) revealed sinus tachycardia with some sinus arrhythmia. A chest radiograph revealed prominent pulmonary vasculature and the presence of Kerley B lines consistent with marked pulmonary edema. Laboratory testing revealed an elevated N-terminal pro b-type natriuretic peptide level of 2420 pg/mL (normal range: <100 pg/mL). Evaluation of thyroid function revealed overt hyperthyroidism with an elevated free thyroxine of 4.6 ng/dL (normal range: 0.8-1.8 ng/dL), a total triiodothyronine of 199 ng/dL (normal range: 60-181 ng/dL), and a suppressed thyroid-stimulating hormone level of <0.02 mcU/mL (normal range: 0.35-5 mcU/mL). A subsequent thyroid ultrasound showed a diffusely enlarged thyroid gland with a thickened isthmus, but no nodules.

The patient’s results were discussed with the on-call endocrinology provider at the time of her revisit to the ED. The patient was started on antithyroid medications (methimazole 20 mg/d) and a beta-blocker (atenolol 25 mg/d). Arrangements were made for an outpatient endocrine consultation within 3 days of her visit to the ED.

Upon evaluation in the outpatient endocrinology clinic, a thyrotropin receptor antibody test was positive, confirming Graves’ disease. The patient was given a diagnosis of thyrotoxicosis secondary to hyperthyroidism due to Graves’ disease. Her marked pulmonary edema was secondary to thyrotoxicosis and aggressive hydration with IV fluids.

DISCUSSION

Hyperthyroidism is a common metabolic disorder with prominent cardiovascular manifestations.¹ Classically, patients with hyperthyroidism develop irritability, heat intolerance, emotional lability, muscle weakness, menstrual abnormalities, and weight loss (despite an increased appetite). Cardiovascular manifestations include palpitations in up to 85% of patients, and dyspnea on exertion and fatigue in approximately 50% of patients.² Hyperthyroidism has also been shown to produce changes in cardiac contractility, myocardial oxygen consumption, cardiac output, blood pressure, and systemic vascular resistance.^3,4 Hyperthyroidism may complicate preexisting cardiac disease or may cause cardiac complications in individuals without structural abnormalities. (Our patient had no known structural abnormalities.)

Hyperthyroidism has been shown to produce changes in cardiac contractility, myocardial oxygen consumption, cardiac output, blood pressure, and systemic vascular resistance.In a small subset of patients with severe hyperthyroidism and exaggerated sinus tachycardia or atrial fibrillation, rate-related left ventricular dysfunction may cause heart failure.⁵ The assessment of thyrotoxic manifestations, especially potential cardiovascular complications, is essential to formulating an appropriate treatment plan.⁶ Cardiac evaluation may require an echocardiogram, EKG, Holter monitor, or myocardial perfusion studies.

Beta-blockers, diuretics among treatment options

Treatment with beta-blockers to reduce heart rate should be first-line therapy.⁷ In patients with overt heart failure involving pulmonary congestion, the use of diuretics may be appropriate.⁸

Our patient continued to take the medications prescribed during her ED visit: methimazole 20 mg/d and atenolol 25 mg/d for her Graves’ disease. A chest radiograph one month later revealed resolution of her pulmonary edema.

THE TAKEAWAY

The cardiovascular manifestations of hyperthyroidism remain some of the most common signs and symptoms of thyroid disease. Pulmonary edema and congestive heart failure, however, are uncommon. Physicians need to be aware of this rare—but important—clinical presentation of a common condition.

THE CASE

A 39-year-old man who worked in construction presented to our clinic with complaints of muscle cramps and muscle pain that had been bothering him for several months. The cramps and pain started in both of his arms and subsequently became diffuse and generalized. He also reported an unintentional 15-pound weight loss.

His exam at that time was unremarkable. He was diagnosed with dehydration and cramping due to overexertion at work. A basic metabolic panel, hemogram, lipid panel, and thyroid stimulating hormone level were ordered. The patient’s triglyceride level, which was 227 mg/dL, was the only significant result (normal level: <150 mg/dL).

The patient’s symptoms continued to worsen until he returned to the clinic 6 months later, again complaining of muscle cramps and pain throughout his body. At that second visit, he also reported profound overall weakness and the development of diffuse muscle twitching, which his wife had observed while he was sleeping. As a result of these worrisome symptoms, he had become anxious and depressed.

A review of his medical record revealed a weight loss of about 20 pounds over the previous year. On exam, he had diffuse fasciculations in all the major muscle groups, including his tongue. The patient’s strength was 4/5 in all muscle groups. His deep tendon reflexes were 3+. He had a negative Babinski reflex (ie, he had downward facing toes with plantar stimulation), and cranial nerves II to XII were all intact. His rapid alternating movements and gait were slow.

THE DIAGNOSIS

Based on the exam, the primary diagnostic consideration for the patient was amyotrophic lateral sclerosis (ALS). Lab tests were ordered and revealed normal calcium and electrolyte levels, a normal erythrocyte sedimentation rate, a normal C-reactive protein level, and a negative test for acetylcholine receptor antibodies. However, the patient had an elevated creatine kinase level of 664 U/L (normal: 30-200 U/L). The patient was sent to a neuromuscular specialist, who identified signs of upper and lower motor neuron disease in all 4 of the patient’s extremities (he had foot drop that had not been present previously) and a very brisk jaw jerk. Along with the tongue fasciculations, the results of the specialist’s physical exam suggested ALS. Four-limb electromyography (EMG) showed widespread fasciculations and some large motor unit potentials and recruitment abnormalities, which were also consistent with ALS. It appeared that the patient’s weight loss was due to both muscle atrophy and the amount of calories burned from his constant twitching.

Extensive testing was done to rule out other potential causes of the patient’s symptoms, including magnetic resonance imaging (MRI) of the spine and brain (which was normal). In addition, the patient’s aldolase level and antineutrophil cytoplasmic antibodies were normal. The patient tested negative for human immunodeficiency virus and antibodies to double-stranded DNA. After serial neurologic exams, the final diagnosis of ALS was made.

DISCUSSION

ALS, also known as Lou Gehrig’s disease, is a degenerative motor neuron disease.^1-3 The incidence in North America is 1.5 to 2.7 per 100,000 per year, and the prevalence is 2.7 to 7.4 per 100,000.⁴ The incidence of ALS increases with each decade of life, especially after age 40, and peaks at 74 years of age.⁴ The male to female ratio is 1:1.5-2.⁴ ALS affects upper and lower motor neurons and is progressive; however, the rate of progression and phenotype vary greatly between individuals.² Most patients with ALS die within 2 to 5 years of onset.⁵

There is no specific test for ALS; the diagnosis is made clinically based on the revised El Escorial World Federation of Neurology criteria, also known as the Airlie House criteria.^2,6,7 These criteria include evidence of lower motor neuron degeneration by clinical, electrophysiologic, or neuropathologic exam; evidence of upper motor neuron disease by clinical exam; progressive spread of symptoms or signs within a region or to other regions (by history or exam); and the absence of electrophysiologic, neuroimaging, or pathologic evidence of other disease processes that could explain the symptoms. If patients have evidence of upper and lower motor neuron disease, they should be reevaluated in 4 weeks to see if symptoms are improving or progressing.

Like our patient, many patients will have an elevated creatine kinase level (some with levels as high as 1000 U/L), and calcium may also be elevated because, rarely, ALS is associated with primary hyperparathyroidism.⁸ Electrophysiologic studies can be helpful in identifying active denervation of lower motor neurons.^4,6,7

The differential diagnosis for ALS includes myasthenia gravis, inclusion-body myositis, multifocal motor neuropathy, benign fasciculations, hereditary spastic paraplegia, primary lateral sclerosis, post-polio progressive muscle atrophy, cervical spondylosis, and multiple sclerosis. A negative acetylcholine receptor antibody test will rule out myasthenia gravis, imaging of the spine can rule out cervical spondylosis, and electrophysiologic testing helps eliminate the other conditions (TABLE 1⁴).

Treatment in specialty clinics can prolong survival

The mainstays of treatment are symptom management, multidisciplinary care (by physicians, physical/occupational/speech therapists, nutritionists, psychologists, psychotherapists, and genetic counselors), palliative care, and counseling about end-of-life issues for patients and family.^1,5 Utilization of an ALS specialty clinic can provide access to all of these services and should be considered, as there is evidence that treatment in such clinics can prolong survival.⁵ The location of ALS specialty clinics can be found on the ALS Association’s Web site at http://www.alsa.org/community/.

Despite treatment, however, ALS is a progressive disease. The prognosis is poor, with a median survival of 2 to 5 years after diagnosis.⁹

The El Escorial World Federation of Neurology criteria for the diagnosis of ALS address how to treat the most common symptoms of ALS that occur as the disease progresses. These symptoms include dyspnea, muscle spasms, spasticity, sialorrhea, and pseudobulbar affect (TABLE 2^1,5).

Our patient was started on baclofen 10 mg 3 times per day (titrated up as needed) for muscle spasms and cramps, which resulted in some improvement of his cramps, but no improvement in the spasms. He was also started on sertraline 50 mg for anxiety and depression. His overall weakness continued to progress, and we recommended that the patient get ankle-foot orthosis braces to help with the mobility impairment caused by foot drop.

We then referred him to an ALS specialty clinic recommended by the neuromuscular specialist. The patient is now enrolled in a clinical trial designed to test a cerebrospinal fluid marker for diagnosis and for a new drug aimed at symptom management.

THE TAKEAWAY

Muscle cramps and pain are early signs of ALS. Although ALS is uncommon, patients who present with muscle cramps and muscle pain should have a creatine kinase test ordered (which, if elevated, should prompt further investigation into ALS as the possible cause). Patients should also undergo a neurologic examination to seek evidence of upper and lower motor neuron disease. They should then be reevaluated in 4 weeks to see if symptoms are improving or progressing. If no improvement is seen and symptoms are progressive, a work-up for ALS should be considered.

The mainstay of treatment for patients with ALS is multidisciplinary symptom management and palliative care. Utilization of an ALS specialty clinic should also be recommended, as it can improve survival.⁵

THE CASE

A 39-year-old man who worked in construction presented to our clinic with complaints of muscle cramps and muscle pain that had been bothering him for several months. The cramps and pain started in both of his arms and subsequently became diffuse and generalized. He also reported an unintentional 15-pound weight loss.

His exam at that time was unremarkable. He was diagnosed with dehydration and cramping due to overexertion at work. A basic metabolic panel, hemogram, lipid panel, and thyroid stimulating hormone level were ordered. The patient’s triglyceride level, which was 227 mg/dL, was the only significant result (normal level: <150 mg/dL).

The patient’s symptoms continued to worsen until he returned to the clinic 6 months later, again complaining of muscle cramps and pain throughout his body. At that second visit, he also reported profound overall weakness and the development of diffuse muscle twitching, which his wife had observed while he was sleeping. As a result of these worrisome symptoms, he had become anxious and depressed.

A review of his medical record revealed a weight loss of about 20 pounds over the previous year. On exam, he had diffuse fasciculations in all the major muscle groups, including his tongue. The patient’s strength was 4/5 in all muscle groups. His deep tendon reflexes were 3+. He had a negative Babinski reflex (ie, he had downward facing toes with plantar stimulation), and cranial nerves II to XII were all intact. His rapid alternating movements and gait were slow.

THE DIAGNOSIS

Based on the exam, the primary diagnostic consideration for the patient was amyotrophic lateral sclerosis (ALS). Lab tests were ordered and revealed normal calcium and electrolyte levels, a normal erythrocyte sedimentation rate, a normal C-reactive protein level, and a negative test for acetylcholine receptor antibodies. However, the patient had an elevated creatine kinase level of 664 U/L (normal: 30-200 U/L). The patient was sent to a neuromuscular specialist, who identified signs of upper and lower motor neuron disease in all 4 of the patient’s extremities (he had foot drop that had not been present previously) and a very brisk jaw jerk. Along with the tongue fasciculations, the results of the specialist’s physical exam suggested ALS. Four-limb electromyography (EMG) showed widespread fasciculations and some large motor unit potentials and recruitment abnormalities, which were also consistent with ALS. It appeared that the patient’s weight loss was due to both muscle atrophy and the amount of calories burned from his constant twitching.

Extensive testing was done to rule out other potential causes of the patient’s symptoms, including magnetic resonance imaging (MRI) of the spine and brain (which was normal). In addition, the patient’s aldolase level and antineutrophil cytoplasmic antibodies were normal. The patient tested negative for human immunodeficiency virus and antibodies to double-stranded DNA. After serial neurologic exams, the final diagnosis of ALS was made.

DISCUSSION

ALS, also known as Lou Gehrig’s disease, is a degenerative motor neuron disease.^1-3 The incidence in North America is 1.5 to 2.7 per 100,000 per year, and the prevalence is 2.7 to 7.4 per 100,000.⁴ The incidence of ALS increases with each decade of life, especially after age 40, and peaks at 74 years of age.⁴ The male to female ratio is 1:1.5-2.⁴ ALS affects upper and lower motor neurons and is progressive; however, the rate of progression and phenotype vary greatly between individuals.² Most patients with ALS die within 2 to 5 years of onset.⁵

There is no specific test for ALS; the diagnosis is made clinically based on the revised El Escorial World Federation of Neurology criteria, also known as the Airlie House criteria.^2,6,7 These criteria include evidence of lower motor neuron degeneration by clinical, electrophysiologic, or neuropathologic exam; evidence of upper motor neuron disease by clinical exam; progressive spread of symptoms or signs within a region or to other regions (by history or exam); and the absence of electrophysiologic, neuroimaging, or pathologic evidence of other disease processes that could explain the symptoms. If patients have evidence of upper and lower motor neuron disease, they should be reevaluated in 4 weeks to see if symptoms are improving or progressing.

Like our patient, many patients will have an elevated creatine kinase level (some with levels as high as 1000 U/L), and calcium may also be elevated because, rarely, ALS is associated with primary hyperparathyroidism.⁸ Electrophysiologic studies can be helpful in identifying active denervation of lower motor neurons.^4,6,7

The differential diagnosis for ALS includes myasthenia gravis, inclusion-body myositis, multifocal motor neuropathy, benign fasciculations, hereditary spastic paraplegia, primary lateral sclerosis, post-polio progressive muscle atrophy, cervical spondylosis, and multiple sclerosis. A negative acetylcholine receptor antibody test will rule out myasthenia gravis, imaging of the spine can rule out cervical spondylosis, and electrophysiologic testing helps eliminate the other conditions (TABLE 1⁴).

Treatment in specialty clinics can prolong survival

The mainstays of treatment are symptom management, multidisciplinary care (by physicians, physical/occupational/speech therapists, nutritionists, psychologists, psychotherapists, and genetic counselors), palliative care, and counseling about end-of-life issues for patients and family.^1,5 Utilization of an ALS specialty clinic can provide access to all of these services and should be considered, as there is evidence that treatment in such clinics can prolong survival.⁵ The location of ALS specialty clinics can be found on the ALS Association’s Web site at http://www.alsa.org/community/.

Despite treatment, however, ALS is a progressive disease. The prognosis is poor, with a median survival of 2 to 5 years after diagnosis.⁹

The El Escorial World Federation of Neurology criteria for the diagnosis of ALS address how to treat the most common symptoms of ALS that occur as the disease progresses. These symptoms include dyspnea, muscle spasms, spasticity, sialorrhea, and pseudobulbar affect (TABLE 2^1,5).

Our patient was started on baclofen 10 mg 3 times per day (titrated up as needed) for muscle spasms and cramps, which resulted in some improvement of his cramps, but no improvement in the spasms. He was also started on sertraline 50 mg for anxiety and depression. His overall weakness continued to progress, and we recommended that the patient get ankle-foot orthosis braces to help with the mobility impairment caused by foot drop.

We then referred him to an ALS specialty clinic recommended by the neuromuscular specialist. The patient is now enrolled in a clinical trial designed to test a cerebrospinal fluid marker for diagnosis and for a new drug aimed at symptom management.

THE TAKEAWAY

Muscle cramps and pain are early signs of ALS. Although ALS is uncommon, patients who present with muscle cramps and muscle pain should have a creatine kinase test ordered (which, if elevated, should prompt further investigation into ALS as the possible cause). Patients should also undergo a neurologic examination to seek evidence of upper and lower motor neuron disease. They should then be reevaluated in 4 weeks to see if symptoms are improving or progressing. If no improvement is seen and symptoms are progressive, a work-up for ALS should be considered.

The mainstay of treatment for patients with ALS is multidisciplinary symptom management and palliative care. Utilization of an ALS specialty clinic should also be recommended, as it can improve survival.⁵

THE CASE

A 39-year-old man who worked in construction presented to our clinic with complaints of muscle cramps and muscle pain that had been bothering him for several months. The cramps and pain started in both of his arms and subsequently became diffuse and generalized. He also reported an unintentional 15-pound weight loss.

His exam at that time was unremarkable. He was diagnosed with dehydration and cramping due to overexertion at work. A basic metabolic panel, hemogram, lipid panel, and thyroid stimulating hormone level were ordered. The patient’s triglyceride level, which was 227 mg/dL, was the only significant result (normal level: <150 mg/dL).

The patient’s symptoms continued to worsen until he returned to the clinic 6 months later, again complaining of muscle cramps and pain throughout his body. At that second visit, he also reported profound overall weakness and the development of diffuse muscle twitching, which his wife had observed while he was sleeping. As a result of these worrisome symptoms, he had become anxious and depressed.

A review of his medical record revealed a weight loss of about 20 pounds over the previous year. On exam, he had diffuse fasciculations in all the major muscle groups, including his tongue. The patient’s strength was 4/5 in all muscle groups. His deep tendon reflexes were 3+. He had a negative Babinski reflex (ie, he had downward facing toes with plantar stimulation), and cranial nerves II to XII were all intact. His rapid alternating movements and gait were slow.

THE DIAGNOSIS

Based on the exam, the primary diagnostic consideration for the patient was amyotrophic lateral sclerosis (ALS). Lab tests were ordered and revealed normal calcium and electrolyte levels, a normal erythrocyte sedimentation rate, a normal C-reactive protein level, and a negative test for acetylcholine receptor antibodies. However, the patient had an elevated creatine kinase level of 664 U/L (normal: 30-200 U/L). The patient was sent to a neuromuscular specialist, who identified signs of upper and lower motor neuron disease in all 4 of the patient’s extremities (he had foot drop that had not been present previously) and a very brisk jaw jerk. Along with the tongue fasciculations, the results of the specialist’s physical exam suggested ALS. Four-limb electromyography (EMG) showed widespread fasciculations and some large motor unit potentials and recruitment abnormalities, which were also consistent with ALS. It appeared that the patient’s weight loss was due to both muscle atrophy and the amount of calories burned from his constant twitching.

Extensive testing was done to rule out other potential causes of the patient’s symptoms, including magnetic resonance imaging (MRI) of the spine and brain (which was normal). In addition, the patient’s aldolase level and antineutrophil cytoplasmic antibodies were normal. The patient tested negative for human immunodeficiency virus and antibodies to double-stranded DNA. After serial neurologic exams, the final diagnosis of ALS was made.

DISCUSSION

ALS, also known as Lou Gehrig’s disease, is a degenerative motor neuron disease.^1-3 The incidence in North America is 1.5 to 2.7 per 100,000 per year, and the prevalence is 2.7 to 7.4 per 100,000.⁴ The incidence of ALS increases with each decade of life, especially after age 40, and peaks at 74 years of age.⁴ The male to female ratio is 1:1.5-2.⁴ ALS affects upper and lower motor neurons and is progressive; however, the rate of progression and phenotype vary greatly between individuals.² Most patients with ALS die within 2 to 5 years of onset.⁵

There is no specific test for ALS; the diagnosis is made clinically based on the revised El Escorial World Federation of Neurology criteria, also known as the Airlie House criteria.^2,6,7 These criteria include evidence of lower motor neuron degeneration by clinical, electrophysiologic, or neuropathologic exam; evidence of upper motor neuron disease by clinical exam; progressive spread of symptoms or signs within a region or to other regions (by history or exam); and the absence of electrophysiologic, neuroimaging, or pathologic evidence of other disease processes that could explain the symptoms. If patients have evidence of upper and lower motor neuron disease, they should be reevaluated in 4 weeks to see if symptoms are improving or progressing.

Like our patient, many patients will have an elevated creatine kinase level (some with levels as high as 1000 U/L), and calcium may also be elevated because, rarely, ALS is associated with primary hyperparathyroidism.⁸ Electrophysiologic studies can be helpful in identifying active denervation of lower motor neurons.^4,6,7

The differential diagnosis for ALS includes myasthenia gravis, inclusion-body myositis, multifocal motor neuropathy, benign fasciculations, hereditary spastic paraplegia, primary lateral sclerosis, post-polio progressive muscle atrophy, cervical spondylosis, and multiple sclerosis. A negative acetylcholine receptor antibody test will rule out myasthenia gravis, imaging of the spine can rule out cervical spondylosis, and electrophysiologic testing helps eliminate the other conditions (TABLE 1⁴).

Treatment in specialty clinics can prolong survival

The mainstays of treatment are symptom management, multidisciplinary care (by physicians, physical/occupational/speech therapists, nutritionists, psychologists, psychotherapists, and genetic counselors), palliative care, and counseling about end-of-life issues for patients and family.^1,5 Utilization of an ALS specialty clinic can provide access to all of these services and should be considered, as there is evidence that treatment in such clinics can prolong survival.⁵ The location of ALS specialty clinics can be found on the ALS Association’s Web site at http://www.alsa.org/community/.

Despite treatment, however, ALS is a progressive disease. The prognosis is poor, with a median survival of 2 to 5 years after diagnosis.⁹

The El Escorial World Federation of Neurology criteria for the diagnosis of ALS address how to treat the most common symptoms of ALS that occur as the disease progresses. These symptoms include dyspnea, muscle spasms, spasticity, sialorrhea, and pseudobulbar affect (TABLE 2^1,5).

Our patient was started on baclofen 10 mg 3 times per day (titrated up as needed) for muscle spasms and cramps, which resulted in some improvement of his cramps, but no improvement in the spasms. He was also started on sertraline 50 mg for anxiety and depression. His overall weakness continued to progress, and we recommended that the patient get ankle-foot orthosis braces to help with the mobility impairment caused by foot drop.

We then referred him to an ALS specialty clinic recommended by the neuromuscular specialist. The patient is now enrolled in a clinical trial designed to test a cerebrospinal fluid marker for diagnosis and for a new drug aimed at symptom management.

THE TAKEAWAY

Muscle cramps and pain are early signs of ALS. Although ALS is uncommon, patients who present with muscle cramps and muscle pain should have a creatine kinase test ordered (which, if elevated, should prompt further investigation into ALS as the possible cause). Patients should also undergo a neurologic examination to seek evidence of upper and lower motor neuron disease. They should then be reevaluated in 4 weeks to see if symptoms are improving or progressing. If no improvement is seen and symptoms are progressive, a work-up for ALS should be considered.

The mainstay of treatment for patients with ALS is multidisciplinary symptom management and palliative care. Utilization of an ALS specialty clinic should also be recommended, as it can improve survival.⁵

A 62-year-old man with end-stage renal disease presented to our dermatology clinic with 2-month-old ulcerations on his distal left ring finger. He was on hemodialysis and had a radiocephalic arteriovenous fistula (AVF) on his left arm. He had been empirically treated elsewhere with oral trimethoprim-sulfamethoxazole for a presumed bacterial infection, without improvement. He was then treated for contact dermatitis with topical clobetasol, which led to ulcer expansion and worsening pain.

At our clinic, the patient reported intermittent pain in his finger and paresthesias during activity and dialysis, but no tenderness of the ulcers. He had atrophy of the intrinsic left hand muscles (his non-dominant hand) with associated weakness. Three weeks earlier, he’d received a blood transfusion for anemia. Afterward, the pain in his hand improved and the ulcers decreased in size.

On exam, the AVF had a palpable thrill over the left forearm. The radial pulses were palpable bilaterally (2+) and the left ulnar artery was palpable, but diminished (1+). The patient’s left hand was cooler than the right (with a slight cyanotic hue and visible intrinsic muscle atrophy) and had decreased sensation to pain and temperature. Four ulcers with dry yellow eschar were located over the dorsal interphalangeal joints (FIGURES 1A AND 1B). They were essentially non-tender, but there was tenderness in the adjacent intact skin. There was violaceous blue edematous congestion noted on the fourth finger, and the distal phalange was constricted, giving it a “pseudoainhum” appearance.

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

Diagnosis: Dialysis access steal syndrome

We suspected dialysis access steal syndrome (also known as AVF steal syndrome), so a duplex ultrasound was performed. The ultrasound was inconclusive. (We couldn’t confirm a limitation in blood flow, nor delineate anatomy.) So, we referred the patient for a thoracic and upper extremity angiogram.

The angiogram demonstrated multifocal, moderate to severe, areas of stenosis at the distal left brachial artery. The radial artery was patent at the level of the wrist, but showed diffuse narrowing beyond the level of the arteriovenous (AV) anastomosis. There was only a faint palmar arch identified on the radial aspect of the hand with digital branches feeding the radial portion of the hand. In contrast, the ulnar artery was not seen within the mid- and distal forearm (FIGURE 2). Palmar branches to the ulnar half of the hand were not identified. The fistula itself didn’t show any stenosis.

Based on these findings, our suspicions of dialysis access steal syndrome were confirmed.

Dialysis access steal syndrome is caused by a significant decrease or reversal of blood flow in the arterial segment distal to the AVF or graft, which is induced by the low resistance of the fistula outflow. Patients with adequate collateral vasculature are able to compensate for the steal effect; however, patients with end-stage renal disease typically have preexisting vascular disease that increases the risk for vascular steal and, ultimately, demand ischemia after placement of an AVF.¹ Interestingly, a steal effect occurs in 73% of patients after AVF construction, yet it is estimated that only 10% of patients demonstrating a steal phenomenon become symptomatic.²

In our patient’s case, the vaso-occlusive properties of topical steroids explain why the superpotent steroid (clobetasol) he was prescribed increased his pain and worsened the underlying problem.

A broad differential; a useful exam maneuver

The differential diagnosis of ulcers includes infection (mainly from bacterial or mycobacterial sources), trauma facilitated by neuropathy (neuropathic ulceration), vasculitis, and ischemia. When the history and physical exam suggest ischemic ulceration, then thromboembolism, thoracic outlet syndrome, vasculitis, atherosclerosis, and steal syndrome become more likely causes.

Signs and symptoms of ischemic steal syndrome are initially subtle and include extremity coolness, neurosensory changes, intrinsic muscle weakness, ulceration, and ultimately, gangrene of the affected extremity.^3,4 A cold, numb, and/or painful hand during dialysis is another clue.³ Factors that increase the likelihood of the syndrome include age >60 years, female sex, and the presence of diabetes or peripheral artery disease.^2,3,5,6

The confirmatory diagnosis of steal syndrome is made via a fistulogram (angiography) with and without manual compression.

One physical exam maneuver that can help make the diagnosis of steal syndrome is manual occlusion of the AVF. If palpable distal pulses disappear when the AVF is patent and reappear when the fistula is occluded with downward pressure, then AVF steal syndrome is likely.⁴ Pain at rest, sensory loss, loss of pulse, and digital gangrene are emergency symptoms that warrant immediate surgical evaluation.³

Tests will confirm suspicions. Doppler ultrasound can be used to assess changes in the blood flow rate of the affected vessels when the AVF is patent vs when it is occluded. Similarly, pulse oximetry can be used with and without AVF occlusion to compare changes in oxygen saturation. The confirmatory diagnosis, however, is made via a fistulogram (angiography) with and without manual compression.⁶ Images taken after dye injection into the AVF show dramatic improvement of distal blood flow with AVF compression.

Treatment requires surgery

Severe steal-related ischemic manifestations that threaten the function and viability of digits require surgical treatment that is primarily directed toward improving distal blood flow and secondarily toward preserving hemodialysis access. Several surgical treatments are commonly used, including access ligation, banding, elongation, distal arterial ligation, and distal revascularization and interval ligation.^2-5,7

Our patient. Distal revascularization was attempted, but unfortunately, the patient’s gangrene was progressive (FIGURE 3) and surgical amputation of the left fourth finger was performed at the metacarpal’s proximal metaphyseal flare. The patient was transitioned to peritoneal dialysis to avoid further ischemia.

CORRESPONDENCE
Sahand Rahnama-Moghadam, MD, Department of Dermatology, Indiana University, 545 Barnhill Drive, Indianapolis, IN 46202; [email protected].

A 62-year-old man with end-stage renal disease presented to our dermatology clinic with 2-month-old ulcerations on his distal left ring finger. He was on hemodialysis and had a radiocephalic arteriovenous fistula (AVF) on his left arm. He had been empirically treated elsewhere with oral trimethoprim-sulfamethoxazole for a presumed bacterial infection, without improvement. He was then treated for contact dermatitis with topical clobetasol, which led to ulcer expansion and worsening pain.

At our clinic, the patient reported intermittent pain in his finger and paresthesias during activity and dialysis, but no tenderness of the ulcers. He had atrophy of the intrinsic left hand muscles (his non-dominant hand) with associated weakness. Three weeks earlier, he’d received a blood transfusion for anemia. Afterward, the pain in his hand improved and the ulcers decreased in size.

On exam, the AVF had a palpable thrill over the left forearm. The radial pulses were palpable bilaterally (2+) and the left ulnar artery was palpable, but diminished (1+). The patient’s left hand was cooler than the right (with a slight cyanotic hue and visible intrinsic muscle atrophy) and had decreased sensation to pain and temperature. Four ulcers with dry yellow eschar were located over the dorsal interphalangeal joints (FIGURES 1A AND 1B). They were essentially non-tender, but there was tenderness in the adjacent intact skin. There was violaceous blue edematous congestion noted on the fourth finger, and the distal phalange was constricted, giving it a “pseudoainhum” appearance.

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

Diagnosis: Dialysis access steal syndrome

We suspected dialysis access steal syndrome (also known as AVF steal syndrome), so a duplex ultrasound was performed. The ultrasound was inconclusive. (We couldn’t confirm a limitation in blood flow, nor delineate anatomy.) So, we referred the patient for a thoracic and upper extremity angiogram.

The angiogram demonstrated multifocal, moderate to severe, areas of stenosis at the distal left brachial artery. The radial artery was patent at the level of the wrist, but showed diffuse narrowing beyond the level of the arteriovenous (AV) anastomosis. There was only a faint palmar arch identified on the radial aspect of the hand with digital branches feeding the radial portion of the hand. In contrast, the ulnar artery was not seen within the mid- and distal forearm (FIGURE 2). Palmar branches to the ulnar half of the hand were not identified. The fistula itself didn’t show any stenosis.

Based on these findings, our suspicions of dialysis access steal syndrome were confirmed.

Dialysis access steal syndrome is caused by a significant decrease or reversal of blood flow in the arterial segment distal to the AVF or graft, which is induced by the low resistance of the fistula outflow. Patients with adequate collateral vasculature are able to compensate for the steal effect; however, patients with end-stage renal disease typically have preexisting vascular disease that increases the risk for vascular steal and, ultimately, demand ischemia after placement of an AVF.¹ Interestingly, a steal effect occurs in 73% of patients after AVF construction, yet it is estimated that only 10% of patients demonstrating a steal phenomenon become symptomatic.²

In our patient’s case, the vaso-occlusive properties of topical steroids explain why the superpotent steroid (clobetasol) he was prescribed increased his pain and worsened the underlying problem.

A broad differential; a useful exam maneuver

The differential diagnosis of ulcers includes infection (mainly from bacterial or mycobacterial sources), trauma facilitated by neuropathy (neuropathic ulceration), vasculitis, and ischemia. When the history and physical exam suggest ischemic ulceration, then thromboembolism, thoracic outlet syndrome, vasculitis, atherosclerosis, and steal syndrome become more likely causes.

Signs and symptoms of ischemic steal syndrome are initially subtle and include extremity coolness, neurosensory changes, intrinsic muscle weakness, ulceration, and ultimately, gangrene of the affected extremity.^3,4 A cold, numb, and/or painful hand during dialysis is another clue.³ Factors that increase the likelihood of the syndrome include age >60 years, female sex, and the presence of diabetes or peripheral artery disease.^2,3,5,6

The confirmatory diagnosis of steal syndrome is made via a fistulogram (angiography) with and without manual compression.

One physical exam maneuver that can help make the diagnosis of steal syndrome is manual occlusion of the AVF. If palpable distal pulses disappear when the AVF is patent and reappear when the fistula is occluded with downward pressure, then AVF steal syndrome is likely.⁴ Pain at rest, sensory loss, loss of pulse, and digital gangrene are emergency symptoms that warrant immediate surgical evaluation.³

Tests will confirm suspicions. Doppler ultrasound can be used to assess changes in the blood flow rate of the affected vessels when the AVF is patent vs when it is occluded. Similarly, pulse oximetry can be used with and without AVF occlusion to compare changes in oxygen saturation. The confirmatory diagnosis, however, is made via a fistulogram (angiography) with and without manual compression.⁶ Images taken after dye injection into the AVF show dramatic improvement of distal blood flow with AVF compression.

Treatment requires surgery

Severe steal-related ischemic manifestations that threaten the function and viability of digits require surgical treatment that is primarily directed toward improving distal blood flow and secondarily toward preserving hemodialysis access. Several surgical treatments are commonly used, including access ligation, banding, elongation, distal arterial ligation, and distal revascularization and interval ligation.^2-5,7

Our patient. Distal revascularization was attempted, but unfortunately, the patient’s gangrene was progressive (FIGURE 3) and surgical amputation of the left fourth finger was performed at the metacarpal’s proximal metaphyseal flare. The patient was transitioned to peritoneal dialysis to avoid further ischemia.

CORRESPONDENCE
Sahand Rahnama-Moghadam, MD, Department of Dermatology, Indiana University, 545 Barnhill Drive, Indianapolis, IN 46202; [email protected].

A 62-year-old man with end-stage renal disease presented to our dermatology clinic with 2-month-old ulcerations on his distal left ring finger. He was on hemodialysis and had a radiocephalic arteriovenous fistula (AVF) on his left arm. He had been empirically treated elsewhere with oral trimethoprim-sulfamethoxazole for a presumed bacterial infection, without improvement. He was then treated for contact dermatitis with topical clobetasol, which led to ulcer expansion and worsening pain.

At our clinic, the patient reported intermittent pain in his finger and paresthesias during activity and dialysis, but no tenderness of the ulcers. He had atrophy of the intrinsic left hand muscles (his non-dominant hand) with associated weakness. Three weeks earlier, he’d received a blood transfusion for anemia. Afterward, the pain in his hand improved and the ulcers decreased in size.

On exam, the AVF had a palpable thrill over the left forearm. The radial pulses were palpable bilaterally (2+) and the left ulnar artery was palpable, but diminished (1+). The patient’s left hand was cooler than the right (with a slight cyanotic hue and visible intrinsic muscle atrophy) and had decreased sensation to pain and temperature. Four ulcers with dry yellow eschar were located over the dorsal interphalangeal joints (FIGURES 1A AND 1B). They were essentially non-tender, but there was tenderness in the adjacent intact skin. There was violaceous blue edematous congestion noted on the fourth finger, and the distal phalange was constricted, giving it a “pseudoainhum” appearance.

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

Diagnosis: Dialysis access steal syndrome

We suspected dialysis access steal syndrome (also known as AVF steal syndrome), so a duplex ultrasound was performed. The ultrasound was inconclusive. (We couldn’t confirm a limitation in blood flow, nor delineate anatomy.) So, we referred the patient for a thoracic and upper extremity angiogram.

The angiogram demonstrated multifocal, moderate to severe, areas of stenosis at the distal left brachial artery. The radial artery was patent at the level of the wrist, but showed diffuse narrowing beyond the level of the arteriovenous (AV) anastomosis. There was only a faint palmar arch identified on the radial aspect of the hand with digital branches feeding the radial portion of the hand. In contrast, the ulnar artery was not seen within the mid- and distal forearm (FIGURE 2). Palmar branches to the ulnar half of the hand were not identified. The fistula itself didn’t show any stenosis.

Based on these findings, our suspicions of dialysis access steal syndrome were confirmed.

Dialysis access steal syndrome is caused by a significant decrease or reversal of blood flow in the arterial segment distal to the AVF or graft, which is induced by the low resistance of the fistula outflow. Patients with adequate collateral vasculature are able to compensate for the steal effect; however, patients with end-stage renal disease typically have preexisting vascular disease that increases the risk for vascular steal and, ultimately, demand ischemia after placement of an AVF.¹ Interestingly, a steal effect occurs in 73% of patients after AVF construction, yet it is estimated that only 10% of patients demonstrating a steal phenomenon become symptomatic.²

In our patient’s case, the vaso-occlusive properties of topical steroids explain why the superpotent steroid (clobetasol) he was prescribed increased his pain and worsened the underlying problem.

A broad differential; a useful exam maneuver

The differential diagnosis of ulcers includes infection (mainly from bacterial or mycobacterial sources), trauma facilitated by neuropathy (neuropathic ulceration), vasculitis, and ischemia. When the history and physical exam suggest ischemic ulceration, then thromboembolism, thoracic outlet syndrome, vasculitis, atherosclerosis, and steal syndrome become more likely causes.

Signs and symptoms of ischemic steal syndrome are initially subtle and include extremity coolness, neurosensory changes, intrinsic muscle weakness, ulceration, and ultimately, gangrene of the affected extremity.^3,4 A cold, numb, and/or painful hand during dialysis is another clue.³ Factors that increase the likelihood of the syndrome include age >60 years, female sex, and the presence of diabetes or peripheral artery disease.^2,3,5,6

The confirmatory diagnosis of steal syndrome is made via a fistulogram (angiography) with and without manual compression.

One physical exam maneuver that can help make the diagnosis of steal syndrome is manual occlusion of the AVF. If palpable distal pulses disappear when the AVF is patent and reappear when the fistula is occluded with downward pressure, then AVF steal syndrome is likely.⁴ Pain at rest, sensory loss, loss of pulse, and digital gangrene are emergency symptoms that warrant immediate surgical evaluation.³

Tests will confirm suspicions. Doppler ultrasound can be used to assess changes in the blood flow rate of the affected vessels when the AVF is patent vs when it is occluded. Similarly, pulse oximetry can be used with and without AVF occlusion to compare changes in oxygen saturation. The confirmatory diagnosis, however, is made via a fistulogram (angiography) with and without manual compression.⁶ Images taken after dye injection into the AVF show dramatic improvement of distal blood flow with AVF compression.

Treatment requires surgery

Severe steal-related ischemic manifestations that threaten the function and viability of digits require surgical treatment that is primarily directed toward improving distal blood flow and secondarily toward preserving hemodialysis access. Several surgical treatments are commonly used, including access ligation, banding, elongation, distal arterial ligation, and distal revascularization and interval ligation.^2-5,7

Our patient. Distal revascularization was attempted, but unfortunately, the patient’s gangrene was progressive (FIGURE 3) and surgical amputation of the left fourth finger was performed at the metacarpal’s proximal metaphyseal flare. The patient was transitioned to peritoneal dialysis to avoid further ischemia.

CORRESPONDENCE
Sahand Rahnama-Moghadam, MD, Department of Dermatology, Indiana University, 545 Barnhill Drive, Indianapolis, IN 46202; [email protected].

EVIDENCE SUMMARY

A systematic review and meta-analysis of 84 moderate- to high-quality RCTs with 24,010 patients evaluated the use of “eHealth” interventions in preventing and treating overweight and obesity in adults 35 to 65 years of age (75% female).¹ The studies included 183 active intervention arms with durations as long as 24 months (64% <6 months, 46% >6 months). The term eHealth included all forms of information technology used to deliver health care, but predominantly the Internet (Web site/Web-based), e-mail, and text messaging. Sixty percent (84) of eHealth interventional arms used one modality and 34% (47) used 2. Some intervention arms included non-eHealth modalities, such as paper-based measures and counseling.

The eHealth interventions were associated with significantly greater weight loss than minimal or no intervention (TABLE).¹ Comparing eHealth interventions with no intervention showed significant differences by eHealth type (P=.05). The greatest weight loss accompanied interventions that combined Web-based measures with a non-eHealth intervention, (mean difference [MD]= −3.7 kg; 95% confidence interval [CI], −4.46 to −2.94), followed by mobile interventions alone (MD= −2.4 kg; 95% CI, −4.09 to −0.71) and Web-based interventions alone (MD= −2.2 kg; 95% CI, −2.98 to −1.44).

Similarly, comparing combined interventions (eHealth + eHealth or eHealth + non-eHealth) with a minimal intervention control showed a trend for difference by eHealth type (P=.005). Only a combination of eHealth with non-eHealth interventions resulted in significantly greater weight loss (Web site + non-eHealth: MD= −2.7 kg; 95% CI, −3.76 to −1.54; text + non-eHealth: MD= −1.8 kg; 95% CI, −2.49 to −1.12; computer + non-eHealth: MD=1.1 kg; 95% CI, −1.36 to −0.89).

Personal coaching plus smartphone monitoring beats interactive app

A 3-arm RCT of 385 overweight and obese participants (mean body mass index [BMI], 35 kg/m²) 18 to 35 years of age compared the effectiveness of weight loss interventions delivered by interactive smartphone application (CP [cell phone]), personal coaching enhanced by smartphone self-monitoring (PC), and usual care (control).² The PC arm attended 6 weekly group sessions and received monthly phone calls. The usual care arm received 3 handouts on healthy eating and physical activity.

The CP arm showed the least amount of weight loss (−0.9 kg, −1.5 kg, and −1.0 kg at 6, 12, and 24 months, respectively) and no significant difference compared with controls at all measurement points. The PC arm had significantly greater weight loss than controls at 6 months (−1.9 kg; 95% CI, −3.17 to −0.67) and significantly greater weight loss than CP at 6 months (−2.2 kg; 95% CI, −3.42 to −0.97) and 12 months (−2.1 kg; 95% CI, −3.94 to −0.27). After 24 months, however, there was no significant difference in mean weight loss among treatment arms.

Automated behavioral program reduced weight and waist circumference

An RCT of 339 prediabetic, overweight, and obese patients 30 to 69 years old (mean BMI, 31 kg/m²) compared the effectiveness of Alive-PD, a fully automated, tailored, behavioral program, to usual care (control) for diabetes prevention.³ In addition to behavioral support, the program included weekly emails, Web-based tracking, a mobile phone app, and automated phone calls.

At 6 months, the intervention group had significantly greater mean weight loss (−3.4 kg vs −1.3 kg; P<.001), mean BMI (−1.1 kg/m² vs −0.4 kg/m²; P<.001), and mean waist circumference (−4.6 cm vs 2.2 cm; P<.001).

Web-based program improves weight loss at 3 months, but not 12 months

An RCT of 65 overweight and obese participants (mean BMI, 32 kg/m²) with at least one cardiovascular risk factor compared the effect of a Web-based program with usual care on weight change at 3, 6, and 12 months.⁴ Participants in the intervention group were provided with Bluetooth-enabled scales and accelerometer activity bands to allow daily uploads. The Web-based program also provided weekly feedback based on the participant’s performance and a food diary.

The Web-based group had significantly greater weight loss at 3 months (mean= −3.4 kg [95% CI, −4.70 to −2.13] vs −0.5 kg [95% CI, −1.55 to 0.52]; P<.001) and 6 months (mean= −3.4 kg [95% CI, −4.95 to −1.98] vs −0.8 kg [95% CI, −2.23 to 0.61]; P=.02). At 12 months, however, the groups showed no significant difference (mean= −2.4 kg [95% CI, −3.48 to −0.97] vs −1.8 kg [95% CI, −3.15 to −0.44]; P=.77).

RECOMMENDATIONS

Guidelines from the American College of Cardiology, American Heart Association, and Obesity Society state that electronically delivered weight-loss programs may be prescribed, but may result in smaller weight loss than face-to-face interventions (SOR: B, moderate evidence from RCTs with some limitations or non-randomized trials).⁵

EVIDENCE SUMMARY

A systematic review and meta-analysis of 84 moderate- to high-quality RCTs with 24,010 patients evaluated the use of “eHealth” interventions in preventing and treating overweight and obesity in adults 35 to 65 years of age (75% female).¹ The studies included 183 active intervention arms with durations as long as 24 months (64% <6 months, 46% >6 months). The term eHealth included all forms of information technology used to deliver health care, but predominantly the Internet (Web site/Web-based), e-mail, and text messaging. Sixty percent (84) of eHealth interventional arms used one modality and 34% (47) used 2. Some intervention arms included non-eHealth modalities, such as paper-based measures and counseling.

The eHealth interventions were associated with significantly greater weight loss than minimal or no intervention (TABLE).¹ Comparing eHealth interventions with no intervention showed significant differences by eHealth type (P=.05). The greatest weight loss accompanied interventions that combined Web-based measures with a non-eHealth intervention, (mean difference [MD]= −3.7 kg; 95% confidence interval [CI], −4.46 to −2.94), followed by mobile interventions alone (MD= −2.4 kg; 95% CI, −4.09 to −0.71) and Web-based interventions alone (MD= −2.2 kg; 95% CI, −2.98 to −1.44).

Similarly, comparing combined interventions (eHealth + eHealth or eHealth + non-eHealth) with a minimal intervention control showed a trend for difference by eHealth type (P=.005). Only a combination of eHealth with non-eHealth interventions resulted in significantly greater weight loss (Web site + non-eHealth: MD= −2.7 kg; 95% CI, −3.76 to −1.54; text + non-eHealth: MD= −1.8 kg; 95% CI, −2.49 to −1.12; computer + non-eHealth: MD=1.1 kg; 95% CI, −1.36 to −0.89).

Personal coaching plus smartphone monitoring beats interactive app

A 3-arm RCT of 385 overweight and obese participants (mean body mass index [BMI], 35 kg/m²) 18 to 35 years of age compared the effectiveness of weight loss interventions delivered by interactive smartphone application (CP [cell phone]), personal coaching enhanced by smartphone self-monitoring (PC), and usual care (control).² The PC arm attended 6 weekly group sessions and received monthly phone calls. The usual care arm received 3 handouts on healthy eating and physical activity.

The CP arm showed the least amount of weight loss (−0.9 kg, −1.5 kg, and −1.0 kg at 6, 12, and 24 months, respectively) and no significant difference compared with controls at all measurement points. The PC arm had significantly greater weight loss than controls at 6 months (−1.9 kg; 95% CI, −3.17 to −0.67) and significantly greater weight loss than CP at 6 months (−2.2 kg; 95% CI, −3.42 to −0.97) and 12 months (−2.1 kg; 95% CI, −3.94 to −0.27). After 24 months, however, there was no significant difference in mean weight loss among treatment arms.

Automated behavioral program reduced weight and waist circumference

An RCT of 339 prediabetic, overweight, and obese patients 30 to 69 years old (mean BMI, 31 kg/m²) compared the effectiveness of Alive-PD, a fully automated, tailored, behavioral program, to usual care (control) for diabetes prevention.³ In addition to behavioral support, the program included weekly emails, Web-based tracking, a mobile phone app, and automated phone calls.

At 6 months, the intervention group had significantly greater mean weight loss (−3.4 kg vs −1.3 kg; P<.001), mean BMI (−1.1 kg/m² vs −0.4 kg/m²; P<.001), and mean waist circumference (−4.6 cm vs 2.2 cm; P<.001).

Web-based program improves weight loss at 3 months, but not 12 months

An RCT of 65 overweight and obese participants (mean BMI, 32 kg/m²) with at least one cardiovascular risk factor compared the effect of a Web-based program with usual care on weight change at 3, 6, and 12 months.⁴ Participants in the intervention group were provided with Bluetooth-enabled scales and accelerometer activity bands to allow daily uploads. The Web-based program also provided weekly feedback based on the participant’s performance and a food diary.

The Web-based group had significantly greater weight loss at 3 months (mean= −3.4 kg [95% CI, −4.70 to −2.13] vs −0.5 kg [95% CI, −1.55 to 0.52]; P<.001) and 6 months (mean= −3.4 kg [95% CI, −4.95 to −1.98] vs −0.8 kg [95% CI, −2.23 to 0.61]; P=.02). At 12 months, however, the groups showed no significant difference (mean= −2.4 kg [95% CI, −3.48 to −0.97] vs −1.8 kg [95% CI, −3.15 to −0.44]; P=.77).

RECOMMENDATIONS

Guidelines from the American College of Cardiology, American Heart Association, and Obesity Society state that electronically delivered weight-loss programs may be prescribed, but may result in smaller weight loss than face-to-face interventions (SOR: B, moderate evidence from RCTs with some limitations or non-randomized trials).⁵

EVIDENCE SUMMARY

A systematic review and meta-analysis of 84 moderate- to high-quality RCTs with 24,010 patients evaluated the use of “eHealth” interventions in preventing and treating overweight and obesity in adults 35 to 65 years of age (75% female).¹ The studies included 183 active intervention arms with durations as long as 24 months (64% <6 months, 46% >6 months). The term eHealth included all forms of information technology used to deliver health care, but predominantly the Internet (Web site/Web-based), e-mail, and text messaging. Sixty percent (84) of eHealth interventional arms used one modality and 34% (47) used 2. Some intervention arms included non-eHealth modalities, such as paper-based measures and counseling.

The eHealth interventions were associated with significantly greater weight loss than minimal or no intervention (TABLE).¹ Comparing eHealth interventions with no intervention showed significant differences by eHealth type (P=.05). The greatest weight loss accompanied interventions that combined Web-based measures with a non-eHealth intervention, (mean difference [MD]= −3.7 kg; 95% confidence interval [CI], −4.46 to −2.94), followed by mobile interventions alone (MD= −2.4 kg; 95% CI, −4.09 to −0.71) and Web-based interventions alone (MD= −2.2 kg; 95% CI, −2.98 to −1.44).

Similarly, comparing combined interventions (eHealth + eHealth or eHealth + non-eHealth) with a minimal intervention control showed a trend for difference by eHealth type (P=.005). Only a combination of eHealth with non-eHealth interventions resulted in significantly greater weight loss (Web site + non-eHealth: MD= −2.7 kg; 95% CI, −3.76 to −1.54; text + non-eHealth: MD= −1.8 kg; 95% CI, −2.49 to −1.12; computer + non-eHealth: MD=1.1 kg; 95% CI, −1.36 to −0.89).

Personal coaching plus smartphone monitoring beats interactive app

A 3-arm RCT of 385 overweight and obese participants (mean body mass index [BMI], 35 kg/m²) 18 to 35 years of age compared the effectiveness of weight loss interventions delivered by interactive smartphone application (CP [cell phone]), personal coaching enhanced by smartphone self-monitoring (PC), and usual care (control).² The PC arm attended 6 weekly group sessions and received monthly phone calls. The usual care arm received 3 handouts on healthy eating and physical activity.

The CP arm showed the least amount of weight loss (−0.9 kg, −1.5 kg, and −1.0 kg at 6, 12, and 24 months, respectively) and no significant difference compared with controls at all measurement points. The PC arm had significantly greater weight loss than controls at 6 months (−1.9 kg; 95% CI, −3.17 to −0.67) and significantly greater weight loss than CP at 6 months (−2.2 kg; 95% CI, −3.42 to −0.97) and 12 months (−2.1 kg; 95% CI, −3.94 to −0.27). After 24 months, however, there was no significant difference in mean weight loss among treatment arms.

Automated behavioral program reduced weight and waist circumference

An RCT of 339 prediabetic, overweight, and obese patients 30 to 69 years old (mean BMI, 31 kg/m²) compared the effectiveness of Alive-PD, a fully automated, tailored, behavioral program, to usual care (control) for diabetes prevention.³ In addition to behavioral support, the program included weekly emails, Web-based tracking, a mobile phone app, and automated phone calls.

At 6 months, the intervention group had significantly greater mean weight loss (−3.4 kg vs −1.3 kg; P<.001), mean BMI (−1.1 kg/m² vs −0.4 kg/m²; P<.001), and mean waist circumference (−4.6 cm vs 2.2 cm; P<.001).

Web-based program improves weight loss at 3 months, but not 12 months

An RCT of 65 overweight and obese participants (mean BMI, 32 kg/m²) with at least one cardiovascular risk factor compared the effect of a Web-based program with usual care on weight change at 3, 6, and 12 months.⁴ Participants in the intervention group were provided with Bluetooth-enabled scales and accelerometer activity bands to allow daily uploads. The Web-based program also provided weekly feedback based on the participant’s performance and a food diary.

The Web-based group had significantly greater weight loss at 3 months (mean= −3.4 kg [95% CI, −4.70 to −2.13] vs −0.5 kg [95% CI, −1.55 to 0.52]; P<.001) and 6 months (mean= −3.4 kg [95% CI, −4.95 to −1.98] vs −0.8 kg [95% CI, −2.23 to 0.61]; P=.02). At 12 months, however, the groups showed no significant difference (mean= −2.4 kg [95% CI, −3.48 to −0.97] vs −1.8 kg [95% CI, −3.15 to −0.44]; P=.77).

RECOMMENDATIONS

Guidelines from the American College of Cardiology, American Heart Association, and Obesity Society state that electronically delivered weight-loss programs may be prescribed, but may result in smaller weight loss than face-to-face interventions (SOR: B, moderate evidence from RCTs with some limitations or non-randomized trials).⁵

When I became a family physician (FP), it never crossed my mind that I would one day be asking school-aged children about bullying. Not so much because bullying didn’t exist, but because I wasn’t aware of the pervasiveness and seriousness of the problem and because there were no professional recommendations to do so.

That said, my family had some first-hand experience with the issue: One of my children was bullied in grade school. When my wife found out, she promptly visited the 2 boys’ homes and told them and their parents that the behavior would stop or else! (She may have used more colorful language.) And it did stop. But times have changed, and so has the nature of bullying, which can now extend beyond the hallway to an entire school body in seconds with a few taps on a cell phone. And the adverse consequences can be significant, as described by McClowry and colleagues.

We need to ask our young patients a single question: "Are you being bullied?"The prevalence of bullying is discouragingly high, estimated to be about 20% in national surveys.¹ Because bullying occurs so frequently, public health, community-based, and school-based approaches, rather than one-on-one office-based interventions, are likely to have the greatest overall impact on decreasing bullying. Randomized trials bear this out, showing that prevention programs in schools can effectively reduce the behavior.^2,3

What is our responsibility as FPs? Screening is a reasonable first step, even in the absence of randomized trials demonstrating benefit. Because there have been no physician office-based trials of screening or interventions for bullying, we must rely on “expert opinion” at this time, with no assurance that what we do will actually help children. Absence of proof of benefit, however, does not mean absence of benefit, and doing nothing will definitely not help anyone. The authors recommend a single screening question: "Are you being bullied?"—especially for children who are at higher risk, such as those with disabilities/special health needs, LGBTQ+ status, and who are under- or overweight.

Clearly we need research to know which interventions truly help these children/adolescents and their parents. In the meantime, however, identifying the problem and offering emotional support are unlikely to harm—and may help. Opening the lines of communication, connecting children and their parents with available community resources, and supporting anti-bullying programs in your schools are additional ways we can make a difference today.

When I became a family physician (FP), it never crossed my mind that I would one day be asking school-aged children about bullying. Not so much because bullying didn’t exist, but because I wasn’t aware of the pervasiveness and seriousness of the problem and because there were no professional recommendations to do so.

That said, my family had some first-hand experience with the issue: One of my children was bullied in grade school. When my wife found out, she promptly visited the 2 boys’ homes and told them and their parents that the behavior would stop or else! (She may have used more colorful language.) And it did stop. But times have changed, and so has the nature of bullying, which can now extend beyond the hallway to an entire school body in seconds with a few taps on a cell phone. And the adverse consequences can be significant, as described by McClowry and colleagues.

We need to ask our young patients a single question: "Are you being bullied?"The prevalence of bullying is discouragingly high, estimated to be about 20% in national surveys.¹ Because bullying occurs so frequently, public health, community-based, and school-based approaches, rather than one-on-one office-based interventions, are likely to have the greatest overall impact on decreasing bullying. Randomized trials bear this out, showing that prevention programs in schools can effectively reduce the behavior.^2,3

What is our responsibility as FPs? Screening is a reasonable first step, even in the absence of randomized trials demonstrating benefit. Because there have been no physician office-based trials of screening or interventions for bullying, we must rely on “expert opinion” at this time, with no assurance that what we do will actually help children. Absence of proof of benefit, however, does not mean absence of benefit, and doing nothing will definitely not help anyone. The authors recommend a single screening question: "Are you being bullied?"—especially for children who are at higher risk, such as those with disabilities/special health needs, LGBTQ+ status, and who are under- or overweight.

Clearly we need research to know which interventions truly help these children/adolescents and their parents. In the meantime, however, identifying the problem and offering emotional support are unlikely to harm—and may help. Opening the lines of communication, connecting children and their parents with available community resources, and supporting anti-bullying programs in your schools are additional ways we can make a difference today.

When I became a family physician (FP), it never crossed my mind that I would one day be asking school-aged children about bullying. Not so much because bullying didn’t exist, but because I wasn’t aware of the pervasiveness and seriousness of the problem and because there were no professional recommendations to do so.

That said, my family had some first-hand experience with the issue: One of my children was bullied in grade school. When my wife found out, she promptly visited the 2 boys’ homes and told them and their parents that the behavior would stop or else! (She may have used more colorful language.) And it did stop. But times have changed, and so has the nature of bullying, which can now extend beyond the hallway to an entire school body in seconds with a few taps on a cell phone. And the adverse consequences can be significant, as described by McClowry and colleagues.

We need to ask our young patients a single question: "Are you being bullied?"The prevalence of bullying is discouragingly high, estimated to be about 20% in national surveys.¹ Because bullying occurs so frequently, public health, community-based, and school-based approaches, rather than one-on-one office-based interventions, are likely to have the greatest overall impact on decreasing bullying. Randomized trials bear this out, showing that prevention programs in schools can effectively reduce the behavior.^2,3

What is our responsibility as FPs? Screening is a reasonable first step, even in the absence of randomized trials demonstrating benefit. Because there have been no physician office-based trials of screening or interventions for bullying, we must rely on “expert opinion” at this time, with no assurance that what we do will actually help children. Absence of proof of benefit, however, does not mean absence of benefit, and doing nothing will definitely not help anyone. The authors recommend a single screening question: "Are you being bullied?"—especially for children who are at higher risk, such as those with disabilities/special health needs, LGBTQ+ status, and who are under- or overweight.

Clearly we need research to know which interventions truly help these children/adolescents and their parents. In the meantime, however, identifying the problem and offering emotional support are unlikely to harm—and may help. Opening the lines of communication, connecting children and their parents with available community resources, and supporting anti-bullying programs in your schools are additional ways we can make a difference today.

CASE › For the third time in 9 months, 28-year-old Joan B comes into the office with complaints of painful, frequent, and urgent urination. Ms B is sexually active and her medical history is otherwise unremarkable. In each of the previous 2 episodes, her urine culture grew Escherichia coli, and she was treated with a 5-day course of nitrofurantoin. At this current visit, she asks about the need for additional work-up, treatment for her symptoms, and whether there is a way to prevent further infections.

Urinary tract infections (UTIs) are the most common bacterial infection in women¹ and account for an estimated 5.4 million primary care office visits and 2.3 million emergency room visits annually.² For women, the lifetime risk of developing a UTI is greater than 50%.³ In one study of UTI in a primary care setting, 36% of women under 55 and 53% of women over 55 had a recurrent infection within a year.⁴ Most women with UTI are treated as outpatients, but 16.7% require hospitalization.⁵ In the United States, direct costs for evaluation and treatment of UTI total $1.6 billion each year.⁵

Accurately characterizing recurrent UTI

Bacteriuria is defined as the presence of 10⁵ colony forming units (ie, viable bacteria) per milliliter of urine collected midstream on 2 consecutive urinations.⁶ UTIs are symptomatic infections of the urinary tract and may involve the urethra, bladder, ureters, or kidneys.⁷ Infections of the lower tract (bladder and urethra) are commonly referred to as cystitis; infections of the upper tract (kidney and ureters) are referred to as pyelonephritis.

Most UTIs are uncomplicated and do not progress to more serious infections. However, patients who are pregnant, have chronic medical conditions (eg, renal insufficiency or use of immunosuppressant medications), urinary obstruction, or calculi may develop complicated UTIs.⁸

Recurrent UTI is an infection that follows resolution of bacteriuria and symptoms of a prior UTI, and the term applies when such an infection occurs within 6 months of the last UTI or when 3 or more UTIs occur within a year.⁷ Recurrent infection can be further characterized as relapse or reinfection. Relapse occurs when the patient has a second UTI caused by the same pathogen within 2 weeks of the original treatment.⁹ Reinfection is a UTI that occurs more than 2 weeks after completion of treatment for the original UTI. The pathogen in a reinfection may be the same one that caused the original UTI or it may be a different agent.⁹

It’s also important to differentiate between recurrent and resistant UTI. In resistant UTI, bacteriuria fails to resolve following 7 to 14 days of appropriate antibiotic treatment.⁹

Factors that increase the risk of recurrent UTI

Premenopausal women

Both modifiable and non-modifiable factors (TABLE 1^10-21) have been associated with increased risk of recurrent UTI in premenopausal women. Among women with specific blood group phenotypes (Lewis non-secretor, in particular), rates of UTI rise secondary to increased adherence of bacteria to epithelial cells in the urinary tract.¹⁰ Other non-modifiable risk factors include congenital urinary tract anomalies, obstruction of the urinary tract, and a history of UTI.^11,12 Women whose mothers had UTIs are at higher risk for recurrent UTI than are women whose mothers had no such history.¹³

Neither cystoscopy nor imaging is routinely recommended for the evaluation of recurrent urinary tract infection.Modifiable risk factors for recurrent UTI include contraceptive use (spermicides, spermicide-coated condoms, and oral contraceptives) and frequency of intercourse (≥4 times/month).¹³ Spermicides alter the normal vaginal flora and lead to increased colonization of E coli, which increases the risk for UTI.¹⁴ Women with recurrent UTIs were 1.27 to 1.45 times more likely to use oral contraceptives than those without recurrent UTIs.¹³ Compared with college women who had not had intercourse during the week, sexually active college women who had engaged in intercourse 3 times had a 2.6-fold increase in relative risk for UTI.¹⁵ Those who had daily intercourse had a 9-fold increase in relative risk of UTI development.¹⁵ This elevated risk is due to trauma to the lower urogenital tract (urethra) and introduction of bacteria into the urethra via mechanical factors.^16,17

Postmenopausal women

Atrophic vaginitis, catheterization, declining functional status, cystocele, incomplete emptying, incontinence, and history of premenopausal UTIs are all risk factors for recurrent UTI in postmenopausal women.^19,20 Decreased estrogen and resulting vaginal atrophy appear to be associated with increased rates of UTI in these women. Additionally, postmenopausal women’s vaginas are more likely to be colonized with E coli and have fewer lactobacilli than those of premenopausal women,²¹ which is thought to predispose them to UTI. These risk factors are summarized in TABLE 1.^10-21

Initial evaluation of recurrent UTI

Patients with recurrent UTI experience signs and symptoms similar to those with isolated uncomplicated UTI: dysuria, frequency, urgency, and hematuria. Focus your history interview on potential causes of complicated UTI (TABLE 2¹⁸). Likewise, perform a pelvic examination to evaluate for predisposing anatomic abnormalities.²² Finally, obtain a urine culture with antibiotic sensitivities to ensure that previous treatment was appropriate and to rule out microbes associated with infected uroliths.¹⁸ Given the low probability of finding abnormalities on cystoscopy or imaging, neither one is routinely recommended for the evaluation of recurrent UTI.¹⁸

Treatment options and precautions

As with isolated UTI, E coli is the most common pathogen in recurrent UTI. However, recurrent UTI is more likely than isolated UTI to result from other pathogens (odds ratio [OR]=1.5; 95% confidence interval [CI], 1.0-2.26), such as Klebsiella, Enterococcus, Proteus, and Citrobacter.²³ Since a patient’s recurrent UTI most likely arises from the same pathogen that caused the prior infection,⁸ start an antibiotic you know is effective against it. Additionally, take into account local resistance rates; antibiotic availability, cost, and adverse effects; and a patient’s drug allergies.

With recurrent UTI, start an antibiotic that's effective against the organism cultured during the prior infection.Preferred antibiotics. Trimethoprim-sulfamethoxazole (TMP-SMX), 160 mg/800 mg twice daily for 3 days, has long been the mainstay of treatment for uncomplicated UTI. Over recent years, however, resistance to TMP-SMX has increased. While it is still appropriate for many situations as first-line treatment, it is not recommended for empiric treatment if local resistance rates are higher than 20%.²⁴ Nitrofurantoin 100 mg twice daily for 5 days has efficacy similar to that of TMP-SMX, but without significant bacterial resistance. While fosfomycin 3 g as a single dose is still recommended as first-line treatment, it is less effective than either TMP-SMX or nitrofurantoin. TABLE 3²⁴ summarizes these ant­ibiotic choices and their efficacies.

Agents to avoid or use only as a last resort. For patients unable to take any of the drugs above, consider beta-lactam antibiotics, although they are typically less effective for this indication. While fluoroquinolones are very effective and have low (but rising) resistance rates, they are also associated with serious and potentially permanent adverse effects. As a result, on May 12, 2016, the Food and Drug Administration issued a Drug Safety Communication recommending that fluoroquinolones be used only in patients without other treatment options.^24,25 Do not use ampicillin or amoxicillin, which lack effectiveness for this indication and are compromised by high levels of bacterial resistance.

Shorter course of treatment? When deciding on the length of treatment for recurrent UTI, remember that shorter antibiotic courses (3-5 days) are associated with similar rates of cure and progression to systemic infections as longer courses (7-10 days). Also, patients adhere better to the shorter treatment regimen and experience fewer adverse effects.^26,27

Standing prescription? Studies have shown that women know when they have a UTI. Therefore, for women who experience recurrent UTI, consider giving them a standing prescription for antibiotics that they can initiate when symptoms arise (TABLE 3²⁴). Patient-initiated treatment yields similar rates of efficacy as physician-initiated treatment, while avoiding the adverse effects and costs associated with preventive strategies²⁸ (which we’ll discuss in a moment).

Time for imaging and referral?

For patients with a high risk of complicated UTI or a surgically amenable condition, either ultrasound or computerized tomography (CT) of the abdomen and pelvis with and without contrast is appropriate to evaluate for anatomic anomalies. While CT is the more sensitive imaging study to identify anomalies, ultrasound is less expensive and minimizes radiation exposure and is therefore also appropriate.¹⁸

Consider referring patients to a urologist if they have an underlying condition that may be amenable to surgery, such as bladder outlet obstruction, cystoceles, urinary tract diverticula, fistulae, pelvic floor dysfunction, ureteral stricture, urolithiasis, or vesicoureteral reflux.¹⁸ Additional risk factors for complicated UTI, which warrant referral as outlined by the Canadian Urologic Association, are summarized in TABLE 2.¹⁸

2 weeks later…and it’s back? Finally, for women who experience recurrent symptoms within 2 weeks of completing treatment, obtain a urine culture with antibiotic sensitivities to ensure that the infecting organism is not one typically associated with urolithiasis (Proteus and Yersinia) and that it is susceptible to planned antibiotic therapy.¹⁸ Proteus and Yersinia are urease-positive bacteria that may cause stone formation in the urinary tract system. Evaluate any patient who has a UTI from either organism for urinary tract stones.

Prevention dos and don’ts

Popular myth suggests that recurrent UTIs are more common in patients who do not void after intercourse or who douche, consume caffeinated beverages, or wear non-cotton underwear. Research, however, has failed to show a relationship between any of these factors and recurrent UTIs.^13,18 Physicians should therefore stop recommending that patients modify these behaviors to decrease recurrent infections.

Popular myth suggests that recurrent UTIs are more common in patients who do not void after intercourse, but there's no research that bears this out.Antibiotic prophylaxis decreases the rate of recurrent UTI by 95%.²⁹ It has been recommended for women who have had 2 or more UTIs in the past 6 months²⁹ or 3 or more UTIs in the past year.³⁰ Effective strategies to prevent recurrent UTI are low-dose continuous antibiotic prophylaxis or post-coital antibiotic prophylaxis.

While a test-of-cure culture is not typically recommended following treatment for uncomplicated UTI, you will want to obtain a confirmatory urine culture one to 2 weeks before starting low-dose antibiotic prophylaxis. Base your choice of antibiotic on known patient allergies and previous culture results. Agents typically used are trimethoprim, TMP-SMX, or nitrofurantoin^31,32 (TABLE 4³¹), none of which demonstrated superiority in a Cochrane review.³³ Although the same review showed no optimal duration of treatment,³³ 6 to 24 months of treatment is usually recommended.²⁹

A single dose of antibiotic following intercourse may be as effective as daily low-dose prophylaxis for women whose UTIs are related to sexual activity.³⁴ Studies have shown that single doses of TMP-SMX, nitrofurantoin, cephalexin, or a fluoroquinolone (see earlier notes about FDA warning on fluoroquinolone use) are similarly effective in decreasing the rate of recurrence^35,36 (TABLE 4³¹).

Several non-pharmacologic strategies have been suggested for preventing recurrent UTI—eg, use of cranberry products, lactobacillus, vaginal estrogen in postmenopausal women, methenamine salts, and D-mannose.

A Cochrane review found that cranberry products were less effective in preventing recurrent UTIs than previously thought.A 2012 Cochrane review of 24 studies found that cranberry products were less effective in preventing recurrent UTIs than previously thought, with no statistically significant difference between women who took them and those who did not.³⁷

Results have been mixed in using lactobacilli or probiotics to prevent recurrent UTIs. One study examining the use of lactobacilli to colonize the vaginal flora found a reduction in the number of recurrent infections in premenopausal women taking intravaginal lactobacillus over 12 months.³⁸ A second study, involving postmenopausal women, found that those who were randomized to take lactobacillus tablets for 12 months had more frequent recurrences of UTIs than women randomized to take daily TMP-SMX.³⁹ However, this last study was designed as a non-inferiority trial and its results do not negate the prior study’s findings. Additionally, vaginal estrogen, which is thought to work through colonization of the vagina with lactobacilli, has prevented recurrent UTIs in postmenopausal women.⁴⁰

Ascorbic acid (which is bacteriostatic), methenamine salts (which are hydrolysed to bactericidal ammonia and formaldehyde), and D-mannose (which inhibits bacterial adherence), have been shown—in limited studies—to decrease recurrence of UTIs.^41-43 Further study is necessary to confirm their efficacy in preventing UTIs.

As noted, the only behavioral modifications that have been shown to decrease the risk of recurrent UTI are discontinuing the use of spermicides/spermicide-coated condoms or oral contraceptives, and decreasing the frequency of intercourse.¹³

CASE › Ms. B is started on a 3-day course of TMP-SMX. Further questioning reveals that each of her 3 UTIs followed sexual intercourse. Her physician discusses the options of self-directed therapy using continuous prophylaxis or postcoital prophylaxis, either of which would be an appropriate evidence-based intervention for her. After engaging in shared decision making, she is prescribed TMP-SMX to be taken as a single dose following intercourse in the future.

CORRESPONDENCE
Jeffrey D. Quinlan, MD, FAAFP, Family Medicine, Room A-1038A, 4301 Jones Bridge Road, Bethesda, MD 20814-4712; [email protected].

CASE › For the third time in 9 months, 28-year-old Joan B comes into the office with complaints of painful, frequent, and urgent urination. Ms B is sexually active and her medical history is otherwise unremarkable. In each of the previous 2 episodes, her urine culture grew Escherichia coli, and she was treated with a 5-day course of nitrofurantoin. At this current visit, she asks about the need for additional work-up, treatment for her symptoms, and whether there is a way to prevent further infections.

Urinary tract infections (UTIs) are the most common bacterial infection in women¹ and account for an estimated 5.4 million primary care office visits and 2.3 million emergency room visits annually.² For women, the lifetime risk of developing a UTI is greater than 50%.³ In one study of UTI in a primary care setting, 36% of women under 55 and 53% of women over 55 had a recurrent infection within a year.⁴ Most women with UTI are treated as outpatients, but 16.7% require hospitalization.⁵ In the United States, direct costs for evaluation and treatment of UTI total $1.6 billion each year.⁵

Accurately characterizing recurrent UTI

Bacteriuria is defined as the presence of 10⁵ colony forming units (ie, viable bacteria) per milliliter of urine collected midstream on 2 consecutive urinations.⁶ UTIs are symptomatic infections of the urinary tract and may involve the urethra, bladder, ureters, or kidneys.⁷ Infections of the lower tract (bladder and urethra) are commonly referred to as cystitis; infections of the upper tract (kidney and ureters) are referred to as pyelonephritis.

Most UTIs are uncomplicated and do not progress to more serious infections. However, patients who are pregnant, have chronic medical conditions (eg, renal insufficiency or use of immunosuppressant medications), urinary obstruction, or calculi may develop complicated UTIs.⁸

Recurrent UTI is an infection that follows resolution of bacteriuria and symptoms of a prior UTI, and the term applies when such an infection occurs within 6 months of the last UTI or when 3 or more UTIs occur within a year.⁷ Recurrent infection can be further characterized as relapse or reinfection. Relapse occurs when the patient has a second UTI caused by the same pathogen within 2 weeks of the original treatment.⁹ Reinfection is a UTI that occurs more than 2 weeks after completion of treatment for the original UTI. The pathogen in a reinfection may be the same one that caused the original UTI or it may be a different agent.⁹

It’s also important to differentiate between recurrent and resistant UTI. In resistant UTI, bacteriuria fails to resolve following 7 to 14 days of appropriate antibiotic treatment.⁹

Factors that increase the risk of recurrent UTI

Premenopausal women

Both modifiable and non-modifiable factors (TABLE 1^10-21) have been associated with increased risk of recurrent UTI in premenopausal women. Among women with specific blood group phenotypes (Lewis non-secretor, in particular), rates of UTI rise secondary to increased adherence of bacteria to epithelial cells in the urinary tract.¹⁰ Other non-modifiable risk factors include congenital urinary tract anomalies, obstruction of the urinary tract, and a history of UTI.^11,12 Women whose mothers had UTIs are at higher risk for recurrent UTI than are women whose mothers had no such history.¹³

Neither cystoscopy nor imaging is routinely recommended for the evaluation of recurrent urinary tract infection.Modifiable risk factors for recurrent UTI include contraceptive use (spermicides, spermicide-coated condoms, and oral contraceptives) and frequency of intercourse (≥4 times/month).¹³ Spermicides alter the normal vaginal flora and lead to increased colonization of E coli, which increases the risk for UTI.¹⁴ Women with recurrent UTIs were 1.27 to 1.45 times more likely to use oral contraceptives than those without recurrent UTIs.¹³ Compared with college women who had not had intercourse during the week, sexually active college women who had engaged in intercourse 3 times had a 2.6-fold increase in relative risk for UTI.¹⁵ Those who had daily intercourse had a 9-fold increase in relative risk of UTI development.¹⁵ This elevated risk is due to trauma to the lower urogenital tract (urethra) and introduction of bacteria into the urethra via mechanical factors.^16,17

Postmenopausal women

Atrophic vaginitis, catheterization, declining functional status, cystocele, incomplete emptying, incontinence, and history of premenopausal UTIs are all risk factors for recurrent UTI in postmenopausal women.^19,20 Decreased estrogen and resulting vaginal atrophy appear to be associated with increased rates of UTI in these women. Additionally, postmenopausal women’s vaginas are more likely to be colonized with E coli and have fewer lactobacilli than those of premenopausal women,²¹ which is thought to predispose them to UTI. These risk factors are summarized in TABLE 1.^10-21

Initial evaluation of recurrent UTI

Patients with recurrent UTI experience signs and symptoms similar to those with isolated uncomplicated UTI: dysuria, frequency, urgency, and hematuria. Focus your history interview on potential causes of complicated UTI (TABLE 2¹⁸). Likewise, perform a pelvic examination to evaluate for predisposing anatomic abnormalities.²² Finally, obtain a urine culture with antibiotic sensitivities to ensure that previous treatment was appropriate and to rule out microbes associated with infected uroliths.¹⁸ Given the low probability of finding abnormalities on cystoscopy or imaging, neither one is routinely recommended for the evaluation of recurrent UTI.¹⁸

Treatment options and precautions

As with isolated UTI, E coli is the most common pathogen in recurrent UTI. However, recurrent UTI is more likely than isolated UTI to result from other pathogens (odds ratio [OR]=1.5; 95% confidence interval [CI], 1.0-2.26), such as Klebsiella, Enterococcus, Proteus, and Citrobacter.²³ Since a patient’s recurrent UTI most likely arises from the same pathogen that caused the prior infection,⁸ start an antibiotic you know is effective against it. Additionally, take into account local resistance rates; antibiotic availability, cost, and adverse effects; and a patient’s drug allergies.

With recurrent UTI, start an antibiotic that's effective against the organism cultured during the prior infection.Preferred antibiotics. Trimethoprim-sulfamethoxazole (TMP-SMX), 160 mg/800 mg twice daily for 3 days, has long been the mainstay of treatment for uncomplicated UTI. Over recent years, however, resistance to TMP-SMX has increased. While it is still appropriate for many situations as first-line treatment, it is not recommended for empiric treatment if local resistance rates are higher than 20%.²⁴ Nitrofurantoin 100 mg twice daily for 5 days has efficacy similar to that of TMP-SMX, but without significant bacterial resistance. While fosfomycin 3 g as a single dose is still recommended as first-line treatment, it is less effective than either TMP-SMX or nitrofurantoin. TABLE 3²⁴ summarizes these ant­ibiotic choices and their efficacies.

Agents to avoid or use only as a last resort. For patients unable to take any of the drugs above, consider beta-lactam antibiotics, although they are typically less effective for this indication. While fluoroquinolones are very effective and have low (but rising) resistance rates, they are also associated with serious and potentially permanent adverse effects. As a result, on May 12, 2016, the Food and Drug Administration issued a Drug Safety Communication recommending that fluoroquinolones be used only in patients without other treatment options.^24,25 Do not use ampicillin or amoxicillin, which lack effectiveness for this indication and are compromised by high levels of bacterial resistance.

Shorter course of treatment? When deciding on the length of treatment for recurrent UTI, remember that shorter antibiotic courses (3-5 days) are associated with similar rates of cure and progression to systemic infections as longer courses (7-10 days). Also, patients adhere better to the shorter treatment regimen and experience fewer adverse effects.^26,27

Standing prescription? Studies have shown that women know when they have a UTI. Therefore, for women who experience recurrent UTI, consider giving them a standing prescription for antibiotics that they can initiate when symptoms arise (TABLE 3²⁴). Patient-initiated treatment yields similar rates of efficacy as physician-initiated treatment, while avoiding the adverse effects and costs associated with preventive strategies²⁸ (which we’ll discuss in a moment).

Time for imaging and referral?

For patients with a high risk of complicated UTI or a surgically amenable condition, either ultrasound or computerized tomography (CT) of the abdomen and pelvis with and without contrast is appropriate to evaluate for anatomic anomalies. While CT is the more sensitive imaging study to identify anomalies, ultrasound is less expensive and minimizes radiation exposure and is therefore also appropriate.¹⁸

Consider referring patients to a urologist if they have an underlying condition that may be amenable to surgery, such as bladder outlet obstruction, cystoceles, urinary tract diverticula, fistulae, pelvic floor dysfunction, ureteral stricture, urolithiasis, or vesicoureteral reflux.¹⁸ Additional risk factors for complicated UTI, which warrant referral as outlined by the Canadian Urologic Association, are summarized in TABLE 2.¹⁸

2 weeks later…and it’s back? Finally, for women who experience recurrent symptoms within 2 weeks of completing treatment, obtain a urine culture with antibiotic sensitivities to ensure that the infecting organism is not one typically associated with urolithiasis (Proteus and Yersinia) and that it is susceptible to planned antibiotic therapy.¹⁸ Proteus and Yersinia are urease-positive bacteria that may cause stone formation in the urinary tract system. Evaluate any patient who has a UTI from either organism for urinary tract stones.

Prevention dos and don’ts

Popular myth suggests that recurrent UTIs are more common in patients who do not void after intercourse or who douche, consume caffeinated beverages, or wear non-cotton underwear. Research, however, has failed to show a relationship between any of these factors and recurrent UTIs.^13,18 Physicians should therefore stop recommending that patients modify these behaviors to decrease recurrent infections.

Popular myth suggests that recurrent UTIs are more common in patients who do not void after intercourse, but there's no research that bears this out.Antibiotic prophylaxis decreases the rate of recurrent UTI by 95%.²⁹ It has been recommended for women who have had 2 or more UTIs in the past 6 months²⁹ or 3 or more UTIs in the past year.³⁰ Effective strategies to prevent recurrent UTI are low-dose continuous antibiotic prophylaxis or post-coital antibiotic prophylaxis.

While a test-of-cure culture is not typically recommended following treatment for uncomplicated UTI, you will want to obtain a confirmatory urine culture one to 2 weeks before starting low-dose antibiotic prophylaxis. Base your choice of antibiotic on known patient allergies and previous culture results. Agents typically used are trimethoprim, TMP-SMX, or nitrofurantoin^31,32 (TABLE 4³¹), none of which demonstrated superiority in a Cochrane review.³³ Although the same review showed no optimal duration of treatment,³³ 6 to 24 months of treatment is usually recommended.²⁹

A single dose of antibiotic following intercourse may be as effective as daily low-dose prophylaxis for women whose UTIs are related to sexual activity.³⁴ Studies have shown that single doses of TMP-SMX, nitrofurantoin, cephalexin, or a fluoroquinolone (see earlier notes about FDA warning on fluoroquinolone use) are similarly effective in decreasing the rate of recurrence^35,36 (TABLE 4³¹).

Several non-pharmacologic strategies have been suggested for preventing recurrent UTI—eg, use of cranberry products, lactobacillus, vaginal estrogen in postmenopausal women, methenamine salts, and D-mannose.

A Cochrane review found that cranberry products were less effective in preventing recurrent UTIs than previously thought.A 2012 Cochrane review of 24 studies found that cranberry products were less effective in preventing recurrent UTIs than previously thought, with no statistically significant difference between women who took them and those who did not.³⁷

Results have been mixed in using lactobacilli or probiotics to prevent recurrent UTIs. One study examining the use of lactobacilli to colonize the vaginal flora found a reduction in the number of recurrent infections in premenopausal women taking intravaginal lactobacillus over 12 months.³⁸ A second study, involving postmenopausal women, found that those who were randomized to take lactobacillus tablets for 12 months had more frequent recurrences of UTIs than women randomized to take daily TMP-SMX.³⁹ However, this last study was designed as a non-inferiority trial and its results do not negate the prior study’s findings. Additionally, vaginal estrogen, which is thought to work through colonization of the vagina with lactobacilli, has prevented recurrent UTIs in postmenopausal women.⁴⁰

Ascorbic acid (which is bacteriostatic), methenamine salts (which are hydrolysed to bactericidal ammonia and formaldehyde), and D-mannose (which inhibits bacterial adherence), have been shown—in limited studies—to decrease recurrence of UTIs.^41-43 Further study is necessary to confirm their efficacy in preventing UTIs.

As noted, the only behavioral modifications that have been shown to decrease the risk of recurrent UTI are discontinuing the use of spermicides/spermicide-coated condoms or oral contraceptives, and decreasing the frequency of intercourse.¹³

CASE › Ms. B is started on a 3-day course of TMP-SMX. Further questioning reveals that each of her 3 UTIs followed sexual intercourse. Her physician discusses the options of self-directed therapy using continuous prophylaxis or postcoital prophylaxis, either of which would be an appropriate evidence-based intervention for her. After engaging in shared decision making, she is prescribed TMP-SMX to be taken as a single dose following intercourse in the future.

CORRESPONDENCE
Jeffrey D. Quinlan, MD, FAAFP, Family Medicine, Room A-1038A, 4301 Jones Bridge Road, Bethesda, MD 20814-4712; [email protected].

CASE › For the third time in 9 months, 28-year-old Joan B comes into the office with complaints of painful, frequent, and urgent urination. Ms B is sexually active and her medical history is otherwise unremarkable. In each of the previous 2 episodes, her urine culture grew Escherichia coli, and she was treated with a 5-day course of nitrofurantoin. At this current visit, she asks about the need for additional work-up, treatment for her symptoms, and whether there is a way to prevent further infections.

Urinary tract infections (UTIs) are the most common bacterial infection in women¹ and account for an estimated 5.4 million primary care office visits and 2.3 million emergency room visits annually.² For women, the lifetime risk of developing a UTI is greater than 50%.³ In one study of UTI in a primary care setting, 36% of women under 55 and 53% of women over 55 had a recurrent infection within a year.⁴ Most women with UTI are treated as outpatients, but 16.7% require hospitalization.⁵ In the United States, direct costs for evaluation and treatment of UTI total $1.6 billion each year.⁵

Accurately characterizing recurrent UTI

Bacteriuria is defined as the presence of 10⁵ colony forming units (ie, viable bacteria) per milliliter of urine collected midstream on 2 consecutive urinations.⁶ UTIs are symptomatic infections of the urinary tract and may involve the urethra, bladder, ureters, or kidneys.⁷ Infections of the lower tract (bladder and urethra) are commonly referred to as cystitis; infections of the upper tract (kidney and ureters) are referred to as pyelonephritis.

Most UTIs are uncomplicated and do not progress to more serious infections. However, patients who are pregnant, have chronic medical conditions (eg, renal insufficiency or use of immunosuppressant medications), urinary obstruction, or calculi may develop complicated UTIs.⁸

Recurrent UTI is an infection that follows resolution of bacteriuria and symptoms of a prior UTI, and the term applies when such an infection occurs within 6 months of the last UTI or when 3 or more UTIs occur within a year.⁷ Recurrent infection can be further characterized as relapse or reinfection. Relapse occurs when the patient has a second UTI caused by the same pathogen within 2 weeks of the original treatment.⁹ Reinfection is a UTI that occurs more than 2 weeks after completion of treatment for the original UTI. The pathogen in a reinfection may be the same one that caused the original UTI or it may be a different agent.⁹

It’s also important to differentiate between recurrent and resistant UTI. In resistant UTI, bacteriuria fails to resolve following 7 to 14 days of appropriate antibiotic treatment.⁹

Factors that increase the risk of recurrent UTI

Premenopausal women

Both modifiable and non-modifiable factors (TABLE 1^10-21) have been associated with increased risk of recurrent UTI in premenopausal women. Among women with specific blood group phenotypes (Lewis non-secretor, in particular), rates of UTI rise secondary to increased adherence of bacteria to epithelial cells in the urinary tract.¹⁰ Other non-modifiable risk factors include congenital urinary tract anomalies, obstruction of the urinary tract, and a history of UTI.^11,12 Women whose mothers had UTIs are at higher risk for recurrent UTI than are women whose mothers had no such history.¹³

Neither cystoscopy nor imaging is routinely recommended for the evaluation of recurrent urinary tract infection.Modifiable risk factors for recurrent UTI include contraceptive use (spermicides, spermicide-coated condoms, and oral contraceptives) and frequency of intercourse (≥4 times/month).¹³ Spermicides alter the normal vaginal flora and lead to increased colonization of E coli, which increases the risk for UTI.¹⁴ Women with recurrent UTIs were 1.27 to 1.45 times more likely to use oral contraceptives than those without recurrent UTIs.¹³ Compared with college women who had not had intercourse during the week, sexually active college women who had engaged in intercourse 3 times had a 2.6-fold increase in relative risk for UTI.¹⁵ Those who had daily intercourse had a 9-fold increase in relative risk of UTI development.¹⁵ This elevated risk is due to trauma to the lower urogenital tract (urethra) and introduction of bacteria into the urethra via mechanical factors.^16,17

Postmenopausal women

Atrophic vaginitis, catheterization, declining functional status, cystocele, incomplete emptying, incontinence, and history of premenopausal UTIs are all risk factors for recurrent UTI in postmenopausal women.^19,20 Decreased estrogen and resulting vaginal atrophy appear to be associated with increased rates of UTI in these women. Additionally, postmenopausal women’s vaginas are more likely to be colonized with E coli and have fewer lactobacilli than those of premenopausal women,²¹ which is thought to predispose them to UTI. These risk factors are summarized in TABLE 1.^10-21

Initial evaluation of recurrent UTI

Patients with recurrent UTI experience signs and symptoms similar to those with isolated uncomplicated UTI: dysuria, frequency, urgency, and hematuria. Focus your history interview on potential causes of complicated UTI (TABLE 2¹⁸). Likewise, perform a pelvic examination to evaluate for predisposing anatomic abnormalities.²² Finally, obtain a urine culture with antibiotic sensitivities to ensure that previous treatment was appropriate and to rule out microbes associated with infected uroliths.¹⁸ Given the low probability of finding abnormalities on cystoscopy or imaging, neither one is routinely recommended for the evaluation of recurrent UTI.¹⁸

Treatment options and precautions

As with isolated UTI, E coli is the most common pathogen in recurrent UTI. However, recurrent UTI is more likely than isolated UTI to result from other pathogens (odds ratio [OR]=1.5; 95% confidence interval [CI], 1.0-2.26), such as Klebsiella, Enterococcus, Proteus, and Citrobacter.²³ Since a patient’s recurrent UTI most likely arises from the same pathogen that caused the prior infection,⁸ start an antibiotic you know is effective against it. Additionally, take into account local resistance rates; antibiotic availability, cost, and adverse effects; and a patient’s drug allergies.

With recurrent UTI, start an antibiotic that's effective against the organism cultured during the prior infection.Preferred antibiotics. Trimethoprim-sulfamethoxazole (TMP-SMX), 160 mg/800 mg twice daily for 3 days, has long been the mainstay of treatment for uncomplicated UTI. Over recent years, however, resistance to TMP-SMX has increased. While it is still appropriate for many situations as first-line treatment, it is not recommended for empiric treatment if local resistance rates are higher than 20%.²⁴ Nitrofurantoin 100 mg twice daily for 5 days has efficacy similar to that of TMP-SMX, but without significant bacterial resistance. While fosfomycin 3 g as a single dose is still recommended as first-line treatment, it is less effective than either TMP-SMX or nitrofurantoin. TABLE 3²⁴ summarizes these ant­ibiotic choices and their efficacies.

Agents to avoid or use only as a last resort. For patients unable to take any of the drugs above, consider beta-lactam antibiotics, although they are typically less effective for this indication. While fluoroquinolones are very effective and have low (but rising) resistance rates, they are also associated with serious and potentially permanent adverse effects. As a result, on May 12, 2016, the Food and Drug Administration issued a Drug Safety Communication recommending that fluoroquinolones be used only in patients without other treatment options.^24,25 Do not use ampicillin or amoxicillin, which lack effectiveness for this indication and are compromised by high levels of bacterial resistance.

Shorter course of treatment? When deciding on the length of treatment for recurrent UTI, remember that shorter antibiotic courses (3-5 days) are associated with similar rates of cure and progression to systemic infections as longer courses (7-10 days). Also, patients adhere better to the shorter treatment regimen and experience fewer adverse effects.^26,27

Standing prescription? Studies have shown that women know when they have a UTI. Therefore, for women who experience recurrent UTI, consider giving them a standing prescription for antibiotics that they can initiate when symptoms arise (TABLE 3²⁴). Patient-initiated treatment yields similar rates of efficacy as physician-initiated treatment, while avoiding the adverse effects and costs associated with preventive strategies²⁸ (which we’ll discuss in a moment).

Time for imaging and referral?

For patients with a high risk of complicated UTI or a surgically amenable condition, either ultrasound or computerized tomography (CT) of the abdomen and pelvis with and without contrast is appropriate to evaluate for anatomic anomalies. While CT is the more sensitive imaging study to identify anomalies, ultrasound is less expensive and minimizes radiation exposure and is therefore also appropriate.¹⁸

Consider referring patients to a urologist if they have an underlying condition that may be amenable to surgery, such as bladder outlet obstruction, cystoceles, urinary tract diverticula, fistulae, pelvic floor dysfunction, ureteral stricture, urolithiasis, or vesicoureteral reflux.¹⁸ Additional risk factors for complicated UTI, which warrant referral as outlined by the Canadian Urologic Association, are summarized in TABLE 2.¹⁸

2 weeks later…and it’s back? Finally, for women who experience recurrent symptoms within 2 weeks of completing treatment, obtain a urine culture with antibiotic sensitivities to ensure that the infecting organism is not one typically associated with urolithiasis (Proteus and Yersinia) and that it is susceptible to planned antibiotic therapy.¹⁸ Proteus and Yersinia are urease-positive bacteria that may cause stone formation in the urinary tract system. Evaluate any patient who has a UTI from either organism for urinary tract stones.

Prevention dos and don’ts

Popular myth suggests that recurrent UTIs are more common in patients who do not void after intercourse or who douche, consume caffeinated beverages, or wear non-cotton underwear. Research, however, has failed to show a relationship between any of these factors and recurrent UTIs.^13,18 Physicians should therefore stop recommending that patients modify these behaviors to decrease recurrent infections.

Popular myth suggests that recurrent UTIs are more common in patients who do not void after intercourse, but there's no research that bears this out.Antibiotic prophylaxis decreases the rate of recurrent UTI by 95%.²⁹ It has been recommended for women who have had 2 or more UTIs in the past 6 months²⁹ or 3 or more UTIs in the past year.³⁰ Effective strategies to prevent recurrent UTI are low-dose continuous antibiotic prophylaxis or post-coital antibiotic prophylaxis.

While a test-of-cure culture is not typically recommended following treatment for uncomplicated UTI, you will want to obtain a confirmatory urine culture one to 2 weeks before starting low-dose antibiotic prophylaxis. Base your choice of antibiotic on known patient allergies and previous culture results. Agents typically used are trimethoprim, TMP-SMX, or nitrofurantoin^31,32 (TABLE 4³¹), none of which demonstrated superiority in a Cochrane review.³³ Although the same review showed no optimal duration of treatment,³³ 6 to 24 months of treatment is usually recommended.²⁹

A single dose of antibiotic following intercourse may be as effective as daily low-dose prophylaxis for women whose UTIs are related to sexual activity.³⁴ Studies have shown that single doses of TMP-SMX, nitrofurantoin, cephalexin, or a fluoroquinolone (see earlier notes about FDA warning on fluoroquinolone use) are similarly effective in decreasing the rate of recurrence^35,36 (TABLE 4³¹).

Several non-pharmacologic strategies have been suggested for preventing recurrent UTI—eg, use of cranberry products, lactobacillus, vaginal estrogen in postmenopausal women, methenamine salts, and D-mannose.

A Cochrane review found that cranberry products were less effective in preventing recurrent UTIs than previously thought.A 2012 Cochrane review of 24 studies found that cranberry products were less effective in preventing recurrent UTIs than previously thought, with no statistically significant difference between women who took them and those who did not.³⁷

Results have been mixed in using lactobacilli or probiotics to prevent recurrent UTIs. One study examining the use of lactobacilli to colonize the vaginal flora found a reduction in the number of recurrent infections in premenopausal women taking intravaginal lactobacillus over 12 months.³⁸ A second study, involving postmenopausal women, found that those who were randomized to take lactobacillus tablets for 12 months had more frequent recurrences of UTIs than women randomized to take daily TMP-SMX.³⁹ However, this last study was designed as a non-inferiority trial and its results do not negate the prior study’s findings. Additionally, vaginal estrogen, which is thought to work through colonization of the vagina with lactobacilli, has prevented recurrent UTIs in postmenopausal women.⁴⁰

Ascorbic acid (which is bacteriostatic), methenamine salts (which are hydrolysed to bactericidal ammonia and formaldehyde), and D-mannose (which inhibits bacterial adherence), have been shown—in limited studies—to decrease recurrence of UTIs.^41-43 Further study is necessary to confirm their efficacy in preventing UTIs.

As noted, the only behavioral modifications that have been shown to decrease the risk of recurrent UTI are discontinuing the use of spermicides/spermicide-coated condoms or oral contraceptives, and decreasing the frequency of intercourse.¹³

CASE › Ms. B is started on a 3-day course of TMP-SMX. Further questioning reveals that each of her 3 UTIs followed sexual intercourse. Her physician discusses the options of self-directed therapy using continuous prophylaxis or postcoital prophylaxis, either of which would be an appropriate evidence-based intervention for her. After engaging in shared decision making, she is prescribed TMP-SMX to be taken as a single dose following intercourse in the future.

CORRESPONDENCE
Jeffrey D. Quinlan, MD, FAAFP, Family Medicine, Room A-1038A, 4301 Jones Bridge Road, Bethesda, MD 20814-4712; [email protected].

Attention-deficit/hyperactivity disorder (ADHD) in adults brings with it unique challenges, not the least of which are arriving at a proper diagnosis and ensuring that any psychostimulant drugs that you prescribe are not misused. A number of conditions such as anxiety, bipolar disorder, and substance abuse can mimic some of the symptoms of ADHD, and diagnostic criteria for the condition in adults changed with the latest edition of the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5).

Furthermore, for many of the estimated 4.4% of adults who have ADHD,¹ psychostimulants provide necessary and effective treatment, but misuse and diversion of these agents are real concerns. In fact, recent research reveals that these issues are more common than previously thought.² Data suggest that the prevalence of misuse and diversion of ADHD medication is 5% to 10% among high school students and 5% to 35% among college students.^2,3

This is not meant to indicate that adults diagnosed with ADHD should go untreated. In fact, adults with ADHD often struggle in their professional and family lives because they do not receive the treatment they need.

Rather, family physicians should take certain steps, first to diagnose ADHD correctly, and then to ascertain and maintain correct use of psychostimulants and other treatments among their adult patient populations. Read on for several practical strategies.

Criteria for adult Dx differ from those in children

ADHD, a common behavioral disorder that often, but not always, begins in childhood, is characterized by deficits in paying attention, difficulty controlling impulses, and marked hyperactivity. Diagnosis of ADHD is based on the DSM-5 criteria and supplemented with historical data and clinical observations.⁴ Using self-report measures may also aid in the diagnosis, and psychological testing may be required for some individuals when the clinical presentation is unclear.

With the DSM-5 changes (TABLE 1⁴), the diagnosis of ADHD in adults (people ≥18 years) requires fewer symptoms than the diagnosis of ADHD in children; just 5 symptoms from either of the 2 categories of diagnostic criteria are sufficient now, whereas 6 symptoms were required previously and still are required to make the diagnosis in young people. People may present with the inattentive profile (5 or more symptoms of inattention), the hyperactive-impulsive profile (5 or more hyperactive-impulsive symptoms), or a combination of the 2 (5 or more symptoms of inattention plus 5 or more symptoms of hyperactivity-impulsivity for a total of 10 or more symptoms). While children are more likely to present with the combined type of ADHD, adults of any age are more likely to present with the inattentive type.⁴

In addition, patients must meet the diagnostic criteria for ADHD for at least 6 months, have had some of the symptoms prior to age 12, and the symptoms must cause significant impairment in 2 or more environments (eg, home, work, school). When the diagnosis is unclear, it is important to obtain collateral information from the family, school, or workplace. The requirement regarding symptomatology before age 12 indicates the need for a review of the patient’s educational history. Research reveals that many adults with ADHD struggled in school and were considered “underachievers” as students.⁵

Common complaints and characteristics. Previous studies have shown the following to be common complaints and characteristics of adult patients diagnosed with ADHD:⁵

• difficulty meeting time limits
• vocational struggles, such as frequent job changes or nonpromotion at work
• anger issues
• addiction
• relationship/social strain
• comprehension problems, and
• a family history of ADHD.

Common correlates include low socioeconomic status, driving violations, frequent injuries, legal problems, alcohol and/or tobacco use, and self-reported maladjustment.⁵ People treated for ADHD have a comorbid DSM diagnosis 81% of the time with the most likely diagnoses being substance abuse, depression, and anxiety.⁶

Psychostimulants provide necessary and effective treatment for adults who have ADHD, but misuse and diversion of these agents are real concerns.Adult-onset ADHD? Even though the DSM-5 criteria for an ADHD diagnosis in adulthood require that some ADHD symptoms were manifest prior to age 12, recent longitudinal research on ADHD in Brazil and the United Kingdom reveals that a large portion of people who meet the criteria for ADHD in adulthood did not meet the criteria as children. The researchers in these studies proposed that there may be a form of ADHD that manifests later in life, a so-called “adult-onset ADHD.”⁷ While this information is something for clinicians to consider, further research is needed to justify a paradigm shift in how ADHD is diagnosed.

Self-rating measures can offer clarification. Whether or not history-gathering leaves the diagnosis murky, self-rating measures can be valuable in rounding out the clinical picture and alerting clinicians to any inconsistencies in symptoms.⁸ Four common ADHD self-rating measures are provided in TABLE 2. As one example, the Adult ADHD Self-Report Scale (ASRS) Symptom Checklist is a valuable ADHD screening tool that is free of charge and takes only 5 to 10 minutes.⁸ Other self-report measures require a similar amount of time, but are not available on a complimentary basis.

The diagnosis of ADHD in adults requires fewer symptoms than in children; just 5 can be sufficient.Psychological testing. Some adults who seem to have symptoms of ADHD may require a referral for psychological testing. These may be patients who present with complicated cases or whose histories and/or findings do not consistently indicate an ADHD diagnosis. In such cases, psychological testing can fill in the holes and provide a more complete picture of the patient’s neurocognitive abilities and deficits.^9,10

Psychostimulant treatment: Opt for longer-acting agents

The standard treatment for ADHD is a psychostimulant. One controlled trial, for example, of a mixed amphetamine salts compound (Adderall) found that the compound effectively treated ADHD symptoms (hyperactivity, impulsivity, inattention) in adults and was well tolerated.¹¹ While far fewer studies have been performed in adult vs youth populations, those that have been conducted in adults indicate that psychostimulants are largely safe and efficacious. In fact, the study mentioned above found that 70% of patients with ADHD ages 18 and older reported improvement of symptoms while on a short-acting psychostimulant, as compared to 7% who reported improvement on placebo.¹¹

Similarly, a meta-analysis of 1991 participants in 11 studies found significant improvement in patients who received medication vs placebo, with stimulant medications demonstrating greater efficacy than non-stimulant treatments for ADHD.¹² In general, psychostimulant treatment for adults is similar to that for children; the only difference is that adults tend to be more forthcoming with information regarding how the treatment is working and what adjustments might be needed.

Longer-acting stimulants (ie, extended release) tend to be preferred by patients to short-acting ones because they typically provide adequate control of symptoms over a longer period of time and thus may be taken less frequently.¹³ Also, the potential for abuse of psychostimulant medication tends to be lower with the longer-acting, extended-release formulations.¹⁴ A shorter acting formulation may be preferred if a patient has a specific window of time when their ADHD symptoms impact them. For example, a patient may request a short-acting form of medication for afternoons if he or she has to attend many business meetings at that time of day. A relatively new category is the intermediate-acting psychostimulants. For more on specific psychostimulants, see Table 3.¹⁵

Adverse effects lead many to discontinue treatment

Regardless of the length of action of the psychostimulant, studies show that about 30% of adults (and, incidentally, 10% to 30% of children) discontinue treatment due to uncontrolled/unwanted symptoms or adverse effects.¹⁶ These include decreased appetite, headache, insomnia, abdominal pain, and irritable mood.¹⁷ If you are prescribing a psychostimulant for an adult with ADHD, it is important to tell the patient that if the effects become intolerable, adjustments can be made, such as tweaking dosages, switching to a different medication, or adding an adjunctive therapy such as cognitive behavioral therapy. Keep in mind, too, that if a medication is to be discontinued, tapering is suggested for most psychostimulants; patients should take a lower (eg, half) dose for about a week prior to complete discontinuation. People who have difficulties with a number of treatments for ADHD should be reevaluated in a year to see if circumstances have changed.⁵

Combatting misuse and diversion

Perhaps the most controversial issues surrounding the treatment of adults with ADHD are abuse and diversion of psychostimulants. Abuse generally refers to misuse of the drug by the person prescribed the agent, whereas diversion refers to use of the drug by people for whom the drug was not intended—with or without the prescribee’s knowledge.³ Although rare, chronic abuse of psychostimulants can lead to serious problems such as aggression, suicidal thoughts/behaviors, psychosis, and mania.⁵

New data reveal that a large portion of people who meet the criteria for ADHD in adulthood did not meet the criteria as children.While earlier studies tended to downplay the likelihood of diversion, recent research indicates that physicians should not underestimate the possibility. In fact, a previous article in this journal about student athletes with ADHD (http://bit.ly/2k1a6TL) indicated that psychostimulants have “great potential for misuse” and that recently there has been “a surge in nonprescription stimulant use among adolescents and young adults.”¹⁷ The authors of the article concluded, however, that while physicians should be aware of the potential for misuse, fear should not preclude treatment.¹⁷

A national multi-cohort study of 4572 US high school seniors who had used psychostimulants either medically or nonmedically indicated that while one in 6 high school seniors had been exposed to psychostimulants, about half were appropriately exposed through prescription use, while the other half was not. The researchers also reported that current nonmedical users of psychostimulants and those with a history of nonmedical use had a greater risk of substance use and abuse when compared to medical users of psychostimulants.¹⁸

Young men are at higher risk for diversion. In a nationwide survey of a sample of adults ages 18 to 49 years who had a prescription for psychostimulant medication in the past month, 17% admitted diverting their medication.¹⁹ The researchers also observed that men were more than twice as likely to divert medication than women.¹⁹

In another study, 483 students ages 17 to 19 years were followed for one year and interviewed frequently regarding their use of medications.²⁰ The researchers reported that the lifetime prevalence of diversion of any medication in those students was around 36%. They also found that of those who diverted medication, 62% diverted ADHD medications at least once. These were most commonly diverted by sharing (34%) and selling (9%) the psychostimulants. Interview analysis revealed that those students who diverted were more likely to have used illicit drugs and to have had conduct problems. The authors advised “vigilance regarding…stimulant medications for young adults.”

Psychostimulant prescriptions do not cause substance abuse. Nevertheless, a salient point in the literature is that there is no causal relationship between psychostimulant prescriptions that are properly prescribed for people who have ADHD and substance abuse. One study that followed young people with ADHD for 8 years into adulthood revealed that psychostimulant treatment did not make adolescents or young adults any more or less likely to abuse drugs.²¹ The study also found that alcohol use was common in young adults whether they were diagnosed with ADHD or not. Nonetheless, family physicians should urge those taking psychostimulants to refrain from alcohol use or at least to drink in moderation.

About 30% of adults discontinue treatment due to unwanted/uncontrolled symptoms or adverse effects.The bottom line is that adults diagnosed with ADHD carry about the same risk of substance abuse as the general population if they are effectively treated for their presenting attention problems.²² If they are taking a psychostimulant, however, they have access to a controlled substance, unlike most of their cohorts. So it's important to teach patients with ADHD that for safety and legal reasons, they should not share or sell their stimulant medication to anyone.

Minimize the risk for abuse, diversion using these strategies

As with any drug regimen, it is important to monitor the patient’s response to treatment and minimize adverse effects and outcomes. When the drug is a psychostimulant for adults diagnosed with ADHD, it’s also important to minimize the risk for abuse and diversion. The following steps can help:

• Obtain a signed controlled substance agreement.²³ This agreement between the physician and the patient usually outlines such specifics as frequency of office visits, circumstances surrounding medication refills, urine drug monitoring, and pill counts. (For more on the specifics of a controlled substance agreement, see "Key points of a controlled substance agreement.")
• Schedule frequent follow-up appointments with open communication about abuse and diversion.^20,23 The age-old adage, “Start low, go slow,” applies to stimulant medications for ADHD. Medication dosage may vary and necessitate titration depending on the person’s weight and tolerance. At the onset of treatment, frequent office visits allow the physician to gauge treatment response and the patient’s commitment to therapy.
• Review your state’s prescription drug monitoring program.²⁴ It is imperative that providers check their state’s medical board rules for prescribing controlled medications to ensure practice compliance. As diversion rates of controlled medications have risen in this country, most states have established monitoring systems through their pharmacy boards.²⁴ Although the names of the programs vary, these prescription drug monitoring programs provide information on any medication prescribed. This allows the prescribing physician to ensure patient compliance and ascertain that no other controlled medications are being prescribed that could interfere with treatment. (For more information about state prescription drug monitoring programs, see https://www.deadiversion.usdoj.gov/faq/rx_monitor.htm.)
• Perform random urine drug screenings (UDS).^20,23 An important strategy for ensuring adherence to the treatment plan and the controlled substance contract is UDS. Explain to patients that this is a way of making sure they are taking the medication exactly as prescribed. If the UDS indicates that the patient has not been taking the medication, then the provider should intervene by either restricting or discontinuing the controlled substance to prevent or counteract potential diversion. Similarly, if a higher dose is requested by a patient, the provider can closely monitor the situation to determine whether the additional drug is actually being taken and whether the dose is optimal. (See JFP’s October 2016 “3 in 3” video on urine drug testing at: http://bit.ly/2iDnfgD.)
• Employ a team-based, multimodal approach.²⁵ A referral to a mental health professional and multimodal treatment are often recommended in the literature as best practices.²⁵ Behavioral therapies are a cornerstone of treatment in adults with ADHD and often serve as important adjuncts to pharmacotherapy. Also, a referral provides a second professional opinion about the patient’s motivations, adherence, and response to treatment.

Trained cognitive behavioral therapists (eg, psychologists, counselors) can be helpful with treatment for ADHD.²³ Therapists can be useful in setting goals for the patient regarding adherence, organization, impulse control, and social skills training. Therapists may wish to involve the family in treatment, depending on the nature of the patient’s presenting issues.

Don’t tempt fate. As with any controlled medication, safe storage of psychostimulants is paramount. Patients should be urged to keep their medication in a locked box or cupboard that is accessible to only the adult for whom the drug is prescribed. Prior research cautions that open access to controlled substances can lead to larger issues with abuse and diversion, particularly when adolescents are in the home.²⁶

Men are more than twice as likely to divert medication as women. Consider atomoxetine. Research has also demonstrated that the non-stimulant medication atomoxetine has some benefit in the treatment of ADHD.¹² Unlike psychostimulants that act on the neurotransmitter dopamine, atomoxetine acts on the neurotransmitter norepinephrine. This different mechanism of action results in a lower potential for abuse and diversion.

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

Attention-deficit/hyperactivity disorder (ADHD) in adults brings with it unique challenges, not the least of which are arriving at a proper diagnosis and ensuring that any psychostimulant drugs that you prescribe are not misused. A number of conditions such as anxiety, bipolar disorder, and substance abuse can mimic some of the symptoms of ADHD, and diagnostic criteria for the condition in adults changed with the latest edition of the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5).

Furthermore, for many of the estimated 4.4% of adults who have ADHD,¹ psychostimulants provide necessary and effective treatment, but misuse and diversion of these agents are real concerns. In fact, recent research reveals that these issues are more common than previously thought.² Data suggest that the prevalence of misuse and diversion of ADHD medication is 5% to 10% among high school students and 5% to 35% among college students.^2,3

This is not meant to indicate that adults diagnosed with ADHD should go untreated. In fact, adults with ADHD often struggle in their professional and family lives because they do not receive the treatment they need.

Rather, family physicians should take certain steps, first to diagnose ADHD correctly, and then to ascertain and maintain correct use of psychostimulants and other treatments among their adult patient populations. Read on for several practical strategies.

Criteria for adult Dx differ from those in children

ADHD, a common behavioral disorder that often, but not always, begins in childhood, is characterized by deficits in paying attention, difficulty controlling impulses, and marked hyperactivity. Diagnosis of ADHD is based on the DSM-5 criteria and supplemented with historical data and clinical observations.⁴ Using self-report measures may also aid in the diagnosis, and psychological testing may be required for some individuals when the clinical presentation is unclear.

With the DSM-5 changes (TABLE 1⁴), the diagnosis of ADHD in adults (people ≥18 years) requires fewer symptoms than the diagnosis of ADHD in children; just 5 symptoms from either of the 2 categories of diagnostic criteria are sufficient now, whereas 6 symptoms were required previously and still are required to make the diagnosis in young people. People may present with the inattentive profile (5 or more symptoms of inattention), the hyperactive-impulsive profile (5 or more hyperactive-impulsive symptoms), or a combination of the 2 (5 or more symptoms of inattention plus 5 or more symptoms of hyperactivity-impulsivity for a total of 10 or more symptoms). While children are more likely to present with the combined type of ADHD, adults of any age are more likely to present with the inattentive type.⁴

In addition, patients must meet the diagnostic criteria for ADHD for at least 6 months, have had some of the symptoms prior to age 12, and the symptoms must cause significant impairment in 2 or more environments (eg, home, work, school). When the diagnosis is unclear, it is important to obtain collateral information from the family, school, or workplace. The requirement regarding symptomatology before age 12 indicates the need for a review of the patient’s educational history. Research reveals that many adults with ADHD struggled in school and were considered “underachievers” as students.⁵

Common complaints and characteristics. Previous studies have shown the following to be common complaints and characteristics of adult patients diagnosed with ADHD:⁵

• difficulty meeting time limits
• vocational struggles, such as frequent job changes or nonpromotion at work
• anger issues
• addiction
• relationship/social strain
• comprehension problems, and
• a family history of ADHD.

Common correlates include low socioeconomic status, driving violations, frequent injuries, legal problems, alcohol and/or tobacco use, and self-reported maladjustment.⁵ People treated for ADHD have a comorbid DSM diagnosis 81% of the time with the most likely diagnoses being substance abuse, depression, and anxiety.⁶

Psychostimulants provide necessary and effective treatment for adults who have ADHD, but misuse and diversion of these agents are real concerns.Adult-onset ADHD? Even though the DSM-5 criteria for an ADHD diagnosis in adulthood require that some ADHD symptoms were manifest prior to age 12, recent longitudinal research on ADHD in Brazil and the United Kingdom reveals that a large portion of people who meet the criteria for ADHD in adulthood did not meet the criteria as children. The researchers in these studies proposed that there may be a form of ADHD that manifests later in life, a so-called “adult-onset ADHD.”⁷ While this information is something for clinicians to consider, further research is needed to justify a paradigm shift in how ADHD is diagnosed.

Self-rating measures can offer clarification. Whether or not history-gathering leaves the diagnosis murky, self-rating measures can be valuable in rounding out the clinical picture and alerting clinicians to any inconsistencies in symptoms.⁸ Four common ADHD self-rating measures are provided in TABLE 2. As one example, the Adult ADHD Self-Report Scale (ASRS) Symptom Checklist is a valuable ADHD screening tool that is free of charge and takes only 5 to 10 minutes.⁸ Other self-report measures require a similar amount of time, but are not available on a complimentary basis.

The diagnosis of ADHD in adults requires fewer symptoms than in children; just 5 can be sufficient.Psychological testing. Some adults who seem to have symptoms of ADHD may require a referral for psychological testing. These may be patients who present with complicated cases or whose histories and/or findings do not consistently indicate an ADHD diagnosis. In such cases, psychological testing can fill in the holes and provide a more complete picture of the patient’s neurocognitive abilities and deficits.^9,10

Psychostimulant treatment: Opt for longer-acting agents

The standard treatment for ADHD is a psychostimulant. One controlled trial, for example, of a mixed amphetamine salts compound (Adderall) found that the compound effectively treated ADHD symptoms (hyperactivity, impulsivity, inattention) in adults and was well tolerated.¹¹ While far fewer studies have been performed in adult vs youth populations, those that have been conducted in adults indicate that psychostimulants are largely safe and efficacious. In fact, the study mentioned above found that 70% of patients with ADHD ages 18 and older reported improvement of symptoms while on a short-acting psychostimulant, as compared to 7% who reported improvement on placebo.¹¹

Similarly, a meta-analysis of 1991 participants in 11 studies found significant improvement in patients who received medication vs placebo, with stimulant medications demonstrating greater efficacy than non-stimulant treatments for ADHD.¹² In general, psychostimulant treatment for adults is similar to that for children; the only difference is that adults tend to be more forthcoming with information regarding how the treatment is working and what adjustments might be needed.

Longer-acting stimulants (ie, extended release) tend to be preferred by patients to short-acting ones because they typically provide adequate control of symptoms over a longer period of time and thus may be taken less frequently.¹³ Also, the potential for abuse of psychostimulant medication tends to be lower with the longer-acting, extended-release formulations.¹⁴ A shorter acting formulation may be preferred if a patient has a specific window of time when their ADHD symptoms impact them. For example, a patient may request a short-acting form of medication for afternoons if he or she has to attend many business meetings at that time of day. A relatively new category is the intermediate-acting psychostimulants. For more on specific psychostimulants, see Table 3.¹⁵

Adverse effects lead many to discontinue treatment

Regardless of the length of action of the psychostimulant, studies show that about 30% of adults (and, incidentally, 10% to 30% of children) discontinue treatment due to uncontrolled/unwanted symptoms or adverse effects.¹⁶ These include decreased appetite, headache, insomnia, abdominal pain, and irritable mood.¹⁷ If you are prescribing a psychostimulant for an adult with ADHD, it is important to tell the patient that if the effects become intolerable, adjustments can be made, such as tweaking dosages, switching to a different medication, or adding an adjunctive therapy such as cognitive behavioral therapy. Keep in mind, too, that if a medication is to be discontinued, tapering is suggested for most psychostimulants; patients should take a lower (eg, half) dose for about a week prior to complete discontinuation. People who have difficulties with a number of treatments for ADHD should be reevaluated in a year to see if circumstances have changed.⁵

Combatting misuse and diversion

Perhaps the most controversial issues surrounding the treatment of adults with ADHD are abuse and diversion of psychostimulants. Abuse generally refers to misuse of the drug by the person prescribed the agent, whereas diversion refers to use of the drug by people for whom the drug was not intended—with or without the prescribee’s knowledge.³ Although rare, chronic abuse of psychostimulants can lead to serious problems such as aggression, suicidal thoughts/behaviors, psychosis, and mania.⁵

New data reveal that a large portion of people who meet the criteria for ADHD in adulthood did not meet the criteria as children.While earlier studies tended to downplay the likelihood of diversion, recent research indicates that physicians should not underestimate the possibility. In fact, a previous article in this journal about student athletes with ADHD (http://bit.ly/2k1a6TL) indicated that psychostimulants have “great potential for misuse” and that recently there has been “a surge in nonprescription stimulant use among adolescents and young adults.”¹⁷ The authors of the article concluded, however, that while physicians should be aware of the potential for misuse, fear should not preclude treatment.¹⁷

A national multi-cohort study of 4572 US high school seniors who had used psychostimulants either medically or nonmedically indicated that while one in 6 high school seniors had been exposed to psychostimulants, about half were appropriately exposed through prescription use, while the other half was not. The researchers also reported that current nonmedical users of psychostimulants and those with a history of nonmedical use had a greater risk of substance use and abuse when compared to medical users of psychostimulants.¹⁸

Young men are at higher risk for diversion. In a nationwide survey of a sample of adults ages 18 to 49 years who had a prescription for psychostimulant medication in the past month, 17% admitted diverting their medication.¹⁹ The researchers also observed that men were more than twice as likely to divert medication than women.¹⁹

In another study, 483 students ages 17 to 19 years were followed for one year and interviewed frequently regarding their use of medications.²⁰ The researchers reported that the lifetime prevalence of diversion of any medication in those students was around 36%. They also found that of those who diverted medication, 62% diverted ADHD medications at least once. These were most commonly diverted by sharing (34%) and selling (9%) the psychostimulants. Interview analysis revealed that those students who diverted were more likely to have used illicit drugs and to have had conduct problems. The authors advised “vigilance regarding…stimulant medications for young adults.”

Psychostimulant prescriptions do not cause substance abuse. Nevertheless, a salient point in the literature is that there is no causal relationship between psychostimulant prescriptions that are properly prescribed for people who have ADHD and substance abuse. One study that followed young people with ADHD for 8 years into adulthood revealed that psychostimulant treatment did not make adolescents or young adults any more or less likely to abuse drugs.²¹ The study also found that alcohol use was common in young adults whether they were diagnosed with ADHD or not. Nonetheless, family physicians should urge those taking psychostimulants to refrain from alcohol use or at least to drink in moderation.

About 30% of adults discontinue treatment due to unwanted/uncontrolled symptoms or adverse effects.The bottom line is that adults diagnosed with ADHD carry about the same risk of substance abuse as the general population if they are effectively treated for their presenting attention problems.²² If they are taking a psychostimulant, however, they have access to a controlled substance, unlike most of their cohorts. So it's important to teach patients with ADHD that for safety and legal reasons, they should not share or sell their stimulant medication to anyone.

Minimize the risk for abuse, diversion using these strategies

As with any drug regimen, it is important to monitor the patient’s response to treatment and minimize adverse effects and outcomes. When the drug is a psychostimulant for adults diagnosed with ADHD, it’s also important to minimize the risk for abuse and diversion. The following steps can help:

• Obtain a signed controlled substance agreement.²³ This agreement between the physician and the patient usually outlines such specifics as frequency of office visits, circumstances surrounding medication refills, urine drug monitoring, and pill counts. (For more on the specifics of a controlled substance agreement, see "Key points of a controlled substance agreement.")
• Schedule frequent follow-up appointments with open communication about abuse and diversion.^20,23 The age-old adage, “Start low, go slow,” applies to stimulant medications for ADHD. Medication dosage may vary and necessitate titration depending on the person’s weight and tolerance. At the onset of treatment, frequent office visits allow the physician to gauge treatment response and the patient’s commitment to therapy.
• Review your state’s prescription drug monitoring program.²⁴ It is imperative that providers check their state’s medical board rules for prescribing controlled medications to ensure practice compliance. As diversion rates of controlled medications have risen in this country, most states have established monitoring systems through their pharmacy boards.²⁴ Although the names of the programs vary, these prescription drug monitoring programs provide information on any medication prescribed. This allows the prescribing physician to ensure patient compliance and ascertain that no other controlled medications are being prescribed that could interfere with treatment. (For more information about state prescription drug monitoring programs, see https://www.deadiversion.usdoj.gov/faq/rx_monitor.htm.)
• Perform random urine drug screenings (UDS).^20,23 An important strategy for ensuring adherence to the treatment plan and the controlled substance contract is UDS. Explain to patients that this is a way of making sure they are taking the medication exactly as prescribed. If the UDS indicates that the patient has not been taking the medication, then the provider should intervene by either restricting or discontinuing the controlled substance to prevent or counteract potential diversion. Similarly, if a higher dose is requested by a patient, the provider can closely monitor the situation to determine whether the additional drug is actually being taken and whether the dose is optimal. (See JFP’s October 2016 “3 in 3” video on urine drug testing at: http://bit.ly/2iDnfgD.)
• Employ a team-based, multimodal approach.²⁵ A referral to a mental health professional and multimodal treatment are often recommended in the literature as best practices.²⁵ Behavioral therapies are a cornerstone of treatment in adults with ADHD and often serve as important adjuncts to pharmacotherapy. Also, a referral provides a second professional opinion about the patient’s motivations, adherence, and response to treatment.

Trained cognitive behavioral therapists (eg, psychologists, counselors) can be helpful with treatment for ADHD.²³ Therapists can be useful in setting goals for the patient regarding adherence, organization, impulse control, and social skills training. Therapists may wish to involve the family in treatment, depending on the nature of the patient’s presenting issues.

Don’t tempt fate. As with any controlled medication, safe storage of psychostimulants is paramount. Patients should be urged to keep their medication in a locked box or cupboard that is accessible to only the adult for whom the drug is prescribed. Prior research cautions that open access to controlled substances can lead to larger issues with abuse and diversion, particularly when adolescents are in the home.²⁶

Men are more than twice as likely to divert medication as women. Consider atomoxetine. Research has also demonstrated that the non-stimulant medication atomoxetine has some benefit in the treatment of ADHD.¹² Unlike psychostimulants that act on the neurotransmitter dopamine, atomoxetine acts on the neurotransmitter norepinephrine. This different mechanism of action results in a lower potential for abuse and diversion.

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

Attention-deficit/hyperactivity disorder (ADHD) in adults brings with it unique challenges, not the least of which are arriving at a proper diagnosis and ensuring that any psychostimulant drugs that you prescribe are not misused. A number of conditions such as anxiety, bipolar disorder, and substance abuse can mimic some of the symptoms of ADHD, and diagnostic criteria for the condition in adults changed with the latest edition of the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5).

Furthermore, for many of the estimated 4.4% of adults who have ADHD,¹ psychostimulants provide necessary and effective treatment, but misuse and diversion of these agents are real concerns. In fact, recent research reveals that these issues are more common than previously thought.² Data suggest that the prevalence of misuse and diversion of ADHD medication is 5% to 10% among high school students and 5% to 35% among college students.^2,3

This is not meant to indicate that adults diagnosed with ADHD should go untreated. In fact, adults with ADHD often struggle in their professional and family lives because they do not receive the treatment they need.

Rather, family physicians should take certain steps, first to diagnose ADHD correctly, and then to ascertain and maintain correct use of psychostimulants and other treatments among their adult patient populations. Read on for several practical strategies.

Criteria for adult Dx differ from those in children

ADHD, a common behavioral disorder that often, but not always, begins in childhood, is characterized by deficits in paying attention, difficulty controlling impulses, and marked hyperactivity. Diagnosis of ADHD is based on the DSM-5 criteria and supplemented with historical data and clinical observations.⁴ Using self-report measures may also aid in the diagnosis, and psychological testing may be required for some individuals when the clinical presentation is unclear.

With the DSM-5 changes (TABLE 1⁴), the diagnosis of ADHD in adults (people ≥18 years) requires fewer symptoms than the diagnosis of ADHD in children; just 5 symptoms from either of the 2 categories of diagnostic criteria are sufficient now, whereas 6 symptoms were required previously and still are required to make the diagnosis in young people. People may present with the inattentive profile (5 or more symptoms of inattention), the hyperactive-impulsive profile (5 or more hyperactive-impulsive symptoms), or a combination of the 2 (5 or more symptoms of inattention plus 5 or more symptoms of hyperactivity-impulsivity for a total of 10 or more symptoms). While children are more likely to present with the combined type of ADHD, adults of any age are more likely to present with the inattentive type.⁴

In addition, patients must meet the diagnostic criteria for ADHD for at least 6 months, have had some of the symptoms prior to age 12, and the symptoms must cause significant impairment in 2 or more environments (eg, home, work, school). When the diagnosis is unclear, it is important to obtain collateral information from the family, school, or workplace. The requirement regarding symptomatology before age 12 indicates the need for a review of the patient’s educational history. Research reveals that many adults with ADHD struggled in school and were considered “underachievers” as students.⁵

Common complaints and characteristics. Previous studies have shown the following to be common complaints and characteristics of adult patients diagnosed with ADHD:⁵

• difficulty meeting time limits
• vocational struggles, such as frequent job changes or nonpromotion at work
• anger issues
• addiction
• relationship/social strain
• comprehension problems, and
• a family history of ADHD.

Common correlates include low socioeconomic status, driving violations, frequent injuries, legal problems, alcohol and/or tobacco use, and self-reported maladjustment.⁵ People treated for ADHD have a comorbid DSM diagnosis 81% of the time with the most likely diagnoses being substance abuse, depression, and anxiety.⁶

Psychostimulants provide necessary and effective treatment for adults who have ADHD, but misuse and diversion of these agents are real concerns.Adult-onset ADHD? Even though the DSM-5 criteria for an ADHD diagnosis in adulthood require that some ADHD symptoms were manifest prior to age 12, recent longitudinal research on ADHD in Brazil and the United Kingdom reveals that a large portion of people who meet the criteria for ADHD in adulthood did not meet the criteria as children. The researchers in these studies proposed that there may be a form of ADHD that manifests later in life, a so-called “adult-onset ADHD.”⁷ While this information is something for clinicians to consider, further research is needed to justify a paradigm shift in how ADHD is diagnosed.

Self-rating measures can offer clarification. Whether or not history-gathering leaves the diagnosis murky, self-rating measures can be valuable in rounding out the clinical picture and alerting clinicians to any inconsistencies in symptoms.⁸ Four common ADHD self-rating measures are provided in TABLE 2. As one example, the Adult ADHD Self-Report Scale (ASRS) Symptom Checklist is a valuable ADHD screening tool that is free of charge and takes only 5 to 10 minutes.⁸ Other self-report measures require a similar amount of time, but are not available on a complimentary basis.

The diagnosis of ADHD in adults requires fewer symptoms than in children; just 5 can be sufficient.Psychological testing. Some adults who seem to have symptoms of ADHD may require a referral for psychological testing. These may be patients who present with complicated cases or whose histories and/or findings do not consistently indicate an ADHD diagnosis. In such cases, psychological testing can fill in the holes and provide a more complete picture of the patient’s neurocognitive abilities and deficits.^9,10

Psychostimulant treatment: Opt for longer-acting agents

The standard treatment for ADHD is a psychostimulant. One controlled trial, for example, of a mixed amphetamine salts compound (Adderall) found that the compound effectively treated ADHD symptoms (hyperactivity, impulsivity, inattention) in adults and was well tolerated.¹¹ While far fewer studies have been performed in adult vs youth populations, those that have been conducted in adults indicate that psychostimulants are largely safe and efficacious. In fact, the study mentioned above found that 70% of patients with ADHD ages 18 and older reported improvement of symptoms while on a short-acting psychostimulant, as compared to 7% who reported improvement on placebo.¹¹

Similarly, a meta-analysis of 1991 participants in 11 studies found significant improvement in patients who received medication vs placebo, with stimulant medications demonstrating greater efficacy than non-stimulant treatments for ADHD.¹² In general, psychostimulant treatment for adults is similar to that for children; the only difference is that adults tend to be more forthcoming with information regarding how the treatment is working and what adjustments might be needed.

Longer-acting stimulants (ie, extended release) tend to be preferred by patients to short-acting ones because they typically provide adequate control of symptoms over a longer period of time and thus may be taken less frequently.¹³ Also, the potential for abuse of psychostimulant medication tends to be lower with the longer-acting, extended-release formulations.¹⁴ A shorter acting formulation may be preferred if a patient has a specific window of time when their ADHD symptoms impact them. For example, a patient may request a short-acting form of medication for afternoons if he or she has to attend many business meetings at that time of day. A relatively new category is the intermediate-acting psychostimulants. For more on specific psychostimulants, see Table 3.¹⁵

Adverse effects lead many to discontinue treatment

Regardless of the length of action of the psychostimulant, studies show that about 30% of adults (and, incidentally, 10% to 30% of children) discontinue treatment due to uncontrolled/unwanted symptoms or adverse effects.¹⁶ These include decreased appetite, headache, insomnia, abdominal pain, and irritable mood.¹⁷ If you are prescribing a psychostimulant for an adult with ADHD, it is important to tell the patient that if the effects become intolerable, adjustments can be made, such as tweaking dosages, switching to a different medication, or adding an adjunctive therapy such as cognitive behavioral therapy. Keep in mind, too, that if a medication is to be discontinued, tapering is suggested for most psychostimulants; patients should take a lower (eg, half) dose for about a week prior to complete discontinuation. People who have difficulties with a number of treatments for ADHD should be reevaluated in a year to see if circumstances have changed.⁵

Combatting misuse and diversion

Perhaps the most controversial issues surrounding the treatment of adults with ADHD are abuse and diversion of psychostimulants. Abuse generally refers to misuse of the drug by the person prescribed the agent, whereas diversion refers to use of the drug by people for whom the drug was not intended—with or without the prescribee’s knowledge.³ Although rare, chronic abuse of psychostimulants can lead to serious problems such as aggression, suicidal thoughts/behaviors, psychosis, and mania.⁵

New data reveal that a large portion of people who meet the criteria for ADHD in adulthood did not meet the criteria as children.While earlier studies tended to downplay the likelihood of diversion, recent research indicates that physicians should not underestimate the possibility. In fact, a previous article in this journal about student athletes with ADHD (http://bit.ly/2k1a6TL) indicated that psychostimulants have “great potential for misuse” and that recently there has been “a surge in nonprescription stimulant use among adolescents and young adults.”¹⁷ The authors of the article concluded, however, that while physicians should be aware of the potential for misuse, fear should not preclude treatment.¹⁷

A national multi-cohort study of 4572 US high school seniors who had used psychostimulants either medically or nonmedically indicated that while one in 6 high school seniors had been exposed to psychostimulants, about half were appropriately exposed through prescription use, while the other half was not. The researchers also reported that current nonmedical users of psychostimulants and those with a history of nonmedical use had a greater risk of substance use and abuse when compared to medical users of psychostimulants.¹⁸

Young men are at higher risk for diversion. In a nationwide survey of a sample of adults ages 18 to 49 years who had a prescription for psychostimulant medication in the past month, 17% admitted diverting their medication.¹⁹ The researchers also observed that men were more than twice as likely to divert medication than women.¹⁹

In another study, 483 students ages 17 to 19 years were followed for one year and interviewed frequently regarding their use of medications.²⁰ The researchers reported that the lifetime prevalence of diversion of any medication in those students was around 36%. They also found that of those who diverted medication, 62% diverted ADHD medications at least once. These were most commonly diverted by sharing (34%) and selling (9%) the psychostimulants. Interview analysis revealed that those students who diverted were more likely to have used illicit drugs and to have had conduct problems. The authors advised “vigilance regarding…stimulant medications for young adults.”

Psychostimulant prescriptions do not cause substance abuse. Nevertheless, a salient point in the literature is that there is no causal relationship between psychostimulant prescriptions that are properly prescribed for people who have ADHD and substance abuse. One study that followed young people with ADHD for 8 years into adulthood revealed that psychostimulant treatment did not make adolescents or young adults any more or less likely to abuse drugs.²¹ The study also found that alcohol use was common in young adults whether they were diagnosed with ADHD or not. Nonetheless, family physicians should urge those taking psychostimulants to refrain from alcohol use or at least to drink in moderation.

About 30% of adults discontinue treatment due to unwanted/uncontrolled symptoms or adverse effects.The bottom line is that adults diagnosed with ADHD carry about the same risk of substance abuse as the general population if they are effectively treated for their presenting attention problems.²² If they are taking a psychostimulant, however, they have access to a controlled substance, unlike most of their cohorts. So it's important to teach patients with ADHD that for safety and legal reasons, they should not share or sell their stimulant medication to anyone.

Minimize the risk for abuse, diversion using these strategies

As with any drug regimen, it is important to monitor the patient’s response to treatment and minimize adverse effects and outcomes. When the drug is a psychostimulant for adults diagnosed with ADHD, it’s also important to minimize the risk for abuse and diversion. The following steps can help:

• Obtain a signed controlled substance agreement.²³ This agreement between the physician and the patient usually outlines such specifics as frequency of office visits, circumstances surrounding medication refills, urine drug monitoring, and pill counts. (For more on the specifics of a controlled substance agreement, see "Key points of a controlled substance agreement.")
• Schedule frequent follow-up appointments with open communication about abuse and diversion.^20,23 The age-old adage, “Start low, go slow,” applies to stimulant medications for ADHD. Medication dosage may vary and necessitate titration depending on the person’s weight and tolerance. At the onset of treatment, frequent office visits allow the physician to gauge treatment response and the patient’s commitment to therapy.
• Review your state’s prescription drug monitoring program.²⁴ It is imperative that providers check their state’s medical board rules for prescribing controlled medications to ensure practice compliance. As diversion rates of controlled medications have risen in this country, most states have established monitoring systems through their pharmacy boards.²⁴ Although the names of the programs vary, these prescription drug monitoring programs provide information on any medication prescribed. This allows the prescribing physician to ensure patient compliance and ascertain that no other controlled medications are being prescribed that could interfere with treatment. (For more information about state prescription drug monitoring programs, see https://www.deadiversion.usdoj.gov/faq/rx_monitor.htm.)
• Perform random urine drug screenings (UDS).^20,23 An important strategy for ensuring adherence to the treatment plan and the controlled substance contract is UDS. Explain to patients that this is a way of making sure they are taking the medication exactly as prescribed. If the UDS indicates that the patient has not been taking the medication, then the provider should intervene by either restricting or discontinuing the controlled substance to prevent or counteract potential diversion. Similarly, if a higher dose is requested by a patient, the provider can closely monitor the situation to determine whether the additional drug is actually being taken and whether the dose is optimal. (See JFP’s October 2016 “3 in 3” video on urine drug testing at: http://bit.ly/2iDnfgD.)
• Employ a team-based, multimodal approach.²⁵ A referral to a mental health professional and multimodal treatment are often recommended in the literature as best practices.²⁵ Behavioral therapies are a cornerstone of treatment in adults with ADHD and often serve as important adjuncts to pharmacotherapy. Also, a referral provides a second professional opinion about the patient’s motivations, adherence, and response to treatment.

Trained cognitive behavioral therapists (eg, psychologists, counselors) can be helpful with treatment for ADHD.²³ Therapists can be useful in setting goals for the patient regarding adherence, organization, impulse control, and social skills training. Therapists may wish to involve the family in treatment, depending on the nature of the patient’s presenting issues.

Don’t tempt fate. As with any controlled medication, safe storage of psychostimulants is paramount. Patients should be urged to keep their medication in a locked box or cupboard that is accessible to only the adult for whom the drug is prescribed. Prior research cautions that open access to controlled substances can lead to larger issues with abuse and diversion, particularly when adolescents are in the home.²⁶

Men are more than twice as likely to divert medication as women. Consider atomoxetine. Research has also demonstrated that the non-stimulant medication atomoxetine has some benefit in the treatment of ADHD.¹² Unlike psychostimulants that act on the neurotransmitter dopamine, atomoxetine acts on the neurotransmitter norepinephrine. This different mechanism of action results in a lower potential for abuse and diversion.

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