CASE › A 68-year-old woman with hypertension and hyperlipidemia comes into your office for evaluation of a 30-minute episode of sudden-onset right-hand weakness and difficulty speaking that occurred 4 days earlier. The patient, who is also a smoker, has come in at the insistence of her daughter. On examination, her blood pressure (BP) is 145/88 mm Hg and her heart rate is 76 beats/minute and regular. She appears well and her language function is normal. The rest of her examination is normal. How would you proceed?

Stroke—the death of nerve cells due to a lack of blood supply from either infarction or hemorrhage—strikes nearly 800,000 people in the United States every year.^1,2 Of these events, 130,000 are fatal, making stroke the fifth leading cause of death.³ Effective, early evaluation and cause-specific treatment are crucial parts of stroke care.

Data indicate that evaluation of symptoms suggestive of stroke within 24 hours of an event confers substantial benefit.

Research has helped to clarify the critical role primary care physicians play in recognizing, triaging, and managing stroke and transient ischemic attacks (TIA). This article reviews what we know about the different ways that a stroke and a TIA can present, the appropriate diagnostic work-up for patients presenting with symptoms of either event, and management strategies for subacute care (24 hours to up to 14 days after a stroke has occurred).^4,5 Unless otherwise specified, this review will focus on ischemic stroke because 87% of strokes are attributable to ischemia.¹

A follow-up to this article on secondary stroke prevention will appear in the journal next month.

IMAGE: © 2017 ALEX NUBAUM C/O THE ISPOT

Look to onset more than type of symptoms for clues

Stroke presents as a sudden onset of neurologic deficits (language, motor, sensory, cerebellar, or brainstem functions) (TABLE 1⁴). Because presenting symptoms can vary widely, sudden onset, rather than particular symptoms, should raise a red flag for potential stroke.

The differential diagnosis includes: seizure, complex migraine, medication effect (eg, slurred speech or confusion after taking a central nervous system [CNS] depressant), toxin exposure, electrolyte abnormalities (especially hypoglycemia), concussion/trauma, infection of the CNS, peripheral vertigo, demyelination, intracranial mass, Bell’s palsy, and psychogenic disorders. The history and physical, along with laboratory findings and brain imaging (detailed later in this article), will guide the FP toward (or away from) these various etiologies.

Optimal triage is a subject of ongoing interest and research

If stroke or TIA remains a possibility after an initial assessment, it’s time to stratify patients by risk.

One of the most widely accepted tools is the ABCD² score (see TABLE 2⁶). Clinicians can employ the ABCD² risk stratification tool when trying to determine whether it is reasonable to pursue an expedited work-up (ie, <1 day) in the outpatient setting or recommend that the patient be evaluated in an emergency department (ED). The 90-day stroke rate following a TIA ranges from 3% with an ABCD² score of 0 to 3 to 18% with a score of 6 or 7. A score of 0 to 3 is considered relatively low risk; in the absence of other compelling factors, rapid outpatient evaluation is appropriate. For patients with an ABCD² score ≥4, referral to the ED or direct admission to the hospital is advised.

The validity of the ABCD² score for risk stratification has been studied extensively with conflicting results.^7-10 As with any assessment tool, it should be used as a guide, and should not supplant a full assessment of the patient or the judgment of the examining physician. In making the decision regarding inpatient or outpatient evaluation, it’s also important to consider available resources, access to specialists, and patient preference.

In a 2016 population-based study, the 30-day recurrent stroke/TIA rate for patients hospitalized for TIA was 3% compared with 10.7% for those discharged from the ED with referral to a stroke clinic and 10.6% for those discharged from the ED without a referral to a stroke clinic.¹¹ These data suggest that only patients for whom you have a low clinical suspicion of stroke/TIA should be worked up as outpatients, and that hospital admission is advised in moderate- and high-risk cases. The findings also highlight the critical role that primary care physicians can play in triaging and managing these patients for secondary prevention.

CASE › This patient’s recent history of sudden-onset right-sided weakness and expressive language dysfunction is suspicious for left hemispheric ischemia. She has several risk factors for stroke, and her ABCD² score is 5 (hypertension, age ≥60 years, unilateral weakness, and duration 10-59 min), which places her at moderate risk. Thus, the recommendation would be to have her go directly to an ED for rapid evaluation.

The diagnostic work-up

Even when a patient is sent to the ED, the FP plays a critical role in his or her continuing care. FPs will often coordinate with inpatient care and manage transition of care to the outpatient setting. (And in many communities, the ED or hospital physicians may themselves be family practitioners.)

In terms of care, not even an aspirin should be administered in a case like this because the patient has not yet had any neuroimaging, and differentiation of ischemic from hemorrhagic stroke cannot be made on clinical grounds alone. Once an ischemic stroke is confirmed, determining the etiology is critical given the significant management differences between the different types of stroke (atherosclerotic, cardioembolic, lacunar, or other).

Which imaging method, and when?

While a computerized tomography (CT) scan is the preferred initial imaging strategy for acute stroke to discern the ischemic type from the hemorrhagic, MRI is preferred for the evaluation of acute ischemic stroke because the method has a higher sensitivity for infarction and a greater ability to identify findings (such as demyelination) that would suggest an alternative diagnosis.

Because presenting symptoms can vary widely, sudden onset, rather than particular symptoms, should raise the red flag for potential stroke.

In addition to evaluating the brain parenchyma, physicians must also assess the cerebral vasculature. CT angiography (CTA) or MR angiography (MRA) of the head and neck are preferred over carotid ultrasound because they are capable of evaluating the entire cerebrovascular system^12,13 and can be instrumental in identifying potential causes of stroke, as well as guiding therapeutic decisions. Carotid ultrasound is a reasonable alternative for patients presenting with symptoms indicative of anterior circulation involvement when CTA and MRA are unavailable or contraindicated, but it will not identify intracranial vascular disease, proximal common carotid disease, or vertebrobasilar disease.

Getting to the cause of suspected stroke: Labs and other diagnostic tests

A routine work-up includes BP checks, routine labs (complete blood count, complete metabolic panel, coagulation profile, and troponin), an electrocardiogram (EKG), a transthoracic echocardiogram (TTE) with bubble study if possible, and a minimum of 24 to 48 hours of cardiac rhythm monitoring. Cardiac rhythm monitoring should be extended in the setting of clinical concern for unidentified paroxysmal atrial fibrillation, such as an embolism without a proximal vascular source, multiple embolic infarcts in different vascular territories, a dilated left atrium, or other risk factors for atrial fibrillation that include smoking, systolic hypertension, diabetes, and heart failure (see TABLE 3^12,13,17,18).^14-16 This standard diagnostic work-up will identify the cause of stroke in 70% to 80% of patients.¹⁹

Additional investigations to consider if the etiology is not yet elucidated include a transesophageal echocardiogram (TEE), cerebral angiography, a coagulopathy evaluation, a lumbar puncture, and a vasculitis work-up. If available, consultation with a neurologist is appropriate for any patient who has had a stroke or TIA. Patients with unclear etiologies or for whom there are questions concerning strategies for preventing secondary stroke should be referred to Neurology and preferably a stroke specialist.

Timing matters, even when symptoms have resolved (ie, TIA).^11,20 The EXPRESS trial¹⁷ (the Early use of eXisting PREventive Strategies for Stroke) looked at the effect of urgent assessment and treatment (≤1 day) of patients presenting with a TIA or minor stroke on the risk of recurrent stroke within 90 days. The diagnostic work-up included brain and vascular imaging together with an EKG. This intensive approach led to an absolute risk reduction of 8.2% (from 10.3% to 2.1%) in the risk of recurrent stroke at 90 days (number needed to treat [NNT]=12).¹⁷

Expedited work-up and treatment was also recently evaluated in a non-trial, real-world setting and was associated with reducing recurrent stroke by more than half the rate reported in older studies.²⁰ Overall, the data suggest that evaluation within 24 hours confers substantial benefit, and that this evaluation can happen in an outpatient setting.^21-23

Acute management: Use of tPA

Once imaging rules out intracranial hemorrhage, patients should be treated with tissue plasminogen activator (tPA) or an endovascular intervention as per guidelines.²⁴ For patients with ischemic stroke ineligible for tPA or endovascular treatments, the initial focus is to determine the etiology of the symptoms so that the best strategies for prevention of secondary stroke may be employed.

Aspirin should be provided within 24 to 48 hours to all patients after intracranial hemorrhage is ruled out. Aspirin should be delayed for 24 hours in those given thrombolytics. The initial recommended dose of aspirin is 325 mg with continued low-dose (81 mg) aspirin daily.¹³ The addition of clopidogrel to aspirin within 24 hours of an event and continued for 21 days, followed by aspirin alone, was shown to be beneficial in a Chinese population with high-risk TIA (ABCD² score ≥4) or minor stroke (National Institutes of Health Stroke Scale [NIHSS] ≤3).²⁵ Anticoagulation with heparin, warfarin, or a novel oral anticoagulant is generally not indicated in the acute setting due to the risk of hemorrhagic transformation.

Acute BP management depends upon the type of stroke (ischemic or hemorrhagic), eligibility for thrombolytics, timing of presentation, and possible comorbidities such as myocardial infarction or aortic dissection (see TABLE 4^13,26). In the absence of contraindications, high-intensity statins should be initiated in all patients able to take oral medications.

CASE › You appropriately referred your patient to the local ED. A head CT with head and neck CTA was performed. While the head CT did not show any abnormalities, the CTA demonstrated high-grade left internal carotid artery stenosis. The patient was given an initial dose of aspirin 325 mg and a high-intensity statin and admitted for further management. An MRI revealed a small shower of emboli in the left hemisphere, confirming the diagnosis of stroke over TIA. Labs were marginally remarkable with a low-density lipoprotein level of 115 mg/dL and an HbA1c of 6.2. Telemetry monitoring did not reveal any arrhythmias, and TTE was normal. BP remained in the high-normal to low-hypertensive range.

Timing matters, even when symptoms have resolved, such as with a TIA.

A Vascular Surgery consultation was obtained and the patient underwent a left carotid endarterectomy the following day. She did well without surgical complications. Her BP medications were adjusted; a combination of an angiotensin-converting enzyme inhibitor and a thiazide diuretic achieved a goal BP <140/90 mm Hg.

Permissive hypertension was not indicated due to her presentation >48 hours beyond the acute event. Low-dose aspirin and a high-intensity statin were continued, for secondary stroke prevention in the setting of atherosclerotic disease. She received smoking cessation counseling, which will continue.

CORRESPONDENCE
Stephen A. Martin, MD, EdM, Barre Family Health Center, 151 Worcester Road, Barre, MA 01005; [email protected].

CASE › A 68-year-old woman with hypertension and hyperlipidemia comes into your office for evaluation of a 30-minute episode of sudden-onset right-hand weakness and difficulty speaking that occurred 4 days earlier. The patient, who is also a smoker, has come in at the insistence of her daughter. On examination, her blood pressure (BP) is 145/88 mm Hg and her heart rate is 76 beats/minute and regular. She appears well and her language function is normal. The rest of her examination is normal. How would you proceed?

Stroke—the death of nerve cells due to a lack of blood supply from either infarction or hemorrhage—strikes nearly 800,000 people in the United States every year.^1,2 Of these events, 130,000 are fatal, making stroke the fifth leading cause of death.³ Effective, early evaluation and cause-specific treatment are crucial parts of stroke care.

Data indicate that evaluation of symptoms suggestive of stroke within 24 hours of an event confers substantial benefit.

Research has helped to clarify the critical role primary care physicians play in recognizing, triaging, and managing stroke and transient ischemic attacks (TIA). This article reviews what we know about the different ways that a stroke and a TIA can present, the appropriate diagnostic work-up for patients presenting with symptoms of either event, and management strategies for subacute care (24 hours to up to 14 days after a stroke has occurred).^4,5 Unless otherwise specified, this review will focus on ischemic stroke because 87% of strokes are attributable to ischemia.¹

A follow-up to this article on secondary stroke prevention will appear in the journal next month.

IMAGE: © 2017 ALEX NUBAUM C/O THE ISPOT

Look to onset more than type of symptoms for clues

Stroke presents as a sudden onset of neurologic deficits (language, motor, sensory, cerebellar, or brainstem functions) (TABLE 1⁴). Because presenting symptoms can vary widely, sudden onset, rather than particular symptoms, should raise a red flag for potential stroke.

The differential diagnosis includes: seizure, complex migraine, medication effect (eg, slurred speech or confusion after taking a central nervous system [CNS] depressant), toxin exposure, electrolyte abnormalities (especially hypoglycemia), concussion/trauma, infection of the CNS, peripheral vertigo, demyelination, intracranial mass, Bell’s palsy, and psychogenic disorders. The history and physical, along with laboratory findings and brain imaging (detailed later in this article), will guide the FP toward (or away from) these various etiologies.

Optimal triage is a subject of ongoing interest and research

If stroke or TIA remains a possibility after an initial assessment, it’s time to stratify patients by risk.

One of the most widely accepted tools is the ABCD² score (see TABLE 2⁶). Clinicians can employ the ABCD² risk stratification tool when trying to determine whether it is reasonable to pursue an expedited work-up (ie, <1 day) in the outpatient setting or recommend that the patient be evaluated in an emergency department (ED). The 90-day stroke rate following a TIA ranges from 3% with an ABCD² score of 0 to 3 to 18% with a score of 6 or 7. A score of 0 to 3 is considered relatively low risk; in the absence of other compelling factors, rapid outpatient evaluation is appropriate. For patients with an ABCD² score ≥4, referral to the ED or direct admission to the hospital is advised.

The validity of the ABCD² score for risk stratification has been studied extensively with conflicting results.^7-10 As with any assessment tool, it should be used as a guide, and should not supplant a full assessment of the patient or the judgment of the examining physician. In making the decision regarding inpatient or outpatient evaluation, it’s also important to consider available resources, access to specialists, and patient preference.

In a 2016 population-based study, the 30-day recurrent stroke/TIA rate for patients hospitalized for TIA was 3% compared with 10.7% for those discharged from the ED with referral to a stroke clinic and 10.6% for those discharged from the ED without a referral to a stroke clinic.¹¹ These data suggest that only patients for whom you have a low clinical suspicion of stroke/TIA should be worked up as outpatients, and that hospital admission is advised in moderate- and high-risk cases. The findings also highlight the critical role that primary care physicians can play in triaging and managing these patients for secondary prevention.

CASE › This patient’s recent history of sudden-onset right-sided weakness and expressive language dysfunction is suspicious for left hemispheric ischemia. She has several risk factors for stroke, and her ABCD² score is 5 (hypertension, age ≥60 years, unilateral weakness, and duration 10-59 min), which places her at moderate risk. Thus, the recommendation would be to have her go directly to an ED for rapid evaluation.

The diagnostic work-up

Even when a patient is sent to the ED, the FP plays a critical role in his or her continuing care. FPs will often coordinate with inpatient care and manage transition of care to the outpatient setting. (And in many communities, the ED or hospital physicians may themselves be family practitioners.)

In terms of care, not even an aspirin should be administered in a case like this because the patient has not yet had any neuroimaging, and differentiation of ischemic from hemorrhagic stroke cannot be made on clinical grounds alone. Once an ischemic stroke is confirmed, determining the etiology is critical given the significant management differences between the different types of stroke (atherosclerotic, cardioembolic, lacunar, or other).

Which imaging method, and when?

While a computerized tomography (CT) scan is the preferred initial imaging strategy for acute stroke to discern the ischemic type from the hemorrhagic, MRI is preferred for the evaluation of acute ischemic stroke because the method has a higher sensitivity for infarction and a greater ability to identify findings (such as demyelination) that would suggest an alternative diagnosis.

Because presenting symptoms can vary widely, sudden onset, rather than particular symptoms, should raise the red flag for potential stroke.

In addition to evaluating the brain parenchyma, physicians must also assess the cerebral vasculature. CT angiography (CTA) or MR angiography (MRA) of the head and neck are preferred over carotid ultrasound because they are capable of evaluating the entire cerebrovascular system^12,13 and can be instrumental in identifying potential causes of stroke, as well as guiding therapeutic decisions. Carotid ultrasound is a reasonable alternative for patients presenting with symptoms indicative of anterior circulation involvement when CTA and MRA are unavailable or contraindicated, but it will not identify intracranial vascular disease, proximal common carotid disease, or vertebrobasilar disease.

Getting to the cause of suspected stroke: Labs and other diagnostic tests

A routine work-up includes BP checks, routine labs (complete blood count, complete metabolic panel, coagulation profile, and troponin), an electrocardiogram (EKG), a transthoracic echocardiogram (TTE) with bubble study if possible, and a minimum of 24 to 48 hours of cardiac rhythm monitoring. Cardiac rhythm monitoring should be extended in the setting of clinical concern for unidentified paroxysmal atrial fibrillation, such as an embolism without a proximal vascular source, multiple embolic infarcts in different vascular territories, a dilated left atrium, or other risk factors for atrial fibrillation that include smoking, systolic hypertension, diabetes, and heart failure (see TABLE 3^12,13,17,18).^14-16 This standard diagnostic work-up will identify the cause of stroke in 70% to 80% of patients.¹⁹

Additional investigations to consider if the etiology is not yet elucidated include a transesophageal echocardiogram (TEE), cerebral angiography, a coagulopathy evaluation, a lumbar puncture, and a vasculitis work-up. If available, consultation with a neurologist is appropriate for any patient who has had a stroke or TIA. Patients with unclear etiologies or for whom there are questions concerning strategies for preventing secondary stroke should be referred to Neurology and preferably a stroke specialist.

Timing matters, even when symptoms have resolved (ie, TIA).^11,20 The EXPRESS trial¹⁷ (the Early use of eXisting PREventive Strategies for Stroke) looked at the effect of urgent assessment and treatment (≤1 day) of patients presenting with a TIA or minor stroke on the risk of recurrent stroke within 90 days. The diagnostic work-up included brain and vascular imaging together with an EKG. This intensive approach led to an absolute risk reduction of 8.2% (from 10.3% to 2.1%) in the risk of recurrent stroke at 90 days (number needed to treat [NNT]=12).¹⁷

Expedited work-up and treatment was also recently evaluated in a non-trial, real-world setting and was associated with reducing recurrent stroke by more than half the rate reported in older studies.²⁰ Overall, the data suggest that evaluation within 24 hours confers substantial benefit, and that this evaluation can happen in an outpatient setting.^21-23

Acute management: Use of tPA

Once imaging rules out intracranial hemorrhage, patients should be treated with tissue plasminogen activator (tPA) or an endovascular intervention as per guidelines.²⁴ For patients with ischemic stroke ineligible for tPA or endovascular treatments, the initial focus is to determine the etiology of the symptoms so that the best strategies for prevention of secondary stroke may be employed.

Aspirin should be provided within 24 to 48 hours to all patients after intracranial hemorrhage is ruled out. Aspirin should be delayed for 24 hours in those given thrombolytics. The initial recommended dose of aspirin is 325 mg with continued low-dose (81 mg) aspirin daily.¹³ The addition of clopidogrel to aspirin within 24 hours of an event and continued for 21 days, followed by aspirin alone, was shown to be beneficial in a Chinese population with high-risk TIA (ABCD² score ≥4) or minor stroke (National Institutes of Health Stroke Scale [NIHSS] ≤3).²⁵ Anticoagulation with heparin, warfarin, or a novel oral anticoagulant is generally not indicated in the acute setting due to the risk of hemorrhagic transformation.

Acute BP management depends upon the type of stroke (ischemic or hemorrhagic), eligibility for thrombolytics, timing of presentation, and possible comorbidities such as myocardial infarction or aortic dissection (see TABLE 4^13,26). In the absence of contraindications, high-intensity statins should be initiated in all patients able to take oral medications.

CASE › You appropriately referred your patient to the local ED. A head CT with head and neck CTA was performed. While the head CT did not show any abnormalities, the CTA demonstrated high-grade left internal carotid artery stenosis. The patient was given an initial dose of aspirin 325 mg and a high-intensity statin and admitted for further management. An MRI revealed a small shower of emboli in the left hemisphere, confirming the diagnosis of stroke over TIA. Labs were marginally remarkable with a low-density lipoprotein level of 115 mg/dL and an HbA1c of 6.2. Telemetry monitoring did not reveal any arrhythmias, and TTE was normal. BP remained in the high-normal to low-hypertensive range.

Timing matters, even when symptoms have resolved, such as with a TIA.

A Vascular Surgery consultation was obtained and the patient underwent a left carotid endarterectomy the following day. She did well without surgical complications. Her BP medications were adjusted; a combination of an angiotensin-converting enzyme inhibitor and a thiazide diuretic achieved a goal BP <140/90 mm Hg.

Permissive hypertension was not indicated due to her presentation >48 hours beyond the acute event. Low-dose aspirin and a high-intensity statin were continued, for secondary stroke prevention in the setting of atherosclerotic disease. She received smoking cessation counseling, which will continue.

CORRESPONDENCE
Stephen A. Martin, MD, EdM, Barre Family Health Center, 151 Worcester Road, Barre, MA 01005; [email protected].

CASE › A 68-year-old woman with hypertension and hyperlipidemia comes into your office for evaluation of a 30-minute episode of sudden-onset right-hand weakness and difficulty speaking that occurred 4 days earlier. The patient, who is also a smoker, has come in at the insistence of her daughter. On examination, her blood pressure (BP) is 145/88 mm Hg and her heart rate is 76 beats/minute and regular. She appears well and her language function is normal. The rest of her examination is normal. How would you proceed?

Stroke—the death of nerve cells due to a lack of blood supply from either infarction or hemorrhage—strikes nearly 800,000 people in the United States every year.^1,2 Of these events, 130,000 are fatal, making stroke the fifth leading cause of death.³ Effective, early evaluation and cause-specific treatment are crucial parts of stroke care.

Data indicate that evaluation of symptoms suggestive of stroke within 24 hours of an event confers substantial benefit.

Research has helped to clarify the critical role primary care physicians play in recognizing, triaging, and managing stroke and transient ischemic attacks (TIA). This article reviews what we know about the different ways that a stroke and a TIA can present, the appropriate diagnostic work-up for patients presenting with symptoms of either event, and management strategies for subacute care (24 hours to up to 14 days after a stroke has occurred).^4,5 Unless otherwise specified, this review will focus on ischemic stroke because 87% of strokes are attributable to ischemia.¹

A follow-up to this article on secondary stroke prevention will appear in the journal next month.

IMAGE: © 2017 ALEX NUBAUM C/O THE ISPOT

Look to onset more than type of symptoms for clues

Stroke presents as a sudden onset of neurologic deficits (language, motor, sensory, cerebellar, or brainstem functions) (TABLE 1⁴). Because presenting symptoms can vary widely, sudden onset, rather than particular symptoms, should raise a red flag for potential stroke.

The differential diagnosis includes: seizure, complex migraine, medication effect (eg, slurred speech or confusion after taking a central nervous system [CNS] depressant), toxin exposure, electrolyte abnormalities (especially hypoglycemia), concussion/trauma, infection of the CNS, peripheral vertigo, demyelination, intracranial mass, Bell’s palsy, and psychogenic disorders. The history and physical, along with laboratory findings and brain imaging (detailed later in this article), will guide the FP toward (or away from) these various etiologies.

Optimal triage is a subject of ongoing interest and research

If stroke or TIA remains a possibility after an initial assessment, it’s time to stratify patients by risk.

One of the most widely accepted tools is the ABCD² score (see TABLE 2⁶). Clinicians can employ the ABCD² risk stratification tool when trying to determine whether it is reasonable to pursue an expedited work-up (ie, <1 day) in the outpatient setting or recommend that the patient be evaluated in an emergency department (ED). The 90-day stroke rate following a TIA ranges from 3% with an ABCD² score of 0 to 3 to 18% with a score of 6 or 7. A score of 0 to 3 is considered relatively low risk; in the absence of other compelling factors, rapid outpatient evaluation is appropriate. For patients with an ABCD² score ≥4, referral to the ED or direct admission to the hospital is advised.

The validity of the ABCD² score for risk stratification has been studied extensively with conflicting results.^7-10 As with any assessment tool, it should be used as a guide, and should not supplant a full assessment of the patient or the judgment of the examining physician. In making the decision regarding inpatient or outpatient evaluation, it’s also important to consider available resources, access to specialists, and patient preference.

In a 2016 population-based study, the 30-day recurrent stroke/TIA rate for patients hospitalized for TIA was 3% compared with 10.7% for those discharged from the ED with referral to a stroke clinic and 10.6% for those discharged from the ED without a referral to a stroke clinic.¹¹ These data suggest that only patients for whom you have a low clinical suspicion of stroke/TIA should be worked up as outpatients, and that hospital admission is advised in moderate- and high-risk cases. The findings also highlight the critical role that primary care physicians can play in triaging and managing these patients for secondary prevention.

CASE › This patient’s recent history of sudden-onset right-sided weakness and expressive language dysfunction is suspicious for left hemispheric ischemia. She has several risk factors for stroke, and her ABCD² score is 5 (hypertension, age ≥60 years, unilateral weakness, and duration 10-59 min), which places her at moderate risk. Thus, the recommendation would be to have her go directly to an ED for rapid evaluation.

The diagnostic work-up

Even when a patient is sent to the ED, the FP plays a critical role in his or her continuing care. FPs will often coordinate with inpatient care and manage transition of care to the outpatient setting. (And in many communities, the ED or hospital physicians may themselves be family practitioners.)

In terms of care, not even an aspirin should be administered in a case like this because the patient has not yet had any neuroimaging, and differentiation of ischemic from hemorrhagic stroke cannot be made on clinical grounds alone. Once an ischemic stroke is confirmed, determining the etiology is critical given the significant management differences between the different types of stroke (atherosclerotic, cardioembolic, lacunar, or other).

Which imaging method, and when?

While a computerized tomography (CT) scan is the preferred initial imaging strategy for acute stroke to discern the ischemic type from the hemorrhagic, MRI is preferred for the evaluation of acute ischemic stroke because the method has a higher sensitivity for infarction and a greater ability to identify findings (such as demyelination) that would suggest an alternative diagnosis.

Because presenting symptoms can vary widely, sudden onset, rather than particular symptoms, should raise the red flag for potential stroke.

In addition to evaluating the brain parenchyma, physicians must also assess the cerebral vasculature. CT angiography (CTA) or MR angiography (MRA) of the head and neck are preferred over carotid ultrasound because they are capable of evaluating the entire cerebrovascular system^12,13 and can be instrumental in identifying potential causes of stroke, as well as guiding therapeutic decisions. Carotid ultrasound is a reasonable alternative for patients presenting with symptoms indicative of anterior circulation involvement when CTA and MRA are unavailable or contraindicated, but it will not identify intracranial vascular disease, proximal common carotid disease, or vertebrobasilar disease.

Getting to the cause of suspected stroke: Labs and other diagnostic tests

A routine work-up includes BP checks, routine labs (complete blood count, complete metabolic panel, coagulation profile, and troponin), an electrocardiogram (EKG), a transthoracic echocardiogram (TTE) with bubble study if possible, and a minimum of 24 to 48 hours of cardiac rhythm monitoring. Cardiac rhythm monitoring should be extended in the setting of clinical concern for unidentified paroxysmal atrial fibrillation, such as an embolism without a proximal vascular source, multiple embolic infarcts in different vascular territories, a dilated left atrium, or other risk factors for atrial fibrillation that include smoking, systolic hypertension, diabetes, and heart failure (see TABLE 3^12,13,17,18).^14-16 This standard diagnostic work-up will identify the cause of stroke in 70% to 80% of patients.¹⁹

Additional investigations to consider if the etiology is not yet elucidated include a transesophageal echocardiogram (TEE), cerebral angiography, a coagulopathy evaluation, a lumbar puncture, and a vasculitis work-up. If available, consultation with a neurologist is appropriate for any patient who has had a stroke or TIA. Patients with unclear etiologies or for whom there are questions concerning strategies for preventing secondary stroke should be referred to Neurology and preferably a stroke specialist.

Timing matters, even when symptoms have resolved (ie, TIA).^11,20 The EXPRESS trial¹⁷ (the Early use of eXisting PREventive Strategies for Stroke) looked at the effect of urgent assessment and treatment (≤1 day) of patients presenting with a TIA or minor stroke on the risk of recurrent stroke within 90 days. The diagnostic work-up included brain and vascular imaging together with an EKG. This intensive approach led to an absolute risk reduction of 8.2% (from 10.3% to 2.1%) in the risk of recurrent stroke at 90 days (number needed to treat [NNT]=12).¹⁷

Expedited work-up and treatment was also recently evaluated in a non-trial, real-world setting and was associated with reducing recurrent stroke by more than half the rate reported in older studies.²⁰ Overall, the data suggest that evaluation within 24 hours confers substantial benefit, and that this evaluation can happen in an outpatient setting.^21-23

Acute management: Use of tPA

Once imaging rules out intracranial hemorrhage, patients should be treated with tissue plasminogen activator (tPA) or an endovascular intervention as per guidelines.²⁴ For patients with ischemic stroke ineligible for tPA or endovascular treatments, the initial focus is to determine the etiology of the symptoms so that the best strategies for prevention of secondary stroke may be employed.

Aspirin should be provided within 24 to 48 hours to all patients after intracranial hemorrhage is ruled out. Aspirin should be delayed for 24 hours in those given thrombolytics. The initial recommended dose of aspirin is 325 mg with continued low-dose (81 mg) aspirin daily.¹³ The addition of clopidogrel to aspirin within 24 hours of an event and continued for 21 days, followed by aspirin alone, was shown to be beneficial in a Chinese population with high-risk TIA (ABCD² score ≥4) or minor stroke (National Institutes of Health Stroke Scale [NIHSS] ≤3).²⁵ Anticoagulation with heparin, warfarin, or a novel oral anticoagulant is generally not indicated in the acute setting due to the risk of hemorrhagic transformation.

Acute BP management depends upon the type of stroke (ischemic or hemorrhagic), eligibility for thrombolytics, timing of presentation, and possible comorbidities such as myocardial infarction or aortic dissection (see TABLE 4^13,26). In the absence of contraindications, high-intensity statins should be initiated in all patients able to take oral medications.

CASE › You appropriately referred your patient to the local ED. A head CT with head and neck CTA was performed. While the head CT did not show any abnormalities, the CTA demonstrated high-grade left internal carotid artery stenosis. The patient was given an initial dose of aspirin 325 mg and a high-intensity statin and admitted for further management. An MRI revealed a small shower of emboli in the left hemisphere, confirming the diagnosis of stroke over TIA. Labs were marginally remarkable with a low-density lipoprotein level of 115 mg/dL and an HbA1c of 6.2. Telemetry monitoring did not reveal any arrhythmias, and TTE was normal. BP remained in the high-normal to low-hypertensive range.

Timing matters, even when symptoms have resolved, such as with a TIA.

A Vascular Surgery consultation was obtained and the patient underwent a left carotid endarterectomy the following day. She did well without surgical complications. Her BP medications were adjusted; a combination of an angiotensin-converting enzyme inhibitor and a thiazide diuretic achieved a goal BP <140/90 mm Hg.

Permissive hypertension was not indicated due to her presentation >48 hours beyond the acute event. Low-dose aspirin and a high-intensity statin were continued, for secondary stroke prevention in the setting of atherosclerotic disease. She received smoking cessation counseling, which will continue.

CORRESPONDENCE
Stephen A. Martin, MD, EdM, Barre Family Health Center, 151 Worcester Road, Barre, MA 01005; [email protected].

Antihemophilic factor

The European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products has issued a positive opinion recommending orphan designation for CB 2679d/ISU304 for the treatment of hemophilia B.

CB 2679d is a coagulation factor IX variant that has demonstrated, in preclinical studies, the potential to normalize factor IX levels via a daily subcutaneous injection.

The product is being developed by Catalyst Biosciences and ISU Abxis. ISU Abxis plans to initiate a phase 1/2 study of CB 2679d in individuals with severe hemophilia B this month in South Korea.

Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval.

The designation also provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure.

The EMA’s Committee for Orphan Medicinal Products adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision. The commission typically makes a decision within 30 days of the submission. 

Antihemophilic factor

The European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products has issued a positive opinion recommending orphan designation for CB 2679d/ISU304 for the treatment of hemophilia B.

CB 2679d is a coagulation factor IX variant that has demonstrated, in preclinical studies, the potential to normalize factor IX levels via a daily subcutaneous injection.

The product is being developed by Catalyst Biosciences and ISU Abxis. ISU Abxis plans to initiate a phase 1/2 study of CB 2679d in individuals with severe hemophilia B this month in South Korea.

Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval.

The designation also provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure.

The EMA’s Committee for Orphan Medicinal Products adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision. The commission typically makes a decision within 30 days of the submission. 

Antihemophilic factor

The European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products has issued a positive opinion recommending orphan designation for CB 2679d/ISU304 for the treatment of hemophilia B.

CB 2679d is a coagulation factor IX variant that has demonstrated, in preclinical studies, the potential to normalize factor IX levels via a daily subcutaneous injection.

The product is being developed by Catalyst Biosciences and ISU Abxis. ISU Abxis plans to initiate a phase 1/2 study of CB 2679d in individuals with severe hemophilia B this month in South Korea.

Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval.

The designation also provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure.

The EMA’s Committee for Orphan Medicinal Products adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision. The commission typically makes a decision within 30 days of the submission. 

Based on the clinical presentation and skin biopsy results, the patient was given a diagnosis of cutaneous sarcoidosis. The biopsy from the right side of his nose demonstrated sarcoidal granulomas. A biopsy of one of the tattoo nodules showed sarcoidal granulomas, and close inspection revealed red tattoo pigment within the granulomatous inflammation. X-rays showed bilateral hilar lymphadenopathy, which was consistent with pulmonary sarcoidosis, and the lace-like appearance of the middle and distal phalanges was consistent with skeletal sarcoidosis.

Systemic sarcoidosis is an idiopathic, granulomatous disease that affects multiple organ systems, but primarily the lungs and lymphatic system. Cutaneous sarcoidosis can occur as a manifestation of systemic sarcoidosis. It may present as asymptomatic red or skin-colored papules and firm nodules within tattoos, old scars, or permanent makeup. Sarcoidosis usually occurs in red, black, or blue-black areas of tattoos, in which the pigment acts as a nidus for granuloma formation.

The first-line treatment for limited papules is a high-potency topical corticosteroid (eg, clobetasol 0.05% ointment applied twice weekly) and an intralesional corticosteroid (eg, triamcinolone, one 5-10 mg/mL injection every 4 weeks). Antimalarials such as hydroxychloroquine or methotrexate can also be helpful. Midpotency topical corticosteroids such as triamcinolone 0.1% cream and doxycycline hyclate have been reported to clear cutaneous lesions in tattoos. Oral corticosteroids are often effective for severe cutaneous sarcoidosis, but their multiple adverse effects (eg, diabetes and adrenal suppression) prevent prolonged use except in very low doses in conjunction with other therapies.

The nodules on this patient’s nose were successfully treated with intralesional triamcinolone 5 mg/mL. No treatment was initiated for the tattoo nodules because they were asymptomatic and the patient wasn’t bothered by their appearance. The patient’s hand swelling improved with a treatment of prednisone 10 mg/d. The rheumatologist considered a steroid-sparing immunosuppressive agent such as methotrexate; however, the patient was lost to follow-up.

Adapted from: Zhang J, Jansen R, Lim HW. Nodules on nose and tattoos. J Fam Pract. 2015;64:241-243.

Based on the clinical presentation and skin biopsy results, the patient was given a diagnosis of cutaneous sarcoidosis. The biopsy from the right side of his nose demonstrated sarcoidal granulomas. A biopsy of one of the tattoo nodules showed sarcoidal granulomas, and close inspection revealed red tattoo pigment within the granulomatous inflammation. X-rays showed bilateral hilar lymphadenopathy, which was consistent with pulmonary sarcoidosis, and the lace-like appearance of the middle and distal phalanges was consistent with skeletal sarcoidosis.

Systemic sarcoidosis is an idiopathic, granulomatous disease that affects multiple organ systems, but primarily the lungs and lymphatic system. Cutaneous sarcoidosis can occur as a manifestation of systemic sarcoidosis. It may present as asymptomatic red or skin-colored papules and firm nodules within tattoos, old scars, or permanent makeup. Sarcoidosis usually occurs in red, black, or blue-black areas of tattoos, in which the pigment acts as a nidus for granuloma formation.

The first-line treatment for limited papules is a high-potency topical corticosteroid (eg, clobetasol 0.05% ointment applied twice weekly) and an intralesional corticosteroid (eg, triamcinolone, one 5-10 mg/mL injection every 4 weeks). Antimalarials such as hydroxychloroquine or methotrexate can also be helpful. Midpotency topical corticosteroids such as triamcinolone 0.1% cream and doxycycline hyclate have been reported to clear cutaneous lesions in tattoos. Oral corticosteroids are often effective for severe cutaneous sarcoidosis, but their multiple adverse effects (eg, diabetes and adrenal suppression) prevent prolonged use except in very low doses in conjunction with other therapies.

The nodules on this patient’s nose were successfully treated with intralesional triamcinolone 5 mg/mL. No treatment was initiated for the tattoo nodules because they were asymptomatic and the patient wasn’t bothered by their appearance. The patient’s hand swelling improved with a treatment of prednisone 10 mg/d. The rheumatologist considered a steroid-sparing immunosuppressive agent such as methotrexate; however, the patient was lost to follow-up.

Adapted from: Zhang J, Jansen R, Lim HW. Nodules on nose and tattoos. J Fam Pract. 2015;64:241-243.

Based on the clinical presentation and skin biopsy results, the patient was given a diagnosis of cutaneous sarcoidosis. The biopsy from the right side of his nose demonstrated sarcoidal granulomas. A biopsy of one of the tattoo nodules showed sarcoidal granulomas, and close inspection revealed red tattoo pigment within the granulomatous inflammation. X-rays showed bilateral hilar lymphadenopathy, which was consistent with pulmonary sarcoidosis, and the lace-like appearance of the middle and distal phalanges was consistent with skeletal sarcoidosis.

Systemic sarcoidosis is an idiopathic, granulomatous disease that affects multiple organ systems, but primarily the lungs and lymphatic system. Cutaneous sarcoidosis can occur as a manifestation of systemic sarcoidosis. It may present as asymptomatic red or skin-colored papules and firm nodules within tattoos, old scars, or permanent makeup. Sarcoidosis usually occurs in red, black, or blue-black areas of tattoos, in which the pigment acts as a nidus for granuloma formation.

The first-line treatment for limited papules is a high-potency topical corticosteroid (eg, clobetasol 0.05% ointment applied twice weekly) and an intralesional corticosteroid (eg, triamcinolone, one 5-10 mg/mL injection every 4 weeks). Antimalarials such as hydroxychloroquine or methotrexate can also be helpful. Midpotency topical corticosteroids such as triamcinolone 0.1% cream and doxycycline hyclate have been reported to clear cutaneous lesions in tattoos. Oral corticosteroids are often effective for severe cutaneous sarcoidosis, but their multiple adverse effects (eg, diabetes and adrenal suppression) prevent prolonged use except in very low doses in conjunction with other therapies.

The nodules on this patient’s nose were successfully treated with intralesional triamcinolone 5 mg/mL. No treatment was initiated for the tattoo nodules because they were asymptomatic and the patient wasn’t bothered by their appearance. The patient’s hand swelling improved with a treatment of prednisone 10 mg/d. The rheumatologist considered a steroid-sparing immunosuppressive agent such as methotrexate; however, the patient was lost to follow-up.

Adapted from: Zhang J, Jansen R, Lim HW. Nodules on nose and tattoos. J Fam Pract. 2015;64:241-243.

EVIDENCE SUMMARY

A meta-analysis of 24 RCTs examined the effect of pseudoephedrine on BP and heart rate.¹ Just 5 of the 24 studies specifically included hypertensive patients. In the population of patients with hypertension, the meta-analysis showed a small (1.2 mm Hg) rise in systolic BP with pseudoephedrine that was statistically significant (95% confidence interval [CI], 0.56-1.84 mm Hg), but the slight changes in diastolic BP and heart rate were not significant. No patient-oriented outcomes were measured.

The highest quality study within this group was a randomized, double-blind, placebo-controlled crossover study with 28 patients given sustained-release pseudoephedrine 120 mg twice daily for 72 hours, with BP measurements taken at 48 and 72 hours.² The study was powered to identify an increase in systolic BP of 11 mm Hg, but the results showed just a 3.1 mm Hg rise in systolic BP at 48 hours (see TABLE^1-7 for CI and other data).

In another double-blind, placebo-controlled RCT of 29 adults with hypertension (only 25 were included in the data analysis), there was no significant elevation in BP when oral pseudoephedrine was administered over the course of 3 days.³

Across the 5 studies in the meta-analysis, immediate-release and sustained-release forms of pseudoephedrine were included, hypertension was described as controlled but definitions of control were not always specified, and study length varied from 2 hours to 4 weeks.^2-6 Patients on antihypertensive medications were included in some of the studies; patients who had active cardiovascular disease, peripheral vascular disease, and/or cerebrovascular disease were excluded.

One study specifically looked at the effects of a single dose of pseudoephedrine on BP in patients treated with 2 different beta-blockers and found no significant change from baseline, but this study was not powered to show differences less than 5 mm Hg.⁶ The study did show a change of 1 to 2 mm Hg in systolic BP, but this was not statistically significant.

An absence of information on older patients

There is a paucity of literature on treating older adults and medically complex patients (eg, those with uncontrolled or secondary causes of hypertension, cerebrovascular disease, coronary artery disease) with decongestants, as they were excluded in all studies. And the available evidence does not include reports of adverse events other than changes in BP.

EVIDENCE SUMMARY

A meta-analysis of 24 RCTs examined the effect of pseudoephedrine on BP and heart rate.¹ Just 5 of the 24 studies specifically included hypertensive patients. In the population of patients with hypertension, the meta-analysis showed a small (1.2 mm Hg) rise in systolic BP with pseudoephedrine that was statistically significant (95% confidence interval [CI], 0.56-1.84 mm Hg), but the slight changes in diastolic BP and heart rate were not significant. No patient-oriented outcomes were measured.

The highest quality study within this group was a randomized, double-blind, placebo-controlled crossover study with 28 patients given sustained-release pseudoephedrine 120 mg twice daily for 72 hours, with BP measurements taken at 48 and 72 hours.² The study was powered to identify an increase in systolic BP of 11 mm Hg, but the results showed just a 3.1 mm Hg rise in systolic BP at 48 hours (see TABLE^1-7 for CI and other data).

In another double-blind, placebo-controlled RCT of 29 adults with hypertension (only 25 were included in the data analysis), there was no significant elevation in BP when oral pseudoephedrine was administered over the course of 3 days.³

Across the 5 studies in the meta-analysis, immediate-release and sustained-release forms of pseudoephedrine were included, hypertension was described as controlled but definitions of control were not always specified, and study length varied from 2 hours to 4 weeks.^2-6 Patients on antihypertensive medications were included in some of the studies; patients who had active cardiovascular disease, peripheral vascular disease, and/or cerebrovascular disease were excluded.

One study specifically looked at the effects of a single dose of pseudoephedrine on BP in patients treated with 2 different beta-blockers and found no significant change from baseline, but this study was not powered to show differences less than 5 mm Hg.⁶ The study did show a change of 1 to 2 mm Hg in systolic BP, but this was not statistically significant.

An absence of information on older patients

There is a paucity of literature on treating older adults and medically complex patients (eg, those with uncontrolled or secondary causes of hypertension, cerebrovascular disease, coronary artery disease) with decongestants, as they were excluded in all studies. And the available evidence does not include reports of adverse events other than changes in BP.

EVIDENCE SUMMARY

A meta-analysis of 24 RCTs examined the effect of pseudoephedrine on BP and heart rate.¹ Just 5 of the 24 studies specifically included hypertensive patients. In the population of patients with hypertension, the meta-analysis showed a small (1.2 mm Hg) rise in systolic BP with pseudoephedrine that was statistically significant (95% confidence interval [CI], 0.56-1.84 mm Hg), but the slight changes in diastolic BP and heart rate were not significant. No patient-oriented outcomes were measured.

The highest quality study within this group was a randomized, double-blind, placebo-controlled crossover study with 28 patients given sustained-release pseudoephedrine 120 mg twice daily for 72 hours, with BP measurements taken at 48 and 72 hours.² The study was powered to identify an increase in systolic BP of 11 mm Hg, but the results showed just a 3.1 mm Hg rise in systolic BP at 48 hours (see TABLE^1-7 for CI and other data).

In another double-blind, placebo-controlled RCT of 29 adults with hypertension (only 25 were included in the data analysis), there was no significant elevation in BP when oral pseudoephedrine was administered over the course of 3 days.³

Across the 5 studies in the meta-analysis, immediate-release and sustained-release forms of pseudoephedrine were included, hypertension was described as controlled but definitions of control were not always specified, and study length varied from 2 hours to 4 weeks.^2-6 Patients on antihypertensive medications were included in some of the studies; patients who had active cardiovascular disease, peripheral vascular disease, and/or cerebrovascular disease were excluded.

One study specifically looked at the effects of a single dose of pseudoephedrine on BP in patients treated with 2 different beta-blockers and found no significant change from baseline, but this study was not powered to show differences less than 5 mm Hg.⁶ The study did show a change of 1 to 2 mm Hg in systolic BP, but this was not statistically significant.

An absence of information on older patients

There is a paucity of literature on treating older adults and medically complex patients (eg, those with uncontrolled or secondary causes of hypertension, cerebrovascular disease, coronary artery disease) with decongestants, as they were excluded in all studies. And the available evidence does not include reports of adverse events other than changes in BP.

THE CASE

A 57-year-old African American woman was being treated at our clinic for neurogenic urinary incontinence (UI). The UI, which occurred day and night, began 2 years earlier following a laminectomy of vertebrae C3 to C6 with spinal fusion of C3 to C7 for cervical spinal stenosis. The UI persisted despite physical therapy and trials of oxybutynin and imipramine. Since the surgery, the patient had also been experiencing chronic (debilitating) neuropathic pain in both legs, and the sensation of incomplete bladder emptying. She denied bowel incontinence or saddle anesthesia. Her prescription medications included hydrocodone-acetaminophen 7.5/325 mg every 6 hours as needed for pain and lisinopril 20 mg/d for essential hypertension. The patient’s body mass index (BMI) was 23.3.

A urine culture initially grew Klebsiella pneumoniae, which we successfully treated with ciprofloxacin. A urinalysis was unremarkable, and blood urea nitrogen and creatinine levels were within normal limits.

We started the patient on oral duloxetine 30 mg/d for her neuropathic pain. The patient hadn’t undergone a urologic evaluation before starting duloxetine, so no urodynamic studies or measurements had been conducted. At that point, we sent the patient to a urologist for an evaluation.

At a follow-up visit with one of our clinic providers <3 months later, the patient reported that the duloxetine was providing her with some pain relief and that she was “waking up dry” in the mornings and having fewer UI symptoms throughout the day, as well as at night. The patient denied any adverse effects such as nausea, gastrointestinal upset, weight changes, xerostomia, fatigue, insomnia, headaches, or dizziness. Duloxetine was titrated up to 60 mg/d for better control of her neuropathic pain. At the next follow-up visit at our clinic 3 months later, her UI was 80% to 90% improved and she was able to stop her opioid pain medications.

DISCUSSION

UI is a significant problem in the United States and around the world. For women, the prevalence of UI ranges from 15% to 69%; among men, the prevalence is 5% to 24%.^1-3 The economic burden of UI includes both medical and nonmedical (eg, pads, diapers, laundry, and dry cleaning) care. The total national cost was estimated at $66 billion in 2007: $49 billion for direct medical costs, $2 billion for direct nonmedical costs, and $15 billion for indirect costs.⁴ And those costs are expected to increase 25% by 2020, mainly because of the aging population.

Risk factors for UI other than gender include advancing age, obesity, non-Hispanic white race, depression, hypertension, type 2 diabetes mellitus, neurologic disease, and functional limitations/general poor health.^5-7 Comorbid depression and BMI >30, as well as the presence and duration of diabetes, increase the odds for developing UI.^7,8

Duloxetine has been shown to be effective for the treatment of stress and mixed urinary incontinence. This case suggests it may be useful for neurogenic urinary incontinence, as well.

Risk factors for women include hysterectomy,⁷ increasing parity, and delivery of at least one infant >9.5 pounds; the risk is the same for both vaginal and cesarean-section delivery.⁶ Specific risk factors for men include prostate cancer, prostate surgery, and prostate radiation.⁵

Significant, chronic comorbidities of UI include depression and chronic pain. While quality of life is negatively affected by UI alone, the coexistence of depression and UI produces an additive negative effect on quality of life.⁹

Types and treatment of UI

There are 5 types of UI: urge, stress, overflow, functional, and mixed.¹⁰

• Urge incontinence is the leakage of urine following a sensation of sudden urgency to void.
• Stress incontinence is urine leakage associated with increased intra-abdominal pressure such as with coughing or sneezing and is typically associated with weakened pelvic floor musculature.
• Overflow incontinence is more common in men, and is typically caused by prostatic disease. The urethral outlet is obstructed leading to increased pressure within the bladder and subsequent leakage of urine.
• Functional incontinence is caused by physical or cognitive impairment leading to a decreased ability to get to a bathroom quickly enough to void.
• Mixed incontinence is when symptoms of stress and urgency incontinence are present.

There are 3 broad categories of treatment methods for urinary incontinence: behavioral, pharmacologic, and surgical. Behavioral interventions are subdivided into caregiver-dependent (prompted voiding, habit retraining, and timed voiding) and patient-directed (bladder training, pelvic floor muscle training, strategies for bladder control, education, and self-monitoring) techniques. Pharmacologic treatment typically consists of antimuscarinics (eg, oxybutynin, tolterodine, solifenacin) and tricyclic antidepressants (eg, imipramine).¹¹ Injections of onabotulinumtoxinA into the detrusor muscle have also been shown to reduce the symptoms of urinary incontinence.¹² Surgical options for treatment of UI include retro-pubic suspension, slings, and, in some instances, artificial urethral sphincters.¹³

A novel treatment for neurogenic UI?

Despite the many treatments available for UI, none comprehensively addresses UI and its common comorbidities.

The role of duloxetine. Normal micturition is regulated by the somatic nervous system and an autonomic reflex arc; the neurotransmitters serotonin and norepinephrine play an important role in the neural regulation of micturition and urinary continence. Duloxetine, alone or as an adjunctive treatment, is a potential novel therapy that treats 2 common comorbidities of UI—chronic pain and depression.

As a selective serotonin norepinephrine reuptake inhibitor (SNRI), duloxetine acts at the molecular level to block the reuptake of serotonin and norepinephrine from synaptic clefts. Specifically, the medication blocks the 5-hydroxytryptamine (5-HT) reuptake transporters, as well as the norepinephrine transporters, of pre-synaptic neurons.¹⁴ Thus, the concentrations of 5-HT and norepinephrine increase in the synaptic cleft.

Functionally, the accumulation of norepinephrine inhibits micturition by relaxing the detrusor muscle and constricting the urethral smooth muscle. In addition, a higher concentration of 5-HT at the neuromuscular junction leads to constriction of the external urethral sphincter.

Duloxetine has been shown to be effective in the treatment of other types of UI, such as stress UI¹⁵ and mixed UI.¹⁶ Additionally, it was found to be effective when compared with placebo in women with overactive bladder syndrome¹⁷ and in women with multiple sclerosis and depression.¹⁸ However, we are not aware of any cases using duloxetine for the treatment of neurogenic UI.

THE TAKEAWAY

Duloxetine is a potential novel drug choice for the treatment of neurogenic UI. Its effects on serotonin and norepinephrine at the synaptic cleft and neuromuscular junction could provide relief for those who have not found relief from other therapies. Further research—particularly a prospective, randomized controlled trial—is needed to determine if duloxetine is, in fact, more than just a theoretical candidate to treat UI and, if so, the most effective dosing.

Offering duloxetine for the treatment of neurogenic urinary incontinence would potentially address coexisting conditions, such as pain or depression.

Offering duloxetine for the treatment of neurogenic UI would potentially address coexisting conditions—such as pain or depression—thus improving patient compliance and reducing health care spending. Before beginning therapy, urodynamic studies to identify the type of UI should be completed, or, at a minimum, post-void residual volume should be measured.

ACKNOWLEDGEMENTS
The authors would like to thank Julie Hughbanks, MLS, Library Manager, Parkview Health Resource Library, for her assistance with the library searches used for this case report.

THE CASE

A 57-year-old African American woman was being treated at our clinic for neurogenic urinary incontinence (UI). The UI, which occurred day and night, began 2 years earlier following a laminectomy of vertebrae C3 to C6 with spinal fusion of C3 to C7 for cervical spinal stenosis. The UI persisted despite physical therapy and trials of oxybutynin and imipramine. Since the surgery, the patient had also been experiencing chronic (debilitating) neuropathic pain in both legs, and the sensation of incomplete bladder emptying. She denied bowel incontinence or saddle anesthesia. Her prescription medications included hydrocodone-acetaminophen 7.5/325 mg every 6 hours as needed for pain and lisinopril 20 mg/d for essential hypertension. The patient’s body mass index (BMI) was 23.3.

A urine culture initially grew Klebsiella pneumoniae, which we successfully treated with ciprofloxacin. A urinalysis was unremarkable, and blood urea nitrogen and creatinine levels were within normal limits.

We started the patient on oral duloxetine 30 mg/d for her neuropathic pain. The patient hadn’t undergone a urologic evaluation before starting duloxetine, so no urodynamic studies or measurements had been conducted. At that point, we sent the patient to a urologist for an evaluation.

At a follow-up visit with one of our clinic providers <3 months later, the patient reported that the duloxetine was providing her with some pain relief and that she was “waking up dry” in the mornings and having fewer UI symptoms throughout the day, as well as at night. The patient denied any adverse effects such as nausea, gastrointestinal upset, weight changes, xerostomia, fatigue, insomnia, headaches, or dizziness. Duloxetine was titrated up to 60 mg/d for better control of her neuropathic pain. At the next follow-up visit at our clinic 3 months later, her UI was 80% to 90% improved and she was able to stop her opioid pain medications.

DISCUSSION

UI is a significant problem in the United States and around the world. For women, the prevalence of UI ranges from 15% to 69%; among men, the prevalence is 5% to 24%.^1-3 The economic burden of UI includes both medical and nonmedical (eg, pads, diapers, laundry, and dry cleaning) care. The total national cost was estimated at $66 billion in 2007: $49 billion for direct medical costs, $2 billion for direct nonmedical costs, and $15 billion for indirect costs.⁴ And those costs are expected to increase 25% by 2020, mainly because of the aging population.

Risk factors for UI other than gender include advancing age, obesity, non-Hispanic white race, depression, hypertension, type 2 diabetes mellitus, neurologic disease, and functional limitations/general poor health.^5-7 Comorbid depression and BMI >30, as well as the presence and duration of diabetes, increase the odds for developing UI.^7,8

Duloxetine has been shown to be effective for the treatment of stress and mixed urinary incontinence. This case suggests it may be useful for neurogenic urinary incontinence, as well.

Risk factors for women include hysterectomy,⁷ increasing parity, and delivery of at least one infant >9.5 pounds; the risk is the same for both vaginal and cesarean-section delivery.⁶ Specific risk factors for men include prostate cancer, prostate surgery, and prostate radiation.⁵

Significant, chronic comorbidities of UI include depression and chronic pain. While quality of life is negatively affected by UI alone, the coexistence of depression and UI produces an additive negative effect on quality of life.⁹

Types and treatment of UI

There are 5 types of UI: urge, stress, overflow, functional, and mixed.¹⁰

• Urge incontinence is the leakage of urine following a sensation of sudden urgency to void.
• Stress incontinence is urine leakage associated with increased intra-abdominal pressure such as with coughing or sneezing and is typically associated with weakened pelvic floor musculature.
• Overflow incontinence is more common in men, and is typically caused by prostatic disease. The urethral outlet is obstructed leading to increased pressure within the bladder and subsequent leakage of urine.
• Functional incontinence is caused by physical or cognitive impairment leading to a decreased ability to get to a bathroom quickly enough to void.
• Mixed incontinence is when symptoms of stress and urgency incontinence are present.

There are 3 broad categories of treatment methods for urinary incontinence: behavioral, pharmacologic, and surgical. Behavioral interventions are subdivided into caregiver-dependent (prompted voiding, habit retraining, and timed voiding) and patient-directed (bladder training, pelvic floor muscle training, strategies for bladder control, education, and self-monitoring) techniques. Pharmacologic treatment typically consists of antimuscarinics (eg, oxybutynin, tolterodine, solifenacin) and tricyclic antidepressants (eg, imipramine).¹¹ Injections of onabotulinumtoxinA into the detrusor muscle have also been shown to reduce the symptoms of urinary incontinence.¹² Surgical options for treatment of UI include retro-pubic suspension, slings, and, in some instances, artificial urethral sphincters.¹³

A novel treatment for neurogenic UI?

Despite the many treatments available for UI, none comprehensively addresses UI and its common comorbidities.

The role of duloxetine. Normal micturition is regulated by the somatic nervous system and an autonomic reflex arc; the neurotransmitters serotonin and norepinephrine play an important role in the neural regulation of micturition and urinary continence. Duloxetine, alone or as an adjunctive treatment, is a potential novel therapy that treats 2 common comorbidities of UI—chronic pain and depression.

As a selective serotonin norepinephrine reuptake inhibitor (SNRI), duloxetine acts at the molecular level to block the reuptake of serotonin and norepinephrine from synaptic clefts. Specifically, the medication blocks the 5-hydroxytryptamine (5-HT) reuptake transporters, as well as the norepinephrine transporters, of pre-synaptic neurons.¹⁴ Thus, the concentrations of 5-HT and norepinephrine increase in the synaptic cleft.

Functionally, the accumulation of norepinephrine inhibits micturition by relaxing the detrusor muscle and constricting the urethral smooth muscle. In addition, a higher concentration of 5-HT at the neuromuscular junction leads to constriction of the external urethral sphincter.

Duloxetine has been shown to be effective in the treatment of other types of UI, such as stress UI¹⁵ and mixed UI.¹⁶ Additionally, it was found to be effective when compared with placebo in women with overactive bladder syndrome¹⁷ and in women with multiple sclerosis and depression.¹⁸ However, we are not aware of any cases using duloxetine for the treatment of neurogenic UI.

THE TAKEAWAY

Duloxetine is a potential novel drug choice for the treatment of neurogenic UI. Its effects on serotonin and norepinephrine at the synaptic cleft and neuromuscular junction could provide relief for those who have not found relief from other therapies. Further research—particularly a prospective, randomized controlled trial—is needed to determine if duloxetine is, in fact, more than just a theoretical candidate to treat UI and, if so, the most effective dosing.

Offering duloxetine for the treatment of neurogenic urinary incontinence would potentially address coexisting conditions, such as pain or depression.

Offering duloxetine for the treatment of neurogenic UI would potentially address coexisting conditions—such as pain or depression—thus improving patient compliance and reducing health care spending. Before beginning therapy, urodynamic studies to identify the type of UI should be completed, or, at a minimum, post-void residual volume should be measured.

ACKNOWLEDGEMENTS
The authors would like to thank Julie Hughbanks, MLS, Library Manager, Parkview Health Resource Library, for her assistance with the library searches used for this case report.

THE CASE

A 57-year-old African American woman was being treated at our clinic for neurogenic urinary incontinence (UI). The UI, which occurred day and night, began 2 years earlier following a laminectomy of vertebrae C3 to C6 with spinal fusion of C3 to C7 for cervical spinal stenosis. The UI persisted despite physical therapy and trials of oxybutynin and imipramine. Since the surgery, the patient had also been experiencing chronic (debilitating) neuropathic pain in both legs, and the sensation of incomplete bladder emptying. She denied bowel incontinence or saddle anesthesia. Her prescription medications included hydrocodone-acetaminophen 7.5/325 mg every 6 hours as needed for pain and lisinopril 20 mg/d for essential hypertension. The patient’s body mass index (BMI) was 23.3.

A urine culture initially grew Klebsiella pneumoniae, which we successfully treated with ciprofloxacin. A urinalysis was unremarkable, and blood urea nitrogen and creatinine levels were within normal limits.

We started the patient on oral duloxetine 30 mg/d for her neuropathic pain. The patient hadn’t undergone a urologic evaluation before starting duloxetine, so no urodynamic studies or measurements had been conducted. At that point, we sent the patient to a urologist for an evaluation.

At a follow-up visit with one of our clinic providers <3 months later, the patient reported that the duloxetine was providing her with some pain relief and that she was “waking up dry” in the mornings and having fewer UI symptoms throughout the day, as well as at night. The patient denied any adverse effects such as nausea, gastrointestinal upset, weight changes, xerostomia, fatigue, insomnia, headaches, or dizziness. Duloxetine was titrated up to 60 mg/d for better control of her neuropathic pain. At the next follow-up visit at our clinic 3 months later, her UI was 80% to 90% improved and she was able to stop her opioid pain medications.

DISCUSSION

UI is a significant problem in the United States and around the world. For women, the prevalence of UI ranges from 15% to 69%; among men, the prevalence is 5% to 24%.^1-3 The economic burden of UI includes both medical and nonmedical (eg, pads, diapers, laundry, and dry cleaning) care. The total national cost was estimated at $66 billion in 2007: $49 billion for direct medical costs, $2 billion for direct nonmedical costs, and $15 billion for indirect costs.⁴ And those costs are expected to increase 25% by 2020, mainly because of the aging population.

Risk factors for UI other than gender include advancing age, obesity, non-Hispanic white race, depression, hypertension, type 2 diabetes mellitus, neurologic disease, and functional limitations/general poor health.^5-7 Comorbid depression and BMI >30, as well as the presence and duration of diabetes, increase the odds for developing UI.^7,8

Duloxetine has been shown to be effective for the treatment of stress and mixed urinary incontinence. This case suggests it may be useful for neurogenic urinary incontinence, as well.

Risk factors for women include hysterectomy,⁷ increasing parity, and delivery of at least one infant >9.5 pounds; the risk is the same for both vaginal and cesarean-section delivery.⁶ Specific risk factors for men include prostate cancer, prostate surgery, and prostate radiation.⁵

Significant, chronic comorbidities of UI include depression and chronic pain. While quality of life is negatively affected by UI alone, the coexistence of depression and UI produces an additive negative effect on quality of life.⁹

Types and treatment of UI

There are 5 types of UI: urge, stress, overflow, functional, and mixed.¹⁰

• Urge incontinence is the leakage of urine following a sensation of sudden urgency to void.
• Stress incontinence is urine leakage associated with increased intra-abdominal pressure such as with coughing or sneezing and is typically associated with weakened pelvic floor musculature.
• Overflow incontinence is more common in men, and is typically caused by prostatic disease. The urethral outlet is obstructed leading to increased pressure within the bladder and subsequent leakage of urine.
• Functional incontinence is caused by physical or cognitive impairment leading to a decreased ability to get to a bathroom quickly enough to void.
• Mixed incontinence is when symptoms of stress and urgency incontinence are present.

There are 3 broad categories of treatment methods for urinary incontinence: behavioral, pharmacologic, and surgical. Behavioral interventions are subdivided into caregiver-dependent (prompted voiding, habit retraining, and timed voiding) and patient-directed (bladder training, pelvic floor muscle training, strategies for bladder control, education, and self-monitoring) techniques. Pharmacologic treatment typically consists of antimuscarinics (eg, oxybutynin, tolterodine, solifenacin) and tricyclic antidepressants (eg, imipramine).¹¹ Injections of onabotulinumtoxinA into the detrusor muscle have also been shown to reduce the symptoms of urinary incontinence.¹² Surgical options for treatment of UI include retro-pubic suspension, slings, and, in some instances, artificial urethral sphincters.¹³

A novel treatment for neurogenic UI?

Despite the many treatments available for UI, none comprehensively addresses UI and its common comorbidities.

The role of duloxetine. Normal micturition is regulated by the somatic nervous system and an autonomic reflex arc; the neurotransmitters serotonin and norepinephrine play an important role in the neural regulation of micturition and urinary continence. Duloxetine, alone or as an adjunctive treatment, is a potential novel therapy that treats 2 common comorbidities of UI—chronic pain and depression.

As a selective serotonin norepinephrine reuptake inhibitor (SNRI), duloxetine acts at the molecular level to block the reuptake of serotonin and norepinephrine from synaptic clefts. Specifically, the medication blocks the 5-hydroxytryptamine (5-HT) reuptake transporters, as well as the norepinephrine transporters, of pre-synaptic neurons.¹⁴ Thus, the concentrations of 5-HT and norepinephrine increase in the synaptic cleft.

Functionally, the accumulation of norepinephrine inhibits micturition by relaxing the detrusor muscle and constricting the urethral smooth muscle. In addition, a higher concentration of 5-HT at the neuromuscular junction leads to constriction of the external urethral sphincter.

Duloxetine has been shown to be effective in the treatment of other types of UI, such as stress UI¹⁵ and mixed UI.¹⁶ Additionally, it was found to be effective when compared with placebo in women with overactive bladder syndrome¹⁷ and in women with multiple sclerosis and depression.¹⁸ However, we are not aware of any cases using duloxetine for the treatment of neurogenic UI.

THE TAKEAWAY

Duloxetine is a potential novel drug choice for the treatment of neurogenic UI. Its effects on serotonin and norepinephrine at the synaptic cleft and neuromuscular junction could provide relief for those who have not found relief from other therapies. Further research—particularly a prospective, randomized controlled trial—is needed to determine if duloxetine is, in fact, more than just a theoretical candidate to treat UI and, if so, the most effective dosing.

Offering duloxetine for the treatment of neurogenic urinary incontinence would potentially address coexisting conditions, such as pain or depression.

Offering duloxetine for the treatment of neurogenic UI would potentially address coexisting conditions—such as pain or depression—thus improving patient compliance and reducing health care spending. Before beginning therapy, urodynamic studies to identify the type of UI should be completed, or, at a minimum, post-void residual volume should be measured.

ACKNOWLEDGEMENTS
The authors would like to thank Julie Hughbanks, MLS, Library Manager, Parkview Health Resource Library, for her assistance with the library searches used for this case report.

The Affordable Care Act (aka Obamacare) may soon be out and the American Health Care Act (AHCA) may soon be in. Despite all of the rhetoric about making health care affordable by reducing insurance premiums, one thing has been conspicuously absent from the debate: how we are going to reduce the actual cost of health care. Yes, the AHCA may help reduce premiums, but what is most likely to result is not less expensive health care, but rather people paying less money on premiums and more out of their pockets for medicines and treatments. Especially troublesome is that older and sicker patients will be hit the hardest.

The American conundrum. Why do Americans pay twice what citizens of most other developed nations pay and get health care outcomes that are worse?^1,2 Two reasons are that those who provide health care charge more in this country for services and medications, and physicians do a lot more testing and treatment here than their counterparts abroad.

If we control the cost of providing care, insurance premiums will follow suit.

One expert estimated that up to $700 billion could be saved by eliminating testing and treatments that provide marginal or no value to patients.³ For example, knee arthroscopy for moderate knee osteoarthritis produces no better outcomes than medical management.⁴ And many medications are much more expensive in the United States than in other countries. It seems that pharmaceutical companies are permitted greater profits here than elsewhere in the world, and these profits are at the expense of sick people and taxpayers.

How do we bend the cost curve downward? This is a tough question with no single correct answer, but we can all help. Some health care organizations have already reduced costs significantly without sacrificing quality by using team-based primary care as their foundation. Two examples are Nuka Health and Iora Health.^5,6

As primary care physicians, we are in an ideal position to constrain unnecessary testing and treatments by establishing trusting relationships with patients, who will believe us when we tell them they don’t need an antibiotic for their chest cold or an MRI for their back pain.

If we control the cost of providing care, insurance premiums will follow suit.

The Affordable Care Act (aka Obamacare) may soon be out and the American Health Care Act (AHCA) may soon be in. Despite all of the rhetoric about making health care affordable by reducing insurance premiums, one thing has been conspicuously absent from the debate: how we are going to reduce the actual cost of health care. Yes, the AHCA may help reduce premiums, but what is most likely to result is not less expensive health care, but rather people paying less money on premiums and more out of their pockets for medicines and treatments. Especially troublesome is that older and sicker patients will be hit the hardest.

The American conundrum. Why do Americans pay twice what citizens of most other developed nations pay and get health care outcomes that are worse?^1,2 Two reasons are that those who provide health care charge more in this country for services and medications, and physicians do a lot more testing and treatment here than their counterparts abroad.

If we control the cost of providing care, insurance premiums will follow suit.

One expert estimated that up to $700 billion could be saved by eliminating testing and treatments that provide marginal or no value to patients.³ For example, knee arthroscopy for moderate knee osteoarthritis produces no better outcomes than medical management.⁴ And many medications are much more expensive in the United States than in other countries. It seems that pharmaceutical companies are permitted greater profits here than elsewhere in the world, and these profits are at the expense of sick people and taxpayers.

How do we bend the cost curve downward? This is a tough question with no single correct answer, but we can all help. Some health care organizations have already reduced costs significantly without sacrificing quality by using team-based primary care as their foundation. Two examples are Nuka Health and Iora Health.^5,6

As primary care physicians, we are in an ideal position to constrain unnecessary testing and treatments by establishing trusting relationships with patients, who will believe us when we tell them they don’t need an antibiotic for their chest cold or an MRI for their back pain.

If we control the cost of providing care, insurance premiums will follow suit.

The Affordable Care Act (aka Obamacare) may soon be out and the American Health Care Act (AHCA) may soon be in. Despite all of the rhetoric about making health care affordable by reducing insurance premiums, one thing has been conspicuously absent from the debate: how we are going to reduce the actual cost of health care. Yes, the AHCA may help reduce premiums, but what is most likely to result is not less expensive health care, but rather people paying less money on premiums and more out of their pockets for medicines and treatments. Especially troublesome is that older and sicker patients will be hit the hardest.

The American conundrum. Why do Americans pay twice what citizens of most other developed nations pay and get health care outcomes that are worse?^1,2 Two reasons are that those who provide health care charge more in this country for services and medications, and physicians do a lot more testing and treatment here than their counterparts abroad.

If we control the cost of providing care, insurance premiums will follow suit.

One expert estimated that up to $700 billion could be saved by eliminating testing and treatments that provide marginal or no value to patients.³ For example, knee arthroscopy for moderate knee osteoarthritis produces no better outcomes than medical management.⁴ And many medications are much more expensive in the United States than in other countries. It seems that pharmaceutical companies are permitted greater profits here than elsewhere in the world, and these profits are at the expense of sick people and taxpayers.

How do we bend the cost curve downward? This is a tough question with no single correct answer, but we can all help. Some health care organizations have already reduced costs significantly without sacrificing quality by using team-based primary care as their foundation. Two examples are Nuka Health and Iora Health.^5,6

As primary care physicians, we are in an ideal position to constrain unnecessary testing and treatments by establishing trusting relationships with patients, who will believe us when we tell them they don’t need an antibiotic for their chest cold or an MRI for their back pain.

If we control the cost of providing care, insurance premiums will follow suit.

More than one-third of American adults and approximately 17% of children and adolescents between the ages of 2 and 19 years are obese.^1,2 Poor diet coupled with a sedentary lifestyle is the highest ranked cause of non-communicable disease and a leading cause of preventable death, according to the National Research Council.³

Bariatric surgery (BS) is a viable therapeutic option for obese patients who do not respond to conventional lifestyle interventions for losing weight. There are multiple gastrointestinal (GI) procedures available that are classified as either malabsorptive (Roux-en-Y gastric bypass [RYGB] and biliopancreatic diversion [BPD] with or without duodenal switch) or restrictive (laparoscopic adjustable gastric banding [LAGB] and vertical sleeve gastrectomy [VSG]).

Approximately half of the 196,000 bariatric procedures performed in the United States in 2015 were of the sleeve variety, another 23% were RYGB, and the remaining percentage was divided among the other types.⁴ Postoperative risks include nutritional deficiencies, decreased bone mineral density (BMD), dumping syndrome (when food rapidly dumps from the stomach to the intestine), and gastroesophageal reflux disease (GERD) with possible ulceration.

Despite these potential complications, a systematic review and meta-analysis found that obese people who underwent BS (gastric banding or gastric bypass) had significantly reduced risks of global, non-cardiovascular (CV), and CV mortality compared with obese controls.⁵ Helping patients to realize these benefits requires that the entire health care team—especially the family physician—is aware of the special considerations for this population.

Patients undergoing bariatric surgery require routine lifetime screening for nutritional deficiencies.

To that end, this article reviews the details of diagnosing and managing post-surgical complications. It also addresses issues unique to managing certain subpopulations, such as post-BS patients who require revision surgery or who want to pursue body contouring surgery; adolescents who undergo BS surgery; and women who want to get pregnant postoperatively.

Monitor patients for these post-surgery complications

Postoperative BS follow-up varies depending on location, surgeon preference, and availability of multidisciplinary resources. At our institution, patients have a minimum of 3 follow-up visits with their surgeon (during hospitalization and 2 weeks and 2 months postoperatively). This is followed by visits with Endocrinology 6 months after surgery and annually thereafter. Given the variability of follow-up, family physicians should coordinate with specialists where appropriate and be aware of postoperative complications and monitoring since it is likely they will have the most frequent contact with these patients.

Nutritional deficiencies are common and require lifelong screening

Nutritional deficiencies are the most common complications of malabsorptive BS. Guidelines from the Endocrine Society, as well as guidelines from the American Association of Clinical Endocrinologists (AACE), The Obesity Society (TOS), and the American Society for Metabolic and Bariatric Surgery (ASMBS), recommend routine lifetime screening for deficiencies after surgery.^6,7 Complete blood cell count, electrolytes, glucose, creatinine, and liver function tests should be obtained at one, 3, 6, 12, 18, and 24 months following surgery and annually thereafter.⁶

Multiple factors contribute to nutritional and micronutrient deficiencies, including reduced oral intake of food, decreased GI absorption, food intolerance, nausea/vomiting, and nonadherence with dietary supplements.⁸ Oral supplementation should be in chewable, powder, or liquid form because pill and capsule absorption may be altered.^8,9 Over-the-counter multivitamins may not contain the requisite daily doses recommended after BS.⁹ Patients and physicians should evaluate supplements together to ensure appropriate nutritional and micronutrient supplementation (TABLE 1^6,8-11).

Bone mineral density can start to decrease soon after surgery

Studies evaluating BMD after BS have produced variable findings. In obese patients, dual-energy x-ray absorptiometry (DEXA) measurements may not be accurate due to adipose tissue artifact and table weight limits. In addition, limited data exist on the incidence of fractures after BS. Of 2 notable studies, only one, a population-based study involving 258 Minnesota residents who underwent a first bariatric surgery between 1985 and 2004, demonstrated a significantly increased incidence of fractures.^12,13

In addition, studies show bone turnover markers, including C-terminal telopeptide, increase as early as 3 months after BS.¹⁴ Several guidelines recommend routine BMD screening after BS (TABLE 2).^6,7 The mechanism of bone demineralization is likely multifactorial—a function of the magnitude of the weight loss and skeletal unloading, calcium and vitamin D deficiencies, and associated secondary hyperparathyroidism.¹⁵ Treatment for secondary hyperparathyroidism is adequate supplementation with vitamin D and calcium.

Optimal dosing for vitamin D has not been determined. One recent systematic review suggests routine prophylaxis with at least 2000 international units (IU)/d and found the greatest improvement for known deficiency with doses of 1500-9100 IU/d following malabsorptive surgeries.¹¹ After laparoscopic sleeve gastrectomy, at least 1000 IU/d vitamin D is recommended.¹¹

Overall, high variability exists among patients, and an individualized approach for dosing is recommended.¹¹ Vitamin D levels should be monitored 2 and 4 weeks after initiation of treatment and every 3 months thereafter.¹¹ Normal levels of serum calcium, 25-OH vitamin D, bone-specific alkaline phosphatase, and 24-hour urinary calcium excretion indicate adequate calcium and vitamin D supplementation.⁶

Dumping syndrome can lead to hypoglycemia

Dumping syndrome is a common complication following BS, with prevalence ranging from 25% to 75%, depending upon the type of procedure performed.^16,17 There are 2 types: early and late. Early dumping syndrome occurs within 30 minutes of eating. Symptoms are related to the robust release of gastrointestinal hormones caused by rapid gastric emptying. Symptoms include nausea, abdominal pain, diarrhea, flushing, hypotension, and tachycardia.

Late dumping is characterized as postprandial hypoglycemia occurring one to 3 hours after eating. Late dumping is likely caused by a combination of changes within the pancreatic beta cells and abnormal insulin response to glucose.^16-18 Rapid gastric emptying leads to rapid release of glucose in the gut, which, in turn, leads to brisk insulin secretion. Since glucose is absorbed faster than insulin’s half-life, the resulting (relatively) high levels of insulin may cause hypoglycemia.^16-18

Sigstad’s scoring system can be used to confirm suspected cases of dumping syndrome (TABLE 3^16,17,19). A diagnosis can also be made with an oral glucose challenge in which pulse, blood pressure, glucose, and hematocrit are measured after ingestion of 50 g glucose. The test is positive if heart rate increases by 10 beats per minute, hematocrit increases by 3% 30 minutes after ingestion, or glucose falls below 60 mg/dL 2 to 3 hours after ingestion.¹⁷

First-line treatment of dumping syndrome consists of dietary modifications. The goal is to slow the rate of gastric emptying by eating smaller, more frequent meals; separating beverages from food; decreasing carbohydrates; and increasing fiber and protein content.

If results are suboptimal after dietary changes, medications can be prescribed including acarbose to prevent postprandial hypoglycemia; anticholinergics such as dicyclomine to slow gastric emptying; and somatostatin to decrease gastric emptying and inhibit GI hormone release.¹⁷ Lastly, for resistant and severe postprandial hypoglycemia, a few patients have undergone pancreatectomy, but only about 65% experienced improvement in symptoms and 12% developed diabetes post-surgically.²⁰

Gout attacks may initially increase, but then decrease

BS affects the incidence of gout attacks in patients with a history of gout. One comparative study of approximately 150 patients demonstrated that those with a history of gout had significantly more gout attacks in the first month after BS compared with obese patients with a history of gout undergoing other upper GI surgeries.²¹ There was no difference between malabsorptive and restrictive procedures. But after the first month, BS patients had significantly fewer gout attacks and lower uric acid levels than their obese counterparts.²¹

Protein rich diets, catabolism potentiated by aggressive caloric restriction following BS, and dehydration contribute to the initial increase. Therefore, patients who have had at least one gout attack in the year prior to surgery or who are on hypouricemic medication may benefit from at least one month of prophylactic therapy (eg, allopurinol and colchicine) after surgery.

GERD and ulceration: How to respond

Obesity is a known risk factor for GERD, but the effect of BS on GERD is uncertain and seems to vary with the procedure performed. RYGB decreases GERD and is, therefore, used as both a secondary treatment in those not responding to medications and a revision treatment for fundoplication and other types of BSs. Sleeve gastrectomy and adjustable gastric banding have mixed effects on GERD. A systematic review by de Jong et al revealed a decreased prevalence of reflux symptoms and GERD medication use after LAGB; however, during longer follow-up, 15% of previously unaffected patients reported experiencing GERD.²² The 2011 International Sleeve Gastrectomy Expert Panel Consensus Statement retrospectively noted a postoperative incidence of GERD as high as 31%.²³

BS patients with GERD should be treated with a proton pump inhibitor. If this fails, refer patients to a gastroenterologist for further evaluation.²⁴

Ulcers after BS may be an indication for revision surgery. Data are mixed regarding increased risk of marginal ulceration from nonsteroidal anti-inflammatory drug (NSAID) use, but NSAIDs have been linked to an increased risk of anastomotic leakage.^25-28 Thus, it seems prudent to avoid NSAIDs in people who have undergone BS.

Keeping watch over psychiatric comorbidities

A recent meta-analysis by Dawes et al²⁹ showed that about 23% of patients pursuing BS have a comorbid mood disorder. Specifically, the preoperative prevalence of depression (19%) and binge-eating disorder (17%) were found to be higher than rates in the general population.²⁹ The meta-analysis found improvement in the prevalence of depression with fewer symptoms and less antidepressant medication use in the first 3 years after surgery and a decrease in the rate of binge-eating disorder, although there were fewer supporting data for the latter. These findings were observed with both restrictive and malabsorptive procedures.

The data are mixed regarding rates of alcohol abuse and suicide. Further research is necessary in this field. Patients who have had BS should receive ongoing psychiatric and psychological care from a multidisciplinary team as a matter of course.

Will a second surgery be needed?

Revision surgery. In 2015, about 14% of the almost 200,000 BSs performed were revisions.⁴ Revision surgery is indicated in BS patients with weight regain, recurrent comorbid diseases (eg, diabetes, hypertension), or complications of primary BS. Restrictive procedures have a higher revision rate than malabsorptive procedures, primarily due to a higher rate of weight regain.^6,30

Because revision surgery is associated with more complications and possibly longer hospital stays than primary BS, it should be performed by a bariatric surgeon with extensive experience.^30,31 Restrictive revisions are typically converted to malabsorptive procedures. Cost is a limiting factor as many patients’ insurance coverage is limited to one BS per lifetime.

Body contouring. Body contouring surgery (BCS) can improve physical and mental well-being and may be a protective factor for weight regain after bariatric surgery.³² Despite its desirability—particularly to women, adolescents, and those with large decreases in body mass index (BMI)—few patients can afford BCS since it is rarely covered by insurance.

Complications of BCS vary, but are most commonly infection and wound dehiscence. This is, in part, due to poorer wound healing in BS patients compared to those with nonsurgical massive weight loss. The cause of poor wound healing is thought to be secondary to nutritional deficiencies and the catabolic state induced by post-surgical weight loss. Recommendations for BCS include weight stability for more than one year after BS, age >16 years, excess skin causing significant functional impairment, non-smoking status, and presence of good social support.³³

Bariatric surgery in adolescents is on the rise

Children in the highest body mass index quartile have more than twice the death rate of those in the lowest BMI quartile.³⁴ Thus, it is not surprising that the rate of BS in adolescents is increasing.⁷ BS in this age group is successful for weight loss and improvement of comorbid conditions, with relatively low complication rates.³⁵ Options include malabsorptive and restrictive procedures, although gastric banding has not been approved by the US Food and Drug Administration for patients under the age of 18 years.

Monitor vitamin D levels 2 and 4 weeks after initiation of treatment and every 3 months thereafter.After BS, adolescent girls should be counseled regarding the possibility of pregnancy (restoration of fertility) and appropriate contraception. Adolescent patients require nutritional supplementation after BS as indicated in TABLE 1.^6,8-11

When determining which adolescents to refer for BS, we recommend the following criteria: ^35-38

• failure of a minimum 6-month trial of a staged treatment approach, as recommended by Barlow et al,³⁶ including diet, exercise, and pharmacologic treatment
• BMI ≥35 with type 2 diabetes or severe sleep apnea (apnea hypopnea index [AHI] >15)³⁷
• BMI ≥40 with mild sleep apnea (AHI >5), hypertension, or pre-diabetes³⁷
• Tanner stage IV or V
• at least 95% skeletal growth (for malabsorptive surgery).³⁷ This can be determined using an estimated adult height from mid-parental height formula and assessing growth plate closure with hand radiographs for bone age
• appropriate maturity level permitting adherence
• good psychological support
• a multidisciplinary team for postoperative and long-term follow-up care.

Planning for the future: Exploring the possibility of pregnancy

Obesity is the primary cause of maternal and fetal morbidity during pregnancy. It is associated with increased rates of early miscarriage, congenital defects, macrosomia, and fetal death. Maternal risks of obesity include: gestational hypertension, gestational diabetes mellitus (GDM), and pre-eclampsia. Obese mothers also have a higher incidence of failed induction, caesarean section, and breastfeeding failure.^10,39 Given that half of all BSs are performed in women of reproductive age, this population deserves special consideration.¹⁰

A recent meta-analysis by Galazis et al⁴⁰ concluded that BS performed prior to pregnancy led to decreased rates of preeclampsia, GDM, large neonates, preterm birth, and neonatal intensive care unit admission. Perinatal mortality did not increase after BS. However, BS led to higher rates of maternal anemia. There was no significant difference between groups in incidence of cesarean section.

The post BS female patient should be advised to use a reliable form of contraception for a minimum of 12 to 18 months after surgery.^6,10,39 Involve high-risk obstetric specialists during pregnancies. Diet should be supplemented as indicated in TABLE 1.^6,8-11

CORRESPONDENCE
Amy Rothberg, MD, PhD, Domino’s Farms, Lobby G, Suite 1500, 24 Frank Lloyd Wright Drive, Ann Arbor, MI 48106; [email protected].

More than one-third of American adults and approximately 17% of children and adolescents between the ages of 2 and 19 years are obese.^1,2 Poor diet coupled with a sedentary lifestyle is the highest ranked cause of non-communicable disease and a leading cause of preventable death, according to the National Research Council.³

Bariatric surgery (BS) is a viable therapeutic option for obese patients who do not respond to conventional lifestyle interventions for losing weight. There are multiple gastrointestinal (GI) procedures available that are classified as either malabsorptive (Roux-en-Y gastric bypass [RYGB] and biliopancreatic diversion [BPD] with or without duodenal switch) or restrictive (laparoscopic adjustable gastric banding [LAGB] and vertical sleeve gastrectomy [VSG]).

Approximately half of the 196,000 bariatric procedures performed in the United States in 2015 were of the sleeve variety, another 23% were RYGB, and the remaining percentage was divided among the other types.⁴ Postoperative risks include nutritional deficiencies, decreased bone mineral density (BMD), dumping syndrome (when food rapidly dumps from the stomach to the intestine), and gastroesophageal reflux disease (GERD) with possible ulceration.

Despite these potential complications, a systematic review and meta-analysis found that obese people who underwent BS (gastric banding or gastric bypass) had significantly reduced risks of global, non-cardiovascular (CV), and CV mortality compared with obese controls.⁵ Helping patients to realize these benefits requires that the entire health care team—especially the family physician—is aware of the special considerations for this population.

Patients undergoing bariatric surgery require routine lifetime screening for nutritional deficiencies.

To that end, this article reviews the details of diagnosing and managing post-surgical complications. It also addresses issues unique to managing certain subpopulations, such as post-BS patients who require revision surgery or who want to pursue body contouring surgery; adolescents who undergo BS surgery; and women who want to get pregnant postoperatively.

Monitor patients for these post-surgery complications

Postoperative BS follow-up varies depending on location, surgeon preference, and availability of multidisciplinary resources. At our institution, patients have a minimum of 3 follow-up visits with their surgeon (during hospitalization and 2 weeks and 2 months postoperatively). This is followed by visits with Endocrinology 6 months after surgery and annually thereafter. Given the variability of follow-up, family physicians should coordinate with specialists where appropriate and be aware of postoperative complications and monitoring since it is likely they will have the most frequent contact with these patients.

Nutritional deficiencies are common and require lifelong screening

Nutritional deficiencies are the most common complications of malabsorptive BS. Guidelines from the Endocrine Society, as well as guidelines from the American Association of Clinical Endocrinologists (AACE), The Obesity Society (TOS), and the American Society for Metabolic and Bariatric Surgery (ASMBS), recommend routine lifetime screening for deficiencies after surgery.^6,7 Complete blood cell count, electrolytes, glucose, creatinine, and liver function tests should be obtained at one, 3, 6, 12, 18, and 24 months following surgery and annually thereafter.⁶

Multiple factors contribute to nutritional and micronutrient deficiencies, including reduced oral intake of food, decreased GI absorption, food intolerance, nausea/vomiting, and nonadherence with dietary supplements.⁸ Oral supplementation should be in chewable, powder, or liquid form because pill and capsule absorption may be altered.^8,9 Over-the-counter multivitamins may not contain the requisite daily doses recommended after BS.⁹ Patients and physicians should evaluate supplements together to ensure appropriate nutritional and micronutrient supplementation (TABLE 1^6,8-11).

Bone mineral density can start to decrease soon after surgery

Studies evaluating BMD after BS have produced variable findings. In obese patients, dual-energy x-ray absorptiometry (DEXA) measurements may not be accurate due to adipose tissue artifact and table weight limits. In addition, limited data exist on the incidence of fractures after BS. Of 2 notable studies, only one, a population-based study involving 258 Minnesota residents who underwent a first bariatric surgery between 1985 and 2004, demonstrated a significantly increased incidence of fractures.^12,13

In addition, studies show bone turnover markers, including C-terminal telopeptide, increase as early as 3 months after BS.¹⁴ Several guidelines recommend routine BMD screening after BS (TABLE 2).^6,7 The mechanism of bone demineralization is likely multifactorial—a function of the magnitude of the weight loss and skeletal unloading, calcium and vitamin D deficiencies, and associated secondary hyperparathyroidism.¹⁵ Treatment for secondary hyperparathyroidism is adequate supplementation with vitamin D and calcium.

Optimal dosing for vitamin D has not been determined. One recent systematic review suggests routine prophylaxis with at least 2000 international units (IU)/d and found the greatest improvement for known deficiency with doses of 1500-9100 IU/d following malabsorptive surgeries.¹¹ After laparoscopic sleeve gastrectomy, at least 1000 IU/d vitamin D is recommended.¹¹

Overall, high variability exists among patients, and an individualized approach for dosing is recommended.¹¹ Vitamin D levels should be monitored 2 and 4 weeks after initiation of treatment and every 3 months thereafter.¹¹ Normal levels of serum calcium, 25-OH vitamin D, bone-specific alkaline phosphatase, and 24-hour urinary calcium excretion indicate adequate calcium and vitamin D supplementation.⁶

Dumping syndrome can lead to hypoglycemia

Dumping syndrome is a common complication following BS, with prevalence ranging from 25% to 75%, depending upon the type of procedure performed.^16,17 There are 2 types: early and late. Early dumping syndrome occurs within 30 minutes of eating. Symptoms are related to the robust release of gastrointestinal hormones caused by rapid gastric emptying. Symptoms include nausea, abdominal pain, diarrhea, flushing, hypotension, and tachycardia.

Late dumping is characterized as postprandial hypoglycemia occurring one to 3 hours after eating. Late dumping is likely caused by a combination of changes within the pancreatic beta cells and abnormal insulin response to glucose.^16-18 Rapid gastric emptying leads to rapid release of glucose in the gut, which, in turn, leads to brisk insulin secretion. Since glucose is absorbed faster than insulin’s half-life, the resulting (relatively) high levels of insulin may cause hypoglycemia.^16-18

Sigstad’s scoring system can be used to confirm suspected cases of dumping syndrome (TABLE 3^16,17,19). A diagnosis can also be made with an oral glucose challenge in which pulse, blood pressure, glucose, and hematocrit are measured after ingestion of 50 g glucose. The test is positive if heart rate increases by 10 beats per minute, hematocrit increases by 3% 30 minutes after ingestion, or glucose falls below 60 mg/dL 2 to 3 hours after ingestion.¹⁷

First-line treatment of dumping syndrome consists of dietary modifications. The goal is to slow the rate of gastric emptying by eating smaller, more frequent meals; separating beverages from food; decreasing carbohydrates; and increasing fiber and protein content.

If results are suboptimal after dietary changes, medications can be prescribed including acarbose to prevent postprandial hypoglycemia; anticholinergics such as dicyclomine to slow gastric emptying; and somatostatin to decrease gastric emptying and inhibit GI hormone release.¹⁷ Lastly, for resistant and severe postprandial hypoglycemia, a few patients have undergone pancreatectomy, but only about 65% experienced improvement in symptoms and 12% developed diabetes post-surgically.²⁰

Gout attacks may initially increase, but then decrease

BS affects the incidence of gout attacks in patients with a history of gout. One comparative study of approximately 150 patients demonstrated that those with a history of gout had significantly more gout attacks in the first month after BS compared with obese patients with a history of gout undergoing other upper GI surgeries.²¹ There was no difference between malabsorptive and restrictive procedures. But after the first month, BS patients had significantly fewer gout attacks and lower uric acid levels than their obese counterparts.²¹

Protein rich diets, catabolism potentiated by aggressive caloric restriction following BS, and dehydration contribute to the initial increase. Therefore, patients who have had at least one gout attack in the year prior to surgery or who are on hypouricemic medication may benefit from at least one month of prophylactic therapy (eg, allopurinol and colchicine) after surgery.

GERD and ulceration: How to respond

Obesity is a known risk factor for GERD, but the effect of BS on GERD is uncertain and seems to vary with the procedure performed. RYGB decreases GERD and is, therefore, used as both a secondary treatment in those not responding to medications and a revision treatment for fundoplication and other types of BSs. Sleeve gastrectomy and adjustable gastric banding have mixed effects on GERD. A systematic review by de Jong et al revealed a decreased prevalence of reflux symptoms and GERD medication use after LAGB; however, during longer follow-up, 15% of previously unaffected patients reported experiencing GERD.²² The 2011 International Sleeve Gastrectomy Expert Panel Consensus Statement retrospectively noted a postoperative incidence of GERD as high as 31%.²³

BS patients with GERD should be treated with a proton pump inhibitor. If this fails, refer patients to a gastroenterologist for further evaluation.²⁴

Ulcers after BS may be an indication for revision surgery. Data are mixed regarding increased risk of marginal ulceration from nonsteroidal anti-inflammatory drug (NSAID) use, but NSAIDs have been linked to an increased risk of anastomotic leakage.^25-28 Thus, it seems prudent to avoid NSAIDs in people who have undergone BS.

Keeping watch over psychiatric comorbidities

A recent meta-analysis by Dawes et al²⁹ showed that about 23% of patients pursuing BS have a comorbid mood disorder. Specifically, the preoperative prevalence of depression (19%) and binge-eating disorder (17%) were found to be higher than rates in the general population.²⁹ The meta-analysis found improvement in the prevalence of depression with fewer symptoms and less antidepressant medication use in the first 3 years after surgery and a decrease in the rate of binge-eating disorder, although there were fewer supporting data for the latter. These findings were observed with both restrictive and malabsorptive procedures.

The data are mixed regarding rates of alcohol abuse and suicide. Further research is necessary in this field. Patients who have had BS should receive ongoing psychiatric and psychological care from a multidisciplinary team as a matter of course.

Will a second surgery be needed?

Revision surgery. In 2015, about 14% of the almost 200,000 BSs performed were revisions.⁴ Revision surgery is indicated in BS patients with weight regain, recurrent comorbid diseases (eg, diabetes, hypertension), or complications of primary BS. Restrictive procedures have a higher revision rate than malabsorptive procedures, primarily due to a higher rate of weight regain.^6,30

Because revision surgery is associated with more complications and possibly longer hospital stays than primary BS, it should be performed by a bariatric surgeon with extensive experience.^30,31 Restrictive revisions are typically converted to malabsorptive procedures. Cost is a limiting factor as many patients’ insurance coverage is limited to one BS per lifetime.

Body contouring. Body contouring surgery (BCS) can improve physical and mental well-being and may be a protective factor for weight regain after bariatric surgery.³² Despite its desirability—particularly to women, adolescents, and those with large decreases in body mass index (BMI)—few patients can afford BCS since it is rarely covered by insurance.

Complications of BCS vary, but are most commonly infection and wound dehiscence. This is, in part, due to poorer wound healing in BS patients compared to those with nonsurgical massive weight loss. The cause of poor wound healing is thought to be secondary to nutritional deficiencies and the catabolic state induced by post-surgical weight loss. Recommendations for BCS include weight stability for more than one year after BS, age >16 years, excess skin causing significant functional impairment, non-smoking status, and presence of good social support.³³

Bariatric surgery in adolescents is on the rise

Children in the highest body mass index quartile have more than twice the death rate of those in the lowest BMI quartile.³⁴ Thus, it is not surprising that the rate of BS in adolescents is increasing.⁷ BS in this age group is successful for weight loss and improvement of comorbid conditions, with relatively low complication rates.³⁵ Options include malabsorptive and restrictive procedures, although gastric banding has not been approved by the US Food and Drug Administration for patients under the age of 18 years.

Monitor vitamin D levels 2 and 4 weeks after initiation of treatment and every 3 months thereafter.After BS, adolescent girls should be counseled regarding the possibility of pregnancy (restoration of fertility) and appropriate contraception. Adolescent patients require nutritional supplementation after BS as indicated in TABLE 1.^6,8-11

When determining which adolescents to refer for BS, we recommend the following criteria: ^35-38

• failure of a minimum 6-month trial of a staged treatment approach, as recommended by Barlow et al,³⁶ including diet, exercise, and pharmacologic treatment
• BMI ≥35 with type 2 diabetes or severe sleep apnea (apnea hypopnea index [AHI] >15)³⁷
• BMI ≥40 with mild sleep apnea (AHI >5), hypertension, or pre-diabetes³⁷
• Tanner stage IV or V
• at least 95% skeletal growth (for malabsorptive surgery).³⁷ This can be determined using an estimated adult height from mid-parental height formula and assessing growth plate closure with hand radiographs for bone age
• appropriate maturity level permitting adherence
• good psychological support
• a multidisciplinary team for postoperative and long-term follow-up care.

Planning for the future: Exploring the possibility of pregnancy

Obesity is the primary cause of maternal and fetal morbidity during pregnancy. It is associated with increased rates of early miscarriage, congenital defects, macrosomia, and fetal death. Maternal risks of obesity include: gestational hypertension, gestational diabetes mellitus (GDM), and pre-eclampsia. Obese mothers also have a higher incidence of failed induction, caesarean section, and breastfeeding failure.^10,39 Given that half of all BSs are performed in women of reproductive age, this population deserves special consideration.¹⁰

A recent meta-analysis by Galazis et al⁴⁰ concluded that BS performed prior to pregnancy led to decreased rates of preeclampsia, GDM, large neonates, preterm birth, and neonatal intensive care unit admission. Perinatal mortality did not increase after BS. However, BS led to higher rates of maternal anemia. There was no significant difference between groups in incidence of cesarean section.

The post BS female patient should be advised to use a reliable form of contraception for a minimum of 12 to 18 months after surgery.^6,10,39 Involve high-risk obstetric specialists during pregnancies. Diet should be supplemented as indicated in TABLE 1.^6,8-11

CORRESPONDENCE
Amy Rothberg, MD, PhD, Domino’s Farms, Lobby G, Suite 1500, 24 Frank Lloyd Wright Drive, Ann Arbor, MI 48106; [email protected].

More than one-third of American adults and approximately 17% of children and adolescents between the ages of 2 and 19 years are obese.^1,2 Poor diet coupled with a sedentary lifestyle is the highest ranked cause of non-communicable disease and a leading cause of preventable death, according to the National Research Council.³

Bariatric surgery (BS) is a viable therapeutic option for obese patients who do not respond to conventional lifestyle interventions for losing weight. There are multiple gastrointestinal (GI) procedures available that are classified as either malabsorptive (Roux-en-Y gastric bypass [RYGB] and biliopancreatic diversion [BPD] with or without duodenal switch) or restrictive (laparoscopic adjustable gastric banding [LAGB] and vertical sleeve gastrectomy [VSG]).

Approximately half of the 196,000 bariatric procedures performed in the United States in 2015 were of the sleeve variety, another 23% were RYGB, and the remaining percentage was divided among the other types.⁴ Postoperative risks include nutritional deficiencies, decreased bone mineral density (BMD), dumping syndrome (when food rapidly dumps from the stomach to the intestine), and gastroesophageal reflux disease (GERD) with possible ulceration.

Despite these potential complications, a systematic review and meta-analysis found that obese people who underwent BS (gastric banding or gastric bypass) had significantly reduced risks of global, non-cardiovascular (CV), and CV mortality compared with obese controls.⁵ Helping patients to realize these benefits requires that the entire health care team—especially the family physician—is aware of the special considerations for this population.

Patients undergoing bariatric surgery require routine lifetime screening for nutritional deficiencies.

To that end, this article reviews the details of diagnosing and managing post-surgical complications. It also addresses issues unique to managing certain subpopulations, such as post-BS patients who require revision surgery or who want to pursue body contouring surgery; adolescents who undergo BS surgery; and women who want to get pregnant postoperatively.

Monitor patients for these post-surgery complications

Postoperative BS follow-up varies depending on location, surgeon preference, and availability of multidisciplinary resources. At our institution, patients have a minimum of 3 follow-up visits with their surgeon (during hospitalization and 2 weeks and 2 months postoperatively). This is followed by visits with Endocrinology 6 months after surgery and annually thereafter. Given the variability of follow-up, family physicians should coordinate with specialists where appropriate and be aware of postoperative complications and monitoring since it is likely they will have the most frequent contact with these patients.

Nutritional deficiencies are common and require lifelong screening

Nutritional deficiencies are the most common complications of malabsorptive BS. Guidelines from the Endocrine Society, as well as guidelines from the American Association of Clinical Endocrinologists (AACE), The Obesity Society (TOS), and the American Society for Metabolic and Bariatric Surgery (ASMBS), recommend routine lifetime screening for deficiencies after surgery.^6,7 Complete blood cell count, electrolytes, glucose, creatinine, and liver function tests should be obtained at one, 3, 6, 12, 18, and 24 months following surgery and annually thereafter.⁶

Multiple factors contribute to nutritional and micronutrient deficiencies, including reduced oral intake of food, decreased GI absorption, food intolerance, nausea/vomiting, and nonadherence with dietary supplements.⁸ Oral supplementation should be in chewable, powder, or liquid form because pill and capsule absorption may be altered.^8,9 Over-the-counter multivitamins may not contain the requisite daily doses recommended after BS.⁹ Patients and physicians should evaluate supplements together to ensure appropriate nutritional and micronutrient supplementation (TABLE 1^6,8-11).

Bone mineral density can start to decrease soon after surgery

Studies evaluating BMD after BS have produced variable findings. In obese patients, dual-energy x-ray absorptiometry (DEXA) measurements may not be accurate due to adipose tissue artifact and table weight limits. In addition, limited data exist on the incidence of fractures after BS. Of 2 notable studies, only one, a population-based study involving 258 Minnesota residents who underwent a first bariatric surgery between 1985 and 2004, demonstrated a significantly increased incidence of fractures.^12,13

In addition, studies show bone turnover markers, including C-terminal telopeptide, increase as early as 3 months after BS.¹⁴ Several guidelines recommend routine BMD screening after BS (TABLE 2).^6,7 The mechanism of bone demineralization is likely multifactorial—a function of the magnitude of the weight loss and skeletal unloading, calcium and vitamin D deficiencies, and associated secondary hyperparathyroidism.¹⁵ Treatment for secondary hyperparathyroidism is adequate supplementation with vitamin D and calcium.

Optimal dosing for vitamin D has not been determined. One recent systematic review suggests routine prophylaxis with at least 2000 international units (IU)/d and found the greatest improvement for known deficiency with doses of 1500-9100 IU/d following malabsorptive surgeries.¹¹ After laparoscopic sleeve gastrectomy, at least 1000 IU/d vitamin D is recommended.¹¹

Overall, high variability exists among patients, and an individualized approach for dosing is recommended.¹¹ Vitamin D levels should be monitored 2 and 4 weeks after initiation of treatment and every 3 months thereafter.¹¹ Normal levels of serum calcium, 25-OH vitamin D, bone-specific alkaline phosphatase, and 24-hour urinary calcium excretion indicate adequate calcium and vitamin D supplementation.⁶

Dumping syndrome can lead to hypoglycemia

Dumping syndrome is a common complication following BS, with prevalence ranging from 25% to 75%, depending upon the type of procedure performed.^16,17 There are 2 types: early and late. Early dumping syndrome occurs within 30 minutes of eating. Symptoms are related to the robust release of gastrointestinal hormones caused by rapid gastric emptying. Symptoms include nausea, abdominal pain, diarrhea, flushing, hypotension, and tachycardia.

Late dumping is characterized as postprandial hypoglycemia occurring one to 3 hours after eating. Late dumping is likely caused by a combination of changes within the pancreatic beta cells and abnormal insulin response to glucose.^16-18 Rapid gastric emptying leads to rapid release of glucose in the gut, which, in turn, leads to brisk insulin secretion. Since glucose is absorbed faster than insulin’s half-life, the resulting (relatively) high levels of insulin may cause hypoglycemia.^16-18

Sigstad’s scoring system can be used to confirm suspected cases of dumping syndrome (TABLE 3^16,17,19). A diagnosis can also be made with an oral glucose challenge in which pulse, blood pressure, glucose, and hematocrit are measured after ingestion of 50 g glucose. The test is positive if heart rate increases by 10 beats per minute, hematocrit increases by 3% 30 minutes after ingestion, or glucose falls below 60 mg/dL 2 to 3 hours after ingestion.¹⁷

First-line treatment of dumping syndrome consists of dietary modifications. The goal is to slow the rate of gastric emptying by eating smaller, more frequent meals; separating beverages from food; decreasing carbohydrates; and increasing fiber and protein content.

If results are suboptimal after dietary changes, medications can be prescribed including acarbose to prevent postprandial hypoglycemia; anticholinergics such as dicyclomine to slow gastric emptying; and somatostatin to decrease gastric emptying and inhibit GI hormone release.¹⁷ Lastly, for resistant and severe postprandial hypoglycemia, a few patients have undergone pancreatectomy, but only about 65% experienced improvement in symptoms and 12% developed diabetes post-surgically.²⁰

Gout attacks may initially increase, but then decrease

BS affects the incidence of gout attacks in patients with a history of gout. One comparative study of approximately 150 patients demonstrated that those with a history of gout had significantly more gout attacks in the first month after BS compared with obese patients with a history of gout undergoing other upper GI surgeries.²¹ There was no difference between malabsorptive and restrictive procedures. But after the first month, BS patients had significantly fewer gout attacks and lower uric acid levels than their obese counterparts.²¹

Protein rich diets, catabolism potentiated by aggressive caloric restriction following BS, and dehydration contribute to the initial increase. Therefore, patients who have had at least one gout attack in the year prior to surgery or who are on hypouricemic medication may benefit from at least one month of prophylactic therapy (eg, allopurinol and colchicine) after surgery.

GERD and ulceration: How to respond

Obesity is a known risk factor for GERD, but the effect of BS on GERD is uncertain and seems to vary with the procedure performed. RYGB decreases GERD and is, therefore, used as both a secondary treatment in those not responding to medications and a revision treatment for fundoplication and other types of BSs. Sleeve gastrectomy and adjustable gastric banding have mixed effects on GERD. A systematic review by de Jong et al revealed a decreased prevalence of reflux symptoms and GERD medication use after LAGB; however, during longer follow-up, 15% of previously unaffected patients reported experiencing GERD.²² The 2011 International Sleeve Gastrectomy Expert Panel Consensus Statement retrospectively noted a postoperative incidence of GERD as high as 31%.²³

BS patients with GERD should be treated with a proton pump inhibitor. If this fails, refer patients to a gastroenterologist for further evaluation.²⁴

Ulcers after BS may be an indication for revision surgery. Data are mixed regarding increased risk of marginal ulceration from nonsteroidal anti-inflammatory drug (NSAID) use, but NSAIDs have been linked to an increased risk of anastomotic leakage.^25-28 Thus, it seems prudent to avoid NSAIDs in people who have undergone BS.

Keeping watch over psychiatric comorbidities

A recent meta-analysis by Dawes et al²⁹ showed that about 23% of patients pursuing BS have a comorbid mood disorder. Specifically, the preoperative prevalence of depression (19%) and binge-eating disorder (17%) were found to be higher than rates in the general population.²⁹ The meta-analysis found improvement in the prevalence of depression with fewer symptoms and less antidepressant medication use in the first 3 years after surgery and a decrease in the rate of binge-eating disorder, although there were fewer supporting data for the latter. These findings were observed with both restrictive and malabsorptive procedures.

The data are mixed regarding rates of alcohol abuse and suicide. Further research is necessary in this field. Patients who have had BS should receive ongoing psychiatric and psychological care from a multidisciplinary team as a matter of course.

Will a second surgery be needed?

Revision surgery. In 2015, about 14% of the almost 200,000 BSs performed were revisions.⁴ Revision surgery is indicated in BS patients with weight regain, recurrent comorbid diseases (eg, diabetes, hypertension), or complications of primary BS. Restrictive procedures have a higher revision rate than malabsorptive procedures, primarily due to a higher rate of weight regain.^6,30

Because revision surgery is associated with more complications and possibly longer hospital stays than primary BS, it should be performed by a bariatric surgeon with extensive experience.^30,31 Restrictive revisions are typically converted to malabsorptive procedures. Cost is a limiting factor as many patients’ insurance coverage is limited to one BS per lifetime.

Body contouring. Body contouring surgery (BCS) can improve physical and mental well-being and may be a protective factor for weight regain after bariatric surgery.³² Despite its desirability—particularly to women, adolescents, and those with large decreases in body mass index (BMI)—few patients can afford BCS since it is rarely covered by insurance.

Complications of BCS vary, but are most commonly infection and wound dehiscence. This is, in part, due to poorer wound healing in BS patients compared to those with nonsurgical massive weight loss. The cause of poor wound healing is thought to be secondary to nutritional deficiencies and the catabolic state induced by post-surgical weight loss. Recommendations for BCS include weight stability for more than one year after BS, age >16 years, excess skin causing significant functional impairment, non-smoking status, and presence of good social support.³³

Bariatric surgery in adolescents is on the rise

Children in the highest body mass index quartile have more than twice the death rate of those in the lowest BMI quartile.³⁴ Thus, it is not surprising that the rate of BS in adolescents is increasing.⁷ BS in this age group is successful for weight loss and improvement of comorbid conditions, with relatively low complication rates.³⁵ Options include malabsorptive and restrictive procedures, although gastric banding has not been approved by the US Food and Drug Administration for patients under the age of 18 years.

Monitor vitamin D levels 2 and 4 weeks after initiation of treatment and every 3 months thereafter.After BS, adolescent girls should be counseled regarding the possibility of pregnancy (restoration of fertility) and appropriate contraception. Adolescent patients require nutritional supplementation after BS as indicated in TABLE 1.^6,8-11

When determining which adolescents to refer for BS, we recommend the following criteria: ^35-38

• failure of a minimum 6-month trial of a staged treatment approach, as recommended by Barlow et al,³⁶ including diet, exercise, and pharmacologic treatment
• BMI ≥35 with type 2 diabetes or severe sleep apnea (apnea hypopnea index [AHI] >15)³⁷
• BMI ≥40 with mild sleep apnea (AHI >5), hypertension, or pre-diabetes³⁷
• Tanner stage IV or V
• at least 95% skeletal growth (for malabsorptive surgery).³⁷ This can be determined using an estimated adult height from mid-parental height formula and assessing growth plate closure with hand radiographs for bone age
• appropriate maturity level permitting adherence
• good psychological support
• a multidisciplinary team for postoperative and long-term follow-up care.

Planning for the future: Exploring the possibility of pregnancy

Obesity is the primary cause of maternal and fetal morbidity during pregnancy. It is associated with increased rates of early miscarriage, congenital defects, macrosomia, and fetal death. Maternal risks of obesity include: gestational hypertension, gestational diabetes mellitus (GDM), and pre-eclampsia. Obese mothers also have a higher incidence of failed induction, caesarean section, and breastfeeding failure.^10,39 Given that half of all BSs are performed in women of reproductive age, this population deserves special consideration.¹⁰

A recent meta-analysis by Galazis et al⁴⁰ concluded that BS performed prior to pregnancy led to decreased rates of preeclampsia, GDM, large neonates, preterm birth, and neonatal intensive care unit admission. Perinatal mortality did not increase after BS. However, BS led to higher rates of maternal anemia. There was no significant difference between groups in incidence of cesarean section.

The post BS female patient should be advised to use a reliable form of contraception for a minimum of 12 to 18 months after surgery.^6,10,39 Involve high-risk obstetric specialists during pregnancies. Diet should be supplemented as indicated in TABLE 1.^6,8-11

CORRESPONDENCE
Amy Rothberg, MD, PhD, Domino’s Farms, Lobby G, Suite 1500, 24 Frank Lloyd Wright Drive, Ann Arbor, MI 48106; [email protected].

ILLUSTRATIVE CASE

A 34-year-old woman presents to your office for unbearable sweating. She notes that the sweating occurs nearly daily on her hands, face, and in her axillary regions, causing social embarrassment. She has tried multiple antiperspirants to no avail. Is there anything she can take to reduce the sweating?

Hyperhidrosis is a common, self-limiting problem affecting 2% to 3% of the population in the United States.² Patients may complain of localized sweating of the hands, feet, face, or underarms or more systemic, generalized sweating in multiple locations. Either way, patients always note a significant impact on their quality of life.

Treatment of hyperhidrosis has traditionally focused on topical therapies to the affected areas. Research has shown that localized treatment with antiperspirants containing aluminum salt is effective by both subjective report and objective measurements at reducing sweating—particularly in the axilla, hands, and feet.^3,4 Additionally, a systematic review of observational and experimental studies found topical glycopyrrolate to be efficacious for craniofacial hyperhidrosis with minimal adverse effects.⁵ The availability of low-cost prescription and over-the-counter aluminum-based antiperspirant agents makes topicals the first-line choice.

More invasive treatments are available for hyperhidrosis that is refractory to topicals. In a double-blind, randomized controlled trial, researchers injected either botulinum toxin type A (BTX-A) 50 U or placebo in patients with bilateral primary axillary hyperhidrosis.⁶ Of the 207 patients who received treatment injections, 96.1% had at least a 50% reduction of axillary sweating at 4 weeks after one injection, as measured by gravimetric assessment. The BTX-A injections also produced a prolonged effect; mean duration between injections was 30.6 weeks.

Other invasive treatments include iontophoresis, surgery, and laser therapy; however, these methods are not suitable for body-wide application and are, thus, not appropriate for patients with generalized hyperhidrosis.

Oxybutynin is the first oral agent to emerge as a treatment option for hyperhidrosis. This cholinergic antagonist had historically been used to treat overactive bladder. As a cholinergic antagonist, oxybutynin not only reduces urinary frequency, but also decreases secretions in various locations and, thus, can cause dry mouth and reduce perspiration.

In one prospective placebo-controlled trial, 50 patients with generalized hyperhidrosis were randomized to receive either oxybutynin titrated from 2.5 mg orally once daily to 5 mg orally twice daily or placebo for 6 weeks.⁷ Seventeen (73.9%) patients receiving oxybutynin for palmar or axillary hyperhidrosis reported moderate to “great” resolution of their symptoms compared with 6 (27.3%) patients in the placebo group. Dry mouth was reported in 34.8% of patients receiving oxybutynin vs 9.1% of those who received placebo (P=.038); however, no patients dropped out of the study due to this adverse effect.⁷

STUDY SUMMARY

This multicenter, randomized controlled trial compared oxybutynin to placebo in 62 adults with localized or generalized hyperhidrosis from 12 outpatient dermatology practices in France. It is the first study to include patients with a localized, as well as a generalized form of the condition.

Patients were included if they were >18 years of age, enrolled in the National Health Insurance system in France, and reported a Hyperhidrosis Disease Severity Scale (HDSS) score ≥2. The HDSS is a validated, one-question tool (“How would you rate the severity of your sweating?”). Patients provide a score of 1 (no perceptible sweating and no interference with everyday life) to 4 (intolerable sweating with constant interference with everyday life).⁸ Patients were excluded if they had any contraindications to the use of an anticholinergic medication.

This trial used a relatively low dose of oxybutynin, which produced significant benefit while minimizing anticholinergic adverse effects.

Patients randomized to oxybutynin took 2.5 mg/d orally initially and increased gradually over 8 days until reaching an effective dose that was not more than 7.5 mg/d. They then continued at that dose for 6 weeks. The primary outcome was improvement on the HDSS by one or more points measured at the beginning of the trial and at 6 weeks. Secondary outcomes included change in quality of life, as measured by the Dermatology Life Quality Index (DLQI) and reported adverse effects. The DLQI is a dermatology-specific quality-of-life measure consisting of 10 questions. Scores range from 0 (where their disease has no impact on their quality of life) to 30 (maximum impact of their disease on their quality of life).⁹

Improved HDSS and DLQI scores. Most patients (83%) in the study had generalized hyperhidrosis. Patients were in their mid-thirties. Sixty percent of the patients in the oxybutynin group had an improvement of one point or more on the 4-point HDSS compared to 27% in the placebo group (P<.01). DLQI scores improved by 6.9 points in the oxybutynin group and 2.3 points in the placebo group (P<.01).

The most common adverse effect was dry mouth, which occurred in 13 patients (43%) in the oxybutynin group and in 3 patients (11%) in the placebo group (P<.01); it did not cause any patients to drop out of the study. The second most common adverse effect was blurred vision, which only occurred in the oxybutynin group (4 patients; 13%).

WHAT'S NEW

This is the first randomized controlled trial to demonstrate the efficacy of an oral agent for generalized primary hyperhidrosis. This trial used a relatively low dose of oxybutynin, which produced significant benefit while minimizing anticholinergic adverse effects.

CAVEATS

There are many situations for which anticholinergic medications are inappropriate, including use by geriatric patients and those with gastrointestinal disorders, urinary retention, or glaucoma.

CHALLENGES TO IMPLEMENTATION

Few if any challenges exist to the utilization of oxybutynin; inexpensive generic versions are widely available.

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 34-year-old woman presents to your office for unbearable sweating. She notes that the sweating occurs nearly daily on her hands, face, and in her axillary regions, causing social embarrassment. She has tried multiple antiperspirants to no avail. Is there anything she can take to reduce the sweating?

Hyperhidrosis is a common, self-limiting problem affecting 2% to 3% of the population in the United States.² Patients may complain of localized sweating of the hands, feet, face, or underarms or more systemic, generalized sweating in multiple locations. Either way, patients always note a significant impact on their quality of life.

Treatment of hyperhidrosis has traditionally focused on topical therapies to the affected areas. Research has shown that localized treatment with antiperspirants containing aluminum salt is effective by both subjective report and objective measurements at reducing sweating—particularly in the axilla, hands, and feet.^3,4 Additionally, a systematic review of observational and experimental studies found topical glycopyrrolate to be efficacious for craniofacial hyperhidrosis with minimal adverse effects.⁵ The availability of low-cost prescription and over-the-counter aluminum-based antiperspirant agents makes topicals the first-line choice.

More invasive treatments are available for hyperhidrosis that is refractory to topicals. In a double-blind, randomized controlled trial, researchers injected either botulinum toxin type A (BTX-A) 50 U or placebo in patients with bilateral primary axillary hyperhidrosis.⁶ Of the 207 patients who received treatment injections, 96.1% had at least a 50% reduction of axillary sweating at 4 weeks after one injection, as measured by gravimetric assessment. The BTX-A injections also produced a prolonged effect; mean duration between injections was 30.6 weeks.

Other invasive treatments include iontophoresis, surgery, and laser therapy; however, these methods are not suitable for body-wide application and are, thus, not appropriate for patients with generalized hyperhidrosis.

Oxybutynin is the first oral agent to emerge as a treatment option for hyperhidrosis. This cholinergic antagonist had historically been used to treat overactive bladder. As a cholinergic antagonist, oxybutynin not only reduces urinary frequency, but also decreases secretions in various locations and, thus, can cause dry mouth and reduce perspiration.

In one prospective placebo-controlled trial, 50 patients with generalized hyperhidrosis were randomized to receive either oxybutynin titrated from 2.5 mg orally once daily to 5 mg orally twice daily or placebo for 6 weeks.⁷ Seventeen (73.9%) patients receiving oxybutynin for palmar or axillary hyperhidrosis reported moderate to “great” resolution of their symptoms compared with 6 (27.3%) patients in the placebo group. Dry mouth was reported in 34.8% of patients receiving oxybutynin vs 9.1% of those who received placebo (P=.038); however, no patients dropped out of the study due to this adverse effect.⁷

STUDY SUMMARY

This multicenter, randomized controlled trial compared oxybutynin to placebo in 62 adults with localized or generalized hyperhidrosis from 12 outpatient dermatology practices in France. It is the first study to include patients with a localized, as well as a generalized form of the condition.

Patients were included if they were >18 years of age, enrolled in the National Health Insurance system in France, and reported a Hyperhidrosis Disease Severity Scale (HDSS) score ≥2. The HDSS is a validated, one-question tool (“How would you rate the severity of your sweating?”). Patients provide a score of 1 (no perceptible sweating and no interference with everyday life) to 4 (intolerable sweating with constant interference with everyday life).⁸ Patients were excluded if they had any contraindications to the use of an anticholinergic medication.

This trial used a relatively low dose of oxybutynin, which produced significant benefit while minimizing anticholinergic adverse effects.

Patients randomized to oxybutynin took 2.5 mg/d orally initially and increased gradually over 8 days until reaching an effective dose that was not more than 7.5 mg/d. They then continued at that dose for 6 weeks. The primary outcome was improvement on the HDSS by one or more points measured at the beginning of the trial and at 6 weeks. Secondary outcomes included change in quality of life, as measured by the Dermatology Life Quality Index (DLQI) and reported adverse effects. The DLQI is a dermatology-specific quality-of-life measure consisting of 10 questions. Scores range from 0 (where their disease has no impact on their quality of life) to 30 (maximum impact of their disease on their quality of life).⁹

Improved HDSS and DLQI scores. Most patients (83%) in the study had generalized hyperhidrosis. Patients were in their mid-thirties. Sixty percent of the patients in the oxybutynin group had an improvement of one point or more on the 4-point HDSS compared to 27% in the placebo group (P<.01). DLQI scores improved by 6.9 points in the oxybutynin group and 2.3 points in the placebo group (P<.01).

The most common adverse effect was dry mouth, which occurred in 13 patients (43%) in the oxybutynin group and in 3 patients (11%) in the placebo group (P<.01); it did not cause any patients to drop out of the study. The second most common adverse effect was blurred vision, which only occurred in the oxybutynin group (4 patients; 13%).

WHAT'S NEW

This is the first randomized controlled trial to demonstrate the efficacy of an oral agent for generalized primary hyperhidrosis. This trial used a relatively low dose of oxybutynin, which produced significant benefit while minimizing anticholinergic adverse effects.

CAVEATS

There are many situations for which anticholinergic medications are inappropriate, including use by geriatric patients and those with gastrointestinal disorders, urinary retention, or glaucoma.

CHALLENGES TO IMPLEMENTATION

Few if any challenges exist to the utilization of oxybutynin; inexpensive generic versions are widely available.

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 34-year-old woman presents to your office for unbearable sweating. She notes that the sweating occurs nearly daily on her hands, face, and in her axillary regions, causing social embarrassment. She has tried multiple antiperspirants to no avail. Is there anything she can take to reduce the sweating?

Hyperhidrosis is a common, self-limiting problem affecting 2% to 3% of the population in the United States.² Patients may complain of localized sweating of the hands, feet, face, or underarms or more systemic, generalized sweating in multiple locations. Either way, patients always note a significant impact on their quality of life.

Treatment of hyperhidrosis has traditionally focused on topical therapies to the affected areas. Research has shown that localized treatment with antiperspirants containing aluminum salt is effective by both subjective report and objective measurements at reducing sweating—particularly in the axilla, hands, and feet.^3,4 Additionally, a systematic review of observational and experimental studies found topical glycopyrrolate to be efficacious for craniofacial hyperhidrosis with minimal adverse effects.⁵ The availability of low-cost prescription and over-the-counter aluminum-based antiperspirant agents makes topicals the first-line choice.

More invasive treatments are available for hyperhidrosis that is refractory to topicals. In a double-blind, randomized controlled trial, researchers injected either botulinum toxin type A (BTX-A) 50 U or placebo in patients with bilateral primary axillary hyperhidrosis.⁶ Of the 207 patients who received treatment injections, 96.1% had at least a 50% reduction of axillary sweating at 4 weeks after one injection, as measured by gravimetric assessment. The BTX-A injections also produced a prolonged effect; mean duration between injections was 30.6 weeks.

Other invasive treatments include iontophoresis, surgery, and laser therapy; however, these methods are not suitable for body-wide application and are, thus, not appropriate for patients with generalized hyperhidrosis.

Oxybutynin is the first oral agent to emerge as a treatment option for hyperhidrosis. This cholinergic antagonist had historically been used to treat overactive bladder. As a cholinergic antagonist, oxybutynin not only reduces urinary frequency, but also decreases secretions in various locations and, thus, can cause dry mouth and reduce perspiration.

In one prospective placebo-controlled trial, 50 patients with generalized hyperhidrosis were randomized to receive either oxybutynin titrated from 2.5 mg orally once daily to 5 mg orally twice daily or placebo for 6 weeks.⁷ Seventeen (73.9%) patients receiving oxybutynin for palmar or axillary hyperhidrosis reported moderate to “great” resolution of their symptoms compared with 6 (27.3%) patients in the placebo group. Dry mouth was reported in 34.8% of patients receiving oxybutynin vs 9.1% of those who received placebo (P=.038); however, no patients dropped out of the study due to this adverse effect.⁷

STUDY SUMMARY

This multicenter, randomized controlled trial compared oxybutynin to placebo in 62 adults with localized or generalized hyperhidrosis from 12 outpatient dermatology practices in France. It is the first study to include patients with a localized, as well as a generalized form of the condition.

Patients were included if they were >18 years of age, enrolled in the National Health Insurance system in France, and reported a Hyperhidrosis Disease Severity Scale (HDSS) score ≥2. The HDSS is a validated, one-question tool (“How would you rate the severity of your sweating?”). Patients provide a score of 1 (no perceptible sweating and no interference with everyday life) to 4 (intolerable sweating with constant interference with everyday life).⁸ Patients were excluded if they had any contraindications to the use of an anticholinergic medication.

This trial used a relatively low dose of oxybutynin, which produced significant benefit while minimizing anticholinergic adverse effects.

Patients randomized to oxybutynin took 2.5 mg/d orally initially and increased gradually over 8 days until reaching an effective dose that was not more than 7.5 mg/d. They then continued at that dose for 6 weeks. The primary outcome was improvement on the HDSS by one or more points measured at the beginning of the trial and at 6 weeks. Secondary outcomes included change in quality of life, as measured by the Dermatology Life Quality Index (DLQI) and reported adverse effects. The DLQI is a dermatology-specific quality-of-life measure consisting of 10 questions. Scores range from 0 (where their disease has no impact on their quality of life) to 30 (maximum impact of their disease on their quality of life).⁹

Improved HDSS and DLQI scores. Most patients (83%) in the study had generalized hyperhidrosis. Patients were in their mid-thirties. Sixty percent of the patients in the oxybutynin group had an improvement of one point or more on the 4-point HDSS compared to 27% in the placebo group (P<.01). DLQI scores improved by 6.9 points in the oxybutynin group and 2.3 points in the placebo group (P<.01).

The most common adverse effect was dry mouth, which occurred in 13 patients (43%) in the oxybutynin group and in 3 patients (11%) in the placebo group (P<.01); it did not cause any patients to drop out of the study. The second most common adverse effect was blurred vision, which only occurred in the oxybutynin group (4 patients; 13%).

WHAT'S NEW

This is the first randomized controlled trial to demonstrate the efficacy of an oral agent for generalized primary hyperhidrosis. This trial used a relatively low dose of oxybutynin, which produced significant benefit while minimizing anticholinergic adverse effects.

CAVEATS

There are many situations for which anticholinergic medications are inappropriate, including use by geriatric patients and those with gastrointestinal disorders, urinary retention, or glaucoma.

CHALLENGES TO IMPLEMENTATION

Few if any challenges exist to the utilization of oxybutynin; inexpensive generic versions are widely available.

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.

A 63-year-old woman with a 3-year history of osteoporosis presented to our clinic with a 2-week history of severe right hip pain. She had been taking a bisphosphonate—oral ibandronate sodium, 150 mg, once monthly—for about 6 years. The postmenopausal patient had a history of degenerative disc disease and lumbar back pain, but no known history of recent trauma or falls.

A clinical exam revealed full passive and active range of motion; however, she had pain with weight bearing. A full metabolic panel revealed no significant abnormalities. A leg length discrepancy was noted, so a bone length study was ordered. Anteroposterior x-rays of the bilateral lower extremities demonstrated a focal convexity along the lateral cortical junction of the proximal right femur (FIGURE).

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

Dx: Bisphosphonate-associated proximal insufficiency fracture

Based on the patient’s clinical history and x-ray findings, we determined that the patient had sustained a bisphosphonate-associated proximal femoral insufficiency fracture. Insufficiency fractures arise from normal physi­­ologic stress on abnormal bone. They commonly occur in conditions that impair normal bone physiology and remodeling, such as osteoporosis, renal insufficiency, rheumatoid arthritis, and diabetes.¹

Could a bisphosphonate be to blame? Bisphosphonate therapy has been associated with significant benefits, including increased bone mineral density (BMD), decreased incidence of fracture, and improved mortality.^2-4 But it’s been postulated that the global suppression of bone turnover caused by these drugs may also impair the bone remodeling process.⁵ Some case reports have suggested an association between chronic bisphosphonate use and atypical insufficiency fractures. These atypical femur fractures are characterized by their location (along the diaphysis in the region distal to the lesser trochanter), the patient’s history (there may be minimal to no trauma), and the potential for “beaking” (localized periosteal or endosteal thickening of the lateral cortex).^6,7

Bisphosphonate therapy has been associated with significant benefits, but it’s been suggested that these drugs may impair the bone remodeling process.

Several large, population-based, case-control studies have found a temporal relationship between bisphosphonate therapy and a statistically significant increased risk of subtrochanteric fractures.^8-10 These studies do note, however, that the absolute risk of insufficiency fracture is very low, and that the benefits of bisphosphonate therapy greatly outweigh the risks. A 2013 meta-analysis came to the same conclusion.¹¹

Treatment options include PT, surgical intervention

When an insufficiency fracture is identified in a patient taking a bisphosphonate, the medication should be discontinued and a consultation with Endocrinology should be arranged. Nonsurgical management ranges from physical therapy to alternative medication regimens, such as teriparatide—a recombinant human parathyroid hormone used to restore bone quality. A variety of surgical stabilization options are also available.⁶

In contrast to typical subtrochanteric fractures, about half of patients with atypical insufficiency fractures demonstrate poor fracture healing that requires surgical intervention.¹² Complete fractures almost always require surgery, while incomplete subtrochanteric femur fractures can usually be managed conservatively by altering pharmacologic prophylaxis (interval dosing or discontinuation of the bisphosphonate and initiation of an alternative therapy like teriparatide) in conjunction with routine radiologic surveillance. Internal fixation may be considered for cases of persistent pain or those that progress to an unstable fracture.¹³

Our patient declined surgical intervention. We switched her monthly ibandronate dosage to a periodic dosing schedule (6 months on, followed by 6 months off) and advised her to rest and take nonsteroidal anti-inflammatory drugs when needed. While consensus guidelines exist for the management of osteoporosis (see Osteoporosis: Assessing your patient’s risk), there is still debate over the optimal length of bisphosphonate therapy and the impact of drug holidays; a recent review in The BMJ discusses bisphosphonate use in detail.⁵

Follow-up x-rays 14 months later revealed that the insufficiency fracture had healed with a bony callus.

CORRESPONDENCE
Joseph S. McMonagle, MD, Eastern Virginia Medical School, Department of Radiology, P.O. Box 1980, Norfolk, VA; [email protected].

A 63-year-old woman with a 3-year history of osteoporosis presented to our clinic with a 2-week history of severe right hip pain. She had been taking a bisphosphonate—oral ibandronate sodium, 150 mg, once monthly—for about 6 years. The postmenopausal patient had a history of degenerative disc disease and lumbar back pain, but no known history of recent trauma or falls.

A clinical exam revealed full passive and active range of motion; however, she had pain with weight bearing. A full metabolic panel revealed no significant abnormalities. A leg length discrepancy was noted, so a bone length study was ordered. Anteroposterior x-rays of the bilateral lower extremities demonstrated a focal convexity along the lateral cortical junction of the proximal right femur (FIGURE).

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

Dx: Bisphosphonate-associated proximal insufficiency fracture

Based on the patient’s clinical history and x-ray findings, we determined that the patient had sustained a bisphosphonate-associated proximal femoral insufficiency fracture. Insufficiency fractures arise from normal physi­­ologic stress on abnormal bone. They commonly occur in conditions that impair normal bone physiology and remodeling, such as osteoporosis, renal insufficiency, rheumatoid arthritis, and diabetes.¹

Could a bisphosphonate be to blame? Bisphosphonate therapy has been associated with significant benefits, including increased bone mineral density (BMD), decreased incidence of fracture, and improved mortality.^2-4 But it’s been postulated that the global suppression of bone turnover caused by these drugs may also impair the bone remodeling process.⁵ Some case reports have suggested an association between chronic bisphosphonate use and atypical insufficiency fractures. These atypical femur fractures are characterized by their location (along the diaphysis in the region distal to the lesser trochanter), the patient’s history (there may be minimal to no trauma), and the potential for “beaking” (localized periosteal or endosteal thickening of the lateral cortex).^6,7

Bisphosphonate therapy has been associated with significant benefits, but it’s been suggested that these drugs may impair the bone remodeling process.

Several large, population-based, case-control studies have found a temporal relationship between bisphosphonate therapy and a statistically significant increased risk of subtrochanteric fractures.^8-10 These studies do note, however, that the absolute risk of insufficiency fracture is very low, and that the benefits of bisphosphonate therapy greatly outweigh the risks. A 2013 meta-analysis came to the same conclusion.¹¹

Treatment options include PT, surgical intervention

When an insufficiency fracture is identified in a patient taking a bisphosphonate, the medication should be discontinued and a consultation with Endocrinology should be arranged. Nonsurgical management ranges from physical therapy to alternative medication regimens, such as teriparatide—a recombinant human parathyroid hormone used to restore bone quality. A variety of surgical stabilization options are also available.⁶

In contrast to typical subtrochanteric fractures, about half of patients with atypical insufficiency fractures demonstrate poor fracture healing that requires surgical intervention.¹² Complete fractures almost always require surgery, while incomplete subtrochanteric femur fractures can usually be managed conservatively by altering pharmacologic prophylaxis (interval dosing or discontinuation of the bisphosphonate and initiation of an alternative therapy like teriparatide) in conjunction with routine radiologic surveillance. Internal fixation may be considered for cases of persistent pain or those that progress to an unstable fracture.¹³

Our patient declined surgical intervention. We switched her monthly ibandronate dosage to a periodic dosing schedule (6 months on, followed by 6 months off) and advised her to rest and take nonsteroidal anti-inflammatory drugs when needed. While consensus guidelines exist for the management of osteoporosis (see Osteoporosis: Assessing your patient’s risk), there is still debate over the optimal length of bisphosphonate therapy and the impact of drug holidays; a recent review in The BMJ discusses bisphosphonate use in detail.⁵

Follow-up x-rays 14 months later revealed that the insufficiency fracture had healed with a bony callus.

CORRESPONDENCE
Joseph S. McMonagle, MD, Eastern Virginia Medical School, Department of Radiology, P.O. Box 1980, Norfolk, VA; [email protected].

A 63-year-old woman with a 3-year history of osteoporosis presented to our clinic with a 2-week history of severe right hip pain. She had been taking a bisphosphonate—oral ibandronate sodium, 150 mg, once monthly—for about 6 years. The postmenopausal patient had a history of degenerative disc disease and lumbar back pain, but no known history of recent trauma or falls.

A clinical exam revealed full passive and active range of motion; however, she had pain with weight bearing. A full metabolic panel revealed no significant abnormalities. A leg length discrepancy was noted, so a bone length study was ordered. Anteroposterior x-rays of the bilateral lower extremities demonstrated a focal convexity along the lateral cortical junction of the proximal right femur (FIGURE).

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

Dx: Bisphosphonate-associated proximal insufficiency fracture

Based on the patient’s clinical history and x-ray findings, we determined that the patient had sustained a bisphosphonate-associated proximal femoral insufficiency fracture. Insufficiency fractures arise from normal physi­­ologic stress on abnormal bone. They commonly occur in conditions that impair normal bone physiology and remodeling, such as osteoporosis, renal insufficiency, rheumatoid arthritis, and diabetes.¹

Could a bisphosphonate be to blame? Bisphosphonate therapy has been associated with significant benefits, including increased bone mineral density (BMD), decreased incidence of fracture, and improved mortality.^2-4 But it’s been postulated that the global suppression of bone turnover caused by these drugs may also impair the bone remodeling process.⁵ Some case reports have suggested an association between chronic bisphosphonate use and atypical insufficiency fractures. These atypical femur fractures are characterized by their location (along the diaphysis in the region distal to the lesser trochanter), the patient’s history (there may be minimal to no trauma), and the potential for “beaking” (localized periosteal or endosteal thickening of the lateral cortex).^6,7

Bisphosphonate therapy has been associated with significant benefits, but it’s been suggested that these drugs may impair the bone remodeling process.

Several large, population-based, case-control studies have found a temporal relationship between bisphosphonate therapy and a statistically significant increased risk of subtrochanteric fractures.^8-10 These studies do note, however, that the absolute risk of insufficiency fracture is very low, and that the benefits of bisphosphonate therapy greatly outweigh the risks. A 2013 meta-analysis came to the same conclusion.¹¹

Treatment options include PT, surgical intervention

When an insufficiency fracture is identified in a patient taking a bisphosphonate, the medication should be discontinued and a consultation with Endocrinology should be arranged. Nonsurgical management ranges from physical therapy to alternative medication regimens, such as teriparatide—a recombinant human parathyroid hormone used to restore bone quality. A variety of surgical stabilization options are also available.⁶

In contrast to typical subtrochanteric fractures, about half of patients with atypical insufficiency fractures demonstrate poor fracture healing that requires surgical intervention.¹² Complete fractures almost always require surgery, while incomplete subtrochanteric femur fractures can usually be managed conservatively by altering pharmacologic prophylaxis (interval dosing or discontinuation of the bisphosphonate and initiation of an alternative therapy like teriparatide) in conjunction with routine radiologic surveillance. Internal fixation may be considered for cases of persistent pain or those that progress to an unstable fracture.¹³

Our patient declined surgical intervention. We switched her monthly ibandronate dosage to a periodic dosing schedule (6 months on, followed by 6 months off) and advised her to rest and take nonsteroidal anti-inflammatory drugs when needed. While consensus guidelines exist for the management of osteoporosis (see Osteoporosis: Assessing your patient’s risk), there is still debate over the optimal length of bisphosphonate therapy and the impact of drug holidays; a recent review in The BMJ discusses bisphosphonate use in detail.⁵

Follow-up x-rays 14 months later revealed that the insufficiency fracture had healed with a bony callus.

CORRESPONDENCE
Joseph S. McMonagle, MD, Eastern Virginia Medical School, Department of Radiology, P.O. Box 1980, Norfolk, VA; [email protected].

THE CASE

A 23-year-old woman seeks medical attention at the request of her boyfriend because she’s been “miserable” for 3 weeks. In the examination room, she slouches in the chair and says her mood is low, her grades have dropped, and she no longer enjoys social gatherings or her other usual activities. She has no thoughts of suicide, no weight loss, and no somatic symptoms.

She says she is generally healthy, does not take any regular medications, and has never been pregnant. When asked about previous similar episodes, she admits to feeling this way about 3 times a year for one to 2 months at a time. She has tried different antidepressants, which haven’t helped much and have made her irritable and interfered with sleep.

When asked about mania or hypomania, she says there are short periods, roughly a couple of weeks 2 or 3 times a year, when she will get a lot of work done and can get by with little sleep. She has never gone on “spending sprees,” though, or indulged in any other unusual or dangerous behavior. And she has never been hospitalized for symptoms.

HOW WOULD YOU PROCEED WITH THIS PATIENT?

Bipolar disorders, over time, typically cause fluctuations in mood, activity, and energy level. If disorders go untreated, a patient’s behavior may cause considerable damage to relationships, finances, and reputations. And for some patients, the disorder can take the ultimate toll, resulting in death by suicide or accident.

Subtypes of bipolar disorder differ in the timing and severity of manic (or hypomanic) and depressive symptoms or episodes. Type I is the classic manic-depressive illness; type II is characterized by chronic treatment-resistant depression punctuated by hypomanic episodes; and cyclothymia leads to chronic fluctuations in mood. The diagnostic category “bipolar disorder not otherwise specified” applies to patients who meet some, but not all, of the criteria for other bipolar disorder subtypes.¹

Prevalence. As with other mood symptoms or disorders, patients with bipolar disorder are often seen first in primary care due, in part, to barriers to obtaining psychiatric care or to avoidance of the perceived stigma in seeking such care.² In a systematic review of patients who were interviewed randomly in primary care settings, 0.5% to 4.3% met criteria for bipolar disorder.³ The average age of onset for bipolar disorder is 15 to 19 years.⁴ In the United States, the prevalence of bipolar disorder type I is 1%; type II is 1.1%.³

The cause of bipolar disorder is unknown, but familial predisposition, biopsychosocial factors, and environment all seem to play a role. Children of parents with bipolar disorder have a 4% to 15% chance of receiving the same diagnosis, compared with children of parents without bipolar disorder, whose risk is only as high as 2%.^5,6

Clinical presentation varies

When patients with bipolar disorder are first seen in the office, their state may be depression, mania, hypomania, or even euthymia. Keep in mind that the first 3 aberrations may indicate other disorders, either psychiatric (TABLE 1)^1,4 or medical (eg, hyperthyroidism, delirium).

Verify a true depressive episode

Symptoms must last for 2 weeks and include anhedonia or depressed mood, as well as some combination of changes in sleep, increased feelings of guilt, poor concentration, changes in appetite, loss of energy, psychomotor agitation or retardation, or suicidal thoughts.¹

Know the criteria for mania

True mania is a distinct period of abnormally and persistently elevated, expansive, or irritable mood, accompanied by abnormally and persistently increased activity or energy, and lasting at least one week for most of the day, nearly every day (or any duration if hospitalization is necessary).

During that time, the patient must also exhibit at least 3 or more of the following symptoms (not counting irritability, if present): ¹

• distractibility,
• insomnia,
• grandiosity,
• flights of ideas,
• increased goal-directed activity or agitation,
• rapid/pressured speech, or
• reckless behaviors.

How hypomania differs from mania. The symptoms of hypomania are less severe than those of mania—eg, social functioning is less impaired or is even normal, and there is no need for hospitalization. Patients may feel they have been much more productive than usual or have needed less sleep to engage in daily activities. Hypomania may be present but not reported by patients who perceive nothing wrong.^1,4

Rule out alternate diagnoses and apply DSM-5 criteria

There are no objective tests to confirm a diagnosis of bipolar disorder. If you suspect bipolar disorder, focus your clinical evaluation on ruling out competing mental health or medical diagnoses, and on determining whether the patient’s history meets criteria for a bipolar disorder as described in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5).¹

Explore the patient’s psychiatric history (including hospitalizations, medications, and electroconvulsive therapy), general medical history, family history of psychiatric disorders (including suicide), and social history (including substance use and abuse). And carefully observe mental status. Confirming a diagnosis of bipolar disorder may take multiple visits, but strongly suggestive symptoms could warrant empirical treatment.

Helpful scales. The Patient Health Questionnaire (PHQ-9; https://www.uspreventiveservicestaskforce.org/Home/GetFileByID/218) and the Beck Depression Inventory (http://www.hr.ucdavis.edu/asap/pdf_files/Beck_Depression_Inventory.pdf) are useful for ruling out depressive disorders. Other scales are available, but they cannot confirm bipolar disorder. Laboratory testing selected according to patient symptoms (TABLE 2⁴) can help rule out alternative diagnoses, but are also useful for establishing a baseline for medications.

Pharmacologic treatment: Match agents to symptoms

When treating bipolar disorder, choose a drug that targets a patient’s specific symptoms (TABLE 3).^7-10 In primary care, the most commonly-used treatments for bipolar disorder type II are lamotrigine, valproic acid, and lithium.¹¹

When to refer

Many cases of bipolar disorder type II can be managed successfully in a primary care practice, as can some cases of stable bipolar disorder type I. Psychiatric consultation may be most beneficial if the patient has recently attempted suicide or has suicidal ideation, has symptoms refractory to treatment, has poor medication adherence, or is misusing medications.

In primary care, up to 4% of patients randomly interviewed met criteria for bipolar disorder.

Even when patients are co-managed with psychiatric consultation, family physicians often ensure patients’ medication adherence, help patients understand their illness, manage overall health-related behaviors (including getting sufficient sleep), and make sure patients follow up as needed with their psychiatrist. Often, once patients have achieved equilibrium on mood-stabilizing (or other) medications, you can manage them and monitor medications with further consultation only as needed for clinical deterioration or other issues. Cognitive behavioral therapy may be useful as adjunctive treatment, particularly when patients are in active treatment.¹²

› CASE

This case is typical for many patients with depressed mood. A few key features in the patient’s history suggest bipolar disorder type II:

• depression that has been refractory to treatment
• multiple failed drug treatments, with mood-related adverse effects
• hypomania perceived as a “productive time,” and not as a problem
• absence of overt manic symptoms.

The patient was given a diagnosis of bipolar disorder type II with current depressed mood and no evidence of acute mania. She was started on valproic acid 250 mg po tid. She reported an initial improvement in mood but stopped the medication after one month because it caused intolerable drowsiness. She was then prescribed lamotrigine progressing gradually in 2-week intervals from 25 mg to 100 mg daily. She tolerated the medication well, and after 3 months of treatment, her mood symptoms improved and she had no further episodes of depressed mood.

CORRESPONDENCE
Michael Jason Wells, MD, Department of Family and Geriatric Medicine, University of Louisville School of Medicine, 201 Abraham Flexner Way, Suite 690, Louisville, KY 40202; [email protected].

THE CASE

A 23-year-old woman seeks medical attention at the request of her boyfriend because she’s been “miserable” for 3 weeks. In the examination room, she slouches in the chair and says her mood is low, her grades have dropped, and she no longer enjoys social gatherings or her other usual activities. She has no thoughts of suicide, no weight loss, and no somatic symptoms.

She says she is generally healthy, does not take any regular medications, and has never been pregnant. When asked about previous similar episodes, she admits to feeling this way about 3 times a year for one to 2 months at a time. She has tried different antidepressants, which haven’t helped much and have made her irritable and interfered with sleep.

When asked about mania or hypomania, she says there are short periods, roughly a couple of weeks 2 or 3 times a year, when she will get a lot of work done and can get by with little sleep. She has never gone on “spending sprees,” though, or indulged in any other unusual or dangerous behavior. And she has never been hospitalized for symptoms.

HOW WOULD YOU PROCEED WITH THIS PATIENT?

Bipolar disorders, over time, typically cause fluctuations in mood, activity, and energy level. If disorders go untreated, a patient’s behavior may cause considerable damage to relationships, finances, and reputations. And for some patients, the disorder can take the ultimate toll, resulting in death by suicide or accident.

Subtypes of bipolar disorder differ in the timing and severity of manic (or hypomanic) and depressive symptoms or episodes. Type I is the classic manic-depressive illness; type II is characterized by chronic treatment-resistant depression punctuated by hypomanic episodes; and cyclothymia leads to chronic fluctuations in mood. The diagnostic category “bipolar disorder not otherwise specified” applies to patients who meet some, but not all, of the criteria for other bipolar disorder subtypes.¹

Prevalence. As with other mood symptoms or disorders, patients with bipolar disorder are often seen first in primary care due, in part, to barriers to obtaining psychiatric care or to avoidance of the perceived stigma in seeking such care.² In a systematic review of patients who were interviewed randomly in primary care settings, 0.5% to 4.3% met criteria for bipolar disorder.³ The average age of onset for bipolar disorder is 15 to 19 years.⁴ In the United States, the prevalence of bipolar disorder type I is 1%; type II is 1.1%.³

The cause of bipolar disorder is unknown, but familial predisposition, biopsychosocial factors, and environment all seem to play a role. Children of parents with bipolar disorder have a 4% to 15% chance of receiving the same diagnosis, compared with children of parents without bipolar disorder, whose risk is only as high as 2%.^5,6

Clinical presentation varies

When patients with bipolar disorder are first seen in the office, their state may be depression, mania, hypomania, or even euthymia. Keep in mind that the first 3 aberrations may indicate other disorders, either psychiatric (TABLE 1)^1,4 or medical (eg, hyperthyroidism, delirium).

Verify a true depressive episode

Symptoms must last for 2 weeks and include anhedonia or depressed mood, as well as some combination of changes in sleep, increased feelings of guilt, poor concentration, changes in appetite, loss of energy, psychomotor agitation or retardation, or suicidal thoughts.¹

Know the criteria for mania

True mania is a distinct period of abnormally and persistently elevated, expansive, or irritable mood, accompanied by abnormally and persistently increased activity or energy, and lasting at least one week for most of the day, nearly every day (or any duration if hospitalization is necessary).

During that time, the patient must also exhibit at least 3 or more of the following symptoms (not counting irritability, if present): ¹

• distractibility,
• insomnia,
• grandiosity,
• flights of ideas,
• increased goal-directed activity or agitation,
• rapid/pressured speech, or
• reckless behaviors.

How hypomania differs from mania. The symptoms of hypomania are less severe than those of mania—eg, social functioning is less impaired or is even normal, and there is no need for hospitalization. Patients may feel they have been much more productive than usual or have needed less sleep to engage in daily activities. Hypomania may be present but not reported by patients who perceive nothing wrong.^1,4

Rule out alternate diagnoses and apply DSM-5 criteria

There are no objective tests to confirm a diagnosis of bipolar disorder. If you suspect bipolar disorder, focus your clinical evaluation on ruling out competing mental health or medical diagnoses, and on determining whether the patient’s history meets criteria for a bipolar disorder as described in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5).¹

Explore the patient’s psychiatric history (including hospitalizations, medications, and electroconvulsive therapy), general medical history, family history of psychiatric disorders (including suicide), and social history (including substance use and abuse). And carefully observe mental status. Confirming a diagnosis of bipolar disorder may take multiple visits, but strongly suggestive symptoms could warrant empirical treatment.

Helpful scales. The Patient Health Questionnaire (PHQ-9; https://www.uspreventiveservicestaskforce.org/Home/GetFileByID/218) and the Beck Depression Inventory (http://www.hr.ucdavis.edu/asap/pdf_files/Beck_Depression_Inventory.pdf) are useful for ruling out depressive disorders. Other scales are available, but they cannot confirm bipolar disorder. Laboratory testing selected according to patient symptoms (TABLE 2⁴) can help rule out alternative diagnoses, but are also useful for establishing a baseline for medications.

Pharmacologic treatment: Match agents to symptoms

When treating bipolar disorder, choose a drug that targets a patient’s specific symptoms (TABLE 3).^7-10 In primary care, the most commonly-used treatments for bipolar disorder type II are lamotrigine, valproic acid, and lithium.¹¹

When to refer

Many cases of bipolar disorder type II can be managed successfully in a primary care practice, as can some cases of stable bipolar disorder type I. Psychiatric consultation may be most beneficial if the patient has recently attempted suicide or has suicidal ideation, has symptoms refractory to treatment, has poor medication adherence, or is misusing medications.

In primary care, up to 4% of patients randomly interviewed met criteria for bipolar disorder.

Even when patients are co-managed with psychiatric consultation, family physicians often ensure patients’ medication adherence, help patients understand their illness, manage overall health-related behaviors (including getting sufficient sleep), and make sure patients follow up as needed with their psychiatrist. Often, once patients have achieved equilibrium on mood-stabilizing (or other) medications, you can manage them and monitor medications with further consultation only as needed for clinical deterioration or other issues. Cognitive behavioral therapy may be useful as adjunctive treatment, particularly when patients are in active treatment.¹²

› CASE

This case is typical for many patients with depressed mood. A few key features in the patient’s history suggest bipolar disorder type II:

• depression that has been refractory to treatment
• multiple failed drug treatments, with mood-related adverse effects
• hypomania perceived as a “productive time,” and not as a problem
• absence of overt manic symptoms.

The patient was given a diagnosis of bipolar disorder type II with current depressed mood and no evidence of acute mania. She was started on valproic acid 250 mg po tid. She reported an initial improvement in mood but stopped the medication after one month because it caused intolerable drowsiness. She was then prescribed lamotrigine progressing gradually in 2-week intervals from 25 mg to 100 mg daily. She tolerated the medication well, and after 3 months of treatment, her mood symptoms improved and she had no further episodes of depressed mood.

CORRESPONDENCE
Michael Jason Wells, MD, Department of Family and Geriatric Medicine, University of Louisville School of Medicine, 201 Abraham Flexner Way, Suite 690, Louisville, KY 40202; [email protected].

THE CASE

A 23-year-old woman seeks medical attention at the request of her boyfriend because she’s been “miserable” for 3 weeks. In the examination room, she slouches in the chair and says her mood is low, her grades have dropped, and she no longer enjoys social gatherings or her other usual activities. She has no thoughts of suicide, no weight loss, and no somatic symptoms.

She says she is generally healthy, does not take any regular medications, and has never been pregnant. When asked about previous similar episodes, she admits to feeling this way about 3 times a year for one to 2 months at a time. She has tried different antidepressants, which haven’t helped much and have made her irritable and interfered with sleep.

When asked about mania or hypomania, she says there are short periods, roughly a couple of weeks 2 or 3 times a year, when she will get a lot of work done and can get by with little sleep. She has never gone on “spending sprees,” though, or indulged in any other unusual or dangerous behavior. And she has never been hospitalized for symptoms.

HOW WOULD YOU PROCEED WITH THIS PATIENT?

Bipolar disorders, over time, typically cause fluctuations in mood, activity, and energy level. If disorders go untreated, a patient’s behavior may cause considerable damage to relationships, finances, and reputations. And for some patients, the disorder can take the ultimate toll, resulting in death by suicide or accident.

Subtypes of bipolar disorder differ in the timing and severity of manic (or hypomanic) and depressive symptoms or episodes. Type I is the classic manic-depressive illness; type II is characterized by chronic treatment-resistant depression punctuated by hypomanic episodes; and cyclothymia leads to chronic fluctuations in mood. The diagnostic category “bipolar disorder not otherwise specified” applies to patients who meet some, but not all, of the criteria for other bipolar disorder subtypes.¹

Prevalence. As with other mood symptoms or disorders, patients with bipolar disorder are often seen first in primary care due, in part, to barriers to obtaining psychiatric care or to avoidance of the perceived stigma in seeking such care.² In a systematic review of patients who were interviewed randomly in primary care settings, 0.5% to 4.3% met criteria for bipolar disorder.³ The average age of onset for bipolar disorder is 15 to 19 years.⁴ In the United States, the prevalence of bipolar disorder type I is 1%; type II is 1.1%.³

The cause of bipolar disorder is unknown, but familial predisposition, biopsychosocial factors, and environment all seem to play a role. Children of parents with bipolar disorder have a 4% to 15% chance of receiving the same diagnosis, compared with children of parents without bipolar disorder, whose risk is only as high as 2%.^5,6

Clinical presentation varies

When patients with bipolar disorder are first seen in the office, their state may be depression, mania, hypomania, or even euthymia. Keep in mind that the first 3 aberrations may indicate other disorders, either psychiatric (TABLE 1)^1,4 or medical (eg, hyperthyroidism, delirium).

Verify a true depressive episode

Symptoms must last for 2 weeks and include anhedonia or depressed mood, as well as some combination of changes in sleep, increased feelings of guilt, poor concentration, changes in appetite, loss of energy, psychomotor agitation or retardation, or suicidal thoughts.¹

Know the criteria for mania

True mania is a distinct period of abnormally and persistently elevated, expansive, or irritable mood, accompanied by abnormally and persistently increased activity or energy, and lasting at least one week for most of the day, nearly every day (or any duration if hospitalization is necessary).

During that time, the patient must also exhibit at least 3 or more of the following symptoms (not counting irritability, if present): ¹

• distractibility,
• insomnia,
• grandiosity,
• flights of ideas,
• increased goal-directed activity or agitation,
• rapid/pressured speech, or
• reckless behaviors.

How hypomania differs from mania. The symptoms of hypomania are less severe than those of mania—eg, social functioning is less impaired or is even normal, and there is no need for hospitalization. Patients may feel they have been much more productive than usual or have needed less sleep to engage in daily activities. Hypomania may be present but not reported by patients who perceive nothing wrong.^1,4

Rule out alternate diagnoses and apply DSM-5 criteria

There are no objective tests to confirm a diagnosis of bipolar disorder. If you suspect bipolar disorder, focus your clinical evaluation on ruling out competing mental health or medical diagnoses, and on determining whether the patient’s history meets criteria for a bipolar disorder as described in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5).¹

Explore the patient’s psychiatric history (including hospitalizations, medications, and electroconvulsive therapy), general medical history, family history of psychiatric disorders (including suicide), and social history (including substance use and abuse). And carefully observe mental status. Confirming a diagnosis of bipolar disorder may take multiple visits, but strongly suggestive symptoms could warrant empirical treatment.

Helpful scales. The Patient Health Questionnaire (PHQ-9; https://www.uspreventiveservicestaskforce.org/Home/GetFileByID/218) and the Beck Depression Inventory (http://www.hr.ucdavis.edu/asap/pdf_files/Beck_Depression_Inventory.pdf) are useful for ruling out depressive disorders. Other scales are available, but they cannot confirm bipolar disorder. Laboratory testing selected according to patient symptoms (TABLE 2⁴) can help rule out alternative diagnoses, but are also useful for establishing a baseline for medications.

Pharmacologic treatment: Match agents to symptoms

When treating bipolar disorder, choose a drug that targets a patient’s specific symptoms (TABLE 3).^7-10 In primary care, the most commonly-used treatments for bipolar disorder type II are lamotrigine, valproic acid, and lithium.¹¹

When to refer

Many cases of bipolar disorder type II can be managed successfully in a primary care practice, as can some cases of stable bipolar disorder type I. Psychiatric consultation may be most beneficial if the patient has recently attempted suicide or has suicidal ideation, has symptoms refractory to treatment, has poor medication adherence, or is misusing medications.

In primary care, up to 4% of patients randomly interviewed met criteria for bipolar disorder.

Even when patients are co-managed with psychiatric consultation, family physicians often ensure patients’ medication adherence, help patients understand their illness, manage overall health-related behaviors (including getting sufficient sleep), and make sure patients follow up as needed with their psychiatrist. Often, once patients have achieved equilibrium on mood-stabilizing (or other) medications, you can manage them and monitor medications with further consultation only as needed for clinical deterioration or other issues. Cognitive behavioral therapy may be useful as adjunctive treatment, particularly when patients are in active treatment.¹²

› CASE

This case is typical for many patients with depressed mood. A few key features in the patient’s history suggest bipolar disorder type II:

• depression that has been refractory to treatment
• multiple failed drug treatments, with mood-related adverse effects
• hypomania perceived as a “productive time,” and not as a problem
• absence of overt manic symptoms.

The patient was given a diagnosis of bipolar disorder type II with current depressed mood and no evidence of acute mania. She was started on valproic acid 250 mg po tid. She reported an initial improvement in mood but stopped the medication after one month because it caused intolerable drowsiness. She was then prescribed lamotrigine progressing gradually in 2-week intervals from 25 mg to 100 mg daily. She tolerated the medication well, and after 3 months of treatment, her mood symptoms improved and she had no further episodes of depressed mood.

CORRESPONDENCE
Michael Jason Wells, MD, Department of Family and Geriatric Medicine, University of Louisville School of Medicine, 201 Abraham Flexner Way, Suite 690, Louisville, KY 40202; [email protected].