Alzheimer disease is the most common form of dementia. In 2016, an estimated 5.2 million Americans age 65 and older had Alzheimer disease. The prevalence is projected to increase to 13.8 million by 2050, including 7 million people age 85 and older.¹

Although no cure for dementia exists, several cognition-enhancing drugs have been approved by the US Food and Drug Administration (FDA) to treat the symptoms of Alzheimer dementia. The purpose of these drugs is to stabilize cognitive and functional status, with a secondary benefit of potentially reducing behavioral problems associated with dementia.

CURRENTLY APPROVED DRUGS

Two classes of drugs are approved to treat Alz­heimer disease: cholinesterase inhibitors and an N-methyl-d-aspartate (NMDA) receptor antagonist (Table 1).

Cholinesterase inhibitors

The cholinesterase inhibitors act by reversibly binding and inactivating acetylcholinesterase, consequently increasing the time the neurotransmitter acetylcholine remains in the synaptic cleft. The 3 FDA-approved cholinesterase inhibitors are donepezil, galantamine, and rivastigmine. Tacrine, the first approved cholinesterase inhibitor, was removed from the US market after reports of severe hepatic toxicity.²

The clinical efficacy of cholinesterase inhibitors in improving cognitive function has been shown in several randomized controlled trials.^3–10 However, benefits were generally modest, and some trials used questionable methodology, leading experts to challenge the overall efficacy of these agents.

All 3 drugs are approved for mild to moderate Alzheimer disease (stages 4–6 on the Global Deterioration Scale; Table 2)^11,12; only donepezil is approved for severe Alzheimer disease. Rivastigmine has an added indication for treating mild to moderate dementia associated with Parkinson disease. Cholinesterase inhibitors are often used off-label to treat other forms of dementia such as vascular dementia, mixed dementia, and dementia with Lewy bodies.¹³

NMDA receptor antagonist

Memantine, currently the only FDA-approved NMDA receptor antagonist, acts by reducing neuronal calcium ion influx and its associated excitation and toxicity. Memantine is approved for moderate to severe Alzheimer disease.

Combination therapy

Often, these 2 classes of medications are prescribed in combination. In a randomized controlled trial that added memantine to stable doses of donepezil, patients had significantly better clinical response on combination therapy than on cholinesterase inhibitor monotherapy.¹⁴

In December 2014, the FDA approved a capsule formulation combining donepezil and memantine to treat symptoms of Alzheimer dementia. However, no novel pharmacologic treatment for Alzheimer disease has been approved since 2003. Furthermore, recently Pfizer announced a plan to eliminate 300 research positions aimed at finding new drugs to treat Alzheimer disease and Parkinson disease.¹⁵

CONSIDERATIONS WHEN STARTING COGNITIVE ENHANCERS

Cholinesterase inhibitors

Adverse effects of cholinesterase inhibitors are generally mild and well tolerated and subside within 1 to 2 weeks. Gastrointestinal effects are common, primarily diarrhea, nausea, and vomiting. They are transient but can occur in about 20% of patients (Table 3).

Other potential adverse effects include bradycardia, syncope, rhabdomyolysis, neuroleptic malignant syndrome, and esophageal rupture. Often, the side-effect profile helps determine which patients are appropriate candidates for these medications.

As expected, higher doses of donepezil (23 mg vs 5–10 mg) are associated with higher rates of nausea, diarrhea, and vomiting.

Dosing. The cholinesterase inhibitors should be slowly titrated to minimize side effects. Starting at the lowest dose and maintaining it for 4 weeks allows sufficient time for transient side effects to abate. Some patients may require a longer titration period.

As the dose is escalated, the probability of side effects may increase. If they do not subside, dose reduction with maintenance at the next lower dose is appropriate.

Gastrointestinal effects. Given the adverse gastrointestinal effects associated with this class of medications, patients experiencing significant anorexia and weight loss should generally avoid cholinesterase inhibitors. However, the rivastigmine patch, a transdermal formulation, is an alternative for patients who experience gastrointestinal side effects.

Bradycardia risk. Patients with significant bradycardia or who are taking medications that lower the heart rate may experience a worsening of their bradycardia or associated symptoms if they take a cholinesterase inhibitor. Syncope from bradycardia is a significant concern, especially in patients already at risk of falls or fracture due to osteoporosis.

NMDA receptor antagonist

The side-effect profile of memantine is generally more favorable than that of cholinesterase inhibitors. In clinical trials, it has been better tolerated with fewer adverse effects than placebo, with the exception of an increased incidence of dizziness, confusion, and delusions.^16,17

Caution is required when treating patients with renal impairment. In patients with a creatinine clearance of 5 to 29 mL/min, the recommended maximum total daily dose is 10 mg (twice-daily formulation) or 14 mg (once-daily formulation).

Off-label use to treat behavioral problems

These medications have been used off-label to treat behavioral problems associated with dementia. A systematic review and meta-analysis showed cholinesterase inhibitor therapy had a statistically significant effect in reducing the severity of behavioral problems.¹⁸ Unfortunately, the number of dropouts increased in the active-treatment groups.

Patients with behavioral problems associated with dementia with Lewy bodies may experience a greater response to cholinesterase inhibitors than those with Alzheimer disease.¹⁹ Published post hoc analyses suggest that patients with moderate to severe Alzheimer disease receiving memantine therapy have less severe agitation, aggression, irritability, and other behavioral disturbances compared with those on placebo.^20,21 However, systematic reviews have not found that memantine has a clinically significant effect on neuropsychiatric symptoms of dementia.^18,22,23

Combination therapy

In early randomized controlled trials, adding memantine to a cholinesterase inhibitor provided additional cognitive benefit in patients with Alzheimer disease.^15,24 However, a more recent randomized controlled trial did not show significant benefits for combined memantine and donepezil vs donepezil alone in moderate to severe dementia.²⁵

In patients who had mild to moderate Alzheimer disease at 14 Veterans Affairs medical centers who were already on cholinesterase inhibitor treatment, adding memantine did not show benefit. However, the group receiving alpha-tocopherol (vitamin E) showed slower functional decline than those on placebo.²⁶ Cognition and function are not expected to improve with memantine.

CONSIDERATIONS WHEN STOPPING COGNITIVE ENHANCERS

The cholinesterase inhibitors are usually prescribed early in the course of dementia, and some patients take these drugs for years, although no studies have investigated benefit or risk beyond 1 year. It is generally recommended that cholinesterase inhibitor therapy be assessed periodically, eg, every 3 to 6 months, for perceived cognitive benefits and adverse gastrointestinal effects.

These medications should be stopped if the desired effects—stabilizing cognitive and functional status—are not perceived within a reasonable time, such as 12 weeks. In some cases, stopping cholinesterase inhibitor therapy may cause negative effects on cognition and neuropsychiatric symptoms.²⁷

Deciding whether benefit has occurred during a trial of cholinesterase inhibitors often requires input and observations from the family and caregivers. Soliciting this information is key for practitioners to determine the correct treatment approach for each patient.

Although some patients with moderately severe disease experience clinical benefits from cholinesterase inhibitor therapy, it is reasonable to consider discontinuing therapy when a patient has progressed to advanced dementia with loss of functional independence, thus making the use of the therapy—ie, to preserve functional status—less relevant. Results from a randomized discontinuation trial of cholinesterase inhibitors in institutionalized patients with moderate to severe dementia suggest that discontinuation is safe and well tolerated in most of these patients.²⁸

Abruptly stopping high-dose cholinesterase inhibitors is not recommended. Most clinical trials tapered these medications over 2 to 4 weeks. Patients taking the maximum dose of a cholinesterase inhibitor should have the dose reduced to the next lowest dose for 2 weeks before the dose is reduced further or stopped completely.

Behavioral and psychiatric problems often accompany dementia; however, no drugs are approved to treat these symptoms in patients with Alzheimer disease. Nonpharmacologic interventions are recommended as the initial treatment.²⁹ Some practitioners prescribe psychotropic drugs off-label for Alzheimer disease, but most clinical trials have not found these therapies to be very effective for psychiatric symptoms associated with Alzheimer disease.^30,31

Recently, a randomized controlled trial of dextromethorphan-quinidine showed mild reduction in agitation in patients with Alzheimer disease, but there were significant increases in falls, dizziness, and diarrhea.³²

Patients prescribed medications for behavioral and psychological symptoms of dementia should be assessed every 3 to 6 months to determine if the medications have been effective in reducing the symptoms they were meant to reduce. If there has been no clear reduction in the target behaviors, a trial off the drug should be initiated, with careful monitoring to see if the target behavior changes. Dementia-related behaviors may worsen off the medication, but a lower dose may be found to be as effective as a higher dose. As dementia advances, behaviors initially encountered during one stage may diminish or abate.

In a long-term care setting, a gradual dose-reduction trial of psychotropic medications should be conducted every year to determine if the medications are still necessary.³³ This should be considered during routine management and follow-up of patients with dementia-associated behavioral problems.

REASONABLE TO TRY

Cognitive enhancers have been around for more than 10 years and are reasonable to try in patients with Alzheimer disease. All the available drugs are FDA-approved for reducing dementia symptoms associated with mild to moderate Alzheimer disease; donepezil and memantine are also approved for severe Alz­heimer disease, either in combination or as monotherapy.

When selecting a cognitive enhancer, practitioners need to consider the potential for adverse effects. And if a cholinesterase inhibitor is prescribed, it is important to periodically assess for perceived cognitive benefits and adverse gastrointestinal effects. The NMDA receptor antagonist has a more favorable side effect profile. Combining the drugs is also an option.

Similarly, patients prescribed psychotropic medications for behavioral problems related to dementia should be reassessed to determine if the dose could be reduced or eliminated, particularly if targeted behaviors have not responded to the treatment or the dementia has advanced.

For patients on cognitive enhancers, discontinuation should be considered when the dementia advances to the point where the patient is totally dependent for all basic activities of daily living, and the initial intended purpose of these medications—preservation of cognitive and functional status—is no longer achievable.

Alzheimer disease is the most common form of dementia. In 2016, an estimated 5.2 million Americans age 65 and older had Alzheimer disease. The prevalence is projected to increase to 13.8 million by 2050, including 7 million people age 85 and older.¹

Although no cure for dementia exists, several cognition-enhancing drugs have been approved by the US Food and Drug Administration (FDA) to treat the symptoms of Alzheimer dementia. The purpose of these drugs is to stabilize cognitive and functional status, with a secondary benefit of potentially reducing behavioral problems associated with dementia.

CURRENTLY APPROVED DRUGS

Two classes of drugs are approved to treat Alz­heimer disease: cholinesterase inhibitors and an N-methyl-d-aspartate (NMDA) receptor antagonist (Table 1).

Cholinesterase inhibitors

The cholinesterase inhibitors act by reversibly binding and inactivating acetylcholinesterase, consequently increasing the time the neurotransmitter acetylcholine remains in the synaptic cleft. The 3 FDA-approved cholinesterase inhibitors are donepezil, galantamine, and rivastigmine. Tacrine, the first approved cholinesterase inhibitor, was removed from the US market after reports of severe hepatic toxicity.²

The clinical efficacy of cholinesterase inhibitors in improving cognitive function has been shown in several randomized controlled trials.^3–10 However, benefits were generally modest, and some trials used questionable methodology, leading experts to challenge the overall efficacy of these agents.

All 3 drugs are approved for mild to moderate Alzheimer disease (stages 4–6 on the Global Deterioration Scale; Table 2)^11,12; only donepezil is approved for severe Alzheimer disease. Rivastigmine has an added indication for treating mild to moderate dementia associated with Parkinson disease. Cholinesterase inhibitors are often used off-label to treat other forms of dementia such as vascular dementia, mixed dementia, and dementia with Lewy bodies.¹³

NMDA receptor antagonist

Memantine, currently the only FDA-approved NMDA receptor antagonist, acts by reducing neuronal calcium ion influx and its associated excitation and toxicity. Memantine is approved for moderate to severe Alzheimer disease.

Combination therapy

Often, these 2 classes of medications are prescribed in combination. In a randomized controlled trial that added memantine to stable doses of donepezil, patients had significantly better clinical response on combination therapy than on cholinesterase inhibitor monotherapy.¹⁴

In December 2014, the FDA approved a capsule formulation combining donepezil and memantine to treat symptoms of Alzheimer dementia. However, no novel pharmacologic treatment for Alzheimer disease has been approved since 2003. Furthermore, recently Pfizer announced a plan to eliminate 300 research positions aimed at finding new drugs to treat Alzheimer disease and Parkinson disease.¹⁵

CONSIDERATIONS WHEN STARTING COGNITIVE ENHANCERS

Cholinesterase inhibitors

Adverse effects of cholinesterase inhibitors are generally mild and well tolerated and subside within 1 to 2 weeks. Gastrointestinal effects are common, primarily diarrhea, nausea, and vomiting. They are transient but can occur in about 20% of patients (Table 3).

Other potential adverse effects include bradycardia, syncope, rhabdomyolysis, neuroleptic malignant syndrome, and esophageal rupture. Often, the side-effect profile helps determine which patients are appropriate candidates for these medications.

As expected, higher doses of donepezil (23 mg vs 5–10 mg) are associated with higher rates of nausea, diarrhea, and vomiting.

Dosing. The cholinesterase inhibitors should be slowly titrated to minimize side effects. Starting at the lowest dose and maintaining it for 4 weeks allows sufficient time for transient side effects to abate. Some patients may require a longer titration period.

As the dose is escalated, the probability of side effects may increase. If they do not subside, dose reduction with maintenance at the next lower dose is appropriate.

Gastrointestinal effects. Given the adverse gastrointestinal effects associated with this class of medications, patients experiencing significant anorexia and weight loss should generally avoid cholinesterase inhibitors. However, the rivastigmine patch, a transdermal formulation, is an alternative for patients who experience gastrointestinal side effects.

Bradycardia risk. Patients with significant bradycardia or who are taking medications that lower the heart rate may experience a worsening of their bradycardia or associated symptoms if they take a cholinesterase inhibitor. Syncope from bradycardia is a significant concern, especially in patients already at risk of falls or fracture due to osteoporosis.

NMDA receptor antagonist

The side-effect profile of memantine is generally more favorable than that of cholinesterase inhibitors. In clinical trials, it has been better tolerated with fewer adverse effects than placebo, with the exception of an increased incidence of dizziness, confusion, and delusions.^16,17

Caution is required when treating patients with renal impairment. In patients with a creatinine clearance of 5 to 29 mL/min, the recommended maximum total daily dose is 10 mg (twice-daily formulation) or 14 mg (once-daily formulation).

Off-label use to treat behavioral problems

These medications have been used off-label to treat behavioral problems associated with dementia. A systematic review and meta-analysis showed cholinesterase inhibitor therapy had a statistically significant effect in reducing the severity of behavioral problems.¹⁸ Unfortunately, the number of dropouts increased in the active-treatment groups.

Patients with behavioral problems associated with dementia with Lewy bodies may experience a greater response to cholinesterase inhibitors than those with Alzheimer disease.¹⁹ Published post hoc analyses suggest that patients with moderate to severe Alzheimer disease receiving memantine therapy have less severe agitation, aggression, irritability, and other behavioral disturbances compared with those on placebo.^20,21 However, systematic reviews have not found that memantine has a clinically significant effect on neuropsychiatric symptoms of dementia.^18,22,23

Combination therapy

In early randomized controlled trials, adding memantine to a cholinesterase inhibitor provided additional cognitive benefit in patients with Alzheimer disease.^15,24 However, a more recent randomized controlled trial did not show significant benefits for combined memantine and donepezil vs donepezil alone in moderate to severe dementia.²⁵

In patients who had mild to moderate Alzheimer disease at 14 Veterans Affairs medical centers who were already on cholinesterase inhibitor treatment, adding memantine did not show benefit. However, the group receiving alpha-tocopherol (vitamin E) showed slower functional decline than those on placebo.²⁶ Cognition and function are not expected to improve with memantine.

CONSIDERATIONS WHEN STOPPING COGNITIVE ENHANCERS

The cholinesterase inhibitors are usually prescribed early in the course of dementia, and some patients take these drugs for years, although no studies have investigated benefit or risk beyond 1 year. It is generally recommended that cholinesterase inhibitor therapy be assessed periodically, eg, every 3 to 6 months, for perceived cognitive benefits and adverse gastrointestinal effects.

These medications should be stopped if the desired effects—stabilizing cognitive and functional status—are not perceived within a reasonable time, such as 12 weeks. In some cases, stopping cholinesterase inhibitor therapy may cause negative effects on cognition and neuropsychiatric symptoms.²⁷

Deciding whether benefit has occurred during a trial of cholinesterase inhibitors often requires input and observations from the family and caregivers. Soliciting this information is key for practitioners to determine the correct treatment approach for each patient.

Although some patients with moderately severe disease experience clinical benefits from cholinesterase inhibitor therapy, it is reasonable to consider discontinuing therapy when a patient has progressed to advanced dementia with loss of functional independence, thus making the use of the therapy—ie, to preserve functional status—less relevant. Results from a randomized discontinuation trial of cholinesterase inhibitors in institutionalized patients with moderate to severe dementia suggest that discontinuation is safe and well tolerated in most of these patients.²⁸

Abruptly stopping high-dose cholinesterase inhibitors is not recommended. Most clinical trials tapered these medications over 2 to 4 weeks. Patients taking the maximum dose of a cholinesterase inhibitor should have the dose reduced to the next lowest dose for 2 weeks before the dose is reduced further or stopped completely.

Behavioral and psychiatric problems often accompany dementia; however, no drugs are approved to treat these symptoms in patients with Alzheimer disease. Nonpharmacologic interventions are recommended as the initial treatment.²⁹ Some practitioners prescribe psychotropic drugs off-label for Alzheimer disease, but most clinical trials have not found these therapies to be very effective for psychiatric symptoms associated with Alzheimer disease.^30,31

Recently, a randomized controlled trial of dextromethorphan-quinidine showed mild reduction in agitation in patients with Alzheimer disease, but there were significant increases in falls, dizziness, and diarrhea.³²

Patients prescribed medications for behavioral and psychological symptoms of dementia should be assessed every 3 to 6 months to determine if the medications have been effective in reducing the symptoms they were meant to reduce. If there has been no clear reduction in the target behaviors, a trial off the drug should be initiated, with careful monitoring to see if the target behavior changes. Dementia-related behaviors may worsen off the medication, but a lower dose may be found to be as effective as a higher dose. As dementia advances, behaviors initially encountered during one stage may diminish or abate.

In a long-term care setting, a gradual dose-reduction trial of psychotropic medications should be conducted every year to determine if the medications are still necessary.³³ This should be considered during routine management and follow-up of patients with dementia-associated behavioral problems.

REASONABLE TO TRY

Cognitive enhancers have been around for more than 10 years and are reasonable to try in patients with Alzheimer disease. All the available drugs are FDA-approved for reducing dementia symptoms associated with mild to moderate Alzheimer disease; donepezil and memantine are also approved for severe Alz­heimer disease, either in combination or as monotherapy.

When selecting a cognitive enhancer, practitioners need to consider the potential for adverse effects. And if a cholinesterase inhibitor is prescribed, it is important to periodically assess for perceived cognitive benefits and adverse gastrointestinal effects. The NMDA receptor antagonist has a more favorable side effect profile. Combining the drugs is also an option.

Similarly, patients prescribed psychotropic medications for behavioral problems related to dementia should be reassessed to determine if the dose could be reduced or eliminated, particularly if targeted behaviors have not responded to the treatment or the dementia has advanced.

For patients on cognitive enhancers, discontinuation should be considered when the dementia advances to the point where the patient is totally dependent for all basic activities of daily living, and the initial intended purpose of these medications—preservation of cognitive and functional status—is no longer achievable.

Alzheimer disease is the most common form of dementia. In 2016, an estimated 5.2 million Americans age 65 and older had Alzheimer disease. The prevalence is projected to increase to 13.8 million by 2050, including 7 million people age 85 and older.¹

Although no cure for dementia exists, several cognition-enhancing drugs have been approved by the US Food and Drug Administration (FDA) to treat the symptoms of Alzheimer dementia. The purpose of these drugs is to stabilize cognitive and functional status, with a secondary benefit of potentially reducing behavioral problems associated with dementia.

CURRENTLY APPROVED DRUGS

Two classes of drugs are approved to treat Alz­heimer disease: cholinesterase inhibitors and an N-methyl-d-aspartate (NMDA) receptor antagonist (Table 1).

Cholinesterase inhibitors

The cholinesterase inhibitors act by reversibly binding and inactivating acetylcholinesterase, consequently increasing the time the neurotransmitter acetylcholine remains in the synaptic cleft. The 3 FDA-approved cholinesterase inhibitors are donepezil, galantamine, and rivastigmine. Tacrine, the first approved cholinesterase inhibitor, was removed from the US market after reports of severe hepatic toxicity.²

The clinical efficacy of cholinesterase inhibitors in improving cognitive function has been shown in several randomized controlled trials.^3–10 However, benefits were generally modest, and some trials used questionable methodology, leading experts to challenge the overall efficacy of these agents.

All 3 drugs are approved for mild to moderate Alzheimer disease (stages 4–6 on the Global Deterioration Scale; Table 2)^11,12; only donepezil is approved for severe Alzheimer disease. Rivastigmine has an added indication for treating mild to moderate dementia associated with Parkinson disease. Cholinesterase inhibitors are often used off-label to treat other forms of dementia such as vascular dementia, mixed dementia, and dementia with Lewy bodies.¹³

NMDA receptor antagonist

Memantine, currently the only FDA-approved NMDA receptor antagonist, acts by reducing neuronal calcium ion influx and its associated excitation and toxicity. Memantine is approved for moderate to severe Alzheimer disease.

Combination therapy

Often, these 2 classes of medications are prescribed in combination. In a randomized controlled trial that added memantine to stable doses of donepezil, patients had significantly better clinical response on combination therapy than on cholinesterase inhibitor monotherapy.¹⁴

In December 2014, the FDA approved a capsule formulation combining donepezil and memantine to treat symptoms of Alzheimer dementia. However, no novel pharmacologic treatment for Alzheimer disease has been approved since 2003. Furthermore, recently Pfizer announced a plan to eliminate 300 research positions aimed at finding new drugs to treat Alzheimer disease and Parkinson disease.¹⁵

CONSIDERATIONS WHEN STARTING COGNITIVE ENHANCERS

Cholinesterase inhibitors

Adverse effects of cholinesterase inhibitors are generally mild and well tolerated and subside within 1 to 2 weeks. Gastrointestinal effects are common, primarily diarrhea, nausea, and vomiting. They are transient but can occur in about 20% of patients (Table 3).

Other potential adverse effects include bradycardia, syncope, rhabdomyolysis, neuroleptic malignant syndrome, and esophageal rupture. Often, the side-effect profile helps determine which patients are appropriate candidates for these medications.

As expected, higher doses of donepezil (23 mg vs 5–10 mg) are associated with higher rates of nausea, diarrhea, and vomiting.

Dosing. The cholinesterase inhibitors should be slowly titrated to minimize side effects. Starting at the lowest dose and maintaining it for 4 weeks allows sufficient time for transient side effects to abate. Some patients may require a longer titration period.

As the dose is escalated, the probability of side effects may increase. If they do not subside, dose reduction with maintenance at the next lower dose is appropriate.

Gastrointestinal effects. Given the adverse gastrointestinal effects associated with this class of medications, patients experiencing significant anorexia and weight loss should generally avoid cholinesterase inhibitors. However, the rivastigmine patch, a transdermal formulation, is an alternative for patients who experience gastrointestinal side effects.

Bradycardia risk. Patients with significant bradycardia or who are taking medications that lower the heart rate may experience a worsening of their bradycardia or associated symptoms if they take a cholinesterase inhibitor. Syncope from bradycardia is a significant concern, especially in patients already at risk of falls or fracture due to osteoporosis.

NMDA receptor antagonist

The side-effect profile of memantine is generally more favorable than that of cholinesterase inhibitors. In clinical trials, it has been better tolerated with fewer adverse effects than placebo, with the exception of an increased incidence of dizziness, confusion, and delusions.^16,17

Caution is required when treating patients with renal impairment. In patients with a creatinine clearance of 5 to 29 mL/min, the recommended maximum total daily dose is 10 mg (twice-daily formulation) or 14 mg (once-daily formulation).

Off-label use to treat behavioral problems

These medications have been used off-label to treat behavioral problems associated with dementia. A systematic review and meta-analysis showed cholinesterase inhibitor therapy had a statistically significant effect in reducing the severity of behavioral problems.¹⁸ Unfortunately, the number of dropouts increased in the active-treatment groups.

Patients with behavioral problems associated with dementia with Lewy bodies may experience a greater response to cholinesterase inhibitors than those with Alzheimer disease.¹⁹ Published post hoc analyses suggest that patients with moderate to severe Alzheimer disease receiving memantine therapy have less severe agitation, aggression, irritability, and other behavioral disturbances compared with those on placebo.^20,21 However, systematic reviews have not found that memantine has a clinically significant effect on neuropsychiatric symptoms of dementia.^18,22,23

Combination therapy

In early randomized controlled trials, adding memantine to a cholinesterase inhibitor provided additional cognitive benefit in patients with Alzheimer disease.^15,24 However, a more recent randomized controlled trial did not show significant benefits for combined memantine and donepezil vs donepezil alone in moderate to severe dementia.²⁵

In patients who had mild to moderate Alzheimer disease at 14 Veterans Affairs medical centers who were already on cholinesterase inhibitor treatment, adding memantine did not show benefit. However, the group receiving alpha-tocopherol (vitamin E) showed slower functional decline than those on placebo.²⁶ Cognition and function are not expected to improve with memantine.

CONSIDERATIONS WHEN STOPPING COGNITIVE ENHANCERS

The cholinesterase inhibitors are usually prescribed early in the course of dementia, and some patients take these drugs for years, although no studies have investigated benefit or risk beyond 1 year. It is generally recommended that cholinesterase inhibitor therapy be assessed periodically, eg, every 3 to 6 months, for perceived cognitive benefits and adverse gastrointestinal effects.

These medications should be stopped if the desired effects—stabilizing cognitive and functional status—are not perceived within a reasonable time, such as 12 weeks. In some cases, stopping cholinesterase inhibitor therapy may cause negative effects on cognition and neuropsychiatric symptoms.²⁷

Deciding whether benefit has occurred during a trial of cholinesterase inhibitors often requires input and observations from the family and caregivers. Soliciting this information is key for practitioners to determine the correct treatment approach for each patient.

Although some patients with moderately severe disease experience clinical benefits from cholinesterase inhibitor therapy, it is reasonable to consider discontinuing therapy when a patient has progressed to advanced dementia with loss of functional independence, thus making the use of the therapy—ie, to preserve functional status—less relevant. Results from a randomized discontinuation trial of cholinesterase inhibitors in institutionalized patients with moderate to severe dementia suggest that discontinuation is safe and well tolerated in most of these patients.²⁸

Abruptly stopping high-dose cholinesterase inhibitors is not recommended. Most clinical trials tapered these medications over 2 to 4 weeks. Patients taking the maximum dose of a cholinesterase inhibitor should have the dose reduced to the next lowest dose for 2 weeks before the dose is reduced further or stopped completely.

Behavioral and psychiatric problems often accompany dementia; however, no drugs are approved to treat these symptoms in patients with Alzheimer disease. Nonpharmacologic interventions are recommended as the initial treatment.²⁹ Some practitioners prescribe psychotropic drugs off-label for Alzheimer disease, but most clinical trials have not found these therapies to be very effective for psychiatric symptoms associated with Alzheimer disease.^30,31

Recently, a randomized controlled trial of dextromethorphan-quinidine showed mild reduction in agitation in patients with Alzheimer disease, but there were significant increases in falls, dizziness, and diarrhea.³²

Patients prescribed medications for behavioral and psychological symptoms of dementia should be assessed every 3 to 6 months to determine if the medications have been effective in reducing the symptoms they were meant to reduce. If there has been no clear reduction in the target behaviors, a trial off the drug should be initiated, with careful monitoring to see if the target behavior changes. Dementia-related behaviors may worsen off the medication, but a lower dose may be found to be as effective as a higher dose. As dementia advances, behaviors initially encountered during one stage may diminish or abate.

In a long-term care setting, a gradual dose-reduction trial of psychotropic medications should be conducted every year to determine if the medications are still necessary.³³ This should be considered during routine management and follow-up of patients with dementia-associated behavioral problems.

REASONABLE TO TRY

Cognitive enhancers have been around for more than 10 years and are reasonable to try in patients with Alzheimer disease. All the available drugs are FDA-approved for reducing dementia symptoms associated with mild to moderate Alzheimer disease; donepezil and memantine are also approved for severe Alz­heimer disease, either in combination or as monotherapy.

When selecting a cognitive enhancer, practitioners need to consider the potential for adverse effects. And if a cholinesterase inhibitor is prescribed, it is important to periodically assess for perceived cognitive benefits and adverse gastrointestinal effects. The NMDA receptor antagonist has a more favorable side effect profile. Combining the drugs is also an option.

Similarly, patients prescribed psychotropic medications for behavioral problems related to dementia should be reassessed to determine if the dose could be reduced or eliminated, particularly if targeted behaviors have not responded to the treatment or the dementia has advanced.

For patients on cognitive enhancers, discontinuation should be considered when the dementia advances to the point where the patient is totally dependent for all basic activities of daily living, and the initial intended purpose of these medications—preservation of cognitive and functional status—is no longer achievable.

Livedo reticularis can be the manifestation of a wide range of conditions: hematologic and hypercoagulable states, embolic events, connective tissue disease, infection, vasculitis, malignancy, neurologic and endocrine conditions, and medication effects.¹ Our patient had no recent history of vascular procedures or peripheral eosinophilia to suggest cholesterol embolization, and he had not recently started taking any new medications. His current medications included aspirin 81 mg, atorvastatin 40 mg, amlodipine 10 mg, and insulin glargine 20 units. Tests for cryoglobulin and antiphospholipid antibodies were negative. There was no evidence of malignancy, and evaluations for infectious and autoimmune diseases were negative.

Biopsy study of a skin lesion showed features consistent with livedo reticularis, with no evidence of vasculitis. The lesions resolved without definitive therapy by hospital day 3. This, in addition to other features of the lesions (eg, uniformity, unbroken reticular segments) and the extensive negative workup for systemic disease, suggested primary livedo reticularis.

CAUSES, TYPES, SUBTYPES

Livedo reticularis results from changes in the cutaneous microvasculature, composed of central arterioles that drain into an interconnecting, netlike venous plexus.^1,2 Conditions such as arteriolar deoxygenation and venous plexus venodilation­ that result in a prominent venous plexus can give rise to clinical livedo reticularis.³

Adapted from information in References 1 and 4.

Primary livedo reticularis is thought to occur from spontaneous arteriolar vasospasm. It is a diagnosis of exclusion. An evaluation for underlying disease is important, as livedo reticularis can be associated with the range of conditions listed above.

In our patient, methamphetamine was considered a possible cause, but the findings of livedo reticularis were delayed and persisted longer than expected if they were drug-related.

Livedo racemosa

Distinguishing livedo reticularis from livedo racemosa is important. Livedo racemosa is always secondary and is often associated with antiphospholipid syndrome. It is present in 25% of cases of primary antiphospholipid syndrome and in up to 70% of cases of antiphospholipid syndrome associated with systemic lupus erythematosus.⁵ The reticular pattern of livedo racemosa is permanent and often has irregular and incomplete segments of reticular lattice, with a distribution that is more generalized,  involving the trunk or buttocks (or both) in addition to the extremities.^3,4 Consequently, a thorough history and physical examination are needed to guide additional workup.

Livedo reticularis can be the manifestation of a wide range of conditions: hematologic and hypercoagulable states, embolic events, connective tissue disease, infection, vasculitis, malignancy, neurologic and endocrine conditions, and medication effects.¹ Our patient had no recent history of vascular procedures or peripheral eosinophilia to suggest cholesterol embolization, and he had not recently started taking any new medications. His current medications included aspirin 81 mg, atorvastatin 40 mg, amlodipine 10 mg, and insulin glargine 20 units. Tests for cryoglobulin and antiphospholipid antibodies were negative. There was no evidence of malignancy, and evaluations for infectious and autoimmune diseases were negative.

Biopsy study of a skin lesion showed features consistent with livedo reticularis, with no evidence of vasculitis. The lesions resolved without definitive therapy by hospital day 3. This, in addition to other features of the lesions (eg, uniformity, unbroken reticular segments) and the extensive negative workup for systemic disease, suggested primary livedo reticularis.

CAUSES, TYPES, SUBTYPES

Livedo reticularis results from changes in the cutaneous microvasculature, composed of central arterioles that drain into an interconnecting, netlike venous plexus.^1,2 Conditions such as arteriolar deoxygenation and venous plexus venodilation­ that result in a prominent venous plexus can give rise to clinical livedo reticularis.³

Adapted from information in References 1 and 4.

Primary livedo reticularis is thought to occur from spontaneous arteriolar vasospasm. It is a diagnosis of exclusion. An evaluation for underlying disease is important, as livedo reticularis can be associated with the range of conditions listed above.

In our patient, methamphetamine was considered a possible cause, but the findings of livedo reticularis were delayed and persisted longer than expected if they were drug-related.

Livedo racemosa

Distinguishing livedo reticularis from livedo racemosa is important. Livedo racemosa is always secondary and is often associated with antiphospholipid syndrome. It is present in 25% of cases of primary antiphospholipid syndrome and in up to 70% of cases of antiphospholipid syndrome associated with systemic lupus erythematosus.⁵ The reticular pattern of livedo racemosa is permanent and often has irregular and incomplete segments of reticular lattice, with a distribution that is more generalized,  involving the trunk or buttocks (or both) in addition to the extremities.^3,4 Consequently, a thorough history and physical examination are needed to guide additional workup.

Livedo reticularis can be the manifestation of a wide range of conditions: hematologic and hypercoagulable states, embolic events, connective tissue disease, infection, vasculitis, malignancy, neurologic and endocrine conditions, and medication effects.¹ Our patient had no recent history of vascular procedures or peripheral eosinophilia to suggest cholesterol embolization, and he had not recently started taking any new medications. His current medications included aspirin 81 mg, atorvastatin 40 mg, amlodipine 10 mg, and insulin glargine 20 units. Tests for cryoglobulin and antiphospholipid antibodies were negative. There was no evidence of malignancy, and evaluations for infectious and autoimmune diseases were negative.

Biopsy study of a skin lesion showed features consistent with livedo reticularis, with no evidence of vasculitis. The lesions resolved without definitive therapy by hospital day 3. This, in addition to other features of the lesions (eg, uniformity, unbroken reticular segments) and the extensive negative workup for systemic disease, suggested primary livedo reticularis.

CAUSES, TYPES, SUBTYPES

Livedo reticularis results from changes in the cutaneous microvasculature, composed of central arterioles that drain into an interconnecting, netlike venous plexus.^1,2 Conditions such as arteriolar deoxygenation and venous plexus venodilation­ that result in a prominent venous plexus can give rise to clinical livedo reticularis.³

Adapted from information in References 1 and 4.

Primary livedo reticularis is thought to occur from spontaneous arteriolar vasospasm. It is a diagnosis of exclusion. An evaluation for underlying disease is important, as livedo reticularis can be associated with the range of conditions listed above.

In our patient, methamphetamine was considered a possible cause, but the findings of livedo reticularis were delayed and persisted longer than expected if they were drug-related.

Livedo racemosa

Distinguishing livedo reticularis from livedo racemosa is important. Livedo racemosa is always secondary and is often associated with antiphospholipid syndrome. It is present in 25% of cases of primary antiphospholipid syndrome and in up to 70% of cases of antiphospholipid syndrome associated with systemic lupus erythematosus.⁵ The reticular pattern of livedo racemosa is permanent and often has irregular and incomplete segments of reticular lattice, with a distribution that is more generalized,  involving the trunk or buttocks (or both) in addition to the extremities.^3,4 Consequently, a thorough history and physical examination are needed to guide additional workup.

We should aim for a standard office systolic pressure lower than 130 mm Hg in most adults age 65 and older if the patient can take multiple antihypertensive medications and be followed closely for adverse effects.

This recommendation is part of the 2017 hypertension guideline from the American College of Cardiology and American Heart Association.¹ This new guideline advocates drug treatment of hypertension to a target less than 130/80 mm Hg for patients of all ages for secondary prevention of cardiovascular disease, and for primary prevention in those at high risk (ie, an estimated 10-year risk of atherosclerotic cardiovascular disease of 10% or higher). The target blood pressure for those at lower risk is less than 140/90 mm Hg.

There are multiple tools to estimate the 10-year risk. All tools incorporate major predictors such as age, blood pressure, cholesterol profile, and other markers, depending on the tool. Although risk increases with age, the tools are inaccurate once the patient is approximately 80 years of age.

The recommendation for older adults omits a target diastolic pressure, since treating elevated systolic pressure has more data supporting it than treating elevated diastolic blood pressure in older people. These recommendations apply only to older adults who can walk and are living in the community, not in an institution, and includes the subset of older adults who have mild cognitive impairment and frailty. The goals of treatment should be patient-centered.

DATA BEHIND THE GUIDELINE: THE SPRINT TRIAL

The Systolic Blood Pressure Intervention Trial (SPRINT)² enrolled 9,361 patients who, to enter, had to be at least 50 years old (the mean age was 67.9), have a systolic blood pressure of 130 to 180 mm Hg (the mean was 139.7 mm Hg), and be at risk of cardiovascular disease due to chronic kidney disease, clinical or subclinical cardiovascular disease, a 10-year Framingham risk score of at least 15%, or age 75 or older. They had few comorbidities, and patients with diabetes mellitus or prior stroke were excluded. The objective was to see if intensive blood pressure treatment reduced the incidence of adverse cardiovascular outcomes compared with standard control.

The participants were randomized to either an intensive treatment goal of systolic pressure less than 120 mm Hg or a standard treatment goal of less than 140 mm Hg. Investigators chose drugs and doses according to their clinical judgment. The study protocol called for blood pressure measurement using an untended automated cuff, which probably resulted in systolic pressure readings 5 to 10 mm Hg lower than with typical methods used in the office.³

The intensive treatment group achieved a mean systolic pressure of 121.5 mm Hg, which required an average of 3 drugs. In contrast, the standard treatment group achieved a systolic pressure of 136.2 mm Hg, which required an average of 1.9 drugs.

Due to an absolute risk reduction in cardiovascular events and mortality, SPRINT was discontinued early after a median follow-up of 3.3 years. In the entire cohort, 61 patients needed to be treated intensively to prevent 1 cardiovascular event, and 90 needed to be treated intensively to prevent 1 death.²

Favorable outcomes in the oldest subgroup

The oldest patients in the SPRINT trial tolerated the intensive treatment as well as the youngest.^2,4

Exploratory analysis of the subgroup of patients age 75 and older, who constituted 28% of the patients in the trial, demonstrated significant benefit from intensive treatment. In this subgroup, 27 patients needed to be treated aggressively (compared with standard treatment) to prevent 1 cardiovascular event,  and 41 needed to be treated intensively to prevent 1 death.⁴ The lower numbers needing to be treated in the older subgroup than in the overall trial reflect the higher absolute risk in this older population.

Serious adverse events were more common with intensive treatment than with standard treatment in the subgroup of older patients who were frail.⁴ Emergency department visits or serious adverse events were more likely when gait speed (a measure of frailty) was missing from the medical record in the intensive treatment group compared with the standard treatment group. Hyponatremia (serum sodium level < 130 mmol/L) was more likely in the intensively treated group than in the standard treatment group. Although the rate of falls was higher in the oldest subgroup than in the overall SPRINT population, within this subgroup the rate of injurious falls resulting in an emergency department visit was lower with intensive treatment than with standard treatment (11.6% vs 14.1%, P = .04).⁴

Most of the oldest patients scored below the nominal cutoff for normal (26 points)⁵ on the 30-point Montreal Cognitive Assessment, and about one-quarter scored below 19, which may be consistent with a major neurocognitive disorder.⁶

The SPRINT investigators validated a frailty scale in the study patients and found that the most frail benefited from intensive blood pressure control, as did the slowest walkers.

SPRINT results do not apply to very frail, sick patients

For older patients with hypertension, a high burden of comorbidity, and a limited life expectancy, the 2017 guidelines defer treatment decisions to clinical judgment and patient preference.

There have been no randomized trials of blood pressure management for older adults with substantial comorbidities or dementia. The “frail” older adults in the SPRINT trial were still living in the community, without dementia. The intensively treated frail older adults had more serious adverse events than with standard treatment. Those who were documented as being unable to walk at the time of enrollment also had more serious adverse events. Institutionalized older adults and nonambulatory adults in the community would likely have even higher rates of serious adverse events with intensive treatment than the SPRINT patients, and there is concern for excessive adverse effects from intensive blood pressure control in more debilitated older patients.

Aging without frailty is an important goal of geriatric care and is likely related to cardiovascular health.⁷ An older adult who becomes slower physically or mentally, with diminished strength and energy, is less likely to be able to live independently.

Would treating systolic blood pressure to a target of 120 to 130 mm Hg reduce the risk of prefrailty or frailty? Unfortunately, the 3-year SPRINT follow-up of the adults age 75 and older did not show any effect of intensive treatment on gait speed or mobility limitation.⁸ It is possible that the early termination of the study limited outcomes.

Regarding cognition, the new guidelines say that lowering blood pressure in adults with hypertension to prevent cognitive decline and dementia is reasonable, giving it a class IIa (moderate) recommendation, but they do not offer a particular blood pressure target.

Two systematic reviews of randomized placebo-controlled trials^9,10 suggested that pharmacologic treatment of hypertension reduces the progression of cognitive impairment. The trials did not use an intensive treatment goal.

The impact of intensive treatment of hypertension (to a target of 120–130 mm Hg) on the development or progression of cognitive impairment is not known at this time. The SPRINT Memory and Cognition in Decreased Hypertension analysis may shed light on the effect of intensive treatment of blood pressure on the incidence of dementia, although the early termination of SPRINT may limit its conclusions as well.

GOALS SHOULD BE PATIENT-CENTERED

The new hypertension guideline gives clinicians 2 things to think about when treating hypertensive, ambulatory, noninstitutionalized, nondemented older adults, including those age 75 and older:

• Older adults tolerate intensive blood pressure treatment as well as standard treatment. In particular, the fall rate is not increased and may even be less with intensive treatment.
• Older adults have better cardiovascular outcomes with blood pressure less than 130 mm Hg than with higher levels.

Adherence to the new guidelines would require many older adults without significant multimorbidity to take 3 drugs and undergo more frequent monitoring. This burden may align with the goals of care for many older adults. However, data do not exist to prove a benefit from intensive blood pressure control in debilitated elderly patients, and there may be harm. Lowering the medication burden may be a more important goal than lowering the pressure for this population. Blood pressure targets and hypertension management should reflect patient-centered goals of care.

We should aim for a standard office systolic pressure lower than 130 mm Hg in most adults age 65 and older if the patient can take multiple antihypertensive medications and be followed closely for adverse effects.

This recommendation is part of the 2017 hypertension guideline from the American College of Cardiology and American Heart Association.¹ This new guideline advocates drug treatment of hypertension to a target less than 130/80 mm Hg for patients of all ages for secondary prevention of cardiovascular disease, and for primary prevention in those at high risk (ie, an estimated 10-year risk of atherosclerotic cardiovascular disease of 10% or higher). The target blood pressure for those at lower risk is less than 140/90 mm Hg.

There are multiple tools to estimate the 10-year risk. All tools incorporate major predictors such as age, blood pressure, cholesterol profile, and other markers, depending on the tool. Although risk increases with age, the tools are inaccurate once the patient is approximately 80 years of age.

The recommendation for older adults omits a target diastolic pressure, since treating elevated systolic pressure has more data supporting it than treating elevated diastolic blood pressure in older people. These recommendations apply only to older adults who can walk and are living in the community, not in an institution, and includes the subset of older adults who have mild cognitive impairment and frailty. The goals of treatment should be patient-centered.

DATA BEHIND THE GUIDELINE: THE SPRINT TRIAL

The Systolic Blood Pressure Intervention Trial (SPRINT)² enrolled 9,361 patients who, to enter, had to be at least 50 years old (the mean age was 67.9), have a systolic blood pressure of 130 to 180 mm Hg (the mean was 139.7 mm Hg), and be at risk of cardiovascular disease due to chronic kidney disease, clinical or subclinical cardiovascular disease, a 10-year Framingham risk score of at least 15%, or age 75 or older. They had few comorbidities, and patients with diabetes mellitus or prior stroke were excluded. The objective was to see if intensive blood pressure treatment reduced the incidence of adverse cardiovascular outcomes compared with standard control.

The participants were randomized to either an intensive treatment goal of systolic pressure less than 120 mm Hg or a standard treatment goal of less than 140 mm Hg. Investigators chose drugs and doses according to their clinical judgment. The study protocol called for blood pressure measurement using an untended automated cuff, which probably resulted in systolic pressure readings 5 to 10 mm Hg lower than with typical methods used in the office.³

The intensive treatment group achieved a mean systolic pressure of 121.5 mm Hg, which required an average of 3 drugs. In contrast, the standard treatment group achieved a systolic pressure of 136.2 mm Hg, which required an average of 1.9 drugs.

Due to an absolute risk reduction in cardiovascular events and mortality, SPRINT was discontinued early after a median follow-up of 3.3 years. In the entire cohort, 61 patients needed to be treated intensively to prevent 1 cardiovascular event, and 90 needed to be treated intensively to prevent 1 death.²

Favorable outcomes in the oldest subgroup

The oldest patients in the SPRINT trial tolerated the intensive treatment as well as the youngest.^2,4

Exploratory analysis of the subgroup of patients age 75 and older, who constituted 28% of the patients in the trial, demonstrated significant benefit from intensive treatment. In this subgroup, 27 patients needed to be treated aggressively (compared with standard treatment) to prevent 1 cardiovascular event,  and 41 needed to be treated intensively to prevent 1 death.⁴ The lower numbers needing to be treated in the older subgroup than in the overall trial reflect the higher absolute risk in this older population.

Serious adverse events were more common with intensive treatment than with standard treatment in the subgroup of older patients who were frail.⁴ Emergency department visits or serious adverse events were more likely when gait speed (a measure of frailty) was missing from the medical record in the intensive treatment group compared with the standard treatment group. Hyponatremia (serum sodium level < 130 mmol/L) was more likely in the intensively treated group than in the standard treatment group. Although the rate of falls was higher in the oldest subgroup than in the overall SPRINT population, within this subgroup the rate of injurious falls resulting in an emergency department visit was lower with intensive treatment than with standard treatment (11.6% vs 14.1%, P = .04).⁴

Most of the oldest patients scored below the nominal cutoff for normal (26 points)⁵ on the 30-point Montreal Cognitive Assessment, and about one-quarter scored below 19, which may be consistent with a major neurocognitive disorder.⁶

The SPRINT investigators validated a frailty scale in the study patients and found that the most frail benefited from intensive blood pressure control, as did the slowest walkers.

SPRINT results do not apply to very frail, sick patients

For older patients with hypertension, a high burden of comorbidity, and a limited life expectancy, the 2017 guidelines defer treatment decisions to clinical judgment and patient preference.

There have been no randomized trials of blood pressure management for older adults with substantial comorbidities or dementia. The “frail” older adults in the SPRINT trial were still living in the community, without dementia. The intensively treated frail older adults had more serious adverse events than with standard treatment. Those who were documented as being unable to walk at the time of enrollment also had more serious adverse events. Institutionalized older adults and nonambulatory adults in the community would likely have even higher rates of serious adverse events with intensive treatment than the SPRINT patients, and there is concern for excessive adverse effects from intensive blood pressure control in more debilitated older patients.

Aging without frailty is an important goal of geriatric care and is likely related to cardiovascular health.⁷ An older adult who becomes slower physically or mentally, with diminished strength and energy, is less likely to be able to live independently.

Would treating systolic blood pressure to a target of 120 to 130 mm Hg reduce the risk of prefrailty or frailty? Unfortunately, the 3-year SPRINT follow-up of the adults age 75 and older did not show any effect of intensive treatment on gait speed or mobility limitation.⁸ It is possible that the early termination of the study limited outcomes.

Regarding cognition, the new guidelines say that lowering blood pressure in adults with hypertension to prevent cognitive decline and dementia is reasonable, giving it a class IIa (moderate) recommendation, but they do not offer a particular blood pressure target.

Two systematic reviews of randomized placebo-controlled trials^9,10 suggested that pharmacologic treatment of hypertension reduces the progression of cognitive impairment. The trials did not use an intensive treatment goal.

The impact of intensive treatment of hypertension (to a target of 120–130 mm Hg) on the development or progression of cognitive impairment is not known at this time. The SPRINT Memory and Cognition in Decreased Hypertension analysis may shed light on the effect of intensive treatment of blood pressure on the incidence of dementia, although the early termination of SPRINT may limit its conclusions as well.

GOALS SHOULD BE PATIENT-CENTERED

The new hypertension guideline gives clinicians 2 things to think about when treating hypertensive, ambulatory, noninstitutionalized, nondemented older adults, including those age 75 and older:

• Older adults tolerate intensive blood pressure treatment as well as standard treatment. In particular, the fall rate is not increased and may even be less with intensive treatment.
• Older adults have better cardiovascular outcomes with blood pressure less than 130 mm Hg than with higher levels.

Adherence to the new guidelines would require many older adults without significant multimorbidity to take 3 drugs and undergo more frequent monitoring. This burden may align with the goals of care for many older adults. However, data do not exist to prove a benefit from intensive blood pressure control in debilitated elderly patients, and there may be harm. Lowering the medication burden may be a more important goal than lowering the pressure for this population. Blood pressure targets and hypertension management should reflect patient-centered goals of care.

We should aim for a standard office systolic pressure lower than 130 mm Hg in most adults age 65 and older if the patient can take multiple antihypertensive medications and be followed closely for adverse effects.

This recommendation is part of the 2017 hypertension guideline from the American College of Cardiology and American Heart Association.¹ This new guideline advocates drug treatment of hypertension to a target less than 130/80 mm Hg for patients of all ages for secondary prevention of cardiovascular disease, and for primary prevention in those at high risk (ie, an estimated 10-year risk of atherosclerotic cardiovascular disease of 10% or higher). The target blood pressure for those at lower risk is less than 140/90 mm Hg.

There are multiple tools to estimate the 10-year risk. All tools incorporate major predictors such as age, blood pressure, cholesterol profile, and other markers, depending on the tool. Although risk increases with age, the tools are inaccurate once the patient is approximately 80 years of age.

The recommendation for older adults omits a target diastolic pressure, since treating elevated systolic pressure has more data supporting it than treating elevated diastolic blood pressure in older people. These recommendations apply only to older adults who can walk and are living in the community, not in an institution, and includes the subset of older adults who have mild cognitive impairment and frailty. The goals of treatment should be patient-centered.

DATA BEHIND THE GUIDELINE: THE SPRINT TRIAL

The Systolic Blood Pressure Intervention Trial (SPRINT)² enrolled 9,361 patients who, to enter, had to be at least 50 years old (the mean age was 67.9), have a systolic blood pressure of 130 to 180 mm Hg (the mean was 139.7 mm Hg), and be at risk of cardiovascular disease due to chronic kidney disease, clinical or subclinical cardiovascular disease, a 10-year Framingham risk score of at least 15%, or age 75 or older. They had few comorbidities, and patients with diabetes mellitus or prior stroke were excluded. The objective was to see if intensive blood pressure treatment reduced the incidence of adverse cardiovascular outcomes compared with standard control.

The participants were randomized to either an intensive treatment goal of systolic pressure less than 120 mm Hg or a standard treatment goal of less than 140 mm Hg. Investigators chose drugs and doses according to their clinical judgment. The study protocol called for blood pressure measurement using an untended automated cuff, which probably resulted in systolic pressure readings 5 to 10 mm Hg lower than with typical methods used in the office.³

The intensive treatment group achieved a mean systolic pressure of 121.5 mm Hg, which required an average of 3 drugs. In contrast, the standard treatment group achieved a systolic pressure of 136.2 mm Hg, which required an average of 1.9 drugs.

Due to an absolute risk reduction in cardiovascular events and mortality, SPRINT was discontinued early after a median follow-up of 3.3 years. In the entire cohort, 61 patients needed to be treated intensively to prevent 1 cardiovascular event, and 90 needed to be treated intensively to prevent 1 death.²

Favorable outcomes in the oldest subgroup

The oldest patients in the SPRINT trial tolerated the intensive treatment as well as the youngest.^2,4

Exploratory analysis of the subgroup of patients age 75 and older, who constituted 28% of the patients in the trial, demonstrated significant benefit from intensive treatment. In this subgroup, 27 patients needed to be treated aggressively (compared with standard treatment) to prevent 1 cardiovascular event,  and 41 needed to be treated intensively to prevent 1 death.⁴ The lower numbers needing to be treated in the older subgroup than in the overall trial reflect the higher absolute risk in this older population.

Serious adverse events were more common with intensive treatment than with standard treatment in the subgroup of older patients who were frail.⁴ Emergency department visits or serious adverse events were more likely when gait speed (a measure of frailty) was missing from the medical record in the intensive treatment group compared with the standard treatment group. Hyponatremia (serum sodium level < 130 mmol/L) was more likely in the intensively treated group than in the standard treatment group. Although the rate of falls was higher in the oldest subgroup than in the overall SPRINT population, within this subgroup the rate of injurious falls resulting in an emergency department visit was lower with intensive treatment than with standard treatment (11.6% vs 14.1%, P = .04).⁴

Most of the oldest patients scored below the nominal cutoff for normal (26 points)⁵ on the 30-point Montreal Cognitive Assessment, and about one-quarter scored below 19, which may be consistent with a major neurocognitive disorder.⁶

The SPRINT investigators validated a frailty scale in the study patients and found that the most frail benefited from intensive blood pressure control, as did the slowest walkers.

SPRINT results do not apply to very frail, sick patients

For older patients with hypertension, a high burden of comorbidity, and a limited life expectancy, the 2017 guidelines defer treatment decisions to clinical judgment and patient preference.

There have been no randomized trials of blood pressure management for older adults with substantial comorbidities or dementia. The “frail” older adults in the SPRINT trial were still living in the community, without dementia. The intensively treated frail older adults had more serious adverse events than with standard treatment. Those who were documented as being unable to walk at the time of enrollment also had more serious adverse events. Institutionalized older adults and nonambulatory adults in the community would likely have even higher rates of serious adverse events with intensive treatment than the SPRINT patients, and there is concern for excessive adverse effects from intensive blood pressure control in more debilitated older patients.

Aging without frailty is an important goal of geriatric care and is likely related to cardiovascular health.⁷ An older adult who becomes slower physically or mentally, with diminished strength and energy, is less likely to be able to live independently.

Would treating systolic blood pressure to a target of 120 to 130 mm Hg reduce the risk of prefrailty or frailty? Unfortunately, the 3-year SPRINT follow-up of the adults age 75 and older did not show any effect of intensive treatment on gait speed or mobility limitation.⁸ It is possible that the early termination of the study limited outcomes.

Regarding cognition, the new guidelines say that lowering blood pressure in adults with hypertension to prevent cognitive decline and dementia is reasonable, giving it a class IIa (moderate) recommendation, but they do not offer a particular blood pressure target.

Two systematic reviews of randomized placebo-controlled trials^9,10 suggested that pharmacologic treatment of hypertension reduces the progression of cognitive impairment. The trials did not use an intensive treatment goal.

The impact of intensive treatment of hypertension (to a target of 120–130 mm Hg) on the development or progression of cognitive impairment is not known at this time. The SPRINT Memory and Cognition in Decreased Hypertension analysis may shed light on the effect of intensive treatment of blood pressure on the incidence of dementia, although the early termination of SPRINT may limit its conclusions as well.

GOALS SHOULD BE PATIENT-CENTERED

The new hypertension guideline gives clinicians 2 things to think about when treating hypertensive, ambulatory, noninstitutionalized, nondemented older adults, including those age 75 and older:

• Older adults tolerate intensive blood pressure treatment as well as standard treatment. In particular, the fall rate is not increased and may even be less with intensive treatment.
• Older adults have better cardiovascular outcomes with blood pressure less than 130 mm Hg than with higher levels.

Adherence to the new guidelines would require many older adults without significant multimorbidity to take 3 drugs and undergo more frequent monitoring. This burden may align with the goals of care for many older adults. However, data do not exist to prove a benefit from intensive blood pressure control in debilitated elderly patients, and there may be harm. Lowering the medication burden may be a more important goal than lowering the pressure for this population. Blood pressure targets and hypertension management should reflect patient-centered goals of care.

A 67-year-old woman presents to the emergency department after 8 weeks of progressive numbness and tingling in both hands, involving all fingers. The numbness has increased in severity in the last 3 days. She also has occasional numbness around her mouth. She reports no numbness in her feet.

She says she underwent thyroid surgery twice for thyroid cancer 10 years ago. Her medical history also includes type 2 diabetes mellitus (diagnosed 1 year ago), hypertension, dyslipidemia, and diastolic heart failure (diagnosed 5 years ago).

Her current medications are:

• Metformin 1 g twice a day
• Candesartan 16 mg once a day
• Atorvastatin 20 mg once a day
• Furosemide 40 mg twice a day
• Levothyroxine 100 μg per day
• Calcium carbonate 1,500 mg twice a day
• A vitamin D tablet twice a day, which she has not taken for the last 2 months.

She admits she has not been taking her medications regularly because she has been feeling depressed.

On physical examination, she is alert and oriented but appears anxious. She is not in res­piratory distress. Her blood pressure is 150/90 mm Hg and her pulse is 92 beats per minute and regular. There is a thyroidectomy scar on the anterior neck. Her jugular venous pressure is not elevated. Her heart sounds are normal without extra sounds. She has no pulmonary rales and no lower-extremity edema.

The Phalen test and Tinel test for carpal tunnel syndrome are negative in both hands. Using a Katz hand diagram, the patient reports tingling and numbness in all fingers, both palms, and the dorsum of both hands. Tapping the area over the facial nerve does not elicit twitching of the facial muscles (ie, no Chvostek sign), but compression of the upper arm elicits carpal spasm (ie, positive Trousseau sign). There is no evidence of motor weakness in her hands. The rest of the physical examination is unremarkable.

POSSIBLE CAUSES OF NUMBNESS

1. Based on the initial evaluation, which of the following is the most likely cause of our patient’s bilateral hand numbness?

• Hypocalcemia due to primary hypoparathyroidism
• Carpal tunnel syndrome due to primary hypothyroidism
• Diabetic peripheral neuropathy
• Vitamin B₁₂ deficiency due to metformin
• Hypocalcemia due to low serum calcitonin

All the conditions above except low serum calcitonin can cause bilateral hand paresthesia. Our patient most likely has hypocalcemia due to primary hypoparathyroidism.

Hypocalcemia

In our patient, bilateral hand numbness and perioral numbness after stopping vitamin D and a positive Trousseau sign strongly suggest hypocalcemia. The classic physical findings in patients with hypocalcemia are the Trousseau sign and the Chvostek sign. The Trousseau sign is elicited by inflating a blood pressure cuff above the systolic blood pressure for 3 minutes and observing for ischemia-induced carpopedal spasm, wrist and metacarpophalangeal joint flexion, thumb adduction, and interphalangeal joint extension. The Chvostek sign is elicited by tapping over the area of the facial nerve below the zygoma in front of the tragus, resulting in ipsilateral twitching of facial muscles.

Although the Trousseau sign is more sensitive and specific than the Chvostek sign, neither is pathognomonic for hypocalcemia.¹ The Chvostek sign has been reported to be negative in 30% of patients with hypocalcemia and positive in 10% of normocalcemic individuals.¹ The Trousseau sign, however, is present in 94% of hypocalcemic patients vs 1% of normocalcemic individuals.²

Primary hypoparathyroidism secondary to thyroidectomy. Postsurgical hypoparathyroidism is the most common cause of primary hypoparathyroidism. It results from ischemic injury or accidental removal of the parathyroid glands during anterior neck surgery.^3,4 The consequent hypocalcemia can be transient, intermittent, or permanent. Permanent postsurgical hypoparathyroidism is defined as persistent hypocalcemia with insufficient parathyroid hormone (PTH) for more than 12 months after neck surgery; however, some consider 6 months to be enough to define the condition.^5–7

The incidence of postsurgical hypoparathyroidism varies considerably with the extent of thyroid surgery and the experience of the surgeon.^6,8 In the hands of experienced surgeons, permanent hypoparathyroidism occurs in fewer than 1% of patients after total thyroidectomy, whereas the rate may be higher than 6% with less-experienced surgeons.^5,9 Other risk factors for postsurgical hypoparathyroidism include female sex, autoimmune thyroid disease, pregnancy, and lactation.⁵

Pseudohypoparathyroidism is a group of disorders characterized by renal resistance to PTH, leading to hypocalcemia, hyperphosphatemia, and elevated serum PTH. It is also associated with phenotypic features such as short stature and short fourth metacarpal bones.

Calcitonin deficiency. Calcitonin is a polypeptide hormone secreted from the parafollicular (C) cells of the thyroid gland. After total thyroidectomy, calcitonin levels are expected to be reduced. However, the role of calcitonin in humans is unclear. One study has shown that calcitonin is possibly a vestigial hormone, given that no calcitonin-related disorders (excess or deficiency) have been reported in humans.¹⁰

Our patient also could have primary hypothyroidism as a result of thyroidectomy. Hypothyroidism can cause bilateral hand numbness due to carpal tunnel syndrome, which is mediated by mucopolysaccharide deposition and synovial membrane swelling.¹¹ One study reported that 29% of patients with hypothyroidism had carpal tunnel syndrome.¹² Symptoms of carpal tunnel syndrome in hypothyroid patients may occur despite thyroid replacement therapy.¹³

Carpal tunnel syndrome is a clinical diagnosis. Patients usually experience hand paresthesia in the distribution of the median nerve. Provocative physical tests for carpal tunnel syndrome include the Tinel test, the Phalen test, and the Katz hand diagram, which is considered the best of the 3 tests.^14,15 Based on how the patient marks the location and type of symptoms on the diagram, carpal tunnel syndrome is rated as classic, probable, possible, or unlikely (Table 1).^14,16,17 The sensitivity of a classic or probable diagram ranges from 64% to 80%, while the specificity ranges from 73% to 90%.^14,15

Carpal tunnel syndrome is less likely to be the cause of our patient’s symptoms, as her Katz hand diagram indicates only “possible” carpal tunnel syndrome. Her perioral numbness and positive Trousseau sign make hypocalcemia a more likely cause.

Diabetic peripheral neuropathy

Sensory peripheral neuropathy is a recognized complication of diabetes mellitus. However, neuropathy in diabetic patients most commonly manifests initially as distal symmetrical ascending neuropathy starting in the lower extremities.¹⁸ Therefore, diabetic peripheral neuropathy is less likely in this patient since her symptoms are limited to her hands.

Vitamin B₁₂ deficiency

Metformin-induced vitamin B₁₂ deficiency is another possible cause of peripheral neuropathy. It might be secondary to metformin-induced changes in intrinsic factor levels and small-intestine motility with resultant bacterial overgrowth, as well as inhibition of vitamin B₁₂ absorption in the terminal ileum.¹⁹

However, metformin-induced vitamin B₁₂ deficiency is not the most likely cause of our patient’s neuropathy, since she has been taking this drug for only 1 year. Vitamin B₁₂ deficiency with consequent peripheral neuropathy is more likely in patients taking metformin in high doses for 10 or more years.²⁰

Laboratory results and electrocardiography

Table 2 shows the patient’s initial laboratory results. Of note, her serum calcium level is 5.7 mg/dL (reference range 8.9–10.1). Electrocardiography in the emergency department shows:

• Prolonged PR interval (23 msec)
• Wide QRS complexes (13 msec)
• Flat T waves
• Prolonged corrected QT interval (475 msec)
• Occasional premature ventricular complexes.

CLINICAL MANIFESTATIONS OF HYPOCALCEMIA

2. Which of the following is not a manifestation of hypocalcemia?

• Tonic-clonic seizures
• Cyanosis
• Cardiac ventricular arrhythmias
• Acute pancreatitis
• Depression

Hypocalcemia can cause a wide range of clinical manifestations (Table 3), the extent and severity of which depend on the severity of hypocalcemia and how quickly it develops. The more acute the hypocalcemia, the more severe the manifestations.²¹

Tetany can cause seizures

Hypocalcemia is characterized by neuromuscular hyperexcitability, manifested clinically by tetany.²² Manifestations of tetany are numerous and include acral paresthesia, perioral numbness, muscle cramps, carpopedal spasm, and seizures. Tetany is the hallmark of hypocalcemia regardless of etiology. However, certain causes are associated with peculiar clinical manifestations. For example, chronic primary hypoparathyroidism may be associated with basal ganglia calcifications that can result in parkinsonism, other extrapyramidal disorders, and dementia (Table 4).⁶

Airway spasm can be fatal

A serious manifestation of acute severe hypocalcemia is spasm of the glottis muscles, which may cause cyanosis and, if untreated, death.²¹

Ventricular arrhythmias

Another potential fatal complication of acute severe hypocalcemia is polymorphic ventricular tachycardia due to prolongation of the QT interval, which is readily identified with electrocardiography.²³

Hypocalcemia does not cause pancreatitis

Hypercalcemia, rather than hypocalcemia, may cause acute pancreatitis.²⁴ Conversely, acute pancreatitis may cause hypocalcemia due to precipitation of calcium in the abdominal cavity.²⁵

Psychiatric manifestations

In addition to depression, hypocalcemia is associated with psychiatric manifestations including anxiety, confusion, and emotional instability.

STEPS TO DIAGNOSIS OF HYPOCALCEMIA

First step: Confirm true hypocalcemia

Calcium circulates in the blood in 3 forms: bound to albumin (40% to 45%), bound to anions (10% to 15%), and free (ionized) (45%). Although ionized calcium is the active form, most laboratories report total serum calcium.

Since changes in serum albumin concentration affect the total serum calcium level, it is imperative to correct the measured serum calcium to the serum albumin concentration. Each 1-g/dL decrease in serum albumin lowers the total serum calcium by 0.8 mg/dL. Thus:

Corrected serum calcium (mg/dL) =
measured total serum calcium (mg/dL) +
0.8 (4 − serum albumin [g/dL]).

If the patient’s serum calcium level remains low when corrected for serum albumin, he or she has true hypocalcemia, which implies a low ionized serum calcium. Conversely, pseudohypocalcemia means that the measured calcium level is low but the corrected serum calcium is normal.

Using this formula, our patient’s corrected calcium level is calculated as 5.7 + 0.8 (4 – 3.2) = 6.3 mg/dL, indicating true hypocalcemia.

PHOSPHATE IS OFTEN HIGH WHEN CALCIUM IS LOW

In addition to hypocalcemia, our patient has an elevated phosphate level (Table 2).

3. Which of the following hypocalcemic disorders is not associated with hyperphosphatemia?

• End-stage renal disease
• Primary hypoparathyroidism
• Pseudohypoparathyroidism
• Vitamin D₃ deficiency
• Rhabdomyolysis

Vitamin D deficiency is not associated with hyperphosphatemia.

Second step in evaluating hypocalcemia: Check phosphate, magnesium, creatinine

The major causes of hypocalcemia can be categorized according to the serum phosphate level: high vs normal or low (Table 5).

High-phosphate, low-calcium states. In the absence of concurrent end-stage renal disease and an excessive phosphate load, primary hypoparathyroidism is the most likely cause of hypocalcemia associated with hyperphosphatemia.

PTH increases serum ionized calcium by^26,27:

• Increasing bone resorption
• Increasing reabsorption of calcium from the distal renal tubules
• Increasing the activity of 1-alpha-hydroxylase, responsible for conversion of 25-hydroxyvitamin D₃ to 1,25-dihydroxyvitamin D₃ (the most biologically active vitamin D metabolite); 1,25-dihydroxyvitamin D increases the absorption of calcium and phosphate from the intestine.

Conversely, PTH decreases reabsorption of phosphate from proximal renal tubules, resulting in hypophosphatemia. Therefore, low serum PTH (primary hypoparathyroidism) or a PTH-resistant state (pseudohypoparathyroidism) results in hypocalcemia and hyperphosphatemia.^26,27

Both end-stage renal disease and rhabdomyolysis are associated with high serum phosphate levels. The kidney normally excretes excess dietary phosphate to maintain phosphate homeostasis; however, this is impaired in end-stage renal disease, leading to hyperphosphatemia. In rhabdomyolysis, it is mainly the transcellular shift of phosphate into the extracellular space from myocyte injury that raises phosphate levels.

Normal- or low-phosphate, low calcium states. Hypocalcemia can also result from vitamin D deficiency, but this cause is associated with a low or normal serum phosphate level. In such cases, hypocalcemia causes secondary hyperparathyroidism with consequent renal phosphate loss and, thus, hypophosphatemia.²⁷

Third step: Check serum intact PTH and 25-hydroxyvitamin D levels

Hypocalcemia stimulates secretion of PTH. Therefore, hypocalcemia with elevated serum PTH is caused by disorders that do not impair PTH secretion, including chronic renal failure and vitamin D deficiency (Table 5). Conversely, hypocalcemia with low or normal serum PTH levels suggests primary hypoparathyroidism.

Our patient’s serum PTH level is 20 ng/mL, which is within the reference range. This does not discount the diagnosis of primary hypoparathyroidism. Although most patients with primary hypoparathyroidism have low or undetectable serum PTH levels, some have normal PTH levels if some degree of PTH production is preserved.^5,7,28–30 In these patients, the remaining functioning parathyroid tissue is not enough to maintain a normal serum calcium level, resulting in hypocalcemia. As a result, hypocalcemia stimulates the remaining parathyroid tissue to its maximum output, producing PTH levels usually within the lower or middle-normal range.³⁰ In such patients, the terms parathyroid insufficiency and relative primary hypoparathyroidism are more precise than primary hypoparathyroidism.

Postsurgical hypoparathyroidism with an inappropriately normal PTH level is usually seen in patients with disorders that impair intestinal calcium absorption or bone resorption.³¹ In our patient’s case, the “normal” serum PTH level is likely due to maximal stimulation of remaining functioning parathyroid tissue by severe hypocalcemia, which is a result of her discontinuation of calcium and calcitriol therapy and her vitamin D deficiency.

CASE RESUMED: NO RESPONSE TO INTRAVENOUS CALCIUM GLUCONATE

The patient is given 2 10-mL ampules of 10% calcium gluconate diluted in 100 mL of 5% dextrose in water over 20 minutes intravenously. Electrocardiographic monitoring is continued. Two hours later, her measured serum calcium is only 5.8 mg/dL, with no improvement in her symptoms.

A continuous infusion of calcium gluconate is started: 12 ampules of calcium gluconate are added to 380 mL of 5% dextrose in water and infused at 40 mL/hour (infused rate of elemental calcium = 1.3 mg/kg/hour); 3 hours later, her measured serum calcium level is still only 5.8 mg//dL; at 6 hours it is 5.9 mg/dL, and her symptoms have not improved.

4. Which of the following is the most appropriate next step?

• Change the calcium gluconate to calcium chloride
• Increase the infusion rate to 1.5 mg of elemental calcium/kg/hour
• Give a bolus of 2 10-mL ampules of 10% calcium gluconate intravenously over 1 minute
• Give additional oral calcium tablets
• Check the serum magnesium level

Treatment of hypocalcemia can involve intravenous or oral calcium therapy.

Intravenous calcium is indicated for patients with any of the following^6,32:

• Moderate to severe neuromuscular irritability (eg, acral paresthesia, carpopedal spasm, prolonged QT interval, seizures, laryngospasm, bronchospasm)
• Acute hypocalcemia with corrected serum calcium level less than 7.6 mg/dL, even if the patient is asymptomatic
• Cardiac failure.

One 10-mL ampule of 10% calcium gluconate contains 93 mg of elemental calcium; 1 or 2 ampules are typically diluted in 50 to 100 mL of 5% dextrose in water and infused slowly over 15 to 20 minutes. Rapid administration of intravenous calcium is contraindicated, as it may produce cardiac arrhythmias and possibly cardiac arrest. Therefore, intravenous calcium should be given slowly while continuing electrocardiographic monitoring.³³

Since the effect of 1 ampule of calcium gluconate lasts only 2 to 3 hours, most patients with symptomatic hypocalcemia require continuous intravenous calcium infusion. The recommended dose of infused elemental calcium is 0.5 to 1.5 mg/kg/hour.³⁴ Several ampules are added to 500 to 1,000 mL of 5% dextrose in water or 0.9% normal saline and infused at a rate appropriate for the patient’s corrected calcium and symptoms.

Oral calcium and vitamin D supplements can be given initially to patients with a corrected serum calcium level of 7.6 mg/dL or greater, with or without mild symptoms, if they can tolerate oral intake. However, this is not the treatment of choice for resistant acute hypocalcemia, as in this case.

Calcium chloride has no advantages over calcium gluconate. Further, it can be associated with local irritation and may result in tissue necrosis if extravasation occurs.³⁵

Increasing the infusion rate of calcium gluconate to the maximum recommended dose may improve the patient’s ionized calcium level and symptoms somewhat. However, it is not the best option for this patient, given that she did not respond to 2 ampules of calcium gluconate followed by continuous infusion of 1.3 mg/kg/hour for 6 hours.

Calcium gluconate bolus. Similarly, giving the patient an additional 2 ampules of calcium gluconate over 1 minute would not be recommended, as rapid administration of intravenous calcium gluconate (eg, over 1 minute) is contraindicated.

Check magnesium

If hypocalcemia persists despite intravenous calcium therapy, as in our patient, further investigation or action is required. An important cause of persistent hypocalcemia is severe hypomagnesemia. Severe hypomagnesemia (serum magnesium < 0.8 mg/dL) causes resistant hypocalcemia by several mechanisms:

• Inducing PTH resistance^32,36,37
• Decreasing PTH secretion^32,36
• Decreasing calcitriol production.

The decrease in calcitriol production is a direct effect of hypomagnesemia, but it is also an indirect effect of low PTH secretion, which inhibits the enzyme 1-alpha-hydroxylase. Thus, conversion of 25-hydroxyvitamin D₃ to calcitriol is impaired, leading to low calcitriol production.

Our patient could have hypomagnesemia due to furosemide use and uncontrolled diabetes mellitus. Hypocalcemia resistant to calcium therapy may occasionally respond to magnesium therapy even if the serum magnesium level is normal. This may be due to depleted intracellular magnesium salt levels.^6,38 Rarely, severe hypermagnesemia can also be associated with hypocalcemia due to inhibition of PTH secretion.^37,39

CASE RESUMED

Our patient’s serum magnesium level is 0.6 mg/dL (reference range 1.7–2.4 mg/dL). She is given 2 g of magnesium sulfate in 60 mL of 0.9% normal saline infused over 1 hour, followed by a continuous infusion of magnesium sulfate (12 g diluted in 250 mL of 0.9% normal saline, infused over 24 hours). On repeat testing 4 hours later, her serum magnesium level is 0.7 mg/dL, and at 8 hours later it is 0.9 mg/dL. She is subsequently started on oral magnesium oxide 600 mg per day. The magnesium sulfate infusion is continued for another 24 hours.

PREVENTING HYPERCALCIURIA

Patients with low PTH (primary hypoparathyroidism) may have hypercalciuria due to decreased renal tubular calcium reabsorption. Two important measures can minimize hypercalciuria in such patients:

• Keeping the serum calcium level in the low-normal range^4,5,40
• Giving a thiazide diuretic (eg, hydrochlorothiazide 12.5–50 mg daily) with a low-salt diet.^41,42

A thiazide diuretic is usually started once the 24-hour urine calcium reaches 250 mg.⁶ Thiazides are thought to enhance both proximal and distal renal tubular calcium reabsorption.^43,44

PRIMARY HYPOPARATHYROIDISM: LONG-TERM MANAGEMENT

Long-term management of primary hypoparathyroidism requires calcium and vitamin D supplementation.

Calcium supplements. The most commonly prescribed calcium preparations are calcium carbonate and calcium citrate (containing 40% and 20% elemental calcium, respectively). Calcium carbonate, which is less expensive than calcium citrate, binds with phosphate intake and requires an acidic environment for absorption, and so it is better absorbed when taken with meals. Because calcium citrate does not require an acidic environment for absorption, it is the calcium preparation of choice for patients on proton pump inhibitors, or patients with achlorhydria or constipation.⁴⁵ Calcium doses vary widely, with most hypoparathyroid patients requiring 1 to 2 g of elemental calcium daily.⁶

Vitamin D supplements. To promote intestinal absorption, calcium is combined with vitamin D in a fixed-dose preparation given in divided doses.⁴⁶ Calcitriol (1,25-dihydroxyvitamin D₃) is the most active metabolite of vitamin D, with rapid onset and offset of action, and it is the preferred form of vitamin D therapy for patients with hypoparathyroidism. If calcitriol is not available or is not affordable, alphacalcidol (1-alpha-hydroxyvitamin D₃) is another option. This is a synthetic analogue of vitamin D that is already hyroxylated at the C1 position. After oral intake, it is hydroxylated in the liver to form calcitriol.

Since renal production of calcitriol is PTH-dependent, in hypoparathyroidism the conversion of 25-hydroxyvitamin D₃ to calcitriol is limited. Therefore, vitamin D₃ (cholecalciferol) and vitamin D₂ (ergocalciferol) are not the preferred forms of vitamin D for such patients. However, either can be added to calcitriol, as they may have extraskeletal benefits.⁷

CASE CONCLUDED

Our patient presented with primary parathyroid insufficiency associated with vitamin D deficiency. Therefore, in addition to calcitriol and calcium combined with vitamin D in a fixed-dose preparation, her management included vitamin D₃ for her vitamin D deficiency.

She was discharged on these medications. At a follow-up visit 3 weeks later, her measured serum calcium level was 8.6 mg/dL. She reported gradual resolution of her symptoms. She was also referred to a psychiatrist for her depression.

TAKE-HOME POINTS

• Hypocalcemia causes neuromuscular excitability, manifested clinically by tetany.
• Common causes of hypocalcemia include vitamin D deficiency, hypomagnesemia, renal failure, and primary hypoparathyroidism.
• The first step in evaluating hypocalcemia is to correct the measured serum calcium to the serum albumin concentration.
• Laboratory testing for hypocalcemia should include serum phosphorus, magnesium, creatinine, PTH, and 25-hydroxyvitamin D₃.
• Primary hypoparathyroidism is characterized by hypocalcemia, hyperphosphatemia, and low serum PTH.
• Moderate to severe manifestations of hypo-
  calcemia and acute hypocalcemia (< 7.6 mg/dL), even if asymptomatic, warrant intravenous calcium therapy.
• Correction of hypomagnesemia is essential to treat hypocalcemia, especially if resistant to intravenous calcium therapy.
• The goal of chronic management of primary hypoparathyroidism includes correcting the serum calcium level to a low-normal range, the serum phosphorus level to an upper-normal range, and prevention of hypercalciuria.

Acknowledgments: The authors wish to thank Mr. Michael Edward Tierney of the School of Medicine, University of Sydney, Australia, for his linguistic editing of the manuscript.

A 67-year-old woman presents to the emergency department after 8 weeks of progressive numbness and tingling in both hands, involving all fingers. The numbness has increased in severity in the last 3 days. She also has occasional numbness around her mouth. She reports no numbness in her feet.

She says she underwent thyroid surgery twice for thyroid cancer 10 years ago. Her medical history also includes type 2 diabetes mellitus (diagnosed 1 year ago), hypertension, dyslipidemia, and diastolic heart failure (diagnosed 5 years ago).

Her current medications are:

• Metformin 1 g twice a day
• Candesartan 16 mg once a day
• Atorvastatin 20 mg once a day
• Furosemide 40 mg twice a day
• Levothyroxine 100 μg per day
• Calcium carbonate 1,500 mg twice a day
• A vitamin D tablet twice a day, which she has not taken for the last 2 months.

She admits she has not been taking her medications regularly because she has been feeling depressed.

On physical examination, she is alert and oriented but appears anxious. She is not in res­piratory distress. Her blood pressure is 150/90 mm Hg and her pulse is 92 beats per minute and regular. There is a thyroidectomy scar on the anterior neck. Her jugular venous pressure is not elevated. Her heart sounds are normal without extra sounds. She has no pulmonary rales and no lower-extremity edema.

The Phalen test and Tinel test for carpal tunnel syndrome are negative in both hands. Using a Katz hand diagram, the patient reports tingling and numbness in all fingers, both palms, and the dorsum of both hands. Tapping the area over the facial nerve does not elicit twitching of the facial muscles (ie, no Chvostek sign), but compression of the upper arm elicits carpal spasm (ie, positive Trousseau sign). There is no evidence of motor weakness in her hands. The rest of the physical examination is unremarkable.

POSSIBLE CAUSES OF NUMBNESS

1. Based on the initial evaluation, which of the following is the most likely cause of our patient’s bilateral hand numbness?

• Hypocalcemia due to primary hypoparathyroidism
• Carpal tunnel syndrome due to primary hypothyroidism
• Diabetic peripheral neuropathy
• Vitamin B₁₂ deficiency due to metformin
• Hypocalcemia due to low serum calcitonin

All the conditions above except low serum calcitonin can cause bilateral hand paresthesia. Our patient most likely has hypocalcemia due to primary hypoparathyroidism.

Hypocalcemia

In our patient, bilateral hand numbness and perioral numbness after stopping vitamin D and a positive Trousseau sign strongly suggest hypocalcemia. The classic physical findings in patients with hypocalcemia are the Trousseau sign and the Chvostek sign. The Trousseau sign is elicited by inflating a blood pressure cuff above the systolic blood pressure for 3 minutes and observing for ischemia-induced carpopedal spasm, wrist and metacarpophalangeal joint flexion, thumb adduction, and interphalangeal joint extension. The Chvostek sign is elicited by tapping over the area of the facial nerve below the zygoma in front of the tragus, resulting in ipsilateral twitching of facial muscles.

Although the Trousseau sign is more sensitive and specific than the Chvostek sign, neither is pathognomonic for hypocalcemia.¹ The Chvostek sign has been reported to be negative in 30% of patients with hypocalcemia and positive in 10% of normocalcemic individuals.¹ The Trousseau sign, however, is present in 94% of hypocalcemic patients vs 1% of normocalcemic individuals.²

Primary hypoparathyroidism secondary to thyroidectomy. Postsurgical hypoparathyroidism is the most common cause of primary hypoparathyroidism. It results from ischemic injury or accidental removal of the parathyroid glands during anterior neck surgery.^3,4 The consequent hypocalcemia can be transient, intermittent, or permanent. Permanent postsurgical hypoparathyroidism is defined as persistent hypocalcemia with insufficient parathyroid hormone (PTH) for more than 12 months after neck surgery; however, some consider 6 months to be enough to define the condition.^5–7

The incidence of postsurgical hypoparathyroidism varies considerably with the extent of thyroid surgery and the experience of the surgeon.^6,8 In the hands of experienced surgeons, permanent hypoparathyroidism occurs in fewer than 1% of patients after total thyroidectomy, whereas the rate may be higher than 6% with less-experienced surgeons.^5,9 Other risk factors for postsurgical hypoparathyroidism include female sex, autoimmune thyroid disease, pregnancy, and lactation.⁵

Pseudohypoparathyroidism is a group of disorders characterized by renal resistance to PTH, leading to hypocalcemia, hyperphosphatemia, and elevated serum PTH. It is also associated with phenotypic features such as short stature and short fourth metacarpal bones.

Calcitonin deficiency. Calcitonin is a polypeptide hormone secreted from the parafollicular (C) cells of the thyroid gland. After total thyroidectomy, calcitonin levels are expected to be reduced. However, the role of calcitonin in humans is unclear. One study has shown that calcitonin is possibly a vestigial hormone, given that no calcitonin-related disorders (excess or deficiency) have been reported in humans.¹⁰

Our patient also could have primary hypothyroidism as a result of thyroidectomy. Hypothyroidism can cause bilateral hand numbness due to carpal tunnel syndrome, which is mediated by mucopolysaccharide deposition and synovial membrane swelling.¹¹ One study reported that 29% of patients with hypothyroidism had carpal tunnel syndrome.¹² Symptoms of carpal tunnel syndrome in hypothyroid patients may occur despite thyroid replacement therapy.¹³

Carpal tunnel syndrome is a clinical diagnosis. Patients usually experience hand paresthesia in the distribution of the median nerve. Provocative physical tests for carpal tunnel syndrome include the Tinel test, the Phalen test, and the Katz hand diagram, which is considered the best of the 3 tests.^14,15 Based on how the patient marks the location and type of symptoms on the diagram, carpal tunnel syndrome is rated as classic, probable, possible, or unlikely (Table 1).^14,16,17 The sensitivity of a classic or probable diagram ranges from 64% to 80%, while the specificity ranges from 73% to 90%.^14,15

Carpal tunnel syndrome is less likely to be the cause of our patient’s symptoms, as her Katz hand diagram indicates only “possible” carpal tunnel syndrome. Her perioral numbness and positive Trousseau sign make hypocalcemia a more likely cause.

Diabetic peripheral neuropathy

Sensory peripheral neuropathy is a recognized complication of diabetes mellitus. However, neuropathy in diabetic patients most commonly manifests initially as distal symmetrical ascending neuropathy starting in the lower extremities.¹⁸ Therefore, diabetic peripheral neuropathy is less likely in this patient since her symptoms are limited to her hands.

Vitamin B₁₂ deficiency

Metformin-induced vitamin B₁₂ deficiency is another possible cause of peripheral neuropathy. It might be secondary to metformin-induced changes in intrinsic factor levels and small-intestine motility with resultant bacterial overgrowth, as well as inhibition of vitamin B₁₂ absorption in the terminal ileum.¹⁹

However, metformin-induced vitamin B₁₂ deficiency is not the most likely cause of our patient’s neuropathy, since she has been taking this drug for only 1 year. Vitamin B₁₂ deficiency with consequent peripheral neuropathy is more likely in patients taking metformin in high doses for 10 or more years.²⁰

Laboratory results and electrocardiography

Table 2 shows the patient’s initial laboratory results. Of note, her serum calcium level is 5.7 mg/dL (reference range 8.9–10.1). Electrocardiography in the emergency department shows:

• Prolonged PR interval (23 msec)
• Wide QRS complexes (13 msec)
• Flat T waves
• Prolonged corrected QT interval (475 msec)
• Occasional premature ventricular complexes.

CLINICAL MANIFESTATIONS OF HYPOCALCEMIA

2. Which of the following is not a manifestation of hypocalcemia?

• Tonic-clonic seizures
• Cyanosis
• Cardiac ventricular arrhythmias
• Acute pancreatitis
• Depression

Hypocalcemia can cause a wide range of clinical manifestations (Table 3), the extent and severity of which depend on the severity of hypocalcemia and how quickly it develops. The more acute the hypocalcemia, the more severe the manifestations.²¹

Tetany can cause seizures

Hypocalcemia is characterized by neuromuscular hyperexcitability, manifested clinically by tetany.²² Manifestations of tetany are numerous and include acral paresthesia, perioral numbness, muscle cramps, carpopedal spasm, and seizures. Tetany is the hallmark of hypocalcemia regardless of etiology. However, certain causes are associated with peculiar clinical manifestations. For example, chronic primary hypoparathyroidism may be associated with basal ganglia calcifications that can result in parkinsonism, other extrapyramidal disorders, and dementia (Table 4).⁶

Airway spasm can be fatal

A serious manifestation of acute severe hypocalcemia is spasm of the glottis muscles, which may cause cyanosis and, if untreated, death.²¹

Ventricular arrhythmias

Another potential fatal complication of acute severe hypocalcemia is polymorphic ventricular tachycardia due to prolongation of the QT interval, which is readily identified with electrocardiography.²³

Hypocalcemia does not cause pancreatitis

Hypercalcemia, rather than hypocalcemia, may cause acute pancreatitis.²⁴ Conversely, acute pancreatitis may cause hypocalcemia due to precipitation of calcium in the abdominal cavity.²⁵

Psychiatric manifestations

In addition to depression, hypocalcemia is associated with psychiatric manifestations including anxiety, confusion, and emotional instability.

STEPS TO DIAGNOSIS OF HYPOCALCEMIA

First step: Confirm true hypocalcemia

Calcium circulates in the blood in 3 forms: bound to albumin (40% to 45%), bound to anions (10% to 15%), and free (ionized) (45%). Although ionized calcium is the active form, most laboratories report total serum calcium.

Since changes in serum albumin concentration affect the total serum calcium level, it is imperative to correct the measured serum calcium to the serum albumin concentration. Each 1-g/dL decrease in serum albumin lowers the total serum calcium by 0.8 mg/dL. Thus:

Corrected serum calcium (mg/dL) =
measured total serum calcium (mg/dL) +
0.8 (4 − serum albumin [g/dL]).

If the patient’s serum calcium level remains low when corrected for serum albumin, he or she has true hypocalcemia, which implies a low ionized serum calcium. Conversely, pseudohypocalcemia means that the measured calcium level is low but the corrected serum calcium is normal.

Using this formula, our patient’s corrected calcium level is calculated as 5.7 + 0.8 (4 – 3.2) = 6.3 mg/dL, indicating true hypocalcemia.

PHOSPHATE IS OFTEN HIGH WHEN CALCIUM IS LOW

In addition to hypocalcemia, our patient has an elevated phosphate level (Table 2).

3. Which of the following hypocalcemic disorders is not associated with hyperphosphatemia?

• End-stage renal disease
• Primary hypoparathyroidism
• Pseudohypoparathyroidism
• Vitamin D₃ deficiency
• Rhabdomyolysis

Vitamin D deficiency is not associated with hyperphosphatemia.

Second step in evaluating hypocalcemia: Check phosphate, magnesium, creatinine

The major causes of hypocalcemia can be categorized according to the serum phosphate level: high vs normal or low (Table 5).

High-phosphate, low-calcium states. In the absence of concurrent end-stage renal disease and an excessive phosphate load, primary hypoparathyroidism is the most likely cause of hypocalcemia associated with hyperphosphatemia.

PTH increases serum ionized calcium by^26,27:

• Increasing bone resorption
• Increasing reabsorption of calcium from the distal renal tubules
• Increasing the activity of 1-alpha-hydroxylase, responsible for conversion of 25-hydroxyvitamin D₃ to 1,25-dihydroxyvitamin D₃ (the most biologically active vitamin D metabolite); 1,25-dihydroxyvitamin D increases the absorption of calcium and phosphate from the intestine.

Conversely, PTH decreases reabsorption of phosphate from proximal renal tubules, resulting in hypophosphatemia. Therefore, low serum PTH (primary hypoparathyroidism) or a PTH-resistant state (pseudohypoparathyroidism) results in hypocalcemia and hyperphosphatemia.^26,27

Both end-stage renal disease and rhabdomyolysis are associated with high serum phosphate levels. The kidney normally excretes excess dietary phosphate to maintain phosphate homeostasis; however, this is impaired in end-stage renal disease, leading to hyperphosphatemia. In rhabdomyolysis, it is mainly the transcellular shift of phosphate into the extracellular space from myocyte injury that raises phosphate levels.

Normal- or low-phosphate, low calcium states. Hypocalcemia can also result from vitamin D deficiency, but this cause is associated with a low or normal serum phosphate level. In such cases, hypocalcemia causes secondary hyperparathyroidism with consequent renal phosphate loss and, thus, hypophosphatemia.²⁷

Third step: Check serum intact PTH and 25-hydroxyvitamin D levels

Hypocalcemia stimulates secretion of PTH. Therefore, hypocalcemia with elevated serum PTH is caused by disorders that do not impair PTH secretion, including chronic renal failure and vitamin D deficiency (Table 5). Conversely, hypocalcemia with low or normal serum PTH levels suggests primary hypoparathyroidism.

Our patient’s serum PTH level is 20 ng/mL, which is within the reference range. This does not discount the diagnosis of primary hypoparathyroidism. Although most patients with primary hypoparathyroidism have low or undetectable serum PTH levels, some have normal PTH levels if some degree of PTH production is preserved.^5,7,28–30 In these patients, the remaining functioning parathyroid tissue is not enough to maintain a normal serum calcium level, resulting in hypocalcemia. As a result, hypocalcemia stimulates the remaining parathyroid tissue to its maximum output, producing PTH levels usually within the lower or middle-normal range.³⁰ In such patients, the terms parathyroid insufficiency and relative primary hypoparathyroidism are more precise than primary hypoparathyroidism.

Postsurgical hypoparathyroidism with an inappropriately normal PTH level is usually seen in patients with disorders that impair intestinal calcium absorption or bone resorption.³¹ In our patient’s case, the “normal” serum PTH level is likely due to maximal stimulation of remaining functioning parathyroid tissue by severe hypocalcemia, which is a result of her discontinuation of calcium and calcitriol therapy and her vitamin D deficiency.

CASE RESUMED: NO RESPONSE TO INTRAVENOUS CALCIUM GLUCONATE

The patient is given 2 10-mL ampules of 10% calcium gluconate diluted in 100 mL of 5% dextrose in water over 20 minutes intravenously. Electrocardiographic monitoring is continued. Two hours later, her measured serum calcium is only 5.8 mg/dL, with no improvement in her symptoms.

A continuous infusion of calcium gluconate is started: 12 ampules of calcium gluconate are added to 380 mL of 5% dextrose in water and infused at 40 mL/hour (infused rate of elemental calcium = 1.3 mg/kg/hour); 3 hours later, her measured serum calcium level is still only 5.8 mg//dL; at 6 hours it is 5.9 mg/dL, and her symptoms have not improved.

4. Which of the following is the most appropriate next step?

• Change the calcium gluconate to calcium chloride
• Increase the infusion rate to 1.5 mg of elemental calcium/kg/hour
• Give a bolus of 2 10-mL ampules of 10% calcium gluconate intravenously over 1 minute
• Give additional oral calcium tablets
• Check the serum magnesium level

Treatment of hypocalcemia can involve intravenous or oral calcium therapy.

Intravenous calcium is indicated for patients with any of the following^6,32:

• Moderate to severe neuromuscular irritability (eg, acral paresthesia, carpopedal spasm, prolonged QT interval, seizures, laryngospasm, bronchospasm)
• Acute hypocalcemia with corrected serum calcium level less than 7.6 mg/dL, even if the patient is asymptomatic
• Cardiac failure.

One 10-mL ampule of 10% calcium gluconate contains 93 mg of elemental calcium; 1 or 2 ampules are typically diluted in 50 to 100 mL of 5% dextrose in water and infused slowly over 15 to 20 minutes. Rapid administration of intravenous calcium is contraindicated, as it may produce cardiac arrhythmias and possibly cardiac arrest. Therefore, intravenous calcium should be given slowly while continuing electrocardiographic monitoring.³³

Since the effect of 1 ampule of calcium gluconate lasts only 2 to 3 hours, most patients with symptomatic hypocalcemia require continuous intravenous calcium infusion. The recommended dose of infused elemental calcium is 0.5 to 1.5 mg/kg/hour.³⁴ Several ampules are added to 500 to 1,000 mL of 5% dextrose in water or 0.9% normal saline and infused at a rate appropriate for the patient’s corrected calcium and symptoms.

Oral calcium and vitamin D supplements can be given initially to patients with a corrected serum calcium level of 7.6 mg/dL or greater, with or without mild symptoms, if they can tolerate oral intake. However, this is not the treatment of choice for resistant acute hypocalcemia, as in this case.

Calcium chloride has no advantages over calcium gluconate. Further, it can be associated with local irritation and may result in tissue necrosis if extravasation occurs.³⁵

Increasing the infusion rate of calcium gluconate to the maximum recommended dose may improve the patient’s ionized calcium level and symptoms somewhat. However, it is not the best option for this patient, given that she did not respond to 2 ampules of calcium gluconate followed by continuous infusion of 1.3 mg/kg/hour for 6 hours.

Calcium gluconate bolus. Similarly, giving the patient an additional 2 ampules of calcium gluconate over 1 minute would not be recommended, as rapid administration of intravenous calcium gluconate (eg, over 1 minute) is contraindicated.

Check magnesium

If hypocalcemia persists despite intravenous calcium therapy, as in our patient, further investigation or action is required. An important cause of persistent hypocalcemia is severe hypomagnesemia. Severe hypomagnesemia (serum magnesium < 0.8 mg/dL) causes resistant hypocalcemia by several mechanisms:

• Inducing PTH resistance^32,36,37
• Decreasing PTH secretion^32,36
• Decreasing calcitriol production.

The decrease in calcitriol production is a direct effect of hypomagnesemia, but it is also an indirect effect of low PTH secretion, which inhibits the enzyme 1-alpha-hydroxylase. Thus, conversion of 25-hydroxyvitamin D₃ to calcitriol is impaired, leading to low calcitriol production.

Our patient could have hypomagnesemia due to furosemide use and uncontrolled diabetes mellitus. Hypocalcemia resistant to calcium therapy may occasionally respond to magnesium therapy even if the serum magnesium level is normal. This may be due to depleted intracellular magnesium salt levels.^6,38 Rarely, severe hypermagnesemia can also be associated with hypocalcemia due to inhibition of PTH secretion.^37,39

CASE RESUMED

Our patient’s serum magnesium level is 0.6 mg/dL (reference range 1.7–2.4 mg/dL). She is given 2 g of magnesium sulfate in 60 mL of 0.9% normal saline infused over 1 hour, followed by a continuous infusion of magnesium sulfate (12 g diluted in 250 mL of 0.9% normal saline, infused over 24 hours). On repeat testing 4 hours later, her serum magnesium level is 0.7 mg/dL, and at 8 hours later it is 0.9 mg/dL. She is subsequently started on oral magnesium oxide 600 mg per day. The magnesium sulfate infusion is continued for another 24 hours.

PREVENTING HYPERCALCIURIA

Patients with low PTH (primary hypoparathyroidism) may have hypercalciuria due to decreased renal tubular calcium reabsorption. Two important measures can minimize hypercalciuria in such patients:

• Keeping the serum calcium level in the low-normal range^4,5,40
• Giving a thiazide diuretic (eg, hydrochlorothiazide 12.5–50 mg daily) with a low-salt diet.^41,42

A thiazide diuretic is usually started once the 24-hour urine calcium reaches 250 mg.⁶ Thiazides are thought to enhance both proximal and distal renal tubular calcium reabsorption.^43,44

PRIMARY HYPOPARATHYROIDISM: LONG-TERM MANAGEMENT

Long-term management of primary hypoparathyroidism requires calcium and vitamin D supplementation.

Calcium supplements. The most commonly prescribed calcium preparations are calcium carbonate and calcium citrate (containing 40% and 20% elemental calcium, respectively). Calcium carbonate, which is less expensive than calcium citrate, binds with phosphate intake and requires an acidic environment for absorption, and so it is better absorbed when taken with meals. Because calcium citrate does not require an acidic environment for absorption, it is the calcium preparation of choice for patients on proton pump inhibitors, or patients with achlorhydria or constipation.⁴⁵ Calcium doses vary widely, with most hypoparathyroid patients requiring 1 to 2 g of elemental calcium daily.⁶

Vitamin D supplements. To promote intestinal absorption, calcium is combined with vitamin D in a fixed-dose preparation given in divided doses.⁴⁶ Calcitriol (1,25-dihydroxyvitamin D₃) is the most active metabolite of vitamin D, with rapid onset and offset of action, and it is the preferred form of vitamin D therapy for patients with hypoparathyroidism. If calcitriol is not available or is not affordable, alphacalcidol (1-alpha-hydroxyvitamin D₃) is another option. This is a synthetic analogue of vitamin D that is already hyroxylated at the C1 position. After oral intake, it is hydroxylated in the liver to form calcitriol.

Since renal production of calcitriol is PTH-dependent, in hypoparathyroidism the conversion of 25-hydroxyvitamin D₃ to calcitriol is limited. Therefore, vitamin D₃ (cholecalciferol) and vitamin D₂ (ergocalciferol) are not the preferred forms of vitamin D for such patients. However, either can be added to calcitriol, as they may have extraskeletal benefits.⁷

CASE CONCLUDED

Our patient presented with primary parathyroid insufficiency associated with vitamin D deficiency. Therefore, in addition to calcitriol and calcium combined with vitamin D in a fixed-dose preparation, her management included vitamin D₃ for her vitamin D deficiency.

She was discharged on these medications. At a follow-up visit 3 weeks later, her measured serum calcium level was 8.6 mg/dL. She reported gradual resolution of her symptoms. She was also referred to a psychiatrist for her depression.

TAKE-HOME POINTS

• Hypocalcemia causes neuromuscular excitability, manifested clinically by tetany.
• Common causes of hypocalcemia include vitamin D deficiency, hypomagnesemia, renal failure, and primary hypoparathyroidism.
• The first step in evaluating hypocalcemia is to correct the measured serum calcium to the serum albumin concentration.
• Laboratory testing for hypocalcemia should include serum phosphorus, magnesium, creatinine, PTH, and 25-hydroxyvitamin D₃.
• Primary hypoparathyroidism is characterized by hypocalcemia, hyperphosphatemia, and low serum PTH.
• Moderate to severe manifestations of hypo-
  calcemia and acute hypocalcemia (< 7.6 mg/dL), even if asymptomatic, warrant intravenous calcium therapy.
• Correction of hypomagnesemia is essential to treat hypocalcemia, especially if resistant to intravenous calcium therapy.
• The goal of chronic management of primary hypoparathyroidism includes correcting the serum calcium level to a low-normal range, the serum phosphorus level to an upper-normal range, and prevention of hypercalciuria.

Acknowledgments: The authors wish to thank Mr. Michael Edward Tierney of the School of Medicine, University of Sydney, Australia, for his linguistic editing of the manuscript.

A 67-year-old woman presents to the emergency department after 8 weeks of progressive numbness and tingling in both hands, involving all fingers. The numbness has increased in severity in the last 3 days. She also has occasional numbness around her mouth. She reports no numbness in her feet.

She says she underwent thyroid surgery twice for thyroid cancer 10 years ago. Her medical history also includes type 2 diabetes mellitus (diagnosed 1 year ago), hypertension, dyslipidemia, and diastolic heart failure (diagnosed 5 years ago).

Her current medications are:

• Metformin 1 g twice a day
• Candesartan 16 mg once a day
• Atorvastatin 20 mg once a day
• Furosemide 40 mg twice a day
• Levothyroxine 100 μg per day
• Calcium carbonate 1,500 mg twice a day
• A vitamin D tablet twice a day, which she has not taken for the last 2 months.

She admits she has not been taking her medications regularly because she has been feeling depressed.

On physical examination, she is alert and oriented but appears anxious. She is not in res­piratory distress. Her blood pressure is 150/90 mm Hg and her pulse is 92 beats per minute and regular. There is a thyroidectomy scar on the anterior neck. Her jugular venous pressure is not elevated. Her heart sounds are normal without extra sounds. She has no pulmonary rales and no lower-extremity edema.

The Phalen test and Tinel test for carpal tunnel syndrome are negative in both hands. Using a Katz hand diagram, the patient reports tingling and numbness in all fingers, both palms, and the dorsum of both hands. Tapping the area over the facial nerve does not elicit twitching of the facial muscles (ie, no Chvostek sign), but compression of the upper arm elicits carpal spasm (ie, positive Trousseau sign). There is no evidence of motor weakness in her hands. The rest of the physical examination is unremarkable.

POSSIBLE CAUSES OF NUMBNESS

1. Based on the initial evaluation, which of the following is the most likely cause of our patient’s bilateral hand numbness?

• Hypocalcemia due to primary hypoparathyroidism
• Carpal tunnel syndrome due to primary hypothyroidism
• Diabetic peripheral neuropathy
• Vitamin B₁₂ deficiency due to metformin
• Hypocalcemia due to low serum calcitonin

All the conditions above except low serum calcitonin can cause bilateral hand paresthesia. Our patient most likely has hypocalcemia due to primary hypoparathyroidism.

Hypocalcemia

In our patient, bilateral hand numbness and perioral numbness after stopping vitamin D and a positive Trousseau sign strongly suggest hypocalcemia. The classic physical findings in patients with hypocalcemia are the Trousseau sign and the Chvostek sign. The Trousseau sign is elicited by inflating a blood pressure cuff above the systolic blood pressure for 3 minutes and observing for ischemia-induced carpopedal spasm, wrist and metacarpophalangeal joint flexion, thumb adduction, and interphalangeal joint extension. The Chvostek sign is elicited by tapping over the area of the facial nerve below the zygoma in front of the tragus, resulting in ipsilateral twitching of facial muscles.

Although the Trousseau sign is more sensitive and specific than the Chvostek sign, neither is pathognomonic for hypocalcemia.¹ The Chvostek sign has been reported to be negative in 30% of patients with hypocalcemia and positive in 10% of normocalcemic individuals.¹ The Trousseau sign, however, is present in 94% of hypocalcemic patients vs 1% of normocalcemic individuals.²

Primary hypoparathyroidism secondary to thyroidectomy. Postsurgical hypoparathyroidism is the most common cause of primary hypoparathyroidism. It results from ischemic injury or accidental removal of the parathyroid glands during anterior neck surgery.^3,4 The consequent hypocalcemia can be transient, intermittent, or permanent. Permanent postsurgical hypoparathyroidism is defined as persistent hypocalcemia with insufficient parathyroid hormone (PTH) for more than 12 months after neck surgery; however, some consider 6 months to be enough to define the condition.^5–7

The incidence of postsurgical hypoparathyroidism varies considerably with the extent of thyroid surgery and the experience of the surgeon.^6,8 In the hands of experienced surgeons, permanent hypoparathyroidism occurs in fewer than 1% of patients after total thyroidectomy, whereas the rate may be higher than 6% with less-experienced surgeons.^5,9 Other risk factors for postsurgical hypoparathyroidism include female sex, autoimmune thyroid disease, pregnancy, and lactation.⁵

Pseudohypoparathyroidism is a group of disorders characterized by renal resistance to PTH, leading to hypocalcemia, hyperphosphatemia, and elevated serum PTH. It is also associated with phenotypic features such as short stature and short fourth metacarpal bones.

Calcitonin deficiency. Calcitonin is a polypeptide hormone secreted from the parafollicular (C) cells of the thyroid gland. After total thyroidectomy, calcitonin levels are expected to be reduced. However, the role of calcitonin in humans is unclear. One study has shown that calcitonin is possibly a vestigial hormone, given that no calcitonin-related disorders (excess or deficiency) have been reported in humans.¹⁰

Our patient also could have primary hypothyroidism as a result of thyroidectomy. Hypothyroidism can cause bilateral hand numbness due to carpal tunnel syndrome, which is mediated by mucopolysaccharide deposition and synovial membrane swelling.¹¹ One study reported that 29% of patients with hypothyroidism had carpal tunnel syndrome.¹² Symptoms of carpal tunnel syndrome in hypothyroid patients may occur despite thyroid replacement therapy.¹³

Carpal tunnel syndrome is a clinical diagnosis. Patients usually experience hand paresthesia in the distribution of the median nerve. Provocative physical tests for carpal tunnel syndrome include the Tinel test, the Phalen test, and the Katz hand diagram, which is considered the best of the 3 tests.^14,15 Based on how the patient marks the location and type of symptoms on the diagram, carpal tunnel syndrome is rated as classic, probable, possible, or unlikely (Table 1).^14,16,17 The sensitivity of a classic or probable diagram ranges from 64% to 80%, while the specificity ranges from 73% to 90%.^14,15

Carpal tunnel syndrome is less likely to be the cause of our patient’s symptoms, as her Katz hand diagram indicates only “possible” carpal tunnel syndrome. Her perioral numbness and positive Trousseau sign make hypocalcemia a more likely cause.

Diabetic peripheral neuropathy

Sensory peripheral neuropathy is a recognized complication of diabetes mellitus. However, neuropathy in diabetic patients most commonly manifests initially as distal symmetrical ascending neuropathy starting in the lower extremities.¹⁸ Therefore, diabetic peripheral neuropathy is less likely in this patient since her symptoms are limited to her hands.

Vitamin B₁₂ deficiency

Metformin-induced vitamin B₁₂ deficiency is another possible cause of peripheral neuropathy. It might be secondary to metformin-induced changes in intrinsic factor levels and small-intestine motility with resultant bacterial overgrowth, as well as inhibition of vitamin B₁₂ absorption in the terminal ileum.¹⁹

However, metformin-induced vitamin B₁₂ deficiency is not the most likely cause of our patient’s neuropathy, since she has been taking this drug for only 1 year. Vitamin B₁₂ deficiency with consequent peripheral neuropathy is more likely in patients taking metformin in high doses for 10 or more years.²⁰

Laboratory results and electrocardiography

Table 2 shows the patient’s initial laboratory results. Of note, her serum calcium level is 5.7 mg/dL (reference range 8.9–10.1). Electrocardiography in the emergency department shows:

• Prolonged PR interval (23 msec)
• Wide QRS complexes (13 msec)
• Flat T waves
• Prolonged corrected QT interval (475 msec)
• Occasional premature ventricular complexes.

CLINICAL MANIFESTATIONS OF HYPOCALCEMIA

2. Which of the following is not a manifestation of hypocalcemia?

• Tonic-clonic seizures
• Cyanosis
• Cardiac ventricular arrhythmias
• Acute pancreatitis
• Depression

Hypocalcemia can cause a wide range of clinical manifestations (Table 3), the extent and severity of which depend on the severity of hypocalcemia and how quickly it develops. The more acute the hypocalcemia, the more severe the manifestations.²¹

Tetany can cause seizures

Hypocalcemia is characterized by neuromuscular hyperexcitability, manifested clinically by tetany.²² Manifestations of tetany are numerous and include acral paresthesia, perioral numbness, muscle cramps, carpopedal spasm, and seizures. Tetany is the hallmark of hypocalcemia regardless of etiology. However, certain causes are associated with peculiar clinical manifestations. For example, chronic primary hypoparathyroidism may be associated with basal ganglia calcifications that can result in parkinsonism, other extrapyramidal disorders, and dementia (Table 4).⁶

Airway spasm can be fatal

A serious manifestation of acute severe hypocalcemia is spasm of the glottis muscles, which may cause cyanosis and, if untreated, death.²¹

Ventricular arrhythmias

Another potential fatal complication of acute severe hypocalcemia is polymorphic ventricular tachycardia due to prolongation of the QT interval, which is readily identified with electrocardiography.²³

Hypocalcemia does not cause pancreatitis

Hypercalcemia, rather than hypocalcemia, may cause acute pancreatitis.²⁴ Conversely, acute pancreatitis may cause hypocalcemia due to precipitation of calcium in the abdominal cavity.²⁵

Psychiatric manifestations

In addition to depression, hypocalcemia is associated with psychiatric manifestations including anxiety, confusion, and emotional instability.

STEPS TO DIAGNOSIS OF HYPOCALCEMIA

First step: Confirm true hypocalcemia

Calcium circulates in the blood in 3 forms: bound to albumin (40% to 45%), bound to anions (10% to 15%), and free (ionized) (45%). Although ionized calcium is the active form, most laboratories report total serum calcium.

Since changes in serum albumin concentration affect the total serum calcium level, it is imperative to correct the measured serum calcium to the serum albumin concentration. Each 1-g/dL decrease in serum albumin lowers the total serum calcium by 0.8 mg/dL. Thus:

Corrected serum calcium (mg/dL) =
measured total serum calcium (mg/dL) +
0.8 (4 − serum albumin [g/dL]).

If the patient’s serum calcium level remains low when corrected for serum albumin, he or she has true hypocalcemia, which implies a low ionized serum calcium. Conversely, pseudohypocalcemia means that the measured calcium level is low but the corrected serum calcium is normal.

Using this formula, our patient’s corrected calcium level is calculated as 5.7 + 0.8 (4 – 3.2) = 6.3 mg/dL, indicating true hypocalcemia.

PHOSPHATE IS OFTEN HIGH WHEN CALCIUM IS LOW

In addition to hypocalcemia, our patient has an elevated phosphate level (Table 2).

3. Which of the following hypocalcemic disorders is not associated with hyperphosphatemia?

• End-stage renal disease
• Primary hypoparathyroidism
• Pseudohypoparathyroidism
• Vitamin D₃ deficiency
• Rhabdomyolysis

Vitamin D deficiency is not associated with hyperphosphatemia.

Second step in evaluating hypocalcemia: Check phosphate, magnesium, creatinine

The major causes of hypocalcemia can be categorized according to the serum phosphate level: high vs normal or low (Table 5).

High-phosphate, low-calcium states. In the absence of concurrent end-stage renal disease and an excessive phosphate load, primary hypoparathyroidism is the most likely cause of hypocalcemia associated with hyperphosphatemia.

PTH increases serum ionized calcium by^26,27:

• Increasing bone resorption
• Increasing reabsorption of calcium from the distal renal tubules
• Increasing the activity of 1-alpha-hydroxylase, responsible for conversion of 25-hydroxyvitamin D₃ to 1,25-dihydroxyvitamin D₃ (the most biologically active vitamin D metabolite); 1,25-dihydroxyvitamin D increases the absorption of calcium and phosphate from the intestine.

Conversely, PTH decreases reabsorption of phosphate from proximal renal tubules, resulting in hypophosphatemia. Therefore, low serum PTH (primary hypoparathyroidism) or a PTH-resistant state (pseudohypoparathyroidism) results in hypocalcemia and hyperphosphatemia.^26,27

Both end-stage renal disease and rhabdomyolysis are associated with high serum phosphate levels. The kidney normally excretes excess dietary phosphate to maintain phosphate homeostasis; however, this is impaired in end-stage renal disease, leading to hyperphosphatemia. In rhabdomyolysis, it is mainly the transcellular shift of phosphate into the extracellular space from myocyte injury that raises phosphate levels.

Normal- or low-phosphate, low calcium states. Hypocalcemia can also result from vitamin D deficiency, but this cause is associated with a low or normal serum phosphate level. In such cases, hypocalcemia causes secondary hyperparathyroidism with consequent renal phosphate loss and, thus, hypophosphatemia.²⁷

Third step: Check serum intact PTH and 25-hydroxyvitamin D levels

Hypocalcemia stimulates secretion of PTH. Therefore, hypocalcemia with elevated serum PTH is caused by disorders that do not impair PTH secretion, including chronic renal failure and vitamin D deficiency (Table 5). Conversely, hypocalcemia with low or normal serum PTH levels suggests primary hypoparathyroidism.

Our patient’s serum PTH level is 20 ng/mL, which is within the reference range. This does not discount the diagnosis of primary hypoparathyroidism. Although most patients with primary hypoparathyroidism have low or undetectable serum PTH levels, some have normal PTH levels if some degree of PTH production is preserved.^5,7,28–30 In these patients, the remaining functioning parathyroid tissue is not enough to maintain a normal serum calcium level, resulting in hypocalcemia. As a result, hypocalcemia stimulates the remaining parathyroid tissue to its maximum output, producing PTH levels usually within the lower or middle-normal range.³⁰ In such patients, the terms parathyroid insufficiency and relative primary hypoparathyroidism are more precise than primary hypoparathyroidism.

Postsurgical hypoparathyroidism with an inappropriately normal PTH level is usually seen in patients with disorders that impair intestinal calcium absorption or bone resorption.³¹ In our patient’s case, the “normal” serum PTH level is likely due to maximal stimulation of remaining functioning parathyroid tissue by severe hypocalcemia, which is a result of her discontinuation of calcium and calcitriol therapy and her vitamin D deficiency.

CASE RESUMED: NO RESPONSE TO INTRAVENOUS CALCIUM GLUCONATE

The patient is given 2 10-mL ampules of 10% calcium gluconate diluted in 100 mL of 5% dextrose in water over 20 minutes intravenously. Electrocardiographic monitoring is continued. Two hours later, her measured serum calcium is only 5.8 mg/dL, with no improvement in her symptoms.

A continuous infusion of calcium gluconate is started: 12 ampules of calcium gluconate are added to 380 mL of 5% dextrose in water and infused at 40 mL/hour (infused rate of elemental calcium = 1.3 mg/kg/hour); 3 hours later, her measured serum calcium level is still only 5.8 mg//dL; at 6 hours it is 5.9 mg/dL, and her symptoms have not improved.

4. Which of the following is the most appropriate next step?

• Change the calcium gluconate to calcium chloride
• Increase the infusion rate to 1.5 mg of elemental calcium/kg/hour
• Give a bolus of 2 10-mL ampules of 10% calcium gluconate intravenously over 1 minute
• Give additional oral calcium tablets
• Check the serum magnesium level

Treatment of hypocalcemia can involve intravenous or oral calcium therapy.

Intravenous calcium is indicated for patients with any of the following^6,32:

• Moderate to severe neuromuscular irritability (eg, acral paresthesia, carpopedal spasm, prolonged QT interval, seizures, laryngospasm, bronchospasm)
• Acute hypocalcemia with corrected serum calcium level less than 7.6 mg/dL, even if the patient is asymptomatic
• Cardiac failure.

One 10-mL ampule of 10% calcium gluconate contains 93 mg of elemental calcium; 1 or 2 ampules are typically diluted in 50 to 100 mL of 5% dextrose in water and infused slowly over 15 to 20 minutes. Rapid administration of intravenous calcium is contraindicated, as it may produce cardiac arrhythmias and possibly cardiac arrest. Therefore, intravenous calcium should be given slowly while continuing electrocardiographic monitoring.³³

Since the effect of 1 ampule of calcium gluconate lasts only 2 to 3 hours, most patients with symptomatic hypocalcemia require continuous intravenous calcium infusion. The recommended dose of infused elemental calcium is 0.5 to 1.5 mg/kg/hour.³⁴ Several ampules are added to 500 to 1,000 mL of 5% dextrose in water or 0.9% normal saline and infused at a rate appropriate for the patient’s corrected calcium and symptoms.

Oral calcium and vitamin D supplements can be given initially to patients with a corrected serum calcium level of 7.6 mg/dL or greater, with or without mild symptoms, if they can tolerate oral intake. However, this is not the treatment of choice for resistant acute hypocalcemia, as in this case.

Calcium chloride has no advantages over calcium gluconate. Further, it can be associated with local irritation and may result in tissue necrosis if extravasation occurs.³⁵

Increasing the infusion rate of calcium gluconate to the maximum recommended dose may improve the patient’s ionized calcium level and symptoms somewhat. However, it is not the best option for this patient, given that she did not respond to 2 ampules of calcium gluconate followed by continuous infusion of 1.3 mg/kg/hour for 6 hours.

Calcium gluconate bolus. Similarly, giving the patient an additional 2 ampules of calcium gluconate over 1 minute would not be recommended, as rapid administration of intravenous calcium gluconate (eg, over 1 minute) is contraindicated.

Check magnesium

If hypocalcemia persists despite intravenous calcium therapy, as in our patient, further investigation or action is required. An important cause of persistent hypocalcemia is severe hypomagnesemia. Severe hypomagnesemia (serum magnesium < 0.8 mg/dL) causes resistant hypocalcemia by several mechanisms:

• Inducing PTH resistance^32,36,37
• Decreasing PTH secretion^32,36
• Decreasing calcitriol production.

The decrease in calcitriol production is a direct effect of hypomagnesemia, but it is also an indirect effect of low PTH secretion, which inhibits the enzyme 1-alpha-hydroxylase. Thus, conversion of 25-hydroxyvitamin D₃ to calcitriol is impaired, leading to low calcitriol production.

Our patient could have hypomagnesemia due to furosemide use and uncontrolled diabetes mellitus. Hypocalcemia resistant to calcium therapy may occasionally respond to magnesium therapy even if the serum magnesium level is normal. This may be due to depleted intracellular magnesium salt levels.^6,38 Rarely, severe hypermagnesemia can also be associated with hypocalcemia due to inhibition of PTH secretion.^37,39

CASE RESUMED

Our patient’s serum magnesium level is 0.6 mg/dL (reference range 1.7–2.4 mg/dL). She is given 2 g of magnesium sulfate in 60 mL of 0.9% normal saline infused over 1 hour, followed by a continuous infusion of magnesium sulfate (12 g diluted in 250 mL of 0.9% normal saline, infused over 24 hours). On repeat testing 4 hours later, her serum magnesium level is 0.7 mg/dL, and at 8 hours later it is 0.9 mg/dL. She is subsequently started on oral magnesium oxide 600 mg per day. The magnesium sulfate infusion is continued for another 24 hours.

PREVENTING HYPERCALCIURIA

Patients with low PTH (primary hypoparathyroidism) may have hypercalciuria due to decreased renal tubular calcium reabsorption. Two important measures can minimize hypercalciuria in such patients:

• Keeping the serum calcium level in the low-normal range^4,5,40
• Giving a thiazide diuretic (eg, hydrochlorothiazide 12.5–50 mg daily) with a low-salt diet.^41,42

A thiazide diuretic is usually started once the 24-hour urine calcium reaches 250 mg.⁶ Thiazides are thought to enhance both proximal and distal renal tubular calcium reabsorption.^43,44

PRIMARY HYPOPARATHYROIDISM: LONG-TERM MANAGEMENT

Long-term management of primary hypoparathyroidism requires calcium and vitamin D supplementation.

Calcium supplements. The most commonly prescribed calcium preparations are calcium carbonate and calcium citrate (containing 40% and 20% elemental calcium, respectively). Calcium carbonate, which is less expensive than calcium citrate, binds with phosphate intake and requires an acidic environment for absorption, and so it is better absorbed when taken with meals. Because calcium citrate does not require an acidic environment for absorption, it is the calcium preparation of choice for patients on proton pump inhibitors, or patients with achlorhydria or constipation.⁴⁵ Calcium doses vary widely, with most hypoparathyroid patients requiring 1 to 2 g of elemental calcium daily.⁶

Vitamin D supplements. To promote intestinal absorption, calcium is combined with vitamin D in a fixed-dose preparation given in divided doses.⁴⁶ Calcitriol (1,25-dihydroxyvitamin D₃) is the most active metabolite of vitamin D, with rapid onset and offset of action, and it is the preferred form of vitamin D therapy for patients with hypoparathyroidism. If calcitriol is not available or is not affordable, alphacalcidol (1-alpha-hydroxyvitamin D₃) is another option. This is a synthetic analogue of vitamin D that is already hyroxylated at the C1 position. After oral intake, it is hydroxylated in the liver to form calcitriol.

Since renal production of calcitriol is PTH-dependent, in hypoparathyroidism the conversion of 25-hydroxyvitamin D₃ to calcitriol is limited. Therefore, vitamin D₃ (cholecalciferol) and vitamin D₂ (ergocalciferol) are not the preferred forms of vitamin D for such patients. However, either can be added to calcitriol, as they may have extraskeletal benefits.⁷

CASE CONCLUDED

Our patient presented with primary parathyroid insufficiency associated with vitamin D deficiency. Therefore, in addition to calcitriol and calcium combined with vitamin D in a fixed-dose preparation, her management included vitamin D₃ for her vitamin D deficiency.

She was discharged on these medications. At a follow-up visit 3 weeks later, her measured serum calcium level was 8.6 mg/dL. She reported gradual resolution of her symptoms. She was also referred to a psychiatrist for her depression.

TAKE-HOME POINTS

• Hypocalcemia causes neuromuscular excitability, manifested clinically by tetany.
• Common causes of hypocalcemia include vitamin D deficiency, hypomagnesemia, renal failure, and primary hypoparathyroidism.
• The first step in evaluating hypocalcemia is to correct the measured serum calcium to the serum albumin concentration.
• Laboratory testing for hypocalcemia should include serum phosphorus, magnesium, creatinine, PTH, and 25-hydroxyvitamin D₃.
• Primary hypoparathyroidism is characterized by hypocalcemia, hyperphosphatemia, and low serum PTH.
• Moderate to severe manifestations of hypo-
  calcemia and acute hypocalcemia (< 7.6 mg/dL), even if asymptomatic, warrant intravenous calcium therapy.
• Correction of hypomagnesemia is essential to treat hypocalcemia, especially if resistant to intravenous calcium therapy.
• The goal of chronic management of primary hypoparathyroidism includes correcting the serum calcium level to a low-normal range, the serum phosphorus level to an upper-normal range, and prevention of hypercalciuria.

Acknowledgments: The authors wish to thank Mr. Michael Edward Tierney of the School of Medicine, University of Sydney, Australia, for his linguistic editing of the manuscript.

A  44-year-old woman was admitted to the  hospital for the second time in 2 months with acute onset of severe abdominal pain. She had a history of cervical cancer treated with total hysterectomy with bilateral salpingo-oophorectomy, chemotherapy, and radiotherapy at age 38.

LONG-TERM EFFECTS OF RADIATION ON THE BLADDER

Urinary ascites from intraperitoneal urine leakage is a rare but clinically important sequel to bladder fistula or bladder wall rupture. Fistula or rupture can be caused by pelvic irradiation, blunt trauma, or surgical procedures, but may also be spontaneous.²

When the total radiation dose to the bladder exceeds 60 Gy, radiation cystitis may occur, leading to bladder fistula.³ Effects of radiation on the bladder are usually seen within 2 to 4 years³ but may occur long after the completion of radiation therapy—10 years² or even 30 to 40 years later.⁴ Therefore, ascites of unknown origin in a patient with a history of pelvic radiation therapy should lead to an evaluation for late radiation cystitis and urinary ascites from bladder rupture.

A  44-year-old woman was admitted to the  hospital for the second time in 2 months with acute onset of severe abdominal pain. She had a history of cervical cancer treated with total hysterectomy with bilateral salpingo-oophorectomy, chemotherapy, and radiotherapy at age 38.

LONG-TERM EFFECTS OF RADIATION ON THE BLADDER

Urinary ascites from intraperitoneal urine leakage is a rare but clinically important sequel to bladder fistula or bladder wall rupture. Fistula or rupture can be caused by pelvic irradiation, blunt trauma, or surgical procedures, but may also be spontaneous.²

When the total radiation dose to the bladder exceeds 60 Gy, radiation cystitis may occur, leading to bladder fistula.³ Effects of radiation on the bladder are usually seen within 2 to 4 years³ but may occur long after the completion of radiation therapy—10 years² or even 30 to 40 years later.⁴ Therefore, ascites of unknown origin in a patient with a history of pelvic radiation therapy should lead to an evaluation for late radiation cystitis and urinary ascites from bladder rupture.

A  44-year-old woman was admitted to the  hospital for the second time in 2 months with acute onset of severe abdominal pain. She had a history of cervical cancer treated with total hysterectomy with bilateral salpingo-oophorectomy, chemotherapy, and radiotherapy at age 38.

LONG-TERM EFFECTS OF RADIATION ON THE BLADDER

Urinary ascites from intraperitoneal urine leakage is a rare but clinically important sequel to bladder fistula or bladder wall rupture. Fistula or rupture can be caused by pelvic irradiation, blunt trauma, or surgical procedures, but may also be spontaneous.²

When the total radiation dose to the bladder exceeds 60 Gy, radiation cystitis may occur, leading to bladder fistula.³ Effects of radiation on the bladder are usually seen within 2 to 4 years³ but may occur long after the completion of radiation therapy—10 years² or even 30 to 40 years later.⁴ Therefore, ascites of unknown origin in a patient with a history of pelvic radiation therapy should lead to an evaluation for late radiation cystitis and urinary ascites from bladder rupture.

A 45-year-old man with known human immunodeficiency virus infection presented with a 5-day history of dyspnea. When his dyspnea had become symptomatic, he had restarted his home dapsone prophylaxis, but his dyspnea had progressively worsened, and his urine became dark.

Based on these test results, the patient’s dapsone was stopped and replaced with atovaquone. Intravenous infusion of methylene blue was started, with subsequent improvement of the hypoxia and cyanosis (Figure 1). His urine became green, but it returned to a normal color in a matter of hours. He was ultimately diagnosed with P jirovecii pneumonia and completed a course of atovaquone with total resolution of his symptoms.

THE MECHANISMS BEHIND METHEMOGLOBINEMIA

Heme iron is normally in the ferrous state (Fe²⁺), which allows for hemoglobin to carry oxygen and release it to tissues.¹ Exposure to an oxidative stress can lead to methemoglobinemia from an increase in abnormal hemoglobin that contains iron in a ferric state (Fe³⁺).^1,2

Methemoglobin reduces oxygen-carrying capacity in two ways: it is unable to carry oxygen, and its presence shifts the oxy­gen dissociation curve to the left, causing any remaining normal hemoglobin to be unable to release oxygen to the tissues.^1,2

Causes of acquired methemoglobinemia include topical anesthetics (eg, benzocaine, lidocaine) and antibiotics (eg, dapsone).^2,3 Signs and symptoms include cyanosis, headache, fatigue, dyspnea, lethargy, respiratory distress, and dark-colored urine.^1,2

MANAGEMENT

Treatment consists of intravenous methylene blue, which reduces the hemoglobin from a ferric state to a ferrous state.^1–4 Methylene blue is a water-soluble dye excreted primarily in the urine, and common side effects include dizziness, nausea, and green urine.^5–7 The blue pigments from methylene blue combine with urobilin (a yellow pigment in the urine), producing a green color.⁷ This is not pathological and requires no treatment, as the urine returns to normal color after the body fully excretes the dye.^5–7

If intravenous methylene blue fails to produce a response, other treatments to consider include hemodialysis, blood transfusion, exchange transfusion, and hyperbaric oxygen therapy.²

A 45-year-old man with known human immunodeficiency virus infection presented with a 5-day history of dyspnea. When his dyspnea had become symptomatic, he had restarted his home dapsone prophylaxis, but his dyspnea had progressively worsened, and his urine became dark.

Based on these test results, the patient’s dapsone was stopped and replaced with atovaquone. Intravenous infusion of methylene blue was started, with subsequent improvement of the hypoxia and cyanosis (Figure 1). His urine became green, but it returned to a normal color in a matter of hours. He was ultimately diagnosed with P jirovecii pneumonia and completed a course of atovaquone with total resolution of his symptoms.

THE MECHANISMS BEHIND METHEMOGLOBINEMIA

Heme iron is normally in the ferrous state (Fe²⁺), which allows for hemoglobin to carry oxygen and release it to tissues.¹ Exposure to an oxidative stress can lead to methemoglobinemia from an increase in abnormal hemoglobin that contains iron in a ferric state (Fe³⁺).^1,2

Methemoglobin reduces oxygen-carrying capacity in two ways: it is unable to carry oxygen, and its presence shifts the oxy­gen dissociation curve to the left, causing any remaining normal hemoglobin to be unable to release oxygen to the tissues.^1,2

Causes of acquired methemoglobinemia include topical anesthetics (eg, benzocaine, lidocaine) and antibiotics (eg, dapsone).^2,3 Signs and symptoms include cyanosis, headache, fatigue, dyspnea, lethargy, respiratory distress, and dark-colored urine.^1,2

MANAGEMENT

Treatment consists of intravenous methylene blue, which reduces the hemoglobin from a ferric state to a ferrous state.^1–4 Methylene blue is a water-soluble dye excreted primarily in the urine, and common side effects include dizziness, nausea, and green urine.^5–7 The blue pigments from methylene blue combine with urobilin (a yellow pigment in the urine), producing a green color.⁷ This is not pathological and requires no treatment, as the urine returns to normal color after the body fully excretes the dye.^5–7

If intravenous methylene blue fails to produce a response, other treatments to consider include hemodialysis, blood transfusion, exchange transfusion, and hyperbaric oxygen therapy.²

A 45-year-old man with known human immunodeficiency virus infection presented with a 5-day history of dyspnea. When his dyspnea had become symptomatic, he had restarted his home dapsone prophylaxis, but his dyspnea had progressively worsened, and his urine became dark.

Based on these test results, the patient’s dapsone was stopped and replaced with atovaquone. Intravenous infusion of methylene blue was started, with subsequent improvement of the hypoxia and cyanosis (Figure 1). His urine became green, but it returned to a normal color in a matter of hours. He was ultimately diagnosed with P jirovecii pneumonia and completed a course of atovaquone with total resolution of his symptoms.

THE MECHANISMS BEHIND METHEMOGLOBINEMIA

Heme iron is normally in the ferrous state (Fe²⁺), which allows for hemoglobin to carry oxygen and release it to tissues.¹ Exposure to an oxidative stress can lead to methemoglobinemia from an increase in abnormal hemoglobin that contains iron in a ferric state (Fe³⁺).^1,2

Methemoglobin reduces oxygen-carrying capacity in two ways: it is unable to carry oxygen, and its presence shifts the oxy­gen dissociation curve to the left, causing any remaining normal hemoglobin to be unable to release oxygen to the tissues.^1,2

Causes of acquired methemoglobinemia include topical anesthetics (eg, benzocaine, lidocaine) and antibiotics (eg, dapsone).^2,3 Signs and symptoms include cyanosis, headache, fatigue, dyspnea, lethargy, respiratory distress, and dark-colored urine.^1,2

MANAGEMENT

Treatment consists of intravenous methylene blue, which reduces the hemoglobin from a ferric state to a ferrous state.^1–4 Methylene blue is a water-soluble dye excreted primarily in the urine, and common side effects include dizziness, nausea, and green urine.^5–7 The blue pigments from methylene blue combine with urobilin (a yellow pigment in the urine), producing a green color.⁷ This is not pathological and requires no treatment, as the urine returns to normal color after the body fully excretes the dye.^5–7

If intravenous methylene blue fails to produce a response, other treatments to consider include hemodialysis, blood transfusion, exchange transfusion, and hyperbaric oxygen therapy.²

Chronic pelvic pain is a common clinical problem in women, as prevalent in primary care as asthma or back pain.^1,2 It is often associated with lost work days and decreased productivity, increased healthcare spending, mood disorders, and negative effects on personal relationships.^1–3

While specialty care referral may eventually be indicated, primary care doctors can take steps to diagnose and effectively manage the condition.

COMPREHENSIVE MANAGEMENT LED BY PRIMARY CARE

Chronic pelvic pain is defined as pain in the lower abdomen persisting for 3 to 6 months and of sufficient severity to require medical care or cause a functional disability.³ It is often detrimental to a woman’s personal life and overall health, making a comprehensive assessment and multidisciplinary approach to management especially important.

The ideal care-delivery model is the patient-centered medical home, whereby a primary care physician coordinates comprehensive care with the help of an interdisciplinary team.^4,5 For complex cases, referral may be needed to other specialties (eg, obstetrics and gynecology, pain medicine) to help manage care.

TARGETED EVALUATION

Chronic pelvic pain often coexists with other systemic pain syndromes or psychiatric conditions common in primary care. Table 1 lists common causes and associated findings.

Detailed history is critical

The history is of utmost importance. Clinicians should query patients about the characteristics of the pain as well as their medical and surgical history. Particular attention should be given to obtaining a complete gynecologic history, including pregnancy, delivery complications, dyspareunia, sexual assault, and trauma. A detailed review of systems should focus on the reproductive, gastroenterologic, musculoskeletal, urologic, and neuropsychiatric systems.

As with many pain syndromes, allowing the patient to “tell her story” helps to establish rapport and obtain a more complete assessment. Chronic pelvic pain has been associated with physical or sexual abuse as a child or adult, so is essential to foster the doctor-patient relationship and create a safe and open space for disclosure.^3,6 It is important to screen women for safety at home as well as for satisfaction or dissatisfaction with their relationships with their spouse or partner and family.

Physical examination

The physical examination should be directed by the history but should always include abdominal and pelvic examinations. These should be conducted slowly and gently, assessing for areas of tenderness, masses, and other abnormalities. Clinicians should aim to pinpoint the exact anatomic locations of tenderness if possible. Ongoing dialogue facilitates this process by inquiring about pain at each point of the examination.

The pelvic examination should begin with visual inspection for redness, discharge, lesions, fissures, excoriations, and other abnormalities. A moistened cotton swab may be used to evaluate the vulva and vestibule for localized tenderness. The manual portion of the pelvic examination should begin with a single digit, noting any introital tenderness or spasm. Next, the levator ani muscles should be directly palpated for tone and tenderness. The pelvic floor should be evaluated with attention to tenderness of the bladder or musculoskeletal structures (Figure 1). A bimanual examination assessing uterine size and tenderness, nodularity, or a fixed, immobile uterus should be conducted.

Because the differential diagnosis of chronic pelvic pain is broad, the diagnostic workup and testing should be based on findings of the history and physical examination. In general, extensive laboratory testing is of limited use for evaluating women with chronic pelvic pain.^3,7

Urinalysis should be obtained for symptoms suggesting bladder involvement such as interstitial cystitis.

Pelvic ultrasonography can help identify pelvic masses palpated during the physical examination, but routine use of imaging is not recommended.^3,7 If pelvic congestion syndrome is suspected, starting with pelvic ultrasonography is reasonable before incurring the risk or cost of computed tomography or magnetic resonance imaging.⁸

GENERAL TREATMENT

Medical therapy

The main goals of medical therapy are to improve function and quality of life while minimizing adverse effects. General treatments include the following:

Analgesics. Nonsteroidal anti-inflammatory drugs and acetaminophen may provide pain relief, although there is weak evidence for their efficacy in treating chronic pelvic pain.⁹

Neuropathic agents. One of several available neuropathic agents commonly used in the treatment of chronic pain can be tried on patients who fail to respond to analgesics. Tricyclic antidepressants such as amitriptyline and imipramine decrease pain, reduce symptoms of depression, and improve sleep.¹⁰ The results of a small randomized controlled trial suggest that gabapentin is more effective than amitriptyline for reducing chronic pelvic pain.^11,12 Published guidelines currently list both amitriptyline and gabapentin as first-line agents; nortriptyline and pregabalin are considered acceptable initial alternatives.⁹

Venlafaxine and duloxetine may help chronic pelvic pain, although specific evidence is lacking. Duloxetine may be an appropriate choice for women with chronic pelvic pain who also experience depression and urinary stress incontinence.⁹

Opioids. Opioid therapy should be considered only when all other reasonable therapies have failed.¹⁰ Patients may develop tolerance or dependence, as well as opioid-induced adverse effects such as hyperalgesia.^9,10 Guidelines recommend that primary care providers consult with a pain management specialist before prescribing opioids, and that patients be thoroughly counseled about the risks and side effects.⁹

Nerve block and neuromodulation. There is weak evidence for the use of these modalities for treating chronic pelvic pain.⁹ If used, they should be part of a broader treatment plan and should be performed by providers who specialize in management of chronic pain.

DISEASE-SPECIFIC TREATMENT

Endometriosis: Hormonal therapy

Pelvic pain that significantly fluctuates with the menstrual cycle may be caused by endometriosis, the most common gynecologic cause of chronic pelvic pain. Women with cyclic chronic pelvic pain should be empirically treated with hormonal therapy for at least 3 to 6 months before diagnostic laparoscopy is performed.¹³

Oral contraceptives, gonadotropin-releasing hormone (GnRH) analogues, progestogens, and danazol have proven efficacy, although side-effect profiles differ significantly. In a comparative trial, patients treated with GnRH analogues had more improvement in pain scores compared with those treated with oral contraceptives, but they experienced a significant decrease in bone mineral density.¹¹ The effects on bone mineral density associated with GnRH analogue therapy can be mitigated by “add-back” low-dose hormonal therapy (norethindrone, low-dose estrogen, or a combination of estrogen and progesterone), which may also provide symptomatic relief for associated hot flashes and vaginal symptoms.¹¹

Interstitial cystitis often accompanies endometriosis

Recognizing that chronic pelvic pain may have more than one cause is important when developing a comprehensive care plan. Interstitial cystitis coexists with endometriosis in up to 60% of patients.¹⁴ Initial treatment is pentosan polysulfate sodium, an oral treatment approved by the US Food and Drug Administration for interstitial cystitis that works by restoring the protective glycosaminoglycan layer in the bladder.^14,15 Amitriptyline may also be used to treat interstitial cystitis-associated nocturia.

Myofascial pain: Neuromuscular blockers

According to a recent systematic review of therapies for chronic pelvic pain, patients with symptoms related to myofascial pain may benefit from neuromuscular blockade.¹² One randomized controlled trial of the effectiveness of botulinum toxin A vs saline for the treatment of chronic pelvic pain secondary to pelvic floor spasm found that after 6 months of observation, women who received botulinum toxin had significantly lower pain scores than those who received saline.¹²

Pelvic congestion syndrome may be treated with hormonal, radiologic, or surgical therapy.¹⁶ A randomized controlled trial involving patients with chronic pelvic pain secondary to pelvic congestion demonstrated that treatment with medroxyprogesterone acetate or a GnRH agonist (goserelin) improved pelvic symptoms.¹⁷

A Cochrane review of nonsurgical interventions for chronic pelvic pain included women with a diagnosis of pelvic congestion syndrome or adhesions. It found that patients treated with medroxyprogesterone acetate were more likely to have 50% pain reduction lasting up to 9 months compared with patients taking placebo.¹² In comparative studies, GnRH analogues were more effective in relieving pelvic pain than progestogen therapy.

Radiologic embolization therapy is as effective as hysterectomy for the relief of chronic pelvic pain related to pelvic congestion syndrome, and it can be performed in the outpatient setting.

Irritable bowel syndrome: Try dietary changes

Symptoms of chronic pelvic pain that are associated with changes in stool consistency and frequency suggest irritable bowel syndrome. Symptoms may improve with dietary changes and fiber supplementation. Antispasmodic agents are frequently used but their anticholinergic effects may worsen constipation.¹⁴

PELVIC PHYSICAL THERAPY

Pelvic physical therapy targets the musculoskeletal components of bowel, bladder, and sexual function to restore strength, flexibility, balance, and coordination to the pelvic floor and surrounding lumbopelvic muscles. Patients with dyspareunia, pain with activity, or a significant musculoskeletal abnormality (eg, vaginismus or point tenderness on examination) are particularly good candidates for this therapy. It is done by a physical therapist with special training in techniques to manipulate the pelvic floor to address pelvic pain.

Educating the patient

Informing the patient before the initial physical therapy visit is essential for success. Referring clinicians should emphasize to patients that treatment response can help to guide further physician intervention. Patients should be counseled that pelvic physical therapy includes a pelvic examination and an expectation to participate in a home program. Although noticeable improvement takes time, encouragement provided by the entire team, including medical providers, can help a patient maintain her care plan.

Therapists typically see a patient once a week for 8 to 12 visits initially. Insurance usually covers pelvic physical therapy through the same policy as routine physical therapy.

During the initial evaluation, the patient receives an external and internal pelvic examination assessing muscle length, strength, and coordination of the back, hip, and internal pelvic floor. Internal evaluation can be done vaginally or rectally, with one gloved finger, without the need for speculum or stirrups. Biofeedback and surface electromyography (using either perianal or internal electrode placement) are used to evaluate muscle activity and to assist the patient in developing appropriate motor control during strengthening or relaxation.¹⁸

Up-training (or strengthening) aims to improve pelvic floor endurance. It can improve pelvic instability and symptoms of heaviness and discomfort from prolapse. Patients learn to appropriately utilize the pelvic floor in isolation. If a patient is too weak to contract on her own, neuromuscular electrical stimulation is used with an internal electrode to provide an assisted contraction.

Down-training (or relaxation) focuses on reducing tone in overactive pelvic muscles. It can improve symptoms of chronic pelvic pain, sexual pain, vulvodynia, and pudendal neuralgias. Patients are made aware of chronic holding patterns that lead to excess tone in the pelvic floor and learn how to release them through stretching, cardiovascular activity, meditation, and manual release of the involved muscle groups internally and externally. Internal musculature can be manipulated by a therapist in clinic or by the patient’s trained partner; the patient can also reach necessary areas with a vaginal dilator.

Functional coordination of the pelvic floor is needed for comfortable vaginal penetration and defecation. Training with biofeedback improves a patient’s ability to relax and open the pelvic floor.¹⁸ Vaginal dilators with surface electromyography are used to treat vaginismus to eliminate reflexive pelvic floor spasm during penetration. Perineal and vaginal compliance can be improved through manual release techniques with hands or vaginal dilators to restore normal mobility of tissues. This can reduce pain from postsurgical changes, postpartum sequelae, atrophic vaginal changes, shortened muscles from chronic holding, and adhesions.

PSYCHOSOCIAL INTERVENTIONS

Pelvic pain is not only a biomedical difficulty; psychosocial factors can contribute to and be affected by pelvic pain. Patients with pelvic pain often experience lower quality of life, higher rates of anxiety and depression, and increased stress compared with others.^19,20 People with pain also have more relationship stress, and patients’ partners often experience emotional distress, isolation, and feelings of powerlessness in the relationship.²¹

Psychosocial interventions, provided along with biomedical treatment, can help to reduce pain, anxiety, and depression and improve relational well-being.^22,23 In addition to attending to pain-related symptoms, comprehensive care involves recognizing and treating coexisting anxiety, depression, stress, and relationship conflict. Interventions for these difficulties are many, and a comprehensive list of interventions is beyond the focus of this section.¹⁹

Cognitive behavioral therapy is based on the idea that maladaptive cognitions can lead to problematic behaviors and emotional distress.²⁴ Interventions are carried out by a provider with specialized training in its use (eg, therapist, pain psychologist, psychiatrist).

Meta-analyses of studies that investigated the efficacy of cognitive behavioral therapy for chronic pain found consistent small to medium improvement in pain-related symptoms.²⁴ Studies that used cognitive behavioral therapy for pelvic pain found reduced overall pain severity and pain during intercourse, increased sexual satisfaction, enhanced sexual function, and less-exaggerated responses to pain.^25–27

Although cognitive behavioral therapy and mindfulness-based interventions produce positive outcomes, research on these interventions typically includes treatment carried out over a span of weeks. Common barriers to such care include lack of patient motivation, financial limitations, transportation problems, and time constraints.

The following psychosocial interventions have been chosen because they can be delivered in a short amount of time and integrated into a patient’s medical care by a medical or behavioral health provider. Because of the brevity and simplicity of these interventions, more patients with pelvic pain can receive psychosocial care as part of their usual medical encounters.

Behavioral activation

People experiencing depressive symptoms tend to isolate themselves and stop participating in activities they enjoy, including spending time with family and friends. Behavioral activation interventions that address such isolating behaviors have been shown to be effective in improving depressive symptoms.^28–30

A simple, brief intervention can be administered during routine medical care,²⁸ involving the following steps:

• Determine activities that the patient might implement that would decrease depressive symptoms. Questions such as, “When do you feel less depressed?” or “What brings you some happiness in your life?” can generate possible activities.
• Ask the patient to identify people in her life who have been supportive and with whom she could engage.
• Create with the patient a list of possible activities and social interactions that may enhance well-being.
• Make a schedule for participating in activities, possibly with rewards for completing them. Patients should be encouraged to follow the prescribed schedule of activities rather than make decisions based on mood or other factors. 

Relaxation strategies

Relaxation can help patients reduce stress and anxiety, and can also help reduce pain.^31–33

Diaphragmatic or “belly breathing” is a deep-breathing technique in which participants are asked to take in air through the nose and fully fill the lungs and lower belly. This technique allows the body to take in more oxygen, helping to lower blood pressure and slow the heartbeat. In addition to physiologic benefits, concentrating on deep breathing can help slow down or stop intrusive thoughts and distressing physical sensations.³⁴

Progressive muscle relaxation involves the systematic tensing and relaxing of each large muscle group in the body.³⁵ The goal is to eliminate physical and emotional stress through focusing on the sensations of tension and relaxation.

Scripts and audio and video resources for belly breathing and progressive muscle relaxation can be found on the Internet. The techniques can be taught during the medical appointment or offered as resources for home practice.

Couple-based care

Targeting couples is more effective for improving well-being than focusing solely on a patient’s psychosocial difficulties, so each of the above interventions may be more effective if tailored to include the patient’s partner.³⁶ If the partner is with the patient during medical visits or is included in long-term psychosocial treatment, he or she can be directly involved in learning and practicing interventions with the patient. If the partner is not present, the patient can be asked to practice newly learned well-being-enhancing strategies with her partner outside the appointment time. Couples therapy can improve psychosocial well-being for both partners.

Setting goals

Chronic pelvic pain is a common clinical problem in women, as prevalent in primary care as asthma or back pain.^1,2 It is often associated with lost work days and decreased productivity, increased healthcare spending, mood disorders, and negative effects on personal relationships.^1–3

While specialty care referral may eventually be indicated, primary care doctors can take steps to diagnose and effectively manage the condition.

COMPREHENSIVE MANAGEMENT LED BY PRIMARY CARE

Chronic pelvic pain is defined as pain in the lower abdomen persisting for 3 to 6 months and of sufficient severity to require medical care or cause a functional disability.³ It is often detrimental to a woman’s personal life and overall health, making a comprehensive assessment and multidisciplinary approach to management especially important.

The ideal care-delivery model is the patient-centered medical home, whereby a primary care physician coordinates comprehensive care with the help of an interdisciplinary team.^4,5 For complex cases, referral may be needed to other specialties (eg, obstetrics and gynecology, pain medicine) to help manage care.

TARGETED EVALUATION

Chronic pelvic pain often coexists with other systemic pain syndromes or psychiatric conditions common in primary care. Table 1 lists common causes and associated findings.

Detailed history is critical

The history is of utmost importance. Clinicians should query patients about the characteristics of the pain as well as their medical and surgical history. Particular attention should be given to obtaining a complete gynecologic history, including pregnancy, delivery complications, dyspareunia, sexual assault, and trauma. A detailed review of systems should focus on the reproductive, gastroenterologic, musculoskeletal, urologic, and neuropsychiatric systems.

As with many pain syndromes, allowing the patient to “tell her story” helps to establish rapport and obtain a more complete assessment. Chronic pelvic pain has been associated with physical or sexual abuse as a child or adult, so is essential to foster the doctor-patient relationship and create a safe and open space for disclosure.^3,6 It is important to screen women for safety at home as well as for satisfaction or dissatisfaction with their relationships with their spouse or partner and family.

Physical examination

The physical examination should be directed by the history but should always include abdominal and pelvic examinations. These should be conducted slowly and gently, assessing for areas of tenderness, masses, and other abnormalities. Clinicians should aim to pinpoint the exact anatomic locations of tenderness if possible. Ongoing dialogue facilitates this process by inquiring about pain at each point of the examination.

The pelvic examination should begin with visual inspection for redness, discharge, lesions, fissures, excoriations, and other abnormalities. A moistened cotton swab may be used to evaluate the vulva and vestibule for localized tenderness. The manual portion of the pelvic examination should begin with a single digit, noting any introital tenderness or spasm. Next, the levator ani muscles should be directly palpated for tone and tenderness. The pelvic floor should be evaluated with attention to tenderness of the bladder or musculoskeletal structures (Figure 1). A bimanual examination assessing uterine size and tenderness, nodularity, or a fixed, immobile uterus should be conducted.

Because the differential diagnosis of chronic pelvic pain is broad, the diagnostic workup and testing should be based on findings of the history and physical examination. In general, extensive laboratory testing is of limited use for evaluating women with chronic pelvic pain.^3,7

Urinalysis should be obtained for symptoms suggesting bladder involvement such as interstitial cystitis.

Pelvic ultrasonography can help identify pelvic masses palpated during the physical examination, but routine use of imaging is not recommended.^3,7 If pelvic congestion syndrome is suspected, starting with pelvic ultrasonography is reasonable before incurring the risk or cost of computed tomography or magnetic resonance imaging.⁸

GENERAL TREATMENT

Medical therapy

The main goals of medical therapy are to improve function and quality of life while minimizing adverse effects. General treatments include the following:

Analgesics. Nonsteroidal anti-inflammatory drugs and acetaminophen may provide pain relief, although there is weak evidence for their efficacy in treating chronic pelvic pain.⁹

Neuropathic agents. One of several available neuropathic agents commonly used in the treatment of chronic pain can be tried on patients who fail to respond to analgesics. Tricyclic antidepressants such as amitriptyline and imipramine decrease pain, reduce symptoms of depression, and improve sleep.¹⁰ The results of a small randomized controlled trial suggest that gabapentin is more effective than amitriptyline for reducing chronic pelvic pain.^11,12 Published guidelines currently list both amitriptyline and gabapentin as first-line agents; nortriptyline and pregabalin are considered acceptable initial alternatives.⁹

Venlafaxine and duloxetine may help chronic pelvic pain, although specific evidence is lacking. Duloxetine may be an appropriate choice for women with chronic pelvic pain who also experience depression and urinary stress incontinence.⁹

Opioids. Opioid therapy should be considered only when all other reasonable therapies have failed.¹⁰ Patients may develop tolerance or dependence, as well as opioid-induced adverse effects such as hyperalgesia.^9,10 Guidelines recommend that primary care providers consult with a pain management specialist before prescribing opioids, and that patients be thoroughly counseled about the risks and side effects.⁹

Nerve block and neuromodulation. There is weak evidence for the use of these modalities for treating chronic pelvic pain.⁹ If used, they should be part of a broader treatment plan and should be performed by providers who specialize in management of chronic pain.

DISEASE-SPECIFIC TREATMENT

Endometriosis: Hormonal therapy

Pelvic pain that significantly fluctuates with the menstrual cycle may be caused by endometriosis, the most common gynecologic cause of chronic pelvic pain. Women with cyclic chronic pelvic pain should be empirically treated with hormonal therapy for at least 3 to 6 months before diagnostic laparoscopy is performed.¹³

Oral contraceptives, gonadotropin-releasing hormone (GnRH) analogues, progestogens, and danazol have proven efficacy, although side-effect profiles differ significantly. In a comparative trial, patients treated with GnRH analogues had more improvement in pain scores compared with those treated with oral contraceptives, but they experienced a significant decrease in bone mineral density.¹¹ The effects on bone mineral density associated with GnRH analogue therapy can be mitigated by “add-back” low-dose hormonal therapy (norethindrone, low-dose estrogen, or a combination of estrogen and progesterone), which may also provide symptomatic relief for associated hot flashes and vaginal symptoms.¹¹

Interstitial cystitis often accompanies endometriosis

Recognizing that chronic pelvic pain may have more than one cause is important when developing a comprehensive care plan. Interstitial cystitis coexists with endometriosis in up to 60% of patients.¹⁴ Initial treatment is pentosan polysulfate sodium, an oral treatment approved by the US Food and Drug Administration for interstitial cystitis that works by restoring the protective glycosaminoglycan layer in the bladder.^14,15 Amitriptyline may also be used to treat interstitial cystitis-associated nocturia.

Myofascial pain: Neuromuscular blockers

According to a recent systematic review of therapies for chronic pelvic pain, patients with symptoms related to myofascial pain may benefit from neuromuscular blockade.¹² One randomized controlled trial of the effectiveness of botulinum toxin A vs saline for the treatment of chronic pelvic pain secondary to pelvic floor spasm found that after 6 months of observation, women who received botulinum toxin had significantly lower pain scores than those who received saline.¹²

Pelvic congestion syndrome may be treated with hormonal, radiologic, or surgical therapy.¹⁶ A randomized controlled trial involving patients with chronic pelvic pain secondary to pelvic congestion demonstrated that treatment with medroxyprogesterone acetate or a GnRH agonist (goserelin) improved pelvic symptoms.¹⁷

A Cochrane review of nonsurgical interventions for chronic pelvic pain included women with a diagnosis of pelvic congestion syndrome or adhesions. It found that patients treated with medroxyprogesterone acetate were more likely to have 50% pain reduction lasting up to 9 months compared with patients taking placebo.¹² In comparative studies, GnRH analogues were more effective in relieving pelvic pain than progestogen therapy.

Radiologic embolization therapy is as effective as hysterectomy for the relief of chronic pelvic pain related to pelvic congestion syndrome, and it can be performed in the outpatient setting.

Irritable bowel syndrome: Try dietary changes

Symptoms of chronic pelvic pain that are associated with changes in stool consistency and frequency suggest irritable bowel syndrome. Symptoms may improve with dietary changes and fiber supplementation. Antispasmodic agents are frequently used but their anticholinergic effects may worsen constipation.¹⁴

PELVIC PHYSICAL THERAPY

Pelvic physical therapy targets the musculoskeletal components of bowel, bladder, and sexual function to restore strength, flexibility, balance, and coordination to the pelvic floor and surrounding lumbopelvic muscles. Patients with dyspareunia, pain with activity, or a significant musculoskeletal abnormality (eg, vaginismus or point tenderness on examination) are particularly good candidates for this therapy. It is done by a physical therapist with special training in techniques to manipulate the pelvic floor to address pelvic pain.

Educating the patient

Informing the patient before the initial physical therapy visit is essential for success. Referring clinicians should emphasize to patients that treatment response can help to guide further physician intervention. Patients should be counseled that pelvic physical therapy includes a pelvic examination and an expectation to participate in a home program. Although noticeable improvement takes time, encouragement provided by the entire team, including medical providers, can help a patient maintain her care plan.

Therapists typically see a patient once a week for 8 to 12 visits initially. Insurance usually covers pelvic physical therapy through the same policy as routine physical therapy.

During the initial evaluation, the patient receives an external and internal pelvic examination assessing muscle length, strength, and coordination of the back, hip, and internal pelvic floor. Internal evaluation can be done vaginally or rectally, with one gloved finger, without the need for speculum or stirrups. Biofeedback and surface electromyography (using either perianal or internal electrode placement) are used to evaluate muscle activity and to assist the patient in developing appropriate motor control during strengthening or relaxation.¹⁸

Up-training (or strengthening) aims to improve pelvic floor endurance. It can improve pelvic instability and symptoms of heaviness and discomfort from prolapse. Patients learn to appropriately utilize the pelvic floor in isolation. If a patient is too weak to contract on her own, neuromuscular electrical stimulation is used with an internal electrode to provide an assisted contraction.

Down-training (or relaxation) focuses on reducing tone in overactive pelvic muscles. It can improve symptoms of chronic pelvic pain, sexual pain, vulvodynia, and pudendal neuralgias. Patients are made aware of chronic holding patterns that lead to excess tone in the pelvic floor and learn how to release them through stretching, cardiovascular activity, meditation, and manual release of the involved muscle groups internally and externally. Internal musculature can be manipulated by a therapist in clinic or by the patient’s trained partner; the patient can also reach necessary areas with a vaginal dilator.

Functional coordination of the pelvic floor is needed for comfortable vaginal penetration and defecation. Training with biofeedback improves a patient’s ability to relax and open the pelvic floor.¹⁸ Vaginal dilators with surface electromyography are used to treat vaginismus to eliminate reflexive pelvic floor spasm during penetration. Perineal and vaginal compliance can be improved through manual release techniques with hands or vaginal dilators to restore normal mobility of tissues. This can reduce pain from postsurgical changes, postpartum sequelae, atrophic vaginal changes, shortened muscles from chronic holding, and adhesions.

PSYCHOSOCIAL INTERVENTIONS

Pelvic pain is not only a biomedical difficulty; psychosocial factors can contribute to and be affected by pelvic pain. Patients with pelvic pain often experience lower quality of life, higher rates of anxiety and depression, and increased stress compared with others.^19,20 People with pain also have more relationship stress, and patients’ partners often experience emotional distress, isolation, and feelings of powerlessness in the relationship.²¹

Psychosocial interventions, provided along with biomedical treatment, can help to reduce pain, anxiety, and depression and improve relational well-being.^22,23 In addition to attending to pain-related symptoms, comprehensive care involves recognizing and treating coexisting anxiety, depression, stress, and relationship conflict. Interventions for these difficulties are many, and a comprehensive list of interventions is beyond the focus of this section.¹⁹

Cognitive behavioral therapy is based on the idea that maladaptive cognitions can lead to problematic behaviors and emotional distress.²⁴ Interventions are carried out by a provider with specialized training in its use (eg, therapist, pain psychologist, psychiatrist).

Meta-analyses of studies that investigated the efficacy of cognitive behavioral therapy for chronic pain found consistent small to medium improvement in pain-related symptoms.²⁴ Studies that used cognitive behavioral therapy for pelvic pain found reduced overall pain severity and pain during intercourse, increased sexual satisfaction, enhanced sexual function, and less-exaggerated responses to pain.^25–27

Although cognitive behavioral therapy and mindfulness-based interventions produce positive outcomes, research on these interventions typically includes treatment carried out over a span of weeks. Common barriers to such care include lack of patient motivation, financial limitations, transportation problems, and time constraints.

The following psychosocial interventions have been chosen because they can be delivered in a short amount of time and integrated into a patient’s medical care by a medical or behavioral health provider. Because of the brevity and simplicity of these interventions, more patients with pelvic pain can receive psychosocial care as part of their usual medical encounters.

Behavioral activation

People experiencing depressive symptoms tend to isolate themselves and stop participating in activities they enjoy, including spending time with family and friends. Behavioral activation interventions that address such isolating behaviors have been shown to be effective in improving depressive symptoms.^28–30

A simple, brief intervention can be administered during routine medical care,²⁸ involving the following steps:

• Determine activities that the patient might implement that would decrease depressive symptoms. Questions such as, “When do you feel less depressed?” or “What brings you some happiness in your life?” can generate possible activities.
• Ask the patient to identify people in her life who have been supportive and with whom she could engage.
• Create with the patient a list of possible activities and social interactions that may enhance well-being.
• Make a schedule for participating in activities, possibly with rewards for completing them. Patients should be encouraged to follow the prescribed schedule of activities rather than make decisions based on mood or other factors. 

Relaxation strategies

Relaxation can help patients reduce stress and anxiety, and can also help reduce pain.^31–33

Diaphragmatic or “belly breathing” is a deep-breathing technique in which participants are asked to take in air through the nose and fully fill the lungs and lower belly. This technique allows the body to take in more oxygen, helping to lower blood pressure and slow the heartbeat. In addition to physiologic benefits, concentrating on deep breathing can help slow down or stop intrusive thoughts and distressing physical sensations.³⁴

Progressive muscle relaxation involves the systematic tensing and relaxing of each large muscle group in the body.³⁵ The goal is to eliminate physical and emotional stress through focusing on the sensations of tension and relaxation.

Scripts and audio and video resources for belly breathing and progressive muscle relaxation can be found on the Internet. The techniques can be taught during the medical appointment or offered as resources for home practice.

Couple-based care

Targeting couples is more effective for improving well-being than focusing solely on a patient’s psychosocial difficulties, so each of the above interventions may be more effective if tailored to include the patient’s partner.³⁶ If the partner is with the patient during medical visits or is included in long-term psychosocial treatment, he or she can be directly involved in learning and practicing interventions with the patient. If the partner is not present, the patient can be asked to practice newly learned well-being-enhancing strategies with her partner outside the appointment time. Couples therapy can improve psychosocial well-being for both partners.

Setting goals

Chronic pelvic pain is a common clinical problem in women, as prevalent in primary care as asthma or back pain.^1,2 It is often associated with lost work days and decreased productivity, increased healthcare spending, mood disorders, and negative effects on personal relationships.^1–3

While specialty care referral may eventually be indicated, primary care doctors can take steps to diagnose and effectively manage the condition.

COMPREHENSIVE MANAGEMENT LED BY PRIMARY CARE

Chronic pelvic pain is defined as pain in the lower abdomen persisting for 3 to 6 months and of sufficient severity to require medical care or cause a functional disability.³ It is often detrimental to a woman’s personal life and overall health, making a comprehensive assessment and multidisciplinary approach to management especially important.

The ideal care-delivery model is the patient-centered medical home, whereby a primary care physician coordinates comprehensive care with the help of an interdisciplinary team.^4,5 For complex cases, referral may be needed to other specialties (eg, obstetrics and gynecology, pain medicine) to help manage care.

TARGETED EVALUATION

Chronic pelvic pain often coexists with other systemic pain syndromes or psychiatric conditions common in primary care. Table 1 lists common causes and associated findings.

Detailed history is critical

The history is of utmost importance. Clinicians should query patients about the characteristics of the pain as well as their medical and surgical history. Particular attention should be given to obtaining a complete gynecologic history, including pregnancy, delivery complications, dyspareunia, sexual assault, and trauma. A detailed review of systems should focus on the reproductive, gastroenterologic, musculoskeletal, urologic, and neuropsychiatric systems.

As with many pain syndromes, allowing the patient to “tell her story” helps to establish rapport and obtain a more complete assessment. Chronic pelvic pain has been associated with physical or sexual abuse as a child or adult, so is essential to foster the doctor-patient relationship and create a safe and open space for disclosure.^3,6 It is important to screen women for safety at home as well as for satisfaction or dissatisfaction with their relationships with their spouse or partner and family.

Physical examination

The physical examination should be directed by the history but should always include abdominal and pelvic examinations. These should be conducted slowly and gently, assessing for areas of tenderness, masses, and other abnormalities. Clinicians should aim to pinpoint the exact anatomic locations of tenderness if possible. Ongoing dialogue facilitates this process by inquiring about pain at each point of the examination.

The pelvic examination should begin with visual inspection for redness, discharge, lesions, fissures, excoriations, and other abnormalities. A moistened cotton swab may be used to evaluate the vulva and vestibule for localized tenderness. The manual portion of the pelvic examination should begin with a single digit, noting any introital tenderness or spasm. Next, the levator ani muscles should be directly palpated for tone and tenderness. The pelvic floor should be evaluated with attention to tenderness of the bladder or musculoskeletal structures (Figure 1). A bimanual examination assessing uterine size and tenderness, nodularity, or a fixed, immobile uterus should be conducted.

Because the differential diagnosis of chronic pelvic pain is broad, the diagnostic workup and testing should be based on findings of the history and physical examination. In general, extensive laboratory testing is of limited use for evaluating women with chronic pelvic pain.^3,7

Urinalysis should be obtained for symptoms suggesting bladder involvement such as interstitial cystitis.

Pelvic ultrasonography can help identify pelvic masses palpated during the physical examination, but routine use of imaging is not recommended.^3,7 If pelvic congestion syndrome is suspected, starting with pelvic ultrasonography is reasonable before incurring the risk or cost of computed tomography or magnetic resonance imaging.⁸

GENERAL TREATMENT

Medical therapy

The main goals of medical therapy are to improve function and quality of life while minimizing adverse effects. General treatments include the following:

Analgesics. Nonsteroidal anti-inflammatory drugs and acetaminophen may provide pain relief, although there is weak evidence for their efficacy in treating chronic pelvic pain.⁹

Neuropathic agents. One of several available neuropathic agents commonly used in the treatment of chronic pain can be tried on patients who fail to respond to analgesics. Tricyclic antidepressants such as amitriptyline and imipramine decrease pain, reduce symptoms of depression, and improve sleep.¹⁰ The results of a small randomized controlled trial suggest that gabapentin is more effective than amitriptyline for reducing chronic pelvic pain.^11,12 Published guidelines currently list both amitriptyline and gabapentin as first-line agents; nortriptyline and pregabalin are considered acceptable initial alternatives.⁹

Venlafaxine and duloxetine may help chronic pelvic pain, although specific evidence is lacking. Duloxetine may be an appropriate choice for women with chronic pelvic pain who also experience depression and urinary stress incontinence.⁹

Opioids. Opioid therapy should be considered only when all other reasonable therapies have failed.¹⁰ Patients may develop tolerance or dependence, as well as opioid-induced adverse effects such as hyperalgesia.^9,10 Guidelines recommend that primary care providers consult with a pain management specialist before prescribing opioids, and that patients be thoroughly counseled about the risks and side effects.⁹

Nerve block and neuromodulation. There is weak evidence for the use of these modalities for treating chronic pelvic pain.⁹ If used, they should be part of a broader treatment plan and should be performed by providers who specialize in management of chronic pain.

DISEASE-SPECIFIC TREATMENT

Endometriosis: Hormonal therapy

Pelvic pain that significantly fluctuates with the menstrual cycle may be caused by endometriosis, the most common gynecologic cause of chronic pelvic pain. Women with cyclic chronic pelvic pain should be empirically treated with hormonal therapy for at least 3 to 6 months before diagnostic laparoscopy is performed.¹³

Oral contraceptives, gonadotropin-releasing hormone (GnRH) analogues, progestogens, and danazol have proven efficacy, although side-effect profiles differ significantly. In a comparative trial, patients treated with GnRH analogues had more improvement in pain scores compared with those treated with oral contraceptives, but they experienced a significant decrease in bone mineral density.¹¹ The effects on bone mineral density associated with GnRH analogue therapy can be mitigated by “add-back” low-dose hormonal therapy (norethindrone, low-dose estrogen, or a combination of estrogen and progesterone), which may also provide symptomatic relief for associated hot flashes and vaginal symptoms.¹¹

Interstitial cystitis often accompanies endometriosis

Recognizing that chronic pelvic pain may have more than one cause is important when developing a comprehensive care plan. Interstitial cystitis coexists with endometriosis in up to 60% of patients.¹⁴ Initial treatment is pentosan polysulfate sodium, an oral treatment approved by the US Food and Drug Administration for interstitial cystitis that works by restoring the protective glycosaminoglycan layer in the bladder.^14,15 Amitriptyline may also be used to treat interstitial cystitis-associated nocturia.

Myofascial pain: Neuromuscular blockers

According to a recent systematic review of therapies for chronic pelvic pain, patients with symptoms related to myofascial pain may benefit from neuromuscular blockade.¹² One randomized controlled trial of the effectiveness of botulinum toxin A vs saline for the treatment of chronic pelvic pain secondary to pelvic floor spasm found that after 6 months of observation, women who received botulinum toxin had significantly lower pain scores than those who received saline.¹²

Pelvic congestion syndrome may be treated with hormonal, radiologic, or surgical therapy.¹⁶ A randomized controlled trial involving patients with chronic pelvic pain secondary to pelvic congestion demonstrated that treatment with medroxyprogesterone acetate or a GnRH agonist (goserelin) improved pelvic symptoms.¹⁷

A Cochrane review of nonsurgical interventions for chronic pelvic pain included women with a diagnosis of pelvic congestion syndrome or adhesions. It found that patients treated with medroxyprogesterone acetate were more likely to have 50% pain reduction lasting up to 9 months compared with patients taking placebo.¹² In comparative studies, GnRH analogues were more effective in relieving pelvic pain than progestogen therapy.

Radiologic embolization therapy is as effective as hysterectomy for the relief of chronic pelvic pain related to pelvic congestion syndrome, and it can be performed in the outpatient setting.

Irritable bowel syndrome: Try dietary changes

Symptoms of chronic pelvic pain that are associated with changes in stool consistency and frequency suggest irritable bowel syndrome. Symptoms may improve with dietary changes and fiber supplementation. Antispasmodic agents are frequently used but their anticholinergic effects may worsen constipation.¹⁴

PELVIC PHYSICAL THERAPY

Pelvic physical therapy targets the musculoskeletal components of bowel, bladder, and sexual function to restore strength, flexibility, balance, and coordination to the pelvic floor and surrounding lumbopelvic muscles. Patients with dyspareunia, pain with activity, or a significant musculoskeletal abnormality (eg, vaginismus or point tenderness on examination) are particularly good candidates for this therapy. It is done by a physical therapist with special training in techniques to manipulate the pelvic floor to address pelvic pain.

Educating the patient

Informing the patient before the initial physical therapy visit is essential for success. Referring clinicians should emphasize to patients that treatment response can help to guide further physician intervention. Patients should be counseled that pelvic physical therapy includes a pelvic examination and an expectation to participate in a home program. Although noticeable improvement takes time, encouragement provided by the entire team, including medical providers, can help a patient maintain her care plan.

Therapists typically see a patient once a week for 8 to 12 visits initially. Insurance usually covers pelvic physical therapy through the same policy as routine physical therapy.

During the initial evaluation, the patient receives an external and internal pelvic examination assessing muscle length, strength, and coordination of the back, hip, and internal pelvic floor. Internal evaluation can be done vaginally or rectally, with one gloved finger, without the need for speculum or stirrups. Biofeedback and surface electromyography (using either perianal or internal electrode placement) are used to evaluate muscle activity and to assist the patient in developing appropriate motor control during strengthening or relaxation.¹⁸

Up-training (or strengthening) aims to improve pelvic floor endurance. It can improve pelvic instability and symptoms of heaviness and discomfort from prolapse. Patients learn to appropriately utilize the pelvic floor in isolation. If a patient is too weak to contract on her own, neuromuscular electrical stimulation is used with an internal electrode to provide an assisted contraction.

Down-training (or relaxation) focuses on reducing tone in overactive pelvic muscles. It can improve symptoms of chronic pelvic pain, sexual pain, vulvodynia, and pudendal neuralgias. Patients are made aware of chronic holding patterns that lead to excess tone in the pelvic floor and learn how to release them through stretching, cardiovascular activity, meditation, and manual release of the involved muscle groups internally and externally. Internal musculature can be manipulated by a therapist in clinic or by the patient’s trained partner; the patient can also reach necessary areas with a vaginal dilator.

Functional coordination of the pelvic floor is needed for comfortable vaginal penetration and defecation. Training with biofeedback improves a patient’s ability to relax and open the pelvic floor.¹⁸ Vaginal dilators with surface electromyography are used to treat vaginismus to eliminate reflexive pelvic floor spasm during penetration. Perineal and vaginal compliance can be improved through manual release techniques with hands or vaginal dilators to restore normal mobility of tissues. This can reduce pain from postsurgical changes, postpartum sequelae, atrophic vaginal changes, shortened muscles from chronic holding, and adhesions.

PSYCHOSOCIAL INTERVENTIONS

Pelvic pain is not only a biomedical difficulty; psychosocial factors can contribute to and be affected by pelvic pain. Patients with pelvic pain often experience lower quality of life, higher rates of anxiety and depression, and increased stress compared with others.^19,20 People with pain also have more relationship stress, and patients’ partners often experience emotional distress, isolation, and feelings of powerlessness in the relationship.²¹

Psychosocial interventions, provided along with biomedical treatment, can help to reduce pain, anxiety, and depression and improve relational well-being.^22,23 In addition to attending to pain-related symptoms, comprehensive care involves recognizing and treating coexisting anxiety, depression, stress, and relationship conflict. Interventions for these difficulties are many, and a comprehensive list of interventions is beyond the focus of this section.¹⁹

Cognitive behavioral therapy is based on the idea that maladaptive cognitions can lead to problematic behaviors and emotional distress.²⁴ Interventions are carried out by a provider with specialized training in its use (eg, therapist, pain psychologist, psychiatrist).

Meta-analyses of studies that investigated the efficacy of cognitive behavioral therapy for chronic pain found consistent small to medium improvement in pain-related symptoms.²⁴ Studies that used cognitive behavioral therapy for pelvic pain found reduced overall pain severity and pain during intercourse, increased sexual satisfaction, enhanced sexual function, and less-exaggerated responses to pain.^25–27

Although cognitive behavioral therapy and mindfulness-based interventions produce positive outcomes, research on these interventions typically includes treatment carried out over a span of weeks. Common barriers to such care include lack of patient motivation, financial limitations, transportation problems, and time constraints.

The following psychosocial interventions have been chosen because they can be delivered in a short amount of time and integrated into a patient’s medical care by a medical or behavioral health provider. Because of the brevity and simplicity of these interventions, more patients with pelvic pain can receive psychosocial care as part of their usual medical encounters.

Behavioral activation

People experiencing depressive symptoms tend to isolate themselves and stop participating in activities they enjoy, including spending time with family and friends. Behavioral activation interventions that address such isolating behaviors have been shown to be effective in improving depressive symptoms.^28–30

A simple, brief intervention can be administered during routine medical care,²⁸ involving the following steps:

• Determine activities that the patient might implement that would decrease depressive symptoms. Questions such as, “When do you feel less depressed?” or “What brings you some happiness in your life?” can generate possible activities.
• Ask the patient to identify people in her life who have been supportive and with whom she could engage.
• Create with the patient a list of possible activities and social interactions that may enhance well-being.
• Make a schedule for participating in activities, possibly with rewards for completing them. Patients should be encouraged to follow the prescribed schedule of activities rather than make decisions based on mood or other factors. 

Relaxation strategies

Relaxation can help patients reduce stress and anxiety, and can also help reduce pain.^31–33

Diaphragmatic or “belly breathing” is a deep-breathing technique in which participants are asked to take in air through the nose and fully fill the lungs and lower belly. This technique allows the body to take in more oxygen, helping to lower blood pressure and slow the heartbeat. In addition to physiologic benefits, concentrating on deep breathing can help slow down or stop intrusive thoughts and distressing physical sensations.³⁴

Progressive muscle relaxation involves the systematic tensing and relaxing of each large muscle group in the body.³⁵ The goal is to eliminate physical and emotional stress through focusing on the sensations of tension and relaxation.

Scripts and audio and video resources for belly breathing and progressive muscle relaxation can be found on the Internet. The techniques can be taught during the medical appointment or offered as resources for home practice.

Couple-based care

Targeting couples is more effective for improving well-being than focusing solely on a patient’s psychosocial difficulties, so each of the above interventions may be more effective if tailored to include the patient’s partner.³⁶ If the partner is with the patient during medical visits or is included in long-term psychosocial treatment, he or she can be directly involved in learning and practicing interventions with the patient. If the partner is not present, the patient can be asked to practice newly learned well-being-enhancing strategies with her partner outside the appointment time. Couples therapy can improve psychosocial well-being for both partners.

Setting goals

Sometimes the answer is straightforward—the pills were started to reduce knee pain, but the pain is still there. But sometimes if I suggest stopping a drug, I get surprising pushback from the patient: “But the pain may be worse without those pills.” And it can be hard to assess whether a medication has attained its therapeutic goal, such as when a drug is given to prevent or reduce the occurrence of intermittent events (eg, hydroxychloroquine to reduce flares in lupus, aspirin to prevent transient ischemic attacks). Unless a medication has been given sufficient time to have its effect and has clearly failed, we often have to trust its efficacy because those events might be more frequent if the drug were stopped.

In this issue of the Journal, Kim and Factora discuss a difficult scenario—discontinuing cognitive-enhancing therapy in patients with Alzheimer dementia. The stakes, hopes, and anxiety are high for the patient and caregivers. These drugs have only modest efficacy, and it is often difficult to know if they are working. To complicate matters, dementia is progressive, but the rate of progression differs among individuals, making it harder to be convinced that the drugs have lost their efficacy and that discontinuation is warranted in order to reduce the side effects, cost, and pill burden. Similar challenges arise for similar reasons when considering discontinuation of antipsychotics or other drugs given for behavioral reasons to elderly patients with dementia.¹

The issues surrounding downsizing medication lists—or deprescribing—extend far beyond patients with Alzheimer dementia. A disease may have progressed beyond the point where the drug can make a significant impact. Patients often develop tachyphylaxis to the newer protein drugs (biologics for rheumatoid arthritis, inflammatory bowel disease, psoriasis, or gout) due to the generation of neutralizing antidrug antibodies. At some point the patient’s life expectancy becomes a factor when considering medications directed at preventing long-term complications of a disease and the increased likelihood of significant adverse effects in patients as they age (eg, from aggressively prescribed antihypertensive and antidiabetic drugs). For drugs such as bisphosphonates, alkylating agents, and metoclopramide, complications of cumulative dosing over time should be considered a reason to discontinue therapy.

The take-home message from this article is to create opportunities to periodically revisit the rationale for all of a patient’s prescriptions, and to make sure patients are comfortable knowing why they should keep taking each of their medications. While revisiting a patient’s prescriptions may indeed reduce the medication burden, I believe it also enhances adherence to the remaining prescribed medications. The medication reconciliation process requires more than simply checking off the box in the EMR to indicate that the medications were “reviewed.”

Sometimes the answer is straightforward—the pills were started to reduce knee pain, but the pain is still there. But sometimes if I suggest stopping a drug, I get surprising pushback from the patient: “But the pain may be worse without those pills.” And it can be hard to assess whether a medication has attained its therapeutic goal, such as when a drug is given to prevent or reduce the occurrence of intermittent events (eg, hydroxychloroquine to reduce flares in lupus, aspirin to prevent transient ischemic attacks). Unless a medication has been given sufficient time to have its effect and has clearly failed, we often have to trust its efficacy because those events might be more frequent if the drug were stopped.

In this issue of the Journal, Kim and Factora discuss a difficult scenario—discontinuing cognitive-enhancing therapy in patients with Alzheimer dementia. The stakes, hopes, and anxiety are high for the patient and caregivers. These drugs have only modest efficacy, and it is often difficult to know if they are working. To complicate matters, dementia is progressive, but the rate of progression differs among individuals, making it harder to be convinced that the drugs have lost their efficacy and that discontinuation is warranted in order to reduce the side effects, cost, and pill burden. Similar challenges arise for similar reasons when considering discontinuation of antipsychotics or other drugs given for behavioral reasons to elderly patients with dementia.¹

The issues surrounding downsizing medication lists—or deprescribing—extend far beyond patients with Alzheimer dementia. A disease may have progressed beyond the point where the drug can make a significant impact. Patients often develop tachyphylaxis to the newer protein drugs (biologics for rheumatoid arthritis, inflammatory bowel disease, psoriasis, or gout) due to the generation of neutralizing antidrug antibodies. At some point the patient’s life expectancy becomes a factor when considering medications directed at preventing long-term complications of a disease and the increased likelihood of significant adverse effects in patients as they age (eg, from aggressively prescribed antihypertensive and antidiabetic drugs). For drugs such as bisphosphonates, alkylating agents, and metoclopramide, complications of cumulative dosing over time should be considered a reason to discontinue therapy.

The take-home message from this article is to create opportunities to periodically revisit the rationale for all of a patient’s prescriptions, and to make sure patients are comfortable knowing why they should keep taking each of their medications. While revisiting a patient’s prescriptions may indeed reduce the medication burden, I believe it also enhances adherence to the remaining prescribed medications. The medication reconciliation process requires more than simply checking off the box in the EMR to indicate that the medications were “reviewed.”

Sometimes the answer is straightforward—the pills were started to reduce knee pain, but the pain is still there. But sometimes if I suggest stopping a drug, I get surprising pushback from the patient: “But the pain may be worse without those pills.” And it can be hard to assess whether a medication has attained its therapeutic goal, such as when a drug is given to prevent or reduce the occurrence of intermittent events (eg, hydroxychloroquine to reduce flares in lupus, aspirin to prevent transient ischemic attacks). Unless a medication has been given sufficient time to have its effect and has clearly failed, we often have to trust its efficacy because those events might be more frequent if the drug were stopped.

In this issue of the Journal, Kim and Factora discuss a difficult scenario—discontinuing cognitive-enhancing therapy in patients with Alzheimer dementia. The stakes, hopes, and anxiety are high for the patient and caregivers. These drugs have only modest efficacy, and it is often difficult to know if they are working. To complicate matters, dementia is progressive, but the rate of progression differs among individuals, making it harder to be convinced that the drugs have lost their efficacy and that discontinuation is warranted in order to reduce the side effects, cost, and pill burden. Similar challenges arise for similar reasons when considering discontinuation of antipsychotics or other drugs given for behavioral reasons to elderly patients with dementia.¹

The issues surrounding downsizing medication lists—or deprescribing—extend far beyond patients with Alzheimer dementia. A disease may have progressed beyond the point where the drug can make a significant impact. Patients often develop tachyphylaxis to the newer protein drugs (biologics for rheumatoid arthritis, inflammatory bowel disease, psoriasis, or gout) due to the generation of neutralizing antidrug antibodies. At some point the patient’s life expectancy becomes a factor when considering medications directed at preventing long-term complications of a disease and the increased likelihood of significant adverse effects in patients as they age (eg, from aggressively prescribed antihypertensive and antidiabetic drugs). For drugs such as bisphosphonates, alkylating agents, and metoclopramide, complications of cumulative dosing over time should be considered a reason to discontinue therapy.

The take-home message from this article is to create opportunities to periodically revisit the rationale for all of a patient’s prescriptions, and to make sure patients are comfortable knowing why they should keep taking each of their medications. While revisiting a patient’s prescriptions may indeed reduce the medication burden, I believe it also enhances adherence to the remaining prescribed medications. The medication reconciliation process requires more than simply checking off the box in the EMR to indicate that the medications were “reviewed.”

In the article, “Update on the management of venous thromboembolism” (Bartholomew JR, Cleve Clin J Med 2017; 84[suppl 3]:39–46), 2 sentences in the text regarding dose reduction for body weight have errors. The corrected sentences follow:

On page 42, left column, the last 5 lines should read: “The recommended dose should be reduced to 2.5 mg twice daily in patients that meet 2 of the following criteria: age 80 or older; body weight of 60 kg or less; or with a serum creatinine 1.5 mg/dL or greater.”

And on page 42, right column, the sentence 10 lines from the top should read: “Edoxaban is given orally at 60 mg once daily but reduced to 30 mg once daily if the CrCL is 30 mL/min to 50 mL/min, if body weight is 60 kg or less, or with use of certain P-glycoprotein inhibitors.”

In the article, “Update on the management of venous thromboembolism” (Bartholomew JR, Cleve Clin J Med 2017; 84[suppl 3]:39–46), 2 sentences in the text regarding dose reduction for body weight have errors. The corrected sentences follow:

On page 42, left column, the last 5 lines should read: “The recommended dose should be reduced to 2.5 mg twice daily in patients that meet 2 of the following criteria: age 80 or older; body weight of 60 kg or less; or with a serum creatinine 1.5 mg/dL or greater.”

And on page 42, right column, the sentence 10 lines from the top should read: “Edoxaban is given orally at 60 mg once daily but reduced to 30 mg once daily if the CrCL is 30 mL/min to 50 mL/min, if body weight is 60 kg or less, or with use of certain P-glycoprotein inhibitors.”

In the article, “Update on the management of venous thromboembolism” (Bartholomew JR, Cleve Clin J Med 2017; 84[suppl 3]:39–46), 2 sentences in the text regarding dose reduction for body weight have errors. The corrected sentences follow:

On page 42, left column, the last 5 lines should read: “The recommended dose should be reduced to 2.5 mg twice daily in patients that meet 2 of the following criteria: age 80 or older; body weight of 60 kg or less; or with a serum creatinine 1.5 mg/dL or greater.”

And on page 42, right column, the sentence 10 lines from the top should read: “Edoxaban is given orally at 60 mg once daily but reduced to 30 mg once daily if the CrCL is 30 mL/min to 50 mL/min, if body weight is 60 kg or less, or with use of certain P-glycoprotein inhibitors.”

Medical students remain protected by DACA – for now. The AIDS epidemic’s skin villains are back, there’s a new leading cause of liver cancer, and how storage of firearms at home affects suicidal teens.

Listen to the MDedge Daily News podcast for all the details on today’s top news.

Medical students remain protected by DACA – for now. The AIDS epidemic’s skin villains are back, there’s a new leading cause of liver cancer, and how storage of firearms at home affects suicidal teens.

Listen to the MDedge Daily News podcast for all the details on today’s top news.

Medical students remain protected by DACA – for now. The AIDS epidemic’s skin villains are back, there’s a new leading cause of liver cancer, and how storage of firearms at home affects suicidal teens.

Listen to the MDedge Daily News podcast for all the details on today’s top news.