Deep brain stimulation is an important therapy for Parkinson disease and other movement disorders. It involves implantation of a pulse generator that can be adjusted by telemetry and can be activated and deactivated by clinicians and patients. It is therefore also a good investigational tool, allowing for double-blind, sham-controlled clinical trials by testing the effects of the stimulation with optimal settings compared with no stimulation.

This article will discuss the approved indications for deep brain stimulation (particularly for managing movement disorders), the benefits that can be expected, the risks, the complications, the maintenance required, how candidates for this treatment are evaluated, and the surgical procedure for implantation of the devices.

DEVICE SIMILAR TO HEART PACEMAKERS

The deep brain stimulation system must be programmed by a physician or midlevel practitioner by observing a symptom and then changing the applied settings to the pulse generator until the symptom improves. This can be a very time-consuming process.

In contrast to heart pacemakers, which run at low frequencies, the brain devices for movement disorders are almost always set to a high frequency, greater than 100 Hz. For this reason, they consume more energy and need larger batteries than those in modern heart pacemakers.

The batteries in these generators typically last 3 to 5 years and are replaced in an outpatient procedure. Newer, smaller, rechargeable devices are expected to last longer but require more maintenance and care by patients, who have to recharge them at home periodically.

INDICATIONS FOR DEEP BRAIN STIMULATION

Deep brain stimulation is approved by the US Food and Drug Administration (FDA) for specific indications:

• Parkinson disease
• Essential tremor
• Primary dystonia (under a humanitarian device exemption)
• Intractable obsessive-compulsive disorder (also under a humanitarian device exemption). We will not discuss this indication further in this paper.

For each of these conditions, deep brain stimulation is considered when nonsurgical management has failed, as is the case for most functional neurosurgical treatments.

Investigations under way in other disorders

Several studies of deep brain stimulation are currently in progress under FDA-approved investigational device exemptions. Some, with funding from industry, are exploring its use in neuropsychiatric conditions other than parkinsonism. Two large clinical trials are evaluating its use for treatment-refractory depression, a common problem and a leading cause of disability in the industrialized world. Multiple investigators are also exploring novel uses of this technology in disorders ranging from obsessive-compulsive disorder to epilepsy.

Investigation is also under way at Cleveland Clinic in a federally funded, prospective, randomized clinical trial of deep brain stimulation for patients with thalamic pain syndrome. The primary hypothesis is that stimulation of the ventral striatal and ventral capsular area will modulate the affective component of this otherwise intractable pain syndrome, reducing pain-related disability and improving quality of life.

DEEP BRAIN STIMULATION VS ABLATION

Before deep brain stimulation became available, the only surgical options for patients with advanced Parkinson disease, tremor, or dystonia were ablative procedures such as pallidotomy (ablation of part of the globus pallidus) and thalamotomy (ablation of part of the thalamus). These procedures had been well known for several decades but fell out of favor when levodopa became available in the 1960s and revolutionized the medical treatment of Parkinson disease.

Surgery for movement disorders, in particular Parkinson disease, had a rebirth in the late 1980s when the limitations and complications associated with the pharmacologic management of Parkinson disease became increasingly evident. Ablative procedures are still used to treat advanced Parkinson disease, but much less commonly in industrialized countries.

Although pallidotomy and thalamotomy can have excellent results, they are not as safe as deep brain stimulation, which has the advantage of being reversible, modulating the function of an area rather than destroying it. Any unwanted effect can be immediately altered or reversed, unlike ablative procedures, in which any change is permanent. In addition, deep brain stimulation is adjustable, and the settings can be optimized as the disease progresses over the years.

Ablative procedures can be risky when performed bilaterally, while deep brain stimulation is routinely done on both hemispheres for patients with bilateral symptoms.

Although deep brain stimulation is today’s surgical treatment of choice, it is not perfect. It has the disadvantage of requiring lifelong maintenance of the hardware, for which the patient remains dependent on a medical center. Patients are usually seen more often at the specialized center in the first few months after surgery for optimization of programming and titration of drugs. (During this time, most patients see a gradual, substantial reduction in medication intake.) They are then followed by their physician and visit the center less often for monitoring of disease status and for further adjustments to the stimulator.

Most patients, to date, receive nonrechargeable pulse generators. As mentioned above, the batteries in these devices typically last 3 to 5 years. Preferably, batteries are replaced before they are completely depleted, to avoid interruption of therapy. Periodic visits to the center allow clinicians to estimate battery expiration ahead of time and plan replacements accordingly.

Rechargeable pulse generators have been recently introduced and are expected to last up to 9 years. They are an option for patients who can comply with the requirements for periodic home recharging of the hardware.

Patients are given a remote control so that they can turn the device on or off and check its status. Most patients keep it turned on all the time, although some turn it off at night to save battery life.

WHAT CAN PARKINSON PATIENTS EXPECT FROM THIS THERAPY?

Typically, some parkinsonian symptoms predominate over others, although some patients with advanced disease present with a severe combination of multiple disabling symptoms. Deep brain stimulation is best suited to address some of the cardinal motor symptoms, particularly tremor, rigidity, and bradykinesia, and motor fluctuations such as “wearing off” and dyskinesia.

Improvement in some motor symptoms

As a general rule, appendicular symptoms such as limb tremor and rigidity are more responsive to this therapy than axial symptoms such as gait and balance problems, but some patients experience improvement in gait as well. Other symptoms, such as swallowing or urinary symptoms, are seldom helped.

Although deep brain stimulation can help manage key motor symptoms and improve quality of life, it does not cure Parkinson disease. Also, there is no evidence to date that it slows disease progression, although this is a topic of ongoing investigation.

Fewer motor fluctuations

A common complaint of patients with advanced Parkinson disease is frequent—and often unpredictable—fluctuations between the “on” state (ie, when the effects of the patient’s levodopa therapy are apparent) and the “off” state (ie, when the levodopa doesn’t seem to be working). Sometimes, in the on state, patients experience involuntary choreic or ballistic movements, called dyskinesias. They also complain that the on time progressively lasts shorter and the day is spent alternating between shorter on states (during which the patient may be dyskinetic) and longer off states, limiting the patient’s independence and quality of life.

Deep brain stimulation can help patients prolong the on time while reducing the amplitude of these fluctuations so that the symptoms are not as severe in the off time and dyskinesias are reduced in the on time.

Some patients undergo deep brain stimulation primarily for managing the adverse effects of levodopa rather than for controlling the symptoms of the disease itself. While these patients need levodopa to address the disabling symptoms of the disease, they also present a greater sensitivity for developing levodopa-induced dyskinesias, quickly fluctuating from a lack of movement (the off state) to a state of uncontrollable movements (during the on state).

Deep brain stimulation typically allows the dosage of levodopa to be significantly reduced and gives patients more on time with fewer side effects and less fluctuation between the on and off states.

Response to levodopa predicts deep brain stimulation’s effects

Whether a patient is likely to be helped by deep brain stimulation can be tested with reasonable predictability by giving a single therapeutic dose of levodopa after the patient has been free of the drug for 12 hours. If there is an obvious difference on objective quantitative testing between the off and on states with a single dose, the patient is likely to benefit from deep brain stimulation. Those who do not respond well or are known to have never been well controlled by levodopa are likely poor candidates.

The test is also used as an indicator of whether the patient’s gait can be improved. Patients whose gait is substantially improved by levodopa, even for only a brief period of time, have a better chance of experiencing improvement in this domain with deep brain stimulation than those who do not show any gait improvement.

An important and notable exception to this rule is tremor control. Even Parkinson patients who do not experience significant improvement in tremor with levodopa (ie, who have medication-resistant tremors) are still likely to benefit from deep brain stimulation. Overall, tremor is the symptom that is most consistently improved with deep brain stimulation.

Results of clinical trials

Several clinical trials have demonstrated that deep brain stimulation plus medication works better than medications alone for advanced Parkinson disease.

Deuschl et al¹ conducted a randomized trial in 156 patients with advanced Parkinson disease. Patients receiving subthalamic deep brain stimulation plus medication had significantly greater improvement in motor symptoms as measured by the Unified Parkinson’s Disease Rating Scale as well as in quality-of-life measures than patients receiving medications only.

Krack et al² reported on the outcomes of 49 patients with advanced Parkinson disease who underwent deep brain stimulation and then were prospectively followed. At 5 years, motor function had improved by approximately 55% from baseline, activities-of-daily-living scores had improved by 49%, and patients continued to need significantly less levodopa and to experience less drug-induced dyskinesia.

Complications related to deep brain stimulation occurred in both studies, including two large intracerebral hemorrhages, one of which was fatal.

Weight gain. During the first 3 months after the device was implanted, patients tended to gain weight (mean 3 kg, maximum 5 kg). Although weight gain is considered an adverse effect, many patients are quite thin by the time they are candidates for deep brain stimulation, and in such cases gaining lean weight can be a benefit.

Patients with poorly controlled Parkinson disease lose weight for several reasons: increased calorie expenditure from shaking and excessive movements; diet modification and protein restriction for some patients who realize that protein competes with levodopa absorption; lack of appetite due to depression or from poor taste sensation (due to anosmia); and decreased overall food consumption due to difficulty swallowing.

DEEP BRAIN STIMULATION FOR ESSENTIAL TREMOR

Essential tremor is more common than Parkinson disease, with a prevalence in the United States estimated at approximately 4,000 per 100,000 people older than 65 years.

The tremor is often bilateral and is characteristically an action tremor, but in many patients it also has a postural, and sometimes a resting, component. It is distinct from parkinsonian tremor, which is usually predominantly a resting tremor. The differential diagnosis includes tremors secondary to central nervous system degenerative disorders as well as psychogenic tremors.

Drinking alcohol tends to relieve essential tremors, a finding that can often be elicited in the patient’s history. Patients whose symptoms improve with an alcoholic beverage are more likely to have essential tremor than another diagnosis.

Response to deep brain stimulation

Most patients with essential tremor respond well to deep brain stimulation of the contralateral ventral intermedius thalamic nucleus.

Treatment is usually started unilaterally, usually aimed at alleviating tremor in the patient’s dominant upper extremity. In selected cases, preference is given to treating the nondominant extremity when it is more severely affected than the dominant extremity.

Implantation of a device on the second side is offered to some patients who continue to be limited in activity and quality of life due to tremor of the untreated extremity. Surgery of the second side can be more complicated than the initial unilateral procedure. In particular, some patients may present with dysarthria, although that seems to be less common in our experience than initially estimated.

In practice, patients with moderate tremors tend to have an excellent response to deep brain stimulation. For this particular indication, if the response is not satisfactory, the treating team tends to consider surgically revising the placement of the lead rather than considering the patient a nonresponder. Patients with very severe tremors may have some residual tremor despite substantial improvement in severity. In our experience, patients with a greater proximal component of tremor tend to have less satisfactory results.

For challenging cases, implantation of additional electrodes in the thalamus or in new targets currently under investigation is sometimes considered, although this is an off-label use.

Treatment of secondary tremors, such as poststroke tremor or tremor due to multiple sclerosis, is sometimes attempted with deep brain stimulation. This is also an off-label option but is considered in selected cases for quality-of-life management.

Patients with axial tremors such as head or voice tremor are less likely to be helped by deep brain stimulation.

DEEP BRAIN STIMULATION FOR PRIMARY DYSTONIA

Generalized dystonia is a less common but severely impairing movement disorder.

Deep brain stimulation is approved for primary dystonia under a humanitarian device exemption, a regulatory mechanism for less common conditions. Deep brain stimulation is an option for patients who have significant impairment related to dystonia and who have not responded to conservative management such as anticholinergic agents, muscle relaxants, benzodiazepines, levodopa, or combinations of these drugs. Surgery has been shown to be effective for patients with primary generalized dystonia, whether or not they tested positive for a dystonia-related gene such as DYT1.

Kupsch et al³ evaluated 40 patients with primary dystonia in a randomized controlled trial of pallidal (globus pallidus pars interna) active deep brain stimulation vs sham stimulation (in which the device was implanted but not activated) for 3 months. Treated patients improved significantly more than controls (39% vs 5%) in the Burke-Fahn- Marsden Dystonia Rating Scale (BFMDRS).⁴ Similar improvement was noted when those receiving sham stimulation were switched to active stimulation.

During long-term follow-up, the results were generally sustained, with substantial improvement from deep brain stimulation in all movement symptoms evaluated except for speech and swallowing. Unlike improvement in tremor, which is quickly evident during testing in the operating room, the improvement in dystonia occurs gradually, and it may take months for patients to notice a change. Similarly, if stimulation stops because of device malfunction or dead batteries, symptoms sometimes do not recur for weeks or months.

Deep brain stimulation is sometimes offered to patients with dystonia secondary to conditions such as cerebral palsy or trauma (an off-label use). Although benefits are less consistent, deep brain stimulation remains an option for these individuals, aimed at alleviating some of the disabling symptoms. In patients with cerebral palsy or other secondary dystonias, it is sometimes difficult to distinguish how much of the disability is related to spasticity vs dystonia. Deep brain stimulation aims to alleviate the dystonic component; the spasticity may be managed with other options such as intrathecal baclofen (Lioresal).

Patients with tardive dystonia, which is usually secondary to treatment with antipsychotic agents, have been reported to respond well to bilateral deep brain stimulation. Gruber et al⁵ reported on a series of nine patients with a mean follow-up of 41 months. Patients improved by a mean of approximately 74% on the BFMDRS after 3 to 6 months of deep brain stimulation compared with baseline. None of the patients presented with long-term adverse effects, and quality of life and disability scores also improved significantly.

CANDIDATES ARE EVALUATED BY A MULTIDISCIPLINARY TEAM

Cleveland Clinic conducts a comprehensive 2-day evaluation for patients being considered for deep brain stimulation surgery, including consultations with specialists in neurology, neurosurgery, neuropsychology, and psychiatry.

Patients with significant cognitive deficits—near or meeting the diagnostic criteria for dementia—are usually not recommended to have surgery for Parkinson disease. Deep brain stimulation is not aimed at alleviating cognitive issues related to Parkinson disease or other concomitant dementia. In addition, there is a risk that neurostimulation could further worsen cognitive function in the already compromised brain. Moreover, patients with significant abnormalities detected by neuroimaging may have their diagnosis reconsidered in some cases, and some patients may not be deemed ideal candidates for surgery.

An important part of the process is a discussion with the patient and family about the risks and the potential short-term and long-term benefits. Informed consent requires a good understanding of this equation. Patients are counseled to have realistic expectations about what the procedure can offer. Deep brain stimulation can help some of the symptoms of Parkinson disease but will not cure it, and there is no evidence to date that it reduces its progress. At 5 or 10 years after surgery, patients are expected to be worse overall than they were in the first year after surgery, because of disease progression. However, patients who receive this treatment are expected, in general, to be doing better 5 or 10 years later (or longer) than those who do not receive it.

In addition to the discussion about risks, benefits, and expectations, a careful discussion is also devoted to hardware maintenance, including how to change the batteries. Particularly, younger patients should be informed about the risk of breakage of the leads and the extension wire, as they are likely to outlive their implant. Patients and caregivers should be able to come to the specialized center should hardware malfunction occur.

Patients are also informed that after the system is implanted they cannot undergo magnetic resonance imaging (MRI) except of the head, performed with a specific head coil and under specific parameters. MRI of any other body part and with a body coil is contraindicated.

HOW THE DEVICE IS IMPLANTED

There are several options for implanting a deep brain stimulation device.

Implantation with the patient awake, using a stereotactic headframe

At Cleveland Clinic, we usually prefer implantation with a stereotactic headframe. The base or “halo” of the frame is applied to the head under local anesthesia, followed by imaging via computed tomography (Figure 1). Typically, the tomographic image is fused to a previously acquired MRI image, but the MRI is sometimes either initially performed or repeated on the day of surgery.

Patients are sedated for the beginning of the procedure, while the surgical team is opening the skin and drilling the opening in the skull for placement of the lead. The patient is awakened for placement of the electrodes, which is not painful.

Microelectrode recording is typically performed in order to refine the targeting based on the stereotactic coordinates derived from neuroimaging. Although cadaver atlases exist and provide a guide to the stereotactic localization of subcortical structures, they are not completely accurate in representing the brain anatomy of all patients.

By “listening” to cells and knowing their characteristic signals in specific areas, landmarks can be created, forming an individualized map of the patient’s brain target. Microelectrode recording is invasive and has risks, including the risk of a brain hemorrhage. It is routinely done in most specialized deep brain stimulation centers because it can provide better accuracy and precision in lead placement.

When the target has been located and refined by microelectrode recording, the permanent electrode is inserted. Fluoroscopy is usually used to verify the direction and stability of placement during the procedure.

An intraoperative test of the effects of deep brain stimulation is routinely performed to verify that some benefits can be achieved with the brain lead in its location, to determine the threshold for side effects, or both. For example, the patient may be asked to hold a cup as if trying to drink from it and to write or to draw a spiral on a clipboard to assess for improvements in tremor. Rigidity and bradykinesia can also be tested for improvements.

This intraoperative test is not aimed at assessing the best possible outcome of deep brain stimulation, and not even to see an improvement in all symptoms that burden the patient. Rather, it is to evaluate the likelihood that programming will be feasible with the implanted lead.

Subsequently, implantation of the pulse generator in the chest and connection to the brain lead is completed, usually with the patient under general anesthesia.

Implantation under general anesthesia, with intraoperative MRI

A new alternative to “awake stereotactic surgery” is implantation with the patient under general anesthesia, with intraoperative MRI. We have started to do this procedure in a new operating suite that is attached to an MRI suite. The magnet can be taken in and out of the operating room, allowing the surgeon to verify the location of the implanted leads right at the time of the procedure. In this fashion, intraoperative images are used to guide implantation instead of awake microelectrode recording. This is a new option for patients who cannot tolerate awake surgery and for those who have a contraindication to the regular stereotactic procedure with the patient awake.

Risks of bleeding and infection

The potential complications of implanting a device and leads in the brain can be significant.

Hemorrhage can occur, resulting in a superficial or deep hematoma.

Infection and erosion may require removal of the hardware for antibiotic treatment and possible reimplantation.

Other risks include those related to tunneling the wires from the head to the chest, to implanting the device in the chest, and to serious medical complications after surgery. Hardware failure can occur and requires additional surgery. Finally, environmental risks and risks related to medical devices such as MRI, electrocautery, and cardioversion should also be considered.

Deep brain stimulation is advantageous for its reversibility. If during postoperative programming the brain leads are considered not to be ideally placed, revisions can be done to reposition the leads.

Deep brain stimulation is an important therapy for Parkinson disease and other movement disorders. It involves implantation of a pulse generator that can be adjusted by telemetry and can be activated and deactivated by clinicians and patients. It is therefore also a good investigational tool, allowing for double-blind, sham-controlled clinical trials by testing the effects of the stimulation with optimal settings compared with no stimulation.

This article will discuss the approved indications for deep brain stimulation (particularly for managing movement disorders), the benefits that can be expected, the risks, the complications, the maintenance required, how candidates for this treatment are evaluated, and the surgical procedure for implantation of the devices.

DEVICE SIMILAR TO HEART PACEMAKERS

The deep brain stimulation system must be programmed by a physician or midlevel practitioner by observing a symptom and then changing the applied settings to the pulse generator until the symptom improves. This can be a very time-consuming process.

In contrast to heart pacemakers, which run at low frequencies, the brain devices for movement disorders are almost always set to a high frequency, greater than 100 Hz. For this reason, they consume more energy and need larger batteries than those in modern heart pacemakers.

The batteries in these generators typically last 3 to 5 years and are replaced in an outpatient procedure. Newer, smaller, rechargeable devices are expected to last longer but require more maintenance and care by patients, who have to recharge them at home periodically.

INDICATIONS FOR DEEP BRAIN STIMULATION

Deep brain stimulation is approved by the US Food and Drug Administration (FDA) for specific indications:

• Parkinson disease
• Essential tremor
• Primary dystonia (under a humanitarian device exemption)
• Intractable obsessive-compulsive disorder (also under a humanitarian device exemption). We will not discuss this indication further in this paper.

For each of these conditions, deep brain stimulation is considered when nonsurgical management has failed, as is the case for most functional neurosurgical treatments.

Investigations under way in other disorders

Several studies of deep brain stimulation are currently in progress under FDA-approved investigational device exemptions. Some, with funding from industry, are exploring its use in neuropsychiatric conditions other than parkinsonism. Two large clinical trials are evaluating its use for treatment-refractory depression, a common problem and a leading cause of disability in the industrialized world. Multiple investigators are also exploring novel uses of this technology in disorders ranging from obsessive-compulsive disorder to epilepsy.

Investigation is also under way at Cleveland Clinic in a federally funded, prospective, randomized clinical trial of deep brain stimulation for patients with thalamic pain syndrome. The primary hypothesis is that stimulation of the ventral striatal and ventral capsular area will modulate the affective component of this otherwise intractable pain syndrome, reducing pain-related disability and improving quality of life.

DEEP BRAIN STIMULATION VS ABLATION

Before deep brain stimulation became available, the only surgical options for patients with advanced Parkinson disease, tremor, or dystonia were ablative procedures such as pallidotomy (ablation of part of the globus pallidus) and thalamotomy (ablation of part of the thalamus). These procedures had been well known for several decades but fell out of favor when levodopa became available in the 1960s and revolutionized the medical treatment of Parkinson disease.

Surgery for movement disorders, in particular Parkinson disease, had a rebirth in the late 1980s when the limitations and complications associated with the pharmacologic management of Parkinson disease became increasingly evident. Ablative procedures are still used to treat advanced Parkinson disease, but much less commonly in industrialized countries.

Although pallidotomy and thalamotomy can have excellent results, they are not as safe as deep brain stimulation, which has the advantage of being reversible, modulating the function of an area rather than destroying it. Any unwanted effect can be immediately altered or reversed, unlike ablative procedures, in which any change is permanent. In addition, deep brain stimulation is adjustable, and the settings can be optimized as the disease progresses over the years.

Ablative procedures can be risky when performed bilaterally, while deep brain stimulation is routinely done on both hemispheres for patients with bilateral symptoms.

Although deep brain stimulation is today’s surgical treatment of choice, it is not perfect. It has the disadvantage of requiring lifelong maintenance of the hardware, for which the patient remains dependent on a medical center. Patients are usually seen more often at the specialized center in the first few months after surgery for optimization of programming and titration of drugs. (During this time, most patients see a gradual, substantial reduction in medication intake.) They are then followed by their physician and visit the center less often for monitoring of disease status and for further adjustments to the stimulator.

Most patients, to date, receive nonrechargeable pulse generators. As mentioned above, the batteries in these devices typically last 3 to 5 years. Preferably, batteries are replaced before they are completely depleted, to avoid interruption of therapy. Periodic visits to the center allow clinicians to estimate battery expiration ahead of time and plan replacements accordingly.

Rechargeable pulse generators have been recently introduced and are expected to last up to 9 years. They are an option for patients who can comply with the requirements for periodic home recharging of the hardware.

Patients are given a remote control so that they can turn the device on or off and check its status. Most patients keep it turned on all the time, although some turn it off at night to save battery life.

WHAT CAN PARKINSON PATIENTS EXPECT FROM THIS THERAPY?

Typically, some parkinsonian symptoms predominate over others, although some patients with advanced disease present with a severe combination of multiple disabling symptoms. Deep brain stimulation is best suited to address some of the cardinal motor symptoms, particularly tremor, rigidity, and bradykinesia, and motor fluctuations such as “wearing off” and dyskinesia.

Improvement in some motor symptoms

As a general rule, appendicular symptoms such as limb tremor and rigidity are more responsive to this therapy than axial symptoms such as gait and balance problems, but some patients experience improvement in gait as well. Other symptoms, such as swallowing or urinary symptoms, are seldom helped.

Although deep brain stimulation can help manage key motor symptoms and improve quality of life, it does not cure Parkinson disease. Also, there is no evidence to date that it slows disease progression, although this is a topic of ongoing investigation.

Fewer motor fluctuations

A common complaint of patients with advanced Parkinson disease is frequent—and often unpredictable—fluctuations between the “on” state (ie, when the effects of the patient’s levodopa therapy are apparent) and the “off” state (ie, when the levodopa doesn’t seem to be working). Sometimes, in the on state, patients experience involuntary choreic or ballistic movements, called dyskinesias. They also complain that the on time progressively lasts shorter and the day is spent alternating between shorter on states (during which the patient may be dyskinetic) and longer off states, limiting the patient’s independence and quality of life.

Deep brain stimulation can help patients prolong the on time while reducing the amplitude of these fluctuations so that the symptoms are not as severe in the off time and dyskinesias are reduced in the on time.

Some patients undergo deep brain stimulation primarily for managing the adverse effects of levodopa rather than for controlling the symptoms of the disease itself. While these patients need levodopa to address the disabling symptoms of the disease, they also present a greater sensitivity for developing levodopa-induced dyskinesias, quickly fluctuating from a lack of movement (the off state) to a state of uncontrollable movements (during the on state).

Deep brain stimulation typically allows the dosage of levodopa to be significantly reduced and gives patients more on time with fewer side effects and less fluctuation between the on and off states.

Response to levodopa predicts deep brain stimulation’s effects

Whether a patient is likely to be helped by deep brain stimulation can be tested with reasonable predictability by giving a single therapeutic dose of levodopa after the patient has been free of the drug for 12 hours. If there is an obvious difference on objective quantitative testing between the off and on states with a single dose, the patient is likely to benefit from deep brain stimulation. Those who do not respond well or are known to have never been well controlled by levodopa are likely poor candidates.

The test is also used as an indicator of whether the patient’s gait can be improved. Patients whose gait is substantially improved by levodopa, even for only a brief period of time, have a better chance of experiencing improvement in this domain with deep brain stimulation than those who do not show any gait improvement.

An important and notable exception to this rule is tremor control. Even Parkinson patients who do not experience significant improvement in tremor with levodopa (ie, who have medication-resistant tremors) are still likely to benefit from deep brain stimulation. Overall, tremor is the symptom that is most consistently improved with deep brain stimulation.

Results of clinical trials

Several clinical trials have demonstrated that deep brain stimulation plus medication works better than medications alone for advanced Parkinson disease.

Deuschl et al¹ conducted a randomized trial in 156 patients with advanced Parkinson disease. Patients receiving subthalamic deep brain stimulation plus medication had significantly greater improvement in motor symptoms as measured by the Unified Parkinson’s Disease Rating Scale as well as in quality-of-life measures than patients receiving medications only.

Krack et al² reported on the outcomes of 49 patients with advanced Parkinson disease who underwent deep brain stimulation and then were prospectively followed. At 5 years, motor function had improved by approximately 55% from baseline, activities-of-daily-living scores had improved by 49%, and patients continued to need significantly less levodopa and to experience less drug-induced dyskinesia.

Complications related to deep brain stimulation occurred in both studies, including two large intracerebral hemorrhages, one of which was fatal.

Weight gain. During the first 3 months after the device was implanted, patients tended to gain weight (mean 3 kg, maximum 5 kg). Although weight gain is considered an adverse effect, many patients are quite thin by the time they are candidates for deep brain stimulation, and in such cases gaining lean weight can be a benefit.

Patients with poorly controlled Parkinson disease lose weight for several reasons: increased calorie expenditure from shaking and excessive movements; diet modification and protein restriction for some patients who realize that protein competes with levodopa absorption; lack of appetite due to depression or from poor taste sensation (due to anosmia); and decreased overall food consumption due to difficulty swallowing.

DEEP BRAIN STIMULATION FOR ESSENTIAL TREMOR

Essential tremor is more common than Parkinson disease, with a prevalence in the United States estimated at approximately 4,000 per 100,000 people older than 65 years.

The tremor is often bilateral and is characteristically an action tremor, but in many patients it also has a postural, and sometimes a resting, component. It is distinct from parkinsonian tremor, which is usually predominantly a resting tremor. The differential diagnosis includes tremors secondary to central nervous system degenerative disorders as well as psychogenic tremors.

Drinking alcohol tends to relieve essential tremors, a finding that can often be elicited in the patient’s history. Patients whose symptoms improve with an alcoholic beverage are more likely to have essential tremor than another diagnosis.

Response to deep brain stimulation

Most patients with essential tremor respond well to deep brain stimulation of the contralateral ventral intermedius thalamic nucleus.

Treatment is usually started unilaterally, usually aimed at alleviating tremor in the patient’s dominant upper extremity. In selected cases, preference is given to treating the nondominant extremity when it is more severely affected than the dominant extremity.

Implantation of a device on the second side is offered to some patients who continue to be limited in activity and quality of life due to tremor of the untreated extremity. Surgery of the second side can be more complicated than the initial unilateral procedure. In particular, some patients may present with dysarthria, although that seems to be less common in our experience than initially estimated.

In practice, patients with moderate tremors tend to have an excellent response to deep brain stimulation. For this particular indication, if the response is not satisfactory, the treating team tends to consider surgically revising the placement of the lead rather than considering the patient a nonresponder. Patients with very severe tremors may have some residual tremor despite substantial improvement in severity. In our experience, patients with a greater proximal component of tremor tend to have less satisfactory results.

For challenging cases, implantation of additional electrodes in the thalamus or in new targets currently under investigation is sometimes considered, although this is an off-label use.

Treatment of secondary tremors, such as poststroke tremor or tremor due to multiple sclerosis, is sometimes attempted with deep brain stimulation. This is also an off-label option but is considered in selected cases for quality-of-life management.

Patients with axial tremors such as head or voice tremor are less likely to be helped by deep brain stimulation.

DEEP BRAIN STIMULATION FOR PRIMARY DYSTONIA

Generalized dystonia is a less common but severely impairing movement disorder.

Deep brain stimulation is approved for primary dystonia under a humanitarian device exemption, a regulatory mechanism for less common conditions. Deep brain stimulation is an option for patients who have significant impairment related to dystonia and who have not responded to conservative management such as anticholinergic agents, muscle relaxants, benzodiazepines, levodopa, or combinations of these drugs. Surgery has been shown to be effective for patients with primary generalized dystonia, whether or not they tested positive for a dystonia-related gene such as DYT1.

Kupsch et al³ evaluated 40 patients with primary dystonia in a randomized controlled trial of pallidal (globus pallidus pars interna) active deep brain stimulation vs sham stimulation (in which the device was implanted but not activated) for 3 months. Treated patients improved significantly more than controls (39% vs 5%) in the Burke-Fahn- Marsden Dystonia Rating Scale (BFMDRS).⁴ Similar improvement was noted when those receiving sham stimulation were switched to active stimulation.

During long-term follow-up, the results were generally sustained, with substantial improvement from deep brain stimulation in all movement symptoms evaluated except for speech and swallowing. Unlike improvement in tremor, which is quickly evident during testing in the operating room, the improvement in dystonia occurs gradually, and it may take months for patients to notice a change. Similarly, if stimulation stops because of device malfunction or dead batteries, symptoms sometimes do not recur for weeks or months.

Deep brain stimulation is sometimes offered to patients with dystonia secondary to conditions such as cerebral palsy or trauma (an off-label use). Although benefits are less consistent, deep brain stimulation remains an option for these individuals, aimed at alleviating some of the disabling symptoms. In patients with cerebral palsy or other secondary dystonias, it is sometimes difficult to distinguish how much of the disability is related to spasticity vs dystonia. Deep brain stimulation aims to alleviate the dystonic component; the spasticity may be managed with other options such as intrathecal baclofen (Lioresal).

Patients with tardive dystonia, which is usually secondary to treatment with antipsychotic agents, have been reported to respond well to bilateral deep brain stimulation. Gruber et al⁵ reported on a series of nine patients with a mean follow-up of 41 months. Patients improved by a mean of approximately 74% on the BFMDRS after 3 to 6 months of deep brain stimulation compared with baseline. None of the patients presented with long-term adverse effects, and quality of life and disability scores also improved significantly.

CANDIDATES ARE EVALUATED BY A MULTIDISCIPLINARY TEAM

Cleveland Clinic conducts a comprehensive 2-day evaluation for patients being considered for deep brain stimulation surgery, including consultations with specialists in neurology, neurosurgery, neuropsychology, and psychiatry.

Patients with significant cognitive deficits—near or meeting the diagnostic criteria for dementia—are usually not recommended to have surgery for Parkinson disease. Deep brain stimulation is not aimed at alleviating cognitive issues related to Parkinson disease or other concomitant dementia. In addition, there is a risk that neurostimulation could further worsen cognitive function in the already compromised brain. Moreover, patients with significant abnormalities detected by neuroimaging may have their diagnosis reconsidered in some cases, and some patients may not be deemed ideal candidates for surgery.

An important part of the process is a discussion with the patient and family about the risks and the potential short-term and long-term benefits. Informed consent requires a good understanding of this equation. Patients are counseled to have realistic expectations about what the procedure can offer. Deep brain stimulation can help some of the symptoms of Parkinson disease but will not cure it, and there is no evidence to date that it reduces its progress. At 5 or 10 years after surgery, patients are expected to be worse overall than they were in the first year after surgery, because of disease progression. However, patients who receive this treatment are expected, in general, to be doing better 5 or 10 years later (or longer) than those who do not receive it.

In addition to the discussion about risks, benefits, and expectations, a careful discussion is also devoted to hardware maintenance, including how to change the batteries. Particularly, younger patients should be informed about the risk of breakage of the leads and the extension wire, as they are likely to outlive their implant. Patients and caregivers should be able to come to the specialized center should hardware malfunction occur.

Patients are also informed that after the system is implanted they cannot undergo magnetic resonance imaging (MRI) except of the head, performed with a specific head coil and under specific parameters. MRI of any other body part and with a body coil is contraindicated.

HOW THE DEVICE IS IMPLANTED

There are several options for implanting a deep brain stimulation device.

Implantation with the patient awake, using a stereotactic headframe

At Cleveland Clinic, we usually prefer implantation with a stereotactic headframe. The base or “halo” of the frame is applied to the head under local anesthesia, followed by imaging via computed tomography (Figure 1). Typically, the tomographic image is fused to a previously acquired MRI image, but the MRI is sometimes either initially performed or repeated on the day of surgery.

Patients are sedated for the beginning of the procedure, while the surgical team is opening the skin and drilling the opening in the skull for placement of the lead. The patient is awakened for placement of the electrodes, which is not painful.

Microelectrode recording is typically performed in order to refine the targeting based on the stereotactic coordinates derived from neuroimaging. Although cadaver atlases exist and provide a guide to the stereotactic localization of subcortical structures, they are not completely accurate in representing the brain anatomy of all patients.

By “listening” to cells and knowing their characteristic signals in specific areas, landmarks can be created, forming an individualized map of the patient’s brain target. Microelectrode recording is invasive and has risks, including the risk of a brain hemorrhage. It is routinely done in most specialized deep brain stimulation centers because it can provide better accuracy and precision in lead placement.

When the target has been located and refined by microelectrode recording, the permanent electrode is inserted. Fluoroscopy is usually used to verify the direction and stability of placement during the procedure.

An intraoperative test of the effects of deep brain stimulation is routinely performed to verify that some benefits can be achieved with the brain lead in its location, to determine the threshold for side effects, or both. For example, the patient may be asked to hold a cup as if trying to drink from it and to write or to draw a spiral on a clipboard to assess for improvements in tremor. Rigidity and bradykinesia can also be tested for improvements.

This intraoperative test is not aimed at assessing the best possible outcome of deep brain stimulation, and not even to see an improvement in all symptoms that burden the patient. Rather, it is to evaluate the likelihood that programming will be feasible with the implanted lead.

Subsequently, implantation of the pulse generator in the chest and connection to the brain lead is completed, usually with the patient under general anesthesia.

Implantation under general anesthesia, with intraoperative MRI

A new alternative to “awake stereotactic surgery” is implantation with the patient under general anesthesia, with intraoperative MRI. We have started to do this procedure in a new operating suite that is attached to an MRI suite. The magnet can be taken in and out of the operating room, allowing the surgeon to verify the location of the implanted leads right at the time of the procedure. In this fashion, intraoperative images are used to guide implantation instead of awake microelectrode recording. This is a new option for patients who cannot tolerate awake surgery and for those who have a contraindication to the regular stereotactic procedure with the patient awake.

Risks of bleeding and infection

The potential complications of implanting a device and leads in the brain can be significant.

Hemorrhage can occur, resulting in a superficial or deep hematoma.

Infection and erosion may require removal of the hardware for antibiotic treatment and possible reimplantation.

Other risks include those related to tunneling the wires from the head to the chest, to implanting the device in the chest, and to serious medical complications after surgery. Hardware failure can occur and requires additional surgery. Finally, environmental risks and risks related to medical devices such as MRI, electrocautery, and cardioversion should also be considered.

Deep brain stimulation is advantageous for its reversibility. If during postoperative programming the brain leads are considered not to be ideally placed, revisions can be done to reposition the leads.

Deep brain stimulation is an important therapy for Parkinson disease and other movement disorders. It involves implantation of a pulse generator that can be adjusted by telemetry and can be activated and deactivated by clinicians and patients. It is therefore also a good investigational tool, allowing for double-blind, sham-controlled clinical trials by testing the effects of the stimulation with optimal settings compared with no stimulation.

This article will discuss the approved indications for deep brain stimulation (particularly for managing movement disorders), the benefits that can be expected, the risks, the complications, the maintenance required, how candidates for this treatment are evaluated, and the surgical procedure for implantation of the devices.

DEVICE SIMILAR TO HEART PACEMAKERS

The deep brain stimulation system must be programmed by a physician or midlevel practitioner by observing a symptom and then changing the applied settings to the pulse generator until the symptom improves. This can be a very time-consuming process.

In contrast to heart pacemakers, which run at low frequencies, the brain devices for movement disorders are almost always set to a high frequency, greater than 100 Hz. For this reason, they consume more energy and need larger batteries than those in modern heart pacemakers.

The batteries in these generators typically last 3 to 5 years and are replaced in an outpatient procedure. Newer, smaller, rechargeable devices are expected to last longer but require more maintenance and care by patients, who have to recharge them at home periodically.

INDICATIONS FOR DEEP BRAIN STIMULATION

Deep brain stimulation is approved by the US Food and Drug Administration (FDA) for specific indications:

• Parkinson disease
• Essential tremor
• Primary dystonia (under a humanitarian device exemption)
• Intractable obsessive-compulsive disorder (also under a humanitarian device exemption). We will not discuss this indication further in this paper.

For each of these conditions, deep brain stimulation is considered when nonsurgical management has failed, as is the case for most functional neurosurgical treatments.

Investigations under way in other disorders

Several studies of deep brain stimulation are currently in progress under FDA-approved investigational device exemptions. Some, with funding from industry, are exploring its use in neuropsychiatric conditions other than parkinsonism. Two large clinical trials are evaluating its use for treatment-refractory depression, a common problem and a leading cause of disability in the industrialized world. Multiple investigators are also exploring novel uses of this technology in disorders ranging from obsessive-compulsive disorder to epilepsy.

Investigation is also under way at Cleveland Clinic in a federally funded, prospective, randomized clinical trial of deep brain stimulation for patients with thalamic pain syndrome. The primary hypothesis is that stimulation of the ventral striatal and ventral capsular area will modulate the affective component of this otherwise intractable pain syndrome, reducing pain-related disability and improving quality of life.

DEEP BRAIN STIMULATION VS ABLATION

Before deep brain stimulation became available, the only surgical options for patients with advanced Parkinson disease, tremor, or dystonia were ablative procedures such as pallidotomy (ablation of part of the globus pallidus) and thalamotomy (ablation of part of the thalamus). These procedures had been well known for several decades but fell out of favor when levodopa became available in the 1960s and revolutionized the medical treatment of Parkinson disease.

Surgery for movement disorders, in particular Parkinson disease, had a rebirth in the late 1980s when the limitations and complications associated with the pharmacologic management of Parkinson disease became increasingly evident. Ablative procedures are still used to treat advanced Parkinson disease, but much less commonly in industrialized countries.

Although pallidotomy and thalamotomy can have excellent results, they are not as safe as deep brain stimulation, which has the advantage of being reversible, modulating the function of an area rather than destroying it. Any unwanted effect can be immediately altered or reversed, unlike ablative procedures, in which any change is permanent. In addition, deep brain stimulation is adjustable, and the settings can be optimized as the disease progresses over the years.

Ablative procedures can be risky when performed bilaterally, while deep brain stimulation is routinely done on both hemispheres for patients with bilateral symptoms.

Although deep brain stimulation is today’s surgical treatment of choice, it is not perfect. It has the disadvantage of requiring lifelong maintenance of the hardware, for which the patient remains dependent on a medical center. Patients are usually seen more often at the specialized center in the first few months after surgery for optimization of programming and titration of drugs. (During this time, most patients see a gradual, substantial reduction in medication intake.) They are then followed by their physician and visit the center less often for monitoring of disease status and for further adjustments to the stimulator.

Most patients, to date, receive nonrechargeable pulse generators. As mentioned above, the batteries in these devices typically last 3 to 5 years. Preferably, batteries are replaced before they are completely depleted, to avoid interruption of therapy. Periodic visits to the center allow clinicians to estimate battery expiration ahead of time and plan replacements accordingly.

Rechargeable pulse generators have been recently introduced and are expected to last up to 9 years. They are an option for patients who can comply with the requirements for periodic home recharging of the hardware.

Patients are given a remote control so that they can turn the device on or off and check its status. Most patients keep it turned on all the time, although some turn it off at night to save battery life.

WHAT CAN PARKINSON PATIENTS EXPECT FROM THIS THERAPY?

Typically, some parkinsonian symptoms predominate over others, although some patients with advanced disease present with a severe combination of multiple disabling symptoms. Deep brain stimulation is best suited to address some of the cardinal motor symptoms, particularly tremor, rigidity, and bradykinesia, and motor fluctuations such as “wearing off” and dyskinesia.

Improvement in some motor symptoms

As a general rule, appendicular symptoms such as limb tremor and rigidity are more responsive to this therapy than axial symptoms such as gait and balance problems, but some patients experience improvement in gait as well. Other symptoms, such as swallowing or urinary symptoms, are seldom helped.

Although deep brain stimulation can help manage key motor symptoms and improve quality of life, it does not cure Parkinson disease. Also, there is no evidence to date that it slows disease progression, although this is a topic of ongoing investigation.

Fewer motor fluctuations

A common complaint of patients with advanced Parkinson disease is frequent—and often unpredictable—fluctuations between the “on” state (ie, when the effects of the patient’s levodopa therapy are apparent) and the “off” state (ie, when the levodopa doesn’t seem to be working). Sometimes, in the on state, patients experience involuntary choreic or ballistic movements, called dyskinesias. They also complain that the on time progressively lasts shorter and the day is spent alternating between shorter on states (during which the patient may be dyskinetic) and longer off states, limiting the patient’s independence and quality of life.

Deep brain stimulation can help patients prolong the on time while reducing the amplitude of these fluctuations so that the symptoms are not as severe in the off time and dyskinesias are reduced in the on time.

Some patients undergo deep brain stimulation primarily for managing the adverse effects of levodopa rather than for controlling the symptoms of the disease itself. While these patients need levodopa to address the disabling symptoms of the disease, they also present a greater sensitivity for developing levodopa-induced dyskinesias, quickly fluctuating from a lack of movement (the off state) to a state of uncontrollable movements (during the on state).

Deep brain stimulation typically allows the dosage of levodopa to be significantly reduced and gives patients more on time with fewer side effects and less fluctuation between the on and off states.

Response to levodopa predicts deep brain stimulation’s effects

Whether a patient is likely to be helped by deep brain stimulation can be tested with reasonable predictability by giving a single therapeutic dose of levodopa after the patient has been free of the drug for 12 hours. If there is an obvious difference on objective quantitative testing between the off and on states with a single dose, the patient is likely to benefit from deep brain stimulation. Those who do not respond well or are known to have never been well controlled by levodopa are likely poor candidates.

The test is also used as an indicator of whether the patient’s gait can be improved. Patients whose gait is substantially improved by levodopa, even for only a brief period of time, have a better chance of experiencing improvement in this domain with deep brain stimulation than those who do not show any gait improvement.

An important and notable exception to this rule is tremor control. Even Parkinson patients who do not experience significant improvement in tremor with levodopa (ie, who have medication-resistant tremors) are still likely to benefit from deep brain stimulation. Overall, tremor is the symptom that is most consistently improved with deep brain stimulation.

Results of clinical trials

Several clinical trials have demonstrated that deep brain stimulation plus medication works better than medications alone for advanced Parkinson disease.

Deuschl et al¹ conducted a randomized trial in 156 patients with advanced Parkinson disease. Patients receiving subthalamic deep brain stimulation plus medication had significantly greater improvement in motor symptoms as measured by the Unified Parkinson’s Disease Rating Scale as well as in quality-of-life measures than patients receiving medications only.

Krack et al² reported on the outcomes of 49 patients with advanced Parkinson disease who underwent deep brain stimulation and then were prospectively followed. At 5 years, motor function had improved by approximately 55% from baseline, activities-of-daily-living scores had improved by 49%, and patients continued to need significantly less levodopa and to experience less drug-induced dyskinesia.

Complications related to deep brain stimulation occurred in both studies, including two large intracerebral hemorrhages, one of which was fatal.

Weight gain. During the first 3 months after the device was implanted, patients tended to gain weight (mean 3 kg, maximum 5 kg). Although weight gain is considered an adverse effect, many patients are quite thin by the time they are candidates for deep brain stimulation, and in such cases gaining lean weight can be a benefit.

Patients with poorly controlled Parkinson disease lose weight for several reasons: increased calorie expenditure from shaking and excessive movements; diet modification and protein restriction for some patients who realize that protein competes with levodopa absorption; lack of appetite due to depression or from poor taste sensation (due to anosmia); and decreased overall food consumption due to difficulty swallowing.

DEEP BRAIN STIMULATION FOR ESSENTIAL TREMOR

Essential tremor is more common than Parkinson disease, with a prevalence in the United States estimated at approximately 4,000 per 100,000 people older than 65 years.

The tremor is often bilateral and is characteristically an action tremor, but in many patients it also has a postural, and sometimes a resting, component. It is distinct from parkinsonian tremor, which is usually predominantly a resting tremor. The differential diagnosis includes tremors secondary to central nervous system degenerative disorders as well as psychogenic tremors.

Drinking alcohol tends to relieve essential tremors, a finding that can often be elicited in the patient’s history. Patients whose symptoms improve with an alcoholic beverage are more likely to have essential tremor than another diagnosis.

Response to deep brain stimulation

Most patients with essential tremor respond well to deep brain stimulation of the contralateral ventral intermedius thalamic nucleus.

Treatment is usually started unilaterally, usually aimed at alleviating tremor in the patient’s dominant upper extremity. In selected cases, preference is given to treating the nondominant extremity when it is more severely affected than the dominant extremity.

Implantation of a device on the second side is offered to some patients who continue to be limited in activity and quality of life due to tremor of the untreated extremity. Surgery of the second side can be more complicated than the initial unilateral procedure. In particular, some patients may present with dysarthria, although that seems to be less common in our experience than initially estimated.

In practice, patients with moderate tremors tend to have an excellent response to deep brain stimulation. For this particular indication, if the response is not satisfactory, the treating team tends to consider surgically revising the placement of the lead rather than considering the patient a nonresponder. Patients with very severe tremors may have some residual tremor despite substantial improvement in severity. In our experience, patients with a greater proximal component of tremor tend to have less satisfactory results.

For challenging cases, implantation of additional electrodes in the thalamus or in new targets currently under investigation is sometimes considered, although this is an off-label use.

Treatment of secondary tremors, such as poststroke tremor or tremor due to multiple sclerosis, is sometimes attempted with deep brain stimulation. This is also an off-label option but is considered in selected cases for quality-of-life management.

Patients with axial tremors such as head or voice tremor are less likely to be helped by deep brain stimulation.

DEEP BRAIN STIMULATION FOR PRIMARY DYSTONIA

Generalized dystonia is a less common but severely impairing movement disorder.

Deep brain stimulation is approved for primary dystonia under a humanitarian device exemption, a regulatory mechanism for less common conditions. Deep brain stimulation is an option for patients who have significant impairment related to dystonia and who have not responded to conservative management such as anticholinergic agents, muscle relaxants, benzodiazepines, levodopa, or combinations of these drugs. Surgery has been shown to be effective for patients with primary generalized dystonia, whether or not they tested positive for a dystonia-related gene such as DYT1.

Kupsch et al³ evaluated 40 patients with primary dystonia in a randomized controlled trial of pallidal (globus pallidus pars interna) active deep brain stimulation vs sham stimulation (in which the device was implanted but not activated) for 3 months. Treated patients improved significantly more than controls (39% vs 5%) in the Burke-Fahn- Marsden Dystonia Rating Scale (BFMDRS).⁴ Similar improvement was noted when those receiving sham stimulation were switched to active stimulation.

During long-term follow-up, the results were generally sustained, with substantial improvement from deep brain stimulation in all movement symptoms evaluated except for speech and swallowing. Unlike improvement in tremor, which is quickly evident during testing in the operating room, the improvement in dystonia occurs gradually, and it may take months for patients to notice a change. Similarly, if stimulation stops because of device malfunction or dead batteries, symptoms sometimes do not recur for weeks or months.

Deep brain stimulation is sometimes offered to patients with dystonia secondary to conditions such as cerebral palsy or trauma (an off-label use). Although benefits are less consistent, deep brain stimulation remains an option for these individuals, aimed at alleviating some of the disabling symptoms. In patients with cerebral palsy or other secondary dystonias, it is sometimes difficult to distinguish how much of the disability is related to spasticity vs dystonia. Deep brain stimulation aims to alleviate the dystonic component; the spasticity may be managed with other options such as intrathecal baclofen (Lioresal).

Patients with tardive dystonia, which is usually secondary to treatment with antipsychotic agents, have been reported to respond well to bilateral deep brain stimulation. Gruber et al⁵ reported on a series of nine patients with a mean follow-up of 41 months. Patients improved by a mean of approximately 74% on the BFMDRS after 3 to 6 months of deep brain stimulation compared with baseline. None of the patients presented with long-term adverse effects, and quality of life and disability scores also improved significantly.

CANDIDATES ARE EVALUATED BY A MULTIDISCIPLINARY TEAM

Cleveland Clinic conducts a comprehensive 2-day evaluation for patients being considered for deep brain stimulation surgery, including consultations with specialists in neurology, neurosurgery, neuropsychology, and psychiatry.

Patients with significant cognitive deficits—near or meeting the diagnostic criteria for dementia—are usually not recommended to have surgery for Parkinson disease. Deep brain stimulation is not aimed at alleviating cognitive issues related to Parkinson disease or other concomitant dementia. In addition, there is a risk that neurostimulation could further worsen cognitive function in the already compromised brain. Moreover, patients with significant abnormalities detected by neuroimaging may have their diagnosis reconsidered in some cases, and some patients may not be deemed ideal candidates for surgery.

An important part of the process is a discussion with the patient and family about the risks and the potential short-term and long-term benefits. Informed consent requires a good understanding of this equation. Patients are counseled to have realistic expectations about what the procedure can offer. Deep brain stimulation can help some of the symptoms of Parkinson disease but will not cure it, and there is no evidence to date that it reduces its progress. At 5 or 10 years after surgery, patients are expected to be worse overall than they were in the first year after surgery, because of disease progression. However, patients who receive this treatment are expected, in general, to be doing better 5 or 10 years later (or longer) than those who do not receive it.

In addition to the discussion about risks, benefits, and expectations, a careful discussion is also devoted to hardware maintenance, including how to change the batteries. Particularly, younger patients should be informed about the risk of breakage of the leads and the extension wire, as they are likely to outlive their implant. Patients and caregivers should be able to come to the specialized center should hardware malfunction occur.

Patients are also informed that after the system is implanted they cannot undergo magnetic resonance imaging (MRI) except of the head, performed with a specific head coil and under specific parameters. MRI of any other body part and with a body coil is contraindicated.

HOW THE DEVICE IS IMPLANTED

There are several options for implanting a deep brain stimulation device.

Implantation with the patient awake, using a stereotactic headframe

At Cleveland Clinic, we usually prefer implantation with a stereotactic headframe. The base or “halo” of the frame is applied to the head under local anesthesia, followed by imaging via computed tomography (Figure 1). Typically, the tomographic image is fused to a previously acquired MRI image, but the MRI is sometimes either initially performed or repeated on the day of surgery.

Patients are sedated for the beginning of the procedure, while the surgical team is opening the skin and drilling the opening in the skull for placement of the lead. The patient is awakened for placement of the electrodes, which is not painful.

Microelectrode recording is typically performed in order to refine the targeting based on the stereotactic coordinates derived from neuroimaging. Although cadaver atlases exist and provide a guide to the stereotactic localization of subcortical structures, they are not completely accurate in representing the brain anatomy of all patients.

By “listening” to cells and knowing their characteristic signals in specific areas, landmarks can be created, forming an individualized map of the patient’s brain target. Microelectrode recording is invasive and has risks, including the risk of a brain hemorrhage. It is routinely done in most specialized deep brain stimulation centers because it can provide better accuracy and precision in lead placement.

When the target has been located and refined by microelectrode recording, the permanent electrode is inserted. Fluoroscopy is usually used to verify the direction and stability of placement during the procedure.

An intraoperative test of the effects of deep brain stimulation is routinely performed to verify that some benefits can be achieved with the brain lead in its location, to determine the threshold for side effects, or both. For example, the patient may be asked to hold a cup as if trying to drink from it and to write or to draw a spiral on a clipboard to assess for improvements in tremor. Rigidity and bradykinesia can also be tested for improvements.

This intraoperative test is not aimed at assessing the best possible outcome of deep brain stimulation, and not even to see an improvement in all symptoms that burden the patient. Rather, it is to evaluate the likelihood that programming will be feasible with the implanted lead.

Subsequently, implantation of the pulse generator in the chest and connection to the brain lead is completed, usually with the patient under general anesthesia.

Implantation under general anesthesia, with intraoperative MRI

A new alternative to “awake stereotactic surgery” is implantation with the patient under general anesthesia, with intraoperative MRI. We have started to do this procedure in a new operating suite that is attached to an MRI suite. The magnet can be taken in and out of the operating room, allowing the surgeon to verify the location of the implanted leads right at the time of the procedure. In this fashion, intraoperative images are used to guide implantation instead of awake microelectrode recording. This is a new option for patients who cannot tolerate awake surgery and for those who have a contraindication to the regular stereotactic procedure with the patient awake.

Risks of bleeding and infection

The potential complications of implanting a device and leads in the brain can be significant.

Hemorrhage can occur, resulting in a superficial or deep hematoma.

Infection and erosion may require removal of the hardware for antibiotic treatment and possible reimplantation.

Other risks include those related to tunneling the wires from the head to the chest, to implanting the device in the chest, and to serious medical complications after surgery. Hardware failure can occur and requires additional surgery. Finally, environmental risks and risks related to medical devices such as MRI, electrocautery, and cardioversion should also be considered.

Deep brain stimulation is advantageous for its reversibility. If during postoperative programming the brain leads are considered not to be ideally placed, revisions can be done to reposition the leads.

Q: Given what we know so far, what is the most likely cause of the ST segment elevation in leads V₁ and V₂?

• Brugada syndrome
• Pulmonary embolism
• Right ventricular injury
• Anterior myocardial infarction

A: The correct answer is right ventricular injury (discussed below).

Brugada syndrome is a genetic disorder caused by a mutation in the cardiac sodium channel gene. It is characterized by a pronounced elevation of the J point, a coved-type ST segment elevation in leads V₁ and V₂, and a propensity to develop malignant ventricular arrhythmias and sudden cardiac death.

In this patient, the pattern of ST segment elevation in leads V₁ and V₂ may be falsely interpreted as the classic type 1 Brugada electrocardiographic pattern. However, the classic type 1 Brugada electrocardiogram is characterized by a coved ST elevation followed by a negative T wave.¹ The absence of T-wave inversion following ST segment elevation in this patient excluded Brugada syndrome. Moreover, the main presentation in patients with Brugada syndrome is either syncopy or sudden cardiac death.

Pulmonary embolism can present with various electrocardiographic patterns. ST segment elevation in the antroseptal leads is an extremely rare sign and has been demonstrated in a few reports.^2,3 Pulmonary embolism can also present with abnormal Q waves in leads III and aVF but not in lead II.⁴ The initial electrocardiographic rhythm in patients who present with cardiac arrest is usually pulseless electrical activity; however, the combination of increased right ventricular oxygen consumption due to increased right ventricular afterload and right ventricular hypoperfusion due to hypotension can lead to right ventricular ischemia and subsequent arrhythmias. Mittal and Arora⁵ described a case of submassive pulmonary embolism with right ventricular infarction presenting with sustained ventricular tachycardia.

The prognosis is usually poor in patients with cardiac arrest due to pulmonary embolism, which is usually caused by a massive embolus and usually necessitates thrombolytic therapy.

In the patient described here, pulmonary embolism was part of the differential diagnosis, given the presence of ST segment elevation in leads V₁ and V₂ in the context of the clinical scenario. However, the restoration of spontaneous circulation without any specific treatment for pulmonary embolism and the normal oxygenation after cardiac arrest excluded pulmonary embolism.

Right ventricular myocardial injury is important to recognize for therapeutic and prognostic reasons. It is usually associated with inferior infarction because it is typically secondary to an acute occlusion of the proximal right coronary artery proximal to the take-off of the right ventricular marginal branch. In the described scenario, the presence of ST segment elevation and Q waves in the inferior leads together with reciprocal ST segment depression in leads I and aVL represents an inferior myocardial infarct. ST segment elevation in the right precordial leads V₃R and V₄R is a marker for right ventricular injury—especially in V₄R, in which it is a powerful predictor of right ventricular involvement. ST segment elevation in leads V₁ and V₂ is not usually demonstrated in patients with right ventricular injury because the electrical current of injury from the left ventricle inferior myocardial infarction dominates the right ventricular electrical forces, blocking the appearance of ST segment elevation in these leads.⁶ Data from the Hirulog and Early Reperfusion or Occlusion-2 trial showed that ST segment elevation of 1 mm or greater in lead V₁ is associated with an increased risk of death in patients with acute inferior myocardial infarction.⁷ Furthermore, the presence of ST-segment elevation in lead V₆ in patients with acute Q-wave inferior myocardial infarction, as evident in the first electrocardiogram, is associated with larger infarct size and a greater incidence of major arrhythmias.⁸

DETERMINING THE CULPRIT VESSEL

In the scenario described here, differentiating between right ventricular injury and anterior myocardial infarction is important to determine the culprit vessel.

CASE CONCLUDED

Q: Given what we know so far, what is the most likely cause of the ST segment elevation in leads V₁ and V₂?

• Brugada syndrome
• Pulmonary embolism
• Right ventricular injury
• Anterior myocardial infarction

A: The correct answer is right ventricular injury (discussed below).

Brugada syndrome is a genetic disorder caused by a mutation in the cardiac sodium channel gene. It is characterized by a pronounced elevation of the J point, a coved-type ST segment elevation in leads V₁ and V₂, and a propensity to develop malignant ventricular arrhythmias and sudden cardiac death.

In this patient, the pattern of ST segment elevation in leads V₁ and V₂ may be falsely interpreted as the classic type 1 Brugada electrocardiographic pattern. However, the classic type 1 Brugada electrocardiogram is characterized by a coved ST elevation followed by a negative T wave.¹ The absence of T-wave inversion following ST segment elevation in this patient excluded Brugada syndrome. Moreover, the main presentation in patients with Brugada syndrome is either syncopy or sudden cardiac death.

Pulmonary embolism can present with various electrocardiographic patterns. ST segment elevation in the antroseptal leads is an extremely rare sign and has been demonstrated in a few reports.^2,3 Pulmonary embolism can also present with abnormal Q waves in leads III and aVF but not in lead II.⁴ The initial electrocardiographic rhythm in patients who present with cardiac arrest is usually pulseless electrical activity; however, the combination of increased right ventricular oxygen consumption due to increased right ventricular afterload and right ventricular hypoperfusion due to hypotension can lead to right ventricular ischemia and subsequent arrhythmias. Mittal and Arora⁵ described a case of submassive pulmonary embolism with right ventricular infarction presenting with sustained ventricular tachycardia.

The prognosis is usually poor in patients with cardiac arrest due to pulmonary embolism, which is usually caused by a massive embolus and usually necessitates thrombolytic therapy.

In the patient described here, pulmonary embolism was part of the differential diagnosis, given the presence of ST segment elevation in leads V₁ and V₂ in the context of the clinical scenario. However, the restoration of spontaneous circulation without any specific treatment for pulmonary embolism and the normal oxygenation after cardiac arrest excluded pulmonary embolism.

Right ventricular myocardial injury is important to recognize for therapeutic and prognostic reasons. It is usually associated with inferior infarction because it is typically secondary to an acute occlusion of the proximal right coronary artery proximal to the take-off of the right ventricular marginal branch. In the described scenario, the presence of ST segment elevation and Q waves in the inferior leads together with reciprocal ST segment depression in leads I and aVL represents an inferior myocardial infarct. ST segment elevation in the right precordial leads V₃R and V₄R is a marker for right ventricular injury—especially in V₄R, in which it is a powerful predictor of right ventricular involvement. ST segment elevation in leads V₁ and V₂ is not usually demonstrated in patients with right ventricular injury because the electrical current of injury from the left ventricle inferior myocardial infarction dominates the right ventricular electrical forces, blocking the appearance of ST segment elevation in these leads.⁶ Data from the Hirulog and Early Reperfusion or Occlusion-2 trial showed that ST segment elevation of 1 mm or greater in lead V₁ is associated with an increased risk of death in patients with acute inferior myocardial infarction.⁷ Furthermore, the presence of ST-segment elevation in lead V₆ in patients with acute Q-wave inferior myocardial infarction, as evident in the first electrocardiogram, is associated with larger infarct size and a greater incidence of major arrhythmias.⁸

DETERMINING THE CULPRIT VESSEL

In the scenario described here, differentiating between right ventricular injury and anterior myocardial infarction is important to determine the culprit vessel.

CASE CONCLUDED

Q: Given what we know so far, what is the most likely cause of the ST segment elevation in leads V₁ and V₂?

• Brugada syndrome
• Pulmonary embolism
• Right ventricular injury
• Anterior myocardial infarction

A: The correct answer is right ventricular injury (discussed below).

Brugada syndrome is a genetic disorder caused by a mutation in the cardiac sodium channel gene. It is characterized by a pronounced elevation of the J point, a coved-type ST segment elevation in leads V₁ and V₂, and a propensity to develop malignant ventricular arrhythmias and sudden cardiac death.

In this patient, the pattern of ST segment elevation in leads V₁ and V₂ may be falsely interpreted as the classic type 1 Brugada electrocardiographic pattern. However, the classic type 1 Brugada electrocardiogram is characterized by a coved ST elevation followed by a negative T wave.¹ The absence of T-wave inversion following ST segment elevation in this patient excluded Brugada syndrome. Moreover, the main presentation in patients with Brugada syndrome is either syncopy or sudden cardiac death.

Pulmonary embolism can present with various electrocardiographic patterns. ST segment elevation in the antroseptal leads is an extremely rare sign and has been demonstrated in a few reports.^2,3 Pulmonary embolism can also present with abnormal Q waves in leads III and aVF but not in lead II.⁴ The initial electrocardiographic rhythm in patients who present with cardiac arrest is usually pulseless electrical activity; however, the combination of increased right ventricular oxygen consumption due to increased right ventricular afterload and right ventricular hypoperfusion due to hypotension can lead to right ventricular ischemia and subsequent arrhythmias. Mittal and Arora⁵ described a case of submassive pulmonary embolism with right ventricular infarction presenting with sustained ventricular tachycardia.

The prognosis is usually poor in patients with cardiac arrest due to pulmonary embolism, which is usually caused by a massive embolus and usually necessitates thrombolytic therapy.

In the patient described here, pulmonary embolism was part of the differential diagnosis, given the presence of ST segment elevation in leads V₁ and V₂ in the context of the clinical scenario. However, the restoration of spontaneous circulation without any specific treatment for pulmonary embolism and the normal oxygenation after cardiac arrest excluded pulmonary embolism.

Right ventricular myocardial injury is important to recognize for therapeutic and prognostic reasons. It is usually associated with inferior infarction because it is typically secondary to an acute occlusion of the proximal right coronary artery proximal to the take-off of the right ventricular marginal branch. In the described scenario, the presence of ST segment elevation and Q waves in the inferior leads together with reciprocal ST segment depression in leads I and aVL represents an inferior myocardial infarct. ST segment elevation in the right precordial leads V₃R and V₄R is a marker for right ventricular injury—especially in V₄R, in which it is a powerful predictor of right ventricular involvement. ST segment elevation in leads V₁ and V₂ is not usually demonstrated in patients with right ventricular injury because the electrical current of injury from the left ventricle inferior myocardial infarction dominates the right ventricular electrical forces, blocking the appearance of ST segment elevation in these leads.⁶ Data from the Hirulog and Early Reperfusion or Occlusion-2 trial showed that ST segment elevation of 1 mm or greater in lead V₁ is associated with an increased risk of death in patients with acute inferior myocardial infarction.⁷ Furthermore, the presence of ST-segment elevation in lead V₆ in patients with acute Q-wave inferior myocardial infarction, as evident in the first electrocardiogram, is associated with larger infarct size and a greater incidence of major arrhythmias.⁸

DETERMINING THE CULPRIT VESSEL

In the scenario described here, differentiating between right ventricular injury and anterior myocardial infarction is important to determine the culprit vessel.

CASE CONCLUDED

She had no constitutional symptoms and no history of venous thromboembolism, stroke, pregnancy loss, recent anticoagulation, or endovascular procedures.

Q: What is the most likely diagnosis?

• Chronic meningococcemia
• Cholesterol embolism
• Antiphospholipid syndrome
• Cryoglobulinemic vasculitis
• Heterozygous protein C deficiency

A: The most likely diagnosis is skin necrosis due to intravascular thrombosis, consistent with antiphospholipid syndrome. By clinical and laboratory criteria, the patient has systemic lupus erythematosus. Pain and swelling in multiple joints is indicative of polyarthritis associated with lupus. Retesting 12 weeks later again detected lupus anticoagulant, confirming the diagnosis of antiphospholipid syndrome.²

In the hospital, the patient was started on unfractionated heparin, later switched to warfarin. Her skin lesions gradually cleared, her pain diminished significantly, and no new lesions appeared after the start of anticoagulation therapy. For her lupus, she was started on hydroxychloroquine (Plaquenil), which has been suggested to also have an adjuvant antithrombotic role in antiphospholipid syndrome.² On a follow-up visit 3 months later, she was doing well.

MORE ABOUT ANTIPHOSPHOLIPID SYNDROME

Antiphospholipid syndrome is termed primary when no underlying disease is identified, and secondary when it occurs in conjunction with an autoimmune rheumatologic disease, an infection, malignancy, or certain drugs.³ It is the most common cause of acquired thrombophilia.⁴ Arterial or venous thromboses and recurrent miscarriages are salient clinical features.

Laboratory abnormalities include the presence of a lupus anticoagulant and anticardiolipin and beta-2-glycoprotein 1 antibodies.

Skin manifestations include livedo reticularis, purpuric macular lesions, atrophie blanche, cutaneous infarcts, ulceration, and painful nodules.⁵ Livedo reticularis, a violaceous, lace-like cutaneous discoloration, is the most commonly described skin lesion, present in 20% to 50% of cases.^5,6 Cutaneous necrosis may involve the legs, face, and ears, or it may be generalized.⁶

The prothrombotic state is believed to be immune-mediated, with complement activation.² Endothelial cells and monocytes are activated by antiphospholipid antibodies with activity against beta-2-glycoprotein 1, resulting in up-regulation of tissue factor and in platelet activation.² Histopathologic examination reveals noninflammatory vascular thromboses with endothelial damage.⁵

Although antiphospholipid syndrome seems to be immune-mediated, immunosuppressive therapy has not proved very effective,³ and anticoagulation is the recommended treatment.^3,7

THE OTHER DIAGNOSTIC POSSIBILITIES

Chronic meningococcemia, sometimes associated with terminal complement deficiency, is associated with a petechial rash in 50% to 80% of cases. The rash can become confluent, resulting in hemorrhagic patches with central necrosis, resembling the lesions in our patient.

However, these skin lesions are due to thrombi in the dermal vessels, associated with leukocytoclastic vasculitis. These dermatopathologic changes were not seen in our patient. Moreover, meningococci were not identified in blood cultures or in the luminal thrombi and vessel walls.

Cholesterol embolism occurs when cholesterol crystals break off from severely atherosclerotic plaques, either spontaneously or after local trauma induced by angiography or aortic injury. The crystals shower downstream through the arterial system, often immediately occluding arterioles 100 to 200 μm in diameter.

Our patient had no such history, and the skin biopsy did not show the characteristic “cholesterol clefts”—biconvex, needle-shaped clefts left by the dissolved crystals of cholesterol within the occluded vessels.

Cryoglobulinemic vasculitis is an immune-complex-mediated condition involving small- to medium-size vessels, often associated with hepatitis C virus infection. Skin lesions appear in dependent areas and include erythematous macules and purpuric papules.

Cryoglobulins were not detected in our patient’s sera, nor did the skin biopsy indicate the typical leukocytoclastic vasculitis seen in this condition.

Heterozygous protein C deficiency causes venous thromboembolism and warfarin-induced skin necrosis. Spontaneous thrombosis of cutaneous arterioles (as in our patient) is not a usual manifestation. Also, our patient had normal protein C levels and no history of warfarin use before the skin lesions developed.
 

Acknowledgment: The authors are grateful to Dr. Judith Drazba, PhD, of Research Core Services (Imaging) at Cleveland Clinic for help in the preparation of the photomicrographs.

She had no constitutional symptoms and no history of venous thromboembolism, stroke, pregnancy loss, recent anticoagulation, or endovascular procedures.

Q: What is the most likely diagnosis?

• Chronic meningococcemia
• Cholesterol embolism
• Antiphospholipid syndrome
• Cryoglobulinemic vasculitis
• Heterozygous protein C deficiency

A: The most likely diagnosis is skin necrosis due to intravascular thrombosis, consistent with antiphospholipid syndrome. By clinical and laboratory criteria, the patient has systemic lupus erythematosus. Pain and swelling in multiple joints is indicative of polyarthritis associated with lupus. Retesting 12 weeks later again detected lupus anticoagulant, confirming the diagnosis of antiphospholipid syndrome.²

In the hospital, the patient was started on unfractionated heparin, later switched to warfarin. Her skin lesions gradually cleared, her pain diminished significantly, and no new lesions appeared after the start of anticoagulation therapy. For her lupus, she was started on hydroxychloroquine (Plaquenil), which has been suggested to also have an adjuvant antithrombotic role in antiphospholipid syndrome.² On a follow-up visit 3 months later, she was doing well.

MORE ABOUT ANTIPHOSPHOLIPID SYNDROME

Antiphospholipid syndrome is termed primary when no underlying disease is identified, and secondary when it occurs in conjunction with an autoimmune rheumatologic disease, an infection, malignancy, or certain drugs.³ It is the most common cause of acquired thrombophilia.⁴ Arterial or venous thromboses and recurrent miscarriages are salient clinical features.

Laboratory abnormalities include the presence of a lupus anticoagulant and anticardiolipin and beta-2-glycoprotein 1 antibodies.

Skin manifestations include livedo reticularis, purpuric macular lesions, atrophie blanche, cutaneous infarcts, ulceration, and painful nodules.⁵ Livedo reticularis, a violaceous, lace-like cutaneous discoloration, is the most commonly described skin lesion, present in 20% to 50% of cases.^5,6 Cutaneous necrosis may involve the legs, face, and ears, or it may be generalized.⁶

The prothrombotic state is believed to be immune-mediated, with complement activation.² Endothelial cells and monocytes are activated by antiphospholipid antibodies with activity against beta-2-glycoprotein 1, resulting in up-regulation of tissue factor and in platelet activation.² Histopathologic examination reveals noninflammatory vascular thromboses with endothelial damage.⁵

Although antiphospholipid syndrome seems to be immune-mediated, immunosuppressive therapy has not proved very effective,³ and anticoagulation is the recommended treatment.^3,7

THE OTHER DIAGNOSTIC POSSIBILITIES

Chronic meningococcemia, sometimes associated with terminal complement deficiency, is associated with a petechial rash in 50% to 80% of cases. The rash can become confluent, resulting in hemorrhagic patches with central necrosis, resembling the lesions in our patient.

However, these skin lesions are due to thrombi in the dermal vessels, associated with leukocytoclastic vasculitis. These dermatopathologic changes were not seen in our patient. Moreover, meningococci were not identified in blood cultures or in the luminal thrombi and vessel walls.

Cholesterol embolism occurs when cholesterol crystals break off from severely atherosclerotic plaques, either spontaneously or after local trauma induced by angiography or aortic injury. The crystals shower downstream through the arterial system, often immediately occluding arterioles 100 to 200 μm in diameter.

Our patient had no such history, and the skin biopsy did not show the characteristic “cholesterol clefts”—biconvex, needle-shaped clefts left by the dissolved crystals of cholesterol within the occluded vessels.

Cryoglobulinemic vasculitis is an immune-complex-mediated condition involving small- to medium-size vessels, often associated with hepatitis C virus infection. Skin lesions appear in dependent areas and include erythematous macules and purpuric papules.

Cryoglobulins were not detected in our patient’s sera, nor did the skin biopsy indicate the typical leukocytoclastic vasculitis seen in this condition.

Heterozygous protein C deficiency causes venous thromboembolism and warfarin-induced skin necrosis. Spontaneous thrombosis of cutaneous arterioles (as in our patient) is not a usual manifestation. Also, our patient had normal protein C levels and no history of warfarin use before the skin lesions developed.
 

Acknowledgment: The authors are grateful to Dr. Judith Drazba, PhD, of Research Core Services (Imaging) at Cleveland Clinic for help in the preparation of the photomicrographs.

She had no constitutional symptoms and no history of venous thromboembolism, stroke, pregnancy loss, recent anticoagulation, or endovascular procedures.

Q: What is the most likely diagnosis?

• Chronic meningococcemia
• Cholesterol embolism
• Antiphospholipid syndrome
• Cryoglobulinemic vasculitis
• Heterozygous protein C deficiency

A: The most likely diagnosis is skin necrosis due to intravascular thrombosis, consistent with antiphospholipid syndrome. By clinical and laboratory criteria, the patient has systemic lupus erythematosus. Pain and swelling in multiple joints is indicative of polyarthritis associated with lupus. Retesting 12 weeks later again detected lupus anticoagulant, confirming the diagnosis of antiphospholipid syndrome.²

In the hospital, the patient was started on unfractionated heparin, later switched to warfarin. Her skin lesions gradually cleared, her pain diminished significantly, and no new lesions appeared after the start of anticoagulation therapy. For her lupus, she was started on hydroxychloroquine (Plaquenil), which has been suggested to also have an adjuvant antithrombotic role in antiphospholipid syndrome.² On a follow-up visit 3 months later, she was doing well.

MORE ABOUT ANTIPHOSPHOLIPID SYNDROME

Antiphospholipid syndrome is termed primary when no underlying disease is identified, and secondary when it occurs in conjunction with an autoimmune rheumatologic disease, an infection, malignancy, or certain drugs.³ It is the most common cause of acquired thrombophilia.⁴ Arterial or venous thromboses and recurrent miscarriages are salient clinical features.

Laboratory abnormalities include the presence of a lupus anticoagulant and anticardiolipin and beta-2-glycoprotein 1 antibodies.

Skin manifestations include livedo reticularis, purpuric macular lesions, atrophie blanche, cutaneous infarcts, ulceration, and painful nodules.⁵ Livedo reticularis, a violaceous, lace-like cutaneous discoloration, is the most commonly described skin lesion, present in 20% to 50% of cases.^5,6 Cutaneous necrosis may involve the legs, face, and ears, or it may be generalized.⁶

The prothrombotic state is believed to be immune-mediated, with complement activation.² Endothelial cells and monocytes are activated by antiphospholipid antibodies with activity against beta-2-glycoprotein 1, resulting in up-regulation of tissue factor and in platelet activation.² Histopathologic examination reveals noninflammatory vascular thromboses with endothelial damage.⁵

Although antiphospholipid syndrome seems to be immune-mediated, immunosuppressive therapy has not proved very effective,³ and anticoagulation is the recommended treatment.^3,7

THE OTHER DIAGNOSTIC POSSIBILITIES

Chronic meningococcemia, sometimes associated with terminal complement deficiency, is associated with a petechial rash in 50% to 80% of cases. The rash can become confluent, resulting in hemorrhagic patches with central necrosis, resembling the lesions in our patient.

However, these skin lesions are due to thrombi in the dermal vessels, associated with leukocytoclastic vasculitis. These dermatopathologic changes were not seen in our patient. Moreover, meningococci were not identified in blood cultures or in the luminal thrombi and vessel walls.

Cholesterol embolism occurs when cholesterol crystals break off from severely atherosclerotic plaques, either spontaneously or after local trauma induced by angiography or aortic injury. The crystals shower downstream through the arterial system, often immediately occluding arterioles 100 to 200 μm in diameter.

Our patient had no such history, and the skin biopsy did not show the characteristic “cholesterol clefts”—biconvex, needle-shaped clefts left by the dissolved crystals of cholesterol within the occluded vessels.

Cryoglobulinemic vasculitis is an immune-complex-mediated condition involving small- to medium-size vessels, often associated with hepatitis C virus infection. Skin lesions appear in dependent areas and include erythematous macules and purpuric papules.

Cryoglobulins were not detected in our patient’s sera, nor did the skin biopsy indicate the typical leukocytoclastic vasculitis seen in this condition.

Heterozygous protein C deficiency causes venous thromboembolism and warfarin-induced skin necrosis. Spontaneous thrombosis of cutaneous arterioles (as in our patient) is not a usual manifestation. Also, our patient had normal protein C levels and no history of warfarin use before the skin lesions developed.
 

Acknowledgment: The authors are grateful to Dr. Judith Drazba, PhD, of Research Core Services (Imaging) at Cleveland Clinic for help in the preparation of the photomicrographs.

In military veterans, depression, posttraumatic stress disorder (PTSD), and suicidal thoughts are common and closely linked. Veterans are less likely to seek care and more likely to act successfully on suicidal thoughts. Therefore, screening, timely diagnosis, and effective intervention are critical.¹

In this article, we review the signs and symptoms of depression and PTSD, the relationship of these conditions to suicidality in veterans, and the role of the non-mental-health clinician in detecting suicidal ideation early and then taking appropriate action. Early identification of suicidality may help save lives of those who otherwise may not seek care.

FROM IDEA TO PLAN TO ACTION

Suicide can be viewed as a process that begins with suicidal ideation, followed by planning and then by a suicidal act,^2–9 and suicidal ideation can be prompted by depression or PTSD.

Suicidal ideation, defined as any thought of being the agent of one’s own death,² is relatively common. Most people who attempt suicide report a history of suicidal ideation.¹⁰ In fact, current suicidal ideation increases suicide risk,^11,12 and death from suicide is especially correlated with the worst previous suicidal ideation.³

Suicidal ideation is an important predictor of suicidal acts in all major psychiatric conditions.^3,13–17 In a longitudinal study in a community sample, adolescents who had suicidal ideation at age 15 were more likely to have attempted suicide by age 30.⁵

The annual incidence of suicidal ideation in the United States is estimated to be 5.6%,¹⁸ while its estimated lifetime prevalence in Western countries ranges from 2.09% to 18.51%.¹⁹ A national survey found that 13.5% of Americans had suicidal ideation at some point during their lifetime.²⁰ About 34% of people who think about suicide report going from seriously thinking about it to making a plan, and 72% of planners move from a plan to an attempt.²⁰ In the European Study of the Epidemiology of Mental Disorders,²¹ the lifetime prevalence of suicidal ideation was 7.8%, and of suicide attempts 1.3%. Being female, younger, divorced, or widowed was associated with a higher prevalence of suicide ideation and attempts.

Although terms such as “acute suicidal ideation,” “chronic suicidal ideation,” “active suicidal ideation,” and “passive suicidal ideation” are used in the clinical and research literature, the difference between them is not clear. Regardless of the term one uses, any suicidal ideation should be taken very seriously.

HABITUATION IN VETERANS

Interestingly, according to the Interpersonal-Psychological Theory of Suicide,²² the suicidal process is related to feelings that one does not belong with other people, feelings that one is a burden on others or society, and an acquired capability to overcome the fear of pain associated with suicide.²² Veterans are likely to have acquired this capability as the result of military training and combat exposure, which may cause habituation to fear of painful experiences, including suicide.

FEATURES AND CAUSES OF PTSD

PTSD—a severe, multifaceted disorder precipitated by exposure to a psychologically distressing experience—first appeared in the Diagnostic and Statistical Manual of Psychiatric Disorders (DSM-III) in 1980,^23,24 arising from studies of veterans of the Vietnam war and of civilian victims of natural and man-made disasters.^44,45 However, the study of PTSD dates back more than 100 years. Before 1980, posttraumatic syndromes were recognized by various names, including railway spine, shell shock, traumatic (war) neurosis, concentration-camp syndrome, and rape-trauma syndrome.^24,25 The symptoms described in these syndromes overlap considerably with what we now recognize as PTSD.

According to the most recent edition of the Diagnostic and Statistical Manual, DSM-IV-TR,²⁷ the basic feature of PTSD is the development of characteristic symptoms following exposure to a stressor event. Examples include:

• Direct personal experience of an event that involves actual or threatened death or serious injury, or other threat to one’s physical integrity
• Witnessing an event that involves death, injury, or a threat to the physical integrity of another person
• Learning about unexpected or violent death, serious harm, or threat of death or injury experienced by a family member or other close associate.

People react to the event with fear and helplessness and try to avoid being reminded of it.

Traumatic events leading to PTSD include military combat, violent personal assault, being kidnapped or taken hostage, experiencing a terrorist attack, torture, incarceration, a natural or man-made disaster, or an automobile accident, or being diagnosed with a life-threatening illness.

PTSD is a potentially fatal disorder through suicide. There may be differences in the psychobiology of PTSD and suicidal behavior between war veterans and civilians.²⁸

PTSD often coexists with other psychiatric illnesses^29,30: the National Comorbidity Survey found that about 80% of patients with PTSD meet the criteria for at least one other psychiatric disorder.³⁰ Symptoms of PTSD and depression overlap significantly. Common features include diminished interest or participation in significant activities; irritability; sleep disturbance; difficulty concentrating; restricted range of affect; and social detachment.

PTSD also often coexists with traumatic brain injury and other neurologic and medical conditions.^31,32 The clinician is more often than not faced with a PTSD patient with multiple diagnoses—psychiatric and medical.

Unfortunately, studies show that PTSD often goes unrecognized by non-mental-health practitioners.^31,33 In a national cohort of primary care patients in Israel, 9% met criteria for current PTSD, but only 2% of actual cases were recognized by their treating physician.³³

SUICIDE RISK IN VETERANS

Suicidal behavior is a critical problem in war veterans. During the wars in Iraq and Afghanistan, the US Army’s suicide rate has increased from 12.4 per 100,000 in 2003 to 18.1 per 100,000 in 2008.³⁴ In the United Kingdom, more veterans have committed suicide since the end of the 1982 Falklands War than the number of servicemen killed in action during the Falklands War.³⁵ The South Atlantic Medal Association, which represents and helps Falklands veterans, believes that 264 veterans had taken their own lives by 2002, a number exceeding the 255 who died in active service. The suicide rate in Falklands War veterans is about three times higher than the rate in those who left the UK armed forces from 1996 to 2005.^36,37

Observations have suggested a relatively high prevalence of suicide ideation and attempts in different generations of war veterans and in different countries.³⁸

Suicidal ideation is more dangerous in war veterans than in the general population because they know how to use firearms and they often own them. In other words, they often possess the lethal means to act on their suicidal thoughts.

And female veterans may be more likely to commit suicide with a firearm. A US study³⁹ observed that female veterans who committed suicide were 1.6 times more likely to have used a firearm and male veterans were 1.3 more likely, compared with nonveterans and adjusting for age, marital status, race, and region of residence.

DEPRESSION, PTSD, AND SUICIDE RISK

Suicidal ideation in war veterans is often associated with PTSD and depression, conditions that often coexist. And PTSD has been shown to be a risk factor for suicidal ideation in American veterans of the wars in Iraq and Afghanistan.⁴⁰ In a survey of 407 veterans, those who screened positive for PTSD (n = 202) were more than four times as likely to endorse having suicidal ideation compared with veterans who screened negative for PTSD. In veterans who screened positive for PTSD, the risk of suicidal ideation was 5.7 times higher in those with two or more coexisting psychiatric disorders compared with veterans with PTSD alone.⁴⁰

Additional risk factors

Factors contributing to the risk of suicidal ideation and behavior in patients with PTSD include comorbid disorders (especially depression and substance abuse), impulsive behavior, feelings of guilt or shame, re-experiencing symptoms, and prewar traumatic experiences.^41–45

Recent studies have analyzed factors associated with suicidal ideation in US veterans of the wars in Iraq and Afghanistan. Pietrzak et al⁴⁶ surveyed 272 veterans, of whom 34 (12.5%) reported contemplating suicide in the 2 weeks prior to completing the survey. Screening positive for PTSD and depression and having psychosocial difficulties were associated with suicidal ideation, while postdeployment social support and a sense of purpose and control were negatively associated with it.

Other authors⁴⁷ found that only the “emotional numbing” cluster of PTSD symptoms and the “cognitive-affective” cluster of depression symptoms were distinctively associated with suicidal ideation. Maguen et al⁴⁸ recently reported that 2.8% of newly discharged US soldiers endorsed suicidal ideation. Prior suicide attempts, prior psychiatric medication, and killing in combat were each significantly associated with suicidal ideation, with killing exerting a mediated effect through depression and PTSD symptoms.

Another recent study⁴⁹ suggests that veterans reporting subthreshold PTSD (ie, having symptoms of PTSD but not meeting all the criteria for the diagnosis) were three times more likely to admit to having suicidal ideation compared with veterans without PTSD,⁴⁹ which indicates that subthreshold PTSD may increase suicide risk.

Lemaire and Graham⁵⁰ reported that prior exposure to physical or sexual abuse and having a history of a prior suicide attempt, a current diagnosis of a psychotic disorder, a depressive disorder, and PTSD were associated with current suicidal ideation. Other factors related to suicidal ideation were female sex, deployment concerns related to training (a protective factor—ie, it reduces suicide risk by enhancing resilience and by counterbalancing risk factors), the deployment environment, family concerns, postdeployment support (a protective factor), and postdeployment stressors.

PTSD and depression: An additive effect

These findings also suggest that the coexistence of PTSD and depression increases the risk of suicidal ideation more than PTSD or depression alone. This is consistent with the concept of posttraumatic mood disorder, ie, that when these diagnoses coexist, they are different than when they occur alone, and that the coexistence increases the risk of suicidal ideation and behavior.^51,52

HOW TO ASSESS SUICIDE RISK

Physicians are in a key position to screen for depression and PTSD in all their patients, including those who are veterans.^31,53

Traumatic events of adulthood can be asked about directly. For example, “Have you ever been physically attacked or assaulted? Have you ever been in an automobile accident? Have you ever been in a war or a disaster?” A positive response should alert the physician to inquire further about the relationship between the event and any current symptoms.

Traumatic childhood experiences require reassuring statements of normality to put the patient at ease. For example, “Many people continue to think about frightening aspects of their childhood. Do you?”

Physicians working with war veterans suffering from PTSD or depression should regularly inquire about suicidal ideation, and if the patient admits to having suicidal ideation, the physician should ask about the possession of firearms or other lethal means.

This type of screening has limitations. Fear of being socially stigmatized or of appearing weak may prevent veterans from disclosing thoughts of suicide. And one study⁵⁴ found little evidence to suggest that inquiring about suicide successfully identifies veterans most at risk of suicide.

Indirect indicators of suicidality

Identifying indirect indicators of suicidal thoughts is also important: these can include pill-seeking behavior; talking or writing about death, dying, or suicide; hopelessness; rage or uncontrolled anger; seeking revenge; reckless or risky behaviors or activities; feeling trapped; and saying or feeling there is no reason for living.⁵⁵

Other warning signs include depressed mood, anhedonia, insomnia, severe anxiety, and panic attacks.⁵⁶ A prior suicide attempt, a family history of suicidal behavior, and comorbidity of depression and alcoholism are associated with a high suicide risk.^56–59

Suicidal behavior is more common after recent, severe, stressful life events and in physical illnesses such as HIV/AIDS, Huntington disease, malignant neoplasm, multiple sclerosis, peptic ulcer, renal disease, spinal cord injury, and systemic lupus erythematosus. This is true in both veterans and nonveterans.⁶⁰

Useful questions

Useful questions in the assessment of suicidal risk can be formulated as follows⁶¹:

• How have you reacted to stress in the past, and how effective are your usual coping strategies?
• Have you contemplated or attempted suicide in the past? If so, how many times and under what circumstances? And how is your current situation compared with past situations when you considered or attempted suicide?
• Do you ever feel hopeless, helpless, powerless, or extremely angry?
• Do you ever have hallucinations or delusions?

The role of guilt

It is important to ask about guilt feelings. Hendin and Haas⁶² observed that in veterans with PTSD related to combat experience, combat-related guilt was the most significant predictor of suicide attempts and of preoccupation with suicide after discharge. Combat veterans may feel guilt about surviving when others have died, acts of omission and commission, and thoughts or feelings.⁶³ Some have suggested that guilt may be a mechanism through which violence is related to PTSD and major depressive disorder in combat veterans.⁶⁴

INTERVENTIONS

Patients with comorbid depression, PTSD, and suicidal ideation are usually very sick and should be referred to a psychiatrist. They are usually treated with antidepressants, such as paroxetine (Paxil) or sertraline (Zoloft), and psychotherapy.⁶⁵ Patients who have a suicidal intent or a plan should be referred to an emergency department for evaluation or hospitalization. All veterans should be given the toll-free phone number of the Veterans Crisis Line (1-800-273-8255), a US Department of Veterans Affairs (VA) resource that connects veterans in crisis and their families and friends, with qualified VA professionals.

As with many illnesses, such as cancer, suicidal behavior is most treatable and yields the best outcome when diagnosed and treated early.⁶⁶ And the earliest manifestation of suicidal behavior is suicidal ideation.

The association of suicidal ideation with PTSD and depression underlines the importance of the timely diagnosis and effective treatment of these conditions among war veterans. Veterans experiencing subthreshold PTSD or depression may be less likely to receive mental health treatment. This indicates that non-mental-health clinicians should be educated about how to detect PTSD and depression symptoms. They may also help to detect suicidality early, which may help save lives.

Promoting social, emotional, and spiritual wellness

Our patients remind us every day that the work we do matters, that we have much more to learn, and that the more we understand suicidal behavior in veterans, the more we can do to reduce their suffering. We need to promote their social, emotional, and spiritual wellness. Encouraging resilience, optimism, and mental health can protect them from depression, suicidal ideation and behavior. Resilience can be promoted by teaching patients to:

• Build relationships with family members and friends who can provide support
• Think well about themselves and identify their areas of strength
• Invest time and energy in developing new skills
• Challenge negative thoughts; try to find optimistic ways of viewing any situation
• Look after their physical health and exercise regularly
• Get involved in community activities to help counter feelings of isolation
• Ask for assistance and support when they need it.⁶⁷

Our knowledge about what works and what does not work in suicide prevention in veterans is evolving. Research addressing combat-related PTSD, depression, and suicidal behavior in war veterans is critically needed to better understand the nature of these conditions.

In military veterans, depression, posttraumatic stress disorder (PTSD), and suicidal thoughts are common and closely linked. Veterans are less likely to seek care and more likely to act successfully on suicidal thoughts. Therefore, screening, timely diagnosis, and effective intervention are critical.¹

In this article, we review the signs and symptoms of depression and PTSD, the relationship of these conditions to suicidality in veterans, and the role of the non-mental-health clinician in detecting suicidal ideation early and then taking appropriate action. Early identification of suicidality may help save lives of those who otherwise may not seek care.

FROM IDEA TO PLAN TO ACTION

Suicide can be viewed as a process that begins with suicidal ideation, followed by planning and then by a suicidal act,^2–9 and suicidal ideation can be prompted by depression or PTSD.

Suicidal ideation, defined as any thought of being the agent of one’s own death,² is relatively common. Most people who attempt suicide report a history of suicidal ideation.¹⁰ In fact, current suicidal ideation increases suicide risk,^11,12 and death from suicide is especially correlated with the worst previous suicidal ideation.³

Suicidal ideation is an important predictor of suicidal acts in all major psychiatric conditions.^3,13–17 In a longitudinal study in a community sample, adolescents who had suicidal ideation at age 15 were more likely to have attempted suicide by age 30.⁵

The annual incidence of suicidal ideation in the United States is estimated to be 5.6%,¹⁸ while its estimated lifetime prevalence in Western countries ranges from 2.09% to 18.51%.¹⁹ A national survey found that 13.5% of Americans had suicidal ideation at some point during their lifetime.²⁰ About 34% of people who think about suicide report going from seriously thinking about it to making a plan, and 72% of planners move from a plan to an attempt.²⁰ In the European Study of the Epidemiology of Mental Disorders,²¹ the lifetime prevalence of suicidal ideation was 7.8%, and of suicide attempts 1.3%. Being female, younger, divorced, or widowed was associated with a higher prevalence of suicide ideation and attempts.

Although terms such as “acute suicidal ideation,” “chronic suicidal ideation,” “active suicidal ideation,” and “passive suicidal ideation” are used in the clinical and research literature, the difference between them is not clear. Regardless of the term one uses, any suicidal ideation should be taken very seriously.

HABITUATION IN VETERANS

Interestingly, according to the Interpersonal-Psychological Theory of Suicide,²² the suicidal process is related to feelings that one does not belong with other people, feelings that one is a burden on others or society, and an acquired capability to overcome the fear of pain associated with suicide.²² Veterans are likely to have acquired this capability as the result of military training and combat exposure, which may cause habituation to fear of painful experiences, including suicide.

FEATURES AND CAUSES OF PTSD

PTSD—a severe, multifaceted disorder precipitated by exposure to a psychologically distressing experience—first appeared in the Diagnostic and Statistical Manual of Psychiatric Disorders (DSM-III) in 1980,^23,24 arising from studies of veterans of the Vietnam war and of civilian victims of natural and man-made disasters.^44,45 However, the study of PTSD dates back more than 100 years. Before 1980, posttraumatic syndromes were recognized by various names, including railway spine, shell shock, traumatic (war) neurosis, concentration-camp syndrome, and rape-trauma syndrome.^24,25 The symptoms described in these syndromes overlap considerably with what we now recognize as PTSD.

According to the most recent edition of the Diagnostic and Statistical Manual, DSM-IV-TR,²⁷ the basic feature of PTSD is the development of characteristic symptoms following exposure to a stressor event. Examples include:

• Direct personal experience of an event that involves actual or threatened death or serious injury, or other threat to one’s physical integrity
• Witnessing an event that involves death, injury, or a threat to the physical integrity of another person
• Learning about unexpected or violent death, serious harm, or threat of death or injury experienced by a family member or other close associate.

People react to the event with fear and helplessness and try to avoid being reminded of it.

Traumatic events leading to PTSD include military combat, violent personal assault, being kidnapped or taken hostage, experiencing a terrorist attack, torture, incarceration, a natural or man-made disaster, or an automobile accident, or being diagnosed with a life-threatening illness.

PTSD is a potentially fatal disorder through suicide. There may be differences in the psychobiology of PTSD and suicidal behavior between war veterans and civilians.²⁸

PTSD often coexists with other psychiatric illnesses^29,30: the National Comorbidity Survey found that about 80% of patients with PTSD meet the criteria for at least one other psychiatric disorder.³⁰ Symptoms of PTSD and depression overlap significantly. Common features include diminished interest or participation in significant activities; irritability; sleep disturbance; difficulty concentrating; restricted range of affect; and social detachment.

PTSD also often coexists with traumatic brain injury and other neurologic and medical conditions.^31,32 The clinician is more often than not faced with a PTSD patient with multiple diagnoses—psychiatric and medical.

Unfortunately, studies show that PTSD often goes unrecognized by non-mental-health practitioners.^31,33 In a national cohort of primary care patients in Israel, 9% met criteria for current PTSD, but only 2% of actual cases were recognized by their treating physician.³³

SUICIDE RISK IN VETERANS

Suicidal behavior is a critical problem in war veterans. During the wars in Iraq and Afghanistan, the US Army’s suicide rate has increased from 12.4 per 100,000 in 2003 to 18.1 per 100,000 in 2008.³⁴ In the United Kingdom, more veterans have committed suicide since the end of the 1982 Falklands War than the number of servicemen killed in action during the Falklands War.³⁵ The South Atlantic Medal Association, which represents and helps Falklands veterans, believes that 264 veterans had taken their own lives by 2002, a number exceeding the 255 who died in active service. The suicide rate in Falklands War veterans is about three times higher than the rate in those who left the UK armed forces from 1996 to 2005.^36,37

Observations have suggested a relatively high prevalence of suicide ideation and attempts in different generations of war veterans and in different countries.³⁸

Suicidal ideation is more dangerous in war veterans than in the general population because they know how to use firearms and they often own them. In other words, they often possess the lethal means to act on their suicidal thoughts.

And female veterans may be more likely to commit suicide with a firearm. A US study³⁹ observed that female veterans who committed suicide were 1.6 times more likely to have used a firearm and male veterans were 1.3 more likely, compared with nonveterans and adjusting for age, marital status, race, and region of residence.

DEPRESSION, PTSD, AND SUICIDE RISK

Suicidal ideation in war veterans is often associated with PTSD and depression, conditions that often coexist. And PTSD has been shown to be a risk factor for suicidal ideation in American veterans of the wars in Iraq and Afghanistan.⁴⁰ In a survey of 407 veterans, those who screened positive for PTSD (n = 202) were more than four times as likely to endorse having suicidal ideation compared with veterans who screened negative for PTSD. In veterans who screened positive for PTSD, the risk of suicidal ideation was 5.7 times higher in those with two or more coexisting psychiatric disorders compared with veterans with PTSD alone.⁴⁰

Additional risk factors

Factors contributing to the risk of suicidal ideation and behavior in patients with PTSD include comorbid disorders (especially depression and substance abuse), impulsive behavior, feelings of guilt or shame, re-experiencing symptoms, and prewar traumatic experiences.^41–45

Recent studies have analyzed factors associated with suicidal ideation in US veterans of the wars in Iraq and Afghanistan. Pietrzak et al⁴⁶ surveyed 272 veterans, of whom 34 (12.5%) reported contemplating suicide in the 2 weeks prior to completing the survey. Screening positive for PTSD and depression and having psychosocial difficulties were associated with suicidal ideation, while postdeployment social support and a sense of purpose and control were negatively associated with it.

Other authors⁴⁷ found that only the “emotional numbing” cluster of PTSD symptoms and the “cognitive-affective” cluster of depression symptoms were distinctively associated with suicidal ideation. Maguen et al⁴⁸ recently reported that 2.8% of newly discharged US soldiers endorsed suicidal ideation. Prior suicide attempts, prior psychiatric medication, and killing in combat were each significantly associated with suicidal ideation, with killing exerting a mediated effect through depression and PTSD symptoms.

Another recent study⁴⁹ suggests that veterans reporting subthreshold PTSD (ie, having symptoms of PTSD but not meeting all the criteria for the diagnosis) were three times more likely to admit to having suicidal ideation compared with veterans without PTSD,⁴⁹ which indicates that subthreshold PTSD may increase suicide risk.

Lemaire and Graham⁵⁰ reported that prior exposure to physical or sexual abuse and having a history of a prior suicide attempt, a current diagnosis of a psychotic disorder, a depressive disorder, and PTSD were associated with current suicidal ideation. Other factors related to suicidal ideation were female sex, deployment concerns related to training (a protective factor—ie, it reduces suicide risk by enhancing resilience and by counterbalancing risk factors), the deployment environment, family concerns, postdeployment support (a protective factor), and postdeployment stressors.

PTSD and depression: An additive effect

These findings also suggest that the coexistence of PTSD and depression increases the risk of suicidal ideation more than PTSD or depression alone. This is consistent with the concept of posttraumatic mood disorder, ie, that when these diagnoses coexist, they are different than when they occur alone, and that the coexistence increases the risk of suicidal ideation and behavior.^51,52

HOW TO ASSESS SUICIDE RISK

Physicians are in a key position to screen for depression and PTSD in all their patients, including those who are veterans.^31,53

Traumatic events of adulthood can be asked about directly. For example, “Have you ever been physically attacked or assaulted? Have you ever been in an automobile accident? Have you ever been in a war or a disaster?” A positive response should alert the physician to inquire further about the relationship between the event and any current symptoms.

Traumatic childhood experiences require reassuring statements of normality to put the patient at ease. For example, “Many people continue to think about frightening aspects of their childhood. Do you?”

Physicians working with war veterans suffering from PTSD or depression should regularly inquire about suicidal ideation, and if the patient admits to having suicidal ideation, the physician should ask about the possession of firearms or other lethal means.

This type of screening has limitations. Fear of being socially stigmatized or of appearing weak may prevent veterans from disclosing thoughts of suicide. And one study⁵⁴ found little evidence to suggest that inquiring about suicide successfully identifies veterans most at risk of suicide.

Indirect indicators of suicidality

Identifying indirect indicators of suicidal thoughts is also important: these can include pill-seeking behavior; talking or writing about death, dying, or suicide; hopelessness; rage or uncontrolled anger; seeking revenge; reckless or risky behaviors or activities; feeling trapped; and saying or feeling there is no reason for living.⁵⁵

Other warning signs include depressed mood, anhedonia, insomnia, severe anxiety, and panic attacks.⁵⁶ A prior suicide attempt, a family history of suicidal behavior, and comorbidity of depression and alcoholism are associated with a high suicide risk.^56–59

Suicidal behavior is more common after recent, severe, stressful life events and in physical illnesses such as HIV/AIDS, Huntington disease, malignant neoplasm, multiple sclerosis, peptic ulcer, renal disease, spinal cord injury, and systemic lupus erythematosus. This is true in both veterans and nonveterans.⁶⁰

Useful questions

Useful questions in the assessment of suicidal risk can be formulated as follows⁶¹:

• How have you reacted to stress in the past, and how effective are your usual coping strategies?
• Have you contemplated or attempted suicide in the past? If so, how many times and under what circumstances? And how is your current situation compared with past situations when you considered or attempted suicide?
• Do you ever feel hopeless, helpless, powerless, or extremely angry?
• Do you ever have hallucinations or delusions?

The role of guilt

It is important to ask about guilt feelings. Hendin and Haas⁶² observed that in veterans with PTSD related to combat experience, combat-related guilt was the most significant predictor of suicide attempts and of preoccupation with suicide after discharge. Combat veterans may feel guilt about surviving when others have died, acts of omission and commission, and thoughts or feelings.⁶³ Some have suggested that guilt may be a mechanism through which violence is related to PTSD and major depressive disorder in combat veterans.⁶⁴

INTERVENTIONS

Patients with comorbid depression, PTSD, and suicidal ideation are usually very sick and should be referred to a psychiatrist. They are usually treated with antidepressants, such as paroxetine (Paxil) or sertraline (Zoloft), and psychotherapy.⁶⁵ Patients who have a suicidal intent or a plan should be referred to an emergency department for evaluation or hospitalization. All veterans should be given the toll-free phone number of the Veterans Crisis Line (1-800-273-8255), a US Department of Veterans Affairs (VA) resource that connects veterans in crisis and their families and friends, with qualified VA professionals.

As with many illnesses, such as cancer, suicidal behavior is most treatable and yields the best outcome when diagnosed and treated early.⁶⁶ And the earliest manifestation of suicidal behavior is suicidal ideation.

The association of suicidal ideation with PTSD and depression underlines the importance of the timely diagnosis and effective treatment of these conditions among war veterans. Veterans experiencing subthreshold PTSD or depression may be less likely to receive mental health treatment. This indicates that non-mental-health clinicians should be educated about how to detect PTSD and depression symptoms. They may also help to detect suicidality early, which may help save lives.

Promoting social, emotional, and spiritual wellness

Our patients remind us every day that the work we do matters, that we have much more to learn, and that the more we understand suicidal behavior in veterans, the more we can do to reduce their suffering. We need to promote their social, emotional, and spiritual wellness. Encouraging resilience, optimism, and mental health can protect them from depression, suicidal ideation and behavior. Resilience can be promoted by teaching patients to:

• Build relationships with family members and friends who can provide support
• Think well about themselves and identify their areas of strength
• Invest time and energy in developing new skills
• Challenge negative thoughts; try to find optimistic ways of viewing any situation
• Look after their physical health and exercise regularly
• Get involved in community activities to help counter feelings of isolation
• Ask for assistance and support when they need it.⁶⁷

Our knowledge about what works and what does not work in suicide prevention in veterans is evolving. Research addressing combat-related PTSD, depression, and suicidal behavior in war veterans is critically needed to better understand the nature of these conditions.

In military veterans, depression, posttraumatic stress disorder (PTSD), and suicidal thoughts are common and closely linked. Veterans are less likely to seek care and more likely to act successfully on suicidal thoughts. Therefore, screening, timely diagnosis, and effective intervention are critical.¹

In this article, we review the signs and symptoms of depression and PTSD, the relationship of these conditions to suicidality in veterans, and the role of the non-mental-health clinician in detecting suicidal ideation early and then taking appropriate action. Early identification of suicidality may help save lives of those who otherwise may not seek care.

FROM IDEA TO PLAN TO ACTION

Suicide can be viewed as a process that begins with suicidal ideation, followed by planning and then by a suicidal act,^2–9 and suicidal ideation can be prompted by depression or PTSD.

Suicidal ideation, defined as any thought of being the agent of one’s own death,² is relatively common. Most people who attempt suicide report a history of suicidal ideation.¹⁰ In fact, current suicidal ideation increases suicide risk,^11,12 and death from suicide is especially correlated with the worst previous suicidal ideation.³

Suicidal ideation is an important predictor of suicidal acts in all major psychiatric conditions.^3,13–17 In a longitudinal study in a community sample, adolescents who had suicidal ideation at age 15 were more likely to have attempted suicide by age 30.⁵

The annual incidence of suicidal ideation in the United States is estimated to be 5.6%,¹⁸ while its estimated lifetime prevalence in Western countries ranges from 2.09% to 18.51%.¹⁹ A national survey found that 13.5% of Americans had suicidal ideation at some point during their lifetime.²⁰ About 34% of people who think about suicide report going from seriously thinking about it to making a plan, and 72% of planners move from a plan to an attempt.²⁰ In the European Study of the Epidemiology of Mental Disorders,²¹ the lifetime prevalence of suicidal ideation was 7.8%, and of suicide attempts 1.3%. Being female, younger, divorced, or widowed was associated with a higher prevalence of suicide ideation and attempts.

Although terms such as “acute suicidal ideation,” “chronic suicidal ideation,” “active suicidal ideation,” and “passive suicidal ideation” are used in the clinical and research literature, the difference between them is not clear. Regardless of the term one uses, any suicidal ideation should be taken very seriously.

HABITUATION IN VETERANS

Interestingly, according to the Interpersonal-Psychological Theory of Suicide,²² the suicidal process is related to feelings that one does not belong with other people, feelings that one is a burden on others or society, and an acquired capability to overcome the fear of pain associated with suicide.²² Veterans are likely to have acquired this capability as the result of military training and combat exposure, which may cause habituation to fear of painful experiences, including suicide.

FEATURES AND CAUSES OF PTSD

PTSD—a severe, multifaceted disorder precipitated by exposure to a psychologically distressing experience—first appeared in the Diagnostic and Statistical Manual of Psychiatric Disorders (DSM-III) in 1980,^23,24 arising from studies of veterans of the Vietnam war and of civilian victims of natural and man-made disasters.^44,45 However, the study of PTSD dates back more than 100 years. Before 1980, posttraumatic syndromes were recognized by various names, including railway spine, shell shock, traumatic (war) neurosis, concentration-camp syndrome, and rape-trauma syndrome.^24,25 The symptoms described in these syndromes overlap considerably with what we now recognize as PTSD.

According to the most recent edition of the Diagnostic and Statistical Manual, DSM-IV-TR,²⁷ the basic feature of PTSD is the development of characteristic symptoms following exposure to a stressor event. Examples include:

• Direct personal experience of an event that involves actual or threatened death or serious injury, or other threat to one’s physical integrity
• Witnessing an event that involves death, injury, or a threat to the physical integrity of another person
• Learning about unexpected or violent death, serious harm, or threat of death or injury experienced by a family member or other close associate.

People react to the event with fear and helplessness and try to avoid being reminded of it.

Traumatic events leading to PTSD include military combat, violent personal assault, being kidnapped or taken hostage, experiencing a terrorist attack, torture, incarceration, a natural or man-made disaster, or an automobile accident, or being diagnosed with a life-threatening illness.

PTSD is a potentially fatal disorder through suicide. There may be differences in the psychobiology of PTSD and suicidal behavior between war veterans and civilians.²⁸

PTSD often coexists with other psychiatric illnesses^29,30: the National Comorbidity Survey found that about 80% of patients with PTSD meet the criteria for at least one other psychiatric disorder.³⁰ Symptoms of PTSD and depression overlap significantly. Common features include diminished interest or participation in significant activities; irritability; sleep disturbance; difficulty concentrating; restricted range of affect; and social detachment.

PTSD also often coexists with traumatic brain injury and other neurologic and medical conditions.^31,32 The clinician is more often than not faced with a PTSD patient with multiple diagnoses—psychiatric and medical.

Unfortunately, studies show that PTSD often goes unrecognized by non-mental-health practitioners.^31,33 In a national cohort of primary care patients in Israel, 9% met criteria for current PTSD, but only 2% of actual cases were recognized by their treating physician.³³

SUICIDE RISK IN VETERANS

Suicidal behavior is a critical problem in war veterans. During the wars in Iraq and Afghanistan, the US Army’s suicide rate has increased from 12.4 per 100,000 in 2003 to 18.1 per 100,000 in 2008.³⁴ In the United Kingdom, more veterans have committed suicide since the end of the 1982 Falklands War than the number of servicemen killed in action during the Falklands War.³⁵ The South Atlantic Medal Association, which represents and helps Falklands veterans, believes that 264 veterans had taken their own lives by 2002, a number exceeding the 255 who died in active service. The suicide rate in Falklands War veterans is about three times higher than the rate in those who left the UK armed forces from 1996 to 2005.^36,37

Observations have suggested a relatively high prevalence of suicide ideation and attempts in different generations of war veterans and in different countries.³⁸

Suicidal ideation is more dangerous in war veterans than in the general population because they know how to use firearms and they often own them. In other words, they often possess the lethal means to act on their suicidal thoughts.

And female veterans may be more likely to commit suicide with a firearm. A US study³⁹ observed that female veterans who committed suicide were 1.6 times more likely to have used a firearm and male veterans were 1.3 more likely, compared with nonveterans and adjusting for age, marital status, race, and region of residence.

DEPRESSION, PTSD, AND SUICIDE RISK

Suicidal ideation in war veterans is often associated with PTSD and depression, conditions that often coexist. And PTSD has been shown to be a risk factor for suicidal ideation in American veterans of the wars in Iraq and Afghanistan.⁴⁰ In a survey of 407 veterans, those who screened positive for PTSD (n = 202) were more than four times as likely to endorse having suicidal ideation compared with veterans who screened negative for PTSD. In veterans who screened positive for PTSD, the risk of suicidal ideation was 5.7 times higher in those with two or more coexisting psychiatric disorders compared with veterans with PTSD alone.⁴⁰

Additional risk factors

Factors contributing to the risk of suicidal ideation and behavior in patients with PTSD include comorbid disorders (especially depression and substance abuse), impulsive behavior, feelings of guilt or shame, re-experiencing symptoms, and prewar traumatic experiences.^41–45

Recent studies have analyzed factors associated with suicidal ideation in US veterans of the wars in Iraq and Afghanistan. Pietrzak et al⁴⁶ surveyed 272 veterans, of whom 34 (12.5%) reported contemplating suicide in the 2 weeks prior to completing the survey. Screening positive for PTSD and depression and having psychosocial difficulties were associated with suicidal ideation, while postdeployment social support and a sense of purpose and control were negatively associated with it.

Other authors⁴⁷ found that only the “emotional numbing” cluster of PTSD symptoms and the “cognitive-affective” cluster of depression symptoms were distinctively associated with suicidal ideation. Maguen et al⁴⁸ recently reported that 2.8% of newly discharged US soldiers endorsed suicidal ideation. Prior suicide attempts, prior psychiatric medication, and killing in combat were each significantly associated with suicidal ideation, with killing exerting a mediated effect through depression and PTSD symptoms.

Another recent study⁴⁹ suggests that veterans reporting subthreshold PTSD (ie, having symptoms of PTSD but not meeting all the criteria for the diagnosis) were three times more likely to admit to having suicidal ideation compared with veterans without PTSD,⁴⁹ which indicates that subthreshold PTSD may increase suicide risk.

Lemaire and Graham⁵⁰ reported that prior exposure to physical or sexual abuse and having a history of a prior suicide attempt, a current diagnosis of a psychotic disorder, a depressive disorder, and PTSD were associated with current suicidal ideation. Other factors related to suicidal ideation were female sex, deployment concerns related to training (a protective factor—ie, it reduces suicide risk by enhancing resilience and by counterbalancing risk factors), the deployment environment, family concerns, postdeployment support (a protective factor), and postdeployment stressors.

PTSD and depression: An additive effect

These findings also suggest that the coexistence of PTSD and depression increases the risk of suicidal ideation more than PTSD or depression alone. This is consistent with the concept of posttraumatic mood disorder, ie, that when these diagnoses coexist, they are different than when they occur alone, and that the coexistence increases the risk of suicidal ideation and behavior.^51,52

HOW TO ASSESS SUICIDE RISK

Physicians are in a key position to screen for depression and PTSD in all their patients, including those who are veterans.^31,53

Traumatic events of adulthood can be asked about directly. For example, “Have you ever been physically attacked or assaulted? Have you ever been in an automobile accident? Have you ever been in a war or a disaster?” A positive response should alert the physician to inquire further about the relationship between the event and any current symptoms.

Traumatic childhood experiences require reassuring statements of normality to put the patient at ease. For example, “Many people continue to think about frightening aspects of their childhood. Do you?”

Physicians working with war veterans suffering from PTSD or depression should regularly inquire about suicidal ideation, and if the patient admits to having suicidal ideation, the physician should ask about the possession of firearms or other lethal means.

This type of screening has limitations. Fear of being socially stigmatized or of appearing weak may prevent veterans from disclosing thoughts of suicide. And one study⁵⁴ found little evidence to suggest that inquiring about suicide successfully identifies veterans most at risk of suicide.

Indirect indicators of suicidality

Identifying indirect indicators of suicidal thoughts is also important: these can include pill-seeking behavior; talking or writing about death, dying, or suicide; hopelessness; rage or uncontrolled anger; seeking revenge; reckless or risky behaviors or activities; feeling trapped; and saying or feeling there is no reason for living.⁵⁵

Other warning signs include depressed mood, anhedonia, insomnia, severe anxiety, and panic attacks.⁵⁶ A prior suicide attempt, a family history of suicidal behavior, and comorbidity of depression and alcoholism are associated with a high suicide risk.^56–59

Suicidal behavior is more common after recent, severe, stressful life events and in physical illnesses such as HIV/AIDS, Huntington disease, malignant neoplasm, multiple sclerosis, peptic ulcer, renal disease, spinal cord injury, and systemic lupus erythematosus. This is true in both veterans and nonveterans.⁶⁰

Useful questions

Useful questions in the assessment of suicidal risk can be formulated as follows⁶¹:

• How have you reacted to stress in the past, and how effective are your usual coping strategies?
• Have you contemplated or attempted suicide in the past? If so, how many times and under what circumstances? And how is your current situation compared with past situations when you considered or attempted suicide?
• Do you ever feel hopeless, helpless, powerless, or extremely angry?
• Do you ever have hallucinations or delusions?

The role of guilt

It is important to ask about guilt feelings. Hendin and Haas⁶² observed that in veterans with PTSD related to combat experience, combat-related guilt was the most significant predictor of suicide attempts and of preoccupation with suicide after discharge. Combat veterans may feel guilt about surviving when others have died, acts of omission and commission, and thoughts or feelings.⁶³ Some have suggested that guilt may be a mechanism through which violence is related to PTSD and major depressive disorder in combat veterans.⁶⁴

INTERVENTIONS

Patients with comorbid depression, PTSD, and suicidal ideation are usually very sick and should be referred to a psychiatrist. They are usually treated with antidepressants, such as paroxetine (Paxil) or sertraline (Zoloft), and psychotherapy.⁶⁵ Patients who have a suicidal intent or a plan should be referred to an emergency department for evaluation or hospitalization. All veterans should be given the toll-free phone number of the Veterans Crisis Line (1-800-273-8255), a US Department of Veterans Affairs (VA) resource that connects veterans in crisis and their families and friends, with qualified VA professionals.

As with many illnesses, such as cancer, suicidal behavior is most treatable and yields the best outcome when diagnosed and treated early.⁶⁶ And the earliest manifestation of suicidal behavior is suicidal ideation.

The association of suicidal ideation with PTSD and depression underlines the importance of the timely diagnosis and effective treatment of these conditions among war veterans. Veterans experiencing subthreshold PTSD or depression may be less likely to receive mental health treatment. This indicates that non-mental-health clinicians should be educated about how to detect PTSD and depression symptoms. They may also help to detect suicidality early, which may help save lives.

Promoting social, emotional, and spiritual wellness

Our patients remind us every day that the work we do matters, that we have much more to learn, and that the more we understand suicidal behavior in veterans, the more we can do to reduce their suffering. We need to promote their social, emotional, and spiritual wellness. Encouraging resilience, optimism, and mental health can protect them from depression, suicidal ideation and behavior. Resilience can be promoted by teaching patients to:

• Build relationships with family members and friends who can provide support
• Think well about themselves and identify their areas of strength
• Invest time and energy in developing new skills
• Challenge negative thoughts; try to find optimistic ways of viewing any situation
• Look after their physical health and exercise regularly
• Get involved in community activities to help counter feelings of isolation
• Ask for assistance and support when they need it.⁶⁷

Our knowledge about what works and what does not work in suicide prevention in veterans is evolving. Research addressing combat-related PTSD, depression, and suicidal behavior in war veterans is critically needed to better understand the nature of these conditions.

Cultural diversity is indeed a barrier we need to clear to provide good health care to all. But the challenge of physician-patient communication goes beyond differences in sex, race, ethnicity, age, and level of literacy. Dialogue between physicians and patients is not always easy. There are barriers everywhere that can obstruct our best plans and impede a successful clinical outcome. And we may not even realize that the patient has hit a barrier until long after the visit, when we discover that medication has been taken “the wrong way” or not at all, that studies were not obtained, or that follow-up visits were not arranged.

Communication barriers include use of medical terms that we assume patients understand, lack of attention to clues of anxiety in our patients or their families that will adversely affect their memory of the visit, not finding out the patient’s actual concerns, and loss of the human connection in our rush to finish charting and to stay on time. But it is this connection that often drives the action plan to a successful conclusion.

What can we do in this era of one patient every 15 minutes? Try to make a genuine connection with every patient. This will enhance engagement and the retention of knowledge. Address the patient’s concerns, not just our own. Write legibly or type in the patient instruction section of the electronic medical record the key messages from the visit—diagnosis, plan, tests yet to be done—and give this to the patient at every visit. It is not insulting to do this, nor is it insulting to explain the details of what may seem like an intuitively obvious procedure or therapy. Ask the patient what his or her major concern is, and be sure to address it.

Often, the biggest barrier is that we physicians forget that each patient comes to us with a unique set of fears, rationalizations, and biases that we need to address (even if initially unspoken), just as we address the challenges of diagnosis and therapy. Patients don’t all think like doctors, but we need to be able to think like patients.

Cultural diversity is indeed a barrier we need to clear to provide good health care to all. But the challenge of physician-patient communication goes beyond differences in sex, race, ethnicity, age, and level of literacy. Dialogue between physicians and patients is not always easy. There are barriers everywhere that can obstruct our best plans and impede a successful clinical outcome. And we may not even realize that the patient has hit a barrier until long after the visit, when we discover that medication has been taken “the wrong way” or not at all, that studies were not obtained, or that follow-up visits were not arranged.

Communication barriers include use of medical terms that we assume patients understand, lack of attention to clues of anxiety in our patients or their families that will adversely affect their memory of the visit, not finding out the patient’s actual concerns, and loss of the human connection in our rush to finish charting and to stay on time. But it is this connection that often drives the action plan to a successful conclusion.

What can we do in this era of one patient every 15 minutes? Try to make a genuine connection with every patient. This will enhance engagement and the retention of knowledge. Address the patient’s concerns, not just our own. Write legibly or type in the patient instruction section of the electronic medical record the key messages from the visit—diagnosis, plan, tests yet to be done—and give this to the patient at every visit. It is not insulting to do this, nor is it insulting to explain the details of what may seem like an intuitively obvious procedure or therapy. Ask the patient what his or her major concern is, and be sure to address it.

Often, the biggest barrier is that we physicians forget that each patient comes to us with a unique set of fears, rationalizations, and biases that we need to address (even if initially unspoken), just as we address the challenges of diagnosis and therapy. Patients don’t all think like doctors, but we need to be able to think like patients.

Cultural diversity is indeed a barrier we need to clear to provide good health care to all. But the challenge of physician-patient communication goes beyond differences in sex, race, ethnicity, age, and level of literacy. Dialogue between physicians and patients is not always easy. There are barriers everywhere that can obstruct our best plans and impede a successful clinical outcome. And we may not even realize that the patient has hit a barrier until long after the visit, when we discover that medication has been taken “the wrong way” or not at all, that studies were not obtained, or that follow-up visits were not arranged.

Communication barriers include use of medical terms that we assume patients understand, lack of attention to clues of anxiety in our patients or their families that will adversely affect their memory of the visit, not finding out the patient’s actual concerns, and loss of the human connection in our rush to finish charting and to stay on time. But it is this connection that often drives the action plan to a successful conclusion.

What can we do in this era of one patient every 15 minutes? Try to make a genuine connection with every patient. This will enhance engagement and the retention of knowledge. Address the patient’s concerns, not just our own. Write legibly or type in the patient instruction section of the electronic medical record the key messages from the visit—diagnosis, plan, tests yet to be done—and give this to the patient at every visit. It is not insulting to do this, nor is it insulting to explain the details of what may seem like an intuitively obvious procedure or therapy. Ask the patient what his or her major concern is, and be sure to address it.

Often, the biggest barrier is that we physicians forget that each patient comes to us with a unique set of fears, rationalizations, and biases that we need to address (even if initially unspoken), just as we address the challenges of diagnosis and therapy. Patients don’t all think like doctors, but we need to be able to think like patients.

An english-speaking middle-aged woman from an ethnic minority group presents to her internist for follow-up of her chronic medical problems, which include diabetes, high blood pressure, asthma, and high cholesterol. Although she sees her physician regularly, her medical conditions are not optimally controlled.

At one of the visits, her physician gives her a list of her medications and, while reviewing it, explains—not for the first time—the importance of taking all of them as prescribed. The patient looks at the paper for a while, and then cautiously tells the physician, “But I can’t read.”

This patient presented to our practice several years ago. The scenario may be familiar to many primary physicians, except for the ending— ie, the patient telling her physician that she cannot read.

Her case raises several questions:

• Why did the physician not realize at the first encounter that she could not read the names of her prescribed medications?
• Why did the patient wait to tell her physician that important fact?
• And to what extent did her inability to read contribute to the poor control of her chronic medical problems?

Patients like this one are the human faces behind the statistics about health disparities—the worse outcomes noted in minority populations. Here, we discuss the issues of cross-cultural communication and health literacy as they relate to health care disparities.

DISPARITY IS NOT ONLY DUE TO LACK OF ACCESS

Health care disparity has been an important topic of discussion in medicine in the past decade.

In a 2003 publication,¹ the Institute of Medicine identified lower quality of health care in minority populations as a serious problem. Further, it disputed the long-held belief that the differences in health care between minority and nonminority populations could be explained by lack of access to medical services in minority groups. Instead, it cited factors at the level of the health care system, the level of the patient, and the “care-process level” (ie, the physician-patient encounter) as contributing in distinct ways to the problem.¹

A CALL FOR CULTURAL COMPETENCE

In a policy paper published in 2010, the American College of Physicians² reviewed the progress made in addressing health care disparities. In addition, noting that an individual’s environment, income, level of education, and other factors all affect health, it called for a concerted effort to improve insurance coverage, health literacy, and the health care delivery system; to address stressors both within and outside the health care system; and to recruit more minority health care workers.

None of these things seems like anything a busy practicing clinician could do much about. However, we can try to improve our cultural competence in our interactions with patients on an individual level.

The report recommends that physicians and other health care professionals be sensitive to cultural diversity among patients. It also says we should recognize our preconceived perceptions of minority patients that may affect their treatment and contribute to disparities in health care in minorities. To those ends, it calls for cultural competence training in medical school to improve cultural awareness and sensitivity.²

The Office of Minority Health broadly defines cultural and linguistic competence in health as “a set of congruent behaviors, attitudes, and policies that come together in a system, agency, or among professionals that enables effective work in cross-cultural situations.”³ Cultural competence training should focus on being aware of one’s personal bias, as well as on education about culture-specific norms or knowledge of possible causes of mistrust in minority groups.

For example, many African Americans may mistrust the medical system, given the awareness of previous inequities such as the notorious Tuskegee syphilis study (in which informed consent was not used and treatment that was needed was withheld). Further, beliefs about health in minority populations may be discordant with the Western medical model.⁴

RECOGNIZING OUR OWN BIASES

Preconceived perceptions on the part of the physician may be shaped by previous experiences with patients from a specific minority group or by personal bias. Unfortunately, even a well-meaning physician who has tried to learn about cultural norms of specific minority groups can be at risk of stereotyping by assuming that all members of that group hold the same beliefs. From the patient’s viewpoint, they can also be molded by previous experiences of health care inequities or unfavorable interactions with physicians.

For example, in the case we described above, perhaps the physician had assumed that the patient was noncompliant and therefore did not look for reasons for the poor control of her medical problems, or maybe the patient did not trust the physician enough to explain the reason for her difficulty with understanding how to take her medications.

Being aware of our own unconscious stereotyping of minority groups is an important step in effectively communicating with patients from different cultural backgrounds or with low health literacy. We also need to reflect about our own health belief system and try to incorporate the patient’s viewpoint into decision-making.

If, on reflection, we recognize that we do harbor biases, we ought to think about ways to better accommodate patients from different backgrounds and literacy levels, including trying to learn more about their culture or mastering techniques to effectively explain treatment plans to low-literacy patients.

ALL ENCOUNTERS WITH PATIENTS ARE ‘CROSS-CULTURAL’

In health care, “cross-cultural communication” does not refer only to interactions between persons from different ethnic backgrounds or with different beliefs about health. Health care has a culture of its own, creating a cross-cultural encounter the moment a person enters your office or clinic in the role of “patient.”

Carillo et al⁵ categorized issues that may pose difficulties in a cross-cultural encounter as those of authority, physical contact, communication styles, gender, sexuality, and family.

Physician-patient communication is a complicated issue. Many patients will not question a physician if their own cultural norms view it as disrespectful—even if they have very specific fears about the diagnosis or treatment plan. They may also defer any important decision to a family member who has the authority to make decisions for the family.

Frequently, miscommunication is unintentional. In a recent study of hospitalized patients,⁶ 77% of the physicians believed that their patients understood their diagnoses, while only 57% of patients could correctly state this information.

WHAT DOES THE PATIENT THINK?

A key issue in cross-cultural communication, and one that is often neglected, is to address a patient’s fears about his or her illness. In the study mentioned above, more than half of the patients who reported having anxieties or fears in the hospital stated that their physicians did not discuss their fears.⁶ But if we fail to do so, patients may be less satisfied with the treatment plan and may not accept our recommendations.

A patient’s understanding of his or her illness may be very different from the biomedical explanation. For example, we once saw an elderly man who was admitted to the hospital with back pain due to metastatic prostate cancer, but who was convinced that his symptoms were caused by a voodoo “hex” placed on him by his ex-wife.

For example, for the man who thought that his ex-wife put a hex on him, asking him “What do you think has caused your problem?” during the initial history-taking would allow him to express his concern about the hex and give the physician an opportunity to learn of this fear and then to offer the biomedical explanation for the problem and for the recommended treatment.

What happens more often in practice is that the specific fear is not addressed at the start of the encounter. Consequently, the patient is less likely to follow through with the treatment plan, as he or she does not feel the prescribed treatment is fixing the real problem. This process of exploring the explanatory model of illness may be viewed on a practical level as a way of managing expectations in the clinical care of culturally diverse populations.

HEALTH LITERACY: MORE THAN THE ABILITY TO READ

The better you know how to read, the healthier you probably are. In fact, a study found that a person’s literacy level correlated more strongly with health than did race or formal education level.⁹ (Apparently, attending school does not necessarily mean that people know how to read, and not attending school doesn’t mean that they don’t.)

Even more important than literacy may be health literacy, defined by Ratzan and Parker as “the degree to which individuals have the capacity to obtain, process, and understand basic health information and services needed to make appropriate health decisions.”⁸ It includes basic math and critical-thinking skills that allow patients to use medications properly and participate in treatment decisions. Thus, health literacy is much more than the ability to read.

Even people who read and write very well may have trouble when confronted with the complexities of navigating our health care system, such as appointment scheduling, specialty referrals, and follow-up testing and procedures: their health literacy may be lower than their general literacy. We had a patient, a highly trained professional, who was confused by instructions for preparing for colonoscopy on a patient handout. Another similar patient could not understand the dosing of eye drops after cataract surgery because the instructions on the discharge paperwork were unclear.

However, limited health literacy disproportionately affects minority groups and is linked to poorer health care outcomes. Thus, addressing limited health literacy is important in addressing health care disparities. Effective physician-patient communication about treatment plans is fundamental to providing equitable care to patients from minority groups, some of whom may be at high risk for low health literacy.

Below, we will review some of the data on health literacy and offer suggestions for screening and interventions for those whose health literacy is limited.

36% have basic or below-basic reading skills

Every 10 years, the US Department of Education completes its National Assessment of Adult Literacy. Its 2003 survey—the most recent—included 19,000 adults in the community and in prison, interviewed at their place of residence.¹⁰ Each participant completed a set of tasks to measure his or her ability to read, understand, and interpret text and to use and interpret numbers.

Participants were divided into four categories based on the results: proficient (12%), intermediate (53%), basic (22%), and below basic (14%). Additionally, 5% of potential participants could not be tested because they had insufficient skills to participate in the survey.

Low literacy puts patients at risk

Although literacy is not the same as health literacy, functionally, those who have basic or below-basic literacy skills (36% of the US population) are at high risk for encountering problems in the US health care system. For example, they would have difficulty with most patient education handouts and health insurance forms.

Limited health literacy exacts both personal and financial costs. Patients with low health literacy are less likely to understand how to take their medications, what prescription warning labels mean, how to schedule follow-up appointments, and how to fill out health insurance forms.^11–14

Medicare managed-care enrollees are more likely to be hospitalized if they have limited health literacy,¹⁵ and diabetic Medicaid patients who have limited health literacy are less likely to have good glycemic control.¹⁶ One study showed annual health care costs of $10,688 for Medicaid enrollees with limited health literacy compared with $2,891 for all enrollees.¹⁷ The total cost of limited health literacy to the US health care system is estimated to be between $50 and $73 billion per year.¹⁸

Screening for limited health literacy: You can’t tell just by looking

Given the high costs of low health literacy, identifying patients who have it is of paramount importance.

Groups who are more likely to have limited health literacy include the elderly, the poor, the unemployed, high school dropouts, members of minority groups, recent immigrants, and people for whom English is a second language.

However, these demographic factors are not sufficient as a screen for low health literacy—you can't tell just by looking. Red flags for low health literacy include difficulty filling out forms in the office, missed appointments, nonadherence to medication regimens, failure to follow up with scheduled testing, and difficulty reading written materials, often masked with a statement such as “I forgot my glasses and will read this at home.”

A number of screening tests have been developed, including the Rapid Estimate of Adult Literacy in Medicine (REALM)¹⁹ and the Test for Functional Health Literacy in Adults (TOFHLA).²⁰ These tests are long, making them difficult to incorporate into a patient visit in a busy primary care practice, but they are useful for research. A newer screening test asks the patient to review a nutrition label and answer six questions.²¹

The most useful screening test for clinical use may consist of a single question. Questions that have been validated:

• “How often do you need to have someone help you when you read instructions, pamphlets, or other written material from your doctor or pharmacy?” Positive answers are “sometimes,” “often,” or “always.”
• “How confident are you filling out medical forms by yourself?” Positive answers are “somewhat,” “a little bit,” or “not at all.”^22–24

These questions can be included either in the initial screening by a nurse or medical assistant or as part of the social history portion of the interview with the physician.

A “brown bag review” can also be helpful. Patients are asked to bring in their medications (often in a brown bag—hence the name). Asking the patient to identify each medication by name and the indication for it can uncover knowledge gaps that indicate low health literacy.

The point to remember is that patients with low health literacy will probably not tell you that they do not understand. However, they would appreciate being asked in a nonthreatening manner.

Many experts advocate a “universal precautions approach,” in which interventions to address low health literacy are incorporated into routine office practice for all patients. Practice sites should adopt a culture of a “shame-free environment,” in which support staff encourage patients to ask questions and are trained to offer assistance to those having difficulty reading or filling out forms.

On a broader level, medical offices and hospitals can partner with adult-learning specialists to help patients gain skills to navigate the health care system. All signage should be clear and should use plain language as opposed to medical terms. Medical forms and questionnaires should be designed to collect only essential information and should be written at a sixth-grade reading level or below. Patient instructions and educational materials should also be clear and free of jargon.

The ‘teach-back’ technique

The “teach-back” technique is a simple method to confirm patient understanding at the end of the visit. This involves asking patients in a nonthreatening way to explain or demonstrate what they have been told. Examples:

• “I want to make sure I have explained things correctly. Can you tell me how you plan to take your medication when you go home?”
• “I want to make sure I have done a good job explaining things to you. When you go home and tell your spouse about your visit today, what will you say?”

These questions should be asked in a nonthreatening way. Put the burden of explanation on yourself as the first step, and let the patient know you are willing to explain again more thoroughly any instructions that may have not been clearly understood.

Other measures

Pictures and computer-based education may be useful for some patients who have difficulty reading.

Weiss²⁵ advocates six steps to improve communication with patients in all encounters: slow down; use plain, nonmedical language; show or draw pictures; limit the amount of information provided; use the teach-back technique; and create a shame-free environment, encouraging questions.

Improving health literacy, as it relates to cross-cultural communication of treatment plans, must encompass understanding of health beliefs often based on cultural norms, in order to come to agreement on a mutually acceptable plan of care. Physicians should be aware of preferences for nontraditional or complementary treatments that may reflect specific cultural beliefs.

IF THE PATIENT DOES NOT SPEAK ENGLISH

Verbal communication across language barriers poses another layer of challenge. A trained interpreter should be used whenever possible when treating a patient who speaks a different language than that of the practitioner. When family members are used as interpreters, there are risks that the patient may not fully disclose facts about the history of illness or specific symptoms, and also that family members may place their own “twist” on the story when translating.

The physician should speak directly to the patient in a normal tone of voice. In this setting, also remember that nonverbal communication can be misinterpreted. Gestures should be avoided. Finally, be aware that personal space is viewed differently depending on cultural background, as is eye contact.

It is helpful to have a pre-interview meeting with the interpreter to explain the format of the interview, as well as a post-interview meeting to ensure all parties felt they effectively communicated during the encounter.

TOWARD EQUITABLE CARE

Health care disparities are the result of multiple determinants. In December 2008, a National Institutes of Health summit conference cited not only barriers to access, but also the interaction of biological, behavioral, social, environmental, economic, cultural, and political factors, and noted that the causes and effects of health disparities transcend health care.²⁶

Clearly, an individual physician’s efforts will not be all that is needed to eliminate health disparities. A team-based approach is essential, using skills of nonphysician members of the health care team such as nurses, medical assistants, social workers, and case managers. Continued opportunity for professional training and development in provider-patient communication skills should be offered.

However, the impact of effective cross-cultural communication and managing low health literacy populations on the physician-patient level should not be understated. As practitioners treating patients from diverse backgrounds, improving self-awareness, eliciting the patient’s explanatory model, and assuring understanding of treatment plans for patients with low health literacy or with language barriers, we can do our part in working toward equitable care for all patients.

An english-speaking middle-aged woman from an ethnic minority group presents to her internist for follow-up of her chronic medical problems, which include diabetes, high blood pressure, asthma, and high cholesterol. Although she sees her physician regularly, her medical conditions are not optimally controlled.

At one of the visits, her physician gives her a list of her medications and, while reviewing it, explains—not for the first time—the importance of taking all of them as prescribed. The patient looks at the paper for a while, and then cautiously tells the physician, “But I can’t read.”

This patient presented to our practice several years ago. The scenario may be familiar to many primary physicians, except for the ending— ie, the patient telling her physician that she cannot read.

Her case raises several questions:

• Why did the physician not realize at the first encounter that she could not read the names of her prescribed medications?
• Why did the patient wait to tell her physician that important fact?
• And to what extent did her inability to read contribute to the poor control of her chronic medical problems?

Patients like this one are the human faces behind the statistics about health disparities—the worse outcomes noted in minority populations. Here, we discuss the issues of cross-cultural communication and health literacy as they relate to health care disparities.

DISPARITY IS NOT ONLY DUE TO LACK OF ACCESS

Health care disparity has been an important topic of discussion in medicine in the past decade.

In a 2003 publication,¹ the Institute of Medicine identified lower quality of health care in minority populations as a serious problem. Further, it disputed the long-held belief that the differences in health care between minority and nonminority populations could be explained by lack of access to medical services in minority groups. Instead, it cited factors at the level of the health care system, the level of the patient, and the “care-process level” (ie, the physician-patient encounter) as contributing in distinct ways to the problem.¹

A CALL FOR CULTURAL COMPETENCE

In a policy paper published in 2010, the American College of Physicians² reviewed the progress made in addressing health care disparities. In addition, noting that an individual’s environment, income, level of education, and other factors all affect health, it called for a concerted effort to improve insurance coverage, health literacy, and the health care delivery system; to address stressors both within and outside the health care system; and to recruit more minority health care workers.

None of these things seems like anything a busy practicing clinician could do much about. However, we can try to improve our cultural competence in our interactions with patients on an individual level.

The report recommends that physicians and other health care professionals be sensitive to cultural diversity among patients. It also says we should recognize our preconceived perceptions of minority patients that may affect their treatment and contribute to disparities in health care in minorities. To those ends, it calls for cultural competence training in medical school to improve cultural awareness and sensitivity.²

The Office of Minority Health broadly defines cultural and linguistic competence in health as “a set of congruent behaviors, attitudes, and policies that come together in a system, agency, or among professionals that enables effective work in cross-cultural situations.”³ Cultural competence training should focus on being aware of one’s personal bias, as well as on education about culture-specific norms or knowledge of possible causes of mistrust in minority groups.

For example, many African Americans may mistrust the medical system, given the awareness of previous inequities such as the notorious Tuskegee syphilis study (in which informed consent was not used and treatment that was needed was withheld). Further, beliefs about health in minority populations may be discordant with the Western medical model.⁴

RECOGNIZING OUR OWN BIASES

Preconceived perceptions on the part of the physician may be shaped by previous experiences with patients from a specific minority group or by personal bias. Unfortunately, even a well-meaning physician who has tried to learn about cultural norms of specific minority groups can be at risk of stereotyping by assuming that all members of that group hold the same beliefs. From the patient’s viewpoint, they can also be molded by previous experiences of health care inequities or unfavorable interactions with physicians.

For example, in the case we described above, perhaps the physician had assumed that the patient was noncompliant and therefore did not look for reasons for the poor control of her medical problems, or maybe the patient did not trust the physician enough to explain the reason for her difficulty with understanding how to take her medications.

Being aware of our own unconscious stereotyping of minority groups is an important step in effectively communicating with patients from different cultural backgrounds or with low health literacy. We also need to reflect about our own health belief system and try to incorporate the patient’s viewpoint into decision-making.

If, on reflection, we recognize that we do harbor biases, we ought to think about ways to better accommodate patients from different backgrounds and literacy levels, including trying to learn more about their culture or mastering techniques to effectively explain treatment plans to low-literacy patients.

ALL ENCOUNTERS WITH PATIENTS ARE ‘CROSS-CULTURAL’

In health care, “cross-cultural communication” does not refer only to interactions between persons from different ethnic backgrounds or with different beliefs about health. Health care has a culture of its own, creating a cross-cultural encounter the moment a person enters your office or clinic in the role of “patient.”

Carillo et al⁵ categorized issues that may pose difficulties in a cross-cultural encounter as those of authority, physical contact, communication styles, gender, sexuality, and family.

Physician-patient communication is a complicated issue. Many patients will not question a physician if their own cultural norms view it as disrespectful—even if they have very specific fears about the diagnosis or treatment plan. They may also defer any important decision to a family member who has the authority to make decisions for the family.

Frequently, miscommunication is unintentional. In a recent study of hospitalized patients,⁶ 77% of the physicians believed that their patients understood their diagnoses, while only 57% of patients could correctly state this information.

WHAT DOES THE PATIENT THINK?

A key issue in cross-cultural communication, and one that is often neglected, is to address a patient’s fears about his or her illness. In the study mentioned above, more than half of the patients who reported having anxieties or fears in the hospital stated that their physicians did not discuss their fears.⁶ But if we fail to do so, patients may be less satisfied with the treatment plan and may not accept our recommendations.

A patient’s understanding of his or her illness may be very different from the biomedical explanation. For example, we once saw an elderly man who was admitted to the hospital with back pain due to metastatic prostate cancer, but who was convinced that his symptoms were caused by a voodoo “hex” placed on him by his ex-wife.

For example, for the man who thought that his ex-wife put a hex on him, asking him “What do you think has caused your problem?” during the initial history-taking would allow him to express his concern about the hex and give the physician an opportunity to learn of this fear and then to offer the biomedical explanation for the problem and for the recommended treatment.

What happens more often in practice is that the specific fear is not addressed at the start of the encounter. Consequently, the patient is less likely to follow through with the treatment plan, as he or she does not feel the prescribed treatment is fixing the real problem. This process of exploring the explanatory model of illness may be viewed on a practical level as a way of managing expectations in the clinical care of culturally diverse populations.

HEALTH LITERACY: MORE THAN THE ABILITY TO READ

The better you know how to read, the healthier you probably are. In fact, a study found that a person’s literacy level correlated more strongly with health than did race or formal education level.⁹ (Apparently, attending school does not necessarily mean that people know how to read, and not attending school doesn’t mean that they don’t.)

Even more important than literacy may be health literacy, defined by Ratzan and Parker as “the degree to which individuals have the capacity to obtain, process, and understand basic health information and services needed to make appropriate health decisions.”⁸ It includes basic math and critical-thinking skills that allow patients to use medications properly and participate in treatment decisions. Thus, health literacy is much more than the ability to read.

Even people who read and write very well may have trouble when confronted with the complexities of navigating our health care system, such as appointment scheduling, specialty referrals, and follow-up testing and procedures: their health literacy may be lower than their general literacy. We had a patient, a highly trained professional, who was confused by instructions for preparing for colonoscopy on a patient handout. Another similar patient could not understand the dosing of eye drops after cataract surgery because the instructions on the discharge paperwork were unclear.

However, limited health literacy disproportionately affects minority groups and is linked to poorer health care outcomes. Thus, addressing limited health literacy is important in addressing health care disparities. Effective physician-patient communication about treatment plans is fundamental to providing equitable care to patients from minority groups, some of whom may be at high risk for low health literacy.

Below, we will review some of the data on health literacy and offer suggestions for screening and interventions for those whose health literacy is limited.

36% have basic or below-basic reading skills

Every 10 years, the US Department of Education completes its National Assessment of Adult Literacy. Its 2003 survey—the most recent—included 19,000 adults in the community and in prison, interviewed at their place of residence.¹⁰ Each participant completed a set of tasks to measure his or her ability to read, understand, and interpret text and to use and interpret numbers.

Participants were divided into four categories based on the results: proficient (12%), intermediate (53%), basic (22%), and below basic (14%). Additionally, 5% of potential participants could not be tested because they had insufficient skills to participate in the survey.

Low literacy puts patients at risk

Although literacy is not the same as health literacy, functionally, those who have basic or below-basic literacy skills (36% of the US population) are at high risk for encountering problems in the US health care system. For example, they would have difficulty with most patient education handouts and health insurance forms.

Limited health literacy exacts both personal and financial costs. Patients with low health literacy are less likely to understand how to take their medications, what prescription warning labels mean, how to schedule follow-up appointments, and how to fill out health insurance forms.^11–14

Medicare managed-care enrollees are more likely to be hospitalized if they have limited health literacy,¹⁵ and diabetic Medicaid patients who have limited health literacy are less likely to have good glycemic control.¹⁶ One study showed annual health care costs of $10,688 for Medicaid enrollees with limited health literacy compared with $2,891 for all enrollees.¹⁷ The total cost of limited health literacy to the US health care system is estimated to be between $50 and $73 billion per year.¹⁸

Screening for limited health literacy: You can’t tell just by looking

Given the high costs of low health literacy, identifying patients who have it is of paramount importance.

Groups who are more likely to have limited health literacy include the elderly, the poor, the unemployed, high school dropouts, members of minority groups, recent immigrants, and people for whom English is a second language.

However, these demographic factors are not sufficient as a screen for low health literacy—you can't tell just by looking. Red flags for low health literacy include difficulty filling out forms in the office, missed appointments, nonadherence to medication regimens, failure to follow up with scheduled testing, and difficulty reading written materials, often masked with a statement such as “I forgot my glasses and will read this at home.”

A number of screening tests have been developed, including the Rapid Estimate of Adult Literacy in Medicine (REALM)¹⁹ and the Test for Functional Health Literacy in Adults (TOFHLA).²⁰ These tests are long, making them difficult to incorporate into a patient visit in a busy primary care practice, but they are useful for research. A newer screening test asks the patient to review a nutrition label and answer six questions.²¹

The most useful screening test for clinical use may consist of a single question. Questions that have been validated:

• “How often do you need to have someone help you when you read instructions, pamphlets, or other written material from your doctor or pharmacy?” Positive answers are “sometimes,” “often,” or “always.”
• “How confident are you filling out medical forms by yourself?” Positive answers are “somewhat,” “a little bit,” or “not at all.”^22–24

These questions can be included either in the initial screening by a nurse or medical assistant or as part of the social history portion of the interview with the physician.

A “brown bag review” can also be helpful. Patients are asked to bring in their medications (often in a brown bag—hence the name). Asking the patient to identify each medication by name and the indication for it can uncover knowledge gaps that indicate low health literacy.

The point to remember is that patients with low health literacy will probably not tell you that they do not understand. However, they would appreciate being asked in a nonthreatening manner.

Many experts advocate a “universal precautions approach,” in which interventions to address low health literacy are incorporated into routine office practice for all patients. Practice sites should adopt a culture of a “shame-free environment,” in which support staff encourage patients to ask questions and are trained to offer assistance to those having difficulty reading or filling out forms.

On a broader level, medical offices and hospitals can partner with adult-learning specialists to help patients gain skills to navigate the health care system. All signage should be clear and should use plain language as opposed to medical terms. Medical forms and questionnaires should be designed to collect only essential information and should be written at a sixth-grade reading level or below. Patient instructions and educational materials should also be clear and free of jargon.

The ‘teach-back’ technique

The “teach-back” technique is a simple method to confirm patient understanding at the end of the visit. This involves asking patients in a nonthreatening way to explain or demonstrate what they have been told. Examples:

• “I want to make sure I have explained things correctly. Can you tell me how you plan to take your medication when you go home?”
• “I want to make sure I have done a good job explaining things to you. When you go home and tell your spouse about your visit today, what will you say?”

These questions should be asked in a nonthreatening way. Put the burden of explanation on yourself as the first step, and let the patient know you are willing to explain again more thoroughly any instructions that may have not been clearly understood.

Other measures

Pictures and computer-based education may be useful for some patients who have difficulty reading.

Weiss²⁵ advocates six steps to improve communication with patients in all encounters: slow down; use plain, nonmedical language; show or draw pictures; limit the amount of information provided; use the teach-back technique; and create a shame-free environment, encouraging questions.

Improving health literacy, as it relates to cross-cultural communication of treatment plans, must encompass understanding of health beliefs often based on cultural norms, in order to come to agreement on a mutually acceptable plan of care. Physicians should be aware of preferences for nontraditional or complementary treatments that may reflect specific cultural beliefs.

IF THE PATIENT DOES NOT SPEAK ENGLISH

Verbal communication across language barriers poses another layer of challenge. A trained interpreter should be used whenever possible when treating a patient who speaks a different language than that of the practitioner. When family members are used as interpreters, there are risks that the patient may not fully disclose facts about the history of illness or specific symptoms, and also that family members may place their own “twist” on the story when translating.

The physician should speak directly to the patient in a normal tone of voice. In this setting, also remember that nonverbal communication can be misinterpreted. Gestures should be avoided. Finally, be aware that personal space is viewed differently depending on cultural background, as is eye contact.

It is helpful to have a pre-interview meeting with the interpreter to explain the format of the interview, as well as a post-interview meeting to ensure all parties felt they effectively communicated during the encounter.

TOWARD EQUITABLE CARE

Health care disparities are the result of multiple determinants. In December 2008, a National Institutes of Health summit conference cited not only barriers to access, but also the interaction of biological, behavioral, social, environmental, economic, cultural, and political factors, and noted that the causes and effects of health disparities transcend health care.²⁶

Clearly, an individual physician’s efforts will not be all that is needed to eliminate health disparities. A team-based approach is essential, using skills of nonphysician members of the health care team such as nurses, medical assistants, social workers, and case managers. Continued opportunity for professional training and development in provider-patient communication skills should be offered.

However, the impact of effective cross-cultural communication and managing low health literacy populations on the physician-patient level should not be understated. As practitioners treating patients from diverse backgrounds, improving self-awareness, eliciting the patient’s explanatory model, and assuring understanding of treatment plans for patients with low health literacy or with language barriers, we can do our part in working toward equitable care for all patients.

An english-speaking middle-aged woman from an ethnic minority group presents to her internist for follow-up of her chronic medical problems, which include diabetes, high blood pressure, asthma, and high cholesterol. Although she sees her physician regularly, her medical conditions are not optimally controlled.

At one of the visits, her physician gives her a list of her medications and, while reviewing it, explains—not for the first time—the importance of taking all of them as prescribed. The patient looks at the paper for a while, and then cautiously tells the physician, “But I can’t read.”

This patient presented to our practice several years ago. The scenario may be familiar to many primary physicians, except for the ending— ie, the patient telling her physician that she cannot read.

Her case raises several questions:

• Why did the physician not realize at the first encounter that she could not read the names of her prescribed medications?
• Why did the patient wait to tell her physician that important fact?
• And to what extent did her inability to read contribute to the poor control of her chronic medical problems?

Patients like this one are the human faces behind the statistics about health disparities—the worse outcomes noted in minority populations. Here, we discuss the issues of cross-cultural communication and health literacy as they relate to health care disparities.

DISPARITY IS NOT ONLY DUE TO LACK OF ACCESS

Health care disparity has been an important topic of discussion in medicine in the past decade.

In a 2003 publication,¹ the Institute of Medicine identified lower quality of health care in minority populations as a serious problem. Further, it disputed the long-held belief that the differences in health care between minority and nonminority populations could be explained by lack of access to medical services in minority groups. Instead, it cited factors at the level of the health care system, the level of the patient, and the “care-process level” (ie, the physician-patient encounter) as contributing in distinct ways to the problem.¹

A CALL FOR CULTURAL COMPETENCE

In a policy paper published in 2010, the American College of Physicians² reviewed the progress made in addressing health care disparities. In addition, noting that an individual’s environment, income, level of education, and other factors all affect health, it called for a concerted effort to improve insurance coverage, health literacy, and the health care delivery system; to address stressors both within and outside the health care system; and to recruit more minority health care workers.

None of these things seems like anything a busy practicing clinician could do much about. However, we can try to improve our cultural competence in our interactions with patients on an individual level.

The report recommends that physicians and other health care professionals be sensitive to cultural diversity among patients. It also says we should recognize our preconceived perceptions of minority patients that may affect their treatment and contribute to disparities in health care in minorities. To those ends, it calls for cultural competence training in medical school to improve cultural awareness and sensitivity.²

The Office of Minority Health broadly defines cultural and linguistic competence in health as “a set of congruent behaviors, attitudes, and policies that come together in a system, agency, or among professionals that enables effective work in cross-cultural situations.”³ Cultural competence training should focus on being aware of one’s personal bias, as well as on education about culture-specific norms or knowledge of possible causes of mistrust in minority groups.

For example, many African Americans may mistrust the medical system, given the awareness of previous inequities such as the notorious Tuskegee syphilis study (in which informed consent was not used and treatment that was needed was withheld). Further, beliefs about health in minority populations may be discordant with the Western medical model.⁴

RECOGNIZING OUR OWN BIASES

Preconceived perceptions on the part of the physician may be shaped by previous experiences with patients from a specific minority group or by personal bias. Unfortunately, even a well-meaning physician who has tried to learn about cultural norms of specific minority groups can be at risk of stereotyping by assuming that all members of that group hold the same beliefs. From the patient’s viewpoint, they can also be molded by previous experiences of health care inequities or unfavorable interactions with physicians.

For example, in the case we described above, perhaps the physician had assumed that the patient was noncompliant and therefore did not look for reasons for the poor control of her medical problems, or maybe the patient did not trust the physician enough to explain the reason for her difficulty with understanding how to take her medications.

Being aware of our own unconscious stereotyping of minority groups is an important step in effectively communicating with patients from different cultural backgrounds or with low health literacy. We also need to reflect about our own health belief system and try to incorporate the patient’s viewpoint into decision-making.

If, on reflection, we recognize that we do harbor biases, we ought to think about ways to better accommodate patients from different backgrounds and literacy levels, including trying to learn more about their culture or mastering techniques to effectively explain treatment plans to low-literacy patients.

ALL ENCOUNTERS WITH PATIENTS ARE ‘CROSS-CULTURAL’

In health care, “cross-cultural communication” does not refer only to interactions between persons from different ethnic backgrounds or with different beliefs about health. Health care has a culture of its own, creating a cross-cultural encounter the moment a person enters your office or clinic in the role of “patient.”

Carillo et al⁵ categorized issues that may pose difficulties in a cross-cultural encounter as those of authority, physical contact, communication styles, gender, sexuality, and family.

Physician-patient communication is a complicated issue. Many patients will not question a physician if their own cultural norms view it as disrespectful—even if they have very specific fears about the diagnosis or treatment plan. They may also defer any important decision to a family member who has the authority to make decisions for the family.

Frequently, miscommunication is unintentional. In a recent study of hospitalized patients,⁶ 77% of the physicians believed that their patients understood their diagnoses, while only 57% of patients could correctly state this information.

WHAT DOES THE PATIENT THINK?

A key issue in cross-cultural communication, and one that is often neglected, is to address a patient’s fears about his or her illness. In the study mentioned above, more than half of the patients who reported having anxieties or fears in the hospital stated that their physicians did not discuss their fears.⁶ But if we fail to do so, patients may be less satisfied with the treatment plan and may not accept our recommendations.

A patient’s understanding of his or her illness may be very different from the biomedical explanation. For example, we once saw an elderly man who was admitted to the hospital with back pain due to metastatic prostate cancer, but who was convinced that his symptoms were caused by a voodoo “hex” placed on him by his ex-wife.

For example, for the man who thought that his ex-wife put a hex on him, asking him “What do you think has caused your problem?” during the initial history-taking would allow him to express his concern about the hex and give the physician an opportunity to learn of this fear and then to offer the biomedical explanation for the problem and for the recommended treatment.

What happens more often in practice is that the specific fear is not addressed at the start of the encounter. Consequently, the patient is less likely to follow through with the treatment plan, as he or she does not feel the prescribed treatment is fixing the real problem. This process of exploring the explanatory model of illness may be viewed on a practical level as a way of managing expectations in the clinical care of culturally diverse populations.

HEALTH LITERACY: MORE THAN THE ABILITY TO READ

The better you know how to read, the healthier you probably are. In fact, a study found that a person’s literacy level correlated more strongly with health than did race or formal education level.⁹ (Apparently, attending school does not necessarily mean that people know how to read, and not attending school doesn’t mean that they don’t.)

Even more important than literacy may be health literacy, defined by Ratzan and Parker as “the degree to which individuals have the capacity to obtain, process, and understand basic health information and services needed to make appropriate health decisions.”⁸ It includes basic math and critical-thinking skills that allow patients to use medications properly and participate in treatment decisions. Thus, health literacy is much more than the ability to read.

Even people who read and write very well may have trouble when confronted with the complexities of navigating our health care system, such as appointment scheduling, specialty referrals, and follow-up testing and procedures: their health literacy may be lower than their general literacy. We had a patient, a highly trained professional, who was confused by instructions for preparing for colonoscopy on a patient handout. Another similar patient could not understand the dosing of eye drops after cataract surgery because the instructions on the discharge paperwork were unclear.

However, limited health literacy disproportionately affects minority groups and is linked to poorer health care outcomes. Thus, addressing limited health literacy is important in addressing health care disparities. Effective physician-patient communication about treatment plans is fundamental to providing equitable care to patients from minority groups, some of whom may be at high risk for low health literacy.

Below, we will review some of the data on health literacy and offer suggestions for screening and interventions for those whose health literacy is limited.

36% have basic or below-basic reading skills

Every 10 years, the US Department of Education completes its National Assessment of Adult Literacy. Its 2003 survey—the most recent—included 19,000 adults in the community and in prison, interviewed at their place of residence.¹⁰ Each participant completed a set of tasks to measure his or her ability to read, understand, and interpret text and to use and interpret numbers.

Participants were divided into four categories based on the results: proficient (12%), intermediate (53%), basic (22%), and below basic (14%). Additionally, 5% of potential participants could not be tested because they had insufficient skills to participate in the survey.

Low literacy puts patients at risk

Although literacy is not the same as health literacy, functionally, those who have basic or below-basic literacy skills (36% of the US population) are at high risk for encountering problems in the US health care system. For example, they would have difficulty with most patient education handouts and health insurance forms.

Limited health literacy exacts both personal and financial costs. Patients with low health literacy are less likely to understand how to take their medications, what prescription warning labels mean, how to schedule follow-up appointments, and how to fill out health insurance forms.^11–14

Medicare managed-care enrollees are more likely to be hospitalized if they have limited health literacy,¹⁵ and diabetic Medicaid patients who have limited health literacy are less likely to have good glycemic control.¹⁶ One study showed annual health care costs of $10,688 for Medicaid enrollees with limited health literacy compared with $2,891 for all enrollees.¹⁷ The total cost of limited health literacy to the US health care system is estimated to be between $50 and $73 billion per year.¹⁸

Screening for limited health literacy: You can’t tell just by looking

Given the high costs of low health literacy, identifying patients who have it is of paramount importance.

Groups who are more likely to have limited health literacy include the elderly, the poor, the unemployed, high school dropouts, members of minority groups, recent immigrants, and people for whom English is a second language.

However, these demographic factors are not sufficient as a screen for low health literacy—you can't tell just by looking. Red flags for low health literacy include difficulty filling out forms in the office, missed appointments, nonadherence to medication regimens, failure to follow up with scheduled testing, and difficulty reading written materials, often masked with a statement such as “I forgot my glasses and will read this at home.”

A number of screening tests have been developed, including the Rapid Estimate of Adult Literacy in Medicine (REALM)¹⁹ and the Test for Functional Health Literacy in Adults (TOFHLA).²⁰ These tests are long, making them difficult to incorporate into a patient visit in a busy primary care practice, but they are useful for research. A newer screening test asks the patient to review a nutrition label and answer six questions.²¹

The most useful screening test for clinical use may consist of a single question. Questions that have been validated:

• “How often do you need to have someone help you when you read instructions, pamphlets, or other written material from your doctor or pharmacy?” Positive answers are “sometimes,” “often,” or “always.”
• “How confident are you filling out medical forms by yourself?” Positive answers are “somewhat,” “a little bit,” or “not at all.”^22–24

These questions can be included either in the initial screening by a nurse or medical assistant or as part of the social history portion of the interview with the physician.

A “brown bag review” can also be helpful. Patients are asked to bring in their medications (often in a brown bag—hence the name). Asking the patient to identify each medication by name and the indication for it can uncover knowledge gaps that indicate low health literacy.

The point to remember is that patients with low health literacy will probably not tell you that they do not understand. However, they would appreciate being asked in a nonthreatening manner.

Many experts advocate a “universal precautions approach,” in which interventions to address low health literacy are incorporated into routine office practice for all patients. Practice sites should adopt a culture of a “shame-free environment,” in which support staff encourage patients to ask questions and are trained to offer assistance to those having difficulty reading or filling out forms.

On a broader level, medical offices and hospitals can partner with adult-learning specialists to help patients gain skills to navigate the health care system. All signage should be clear and should use plain language as opposed to medical terms. Medical forms and questionnaires should be designed to collect only essential information and should be written at a sixth-grade reading level or below. Patient instructions and educational materials should also be clear and free of jargon.

The ‘teach-back’ technique

The “teach-back” technique is a simple method to confirm patient understanding at the end of the visit. This involves asking patients in a nonthreatening way to explain or demonstrate what they have been told. Examples:

• “I want to make sure I have explained things correctly. Can you tell me how you plan to take your medication when you go home?”
• “I want to make sure I have done a good job explaining things to you. When you go home and tell your spouse about your visit today, what will you say?”

These questions should be asked in a nonthreatening way. Put the burden of explanation on yourself as the first step, and let the patient know you are willing to explain again more thoroughly any instructions that may have not been clearly understood.

Other measures

Pictures and computer-based education may be useful for some patients who have difficulty reading.

Weiss²⁵ advocates six steps to improve communication with patients in all encounters: slow down; use plain, nonmedical language; show or draw pictures; limit the amount of information provided; use the teach-back technique; and create a shame-free environment, encouraging questions.

Improving health literacy, as it relates to cross-cultural communication of treatment plans, must encompass understanding of health beliefs often based on cultural norms, in order to come to agreement on a mutually acceptable plan of care. Physicians should be aware of preferences for nontraditional or complementary treatments that may reflect specific cultural beliefs.

IF THE PATIENT DOES NOT SPEAK ENGLISH

Verbal communication across language barriers poses another layer of challenge. A trained interpreter should be used whenever possible when treating a patient who speaks a different language than that of the practitioner. When family members are used as interpreters, there are risks that the patient may not fully disclose facts about the history of illness or specific symptoms, and also that family members may place their own “twist” on the story when translating.

The physician should speak directly to the patient in a normal tone of voice. In this setting, also remember that nonverbal communication can be misinterpreted. Gestures should be avoided. Finally, be aware that personal space is viewed differently depending on cultural background, as is eye contact.

It is helpful to have a pre-interview meeting with the interpreter to explain the format of the interview, as well as a post-interview meeting to ensure all parties felt they effectively communicated during the encounter.

TOWARD EQUITABLE CARE

Health care disparities are the result of multiple determinants. In December 2008, a National Institutes of Health summit conference cited not only barriers to access, but also the interaction of biological, behavioral, social, environmental, economic, cultural, and political factors, and noted that the causes and effects of health disparities transcend health care.²⁶

Clearly, an individual physician’s efforts will not be all that is needed to eliminate health disparities. A team-based approach is essential, using skills of nonphysician members of the health care team such as nurses, medical assistants, social workers, and case managers. Continued opportunity for professional training and development in provider-patient communication skills should be offered.

However, the impact of effective cross-cultural communication and managing low health literacy populations on the physician-patient level should not be understated. As practitioners treating patients from diverse backgrounds, improving self-awareness, eliciting the patient’s explanatory model, and assuring understanding of treatment plans for patients with low health literacy or with language barriers, we can do our part in working toward equitable care for all patients.

A 29-year-old woman with a history of frequent migraines presented to her primary care provider for a refill of medication. For the past two years she had been taking rizatriptan 10 mg, but with little relief. She stated that she had continued to experience discrete migraines several days per month, often clustered around menses. The severity of the headaches had negatively affected her work attendance, productivity, and social interactions. She wondered if she should be taking a different kind of medication.

The patient had been diagnosed with migraines at age 12, just prior to menarche. She described her headache as a unilateral, sharp throbbing pain associated with increased sensitivity to light and sound as well as nausea. She denied any history of head trauma. She had no allergies, and the only other medications she was taking at the time were an oral contraceptive (ethinyl estradiol/norgestimate 0.035 mg/0.18 mg with an oral triphasic 21/7 treatment cycle) and fluoxetine 20 mg for depression.

The patient worked daytime hours as a sales representative. She considered herself active, exercised regularly, ate a balanced diet, and slept well. She consumed no more than two to four alcoholic drinks per month and denied the use of herbals, dietary supplements, tobacco, or illegal drugs.

The patient stated that her mother had frequent headaches but had never sought a medical explanation or treatment. She was unaware of any other family history of headaches, and there was no family history of cardiovascular disease. Her sister had been diagnosed with a prolactinoma at age 25. At age 26, the patient had undergone a pituitary protocol MRI of the head with and without contrast, with negative results.

On examination, the patient was alert and oriented with normal vital signs. Her pupils were equal and reactive to light, and no papilledema was evident on fundoscopic examination. The cranial nerves were grossly intact and no other neurologic deficits were appreciated. No carotid bruits were present on cardiovascular exam.

Based on the patient’s history and physical exam, she met the International Classification of Headache Disorders (ICHD-II)¹ diagnostic criteria for migraine without aura (1.1). When asked to recall the onset and frequency of attacks she had had in the previous four weeks, she noted that they regularly occurred during her menstrual cycle.

She was subsequently asked to begin a diary to record her headache characteristics, severity, and duration, with days of menstruation noted. The Migraine Disability Assessment (MIDAS) questionnaire² (see Tables 1 and 2²) was performed to measure the migraine attacks’ impact on the patient’s life; her score indicated that the headaches were causing her severe disability.

The patient’s abortive migraine medication was changed from rizatriptan 10 mg to the combination sumatriptan/naproxen sodium 85 mg/500 mg. She was instructed to take the initial dose as soon as she noticed signs of an impending migraine and to repeat the dose in two hours if symptoms persisted. The possibility of starting a preventive medication was discussed, but the patient wanted to evaluate her response to the combination triptan/NSAID before considering migraine prophylaxis.

Three months later, the patient returned for follow-up, including a review of her headache diary. She stated that the frequency and intensity of attacks had not decreased; acute treatment with sumatriptan/naproxen sodium made her headaches more bearable but did not ameliorate symptoms. The patient had recorded a detailed account of each migraine which, based on the ICHD-II criteria,¹ demonstrated a pattern of headache occurrences consistent with menstrually related migraine. She reported a total of 18 headaches in the previous three months, 12 of which had occurred within the five-day perimenstrual period (see Figure 1).

Based on this information and the fact that the patient’s headaches were resistant to previous treatments, it was decided to alter the approach to her migraine management once more. In an effort to limit estrogen fluctuations during her menstrual cycle, her oral contraceptive was changed from ethinyl estradiol/norgestimate to a 12-week placebo-free monophasic regimen of ethinyl estradiol/levonorgestrel 20 mg/90 mcg. For intermittent prophylaxis, she was instructed to take frovatriptan 2.5 mg twice daily, beginning two days prior to the start of menses and continuing through the last day of her cycle. For acute treatment of breakthrough migraines, she was prescribed sumatriptan 20-mg nasal spray to take at the first sign of migraine symptoms and instructed to repeat the dose if the pain persisted or returned.

The patient continued to track her headaches in the diary and was seen in the office after three months of following the revised menstrual migraine management plan. She reported fewer migraines associated with her menstrual cycle and noted that they were less severe and shorter in duration. When she repeated the MIDAS test, her score was reduced from 23 to 10. In the subsequent nine months she has reported a consistent decrease in migraine prevalence and now rarely needs the abortive therapy.

DISCUSSION
Migraine, though commonly encountered in clinical practice, is a complex disorder. For women, migraine headaches have been recognized by the World Health Organization as the 12th leading cause of “life lived with a disabling condition.”³ Pure menstrual migraine and menstrually related migraine will be the focus of discussion here.

Etiology
Menstrually related migraine (comparable to pure menstrual migraine, although the latter is distinguished by occurring only during the perimenstrual period¹) is recognized as a distinct type of migraine associated with perimenstrual hormone fluctuations.⁴ Of women who experience migraine, 42% to 61% can associate their attacks with the perimenstrual period⁵; this is defined as two days before to three days after the start of menstruation.

It has also been determined that women are more likely to have migraine attacks during the late luteal and early follicular phases (when there is a natural drop in estrogen levels) than in other phases (when estrogen levels are higher).⁶ Despite clinical evidence to support this estrogen withdrawal theory, the pathophysiology is not completely understood. It is possible that affected women are more sensitive than other women to the decrease in estrogen levels that occurs with menstruation.⁷

History and Physical Findings of Menstrual Migraines
Almost every woman with perimenstrual migraines reports an absence of aura.⁷ In the evaluation of headache, the same criteria for migraine without aura pertain to the classifications of pure menstrual migraine (PMM) or menstrually related migraine (MRM).¹ Correlation of migraine attacks to the onset of menses is the key finding in the patient history to differentiate menstrual migraine from migraine without aura in women.⁸ Furthermore, perimenstrual migraines are often of longer duration and more difficult to treat than migraines not associated with hormone fluctuations.⁹

In order to distinguish between PMM and MRM, it is important to understand that pure menstrual migraine attacks take place exclusively in the five-day perimenstrual window and at no other times of the cycle. The criteria for MRM allow for attacks at other times of the cycle.¹

In addition to causing physical pain, menstrual migraines can impact work performance, household activities, and personal relationships. The MIDAS questionnaire is a disability assessment tool that can reveal to the practitioner how migraines have affected the patient’s life over the previous three months.¹⁰ This is a useful method to identify patients with disabling migraines, determine their need for treatment, and monitor treatment efficacy.

Diagnosis
Menstrual migraine is a clinical diagnosis made by findings from the patient’s history. The International Headache Society has established specific diagnostic criteria in the ICHD-II for both PMM and MRM.¹ An accurate and detailed migraine history is invaluable for the diagnosis of menstrual migraine. Although a formal questionnaire can serve as a good screening tool, it relies on the patient’s ability to recall specific times and dates with accuracy.¹¹ Recall bias can be misleading in any attempt to confirm a diagnosis. The patient’s conscientious use of a daily headache diary or calendar (see Figure 2, for example) can lead to a precise record of the characteristics and timing of migraines, overcoming these obstacles.

Brain imaging is necessary if the patient’s symptoms suggest a critical etiology that requires immediate diagnosis and management. Red flags include sudden onset of a severe headache, a headache characterized as “the worst headache of the patient’s life,” a change in headache pattern, altered mental status, an abnormal neurologic examination, or fever with neck stiffness.¹²

Treatment Options for Menstrual Migraine
There is no FDA-approved treatment specific for menstrual migraines; however, medications used for management of nonmenstrual migraines are also those most commonly prescribed for women with menstrual migraine headaches.¹³ Because these headaches are frequently more severe and of longer duration than nonmenstrual migraine headaches, a combination of intermittent preventive therapy, hormone manipulation, and acute treatment strategies is often necessary.⁴

Acute therapy is aimed to treat migraine pain quickly and effectively with minimal adverse effects or need for additional medication. Triptans have been the mainstay of menstrual migraine treatment and have been proven effective for both acute attacks and prevention.⁴ Sumatriptan has a rapid onset of action and may be given orally as a 50- or 100-mg tablet, as a 6-mg subcutaneous injection, or as a 20-mg nasal spray.¹⁴

Abortive therapies are most effective when taken at the first sign of an attack. Patients can repeat the dose in two hours if the headache persists or recurs, to a maximum of two doses in 24 hours.¹⁵ Rizatriptan is another triptan used for acute treatment of menstrual migraine headaches. Its initial 10-mg dose can be repeated every two hours, to a maximum of 30 mg per 24 hours. NSAIDs, such as naproxen sodium, have also been recommended in acute migraine attacks. They seem to work synergistically with triptans, inhibiting prostaglandin synthesis and blocking neurogenic inflammation.¹⁵

Clinical study results have demonstrated superior pain relief and decreased migraine recurrence when a triptan and NSAID are used in combination, compared with use of either medication alone.⁴ A single-tablet formulation of sumatriptan 85 mg and naproxen sodium 500 mg may be considered for initial therapy in hard-to-treat patients.¹⁴ 

Preventive therapy should be considered when responsiveness to acute treatment is inadequate.⁴ Nonhormonal intermittent prophylactic treatment is recommended two days prior to the beginning of menses, continuing for five days.¹⁶ Longer-acting triptans, such as frova­triptan 2.5 mg and naratriptan 1.0 mg, dosed twice daily, have been demonstrated as effective in clinical trials when used during the perimenstrual period.^17,18

The advantage of short-term therapy over daily prophylaxis is the potential to avoid adverse effects seen with continuous exposure to the drug.³ However, successful therapy relies on consistency in menstruation, and therefore may not be ideal for women with irregular cycles or those with coexisting nonmenstrual migraines.¹⁶ Estrogen-based therapy is an option for these women and for those who have failed nonhormonal methods.¹⁹

The goal of hormone prophylaxis is to prevent or reduce the physiologic decline in estradiol that occurs in the late luteal phase.⁴ Clinical studies have been conducted using various hormonal strategies to maintain steady estradiol levels, all of which decreased migraine prevalence.¹⁹ Estrogen fluctuations can be minimized by eliminating the placebo week in traditional estrogen/progestin oral contraceptives to achieve an extended-cycle regimen, resembling that of the 12-week ethinyl estradiol/levonorgestrel formulation.¹⁹

Continuous use of combined oral contraceptives is also an option for relief of menstrual migraine. When cyclic or extended-cycle regimens allow for menses, supplemental estrogen (10- to 20-mg ethinyl estradiol) is recommended during the hormone-free week.¹⁴

CONCLUSION
Proper diagnosis of menstrual migraines, using screening tools and the MIDAS questionnaire, can help practitioners provide the most effective migraine management for their patients. The most important step toward a good prognosis is acknowledging menstrual migraine as a unique headache disorder and formulating a precise diagnosis in order to identify individually tailored treatment options. With proper identification and integrated acute and prophylactic treatment, women with menstrual migraines are able to lead a healthier, more satisfying life.

REFERENCES
1. International Headache Society. The International Classification of Headache Disorders. 2nd ed. Cephalalgia. 2004;24(suppl 1):1-160.

2. Stewart WF, Lipton RB, Dowson AJ, Sawyer J. Development and testing of the Migraine Disability Assessment (MIDAS) Questionnaire to assess headache-related disability. Neurology. 2001;56(6 suppl 1):S20-S28.

3. MacGregor EA. Perimenstrual headaches: unmet needs. Curr Pain Headache Rep. 2008;12(6):468-474.

4. Mannix LK. Menstrual-related pain conditions: dysmenorrhea and migraine. J Womens Health (Larchmt). 2008;17(5):879-891.

5. Martin VT. New theories in the pathogenesis of menstrual migraine. Curr Pain Headache Rep. 2008;12(6):453-462.

6. MacGregor EA. Migraine headache in perimenopausal and menopausal women. Curr Pain Headache Rep. 2009;13(5):399-403.

7. Martin VT, Wernke S, Mandell K, et al. Symptoms of premenstrual syndrome and their association with migraine headache. Headache. 2006; 46(1):125-137.

8. Martin VT, Behbehani M. Ovarian hormones and migraine headache: understanding mechanisms and pathogenesis—part 2. Headache. 2006;46(3):365-386.

9. Granella F, Sances G, Allais G, et al. Characteristics of menstrual and nonmenstrual attacks in women with menstrually related migraine referred to headache centres. Cephalalgia. 2004;24(9):707-716.

10. Hutchinson SL, Silberstein SD. Menstrual migraine: case studies of women with estrogen-related headaches. Headache. 2008;48 suppl 3:S131-S141.

11. Tepper SJ, Zatochill M, Szeto M, et al. Development of a simple menstrual migraine screening tool for obstetric and gynecology clinics: the Menstrual Migraine Assessment Tool. Headache. 2008; 48(10):1419-1425.

12. Marcus DA. Focus on primary care diagnosis and management of headache in women. Obstet Gynecol Surv. 1999;54(6):395-402.

13. Tepper SJ. Tailoring management strategies for the patient with menstrual migraine: focus on prevention and treatment. Headache. 2006;46(suppl 2):S61-S68.

14. Lay CL, Payne R. Recognition and treatment of menstrual migraine. Neurologist. 2007;13(4):197-204.

15. Henry KA, Cohen CI. Perimenstrual headache: treatment options. Curr Pain Headache Rep. 2009;13(1):82-88.

16. Calhoun AH. Estrogen-associated migraine. www.uptodate.com/contents/estrogen-associated-migraine. Accessed May 4, 2011.

17. Silberstein SD, Elkind AH, Schreiber C, et al. A randomized trial of frovatriptan for the intermittent prevention of menstrual migraine. Neurology. 2004;63:261-269.

18. Mannix LK, Savani N, Landy S, et al. Efficacy and tolerability of naratriptan for short-term prevention of menstrually related migraine: data from two randomized, double-blind, placebo-controlled studies. Headache. 2007;47(7):1037-1049.

19. Calhoun AH, Hutchinson S. Hormonal therapies for menstrual migraine. Curr Pain Headache Rep. 2009;13(5):381-385.

A 29-year-old woman with a history of frequent migraines presented to her primary care provider for a refill of medication. For the past two years she had been taking rizatriptan 10 mg, but with little relief. She stated that she had continued to experience discrete migraines several days per month, often clustered around menses. The severity of the headaches had negatively affected her work attendance, productivity, and social interactions. She wondered if she should be taking a different kind of medication.

The patient had been diagnosed with migraines at age 12, just prior to menarche. She described her headache as a unilateral, sharp throbbing pain associated with increased sensitivity to light and sound as well as nausea. She denied any history of head trauma. She had no allergies, and the only other medications she was taking at the time were an oral contraceptive (ethinyl estradiol/norgestimate 0.035 mg/0.18 mg with an oral triphasic 21/7 treatment cycle) and fluoxetine 20 mg for depression.

The patient worked daytime hours as a sales representative. She considered herself active, exercised regularly, ate a balanced diet, and slept well. She consumed no more than two to four alcoholic drinks per month and denied the use of herbals, dietary supplements, tobacco, or illegal drugs.

The patient stated that her mother had frequent headaches but had never sought a medical explanation or treatment. She was unaware of any other family history of headaches, and there was no family history of cardiovascular disease. Her sister had been diagnosed with a prolactinoma at age 25. At age 26, the patient had undergone a pituitary protocol MRI of the head with and without contrast, with negative results.

On examination, the patient was alert and oriented with normal vital signs. Her pupils were equal and reactive to light, and no papilledema was evident on fundoscopic examination. The cranial nerves were grossly intact and no other neurologic deficits were appreciated. No carotid bruits were present on cardiovascular exam.

Based on the patient’s history and physical exam, she met the International Classification of Headache Disorders (ICHD-II)¹ diagnostic criteria for migraine without aura (1.1). When asked to recall the onset and frequency of attacks she had had in the previous four weeks, she noted that they regularly occurred during her menstrual cycle.

She was subsequently asked to begin a diary to record her headache characteristics, severity, and duration, with days of menstruation noted. The Migraine Disability Assessment (MIDAS) questionnaire² (see Tables 1 and 2²) was performed to measure the migraine attacks’ impact on the patient’s life; her score indicated that the headaches were causing her severe disability.

The patient’s abortive migraine medication was changed from rizatriptan 10 mg to the combination sumatriptan/naproxen sodium 85 mg/500 mg. She was instructed to take the initial dose as soon as she noticed signs of an impending migraine and to repeat the dose in two hours if symptoms persisted. The possibility of starting a preventive medication was discussed, but the patient wanted to evaluate her response to the combination triptan/NSAID before considering migraine prophylaxis.

Three months later, the patient returned for follow-up, including a review of her headache diary. She stated that the frequency and intensity of attacks had not decreased; acute treatment with sumatriptan/naproxen sodium made her headaches more bearable but did not ameliorate symptoms. The patient had recorded a detailed account of each migraine which, based on the ICHD-II criteria,¹ demonstrated a pattern of headache occurrences consistent with menstrually related migraine. She reported a total of 18 headaches in the previous three months, 12 of which had occurred within the five-day perimenstrual period (see Figure 1).

Based on this information and the fact that the patient’s headaches were resistant to previous treatments, it was decided to alter the approach to her migraine management once more. In an effort to limit estrogen fluctuations during her menstrual cycle, her oral contraceptive was changed from ethinyl estradiol/norgestimate to a 12-week placebo-free monophasic regimen of ethinyl estradiol/levonorgestrel 20 mg/90 mcg. For intermittent prophylaxis, she was instructed to take frovatriptan 2.5 mg twice daily, beginning two days prior to the start of menses and continuing through the last day of her cycle. For acute treatment of breakthrough migraines, she was prescribed sumatriptan 20-mg nasal spray to take at the first sign of migraine symptoms and instructed to repeat the dose if the pain persisted or returned.

The patient continued to track her headaches in the diary and was seen in the office after three months of following the revised menstrual migraine management plan. She reported fewer migraines associated with her menstrual cycle and noted that they were less severe and shorter in duration. When she repeated the MIDAS test, her score was reduced from 23 to 10. In the subsequent nine months she has reported a consistent decrease in migraine prevalence and now rarely needs the abortive therapy.

DISCUSSION
Migraine, though commonly encountered in clinical practice, is a complex disorder. For women, migraine headaches have been recognized by the World Health Organization as the 12th leading cause of “life lived with a disabling condition.”³ Pure menstrual migraine and menstrually related migraine will be the focus of discussion here.

Etiology
Menstrually related migraine (comparable to pure menstrual migraine, although the latter is distinguished by occurring only during the perimenstrual period¹) is recognized as a distinct type of migraine associated with perimenstrual hormone fluctuations.⁴ Of women who experience migraine, 42% to 61% can associate their attacks with the perimenstrual period⁵; this is defined as two days before to three days after the start of menstruation.

It has also been determined that women are more likely to have migraine attacks during the late luteal and early follicular phases (when there is a natural drop in estrogen levels) than in other phases (when estrogen levels are higher).⁶ Despite clinical evidence to support this estrogen withdrawal theory, the pathophysiology is not completely understood. It is possible that affected women are more sensitive than other women to the decrease in estrogen levels that occurs with menstruation.⁷

History and Physical Findings of Menstrual Migraines
Almost every woman with perimenstrual migraines reports an absence of aura.⁷ In the evaluation of headache, the same criteria for migraine without aura pertain to the classifications of pure menstrual migraine (PMM) or menstrually related migraine (MRM).¹ Correlation of migraine attacks to the onset of menses is the key finding in the patient history to differentiate menstrual migraine from migraine without aura in women.⁸ Furthermore, perimenstrual migraines are often of longer duration and more difficult to treat than migraines not associated with hormone fluctuations.⁹

In order to distinguish between PMM and MRM, it is important to understand that pure menstrual migraine attacks take place exclusively in the five-day perimenstrual window and at no other times of the cycle. The criteria for MRM allow for attacks at other times of the cycle.¹

In addition to causing physical pain, menstrual migraines can impact work performance, household activities, and personal relationships. The MIDAS questionnaire is a disability assessment tool that can reveal to the practitioner how migraines have affected the patient’s life over the previous three months.¹⁰ This is a useful method to identify patients with disabling migraines, determine their need for treatment, and monitor treatment efficacy.

Diagnosis
Menstrual migraine is a clinical diagnosis made by findings from the patient’s history. The International Headache Society has established specific diagnostic criteria in the ICHD-II for both PMM and MRM.¹ An accurate and detailed migraine history is invaluable for the diagnosis of menstrual migraine. Although a formal questionnaire can serve as a good screening tool, it relies on the patient’s ability to recall specific times and dates with accuracy.¹¹ Recall bias can be misleading in any attempt to confirm a diagnosis. The patient’s conscientious use of a daily headache diary or calendar (see Figure 2, for example) can lead to a precise record of the characteristics and timing of migraines, overcoming these obstacles.

Brain imaging is necessary if the patient’s symptoms suggest a critical etiology that requires immediate diagnosis and management. Red flags include sudden onset of a severe headache, a headache characterized as “the worst headache of the patient’s life,” a change in headache pattern, altered mental status, an abnormal neurologic examination, or fever with neck stiffness.¹²

Treatment Options for Menstrual Migraine
There is no FDA-approved treatment specific for menstrual migraines; however, medications used for management of nonmenstrual migraines are also those most commonly prescribed for women with menstrual migraine headaches.¹³ Because these headaches are frequently more severe and of longer duration than nonmenstrual migraine headaches, a combination of intermittent preventive therapy, hormone manipulation, and acute treatment strategies is often necessary.⁴

Acute therapy is aimed to treat migraine pain quickly and effectively with minimal adverse effects or need for additional medication. Triptans have been the mainstay of menstrual migraine treatment and have been proven effective for both acute attacks and prevention.⁴ Sumatriptan has a rapid onset of action and may be given orally as a 50- or 100-mg tablet, as a 6-mg subcutaneous injection, or as a 20-mg nasal spray.¹⁴

Abortive therapies are most effective when taken at the first sign of an attack. Patients can repeat the dose in two hours if the headache persists or recurs, to a maximum of two doses in 24 hours.¹⁵ Rizatriptan is another triptan used for acute treatment of menstrual migraine headaches. Its initial 10-mg dose can be repeated every two hours, to a maximum of 30 mg per 24 hours. NSAIDs, such as naproxen sodium, have also been recommended in acute migraine attacks. They seem to work synergistically with triptans, inhibiting prostaglandin synthesis and blocking neurogenic inflammation.¹⁵

Clinical study results have demonstrated superior pain relief and decreased migraine recurrence when a triptan and NSAID are used in combination, compared with use of either medication alone.⁴ A single-tablet formulation of sumatriptan 85 mg and naproxen sodium 500 mg may be considered for initial therapy in hard-to-treat patients.¹⁴ 

Preventive therapy should be considered when responsiveness to acute treatment is inadequate.⁴ Nonhormonal intermittent prophylactic treatment is recommended two days prior to the beginning of menses, continuing for five days.¹⁶ Longer-acting triptans, such as frova­triptan 2.5 mg and naratriptan 1.0 mg, dosed twice daily, have been demonstrated as effective in clinical trials when used during the perimenstrual period.^17,18

The advantage of short-term therapy over daily prophylaxis is the potential to avoid adverse effects seen with continuous exposure to the drug.³ However, successful therapy relies on consistency in menstruation, and therefore may not be ideal for women with irregular cycles or those with coexisting nonmenstrual migraines.¹⁶ Estrogen-based therapy is an option for these women and for those who have failed nonhormonal methods.¹⁹

The goal of hormone prophylaxis is to prevent or reduce the physiologic decline in estradiol that occurs in the late luteal phase.⁴ Clinical studies have been conducted using various hormonal strategies to maintain steady estradiol levels, all of which decreased migraine prevalence.¹⁹ Estrogen fluctuations can be minimized by eliminating the placebo week in traditional estrogen/progestin oral contraceptives to achieve an extended-cycle regimen, resembling that of the 12-week ethinyl estradiol/levonorgestrel formulation.¹⁹

Continuous use of combined oral contraceptives is also an option for relief of menstrual migraine. When cyclic or extended-cycle regimens allow for menses, supplemental estrogen (10- to 20-mg ethinyl estradiol) is recommended during the hormone-free week.¹⁴

CONCLUSION
Proper diagnosis of menstrual migraines, using screening tools and the MIDAS questionnaire, can help practitioners provide the most effective migraine management for their patients. The most important step toward a good prognosis is acknowledging menstrual migraine as a unique headache disorder and formulating a precise diagnosis in order to identify individually tailored treatment options. With proper identification and integrated acute and prophylactic treatment, women with menstrual migraines are able to lead a healthier, more satisfying life.

REFERENCES
1. International Headache Society. The International Classification of Headache Disorders. 2nd ed. Cephalalgia. 2004;24(suppl 1):1-160.

2. Stewart WF, Lipton RB, Dowson AJ, Sawyer J. Development and testing of the Migraine Disability Assessment (MIDAS) Questionnaire to assess headache-related disability. Neurology. 2001;56(6 suppl 1):S20-S28.

3. MacGregor EA. Perimenstrual headaches: unmet needs. Curr Pain Headache Rep. 2008;12(6):468-474.

4. Mannix LK. Menstrual-related pain conditions: dysmenorrhea and migraine. J Womens Health (Larchmt). 2008;17(5):879-891.

5. Martin VT. New theories in the pathogenesis of menstrual migraine. Curr Pain Headache Rep. 2008;12(6):453-462.

6. MacGregor EA. Migraine headache in perimenopausal and menopausal women. Curr Pain Headache Rep. 2009;13(5):399-403.

7. Martin VT, Wernke S, Mandell K, et al. Symptoms of premenstrual syndrome and their association with migraine headache. Headache. 2006; 46(1):125-137.

8. Martin VT, Behbehani M. Ovarian hormones and migraine headache: understanding mechanisms and pathogenesis—part 2. Headache. 2006;46(3):365-386.

9. Granella F, Sances G, Allais G, et al. Characteristics of menstrual and nonmenstrual attacks in women with menstrually related migraine referred to headache centres. Cephalalgia. 2004;24(9):707-716.

10. Hutchinson SL, Silberstein SD. Menstrual migraine: case studies of women with estrogen-related headaches. Headache. 2008;48 suppl 3:S131-S141.

11. Tepper SJ, Zatochill M, Szeto M, et al. Development of a simple menstrual migraine screening tool for obstetric and gynecology clinics: the Menstrual Migraine Assessment Tool. Headache. 2008; 48(10):1419-1425.

12. Marcus DA. Focus on primary care diagnosis and management of headache in women. Obstet Gynecol Surv. 1999;54(6):395-402.

13. Tepper SJ. Tailoring management strategies for the patient with menstrual migraine: focus on prevention and treatment. Headache. 2006;46(suppl 2):S61-S68.

14. Lay CL, Payne R. Recognition and treatment of menstrual migraine. Neurologist. 2007;13(4):197-204.

15. Henry KA, Cohen CI. Perimenstrual headache: treatment options. Curr Pain Headache Rep. 2009;13(1):82-88.

16. Calhoun AH. Estrogen-associated migraine. www.uptodate.com/contents/estrogen-associated-migraine. Accessed May 4, 2011.

17. Silberstein SD, Elkind AH, Schreiber C, et al. A randomized trial of frovatriptan for the intermittent prevention of menstrual migraine. Neurology. 2004;63:261-269.

18. Mannix LK, Savani N, Landy S, et al. Efficacy and tolerability of naratriptan for short-term prevention of menstrually related migraine: data from two randomized, double-blind, placebo-controlled studies. Headache. 2007;47(7):1037-1049.

19. Calhoun AH, Hutchinson S. Hormonal therapies for menstrual migraine. Curr Pain Headache Rep. 2009;13(5):381-385.

A 29-year-old woman with a history of frequent migraines presented to her primary care provider for a refill of medication. For the past two years she had been taking rizatriptan 10 mg, but with little relief. She stated that she had continued to experience discrete migraines several days per month, often clustered around menses. The severity of the headaches had negatively affected her work attendance, productivity, and social interactions. She wondered if she should be taking a different kind of medication.

The patient had been diagnosed with migraines at age 12, just prior to menarche. She described her headache as a unilateral, sharp throbbing pain associated with increased sensitivity to light and sound as well as nausea. She denied any history of head trauma. She had no allergies, and the only other medications she was taking at the time were an oral contraceptive (ethinyl estradiol/norgestimate 0.035 mg/0.18 mg with an oral triphasic 21/7 treatment cycle) and fluoxetine 20 mg for depression.

The patient worked daytime hours as a sales representative. She considered herself active, exercised regularly, ate a balanced diet, and slept well. She consumed no more than two to four alcoholic drinks per month and denied the use of herbals, dietary supplements, tobacco, or illegal drugs.

The patient stated that her mother had frequent headaches but had never sought a medical explanation or treatment. She was unaware of any other family history of headaches, and there was no family history of cardiovascular disease. Her sister had been diagnosed with a prolactinoma at age 25. At age 26, the patient had undergone a pituitary protocol MRI of the head with and without contrast, with negative results.

On examination, the patient was alert and oriented with normal vital signs. Her pupils were equal and reactive to light, and no papilledema was evident on fundoscopic examination. The cranial nerves were grossly intact and no other neurologic deficits were appreciated. No carotid bruits were present on cardiovascular exam.

Based on the patient’s history and physical exam, she met the International Classification of Headache Disorders (ICHD-II)¹ diagnostic criteria for migraine without aura (1.1). When asked to recall the onset and frequency of attacks she had had in the previous four weeks, she noted that they regularly occurred during her menstrual cycle.

She was subsequently asked to begin a diary to record her headache characteristics, severity, and duration, with days of menstruation noted. The Migraine Disability Assessment (MIDAS) questionnaire² (see Tables 1 and 2²) was performed to measure the migraine attacks’ impact on the patient’s life; her score indicated that the headaches were causing her severe disability.

The patient’s abortive migraine medication was changed from rizatriptan 10 mg to the combination sumatriptan/naproxen sodium 85 mg/500 mg. She was instructed to take the initial dose as soon as she noticed signs of an impending migraine and to repeat the dose in two hours if symptoms persisted. The possibility of starting a preventive medication was discussed, but the patient wanted to evaluate her response to the combination triptan/NSAID before considering migraine prophylaxis.

Three months later, the patient returned for follow-up, including a review of her headache diary. She stated that the frequency and intensity of attacks had not decreased; acute treatment with sumatriptan/naproxen sodium made her headaches more bearable but did not ameliorate symptoms. The patient had recorded a detailed account of each migraine which, based on the ICHD-II criteria,¹ demonstrated a pattern of headache occurrences consistent with menstrually related migraine. She reported a total of 18 headaches in the previous three months, 12 of which had occurred within the five-day perimenstrual period (see Figure 1).

Based on this information and the fact that the patient’s headaches were resistant to previous treatments, it was decided to alter the approach to her migraine management once more. In an effort to limit estrogen fluctuations during her menstrual cycle, her oral contraceptive was changed from ethinyl estradiol/norgestimate to a 12-week placebo-free monophasic regimen of ethinyl estradiol/levonorgestrel 20 mg/90 mcg. For intermittent prophylaxis, she was instructed to take frovatriptan 2.5 mg twice daily, beginning two days prior to the start of menses and continuing through the last day of her cycle. For acute treatment of breakthrough migraines, she was prescribed sumatriptan 20-mg nasal spray to take at the first sign of migraine symptoms and instructed to repeat the dose if the pain persisted or returned.

The patient continued to track her headaches in the diary and was seen in the office after three months of following the revised menstrual migraine management plan. She reported fewer migraines associated with her menstrual cycle and noted that they were less severe and shorter in duration. When she repeated the MIDAS test, her score was reduced from 23 to 10. In the subsequent nine months she has reported a consistent decrease in migraine prevalence and now rarely needs the abortive therapy.

DISCUSSION
Migraine, though commonly encountered in clinical practice, is a complex disorder. For women, migraine headaches have been recognized by the World Health Organization as the 12th leading cause of “life lived with a disabling condition.”³ Pure menstrual migraine and menstrually related migraine will be the focus of discussion here.

Etiology
Menstrually related migraine (comparable to pure menstrual migraine, although the latter is distinguished by occurring only during the perimenstrual period¹) is recognized as a distinct type of migraine associated with perimenstrual hormone fluctuations.⁴ Of women who experience migraine, 42% to 61% can associate their attacks with the perimenstrual period⁵; this is defined as two days before to three days after the start of menstruation.

It has also been determined that women are more likely to have migraine attacks during the late luteal and early follicular phases (when there is a natural drop in estrogen levels) than in other phases (when estrogen levels are higher).⁶ Despite clinical evidence to support this estrogen withdrawal theory, the pathophysiology is not completely understood. It is possible that affected women are more sensitive than other women to the decrease in estrogen levels that occurs with menstruation.⁷

History and Physical Findings of Menstrual Migraines
Almost every woman with perimenstrual migraines reports an absence of aura.⁷ In the evaluation of headache, the same criteria for migraine without aura pertain to the classifications of pure menstrual migraine (PMM) or menstrually related migraine (MRM).¹ Correlation of migraine attacks to the onset of menses is the key finding in the patient history to differentiate menstrual migraine from migraine without aura in women.⁸ Furthermore, perimenstrual migraines are often of longer duration and more difficult to treat than migraines not associated with hormone fluctuations.⁹

In order to distinguish between PMM and MRM, it is important to understand that pure menstrual migraine attacks take place exclusively in the five-day perimenstrual window and at no other times of the cycle. The criteria for MRM allow for attacks at other times of the cycle.¹

In addition to causing physical pain, menstrual migraines can impact work performance, household activities, and personal relationships. The MIDAS questionnaire is a disability assessment tool that can reveal to the practitioner how migraines have affected the patient’s life over the previous three months.¹⁰ This is a useful method to identify patients with disabling migraines, determine their need for treatment, and monitor treatment efficacy.

Diagnosis
Menstrual migraine is a clinical diagnosis made by findings from the patient’s history. The International Headache Society has established specific diagnostic criteria in the ICHD-II for both PMM and MRM.¹ An accurate and detailed migraine history is invaluable for the diagnosis of menstrual migraine. Although a formal questionnaire can serve as a good screening tool, it relies on the patient’s ability to recall specific times and dates with accuracy.¹¹ Recall bias can be misleading in any attempt to confirm a diagnosis. The patient’s conscientious use of a daily headache diary or calendar (see Figure 2, for example) can lead to a precise record of the characteristics and timing of migraines, overcoming these obstacles.

Brain imaging is necessary if the patient’s symptoms suggest a critical etiology that requires immediate diagnosis and management. Red flags include sudden onset of a severe headache, a headache characterized as “the worst headache of the patient’s life,” a change in headache pattern, altered mental status, an abnormal neurologic examination, or fever with neck stiffness.¹²

Treatment Options for Menstrual Migraine
There is no FDA-approved treatment specific for menstrual migraines; however, medications used for management of nonmenstrual migraines are also those most commonly prescribed for women with menstrual migraine headaches.¹³ Because these headaches are frequently more severe and of longer duration than nonmenstrual migraine headaches, a combination of intermittent preventive therapy, hormone manipulation, and acute treatment strategies is often necessary.⁴

Acute therapy is aimed to treat migraine pain quickly and effectively with minimal adverse effects or need for additional medication. Triptans have been the mainstay of menstrual migraine treatment and have been proven effective for both acute attacks and prevention.⁴ Sumatriptan has a rapid onset of action and may be given orally as a 50- or 100-mg tablet, as a 6-mg subcutaneous injection, or as a 20-mg nasal spray.¹⁴

Abortive therapies are most effective when taken at the first sign of an attack. Patients can repeat the dose in two hours if the headache persists or recurs, to a maximum of two doses in 24 hours.¹⁵ Rizatriptan is another triptan used for acute treatment of menstrual migraine headaches. Its initial 10-mg dose can be repeated every two hours, to a maximum of 30 mg per 24 hours. NSAIDs, such as naproxen sodium, have also been recommended in acute migraine attacks. They seem to work synergistically with triptans, inhibiting prostaglandin synthesis and blocking neurogenic inflammation.¹⁵

Clinical study results have demonstrated superior pain relief and decreased migraine recurrence when a triptan and NSAID are used in combination, compared with use of either medication alone.⁴ A single-tablet formulation of sumatriptan 85 mg and naproxen sodium 500 mg may be considered for initial therapy in hard-to-treat patients.¹⁴ 

Preventive therapy should be considered when responsiveness to acute treatment is inadequate.⁴ Nonhormonal intermittent prophylactic treatment is recommended two days prior to the beginning of menses, continuing for five days.¹⁶ Longer-acting triptans, such as frova­triptan 2.5 mg and naratriptan 1.0 mg, dosed twice daily, have been demonstrated as effective in clinical trials when used during the perimenstrual period.^17,18

The advantage of short-term therapy over daily prophylaxis is the potential to avoid adverse effects seen with continuous exposure to the drug.³ However, successful therapy relies on consistency in menstruation, and therefore may not be ideal for women with irregular cycles or those with coexisting nonmenstrual migraines.¹⁶ Estrogen-based therapy is an option for these women and for those who have failed nonhormonal methods.¹⁹

The goal of hormone prophylaxis is to prevent or reduce the physiologic decline in estradiol that occurs in the late luteal phase.⁴ Clinical studies have been conducted using various hormonal strategies to maintain steady estradiol levels, all of which decreased migraine prevalence.¹⁹ Estrogen fluctuations can be minimized by eliminating the placebo week in traditional estrogen/progestin oral contraceptives to achieve an extended-cycle regimen, resembling that of the 12-week ethinyl estradiol/levonorgestrel formulation.¹⁹

Continuous use of combined oral contraceptives is also an option for relief of menstrual migraine. When cyclic or extended-cycle regimens allow for menses, supplemental estrogen (10- to 20-mg ethinyl estradiol) is recommended during the hormone-free week.¹⁴

CONCLUSION
Proper diagnosis of menstrual migraines, using screening tools and the MIDAS questionnaire, can help practitioners provide the most effective migraine management for their patients. The most important step toward a good prognosis is acknowledging menstrual migraine as a unique headache disorder and formulating a precise diagnosis in order to identify individually tailored treatment options. With proper identification and integrated acute and prophylactic treatment, women with menstrual migraines are able to lead a healthier, more satisfying life.

REFERENCES
1. International Headache Society. The International Classification of Headache Disorders. 2nd ed. Cephalalgia. 2004;24(suppl 1):1-160.

2. Stewart WF, Lipton RB, Dowson AJ, Sawyer J. Development and testing of the Migraine Disability Assessment (MIDAS) Questionnaire to assess headache-related disability. Neurology. 2001;56(6 suppl 1):S20-S28.

3. MacGregor EA. Perimenstrual headaches: unmet needs. Curr Pain Headache Rep. 2008;12(6):468-474.

4. Mannix LK. Menstrual-related pain conditions: dysmenorrhea and migraine. J Womens Health (Larchmt). 2008;17(5):879-891.

5. Martin VT. New theories in the pathogenesis of menstrual migraine. Curr Pain Headache Rep. 2008;12(6):453-462.

6. MacGregor EA. Migraine headache in perimenopausal and menopausal women. Curr Pain Headache Rep. 2009;13(5):399-403.

7. Martin VT, Wernke S, Mandell K, et al. Symptoms of premenstrual syndrome and their association with migraine headache. Headache. 2006; 46(1):125-137.

8. Martin VT, Behbehani M. Ovarian hormones and migraine headache: understanding mechanisms and pathogenesis—part 2. Headache. 2006;46(3):365-386.

9. Granella F, Sances G, Allais G, et al. Characteristics of menstrual and nonmenstrual attacks in women with menstrually related migraine referred to headache centres. Cephalalgia. 2004;24(9):707-716.

10. Hutchinson SL, Silberstein SD. Menstrual migraine: case studies of women with estrogen-related headaches. Headache. 2008;48 suppl 3:S131-S141.

11. Tepper SJ, Zatochill M, Szeto M, et al. Development of a simple menstrual migraine screening tool for obstetric and gynecology clinics: the Menstrual Migraine Assessment Tool. Headache. 2008; 48(10):1419-1425.

12. Marcus DA. Focus on primary care diagnosis and management of headache in women. Obstet Gynecol Surv. 1999;54(6):395-402.

13. Tepper SJ. Tailoring management strategies for the patient with menstrual migraine: focus on prevention and treatment. Headache. 2006;46(suppl 2):S61-S68.

14. Lay CL, Payne R. Recognition and treatment of menstrual migraine. Neurologist. 2007;13(4):197-204.

15. Henry KA, Cohen CI. Perimenstrual headache: treatment options. Curr Pain Headache Rep. 2009;13(1):82-88.

16. Calhoun AH. Estrogen-associated migraine. www.uptodate.com/contents/estrogen-associated-migraine. Accessed May 4, 2011.

17. Silberstein SD, Elkind AH, Schreiber C, et al. A randomized trial of frovatriptan for the intermittent prevention of menstrual migraine. Neurology. 2004;63:261-269.

18. Mannix LK, Savani N, Landy S, et al. Efficacy and tolerability of naratriptan for short-term prevention of menstrually related migraine: data from two randomized, double-blind, placebo-controlled studies. Headache. 2007;47(7):1037-1049.

19. Calhoun AH, Hutchinson S. Hormonal therapies for menstrual migraine. Curr Pain Headache Rep. 2009;13(5):381-385.

A 21-year-old woman presents with a history of recurrent renal stones. Her serum calcium level is 11.5 mg/dL (normal, 8.6 to 10.5 mg/dL); serum phosphorus, 2.4 mg/dL (2.5 to 4.8 mg/dL); intact parathyroid hormone (PTH), 198 pg/mL (7 to 53 pg/mL); and serum 25-hydroxyvitamin D [25(OH)D], 12.6 ng/mL (30 to 60 ng/mL). After six weeks of therapy with vitamin D (50,000 IU three times/week), the serum calcium level is 11 mg/dL; PTH, 164 pg/mL; and 25(OH)D, 28 ng/mL. With all lab results improved but still abnormal, what other information would be helpful?

With this particular case, the striking history is recurrent renal stones. Analysis of one of the stones to determine if they are calcium oxalate would be beneficial; however, a 24-hour urine calcium measurement would provide useful information about the potential cause of the renal stones. Vitamin D deficiency can cause mild hypercalcemia but can also mask underlying primary hyperparathyroidism—as it did in this case. A Tc-99 sestamibi parathyroid scan will often localize a parathyroid adenoma.

This patient’s 24-hour urine calcium was high, and her parathyroid scan suggested an adenoma in the left lower lobe of the thyroid. An experienced parathyroid surgeon was consulted, and surgical excision of a 1.5-cm parathyroid adenoma followed. The intraoperative PTH went from 183 to 39 pg/mL, and the intraoperative calcium from 11.6 to 9.2 mg/dL. There was no postoperative hypocalcemia.

Q: What is the differential diagnosis for hypercalcemia?

• Parathyroid adenoma or carcinoma

• Hypercalcemia of malignancy (eg, breast, lung, pancreas)

• Multiple myeloma

• Multiple endocrine neoplasia types 1 and 2

• Familial hypocalciuric hypercalcemia

• Excess 1,25 dihydroxy vitamin D [1,25(OH)2D] production: sarcoid or other granulomatous disorders, lymphomas

• Miscellaneous: immobilization, milk-alkali syndrome, and parenteral nutrition

• Drug-related: vitamin D deficiency or intoxication; use of thiazide diuretics or lithium

• Nonparathyroid endocrine causes: hyperthyroidism, pheo­chromocytoma, Addison’s disease, islet cell tumors

Q: What are the clinical manifestations of hypercalcemia?

Mild hypercalcemia is usually asymp­tomatic, especially if serum calcium is 10.5 to 11.5 mg/dL. Polyuria and polydypsia, renal stones, constipation, nausea, and weight loss are nonspecific symptoms. Decreased mental alertness and depression can be seen, especially if calcium is higher than 12 mg/dL. Bone pain, arthralgias, and decreased bone density can occur with longstanding hypercalcemia. ECG changes, including bradycardia, atrioventricular block, and short QT interval, are sometimes noted.

Q: What is the significance of familial hypocalciuric hypercalcemia (FHH)?   

Patients with this genetic disorder, which involves mutated calcium-sensor receptors, often have a mildly elevated PTH but may have a normal PTH in the presence of hypercalcemia. A 24-hour urine calcium level below 100 mg is indicative of FHH.

A calcium/creatinine clearance ratio (calculated as urine calcium/serum calcium divided by urine creatinine/serum creatinine) of < 0.01 is suggestive of FHH, particularly if there is a family history of mild hypercalcemia.

An important point is that parathyroid surgery is ineffective in these patients, and they seldom develop clinical symptoms or stones.

Q: Often, hypercalcemia is identified through routine labs. What diagnostic studies should be obtained with the initial work-up?

Since it is not uncommon to discover mild hypercalcemia on routine labs, it may be prudent to simply recheck serum calcium before launching into an extensive work-up. A comprehensive metabolic panel will give you the calcium, albumin, and serum protein. 

When serum albumin is reduced, a corrected calcium level is calculated by adding 0.8 mg/dL to the total calcium for every decrement of 1 g/dL in serum albumin below the reference value of 4 g/dL. Serum phosphate is often low, except in secondary hyperparathyroidism due to renal failure, in which case phosphate is high. Urine calcium excretion may be high or normal. 

A 25(OH)D level should also be obtained, as vitamin D deficiency is a common cause of hypercalcemia. Adequate vitamin D replacement will often correct the hypercalcemia; however, vitamin D deficiency may be masking underlying primary hyperparathyroidism. 

The PTH level will be high in primary hyperparathyroidism, although it is possible to have a normal intact PTH in patients who have had long-standing mild primary hyperparathyroidism. Secondary hyperparathyroidism due to vitamin D deficiency will also result in an elevated PTH.

A suppressed PTH level in the presence of severe hypercalcemia suggests nonparathyroid-mediated hypercalcemia, often due to malignancy. Hypercalcemia of malignancy is usually symptomatic and severe (≥ 15 mg/dL). 

Q: What other nonroutine studies should be considered in the work-up?

A 24-hour urine for calcium, phosphorus, and creatinine clearance, as well as a DXA bone density test, are important for making treatment decisions. A Tc-99 sestamibi parathyroid scan is important to localize a parathyroid adenoma.

Ultrasound of the neck may help to localize an enlarged parathyroid gland, especially if the scan is negative or equivocal. 

Q: What are the complications of untreated hypercalcemia?

These include renal stones and urinary tract infections; peptic ulcer; altered mental status; pancreatitis; and during pregnancy, neonatal hypocalcemia.

Q: What is the medical treatment for hypercalcemia?

For acute hypercalcemia, use IV fluids at a high rate, such as normal saline 2,000 cc/hr, unless contraindicated.

Bisphosphonates, such as IV zoledronic acid, are potent inhibitors of bone resorption of calcium and can temporarily treat hypercalcemia, especially in cases of malignancy or severe hyperparathyroidism. It is important to know that oral bisphosphonates are not effective in treating hypercalcemia.

Avoid thiazide diuretics, as well as vitamin A, vitamin D, and calcium supplements. Another caveat: In the face of vitamin D deficiency, correct the vitamin D level to 40 to 60 ng/dL. Patients with 1,25(OH)2D-mediated hypercalcemia should be treated with glucocorticoids (prednisone or IV hydrocortisone), as they decrease 1,25(OH)2D.

Cinacalcet is approved for treatment of secondary hyperparathyroidism due to chronic renal failure, parathyroid carcinoma, and severe hypercalcemia in patients with primary hyperparathyroidism who are unable to undergo parathyroidectomy. The mode of action of cinacalcet is by binding to the parathyroid glands’ extracellular calcium-sensing receptors (CaSRs) to increase their affinity for extracellular calcium and decrease PTH secretion production.

Q: What are the indications for surgical intervention?

Surgery is recommended for patients with kidney stones or bone disease or with notable symptoms; those who have osteoporosis (identified on DXA scan); patients younger than 50; and those with a glomerular filtration rate below 60 mL/min and calcium 1.0 mg/dL or more above the upper limit of normal. Surgical removal of a parathyroid adenoma usually results in a cure.

Q: What causes secondary hyperparathyroidism?

Chronic renal failure is usually the cause. Hyperphosphatemia and decreased 1,25(OH)2D produce a decrease in ionized calcium. The parathyroid glands are thus stimulated and enlarge.

Vitamin D deficiency is another common cause; it is corrected with adequate vitamin D replacement. Once the vitamin D level is corrected, additional calcium supplementation should be given.

Q: What is the prognosis of hypercalcemia?

Primary hyperparathyroidism is usually chronic and progressive unless surgically cured or medically corrected. The prognosis of hypercalcemia is directly related to the degree of renal impairment or the underlying cause, such as malignancy. The presence of pancreatitis increases the mortality rate.

Regular monitoring and follow-up are important, especially if there is a trend of worsening hypercalcemia and etiology has not been identified. Monitor calcium and albumin at least every three months and renal function at least every six months.

Furthermore, check the 24-hour urine calcium and order DXA bone density testing annually.           

SUGGESTED READING
American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons. AACE/AAES position statement on the diagnosis and management of primary hyperparathyroidism. Endocr Prac. 2005;11(1): 49-54.

McPhee SJ, Papadakis MA, eds. 2011 Current Medical Diagnosis and Treatment. McGraw Hill; 2011:1090-1097; 1098-1105; 1575-1579.

Jameson J, ed. Harrison’s Endocrinology. 2nd ed. McGraw Hill; 2010:367-378; 406-410; 411-442.

Brown SA. Hyperparathyroidism. In: Runge MS, Greganti MA, eds. Netter’s Internal Medicine. 2nd ed. Saunders; 2009:316-320.

Bilezikian JP, Khan AA, Potts JT Jr. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the Third International Workshop. J Clin Endocrinol Metab. 2009;94(2):335-339.

A 21-year-old woman presents with a history of recurrent renal stones. Her serum calcium level is 11.5 mg/dL (normal, 8.6 to 10.5 mg/dL); serum phosphorus, 2.4 mg/dL (2.5 to 4.8 mg/dL); intact parathyroid hormone (PTH), 198 pg/mL (7 to 53 pg/mL); and serum 25-hydroxyvitamin D [25(OH)D], 12.6 ng/mL (30 to 60 ng/mL). After six weeks of therapy with vitamin D (50,000 IU three times/week), the serum calcium level is 11 mg/dL; PTH, 164 pg/mL; and 25(OH)D, 28 ng/mL. With all lab results improved but still abnormal, what other information would be helpful?

With this particular case, the striking history is recurrent renal stones. Analysis of one of the stones to determine if they are calcium oxalate would be beneficial; however, a 24-hour urine calcium measurement would provide useful information about the potential cause of the renal stones. Vitamin D deficiency can cause mild hypercalcemia but can also mask underlying primary hyperparathyroidism—as it did in this case. A Tc-99 sestamibi parathyroid scan will often localize a parathyroid adenoma.

This patient’s 24-hour urine calcium was high, and her parathyroid scan suggested an adenoma in the left lower lobe of the thyroid. An experienced parathyroid surgeon was consulted, and surgical excision of a 1.5-cm parathyroid adenoma followed. The intraoperative PTH went from 183 to 39 pg/mL, and the intraoperative calcium from 11.6 to 9.2 mg/dL. There was no postoperative hypocalcemia.

Q: What is the differential diagnosis for hypercalcemia?

• Parathyroid adenoma or carcinoma

• Hypercalcemia of malignancy (eg, breast, lung, pancreas)

• Multiple myeloma

• Multiple endocrine neoplasia types 1 and 2

• Familial hypocalciuric hypercalcemia

• Excess 1,25 dihydroxy vitamin D [1,25(OH)2D] production: sarcoid or other granulomatous disorders, lymphomas

• Miscellaneous: immobilization, milk-alkali syndrome, and parenteral nutrition

• Drug-related: vitamin D deficiency or intoxication; use of thiazide diuretics or lithium

• Nonparathyroid endocrine causes: hyperthyroidism, pheo­chromocytoma, Addison’s disease, islet cell tumors

Q: What are the clinical manifestations of hypercalcemia?

Mild hypercalcemia is usually asymp­tomatic, especially if serum calcium is 10.5 to 11.5 mg/dL. Polyuria and polydypsia, renal stones, constipation, nausea, and weight loss are nonspecific symptoms. Decreased mental alertness and depression can be seen, especially if calcium is higher than 12 mg/dL. Bone pain, arthralgias, and decreased bone density can occur with longstanding hypercalcemia. ECG changes, including bradycardia, atrioventricular block, and short QT interval, are sometimes noted.

Q: What is the significance of familial hypocalciuric hypercalcemia (FHH)?   

Patients with this genetic disorder, which involves mutated calcium-sensor receptors, often have a mildly elevated PTH but may have a normal PTH in the presence of hypercalcemia. A 24-hour urine calcium level below 100 mg is indicative of FHH.

A calcium/creatinine clearance ratio (calculated as urine calcium/serum calcium divided by urine creatinine/serum creatinine) of < 0.01 is suggestive of FHH, particularly if there is a family history of mild hypercalcemia.

An important point is that parathyroid surgery is ineffective in these patients, and they seldom develop clinical symptoms or stones.

Q: Often, hypercalcemia is identified through routine labs. What diagnostic studies should be obtained with the initial work-up?

Since it is not uncommon to discover mild hypercalcemia on routine labs, it may be prudent to simply recheck serum calcium before launching into an extensive work-up. A comprehensive metabolic panel will give you the calcium, albumin, and serum protein. 

When serum albumin is reduced, a corrected calcium level is calculated by adding 0.8 mg/dL to the total calcium for every decrement of 1 g/dL in serum albumin below the reference value of 4 g/dL. Serum phosphate is often low, except in secondary hyperparathyroidism due to renal failure, in which case phosphate is high. Urine calcium excretion may be high or normal. 

A 25(OH)D level should also be obtained, as vitamin D deficiency is a common cause of hypercalcemia. Adequate vitamin D replacement will often correct the hypercalcemia; however, vitamin D deficiency may be masking underlying primary hyperparathyroidism. 

The PTH level will be high in primary hyperparathyroidism, although it is possible to have a normal intact PTH in patients who have had long-standing mild primary hyperparathyroidism. Secondary hyperparathyroidism due to vitamin D deficiency will also result in an elevated PTH.

A suppressed PTH level in the presence of severe hypercalcemia suggests nonparathyroid-mediated hypercalcemia, often due to malignancy. Hypercalcemia of malignancy is usually symptomatic and severe (≥ 15 mg/dL). 

Q: What other nonroutine studies should be considered in the work-up?

A 24-hour urine for calcium, phosphorus, and creatinine clearance, as well as a DXA bone density test, are important for making treatment decisions. A Tc-99 sestamibi parathyroid scan is important to localize a parathyroid adenoma.

Ultrasound of the neck may help to localize an enlarged parathyroid gland, especially if the scan is negative or equivocal. 

Q: What are the complications of untreated hypercalcemia?

These include renal stones and urinary tract infections; peptic ulcer; altered mental status; pancreatitis; and during pregnancy, neonatal hypocalcemia.

Q: What is the medical treatment for hypercalcemia?

For acute hypercalcemia, use IV fluids at a high rate, such as normal saline 2,000 cc/hr, unless contraindicated.

Bisphosphonates, such as IV zoledronic acid, are potent inhibitors of bone resorption of calcium and can temporarily treat hypercalcemia, especially in cases of malignancy or severe hyperparathyroidism. It is important to know that oral bisphosphonates are not effective in treating hypercalcemia.

Avoid thiazide diuretics, as well as vitamin A, vitamin D, and calcium supplements. Another caveat: In the face of vitamin D deficiency, correct the vitamin D level to 40 to 60 ng/dL. Patients with 1,25(OH)2D-mediated hypercalcemia should be treated with glucocorticoids (prednisone or IV hydrocortisone), as they decrease 1,25(OH)2D.

Cinacalcet is approved for treatment of secondary hyperparathyroidism due to chronic renal failure, parathyroid carcinoma, and severe hypercalcemia in patients with primary hyperparathyroidism who are unable to undergo parathyroidectomy. The mode of action of cinacalcet is by binding to the parathyroid glands’ extracellular calcium-sensing receptors (CaSRs) to increase their affinity for extracellular calcium and decrease PTH secretion production.

Q: What are the indications for surgical intervention?

Surgery is recommended for patients with kidney stones or bone disease or with notable symptoms; those who have osteoporosis (identified on DXA scan); patients younger than 50; and those with a glomerular filtration rate below 60 mL/min and calcium 1.0 mg/dL or more above the upper limit of normal. Surgical removal of a parathyroid adenoma usually results in a cure.

Q: What causes secondary hyperparathyroidism?

Chronic renal failure is usually the cause. Hyperphosphatemia and decreased 1,25(OH)2D produce a decrease in ionized calcium. The parathyroid glands are thus stimulated and enlarge.

Vitamin D deficiency is another common cause; it is corrected with adequate vitamin D replacement. Once the vitamin D level is corrected, additional calcium supplementation should be given.

Q: What is the prognosis of hypercalcemia?

Primary hyperparathyroidism is usually chronic and progressive unless surgically cured or medically corrected. The prognosis of hypercalcemia is directly related to the degree of renal impairment or the underlying cause, such as malignancy. The presence of pancreatitis increases the mortality rate.

Regular monitoring and follow-up are important, especially if there is a trend of worsening hypercalcemia and etiology has not been identified. Monitor calcium and albumin at least every three months and renal function at least every six months.

Furthermore, check the 24-hour urine calcium and order DXA bone density testing annually.           

SUGGESTED READING
American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons. AACE/AAES position statement on the diagnosis and management of primary hyperparathyroidism. Endocr Prac. 2005;11(1): 49-54.

McPhee SJ, Papadakis MA, eds. 2011 Current Medical Diagnosis and Treatment. McGraw Hill; 2011:1090-1097; 1098-1105; 1575-1579.

Jameson J, ed. Harrison’s Endocrinology. 2nd ed. McGraw Hill; 2010:367-378; 406-410; 411-442.

Brown SA. Hyperparathyroidism. In: Runge MS, Greganti MA, eds. Netter’s Internal Medicine. 2nd ed. Saunders; 2009:316-320.

Bilezikian JP, Khan AA, Potts JT Jr. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the Third International Workshop. J Clin Endocrinol Metab. 2009;94(2):335-339.

A 21-year-old woman presents with a history of recurrent renal stones. Her serum calcium level is 11.5 mg/dL (normal, 8.6 to 10.5 mg/dL); serum phosphorus, 2.4 mg/dL (2.5 to 4.8 mg/dL); intact parathyroid hormone (PTH), 198 pg/mL (7 to 53 pg/mL); and serum 25-hydroxyvitamin D [25(OH)D], 12.6 ng/mL (30 to 60 ng/mL). After six weeks of therapy with vitamin D (50,000 IU three times/week), the serum calcium level is 11 mg/dL; PTH, 164 pg/mL; and 25(OH)D, 28 ng/mL. With all lab results improved but still abnormal, what other information would be helpful?

With this particular case, the striking history is recurrent renal stones. Analysis of one of the stones to determine if they are calcium oxalate would be beneficial; however, a 24-hour urine calcium measurement would provide useful information about the potential cause of the renal stones. Vitamin D deficiency can cause mild hypercalcemia but can also mask underlying primary hyperparathyroidism—as it did in this case. A Tc-99 sestamibi parathyroid scan will often localize a parathyroid adenoma.

This patient’s 24-hour urine calcium was high, and her parathyroid scan suggested an adenoma in the left lower lobe of the thyroid. An experienced parathyroid surgeon was consulted, and surgical excision of a 1.5-cm parathyroid adenoma followed. The intraoperative PTH went from 183 to 39 pg/mL, and the intraoperative calcium from 11.6 to 9.2 mg/dL. There was no postoperative hypocalcemia.

Q: What is the differential diagnosis for hypercalcemia?

• Parathyroid adenoma or carcinoma

• Hypercalcemia of malignancy (eg, breast, lung, pancreas)

• Multiple myeloma

• Multiple endocrine neoplasia types 1 and 2

• Familial hypocalciuric hypercalcemia

• Excess 1,25 dihydroxy vitamin D [1,25(OH)2D] production: sarcoid or other granulomatous disorders, lymphomas

• Miscellaneous: immobilization, milk-alkali syndrome, and parenteral nutrition

• Drug-related: vitamin D deficiency or intoxication; use of thiazide diuretics or lithium

• Nonparathyroid endocrine causes: hyperthyroidism, pheo­chromocytoma, Addison’s disease, islet cell tumors

Q: What are the clinical manifestations of hypercalcemia?

Mild hypercalcemia is usually asymp­tomatic, especially if serum calcium is 10.5 to 11.5 mg/dL. Polyuria and polydypsia, renal stones, constipation, nausea, and weight loss are nonspecific symptoms. Decreased mental alertness and depression can be seen, especially if calcium is higher than 12 mg/dL. Bone pain, arthralgias, and decreased bone density can occur with longstanding hypercalcemia. ECG changes, including bradycardia, atrioventricular block, and short QT interval, are sometimes noted.

Q: What is the significance of familial hypocalciuric hypercalcemia (FHH)?   

Patients with this genetic disorder, which involves mutated calcium-sensor receptors, often have a mildly elevated PTH but may have a normal PTH in the presence of hypercalcemia. A 24-hour urine calcium level below 100 mg is indicative of FHH.

A calcium/creatinine clearance ratio (calculated as urine calcium/serum calcium divided by urine creatinine/serum creatinine) of < 0.01 is suggestive of FHH, particularly if there is a family history of mild hypercalcemia.

An important point is that parathyroid surgery is ineffective in these patients, and they seldom develop clinical symptoms or stones.

Q: Often, hypercalcemia is identified through routine labs. What diagnostic studies should be obtained with the initial work-up?

Since it is not uncommon to discover mild hypercalcemia on routine labs, it may be prudent to simply recheck serum calcium before launching into an extensive work-up. A comprehensive metabolic panel will give you the calcium, albumin, and serum protein. 

When serum albumin is reduced, a corrected calcium level is calculated by adding 0.8 mg/dL to the total calcium for every decrement of 1 g/dL in serum albumin below the reference value of 4 g/dL. Serum phosphate is often low, except in secondary hyperparathyroidism due to renal failure, in which case phosphate is high. Urine calcium excretion may be high or normal. 

A 25(OH)D level should also be obtained, as vitamin D deficiency is a common cause of hypercalcemia. Adequate vitamin D replacement will often correct the hypercalcemia; however, vitamin D deficiency may be masking underlying primary hyperparathyroidism. 

The PTH level will be high in primary hyperparathyroidism, although it is possible to have a normal intact PTH in patients who have had long-standing mild primary hyperparathyroidism. Secondary hyperparathyroidism due to vitamin D deficiency will also result in an elevated PTH.

A suppressed PTH level in the presence of severe hypercalcemia suggests nonparathyroid-mediated hypercalcemia, often due to malignancy. Hypercalcemia of malignancy is usually symptomatic and severe (≥ 15 mg/dL). 

Q: What other nonroutine studies should be considered in the work-up?

A 24-hour urine for calcium, phosphorus, and creatinine clearance, as well as a DXA bone density test, are important for making treatment decisions. A Tc-99 sestamibi parathyroid scan is important to localize a parathyroid adenoma.

Ultrasound of the neck may help to localize an enlarged parathyroid gland, especially if the scan is negative or equivocal. 

Q: What are the complications of untreated hypercalcemia?

These include renal stones and urinary tract infections; peptic ulcer; altered mental status; pancreatitis; and during pregnancy, neonatal hypocalcemia.

Q: What is the medical treatment for hypercalcemia?

For acute hypercalcemia, use IV fluids at a high rate, such as normal saline 2,000 cc/hr, unless contraindicated.

Bisphosphonates, such as IV zoledronic acid, are potent inhibitors of bone resorption of calcium and can temporarily treat hypercalcemia, especially in cases of malignancy or severe hyperparathyroidism. It is important to know that oral bisphosphonates are not effective in treating hypercalcemia.

Avoid thiazide diuretics, as well as vitamin A, vitamin D, and calcium supplements. Another caveat: In the face of vitamin D deficiency, correct the vitamin D level to 40 to 60 ng/dL. Patients with 1,25(OH)2D-mediated hypercalcemia should be treated with glucocorticoids (prednisone or IV hydrocortisone), as they decrease 1,25(OH)2D.

Cinacalcet is approved for treatment of secondary hyperparathyroidism due to chronic renal failure, parathyroid carcinoma, and severe hypercalcemia in patients with primary hyperparathyroidism who are unable to undergo parathyroidectomy. The mode of action of cinacalcet is by binding to the parathyroid glands’ extracellular calcium-sensing receptors (CaSRs) to increase their affinity for extracellular calcium and decrease PTH secretion production.

Q: What are the indications for surgical intervention?

Surgery is recommended for patients with kidney stones or bone disease or with notable symptoms; those who have osteoporosis (identified on DXA scan); patients younger than 50; and those with a glomerular filtration rate below 60 mL/min and calcium 1.0 mg/dL or more above the upper limit of normal. Surgical removal of a parathyroid adenoma usually results in a cure.

Q: What causes secondary hyperparathyroidism?

Chronic renal failure is usually the cause. Hyperphosphatemia and decreased 1,25(OH)2D produce a decrease in ionized calcium. The parathyroid glands are thus stimulated and enlarge.

Vitamin D deficiency is another common cause; it is corrected with adequate vitamin D replacement. Once the vitamin D level is corrected, additional calcium supplementation should be given.

Q: What is the prognosis of hypercalcemia?

Primary hyperparathyroidism is usually chronic and progressive unless surgically cured or medically corrected. The prognosis of hypercalcemia is directly related to the degree of renal impairment or the underlying cause, such as malignancy. The presence of pancreatitis increases the mortality rate.

Regular monitoring and follow-up are important, especially if there is a trend of worsening hypercalcemia and etiology has not been identified. Monitor calcium and albumin at least every three months and renal function at least every six months.

Furthermore, check the 24-hour urine calcium and order DXA bone density testing annually.           

SUGGESTED READING
American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons. AACE/AAES position statement on the diagnosis and management of primary hyperparathyroidism. Endocr Prac. 2005;11(1): 49-54.

McPhee SJ, Papadakis MA, eds. 2011 Current Medical Diagnosis and Treatment. McGraw Hill; 2011:1090-1097; 1098-1105; 1575-1579.

Jameson J, ed. Harrison’s Endocrinology. 2nd ed. McGraw Hill; 2010:367-378; 406-410; 411-442.

Brown SA. Hyperparathyroidism. In: Runge MS, Greganti MA, eds. Netter’s Internal Medicine. 2nd ed. Saunders; 2009:316-320.

Bilezikian JP, Khan AA, Potts JT Jr. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the Third International Workshop. J Clin Endocrinol Metab. 2009;94(2):335-339.