Cleveland Clinic Journal of Medicine

An acute kidney injury can result from a myriad of causes and pathogenic pathways. Of these, the two main categories are prerenal causes (eg, heart failure, volume depletion) and causes that are intrinsic to the kidney (eg, acute tubular necrosis). Together, these categories account for more than 70% of all cases.^1–3

While early intervention improves outcomes in both of these categories, the physician in the acute care setting must quickly distinguish between them, as their treatments differ. Similar clinical presentations along with confounding laboratory values make this distinction difficult. Furthermore, prolonged prerenal azotemia can eventually lead to acute tubular necrosis.

Therefore, several methods for distinguishing prerenal from intrinsic causes of acute kidney injury have been developed, including urinalysis, response to fluid challenge, the blood urea nitrogen-to-plasma creatinine ratio, levels of various urine electrolytes and biomarkers, and, the topics of our discussion here, the fractional excretion of sodium (FENa) and the fractional excretion of urea (FEU).⁴ While each method offers a unique picture of renal function, the validity of each may be affected by specific clinical factors.

In light of the frequent use of diuretics in inpatients and outpatients, a review of the utility of the FEU test is warranted. We will therefore present the theory behind the use of the FENa and the FEU for distinguishing intrinsic from prerenal causes of acute kidney injury, the relevant literature comparing the utility of these investigations, and our suggestions for clinical practice.

ACUTE KIDNEY INJURY DEFINED

Acute kidney injury (formerly called acute renal failure) describes an abrupt decline in renal function. Consensus definitions of it have been published and are gaining more widespread acceptance and use.^9,10 The current definition is¹⁰:

• An absolute increase in serum creatinine ≥ 0.3 mg/dL (26.4 μmol/L) in 48 hours, or
• A percentage increase in serum creatinine ≥ 50% in 48 hours, or
• Urine output < 0.5 mL/kg/hour for > 6 hours.

These clear criteria allow for earlier recognition and treatment of this condition.

Acute kidney injury is fairly common in hospitalized patients, with 172 to 620 cases per million patients per year.^11–14 Furthermore, hospitalized patients with acute kidney injury continue to have high rates of morbidity and death, especially those with more severe cases, in which the mortality rate remains as high as 40%.¹⁵

FRACTIONAL EXCRETION OF SODIUM

The FENa is a measure of the extraction of sodium and water from the glomerular filtrate. It is the ratio of the rate of sodium filtration (the urinary sodium concentration times the urinary flow rate, divided by the plasma sodium concentration) to the overall glomerular filtration rate, estimated by the renal filtration of creatinine. It can be calculated as the ratio of plasma creatinine to urine creatinine divided by the ratio of plasma sodium to urine sodium:

A euvolemic person with normal renal function and moderate salt intake in a steady state will have an FENa of approximately 1%.¹⁶

In 1976, Espinel¹⁷ originally showed that the FENa could be used during the oliguric phase in patients in acute renal failure to differentiate between prerenal acute kidney injury and acute tubular necrosis. Given the kidney’s ability to reabsorb more sodium during times of volume depletion, Espinel suggested that an FENa of less than 1% reflected normal sodium retention, indicating a prerenal cause, ie, diminished effective circulating volume. A value greater than 3% likely represented tubular damage, indicating that the nephrons were unable to properly reabsorb sodium.

The clinical utility of this index was apparent, as the management of prerenal azotemia and acute tubular necrosis differ.¹⁸ While both require fluid repletion, the risk of volume overload in acute tubular necrosis is high. Furthermore, acute tubular necrosis secondary to nephrotoxins could require hemodialysis to facilitate clearance of the offending agent.

The FENa test was subsequently validated in a number of studies in different populations and is still widely used.^19–21

Limitations to the use of the FENa have been noted in various clinical settings. Notably, it can be falsely depressed in a number of intrinsic renal conditions, such as contrast-induced nephropathy, rhabdomyolysis, and acute glomerulonephritis. Conversely, patients with prerenal acute kidney injury who take diuretics can have a falsely elevated value due to the pharmacologically induced renal excretion of sodium independent of volume status. This is commonly seen in patients on diuretic therapy with baseline low effective circulating volumes, such those with congestive heart failure and hepatic cirrhosis.

FRACTIONAL EXCRETION OF UREA

Urea is continuously produced in the liver as the end product of protein metabolism. It is a small, water-soluble molecule that freely passes across cell membranes and is therefore continuously filtered and excreted by the kidneys. Not merely a waste product, urea is also important in water balance and constitutes approximately half of the normal solute content of urine.²²

Urea’s excretion mechanisms are well characterized.^22,23 It is absorbed in the proximal tubule, the medullary loop of Henle, and the medullary collecting ducts via facilitated diffusion through specific urea transporters.²⁴ After being absorbed in the loop of Henle, urea is resecreted, a process that creates an osmotic gradient along the medulla that ultimately regulates urea excretion and reabsorption in the medullary collecting duct. Low-volume states are associated with decreased urea excretion due to a physiologic increase in antidiuretic hormone secretion, and the reverse is true for high-volume states.

The FEU has been recognized as a clinically useful tool. The correlation between serum and urine urea concentrations was investigated as early as 1904.²⁵ However, most studies during the ensuing century focused on the serum urea concentration or the creatinine-to-urea ratio as a measure of glomerular failure.^26–28 In 1992, Kaplan and Kohn²⁹ proposed that the FEU could be a useful measure for assessing renal dysfunction in acute kidney injury. Conceptually similar to the FENa, the FEU is calculated as:

An FEU less than 35% suggests a prerenal cause of acute kidney injury, while a value greater than 50% suggests an intrinsic one.

FRACTIONAL EXCRETION OF UREA VS FRACTIONAL EXCRETION OF SODIUM

Kaplan and Kohn (1992)

Kaplan and Kohn,²⁹ in their 1992 study, retrospectively analyzed 87 urine samples from 40 patients with renal dysfunction (not specifically acute kidney injury) thought to be secondary to volume depletion in which the FENa was discordant with the FEU.

Findings. Thirty-nine of the 40 patients treated with diuretics had a high FENa value. However, the FEU was low in all of these patients, leading the authors to conclude that the latter may be the more useful of the two indices in evaluating patients receiving diuretics who present with symptoms that suggest prerenal azotemia.

Limitations of the study. On closer inspection, these findings were not generalizable, for several reasons. First, the time that elapsed between administration of diuretics and evaluation of urinary electrolytes varied widely. Additionally, the study was a retrospective analysis of isolated urine specimens without clear correlation to a clinical patient or context. For these reasons, prospective analyses to investigate the utility of the fractional excretion of urea needed to be conducted.

Carvounis et al (2002)

Carvounis et al³⁰ prospectively evaluated the FENa and the FEU in 102 consecutive intensive care patients with acute kidney injury (defined as a serum creatinine concentration > 1.5 mg/dL or an increase of more than 0.5 mg/dL in less than 48 hours). Oliguria was not an inclusion criterion for the study, but patients with acute glomerulonephritis and obstructive nephropathy were excluded. The study grouped subjects into those with prerenal azotemia, prerenal azotemia plus diuretic use, or acute tubular necrosis on the basis of the clinical diagnosis of the attending nephrologist.

Findings. The FEU was more sensitive than the FENa in detecting prerenal azotemia, especially in those with prerenal azotemia who were receiving diuretics. Overall, the FEU had higher sensitivity and specificity for prerenal azotemia regardless of diuretic usage, and more importantly, the best overall positive and negative predictive value for detecting it (99% and 75% respectively).

These results indicate that, in patients given diuretics, the FENa fails to discriminate between prerenal azotemia and acute tubular necrosis. Conversely, the FEU was excellent in discriminating between all cases of prerenal azotemia and acute tubular necrosis irrespective of the use of diuretics. This has significant practical application, given the frequency of diuretic use in the hospital, particularly in intensive care patients.

Limitations of the study. While the findings supported the utility of the FEU, the study population was limited to intensive care patients. Furthermore, the authors did not report the statistical significance of their findings.³⁰

Pépin et al (2007)

Pépin et al⁸ performed a similar study, investigating the diagnostic utility of the FENa and the FEU in patients with acute kidney injury, with or without diuretic therapy.

The authors prospectively studied 99 consecutive patients confirmed by an independent nephrologist to have acute kidney injury (defined as an increase in serum creatinine of more than 30% over baseline values within less than 1 week) due to either volume depletion or ischemia. They excluded patients with less common causes of acute kidney injury, such as rhabdomyolysis, obstructive nephropathy, adrenal insufficiency, acute glomerulonephritis, and nephrotoxic acute kidney injury, as well as patients with chronic kidney disease.

Patients were grouped into those with transient acute kidney injury (from decreased kidney perfusion) and persistent acute kidney injury (attributed to acute tubular necrosis), with or without diuretic therapy, according to predefined clinical criteria. They were considered to have diuretic exposure if they had received furosemide (Lasix) within 24 hours or a thiazide within 48 hours of sampling.

Findings. The FENa proved superior to the FEU in patients not taking diuretics and, contrary to the findings of Carvounis et al,³⁰ exhibited diagnostic utility in patients taking diuretics as well. Neither index discriminated between the different etiologies exceptionally well, however.

Of note, the study population was more inclusive than in previous studies, with only 63 intensive care patients, thus making the results more generalizable to all cases of inpatient acute kidney injury. Furthermore, the study included patients with and without oliguria, and the sensitivity and specificity of both the FENa and the FEU were higher in the nonoliguric group (n = 25).

Limitations of the study. The authors admit that a long time may have elapsed between diuretic administration and urine measurements, thereby mitigating the diuretic’s natriuretic effect independent of the patient’s volume status. While this variable may account for the better performance of the FENa than in the other studies, it does not account for the poor performance of the FEU.

Additionally, few of the findings reached statistical significance.

Lastly, a high percentage (30%) of patients had sepsis. The FEU is less effective in patients with infection, as cytokines interfere with the urea transporters in the kidney and colon.³¹

Lim et al (2009)

Lim et al³² conducted a study similar in design to that of Pépin et al.⁸

Findings. The FEU was as clinically useful as the FENa at distinguishing transient from persistent acute kidney injury in patients on diuretics. Using a cutoff FEU of less than 30% and a cutoff FENa of less than 1.5% for transient acute kidney injury (based on calculated receiver operating characteristic curves), FENa was more sensitive and specific than FEU in the nondiuretic groups. In patients exposed to diuretics, FEU was more sensitive but less specific than FENa.

FRACTIONAL EXCRETION OF UREA IN OLIGURIA

Diskin et al (2010)

In 2010, Diskin et al³³ published a prospective, observational study of 100 consecutive patients with oliguric azotemia referred to a nephrology service. They defined acute kidney injury as serum creatinine concentration greater than 1.9 mg/dL and urine output less than 100 mL in 24 hours. They used a higher FEU cutoff for prerenal azotemia of less than 40% to reflect the known urea secretion rate in oliguric patients (600 mL/24 hours). They used an FENa of less than 1% and greater than 3% to distinguish prerenal azotemia from acute tubular necrosis.

Findings. The FEU was more accurate than the FENa, giving the right diagnosis in 95% vs 54% of cases (P < .0001). The difference was exclusively due to the FEU’s greater utility in the 67 patients who had received diuretics (98% vs 49%, P < .0001). Both the FEU and the FENa accurately detected acute tubular necrosis. As expected, the FENa outperformed FEU in the setting of infection, in which cytokine stimulation interferes with urea excretion.

Limitations of the study. Approximately 80% of the patients had prerenal azotemia, potentially biasing the results toward a test geared toward detecting this condition. However, since prerenal causes are more common than intrinsic causes, the authors argued that their cohort more accurately reflected the population encountered in clinical practice.

Additionally, only patients with oliguria and more advanced kidney injury (serum creatinine > 1.9 mg/dL) were included in the study, potentially limiting the applicability of these results in patients with preserved urine output in the early stages of renal failure.

Table 2 summarizes the findings of the studies discussed above.^{8,15,30,32,33}

FRACTIONAL EXCRETION OF UREA IN CHILDREN AND THE ELDERLY

The FEU has also been validated in populations at the extremes of age.

In children, Fahimi et al³⁴ performed a cross-sectional study in 43 patients referred to a nephrology service because of acute kidney injury.

An FEU less than 35% had greater sensitivity and specificity than an FENa less than 1% for differentiating prerenal from intrinsic causes in pediatric populations. An FEU of less than 30% had an even greater power of distinguishing between the two. Interestingly, 15 of the 26 patients in the group with prerenal azotemia had an FENa greater than 1%, 8 of whom had an obvious cause (diuretic therapy in 5, salt-losing congenital adrenal hyperplasia in 2, and metabolic alkalosis in 1).

In elderly people, urinary indices are less reliable because of reduced sodium and urea reabsorption and urinary concentrating capability. Thus, the FENa and FEU are increased, making the standard cutoff values unreliable and unpredictable for distinguishing prerenal from intrinsic causes of acute kidney injury.³⁵

WHICH TEST SHOULD BE USED?

Both the FENa and the FEU have been validated in prospective trials as useful clinical indices in identifying prerenal azotemia. Results of these studies vary as to which index is superior and when. This may be attributable to the various definitions of acute kidney injury and diagnostic criteria used in the studies as well as the heterogeneity of patients in each study.

However, the preponderance of evidence indicates that the FEU is more useful than the FENa in patients on diuretics. Since diuretics are widely used, particularly in acute care settings in which acute kidney injury is prevalent, the FEU is a useful clinical tool and should be utilized in this context accordingly. Specifically, when there is a history of recent diuretic use, the evidence supports ordering the FEU alone, or at least in conjunction with the FENa. If the two indices yield disparate results, the physician should look for circumstances that would alter each one of them, such as sepsis or an unrecognized dose of diuretic.

In managing acute kidney injury, distinguishing prerenal from intrinsic causes is a difficult task, particularly because prolonged prerenal azotemia can develop into acute tubular necrosis. Therefore, a single index, calculated at a specific time, often is insufficient to properly characterize the pathogenesis of acute kidney injury, and a combination of both of these indices may increase diagnostic sensitivity and specificity.³⁶ Moreover, urine samples collected after acute changes in volume or osmolarity, such as blood loss, administration of intravenous fluids or parenteral nutrition, or dialysis may compromise their diagnostic utility, and care must be taken to interpret the results in the appropriate clinical context.

The clinician must be aware of both the respective applications and limitations of these indices when using them to guide management and navigate the differential diagnosis in the appropriate clinical settings.

An acute kidney injury can result from a myriad of causes and pathogenic pathways. Of these, the two main categories are prerenal causes (eg, heart failure, volume depletion) and causes that are intrinsic to the kidney (eg, acute tubular necrosis). Together, these categories account for more than 70% of all cases.^1–3

While early intervention improves outcomes in both of these categories, the physician in the acute care setting must quickly distinguish between them, as their treatments differ. Similar clinical presentations along with confounding laboratory values make this distinction difficult. Furthermore, prolonged prerenal azotemia can eventually lead to acute tubular necrosis.

Therefore, several methods for distinguishing prerenal from intrinsic causes of acute kidney injury have been developed, including urinalysis, response to fluid challenge, the blood urea nitrogen-to-plasma creatinine ratio, levels of various urine electrolytes and biomarkers, and, the topics of our discussion here, the fractional excretion of sodium (FENa) and the fractional excretion of urea (FEU).⁴ While each method offers a unique picture of renal function, the validity of each may be affected by specific clinical factors.

In light of the frequent use of diuretics in inpatients and outpatients, a review of the utility of the FEU test is warranted. We will therefore present the theory behind the use of the FENa and the FEU for distinguishing intrinsic from prerenal causes of acute kidney injury, the relevant literature comparing the utility of these investigations, and our suggestions for clinical practice.

ACUTE KIDNEY INJURY DEFINED

Acute kidney injury (formerly called acute renal failure) describes an abrupt decline in renal function. Consensus definitions of it have been published and are gaining more widespread acceptance and use.^9,10 The current definition is¹⁰:

• An absolute increase in serum creatinine ≥ 0.3 mg/dL (26.4 μmol/L) in 48 hours, or
• A percentage increase in serum creatinine ≥ 50% in 48 hours, or
• Urine output < 0.5 mL/kg/hour for > 6 hours.

These clear criteria allow for earlier recognition and treatment of this condition.

Acute kidney injury is fairly common in hospitalized patients, with 172 to 620 cases per million patients per year.^11–14 Furthermore, hospitalized patients with acute kidney injury continue to have high rates of morbidity and death, especially those with more severe cases, in which the mortality rate remains as high as 40%.¹⁵

FRACTIONAL EXCRETION OF SODIUM

The FENa is a measure of the extraction of sodium and water from the glomerular filtrate. It is the ratio of the rate of sodium filtration (the urinary sodium concentration times the urinary flow rate, divided by the plasma sodium concentration) to the overall glomerular filtration rate, estimated by the renal filtration of creatinine. It can be calculated as the ratio of plasma creatinine to urine creatinine divided by the ratio of plasma sodium to urine sodium:

A euvolemic person with normal renal function and moderate salt intake in a steady state will have an FENa of approximately 1%.¹⁶

In 1976, Espinel¹⁷ originally showed that the FENa could be used during the oliguric phase in patients in acute renal failure to differentiate between prerenal acute kidney injury and acute tubular necrosis. Given the kidney’s ability to reabsorb more sodium during times of volume depletion, Espinel suggested that an FENa of less than 1% reflected normal sodium retention, indicating a prerenal cause, ie, diminished effective circulating volume. A value greater than 3% likely represented tubular damage, indicating that the nephrons were unable to properly reabsorb sodium.

The clinical utility of this index was apparent, as the management of prerenal azotemia and acute tubular necrosis differ.¹⁸ While both require fluid repletion, the risk of volume overload in acute tubular necrosis is high. Furthermore, acute tubular necrosis secondary to nephrotoxins could require hemodialysis to facilitate clearance of the offending agent.

The FENa test was subsequently validated in a number of studies in different populations and is still widely used.^19–21

Limitations to the use of the FENa have been noted in various clinical settings. Notably, it can be falsely depressed in a number of intrinsic renal conditions, such as contrast-induced nephropathy, rhabdomyolysis, and acute glomerulonephritis. Conversely, patients with prerenal acute kidney injury who take diuretics can have a falsely elevated value due to the pharmacologically induced renal excretion of sodium independent of volume status. This is commonly seen in patients on diuretic therapy with baseline low effective circulating volumes, such those with congestive heart failure and hepatic cirrhosis.

FRACTIONAL EXCRETION OF UREA

Urea is continuously produced in the liver as the end product of protein metabolism. It is a small, water-soluble molecule that freely passes across cell membranes and is therefore continuously filtered and excreted by the kidneys. Not merely a waste product, urea is also important in water balance and constitutes approximately half of the normal solute content of urine.²²

Urea’s excretion mechanisms are well characterized.^22,23 It is absorbed in the proximal tubule, the medullary loop of Henle, and the medullary collecting ducts via facilitated diffusion through specific urea transporters.²⁴ After being absorbed in the loop of Henle, urea is resecreted, a process that creates an osmotic gradient along the medulla that ultimately regulates urea excretion and reabsorption in the medullary collecting duct. Low-volume states are associated with decreased urea excretion due to a physiologic increase in antidiuretic hormone secretion, and the reverse is true for high-volume states.

The FEU has been recognized as a clinically useful tool. The correlation between serum and urine urea concentrations was investigated as early as 1904.²⁵ However, most studies during the ensuing century focused on the serum urea concentration or the creatinine-to-urea ratio as a measure of glomerular failure.^26–28 In 1992, Kaplan and Kohn²⁹ proposed that the FEU could be a useful measure for assessing renal dysfunction in acute kidney injury. Conceptually similar to the FENa, the FEU is calculated as:

An FEU less than 35% suggests a prerenal cause of acute kidney injury, while a value greater than 50% suggests an intrinsic one.

FRACTIONAL EXCRETION OF UREA VS FRACTIONAL EXCRETION OF SODIUM

Kaplan and Kohn (1992)

Kaplan and Kohn,²⁹ in their 1992 study, retrospectively analyzed 87 urine samples from 40 patients with renal dysfunction (not specifically acute kidney injury) thought to be secondary to volume depletion in which the FENa was discordant with the FEU.

Findings. Thirty-nine of the 40 patients treated with diuretics had a high FENa value. However, the FEU was low in all of these patients, leading the authors to conclude that the latter may be the more useful of the two indices in evaluating patients receiving diuretics who present with symptoms that suggest prerenal azotemia.

Limitations of the study. On closer inspection, these findings were not generalizable, for several reasons. First, the time that elapsed between administration of diuretics and evaluation of urinary electrolytes varied widely. Additionally, the study was a retrospective analysis of isolated urine specimens without clear correlation to a clinical patient or context. For these reasons, prospective analyses to investigate the utility of the fractional excretion of urea needed to be conducted.

Carvounis et al (2002)

Carvounis et al³⁰ prospectively evaluated the FENa and the FEU in 102 consecutive intensive care patients with acute kidney injury (defined as a serum creatinine concentration > 1.5 mg/dL or an increase of more than 0.5 mg/dL in less than 48 hours). Oliguria was not an inclusion criterion for the study, but patients with acute glomerulonephritis and obstructive nephropathy were excluded. The study grouped subjects into those with prerenal azotemia, prerenal azotemia plus diuretic use, or acute tubular necrosis on the basis of the clinical diagnosis of the attending nephrologist.

Findings. The FEU was more sensitive than the FENa in detecting prerenal azotemia, especially in those with prerenal azotemia who were receiving diuretics. Overall, the FEU had higher sensitivity and specificity for prerenal azotemia regardless of diuretic usage, and more importantly, the best overall positive and negative predictive value for detecting it (99% and 75% respectively).

These results indicate that, in patients given diuretics, the FENa fails to discriminate between prerenal azotemia and acute tubular necrosis. Conversely, the FEU was excellent in discriminating between all cases of prerenal azotemia and acute tubular necrosis irrespective of the use of diuretics. This has significant practical application, given the frequency of diuretic use in the hospital, particularly in intensive care patients.

Limitations of the study. While the findings supported the utility of the FEU, the study population was limited to intensive care patients. Furthermore, the authors did not report the statistical significance of their findings.³⁰

Pépin et al (2007)

Pépin et al⁸ performed a similar study, investigating the diagnostic utility of the FENa and the FEU in patients with acute kidney injury, with or without diuretic therapy.

The authors prospectively studied 99 consecutive patients confirmed by an independent nephrologist to have acute kidney injury (defined as an increase in serum creatinine of more than 30% over baseline values within less than 1 week) due to either volume depletion or ischemia. They excluded patients with less common causes of acute kidney injury, such as rhabdomyolysis, obstructive nephropathy, adrenal insufficiency, acute glomerulonephritis, and nephrotoxic acute kidney injury, as well as patients with chronic kidney disease.

Patients were grouped into those with transient acute kidney injury (from decreased kidney perfusion) and persistent acute kidney injury (attributed to acute tubular necrosis), with or without diuretic therapy, according to predefined clinical criteria. They were considered to have diuretic exposure if they had received furosemide (Lasix) within 24 hours or a thiazide within 48 hours of sampling.

Findings. The FENa proved superior to the FEU in patients not taking diuretics and, contrary to the findings of Carvounis et al,³⁰ exhibited diagnostic utility in patients taking diuretics as well. Neither index discriminated between the different etiologies exceptionally well, however.

Of note, the study population was more inclusive than in previous studies, with only 63 intensive care patients, thus making the results more generalizable to all cases of inpatient acute kidney injury. Furthermore, the study included patients with and without oliguria, and the sensitivity and specificity of both the FENa and the FEU were higher in the nonoliguric group (n = 25).

Limitations of the study. The authors admit that a long time may have elapsed between diuretic administration and urine measurements, thereby mitigating the diuretic’s natriuretic effect independent of the patient’s volume status. While this variable may account for the better performance of the FENa than in the other studies, it does not account for the poor performance of the FEU.

Additionally, few of the findings reached statistical significance.

Lastly, a high percentage (30%) of patients had sepsis. The FEU is less effective in patients with infection, as cytokines interfere with the urea transporters in the kidney and colon.³¹

Lim et al (2009)

Lim et al³² conducted a study similar in design to that of Pépin et al.⁸

Findings. The FEU was as clinically useful as the FENa at distinguishing transient from persistent acute kidney injury in patients on diuretics. Using a cutoff FEU of less than 30% and a cutoff FENa of less than 1.5% for transient acute kidney injury (based on calculated receiver operating characteristic curves), FENa was more sensitive and specific than FEU in the nondiuretic groups. In patients exposed to diuretics, FEU was more sensitive but less specific than FENa.

FRACTIONAL EXCRETION OF UREA IN OLIGURIA

Diskin et al (2010)

In 2010, Diskin et al³³ published a prospective, observational study of 100 consecutive patients with oliguric azotemia referred to a nephrology service. They defined acute kidney injury as serum creatinine concentration greater than 1.9 mg/dL and urine output less than 100 mL in 24 hours. They used a higher FEU cutoff for prerenal azotemia of less than 40% to reflect the known urea secretion rate in oliguric patients (600 mL/24 hours). They used an FENa of less than 1% and greater than 3% to distinguish prerenal azotemia from acute tubular necrosis.

Findings. The FEU was more accurate than the FENa, giving the right diagnosis in 95% vs 54% of cases (P < .0001). The difference was exclusively due to the FEU’s greater utility in the 67 patients who had received diuretics (98% vs 49%, P < .0001). Both the FEU and the FENa accurately detected acute tubular necrosis. As expected, the FENa outperformed FEU in the setting of infection, in which cytokine stimulation interferes with urea excretion.

Limitations of the study. Approximately 80% of the patients had prerenal azotemia, potentially biasing the results toward a test geared toward detecting this condition. However, since prerenal causes are more common than intrinsic causes, the authors argued that their cohort more accurately reflected the population encountered in clinical practice.

Additionally, only patients with oliguria and more advanced kidney injury (serum creatinine > 1.9 mg/dL) were included in the study, potentially limiting the applicability of these results in patients with preserved urine output in the early stages of renal failure.

Table 2 summarizes the findings of the studies discussed above.^{8,15,30,32,33}

FRACTIONAL EXCRETION OF UREA IN CHILDREN AND THE ELDERLY

The FEU has also been validated in populations at the extremes of age.

In children, Fahimi et al³⁴ performed a cross-sectional study in 43 patients referred to a nephrology service because of acute kidney injury.

An FEU less than 35% had greater sensitivity and specificity than an FENa less than 1% for differentiating prerenal from intrinsic causes in pediatric populations. An FEU of less than 30% had an even greater power of distinguishing between the two. Interestingly, 15 of the 26 patients in the group with prerenal azotemia had an FENa greater than 1%, 8 of whom had an obvious cause (diuretic therapy in 5, salt-losing congenital adrenal hyperplasia in 2, and metabolic alkalosis in 1).

In elderly people, urinary indices are less reliable because of reduced sodium and urea reabsorption and urinary concentrating capability. Thus, the FENa and FEU are increased, making the standard cutoff values unreliable and unpredictable for distinguishing prerenal from intrinsic causes of acute kidney injury.³⁵

WHICH TEST SHOULD BE USED?

Both the FENa and the FEU have been validated in prospective trials as useful clinical indices in identifying prerenal azotemia. Results of these studies vary as to which index is superior and when. This may be attributable to the various definitions of acute kidney injury and diagnostic criteria used in the studies as well as the heterogeneity of patients in each study.

However, the preponderance of evidence indicates that the FEU is more useful than the FENa in patients on diuretics. Since diuretics are widely used, particularly in acute care settings in which acute kidney injury is prevalent, the FEU is a useful clinical tool and should be utilized in this context accordingly. Specifically, when there is a history of recent diuretic use, the evidence supports ordering the FEU alone, or at least in conjunction with the FENa. If the two indices yield disparate results, the physician should look for circumstances that would alter each one of them, such as sepsis or an unrecognized dose of diuretic.

In managing acute kidney injury, distinguishing prerenal from intrinsic causes is a difficult task, particularly because prolonged prerenal azotemia can develop into acute tubular necrosis. Therefore, a single index, calculated at a specific time, often is insufficient to properly characterize the pathogenesis of acute kidney injury, and a combination of both of these indices may increase diagnostic sensitivity and specificity.³⁶ Moreover, urine samples collected after acute changes in volume or osmolarity, such as blood loss, administration of intravenous fluids or parenteral nutrition, or dialysis may compromise their diagnostic utility, and care must be taken to interpret the results in the appropriate clinical context.

The clinician must be aware of both the respective applications and limitations of these indices when using them to guide management and navigate the differential diagnosis in the appropriate clinical settings.

An acute kidney injury can result from a myriad of causes and pathogenic pathways. Of these, the two main categories are prerenal causes (eg, heart failure, volume depletion) and causes that are intrinsic to the kidney (eg, acute tubular necrosis). Together, these categories account for more than 70% of all cases.^1–3

While early intervention improves outcomes in both of these categories, the physician in the acute care setting must quickly distinguish between them, as their treatments differ. Similar clinical presentations along with confounding laboratory values make this distinction difficult. Furthermore, prolonged prerenal azotemia can eventually lead to acute tubular necrosis.

Therefore, several methods for distinguishing prerenal from intrinsic causes of acute kidney injury have been developed, including urinalysis, response to fluid challenge, the blood urea nitrogen-to-plasma creatinine ratio, levels of various urine electrolytes and biomarkers, and, the topics of our discussion here, the fractional excretion of sodium (FENa) and the fractional excretion of urea (FEU).⁴ While each method offers a unique picture of renal function, the validity of each may be affected by specific clinical factors.

In light of the frequent use of diuretics in inpatients and outpatients, a review of the utility of the FEU test is warranted. We will therefore present the theory behind the use of the FENa and the FEU for distinguishing intrinsic from prerenal causes of acute kidney injury, the relevant literature comparing the utility of these investigations, and our suggestions for clinical practice.

ACUTE KIDNEY INJURY DEFINED

Acute kidney injury (formerly called acute renal failure) describes an abrupt decline in renal function. Consensus definitions of it have been published and are gaining more widespread acceptance and use.^9,10 The current definition is¹⁰:

• An absolute increase in serum creatinine ≥ 0.3 mg/dL (26.4 μmol/L) in 48 hours, or
• A percentage increase in serum creatinine ≥ 50% in 48 hours, or
• Urine output < 0.5 mL/kg/hour for > 6 hours.

These clear criteria allow for earlier recognition and treatment of this condition.

Acute kidney injury is fairly common in hospitalized patients, with 172 to 620 cases per million patients per year.^11–14 Furthermore, hospitalized patients with acute kidney injury continue to have high rates of morbidity and death, especially those with more severe cases, in which the mortality rate remains as high as 40%.¹⁵

FRACTIONAL EXCRETION OF SODIUM

The FENa is a measure of the extraction of sodium and water from the glomerular filtrate. It is the ratio of the rate of sodium filtration (the urinary sodium concentration times the urinary flow rate, divided by the plasma sodium concentration) to the overall glomerular filtration rate, estimated by the renal filtration of creatinine. It can be calculated as the ratio of plasma creatinine to urine creatinine divided by the ratio of plasma sodium to urine sodium:

A euvolemic person with normal renal function and moderate salt intake in a steady state will have an FENa of approximately 1%.¹⁶

In 1976, Espinel¹⁷ originally showed that the FENa could be used during the oliguric phase in patients in acute renal failure to differentiate between prerenal acute kidney injury and acute tubular necrosis. Given the kidney’s ability to reabsorb more sodium during times of volume depletion, Espinel suggested that an FENa of less than 1% reflected normal sodium retention, indicating a prerenal cause, ie, diminished effective circulating volume. A value greater than 3% likely represented tubular damage, indicating that the nephrons were unable to properly reabsorb sodium.

The clinical utility of this index was apparent, as the management of prerenal azotemia and acute tubular necrosis differ.¹⁸ While both require fluid repletion, the risk of volume overload in acute tubular necrosis is high. Furthermore, acute tubular necrosis secondary to nephrotoxins could require hemodialysis to facilitate clearance of the offending agent.

The FENa test was subsequently validated in a number of studies in different populations and is still widely used.^19–21

Limitations to the use of the FENa have been noted in various clinical settings. Notably, it can be falsely depressed in a number of intrinsic renal conditions, such as contrast-induced nephropathy, rhabdomyolysis, and acute glomerulonephritis. Conversely, patients with prerenal acute kidney injury who take diuretics can have a falsely elevated value due to the pharmacologically induced renal excretion of sodium independent of volume status. This is commonly seen in patients on diuretic therapy with baseline low effective circulating volumes, such those with congestive heart failure and hepatic cirrhosis.

FRACTIONAL EXCRETION OF UREA

Urea is continuously produced in the liver as the end product of protein metabolism. It is a small, water-soluble molecule that freely passes across cell membranes and is therefore continuously filtered and excreted by the kidneys. Not merely a waste product, urea is also important in water balance and constitutes approximately half of the normal solute content of urine.²²

Urea’s excretion mechanisms are well characterized.^22,23 It is absorbed in the proximal tubule, the medullary loop of Henle, and the medullary collecting ducts via facilitated diffusion through specific urea transporters.²⁴ After being absorbed in the loop of Henle, urea is resecreted, a process that creates an osmotic gradient along the medulla that ultimately regulates urea excretion and reabsorption in the medullary collecting duct. Low-volume states are associated with decreased urea excretion due to a physiologic increase in antidiuretic hormone secretion, and the reverse is true for high-volume states.

The FEU has been recognized as a clinically useful tool. The correlation between serum and urine urea concentrations was investigated as early as 1904.²⁵ However, most studies during the ensuing century focused on the serum urea concentration or the creatinine-to-urea ratio as a measure of glomerular failure.^26–28 In 1992, Kaplan and Kohn²⁹ proposed that the FEU could be a useful measure for assessing renal dysfunction in acute kidney injury. Conceptually similar to the FENa, the FEU is calculated as:

An FEU less than 35% suggests a prerenal cause of acute kidney injury, while a value greater than 50% suggests an intrinsic one.

FRACTIONAL EXCRETION OF UREA VS FRACTIONAL EXCRETION OF SODIUM

Kaplan and Kohn (1992)

Kaplan and Kohn,²⁹ in their 1992 study, retrospectively analyzed 87 urine samples from 40 patients with renal dysfunction (not specifically acute kidney injury) thought to be secondary to volume depletion in which the FENa was discordant with the FEU.

Findings. Thirty-nine of the 40 patients treated with diuretics had a high FENa value. However, the FEU was low in all of these patients, leading the authors to conclude that the latter may be the more useful of the two indices in evaluating patients receiving diuretics who present with symptoms that suggest prerenal azotemia.

Limitations of the study. On closer inspection, these findings were not generalizable, for several reasons. First, the time that elapsed between administration of diuretics and evaluation of urinary electrolytes varied widely. Additionally, the study was a retrospective analysis of isolated urine specimens without clear correlation to a clinical patient or context. For these reasons, prospective analyses to investigate the utility of the fractional excretion of urea needed to be conducted.

Carvounis et al (2002)

Carvounis et al³⁰ prospectively evaluated the FENa and the FEU in 102 consecutive intensive care patients with acute kidney injury (defined as a serum creatinine concentration > 1.5 mg/dL or an increase of more than 0.5 mg/dL in less than 48 hours). Oliguria was not an inclusion criterion for the study, but patients with acute glomerulonephritis and obstructive nephropathy were excluded. The study grouped subjects into those with prerenal azotemia, prerenal azotemia plus diuretic use, or acute tubular necrosis on the basis of the clinical diagnosis of the attending nephrologist.

Findings. The FEU was more sensitive than the FENa in detecting prerenal azotemia, especially in those with prerenal azotemia who were receiving diuretics. Overall, the FEU had higher sensitivity and specificity for prerenal azotemia regardless of diuretic usage, and more importantly, the best overall positive and negative predictive value for detecting it (99% and 75% respectively).

These results indicate that, in patients given diuretics, the FENa fails to discriminate between prerenal azotemia and acute tubular necrosis. Conversely, the FEU was excellent in discriminating between all cases of prerenal azotemia and acute tubular necrosis irrespective of the use of diuretics. This has significant practical application, given the frequency of diuretic use in the hospital, particularly in intensive care patients.

Limitations of the study. While the findings supported the utility of the FEU, the study population was limited to intensive care patients. Furthermore, the authors did not report the statistical significance of their findings.³⁰

Pépin et al (2007)

Pépin et al⁸ performed a similar study, investigating the diagnostic utility of the FENa and the FEU in patients with acute kidney injury, with or without diuretic therapy.

The authors prospectively studied 99 consecutive patients confirmed by an independent nephrologist to have acute kidney injury (defined as an increase in serum creatinine of more than 30% over baseline values within less than 1 week) due to either volume depletion or ischemia. They excluded patients with less common causes of acute kidney injury, such as rhabdomyolysis, obstructive nephropathy, adrenal insufficiency, acute glomerulonephritis, and nephrotoxic acute kidney injury, as well as patients with chronic kidney disease.

Patients were grouped into those with transient acute kidney injury (from decreased kidney perfusion) and persistent acute kidney injury (attributed to acute tubular necrosis), with or without diuretic therapy, according to predefined clinical criteria. They were considered to have diuretic exposure if they had received furosemide (Lasix) within 24 hours or a thiazide within 48 hours of sampling.

Findings. The FENa proved superior to the FEU in patients not taking diuretics and, contrary to the findings of Carvounis et al,³⁰ exhibited diagnostic utility in patients taking diuretics as well. Neither index discriminated between the different etiologies exceptionally well, however.

Of note, the study population was more inclusive than in previous studies, with only 63 intensive care patients, thus making the results more generalizable to all cases of inpatient acute kidney injury. Furthermore, the study included patients with and without oliguria, and the sensitivity and specificity of both the FENa and the FEU were higher in the nonoliguric group (n = 25).

Limitations of the study. The authors admit that a long time may have elapsed between diuretic administration and urine measurements, thereby mitigating the diuretic’s natriuretic effect independent of the patient’s volume status. While this variable may account for the better performance of the FENa than in the other studies, it does not account for the poor performance of the FEU.

Additionally, few of the findings reached statistical significance.

Lastly, a high percentage (30%) of patients had sepsis. The FEU is less effective in patients with infection, as cytokines interfere with the urea transporters in the kidney and colon.³¹

Lim et al (2009)

Lim et al³² conducted a study similar in design to that of Pépin et al.⁸

Findings. The FEU was as clinically useful as the FENa at distinguishing transient from persistent acute kidney injury in patients on diuretics. Using a cutoff FEU of less than 30% and a cutoff FENa of less than 1.5% for transient acute kidney injury (based on calculated receiver operating characteristic curves), FENa was more sensitive and specific than FEU in the nondiuretic groups. In patients exposed to diuretics, FEU was more sensitive but less specific than FENa.

FRACTIONAL EXCRETION OF UREA IN OLIGURIA

Diskin et al (2010)

In 2010, Diskin et al³³ published a prospective, observational study of 100 consecutive patients with oliguric azotemia referred to a nephrology service. They defined acute kidney injury as serum creatinine concentration greater than 1.9 mg/dL and urine output less than 100 mL in 24 hours. They used a higher FEU cutoff for prerenal azotemia of less than 40% to reflect the known urea secretion rate in oliguric patients (600 mL/24 hours). They used an FENa of less than 1% and greater than 3% to distinguish prerenal azotemia from acute tubular necrosis.

Findings. The FEU was more accurate than the FENa, giving the right diagnosis in 95% vs 54% of cases (P < .0001). The difference was exclusively due to the FEU’s greater utility in the 67 patients who had received diuretics (98% vs 49%, P < .0001). Both the FEU and the FENa accurately detected acute tubular necrosis. As expected, the FENa outperformed FEU in the setting of infection, in which cytokine stimulation interferes with urea excretion.

Limitations of the study. Approximately 80% of the patients had prerenal azotemia, potentially biasing the results toward a test geared toward detecting this condition. However, since prerenal causes are more common than intrinsic causes, the authors argued that their cohort more accurately reflected the population encountered in clinical practice.

Additionally, only patients with oliguria and more advanced kidney injury (serum creatinine > 1.9 mg/dL) were included in the study, potentially limiting the applicability of these results in patients with preserved urine output in the early stages of renal failure.

Table 2 summarizes the findings of the studies discussed above.^{8,15,30,32,33}

FRACTIONAL EXCRETION OF UREA IN CHILDREN AND THE ELDERLY

The FEU has also been validated in populations at the extremes of age.

In children, Fahimi et al³⁴ performed a cross-sectional study in 43 patients referred to a nephrology service because of acute kidney injury.

An FEU less than 35% had greater sensitivity and specificity than an FENa less than 1% for differentiating prerenal from intrinsic causes in pediatric populations. An FEU of less than 30% had an even greater power of distinguishing between the two. Interestingly, 15 of the 26 patients in the group with prerenal azotemia had an FENa greater than 1%, 8 of whom had an obvious cause (diuretic therapy in 5, salt-losing congenital adrenal hyperplasia in 2, and metabolic alkalosis in 1).

In elderly people, urinary indices are less reliable because of reduced sodium and urea reabsorption and urinary concentrating capability. Thus, the FENa and FEU are increased, making the standard cutoff values unreliable and unpredictable for distinguishing prerenal from intrinsic causes of acute kidney injury.³⁵

WHICH TEST SHOULD BE USED?

Both the FENa and the FEU have been validated in prospective trials as useful clinical indices in identifying prerenal azotemia. Results of these studies vary as to which index is superior and when. This may be attributable to the various definitions of acute kidney injury and diagnostic criteria used in the studies as well as the heterogeneity of patients in each study.

However, the preponderance of evidence indicates that the FEU is more useful than the FENa in patients on diuretics. Since diuretics are widely used, particularly in acute care settings in which acute kidney injury is prevalent, the FEU is a useful clinical tool and should be utilized in this context accordingly. Specifically, when there is a history of recent diuretic use, the evidence supports ordering the FEU alone, or at least in conjunction with the FENa. If the two indices yield disparate results, the physician should look for circumstances that would alter each one of them, such as sepsis or an unrecognized dose of diuretic.

In managing acute kidney injury, distinguishing prerenal from intrinsic causes is a difficult task, particularly because prolonged prerenal azotemia can develop into acute tubular necrosis. Therefore, a single index, calculated at a specific time, often is insufficient to properly characterize the pathogenesis of acute kidney injury, and a combination of both of these indices may increase diagnostic sensitivity and specificity.³⁶ Moreover, urine samples collected after acute changes in volume or osmolarity, such as blood loss, administration of intravenous fluids or parenteral nutrition, or dialysis may compromise their diagnostic utility, and care must be taken to interpret the results in the appropriate clinical context.

The clinician must be aware of both the respective applications and limitations of these indices when using them to guide management and navigate the differential diagnosis in the appropriate clinical settings.

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.