Did you know? When October 1 rolled around a short time ago, so did new codes for you to learn in the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM).

If you consider that unpleasant news for your billing efforts, I also have what I consider good news: The 2012 fiscal year is the final year for changes to ICD-9-CM codes: On October 1, 2013, the nation switches to 10^th Revision (that is, ICD-10-CM) codes. The National Center for Health Statistics has indicated that the only changes to ICD-9 codes permitted from now on are ones describing new diseases that require immediate reporting during this transition/freeze period.

This last set of changes isn’t as massive as what we saw in previous years. Nevertheless, the changes certainly enhance the ability of ObGyn practices to report the reasons for patient encounters.

The major gyn change this year involves reporting vaginal mesh complications. There are several new obstetric codes, too, to enhance reporting of cesarean delivery and management of high-risk OB conditions.

The new codes were added to the national code set on October 1. As in prior years, there is no grace period.

Changes to obstetric codes

ANTIPHOSPHOLIPID ANTIBODY

Antiphospholipid syndrome and lupus anticoagulant are associated with complications of pregnancy that include fetal loss, fetal growth restriction, preeclampsia, thrombosis, and autoimmune thrombocytopenia. Until now, the obstetrician reporting 649.3x (Coagulation defects complicating pregnancy, childbirth, or the puerperium), had only two secondary code options to further describe the patient’s condition: 795.79, used to report a finding of antiphospholipid antibody in a blood specimen, and 289.81, antiphospholipid antibody with hypercoagulable state.

A new code, 286.53 (Antiphospholipid antibody with hemorrhagic disorder), provides a third option when reporting 649.3x.

CHEMICAL PREGNANCY AND BLIGHTED OVUM

Fertility clinics and physicians who specialize in the use of assisted reproductive technology requested a code to identify patients who have what is referred to (imprecisely) as a “false-positive pregnancy,” “chemical pregnancy,” or “biochemical pregnancy.” These terms do not, however, accurately describe a pregnancy achieved using hormone stimulation or other such “chemical” methods.

In some cases, of course, a woman’s pregnancy test comes back positive, indicating a serum human chorionic gonadotropin (hCG) level, but, when she is followed with ultrasonography, no fetus is present—in effect, she has had an early miscarriage. But there has been no ICD-9 code to use at this stage that discriminates between confirmed ectopic pregnancy and confirmed miscarriage—only a code for a laboratory finding.

To improve the specificity of coding, therefore, and to track such pregnancies, existing code 631 (Other abnormal product of conception) has been expanded and divided in two:

Documentation by the physician that signals that 631.0 should be reported might include a reference to biochemical pregnancy, chemical pregnancy, or an inappropriate level of quantitative hCG for gestational age in early pregnancy. For 631.8 to be reported, documentation might mention such findings as a “blighted ovum” or “fleshy mole.”

Note: Because of this code expansion, the three-digit code 631 will no longer be a valid code for billing purposes.

ELECTIVE CESAREAN DELIVERY BEFORE 39 WEEKS’ GESTATION

ACOG requested new codes for elective cesarean delivery before 39 weeks’ gestation—a scenario that is one of the new markers of quality of care. Whereas ICD-9 has two diagnosis codes that mention cesarean delivery (654.2x, [Previous cesarean delivery not otherwise specified] and 669.71 [Cesarean delivery, without mention of indication]), neither code captures a case in which a woman presents in labor at 37 to 38 weeks’ gestation and the physician determines that it is best to deliver at that time rather than try to take measures that will forestall delivery until the 39th week.

Although ICD-9 already also has a code for early onset of delivery (644.21), it applies only to pregnancies before 37 completed weeks.

The new codes are:

Note: The new code has two options for a fifth digit:

• Reporting a fifth digit 1 indicates that the patient may, or may not, have had a complication in the antepartum period that is related to early onset of labor.
• Reporting a fifth digit 2 indicates that the patient developed a complication after delivery (but before discharge) that is related to the delivery.

For any hospitalization that results in a delivery, you must select a fifth digit 1 or 2; the choice depends on the overriding complication. You may not list code 649.8 twice—i.e., once with a fifth digit 1 and once with a fifth digit 2.

If the patient had a condition that was documented to be why cesarean delivery was medically indicated, list that as a secondary diagnosis—for example, cephalopelvic disproportion (653.4x) or prior cesarean delivery (654.2x).

SUPERVISION OF HIGH-RISK PREGNANCY

Code subcategory V23.4 (Pregnancy with other poor obstetric history) had only two coding options before October 1, 2011: V23.41 (Pregnancy with history of pre-term labor) and V23.49 (Pregnancy with other poor obstetric history).

Ectopic pregnancy. ACOG considers that it is important to track patients who had a prior ectopic pregnancy because such a history gives rise to an increased risk of ectopic pregnancy during the current pregnancy. Therefore, a new code for this status was requested by ACOG, and provided.

Note: Use the new history code only until the patient is confirmed not to have an ectopic pregnancy, if that is the outcome. Once you’ve confirmed that she has only a normal, intrauterine pregnancy, the risk posed by her history no longer has an impact on the current pregnancy. (ICD-9 rules direct you to report conditions that require active intervention or a change in routine care of the pregnancy—not conditions that merely exist without the need for intervention or additional monitoring.)

The new code is:

Fetal viability. There was also no specific code before October 1 to report the need for a sonogram to check fetal viability, especially when a previously confirmed pregnancy comes into question because of the apparent absence of a fetal heartbeat on examination of the mother. In such a case, an additional sonogram might be required beyond the initial scan to confirm fetal demise or a continuing viable pregnancy. Until now, either of these findings could have been reported only with codes that do not accurately describe the situation, such as 659.7 (Abnormality in fetal heart rate or rhythm); V28.89 (Other specified antenatal screening); and V23.89 (Other high-risk pregnancy).

The new code is:

Changes to gyn codes

COMPLICATIONS OF VAGINAL MESH

An effective surgical treatment for vaginal vault prolapse is sacrocolpopexy that uses a graft to suspend the upper vagina to the anterior longitudinal ligament of the sacrum. But, regrettably, synthetic graft material has also been associated with erosion of the mesh and subsequent pelvic infection (by erosion into surrounding organs or tissue). Exposure of the mesh in the vagina can also occur (see “Take this simplified approach to correcting exposure of vaginal mesh” in the July 2011 issue, available at obgmanagement.com).

Before October 1, erosion or exposure of mesh (without infection) would have been reported with code 996.39 (Mechanical complication of a genitourinary device, implant and graft) or 996.76 (Other complications due to genitourinary device, implant, and graft). With creation of a new subcategory code, 629.3 (Complication of implanted vaginal mesh and other prosthetic materials), however, these specific complications can be reported and tracked. The new codes also give you a specific linking diagnosis for revision of the mesh.

The two new codes are:

Note: If the patient’s graft material has caused fibrosis, hemorrhage, occlusion, or pain, continue to report 996.76. And, of course, any infection or inflammatory reaction caused by mesh is reported with existing code 996.65.

Because erosion and exposure can occur at the same time, it is proper to report both new codes, if that is the case.

HISTORY OF GESTATIONAL DIABETES

Code V12.2 (Personal history of endocrine, metabolic, and immunity disorders) has been expanded and divided into two five-digit codes:

With this change, four-digit code V12.2 became an invalid diagnosis code; your claim will be denied if you report it as the reason for an encounter.

Note: Code V12.21 may not be reported as a primary diagnosis for an obstetrical patient. Instead, a personal history that may be having an impact on the current pregnancy should be reported with a V23.xx code (Supervision of high risk pregnancy), until (and if) the patient develops a condition.

For example: If a patient had gestational diabetes during a prior pregnancy, she risks developing it again in the current pregnancy. In that case, report V23.49 (Pregnancy with other poor obstetric history) as the primary code and assign V12.21 as the secondary code.

LONG-TERM USE OF BISPHOSPHONATES

In a woman being treated to prevent loss of bone mass, the side-effect profile of the medication and the need to measure its effectiveness require regular follow-up visits. Effective October 1, code V58.68 (Long-term [current] use of bisphosphonates) should be reported for these follow-up visits. The code can be also used to support ordering follow-up bone densitometry.

Medications that might be applicable here are alendronate (Fosamax), ibandronate (Boniva), risedronate (Actonel), and zoledronic acid (Reclast).

We want to hear from you! Tell us what you think.

Did you know? When October 1 rolled around a short time ago, so did new codes for you to learn in the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM).

If you consider that unpleasant news for your billing efforts, I also have what I consider good news: The 2012 fiscal year is the final year for changes to ICD-9-CM codes: On October 1, 2013, the nation switches to 10^th Revision (that is, ICD-10-CM) codes. The National Center for Health Statistics has indicated that the only changes to ICD-9 codes permitted from now on are ones describing new diseases that require immediate reporting during this transition/freeze period.

This last set of changes isn’t as massive as what we saw in previous years. Nevertheless, the changes certainly enhance the ability of ObGyn practices to report the reasons for patient encounters.

The major gyn change this year involves reporting vaginal mesh complications. There are several new obstetric codes, too, to enhance reporting of cesarean delivery and management of high-risk OB conditions.

The new codes were added to the national code set on October 1. As in prior years, there is no grace period.

Changes to obstetric codes

ANTIPHOSPHOLIPID ANTIBODY

Antiphospholipid syndrome and lupus anticoagulant are associated with complications of pregnancy that include fetal loss, fetal growth restriction, preeclampsia, thrombosis, and autoimmune thrombocytopenia. Until now, the obstetrician reporting 649.3x (Coagulation defects complicating pregnancy, childbirth, or the puerperium), had only two secondary code options to further describe the patient’s condition: 795.79, used to report a finding of antiphospholipid antibody in a blood specimen, and 289.81, antiphospholipid antibody with hypercoagulable state.

A new code, 286.53 (Antiphospholipid antibody with hemorrhagic disorder), provides a third option when reporting 649.3x.

CHEMICAL PREGNANCY AND BLIGHTED OVUM

Fertility clinics and physicians who specialize in the use of assisted reproductive technology requested a code to identify patients who have what is referred to (imprecisely) as a “false-positive pregnancy,” “chemical pregnancy,” or “biochemical pregnancy.” These terms do not, however, accurately describe a pregnancy achieved using hormone stimulation or other such “chemical” methods.

In some cases, of course, a woman’s pregnancy test comes back positive, indicating a serum human chorionic gonadotropin (hCG) level, but, when she is followed with ultrasonography, no fetus is present—in effect, she has had an early miscarriage. But there has been no ICD-9 code to use at this stage that discriminates between confirmed ectopic pregnancy and confirmed miscarriage—only a code for a laboratory finding.

To improve the specificity of coding, therefore, and to track such pregnancies, existing code 631 (Other abnormal product of conception) has been expanded and divided in two:

Documentation by the physician that signals that 631.0 should be reported might include a reference to biochemical pregnancy, chemical pregnancy, or an inappropriate level of quantitative hCG for gestational age in early pregnancy. For 631.8 to be reported, documentation might mention such findings as a “blighted ovum” or “fleshy mole.”

Note: Because of this code expansion, the three-digit code 631 will no longer be a valid code for billing purposes.

ELECTIVE CESAREAN DELIVERY BEFORE 39 WEEKS’ GESTATION

ACOG requested new codes for elective cesarean delivery before 39 weeks’ gestation—a scenario that is one of the new markers of quality of care. Whereas ICD-9 has two diagnosis codes that mention cesarean delivery (654.2x, [Previous cesarean delivery not otherwise specified] and 669.71 [Cesarean delivery, without mention of indication]), neither code captures a case in which a woman presents in labor at 37 to 38 weeks’ gestation and the physician determines that it is best to deliver at that time rather than try to take measures that will forestall delivery until the 39th week.

Although ICD-9 already also has a code for early onset of delivery (644.21), it applies only to pregnancies before 37 completed weeks.

The new codes are:

Note: The new code has two options for a fifth digit:

• Reporting a fifth digit 1 indicates that the patient may, or may not, have had a complication in the antepartum period that is related to early onset of labor.
• Reporting a fifth digit 2 indicates that the patient developed a complication after delivery (but before discharge) that is related to the delivery.

For any hospitalization that results in a delivery, you must select a fifth digit 1 or 2; the choice depends on the overriding complication. You may not list code 649.8 twice—i.e., once with a fifth digit 1 and once with a fifth digit 2.

If the patient had a condition that was documented to be why cesarean delivery was medically indicated, list that as a secondary diagnosis—for example, cephalopelvic disproportion (653.4x) or prior cesarean delivery (654.2x).

SUPERVISION OF HIGH-RISK PREGNANCY

Code subcategory V23.4 (Pregnancy with other poor obstetric history) had only two coding options before October 1, 2011: V23.41 (Pregnancy with history of pre-term labor) and V23.49 (Pregnancy with other poor obstetric history).

Ectopic pregnancy. ACOG considers that it is important to track patients who had a prior ectopic pregnancy because such a history gives rise to an increased risk of ectopic pregnancy during the current pregnancy. Therefore, a new code for this status was requested by ACOG, and provided.

Note: Use the new history code only until the patient is confirmed not to have an ectopic pregnancy, if that is the outcome. Once you’ve confirmed that she has only a normal, intrauterine pregnancy, the risk posed by her history no longer has an impact on the current pregnancy. (ICD-9 rules direct you to report conditions that require active intervention or a change in routine care of the pregnancy—not conditions that merely exist without the need for intervention or additional monitoring.)

The new code is:

Fetal viability. There was also no specific code before October 1 to report the need for a sonogram to check fetal viability, especially when a previously confirmed pregnancy comes into question because of the apparent absence of a fetal heartbeat on examination of the mother. In such a case, an additional sonogram might be required beyond the initial scan to confirm fetal demise or a continuing viable pregnancy. Until now, either of these findings could have been reported only with codes that do not accurately describe the situation, such as 659.7 (Abnormality in fetal heart rate or rhythm); V28.89 (Other specified antenatal screening); and V23.89 (Other high-risk pregnancy).

The new code is:

Changes to gyn codes

COMPLICATIONS OF VAGINAL MESH

An effective surgical treatment for vaginal vault prolapse is sacrocolpopexy that uses a graft to suspend the upper vagina to the anterior longitudinal ligament of the sacrum. But, regrettably, synthetic graft material has also been associated with erosion of the mesh and subsequent pelvic infection (by erosion into surrounding organs or tissue). Exposure of the mesh in the vagina can also occur (see “Take this simplified approach to correcting exposure of vaginal mesh” in the July 2011 issue, available at obgmanagement.com).

Before October 1, erosion or exposure of mesh (without infection) would have been reported with code 996.39 (Mechanical complication of a genitourinary device, implant and graft) or 996.76 (Other complications due to genitourinary device, implant, and graft). With creation of a new subcategory code, 629.3 (Complication of implanted vaginal mesh and other prosthetic materials), however, these specific complications can be reported and tracked. The new codes also give you a specific linking diagnosis for revision of the mesh.

The two new codes are:

Note: If the patient’s graft material has caused fibrosis, hemorrhage, occlusion, or pain, continue to report 996.76. And, of course, any infection or inflammatory reaction caused by mesh is reported with existing code 996.65.

Because erosion and exposure can occur at the same time, it is proper to report both new codes, if that is the case.

HISTORY OF GESTATIONAL DIABETES

Code V12.2 (Personal history of endocrine, metabolic, and immunity disorders) has been expanded and divided into two five-digit codes:

With this change, four-digit code V12.2 became an invalid diagnosis code; your claim will be denied if you report it as the reason for an encounter.

Note: Code V12.21 may not be reported as a primary diagnosis for an obstetrical patient. Instead, a personal history that may be having an impact on the current pregnancy should be reported with a V23.xx code (Supervision of high risk pregnancy), until (and if) the patient develops a condition.

For example: If a patient had gestational diabetes during a prior pregnancy, she risks developing it again in the current pregnancy. In that case, report V23.49 (Pregnancy with other poor obstetric history) as the primary code and assign V12.21 as the secondary code.

LONG-TERM USE OF BISPHOSPHONATES

In a woman being treated to prevent loss of bone mass, the side-effect profile of the medication and the need to measure its effectiveness require regular follow-up visits. Effective October 1, code V58.68 (Long-term [current] use of bisphosphonates) should be reported for these follow-up visits. The code can be also used to support ordering follow-up bone densitometry.

Medications that might be applicable here are alendronate (Fosamax), ibandronate (Boniva), risedronate (Actonel), and zoledronic acid (Reclast).

We want to hear from you! Tell us what you think.

Did you know? When October 1 rolled around a short time ago, so did new codes for you to learn in the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM).

If you consider that unpleasant news for your billing efforts, I also have what I consider good news: The 2012 fiscal year is the final year for changes to ICD-9-CM codes: On October 1, 2013, the nation switches to 10^th Revision (that is, ICD-10-CM) codes. The National Center for Health Statistics has indicated that the only changes to ICD-9 codes permitted from now on are ones describing new diseases that require immediate reporting during this transition/freeze period.

This last set of changes isn’t as massive as what we saw in previous years. Nevertheless, the changes certainly enhance the ability of ObGyn practices to report the reasons for patient encounters.

The major gyn change this year involves reporting vaginal mesh complications. There are several new obstetric codes, too, to enhance reporting of cesarean delivery and management of high-risk OB conditions.

The new codes were added to the national code set on October 1. As in prior years, there is no grace period.

Changes to obstetric codes

ANTIPHOSPHOLIPID ANTIBODY

Antiphospholipid syndrome and lupus anticoagulant are associated with complications of pregnancy that include fetal loss, fetal growth restriction, preeclampsia, thrombosis, and autoimmune thrombocytopenia. Until now, the obstetrician reporting 649.3x (Coagulation defects complicating pregnancy, childbirth, or the puerperium), had only two secondary code options to further describe the patient’s condition: 795.79, used to report a finding of antiphospholipid antibody in a blood specimen, and 289.81, antiphospholipid antibody with hypercoagulable state.

A new code, 286.53 (Antiphospholipid antibody with hemorrhagic disorder), provides a third option when reporting 649.3x.

CHEMICAL PREGNANCY AND BLIGHTED OVUM

Fertility clinics and physicians who specialize in the use of assisted reproductive technology requested a code to identify patients who have what is referred to (imprecisely) as a “false-positive pregnancy,” “chemical pregnancy,” or “biochemical pregnancy.” These terms do not, however, accurately describe a pregnancy achieved using hormone stimulation or other such “chemical” methods.

In some cases, of course, a woman’s pregnancy test comes back positive, indicating a serum human chorionic gonadotropin (hCG) level, but, when she is followed with ultrasonography, no fetus is present—in effect, she has had an early miscarriage. But there has been no ICD-9 code to use at this stage that discriminates between confirmed ectopic pregnancy and confirmed miscarriage—only a code for a laboratory finding.

To improve the specificity of coding, therefore, and to track such pregnancies, existing code 631 (Other abnormal product of conception) has been expanded and divided in two:

Documentation by the physician that signals that 631.0 should be reported might include a reference to biochemical pregnancy, chemical pregnancy, or an inappropriate level of quantitative hCG for gestational age in early pregnancy. For 631.8 to be reported, documentation might mention such findings as a “blighted ovum” or “fleshy mole.”

Note: Because of this code expansion, the three-digit code 631 will no longer be a valid code for billing purposes.

ELECTIVE CESAREAN DELIVERY BEFORE 39 WEEKS’ GESTATION

ACOG requested new codes for elective cesarean delivery before 39 weeks’ gestation—a scenario that is one of the new markers of quality of care. Whereas ICD-9 has two diagnosis codes that mention cesarean delivery (654.2x, [Previous cesarean delivery not otherwise specified] and 669.71 [Cesarean delivery, without mention of indication]), neither code captures a case in which a woman presents in labor at 37 to 38 weeks’ gestation and the physician determines that it is best to deliver at that time rather than try to take measures that will forestall delivery until the 39th week.

Although ICD-9 already also has a code for early onset of delivery (644.21), it applies only to pregnancies before 37 completed weeks.

The new codes are:

Note: The new code has two options for a fifth digit:

• Reporting a fifth digit 1 indicates that the patient may, or may not, have had a complication in the antepartum period that is related to early onset of labor.
• Reporting a fifth digit 2 indicates that the patient developed a complication after delivery (but before discharge) that is related to the delivery.

For any hospitalization that results in a delivery, you must select a fifth digit 1 or 2; the choice depends on the overriding complication. You may not list code 649.8 twice—i.e., once with a fifth digit 1 and once with a fifth digit 2.

If the patient had a condition that was documented to be why cesarean delivery was medically indicated, list that as a secondary diagnosis—for example, cephalopelvic disproportion (653.4x) or prior cesarean delivery (654.2x).

SUPERVISION OF HIGH-RISK PREGNANCY

Code subcategory V23.4 (Pregnancy with other poor obstetric history) had only two coding options before October 1, 2011: V23.41 (Pregnancy with history of pre-term labor) and V23.49 (Pregnancy with other poor obstetric history).

Ectopic pregnancy. ACOG considers that it is important to track patients who had a prior ectopic pregnancy because such a history gives rise to an increased risk of ectopic pregnancy during the current pregnancy. Therefore, a new code for this status was requested by ACOG, and provided.

Note: Use the new history code only until the patient is confirmed not to have an ectopic pregnancy, if that is the outcome. Once you’ve confirmed that she has only a normal, intrauterine pregnancy, the risk posed by her history no longer has an impact on the current pregnancy. (ICD-9 rules direct you to report conditions that require active intervention or a change in routine care of the pregnancy—not conditions that merely exist without the need for intervention or additional monitoring.)

The new code is:

Fetal viability. There was also no specific code before October 1 to report the need for a sonogram to check fetal viability, especially when a previously confirmed pregnancy comes into question because of the apparent absence of a fetal heartbeat on examination of the mother. In such a case, an additional sonogram might be required beyond the initial scan to confirm fetal demise or a continuing viable pregnancy. Until now, either of these findings could have been reported only with codes that do not accurately describe the situation, such as 659.7 (Abnormality in fetal heart rate or rhythm); V28.89 (Other specified antenatal screening); and V23.89 (Other high-risk pregnancy).

The new code is:

Changes to gyn codes

COMPLICATIONS OF VAGINAL MESH

An effective surgical treatment for vaginal vault prolapse is sacrocolpopexy that uses a graft to suspend the upper vagina to the anterior longitudinal ligament of the sacrum. But, regrettably, synthetic graft material has also been associated with erosion of the mesh and subsequent pelvic infection (by erosion into surrounding organs or tissue). Exposure of the mesh in the vagina can also occur (see “Take this simplified approach to correcting exposure of vaginal mesh” in the July 2011 issue, available at obgmanagement.com).

Before October 1, erosion or exposure of mesh (without infection) would have been reported with code 996.39 (Mechanical complication of a genitourinary device, implant and graft) or 996.76 (Other complications due to genitourinary device, implant, and graft). With creation of a new subcategory code, 629.3 (Complication of implanted vaginal mesh and other prosthetic materials), however, these specific complications can be reported and tracked. The new codes also give you a specific linking diagnosis for revision of the mesh.

The two new codes are:

Note: If the patient’s graft material has caused fibrosis, hemorrhage, occlusion, or pain, continue to report 996.76. And, of course, any infection or inflammatory reaction caused by mesh is reported with existing code 996.65.

Because erosion and exposure can occur at the same time, it is proper to report both new codes, if that is the case.

HISTORY OF GESTATIONAL DIABETES

Code V12.2 (Personal history of endocrine, metabolic, and immunity disorders) has been expanded and divided into two five-digit codes:

With this change, four-digit code V12.2 became an invalid diagnosis code; your claim will be denied if you report it as the reason for an encounter.

Note: Code V12.21 may not be reported as a primary diagnosis for an obstetrical patient. Instead, a personal history that may be having an impact on the current pregnancy should be reported with a V23.xx code (Supervision of high risk pregnancy), until (and if) the patient develops a condition.

For example: If a patient had gestational diabetes during a prior pregnancy, she risks developing it again in the current pregnancy. In that case, report V23.49 (Pregnancy with other poor obstetric history) as the primary code and assign V12.21 as the secondary code.

LONG-TERM USE OF BISPHOSPHONATES

In a woman being treated to prevent loss of bone mass, the side-effect profile of the medication and the need to measure its effectiveness require regular follow-up visits. Effective October 1, code V58.68 (Long-term [current] use of bisphosphonates) should be reported for these follow-up visits. The code can be also used to support ordering follow-up bone densitometry.

Medications that might be applicable here are alendronate (Fosamax), ibandronate (Boniva), risedronate (Actonel), and zoledronic acid (Reclast).

We want to hear from you! Tell us what you think.

Endometriosis affects 7% to 10% of women in the United States, mostly during reproductive years.¹ The estimated annual cost for managing the approximately 10 million affected women? More than $17 billion.² The added cost of this chronic disease, with recurrences of pain and infertility, comes in the form of serious life disruption, emotional suffering, marital and social dysfunction, and diminished productivity.

Although the prevalence of endometriosis is highest during the third and fourth decades of life, the disease is also common in adolescent girls. Indeed, 45% of adolescents who have chronic pelvic pain are found to have endometriosis; if their pain does not respond to an oral contraceptive (OC) or a non-steroidal anti-inflammatory drug, 70% are subsequently found at laparoscopy to have endometriosis.³

What is it?

Endometriosis is the presence of functional endometrial tissue outside the uterus, such as eutopic endometrium. The disease responds to effects of cyclic ovarian hormones, proliferating and bleeding with each menstrual cycle, which often leads to diffuse inflammation, adhesions, and growth of endometriotic nodules or cysts (FIGURE 1).

FIGURE 1 Drainage will not suffice
Surgical management of ovarian endometriomas must go beyond simple drainage, which has little therapeutic value because symptoms recur and endometriomas re-form quickly after simple drainage in almost all patients.Symptoms tend to reflect affected organs:

• Because the pelvic organs are most often involved, the classic symptom triad of the disease comprises dysmenorrhea, dyspareunia, and infertility.
• Urinary urgency, dysuria, dyschezia, and tenesmus are frequent complaints when the bladder or rectosigmoid is involved.
• When distant organs are affected, such as the upper abdomen, diaphragm, lungs, and bowel, the patient may complain of respiratory symptoms, hemoptysis, pneumothorax, shoulder pain, upper abdominal pain, and episodic gastrointestinal dysfunction.

The hallmark of endometriosis is catamenial symptoms, which are usually cyclic and most severe around the time of menses. Clinical signs include palpable tender nodules and fibrosis on the anterior and posterior cul de sac, fixed retroverted or anteverted uterus, and adnexal cystic masses.

Because none of these symptoms or signs is specific for endometriosis, diagnosis relies on laparoscopy, which allows the surgeon to:

• visualize it in its various appearances and locations (FIGURE 2)
• confirm the diagnosis histologically with directed excisional biopsy
• treat it surgically with either excision or ablation.

In this article, we describe various surgical techniques for the management of endometriosis. Beyond resection or ablation of lesions, however, your care should also be directed to postoperative measures to prevent its recurrence and to avoid repeated surgical interventions—which, regrettably, are much too common in women who are afflicted by this enigmatic disease.

FIGURE 2 Endometriosis: A disease of varying appearance
Lesions of endometriosis can be pink, dark, clear, or white on the pelvic sidewall (A), bowel (B), and diaphragm (C); under the rib cage (D); and on the ureter (E) (left ureter shown here).

CASE Severe disease in a young woman

S. D. is a 22-year-old unmarried nulligravida who came to the emergency service complaining of acute onset of severe low abdominal pain, which developed while she was running. She was afebrile and in obvious distress, with diffuse lower abdominal tenderness and guarding, especially on the left side.

Ultrasonography revealed a 7-cm adnexal cystic mass suggestive of endometrioma (FIGURE 3).

Two years before this episode, S. D. underwent laparoscopic resection of a 5-cm endometrioma on the right ovary. Subsequently, she was treated with a cyclic OC, which she discontinued after 1 year because she was not sexually active.

The family history is positive for endometriosis in her mother, who had undergone multiple laparoscopic investigations and, eventually, total hysterectomy with bilateral salpingo-oophorectomy at 40 years of age.

S. D. was treated on the emergency service with analgesics and referred to you for surgical management.

S. D. has severe disease that requires aggressive surgical resection and a lifelong management plan. That plan includes liberal use of medical therapy to prevent recurrence of symptoms and avoid repeated surgical procedures—including the total hysterectomy with bilateral salpingo-oophorectomy that her mother underwent.

What is the best immediate treatment plan? Should you:

• drain the cyst?
• drain it and coagulate or ablate its wall?
• resect the wall of the cyst?
• perform salpingo-oophorectomy?

You also ask yourself: What is the risk of recurrence of endometrioma and its symptoms after each of those treatments? And how can I reduce those risks?

FIGURE 3 Endometrioma
Endometrioma on ultrasonography (A), with its characteristic homogeneous, echogenic appearance and “ground glass” pattern, and through the laparoscope (B). These images are from the patient whose case is described in the text.

Focal point: Ovary

The ovary is the most common organ affected by endometriosis. The presence of ovarian endometriomas, in 17% to 44% of patients who have this disease,⁴ is often associated with an advanced stage of disease.

In a population of 1,785 patients who were surgically treated for ovarian endometriosis, Redwine reported that only 1% had exclusively ovarian involvement; 99% also had diffuse pelvic disease,⁵ suggesting that ovarian endometrioma is a marker of extensive disease, which often requires a gynecologic surgeon who has advanced skills and experience in the surgical management of severe endometriosis.

Simple drainage is inadequate

Surgical management of ovarian endometrioma must go beyond simple drainage, which has little therapeutic value because symptoms recur and endometriomas re-form quickly after simple drainage in almost all patients.⁶ The currently accepted surgical management of endometrioma involves either 1) coagulation and ablation of the wall of the cyst with electrosurgery or laser or 2) removal of the cyst wall from the ovary with blunt and sharp dissection.

Several studies have compared these two techniques, but only two^7,8 were prospectively randomized.

Study #1. Beretta and co-workers⁷ studied 64 patients who had ovarian endometriomas larger than 3 cm and randomized them to cystectomy by complete stripping of the cyst wall or to drainage of fluid followed by electrocoagulation to ablate the endometriosis lesions within the cyst wall. The two groups were followed for 2 years to assess the recurrence of symptoms and the pregnancy rate in the patients who were infertile.

Recurrence of symptoms and the need for medical or surgical intervention occurred with less frequency and much later in the resection group than in the ablation group: 19 months, compared to 9.5 months, postoperatively. The cumulative pregnancy rate 24 months postoperatively was also much higher in the resection group (66.7%) than in the ablative group (23.5%).

Study #2. In a later study,⁸ Alborzi and colleagues randomized 100 patients who had endometrioma to cystectomy or to drainage and coagulation of the cyst wall. The mean recurrence rate, 2 years postoperatively, was much lower in the excision group (15.8%) than in the ablative group (56.7%). The cumulative pregnancy rate at 12 months was higher in the excision group (54.9%, compared to 23.3%). Furthermore, the reoperation rate at 24 months was much lower in the excision group (5.8%) than in the ablative group (22.9%).

These favorable results for cystectomy over ablation were validated by a Cochrane Review, which concluded that excision of endometriomas is the preferred approach because it provides 1) a more favorable outcome than drainage and ablation, 2) lower rates of recurrence of endometriomas and symptoms, and 3) a much higher spontaneous pregnancy rate in infertile women.⁹

Although resection of the cyst wall is technically more challenging and takes longer to perform than drainage and ablation, we exclusively perform resection rather than ablation of endometriomas because we believe that more lasting therapeutic effects and reduced recurrence of symptoms and disease justify the extra effort and a longer procedure.

Drawback of cystectomy

A potential risk of cystectomy is that it can diminish ovarian reserve and, in rare cases, induce premature menopause, which can be devastating for women whose main purpose for having surgery is to restore or improve their fertility.

The impact of laparoscopic ovarian cystectomy on ovarian reserve was prospectively studied by Chang and co-workers,¹⁰ who measured preoperative and postoperative levels of anti-müllerian hormone (AMH) in 13 women who had endometrioma, 6 who had mature teratoma, and 1 who had mucinous cystadenoma. One week postoperatively, the AMH level decreased significantly overall in all groups. At 4 and 12 weeks postoperatively, however, the AMH level returned to preoperative levels among subjects in the non-endometrioma group but not among subjects who had endometrioma; rather, their level remained statistically lower than the preoperative level during the entire 3 months of follow-up.

Stripping the wall of an endometrioma cyst is more difficult than it is for other benign cysts, such as cystic teratoma or cystadenoma, in which there usually is a well-defined dissection plane between the wall of the cyst and surrounding stromal tissue—allowing for easy and clean separation of the wall. The cyst wall of an endometrioma, on the other hand, is intimately attached to underlying ovarian stroma; lack of a clear cleavage plane between cyst and ovarian stroma often results in unintentional removal of layers of ovarian cortex with underlying follicles, which, in turn, may lead to a reduction in ovarian reserve.

Histologic analyses of resected endometrioma cyst walls have reported follicle-containing ovarian tissue attached to the stripped cyst wall in 54% of cases.^11,12 That observation explains why, and how, ovarian reserve can be compromised after resection of endometrioma.

Further risk: Ovarian failure

In rare cases, excision of endometriomas results in complete ovarian failure, described by Busacca and colleagues, who reported three cases of ovarian failure (2.4%) after resection of bilateral endometriomas in 126 patients.¹³ They attributed ovarian failure to excessive cauterization that compromised vascularization, as well as to excessive removal of ovarian tissue.

It is important, therefore, to strip the thinnest layer of the cyst capsule and to reduce the amount of electrocoagulation of ovarian stroma as much as possible to safeguard functional ovarian tissue.

CASE continued

S. D. was scheduled for laparoscopy to remove the endometrioma and other concurrent pelvic and peritoneal pathology, such as endometriosis and pelvic adhesions. You also scheduled her for hysteroscopy to evaluate the endometrial cavity for potential pathology, such as endometrial polyps and uterine septum, which appear to be more common in women who have endometriosis.

Nawroth and co-workers¹⁴ found a much higher incidence of endometriosis in patients who had a septate uterus. Metalliotakis and co-workers¹⁵ found congenital uterine malformations to be more common in patients who had endometriosis, compared with controls; uterine septum was, by far, the most common anomaly.

CASE continued

Hysteroscopy revealed a small and broad septum, which was resected sharply with hysteroscopic scissors (FIGURE 4). Laparoscopy revealed a 7-cm endometrioma on the left ovary, with adhesions to the posterior broad ligament and pelvic sidewall. S. D. also had deep implants of endometriosis on the left pelvic sidewall, the posterior cul de sac, the right pelvic sidewall, and the right ovary, which was cohesively adherent to the ovarian fossa.

As you expected, S. D. has stage-IV disease, according to the revised American Fertility Society Classification.

Following adhesiolysis, the endometrioma was resected (see VIDEO 1). Because of the large ovarian defect, the edges of the ovary were approximated with imbricating running 3-0 Vicryl suture. Deep endometriosis was also resected. Superficial endometriosis was peeled off or coagulated using bipolar forceps.

Note: Alternatively, and with comparable results, resection may be performed with a laser or other energy source. We prefer resection, rather than ablation, of deep endometriosis, but no data exists to support one technique over the other.

FIGURE 4 Septate uterus with deep cornua
Through the hysteroscope, a shallow septum is visible at the fundus of the uterus, dividing the upper endometrial cavity into two chambers (A), with deep cornua on the left (B) and right (C). Normal fundal anatomy is restored by septolysis along the avascular plane (D).

Technique: How we resect endometrioma

In removing endometrioma (see VIDEO 2), it is important to grasp the thinnest part of the cyst wall and progressively strip it, to avoid removing excess ovarian tissue and to reduce the risk of compromising ovarian reserve.

After draining the endometrioma of its chocolate-colored fluid, we irrigate and drain the cyst several times with warm lactated Ringers’ solution to promote separation of the cyst wall from underlying stroma and better identify the dissection plane. The cyst wall is inspected by introducing the laparoscope into the cyst to examine its surface, which is often laden with implants of deep and superficial endometriosis.

If we cannot easily identify the plane of dissection along the edges, we may evert the cyst and make an incision at its base to create a wedge between the wall of the cyst and underlying stroma. The edge of the incised wall is then grasped and retracted to create a space between the wall and the underlying stroma, from which it is progressively stripped from the ovary.

Traction and counter-traction are the hallmarks of dissection here; sometimes, we use laparoscopic scissors to sharply resect the ovarian stromal attachments that adhere cohesively to the cyst wall. This technique is continued until the entire cyst wall is removed. When follicle-containing ovarian tissue remains attached to the cyst wall, we introduce the closed tips of the Dolphin forceps between the cyst wall and adjacent follicle-containing stroma, spread the tips apart, and recover the true plane of dissection between the thin wall of the cyst and stroma.

After the wall of the cyst is removed, the ovarian crater invariably bleeds because blood vessels supplying the wall have been separated and opened. Utilizing warm lactated Ringers’ solution, we copiously irrigate the bleeding ovarian stroma to identify each bleeding vessel and, by placing the tips of the micro-bipolar forceps on either side of the bleeder, individually coagulate each vessel, thus inflicting minimal thermal damage to the surrounding stroma.

Pearl. Avoid using Kleppinger forceps to indiscriminately coagulate the bloody stroma in the crater created after the cystectomy, because doing so can result in excessive destruction of ovarian tissue or inadvertent coagulation of hylar vessels that would interrupt the blood supply to the ovary, compromising its function.¹⁶

Suturing. Some surgeons find that fenestration, drainage, and coagulation of the cyst wall is acceptable, but we have concerns not only about incomplete ablation of the endometriosis on the cyst wall, which may be responsible for the higher recurrence rate of disease, but also about the risk of thermal injury to underlying follicles, which may compromise ovarian reserve.¹⁶

Hemostasis. Once complete hemostasis has been achieved, the decision to approximate (or not) the edges, preferably with fine absorbable suture, is based on how large the defect is and whether or not the edges of the crater spontaneously come together. For large craters, we usually close the ovary with a 3-0 or 4-0 Vicryl continuous suture, imbricating the edges to expose as little suture material as possible to reduce postoperative formation of adhesions, which is common after ovarian surgery.¹⁷

Last, we ensure that hemostasis is present. Often we apply an anti-adhesion solution, such as icodextrin 4% (Adept). This agent has been shown to reduce postoperative adhesion formation, especially after laparoscopic surgery for endometriosis.¹⁸

A high level of skill is needed

Ovarian endometriomas signal advanced disease; advanced surgical skills are required to treat them adequately. Simple drainage is of little therapeutic value and should seldom be considered a treatment option. Although drainage plus ablation of the cyst wall ameliorates symptoms, excision of endometriomas should be considered preferable because it provides a more favorable outcome, a lower risk of recurrence of endometriomas and symptoms, and a higher rate of spontaneous pregnancy in previously infertile women.^7-9

To recap, we advise the surgeon to:

• Manage ovarian endometriomas with resection of the entire cyst wall, grasping and stripping the thinnest layer of the cyst wall without removing underlying functional ovarian stroma.
• Avoid excessive cauterization of the underlying ovarian stroma by utilizing micro-bipolar forceps and applying energy only around bleeding vessels.
• Close stromal defects, when the crater is large and its edges do not spontaneously come together, by approximating the edges with an imbricating resorbable suture.

CASE continued

As in most cases of advanced endometriosis, S. D. also had diffuse implants of deep and superficial endometriosis on the peritoneum of the pelvic sidewalls and on the anterior and posterior cul de sac.

Should you ablate or resect these lesions? Are there advantages to either approach?

Ablation of endometriosis implants may involve either electrocoagulation of the lesion with bipolar energy or laser vaporization/coagulation, which destroys or devitalizes active endometriosis but does not actually remove the lesion. Ablation destroys the lesion without getting a specimen for histologic diagnosis.

Resection of endometriosis implants involves complete removal of the lesion from its epithelial surface to the depth of its base. Resection can be performed with scissors, laser, or monopolar electrosurgery. Resection removes the lesion in its entirety, yielding a histologic diagnosis and allowing you to determine whether, indeed, the entire specimen has been removed.

The question of what is more effective—ablating or resecting endometriosis implants?—was addressed in a prospective study in which 141 patients with endometriosis-related pain were randomized at laparoscopic surgery to either excision or ablation/coagulation of endometriosis lesions.¹⁹ Six months postoperatively, the pain score decreased by, on average, 11.2 points in the excision group and 8.7 points in the coagulation/ablative group.

Because the difference in those average pain scores was not statistically significant, however, investigators concluded that the techniques are comparable, with similar efficacy. That interpretation has been criticized because the study was underpowered and included only patients who had mild endometriosis—leaving open the possibility that deep endometriosis may not be adequately treated by electrocoagulation or ablation.

In contrast to superficial endometriosis, which may respond similarly to ablation or resection, deep endometriosis is difficult to ablate either with electrosurgery or a laser because the energy cannot reach deeper layers and active disease is therefore likely to be left behind. Moreover, when endometriosis overlies vital structures, such as the ureter or bowel, ablation of the lesion may cause thermal damage to the underlying organ, and such damage may not manifest until several days later, when the patient experiences, say, urinary leakage in the peritoneum or symptoms of bowel perforation.

FIGURE 5 illustrates a case in which CO₂ laser ablation of endometriosis that had been causing deep dyspareunia did not alleviate symptoms. Because those symptoms persisted, the patient was referred to our center, where a second laparoscopy revealed deep nodules of endometriosis, 1 to 2 cm in diameter, extending from the right and the left uterosacral ligaments deep into the perirectal space, bilaterally.

As the bottom panel of FIGURE 5 shows, excised nodules were deep and large; neither laser nor electrosurgery would have been able to ablate or devitalize the deep endometriosis at the base of these 2-cm nodules.

FIGURE 5 Deep nodules present a surgical challenge
These nodules of endometriosis on the right and left uterosacral ligaments (panel A) did not respond to CO₂ laser ablation. Upon progressive resection, the implants were found to be deep, extending into the perirectal space (panel B). (See also VIDEO 3, resection of endometriosis from the left uterosacal ligament, close to the ureter.) FIGURE 6, illustrates endometriosis overlying the bladder and left ureter (see also VIDEO 4). Ablation of endometriosis in these areas may be inadequate if it is not deep enough, and dangerous if it goes too deep. As FIGURE 6 shows, excision assures the surgeon that the entire lesion has been removed and that underlying vital structures have been safeguarded.

FIGURE 6 Urinary tract involvement
Endometriosis overlying the bladder is grasped, retracted, and resected (panel A). Endometriosis compresses the left ureter (panel B). The peritoneum above the lesion is entered, the ureter is displaced laterally, and the lesion is safely resected.

What we do, and recommend

When endometriosis is superficial and does not overlie vital organs, such as the bladder, ureter, and bowel, ablation and resection may be equally safe and effective. When endometriosis is deep and overlying vital organs, however, complete resection—with careful dissection of the lesion off underlying structures—offers a more complete and a safer surgical approach.

CASE continued

Now that S. D. has been treated surgically by complete excision of endometriosis, adhesions, and endometriomas, you must consider a management plan that will reduce the risks 1) of recurrence of symptoms and disease and 2) that further surgery will be necessary in the future—a risk that, in her case, exceeds 50% because of her young age, nulliparity, and the severity of her disease.^20,21 Indeed, you are aware that, had preventive measures been implemented after her initial surgery 2 years earlier, it is unlikely that S. D. would have developed the second endometrioma and most likely that she would not have needed the second surgery.

Prevention of recurrence is necessary—and doable

The importance of implementing preventive measures to reduce the risk of recurrence of endometriosis and its symptoms has been suggested by several studies. It was underscored recently in a prospective, randomized study conducted by Serracchioli and colleagues,²² in which 239 women who had undergone laparoscopic resection of endometriomas were randomly assigned to expectant management (control group), a cyclic oral contraceptive (OC), or a continuous oral contraceptives for 24 months, and evaluated every 6 months.

At the end of the study, recurrence of symptoms occurred in 30% of controls; 15% of subjects taking a cyclic OC; and 7.5% of the subjects taking a continuous OC. The recurrence rate of endometrioma in this study was reduced by 50% (cyclic OC) and 75% (continuous OC).²²

Similar results were reported in a case-controlled study by Vercellini and co-workers,²³ who found that the risk of recurrence of endometrioma was reduced by 60% when postoperative OCs were used long-term and by 30% when used for a duration of less than 12 months.

These studies suggest that, by suppressing ovulation and inducing a state of hypomenorrhea or amenorrhea, the risk of recurrence of endometriosis and its symptoms can be significantly reduced.

The importance of amenorrhea in reducing the postoperative recurrence of endometriosis and symptoms has been underscored by two important studies that evaluated the role of postoperative endometrial ablation or postoperative insertion of the levonorgestrel intrauterine system (LNG-IUS; Mirena), neither of which suppresses ovulation but both of which induce a state of hypomenorrhea or amenorrhea.^24,25

In a prospective randomized study by Bulletti and co-workers,²⁴ 28 patients who had symptomatic endometriosis underwent laparoscopic conservative surgery. Endometrial ablation was performed in 14 of the 28. Two years later, all patients underwent second-look laparoscopy; recurrence of endometriosis was found in 9 of the 14 non-ablation patients but in none in the ablation group. Resolution or significant improvement of symptoms were reported in 13 of 14 women in the ablation group but only in 3 of 14 in the non-ablation group—supporting the premise that amenorrhea or hypomenorrhea by itself, without suppressing ovulation, significantly reduces the risk that endometriosis will recur.

Similar beneficial results from hypomenorrhea/amenorrhea on the risk of recurrence of symptoms have been reported when the LNG-IUS is inserted following conservative surgery for endometriosis. In a prospective study by Vercellini and colleagues,²⁵ 40 symptomatic patients who had stage-III or stage-IV disease were randomized to either insertion of the LNG-IUS or a control group after conservative laparoscopic surgery. Recurrence of pain was significantly (P = .012) reduced in the LNG-IUS group (45%), compared with the control group (10%). Control subjects were also much less satisfied with their treatment than those who were treated with the LNG-IUS.

The importance of inducing a state of amenorrhea to reduce the risk of disease recurrence was further underscored by a recent study. Shakiba and colleagues²⁶ reported on the recurrence of endometriosis that required further surgery as long as 7 years after the subjects had been surgically treated for symptomatic endometriosis. The need for subsequent surgery was 8% after hysterectomy and bilateral salpingo-oophorectomy; 12% after hysterectomy alone; and 60% after conservative laparoscopy with preservation of both uterus and ovaries.

Taken together, these data show that, unless the patient is rendered amenorrheic or hypomenorrheic, her risk of recurrence exceeds 50%.

It is important, therefore, to consider conservative surgical management of endometriosis as only the beginning of a lifelong management plan. That plan begins with complete resection of all visible endometriosis and adhesions, resection of endometriomas, and restoration of normal anatomy as much as possible.

When endometriosis cannot be completely resected—as when it involves small bowel or the diaphragm, or is diffusely on the large bowel—we recommend medical suppressive therapy. Our preference is depot leuprolide acetate (Lupron Depot), always with add-back therapy to minimize side effects, which include vasomotor symptoms, vaginal dryness, and bone loss,²⁷ until the patient is significantly asymptomatic, which may take 6 to 9 months.

CASE Concluded, with long-term intervention

You counsel S. D. to remain on a low-dose hormonal OC continuously, until such time that she wants to conceive. If a patient does not want to conceive for at least 5 years, the LNG-IUS may be inserted at surgery to induce hypomenorrhea and reduce the risk of recurrence for the next 5 years.

When hormonal contraceptives are inadequate to control symptoms, adding the aromatase enzyme inhibitor letrozole (Femara), 2.5 mg daily for 6 to 9 months, usually alleviates symptoms with minimal side effects, as long as the patient keeps taking a hormonal contraceptive. Using letrozole without hormonal contraception has not been studied; doing so may lead to formation of ovarian cysts, and is therefore not recommended for managing symptomatic endometriosis.

If the patient wants to become pregnant, encourage her to actively undertake fertility treatment as soon as possible after surgery, thereby minimizing the risk of recurrence of symptoms and disease. The best option may be to employ assisted reproductive technology, but patients cannot always afford it; when that is the case, consider controlled ovarian stimulation and intrauterine insemination.

We want to hear from you! Tell us what you think.

Endometriosis affects 7% to 10% of women in the United States, mostly during reproductive years.¹ The estimated annual cost for managing the approximately 10 million affected women? More than $17 billion.² The added cost of this chronic disease, with recurrences of pain and infertility, comes in the form of serious life disruption, emotional suffering, marital and social dysfunction, and diminished productivity.

Although the prevalence of endometriosis is highest during the third and fourth decades of life, the disease is also common in adolescent girls. Indeed, 45% of adolescents who have chronic pelvic pain are found to have endometriosis; if their pain does not respond to an oral contraceptive (OC) or a non-steroidal anti-inflammatory drug, 70% are subsequently found at laparoscopy to have endometriosis.³

What is it?

Endometriosis is the presence of functional endometrial tissue outside the uterus, such as eutopic endometrium. The disease responds to effects of cyclic ovarian hormones, proliferating and bleeding with each menstrual cycle, which often leads to diffuse inflammation, adhesions, and growth of endometriotic nodules or cysts (FIGURE 1).

FIGURE 1 Drainage will not suffice
Surgical management of ovarian endometriomas must go beyond simple drainage, which has little therapeutic value because symptoms recur and endometriomas re-form quickly after simple drainage in almost all patients.Symptoms tend to reflect affected organs:

• Because the pelvic organs are most often involved, the classic symptom triad of the disease comprises dysmenorrhea, dyspareunia, and infertility.
• Urinary urgency, dysuria, dyschezia, and tenesmus are frequent complaints when the bladder or rectosigmoid is involved.
• When distant organs are affected, such as the upper abdomen, diaphragm, lungs, and bowel, the patient may complain of respiratory symptoms, hemoptysis, pneumothorax, shoulder pain, upper abdominal pain, and episodic gastrointestinal dysfunction.

The hallmark of endometriosis is catamenial symptoms, which are usually cyclic and most severe around the time of menses. Clinical signs include palpable tender nodules and fibrosis on the anterior and posterior cul de sac, fixed retroverted or anteverted uterus, and adnexal cystic masses.

Because none of these symptoms or signs is specific for endometriosis, diagnosis relies on laparoscopy, which allows the surgeon to:

• visualize it in its various appearances and locations (FIGURE 2)
• confirm the diagnosis histologically with directed excisional biopsy
• treat it surgically with either excision or ablation.

In this article, we describe various surgical techniques for the management of endometriosis. Beyond resection or ablation of lesions, however, your care should also be directed to postoperative measures to prevent its recurrence and to avoid repeated surgical interventions—which, regrettably, are much too common in women who are afflicted by this enigmatic disease.

FIGURE 2 Endometriosis: A disease of varying appearance
Lesions of endometriosis can be pink, dark, clear, or white on the pelvic sidewall (A), bowel (B), and diaphragm (C); under the rib cage (D); and on the ureter (E) (left ureter shown here).

CASE Severe disease in a young woman

S. D. is a 22-year-old unmarried nulligravida who came to the emergency service complaining of acute onset of severe low abdominal pain, which developed while she was running. She was afebrile and in obvious distress, with diffuse lower abdominal tenderness and guarding, especially on the left side.

Ultrasonography revealed a 7-cm adnexal cystic mass suggestive of endometrioma (FIGURE 3).

Two years before this episode, S. D. underwent laparoscopic resection of a 5-cm endometrioma on the right ovary. Subsequently, she was treated with a cyclic OC, which she discontinued after 1 year because she was not sexually active.

The family history is positive for endometriosis in her mother, who had undergone multiple laparoscopic investigations and, eventually, total hysterectomy with bilateral salpingo-oophorectomy at 40 years of age.

S. D. was treated on the emergency service with analgesics and referred to you for surgical management.

S. D. has severe disease that requires aggressive surgical resection and a lifelong management plan. That plan includes liberal use of medical therapy to prevent recurrence of symptoms and avoid repeated surgical procedures—including the total hysterectomy with bilateral salpingo-oophorectomy that her mother underwent.

What is the best immediate treatment plan? Should you:

• drain the cyst?
• drain it and coagulate or ablate its wall?
• resect the wall of the cyst?
• perform salpingo-oophorectomy?

You also ask yourself: What is the risk of recurrence of endometrioma and its symptoms after each of those treatments? And how can I reduce those risks?

FIGURE 3 Endometrioma
Endometrioma on ultrasonography (A), with its characteristic homogeneous, echogenic appearance and “ground glass” pattern, and through the laparoscope (B). These images are from the patient whose case is described in the text.

Focal point: Ovary

The ovary is the most common organ affected by endometriosis. The presence of ovarian endometriomas, in 17% to 44% of patients who have this disease,⁴ is often associated with an advanced stage of disease.

In a population of 1,785 patients who were surgically treated for ovarian endometriosis, Redwine reported that only 1% had exclusively ovarian involvement; 99% also had diffuse pelvic disease,⁵ suggesting that ovarian endometrioma is a marker of extensive disease, which often requires a gynecologic surgeon who has advanced skills and experience in the surgical management of severe endometriosis.

Simple drainage is inadequate

Surgical management of ovarian endometrioma must go beyond simple drainage, which has little therapeutic value because symptoms recur and endometriomas re-form quickly after simple drainage in almost all patients.⁶ The currently accepted surgical management of endometrioma involves either 1) coagulation and ablation of the wall of the cyst with electrosurgery or laser or 2) removal of the cyst wall from the ovary with blunt and sharp dissection.

Several studies have compared these two techniques, but only two^7,8 were prospectively randomized.

Study #1. Beretta and co-workers⁷ studied 64 patients who had ovarian endometriomas larger than 3 cm and randomized them to cystectomy by complete stripping of the cyst wall or to drainage of fluid followed by electrocoagulation to ablate the endometriosis lesions within the cyst wall. The two groups were followed for 2 years to assess the recurrence of symptoms and the pregnancy rate in the patients who were infertile.

Recurrence of symptoms and the need for medical or surgical intervention occurred with less frequency and much later in the resection group than in the ablation group: 19 months, compared to 9.5 months, postoperatively. The cumulative pregnancy rate 24 months postoperatively was also much higher in the resection group (66.7%) than in the ablative group (23.5%).

Study #2. In a later study,⁸ Alborzi and colleagues randomized 100 patients who had endometrioma to cystectomy or to drainage and coagulation of the cyst wall. The mean recurrence rate, 2 years postoperatively, was much lower in the excision group (15.8%) than in the ablative group (56.7%). The cumulative pregnancy rate at 12 months was higher in the excision group (54.9%, compared to 23.3%). Furthermore, the reoperation rate at 24 months was much lower in the excision group (5.8%) than in the ablative group (22.9%).

These favorable results for cystectomy over ablation were validated by a Cochrane Review, which concluded that excision of endometriomas is the preferred approach because it provides 1) a more favorable outcome than drainage and ablation, 2) lower rates of recurrence of endometriomas and symptoms, and 3) a much higher spontaneous pregnancy rate in infertile women.⁹

Although resection of the cyst wall is technically more challenging and takes longer to perform than drainage and ablation, we exclusively perform resection rather than ablation of endometriomas because we believe that more lasting therapeutic effects and reduced recurrence of symptoms and disease justify the extra effort and a longer procedure.

Drawback of cystectomy

A potential risk of cystectomy is that it can diminish ovarian reserve and, in rare cases, induce premature menopause, which can be devastating for women whose main purpose for having surgery is to restore or improve their fertility.

The impact of laparoscopic ovarian cystectomy on ovarian reserve was prospectively studied by Chang and co-workers,¹⁰ who measured preoperative and postoperative levels of anti-müllerian hormone (AMH) in 13 women who had endometrioma, 6 who had mature teratoma, and 1 who had mucinous cystadenoma. One week postoperatively, the AMH level decreased significantly overall in all groups. At 4 and 12 weeks postoperatively, however, the AMH level returned to preoperative levels among subjects in the non-endometrioma group but not among subjects who had endometrioma; rather, their level remained statistically lower than the preoperative level during the entire 3 months of follow-up.

Stripping the wall of an endometrioma cyst is more difficult than it is for other benign cysts, such as cystic teratoma or cystadenoma, in which there usually is a well-defined dissection plane between the wall of the cyst and surrounding stromal tissue—allowing for easy and clean separation of the wall. The cyst wall of an endometrioma, on the other hand, is intimately attached to underlying ovarian stroma; lack of a clear cleavage plane between cyst and ovarian stroma often results in unintentional removal of layers of ovarian cortex with underlying follicles, which, in turn, may lead to a reduction in ovarian reserve.

Histologic analyses of resected endometrioma cyst walls have reported follicle-containing ovarian tissue attached to the stripped cyst wall in 54% of cases.^11,12 That observation explains why, and how, ovarian reserve can be compromised after resection of endometrioma.

Further risk: Ovarian failure

In rare cases, excision of endometriomas results in complete ovarian failure, described by Busacca and colleagues, who reported three cases of ovarian failure (2.4%) after resection of bilateral endometriomas in 126 patients.¹³ They attributed ovarian failure to excessive cauterization that compromised vascularization, as well as to excessive removal of ovarian tissue.

It is important, therefore, to strip the thinnest layer of the cyst capsule and to reduce the amount of electrocoagulation of ovarian stroma as much as possible to safeguard functional ovarian tissue.

CASE continued

S. D. was scheduled for laparoscopy to remove the endometrioma and other concurrent pelvic and peritoneal pathology, such as endometriosis and pelvic adhesions. You also scheduled her for hysteroscopy to evaluate the endometrial cavity for potential pathology, such as endometrial polyps and uterine septum, which appear to be more common in women who have endometriosis.

Nawroth and co-workers¹⁴ found a much higher incidence of endometriosis in patients who had a septate uterus. Metalliotakis and co-workers¹⁵ found congenital uterine malformations to be more common in patients who had endometriosis, compared with controls; uterine septum was, by far, the most common anomaly.

CASE continued

Hysteroscopy revealed a small and broad septum, which was resected sharply with hysteroscopic scissors (FIGURE 4). Laparoscopy revealed a 7-cm endometrioma on the left ovary, with adhesions to the posterior broad ligament and pelvic sidewall. S. D. also had deep implants of endometriosis on the left pelvic sidewall, the posterior cul de sac, the right pelvic sidewall, and the right ovary, which was cohesively adherent to the ovarian fossa.

As you expected, S. D. has stage-IV disease, according to the revised American Fertility Society Classification.

Following adhesiolysis, the endometrioma was resected (see VIDEO 1). Because of the large ovarian defect, the edges of the ovary were approximated with imbricating running 3-0 Vicryl suture. Deep endometriosis was also resected. Superficial endometriosis was peeled off or coagulated using bipolar forceps.

Note: Alternatively, and with comparable results, resection may be performed with a laser or other energy source. We prefer resection, rather than ablation, of deep endometriosis, but no data exists to support one technique over the other.

FIGURE 4 Septate uterus with deep cornua
Through the hysteroscope, a shallow septum is visible at the fundus of the uterus, dividing the upper endometrial cavity into two chambers (A), with deep cornua on the left (B) and right (C). Normal fundal anatomy is restored by septolysis along the avascular plane (D).

Technique: How we resect endometrioma

In removing endometrioma (see VIDEO 2), it is important to grasp the thinnest part of the cyst wall and progressively strip it, to avoid removing excess ovarian tissue and to reduce the risk of compromising ovarian reserve.

After draining the endometrioma of its chocolate-colored fluid, we irrigate and drain the cyst several times with warm lactated Ringers’ solution to promote separation of the cyst wall from underlying stroma and better identify the dissection plane. The cyst wall is inspected by introducing the laparoscope into the cyst to examine its surface, which is often laden with implants of deep and superficial endometriosis.

If we cannot easily identify the plane of dissection along the edges, we may evert the cyst and make an incision at its base to create a wedge between the wall of the cyst and underlying stroma. The edge of the incised wall is then grasped and retracted to create a space between the wall and the underlying stroma, from which it is progressively stripped from the ovary.

Traction and counter-traction are the hallmarks of dissection here; sometimes, we use laparoscopic scissors to sharply resect the ovarian stromal attachments that adhere cohesively to the cyst wall. This technique is continued until the entire cyst wall is removed. When follicle-containing ovarian tissue remains attached to the cyst wall, we introduce the closed tips of the Dolphin forceps between the cyst wall and adjacent follicle-containing stroma, spread the tips apart, and recover the true plane of dissection between the thin wall of the cyst and stroma.

After the wall of the cyst is removed, the ovarian crater invariably bleeds because blood vessels supplying the wall have been separated and opened. Utilizing warm lactated Ringers’ solution, we copiously irrigate the bleeding ovarian stroma to identify each bleeding vessel and, by placing the tips of the micro-bipolar forceps on either side of the bleeder, individually coagulate each vessel, thus inflicting minimal thermal damage to the surrounding stroma.

Pearl. Avoid using Kleppinger forceps to indiscriminately coagulate the bloody stroma in the crater created after the cystectomy, because doing so can result in excessive destruction of ovarian tissue or inadvertent coagulation of hylar vessels that would interrupt the blood supply to the ovary, compromising its function.¹⁶

Suturing. Some surgeons find that fenestration, drainage, and coagulation of the cyst wall is acceptable, but we have concerns not only about incomplete ablation of the endometriosis on the cyst wall, which may be responsible for the higher recurrence rate of disease, but also about the risk of thermal injury to underlying follicles, which may compromise ovarian reserve.¹⁶

Hemostasis. Once complete hemostasis has been achieved, the decision to approximate (or not) the edges, preferably with fine absorbable suture, is based on how large the defect is and whether or not the edges of the crater spontaneously come together. For large craters, we usually close the ovary with a 3-0 or 4-0 Vicryl continuous suture, imbricating the edges to expose as little suture material as possible to reduce postoperative formation of adhesions, which is common after ovarian surgery.¹⁷

Last, we ensure that hemostasis is present. Often we apply an anti-adhesion solution, such as icodextrin 4% (Adept). This agent has been shown to reduce postoperative adhesion formation, especially after laparoscopic surgery for endometriosis.¹⁸

A high level of skill is needed

Ovarian endometriomas signal advanced disease; advanced surgical skills are required to treat them adequately. Simple drainage is of little therapeutic value and should seldom be considered a treatment option. Although drainage plus ablation of the cyst wall ameliorates symptoms, excision of endometriomas should be considered preferable because it provides a more favorable outcome, a lower risk of recurrence of endometriomas and symptoms, and a higher rate of spontaneous pregnancy in previously infertile women.^7-9

To recap, we advise the surgeon to:

• Manage ovarian endometriomas with resection of the entire cyst wall, grasping and stripping the thinnest layer of the cyst wall without removing underlying functional ovarian stroma.
• Avoid excessive cauterization of the underlying ovarian stroma by utilizing micro-bipolar forceps and applying energy only around bleeding vessels.
• Close stromal defects, when the crater is large and its edges do not spontaneously come together, by approximating the edges with an imbricating resorbable suture.

CASE continued

As in most cases of advanced endometriosis, S. D. also had diffuse implants of deep and superficial endometriosis on the peritoneum of the pelvic sidewalls and on the anterior and posterior cul de sac.

Should you ablate or resect these lesions? Are there advantages to either approach?

Ablation of endometriosis implants may involve either electrocoagulation of the lesion with bipolar energy or laser vaporization/coagulation, which destroys or devitalizes active endometriosis but does not actually remove the lesion. Ablation destroys the lesion without getting a specimen for histologic diagnosis.

Resection of endometriosis implants involves complete removal of the lesion from its epithelial surface to the depth of its base. Resection can be performed with scissors, laser, or monopolar electrosurgery. Resection removes the lesion in its entirety, yielding a histologic diagnosis and allowing you to determine whether, indeed, the entire specimen has been removed.

The question of what is more effective—ablating or resecting endometriosis implants?—was addressed in a prospective study in which 141 patients with endometriosis-related pain were randomized at laparoscopic surgery to either excision or ablation/coagulation of endometriosis lesions.¹⁹ Six months postoperatively, the pain score decreased by, on average, 11.2 points in the excision group and 8.7 points in the coagulation/ablative group.

Because the difference in those average pain scores was not statistically significant, however, investigators concluded that the techniques are comparable, with similar efficacy. That interpretation has been criticized because the study was underpowered and included only patients who had mild endometriosis—leaving open the possibility that deep endometriosis may not be adequately treated by electrocoagulation or ablation.

In contrast to superficial endometriosis, which may respond similarly to ablation or resection, deep endometriosis is difficult to ablate either with electrosurgery or a laser because the energy cannot reach deeper layers and active disease is therefore likely to be left behind. Moreover, when endometriosis overlies vital structures, such as the ureter or bowel, ablation of the lesion may cause thermal damage to the underlying organ, and such damage may not manifest until several days later, when the patient experiences, say, urinary leakage in the peritoneum or symptoms of bowel perforation.

FIGURE 5 illustrates a case in which CO₂ laser ablation of endometriosis that had been causing deep dyspareunia did not alleviate symptoms. Because those symptoms persisted, the patient was referred to our center, where a second laparoscopy revealed deep nodules of endometriosis, 1 to 2 cm in diameter, extending from the right and the left uterosacral ligaments deep into the perirectal space, bilaterally.

As the bottom panel of FIGURE 5 shows, excised nodules were deep and large; neither laser nor electrosurgery would have been able to ablate or devitalize the deep endometriosis at the base of these 2-cm nodules.

FIGURE 5 Deep nodules present a surgical challenge
These nodules of endometriosis on the right and left uterosacral ligaments (panel A) did not respond to CO₂ laser ablation. Upon progressive resection, the implants were found to be deep, extending into the perirectal space (panel B). (See also VIDEO 3, resection of endometriosis from the left uterosacal ligament, close to the ureter.) FIGURE 6, illustrates endometriosis overlying the bladder and left ureter (see also VIDEO 4). Ablation of endometriosis in these areas may be inadequate if it is not deep enough, and dangerous if it goes too deep. As FIGURE 6 shows, excision assures the surgeon that the entire lesion has been removed and that underlying vital structures have been safeguarded.

FIGURE 6 Urinary tract involvement
Endometriosis overlying the bladder is grasped, retracted, and resected (panel A). Endometriosis compresses the left ureter (panel B). The peritoneum above the lesion is entered, the ureter is displaced laterally, and the lesion is safely resected.

What we do, and recommend

When endometriosis is superficial and does not overlie vital organs, such as the bladder, ureter, and bowel, ablation and resection may be equally safe and effective. When endometriosis is deep and overlying vital organs, however, complete resection—with careful dissection of the lesion off underlying structures—offers a more complete and a safer surgical approach.

CASE continued

Now that S. D. has been treated surgically by complete excision of endometriosis, adhesions, and endometriomas, you must consider a management plan that will reduce the risks 1) of recurrence of symptoms and disease and 2) that further surgery will be necessary in the future—a risk that, in her case, exceeds 50% because of her young age, nulliparity, and the severity of her disease.^20,21 Indeed, you are aware that, had preventive measures been implemented after her initial surgery 2 years earlier, it is unlikely that S. D. would have developed the second endometrioma and most likely that she would not have needed the second surgery.

Prevention of recurrence is necessary—and doable

The importance of implementing preventive measures to reduce the risk of recurrence of endometriosis and its symptoms has been suggested by several studies. It was underscored recently in a prospective, randomized study conducted by Serracchioli and colleagues,²² in which 239 women who had undergone laparoscopic resection of endometriomas were randomly assigned to expectant management (control group), a cyclic oral contraceptive (OC), or a continuous oral contraceptives for 24 months, and evaluated every 6 months.

At the end of the study, recurrence of symptoms occurred in 30% of controls; 15% of subjects taking a cyclic OC; and 7.5% of the subjects taking a continuous OC. The recurrence rate of endometrioma in this study was reduced by 50% (cyclic OC) and 75% (continuous OC).²²

Similar results were reported in a case-controlled study by Vercellini and co-workers,²³ who found that the risk of recurrence of endometrioma was reduced by 60% when postoperative OCs were used long-term and by 30% when used for a duration of less than 12 months.

These studies suggest that, by suppressing ovulation and inducing a state of hypomenorrhea or amenorrhea, the risk of recurrence of endometriosis and its symptoms can be significantly reduced.

The importance of amenorrhea in reducing the postoperative recurrence of endometriosis and symptoms has been underscored by two important studies that evaluated the role of postoperative endometrial ablation or postoperative insertion of the levonorgestrel intrauterine system (LNG-IUS; Mirena), neither of which suppresses ovulation but both of which induce a state of hypomenorrhea or amenorrhea.^24,25

In a prospective randomized study by Bulletti and co-workers,²⁴ 28 patients who had symptomatic endometriosis underwent laparoscopic conservative surgery. Endometrial ablation was performed in 14 of the 28. Two years later, all patients underwent second-look laparoscopy; recurrence of endometriosis was found in 9 of the 14 non-ablation patients but in none in the ablation group. Resolution or significant improvement of symptoms were reported in 13 of 14 women in the ablation group but only in 3 of 14 in the non-ablation group—supporting the premise that amenorrhea or hypomenorrhea by itself, without suppressing ovulation, significantly reduces the risk that endometriosis will recur.

Similar beneficial results from hypomenorrhea/amenorrhea on the risk of recurrence of symptoms have been reported when the LNG-IUS is inserted following conservative surgery for endometriosis. In a prospective study by Vercellini and colleagues,²⁵ 40 symptomatic patients who had stage-III or stage-IV disease were randomized to either insertion of the LNG-IUS or a control group after conservative laparoscopic surgery. Recurrence of pain was significantly (P = .012) reduced in the LNG-IUS group (45%), compared with the control group (10%). Control subjects were also much less satisfied with their treatment than those who were treated with the LNG-IUS.

The importance of inducing a state of amenorrhea to reduce the risk of disease recurrence was further underscored by a recent study. Shakiba and colleagues²⁶ reported on the recurrence of endometriosis that required further surgery as long as 7 years after the subjects had been surgically treated for symptomatic endometriosis. The need for subsequent surgery was 8% after hysterectomy and bilateral salpingo-oophorectomy; 12% after hysterectomy alone; and 60% after conservative laparoscopy with preservation of both uterus and ovaries.

Taken together, these data show that, unless the patient is rendered amenorrheic or hypomenorrheic, her risk of recurrence exceeds 50%.

It is important, therefore, to consider conservative surgical management of endometriosis as only the beginning of a lifelong management plan. That plan begins with complete resection of all visible endometriosis and adhesions, resection of endometriomas, and restoration of normal anatomy as much as possible.

When endometriosis cannot be completely resected—as when it involves small bowel or the diaphragm, or is diffusely on the large bowel—we recommend medical suppressive therapy. Our preference is depot leuprolide acetate (Lupron Depot), always with add-back therapy to minimize side effects, which include vasomotor symptoms, vaginal dryness, and bone loss,²⁷ until the patient is significantly asymptomatic, which may take 6 to 9 months.

CASE Concluded, with long-term intervention

You counsel S. D. to remain on a low-dose hormonal OC continuously, until such time that she wants to conceive. If a patient does not want to conceive for at least 5 years, the LNG-IUS may be inserted at surgery to induce hypomenorrhea and reduce the risk of recurrence for the next 5 years.

When hormonal contraceptives are inadequate to control symptoms, adding the aromatase enzyme inhibitor letrozole (Femara), 2.5 mg daily for 6 to 9 months, usually alleviates symptoms with minimal side effects, as long as the patient keeps taking a hormonal contraceptive. Using letrozole without hormonal contraception has not been studied; doing so may lead to formation of ovarian cysts, and is therefore not recommended for managing symptomatic endometriosis.

If the patient wants to become pregnant, encourage her to actively undertake fertility treatment as soon as possible after surgery, thereby minimizing the risk of recurrence of symptoms and disease. The best option may be to employ assisted reproductive technology, but patients cannot always afford it; when that is the case, consider controlled ovarian stimulation and intrauterine insemination.

We want to hear from you! Tell us what you think.

Endometriosis affects 7% to 10% of women in the United States, mostly during reproductive years.¹ The estimated annual cost for managing the approximately 10 million affected women? More than $17 billion.² The added cost of this chronic disease, with recurrences of pain and infertility, comes in the form of serious life disruption, emotional suffering, marital and social dysfunction, and diminished productivity.

Although the prevalence of endometriosis is highest during the third and fourth decades of life, the disease is also common in adolescent girls. Indeed, 45% of adolescents who have chronic pelvic pain are found to have endometriosis; if their pain does not respond to an oral contraceptive (OC) or a non-steroidal anti-inflammatory drug, 70% are subsequently found at laparoscopy to have endometriosis.³

What is it?

Endometriosis is the presence of functional endometrial tissue outside the uterus, such as eutopic endometrium. The disease responds to effects of cyclic ovarian hormones, proliferating and bleeding with each menstrual cycle, which often leads to diffuse inflammation, adhesions, and growth of endometriotic nodules or cysts (FIGURE 1).

FIGURE 1 Drainage will not suffice
Surgical management of ovarian endometriomas must go beyond simple drainage, which has little therapeutic value because symptoms recur and endometriomas re-form quickly after simple drainage in almost all patients.Symptoms tend to reflect affected organs:

• Because the pelvic organs are most often involved, the classic symptom triad of the disease comprises dysmenorrhea, dyspareunia, and infertility.
• Urinary urgency, dysuria, dyschezia, and tenesmus are frequent complaints when the bladder or rectosigmoid is involved.
• When distant organs are affected, such as the upper abdomen, diaphragm, lungs, and bowel, the patient may complain of respiratory symptoms, hemoptysis, pneumothorax, shoulder pain, upper abdominal pain, and episodic gastrointestinal dysfunction.

The hallmark of endometriosis is catamenial symptoms, which are usually cyclic and most severe around the time of menses. Clinical signs include palpable tender nodules and fibrosis on the anterior and posterior cul de sac, fixed retroverted or anteverted uterus, and adnexal cystic masses.

Because none of these symptoms or signs is specific for endometriosis, diagnosis relies on laparoscopy, which allows the surgeon to:

• visualize it in its various appearances and locations (FIGURE 2)
• confirm the diagnosis histologically with directed excisional biopsy
• treat it surgically with either excision or ablation.

In this article, we describe various surgical techniques for the management of endometriosis. Beyond resection or ablation of lesions, however, your care should also be directed to postoperative measures to prevent its recurrence and to avoid repeated surgical interventions—which, regrettably, are much too common in women who are afflicted by this enigmatic disease.

FIGURE 2 Endometriosis: A disease of varying appearance
Lesions of endometriosis can be pink, dark, clear, or white on the pelvic sidewall (A), bowel (B), and diaphragm (C); under the rib cage (D); and on the ureter (E) (left ureter shown here).

CASE Severe disease in a young woman

S. D. is a 22-year-old unmarried nulligravida who came to the emergency service complaining of acute onset of severe low abdominal pain, which developed while she was running. She was afebrile and in obvious distress, with diffuse lower abdominal tenderness and guarding, especially on the left side.

Ultrasonography revealed a 7-cm adnexal cystic mass suggestive of endometrioma (FIGURE 3).

Two years before this episode, S. D. underwent laparoscopic resection of a 5-cm endometrioma on the right ovary. Subsequently, she was treated with a cyclic OC, which she discontinued after 1 year because she was not sexually active.

The family history is positive for endometriosis in her mother, who had undergone multiple laparoscopic investigations and, eventually, total hysterectomy with bilateral salpingo-oophorectomy at 40 years of age.

S. D. was treated on the emergency service with analgesics and referred to you for surgical management.

S. D. has severe disease that requires aggressive surgical resection and a lifelong management plan. That plan includes liberal use of medical therapy to prevent recurrence of symptoms and avoid repeated surgical procedures—including the total hysterectomy with bilateral salpingo-oophorectomy that her mother underwent.

What is the best immediate treatment plan? Should you:

• drain the cyst?
• drain it and coagulate or ablate its wall?
• resect the wall of the cyst?
• perform salpingo-oophorectomy?

You also ask yourself: What is the risk of recurrence of endometrioma and its symptoms after each of those treatments? And how can I reduce those risks?

FIGURE 3 Endometrioma
Endometrioma on ultrasonography (A), with its characteristic homogeneous, echogenic appearance and “ground glass” pattern, and through the laparoscope (B). These images are from the patient whose case is described in the text.

Focal point: Ovary

The ovary is the most common organ affected by endometriosis. The presence of ovarian endometriomas, in 17% to 44% of patients who have this disease,⁴ is often associated with an advanced stage of disease.

In a population of 1,785 patients who were surgically treated for ovarian endometriosis, Redwine reported that only 1% had exclusively ovarian involvement; 99% also had diffuse pelvic disease,⁵ suggesting that ovarian endometrioma is a marker of extensive disease, which often requires a gynecologic surgeon who has advanced skills and experience in the surgical management of severe endometriosis.

Simple drainage is inadequate

Surgical management of ovarian endometrioma must go beyond simple drainage, which has little therapeutic value because symptoms recur and endometriomas re-form quickly after simple drainage in almost all patients.⁶ The currently accepted surgical management of endometrioma involves either 1) coagulation and ablation of the wall of the cyst with electrosurgery or laser or 2) removal of the cyst wall from the ovary with blunt and sharp dissection.

Several studies have compared these two techniques, but only two^7,8 were prospectively randomized.

Study #1. Beretta and co-workers⁷ studied 64 patients who had ovarian endometriomas larger than 3 cm and randomized them to cystectomy by complete stripping of the cyst wall or to drainage of fluid followed by electrocoagulation to ablate the endometriosis lesions within the cyst wall. The two groups were followed for 2 years to assess the recurrence of symptoms and the pregnancy rate in the patients who were infertile.

Recurrence of symptoms and the need for medical or surgical intervention occurred with less frequency and much later in the resection group than in the ablation group: 19 months, compared to 9.5 months, postoperatively. The cumulative pregnancy rate 24 months postoperatively was also much higher in the resection group (66.7%) than in the ablative group (23.5%).

Study #2. In a later study,⁸ Alborzi and colleagues randomized 100 patients who had endometrioma to cystectomy or to drainage and coagulation of the cyst wall. The mean recurrence rate, 2 years postoperatively, was much lower in the excision group (15.8%) than in the ablative group (56.7%). The cumulative pregnancy rate at 12 months was higher in the excision group (54.9%, compared to 23.3%). Furthermore, the reoperation rate at 24 months was much lower in the excision group (5.8%) than in the ablative group (22.9%).

These favorable results for cystectomy over ablation were validated by a Cochrane Review, which concluded that excision of endometriomas is the preferred approach because it provides 1) a more favorable outcome than drainage and ablation, 2) lower rates of recurrence of endometriomas and symptoms, and 3) a much higher spontaneous pregnancy rate in infertile women.⁹

Although resection of the cyst wall is technically more challenging and takes longer to perform than drainage and ablation, we exclusively perform resection rather than ablation of endometriomas because we believe that more lasting therapeutic effects and reduced recurrence of symptoms and disease justify the extra effort and a longer procedure.

Drawback of cystectomy

A potential risk of cystectomy is that it can diminish ovarian reserve and, in rare cases, induce premature menopause, which can be devastating for women whose main purpose for having surgery is to restore or improve their fertility.

The impact of laparoscopic ovarian cystectomy on ovarian reserve was prospectively studied by Chang and co-workers,¹⁰ who measured preoperative and postoperative levels of anti-müllerian hormone (AMH) in 13 women who had endometrioma, 6 who had mature teratoma, and 1 who had mucinous cystadenoma. One week postoperatively, the AMH level decreased significantly overall in all groups. At 4 and 12 weeks postoperatively, however, the AMH level returned to preoperative levels among subjects in the non-endometrioma group but not among subjects who had endometrioma; rather, their level remained statistically lower than the preoperative level during the entire 3 months of follow-up.

Stripping the wall of an endometrioma cyst is more difficult than it is for other benign cysts, such as cystic teratoma or cystadenoma, in which there usually is a well-defined dissection plane between the wall of the cyst and surrounding stromal tissue—allowing for easy and clean separation of the wall. The cyst wall of an endometrioma, on the other hand, is intimately attached to underlying ovarian stroma; lack of a clear cleavage plane between cyst and ovarian stroma often results in unintentional removal of layers of ovarian cortex with underlying follicles, which, in turn, may lead to a reduction in ovarian reserve.

Histologic analyses of resected endometrioma cyst walls have reported follicle-containing ovarian tissue attached to the stripped cyst wall in 54% of cases.^11,12 That observation explains why, and how, ovarian reserve can be compromised after resection of endometrioma.

Further risk: Ovarian failure

In rare cases, excision of endometriomas results in complete ovarian failure, described by Busacca and colleagues, who reported three cases of ovarian failure (2.4%) after resection of bilateral endometriomas in 126 patients.¹³ They attributed ovarian failure to excessive cauterization that compromised vascularization, as well as to excessive removal of ovarian tissue.

It is important, therefore, to strip the thinnest layer of the cyst capsule and to reduce the amount of electrocoagulation of ovarian stroma as much as possible to safeguard functional ovarian tissue.

CASE continued

S. D. was scheduled for laparoscopy to remove the endometrioma and other concurrent pelvic and peritoneal pathology, such as endometriosis and pelvic adhesions. You also scheduled her for hysteroscopy to evaluate the endometrial cavity for potential pathology, such as endometrial polyps and uterine septum, which appear to be more common in women who have endometriosis.

Nawroth and co-workers¹⁴ found a much higher incidence of endometriosis in patients who had a septate uterus. Metalliotakis and co-workers¹⁵ found congenital uterine malformations to be more common in patients who had endometriosis, compared with controls; uterine septum was, by far, the most common anomaly.

CASE continued

Hysteroscopy revealed a small and broad septum, which was resected sharply with hysteroscopic scissors (FIGURE 4). Laparoscopy revealed a 7-cm endometrioma on the left ovary, with adhesions to the posterior broad ligament and pelvic sidewall. S. D. also had deep implants of endometriosis on the left pelvic sidewall, the posterior cul de sac, the right pelvic sidewall, and the right ovary, which was cohesively adherent to the ovarian fossa.

As you expected, S. D. has stage-IV disease, according to the revised American Fertility Society Classification.

Following adhesiolysis, the endometrioma was resected (see VIDEO 1). Because of the large ovarian defect, the edges of the ovary were approximated with imbricating running 3-0 Vicryl suture. Deep endometriosis was also resected. Superficial endometriosis was peeled off or coagulated using bipolar forceps.

Note: Alternatively, and with comparable results, resection may be performed with a laser or other energy source. We prefer resection, rather than ablation, of deep endometriosis, but no data exists to support one technique over the other.

FIGURE 4 Septate uterus with deep cornua
Through the hysteroscope, a shallow septum is visible at the fundus of the uterus, dividing the upper endometrial cavity into two chambers (A), with deep cornua on the left (B) and right (C). Normal fundal anatomy is restored by septolysis along the avascular plane (D).

Technique: How we resect endometrioma

In removing endometrioma (see VIDEO 2), it is important to grasp the thinnest part of the cyst wall and progressively strip it, to avoid removing excess ovarian tissue and to reduce the risk of compromising ovarian reserve.

After draining the endometrioma of its chocolate-colored fluid, we irrigate and drain the cyst several times with warm lactated Ringers’ solution to promote separation of the cyst wall from underlying stroma and better identify the dissection plane. The cyst wall is inspected by introducing the laparoscope into the cyst to examine its surface, which is often laden with implants of deep and superficial endometriosis.

If we cannot easily identify the plane of dissection along the edges, we may evert the cyst and make an incision at its base to create a wedge between the wall of the cyst and underlying stroma. The edge of the incised wall is then grasped and retracted to create a space between the wall and the underlying stroma, from which it is progressively stripped from the ovary.

Traction and counter-traction are the hallmarks of dissection here; sometimes, we use laparoscopic scissors to sharply resect the ovarian stromal attachments that adhere cohesively to the cyst wall. This technique is continued until the entire cyst wall is removed. When follicle-containing ovarian tissue remains attached to the cyst wall, we introduce the closed tips of the Dolphin forceps between the cyst wall and adjacent follicle-containing stroma, spread the tips apart, and recover the true plane of dissection between the thin wall of the cyst and stroma.

After the wall of the cyst is removed, the ovarian crater invariably bleeds because blood vessels supplying the wall have been separated and opened. Utilizing warm lactated Ringers’ solution, we copiously irrigate the bleeding ovarian stroma to identify each bleeding vessel and, by placing the tips of the micro-bipolar forceps on either side of the bleeder, individually coagulate each vessel, thus inflicting minimal thermal damage to the surrounding stroma.

Pearl. Avoid using Kleppinger forceps to indiscriminately coagulate the bloody stroma in the crater created after the cystectomy, because doing so can result in excessive destruction of ovarian tissue or inadvertent coagulation of hylar vessels that would interrupt the blood supply to the ovary, compromising its function.¹⁶

Suturing. Some surgeons find that fenestration, drainage, and coagulation of the cyst wall is acceptable, but we have concerns not only about incomplete ablation of the endometriosis on the cyst wall, which may be responsible for the higher recurrence rate of disease, but also about the risk of thermal injury to underlying follicles, which may compromise ovarian reserve.¹⁶

Hemostasis. Once complete hemostasis has been achieved, the decision to approximate (or not) the edges, preferably with fine absorbable suture, is based on how large the defect is and whether or not the edges of the crater spontaneously come together. For large craters, we usually close the ovary with a 3-0 or 4-0 Vicryl continuous suture, imbricating the edges to expose as little suture material as possible to reduce postoperative formation of adhesions, which is common after ovarian surgery.¹⁷

Last, we ensure that hemostasis is present. Often we apply an anti-adhesion solution, such as icodextrin 4% (Adept). This agent has been shown to reduce postoperative adhesion formation, especially after laparoscopic surgery for endometriosis.¹⁸

A high level of skill is needed

Ovarian endometriomas signal advanced disease; advanced surgical skills are required to treat them adequately. Simple drainage is of little therapeutic value and should seldom be considered a treatment option. Although drainage plus ablation of the cyst wall ameliorates symptoms, excision of endometriomas should be considered preferable because it provides a more favorable outcome, a lower risk of recurrence of endometriomas and symptoms, and a higher rate of spontaneous pregnancy in previously infertile women.^7-9

To recap, we advise the surgeon to:

• Manage ovarian endometriomas with resection of the entire cyst wall, grasping and stripping the thinnest layer of the cyst wall without removing underlying functional ovarian stroma.
• Avoid excessive cauterization of the underlying ovarian stroma by utilizing micro-bipolar forceps and applying energy only around bleeding vessels.
• Close stromal defects, when the crater is large and its edges do not spontaneously come together, by approximating the edges with an imbricating resorbable suture.

CASE continued

As in most cases of advanced endometriosis, S. D. also had diffuse implants of deep and superficial endometriosis on the peritoneum of the pelvic sidewalls and on the anterior and posterior cul de sac.

Should you ablate or resect these lesions? Are there advantages to either approach?

Ablation of endometriosis implants may involve either electrocoagulation of the lesion with bipolar energy or laser vaporization/coagulation, which destroys or devitalizes active endometriosis but does not actually remove the lesion. Ablation destroys the lesion without getting a specimen for histologic diagnosis.

Resection of endometriosis implants involves complete removal of the lesion from its epithelial surface to the depth of its base. Resection can be performed with scissors, laser, or monopolar electrosurgery. Resection removes the lesion in its entirety, yielding a histologic diagnosis and allowing you to determine whether, indeed, the entire specimen has been removed.

The question of what is more effective—ablating or resecting endometriosis implants?—was addressed in a prospective study in which 141 patients with endometriosis-related pain were randomized at laparoscopic surgery to either excision or ablation/coagulation of endometriosis lesions.¹⁹ Six months postoperatively, the pain score decreased by, on average, 11.2 points in the excision group and 8.7 points in the coagulation/ablative group.

Because the difference in those average pain scores was not statistically significant, however, investigators concluded that the techniques are comparable, with similar efficacy. That interpretation has been criticized because the study was underpowered and included only patients who had mild endometriosis—leaving open the possibility that deep endometriosis may not be adequately treated by electrocoagulation or ablation.

In contrast to superficial endometriosis, which may respond similarly to ablation or resection, deep endometriosis is difficult to ablate either with electrosurgery or a laser because the energy cannot reach deeper layers and active disease is therefore likely to be left behind. Moreover, when endometriosis overlies vital structures, such as the ureter or bowel, ablation of the lesion may cause thermal damage to the underlying organ, and such damage may not manifest until several days later, when the patient experiences, say, urinary leakage in the peritoneum or symptoms of bowel perforation.

FIGURE 5 illustrates a case in which CO₂ laser ablation of endometriosis that had been causing deep dyspareunia did not alleviate symptoms. Because those symptoms persisted, the patient was referred to our center, where a second laparoscopy revealed deep nodules of endometriosis, 1 to 2 cm in diameter, extending from the right and the left uterosacral ligaments deep into the perirectal space, bilaterally.

As the bottom panel of FIGURE 5 shows, excised nodules were deep and large; neither laser nor electrosurgery would have been able to ablate or devitalize the deep endometriosis at the base of these 2-cm nodules.

FIGURE 5 Deep nodules present a surgical challenge
These nodules of endometriosis on the right and left uterosacral ligaments (panel A) did not respond to CO₂ laser ablation. Upon progressive resection, the implants were found to be deep, extending into the perirectal space (panel B). (See also VIDEO 3, resection of endometriosis from the left uterosacal ligament, close to the ureter.) FIGURE 6, illustrates endometriosis overlying the bladder and left ureter (see also VIDEO 4). Ablation of endometriosis in these areas may be inadequate if it is not deep enough, and dangerous if it goes too deep. As FIGURE 6 shows, excision assures the surgeon that the entire lesion has been removed and that underlying vital structures have been safeguarded.

FIGURE 6 Urinary tract involvement
Endometriosis overlying the bladder is grasped, retracted, and resected (panel A). Endometriosis compresses the left ureter (panel B). The peritoneum above the lesion is entered, the ureter is displaced laterally, and the lesion is safely resected.

What we do, and recommend

When endometriosis is superficial and does not overlie vital organs, such as the bladder, ureter, and bowel, ablation and resection may be equally safe and effective. When endometriosis is deep and overlying vital organs, however, complete resection—with careful dissection of the lesion off underlying structures—offers a more complete and a safer surgical approach.

CASE continued

Now that S. D. has been treated surgically by complete excision of endometriosis, adhesions, and endometriomas, you must consider a management plan that will reduce the risks 1) of recurrence of symptoms and disease and 2) that further surgery will be necessary in the future—a risk that, in her case, exceeds 50% because of her young age, nulliparity, and the severity of her disease.^20,21 Indeed, you are aware that, had preventive measures been implemented after her initial surgery 2 years earlier, it is unlikely that S. D. would have developed the second endometrioma and most likely that she would not have needed the second surgery.

Prevention of recurrence is necessary—and doable

The importance of implementing preventive measures to reduce the risk of recurrence of endometriosis and its symptoms has been suggested by several studies. It was underscored recently in a prospective, randomized study conducted by Serracchioli and colleagues,²² in which 239 women who had undergone laparoscopic resection of endometriomas were randomly assigned to expectant management (control group), a cyclic oral contraceptive (OC), or a continuous oral contraceptives for 24 months, and evaluated every 6 months.

At the end of the study, recurrence of symptoms occurred in 30% of controls; 15% of subjects taking a cyclic OC; and 7.5% of the subjects taking a continuous OC. The recurrence rate of endometrioma in this study was reduced by 50% (cyclic OC) and 75% (continuous OC).²²

Similar results were reported in a case-controlled study by Vercellini and co-workers,²³ who found that the risk of recurrence of endometrioma was reduced by 60% when postoperative OCs were used long-term and by 30% when used for a duration of less than 12 months.

These studies suggest that, by suppressing ovulation and inducing a state of hypomenorrhea or amenorrhea, the risk of recurrence of endometriosis and its symptoms can be significantly reduced.

The importance of amenorrhea in reducing the postoperative recurrence of endometriosis and symptoms has been underscored by two important studies that evaluated the role of postoperative endometrial ablation or postoperative insertion of the levonorgestrel intrauterine system (LNG-IUS; Mirena), neither of which suppresses ovulation but both of which induce a state of hypomenorrhea or amenorrhea.^24,25

In a prospective randomized study by Bulletti and co-workers,²⁴ 28 patients who had symptomatic endometriosis underwent laparoscopic conservative surgery. Endometrial ablation was performed in 14 of the 28. Two years later, all patients underwent second-look laparoscopy; recurrence of endometriosis was found in 9 of the 14 non-ablation patients but in none in the ablation group. Resolution or significant improvement of symptoms were reported in 13 of 14 women in the ablation group but only in 3 of 14 in the non-ablation group—supporting the premise that amenorrhea or hypomenorrhea by itself, without suppressing ovulation, significantly reduces the risk that endometriosis will recur.

Similar beneficial results from hypomenorrhea/amenorrhea on the risk of recurrence of symptoms have been reported when the LNG-IUS is inserted following conservative surgery for endometriosis. In a prospective study by Vercellini and colleagues,²⁵ 40 symptomatic patients who had stage-III or stage-IV disease were randomized to either insertion of the LNG-IUS or a control group after conservative laparoscopic surgery. Recurrence of pain was significantly (P = .012) reduced in the LNG-IUS group (45%), compared with the control group (10%). Control subjects were also much less satisfied with their treatment than those who were treated with the LNG-IUS.

The importance of inducing a state of amenorrhea to reduce the risk of disease recurrence was further underscored by a recent study. Shakiba and colleagues²⁶ reported on the recurrence of endometriosis that required further surgery as long as 7 years after the subjects had been surgically treated for symptomatic endometriosis. The need for subsequent surgery was 8% after hysterectomy and bilateral salpingo-oophorectomy; 12% after hysterectomy alone; and 60% after conservative laparoscopy with preservation of both uterus and ovaries.

Taken together, these data show that, unless the patient is rendered amenorrheic or hypomenorrheic, her risk of recurrence exceeds 50%.

It is important, therefore, to consider conservative surgical management of endometriosis as only the beginning of a lifelong management plan. That plan begins with complete resection of all visible endometriosis and adhesions, resection of endometriomas, and restoration of normal anatomy as much as possible.

When endometriosis cannot be completely resected—as when it involves small bowel or the diaphragm, or is diffusely on the large bowel—we recommend medical suppressive therapy. Our preference is depot leuprolide acetate (Lupron Depot), always with add-back therapy to minimize side effects, which include vasomotor symptoms, vaginal dryness, and bone loss,²⁷ until the patient is significantly asymptomatic, which may take 6 to 9 months.

CASE Concluded, with long-term intervention

You counsel S. D. to remain on a low-dose hormonal OC continuously, until such time that she wants to conceive. If a patient does not want to conceive for at least 5 years, the LNG-IUS may be inserted at surgery to induce hypomenorrhea and reduce the risk of recurrence for the next 5 years.

When hormonal contraceptives are inadequate to control symptoms, adding the aromatase enzyme inhibitor letrozole (Femara), 2.5 mg daily for 6 to 9 months, usually alleviates symptoms with minimal side effects, as long as the patient keeps taking a hormonal contraceptive. Using letrozole without hormonal contraception has not been studied; doing so may lead to formation of ovarian cysts, and is therefore not recommended for managing symptomatic endometriosis.

If the patient wants to become pregnant, encourage her to actively undertake fertility treatment as soon as possible after surgery, thereby minimizing the risk of recurrence of symptoms and disease. The best option may be to employ assisted reproductive technology, but patients cannot always afford it; when that is the case, consider controlled ovarian stimulation and intrauterine insemination.

We want to hear from you! Tell us what you think.

As of January 2011, physicians are required to include detection of cognitive impairment as part of their health risk assessment in the Medicare Annual Wellness Visit.¹ The Centers for Medicare and Medicaid Services (CMS) specifically mandate an “assessment of an individual’s cognitive function by direct observation, with due consideration of information obtained by way of patient report, concerns raised by family members, friends, caretakers, or others.”² Unfortunately, these means of assessment may be unreliable.

Why observation alone won’t work. Physicians often fail to identify cognitive impairment^3-5 until it becomes quite severe.^6-8 This failure to diagnose may be due to time constraints,⁹,¹⁰ a focus on other health measures,¹¹ or the lack of appropriate and usable tools.^11-14 Reliance on patient self-report is also likely to be a flawed approach.¹⁵ A recent study found that most patients with dementia in a community sample denied they had memory problems.¹⁶ This is consistent with our clinical experience of 30 years in a tertiary memory assessment practice. These patients believe they are no worse off than their contemporaries and minimize or rationalize even demonstrable memory and functional problems. “I remember everything I need to remember” is a common response to the question, “How is your memory?”

During the comment period preceding implementation of the CMS regulation, 38 national organizations comprising the Partnership to Fight Chronic Disease¹⁷ argued that reliance on subjective measures alone is inadequate to achieve the stated goal of the legislation. We share this concern.

Improving cognition assessment. Although family complaints have been viewed as valid in at least 1 commonly used screening instrument, the AD8 (with more than 2 of 8 complaints likely to aid in dementia detection)¹⁸ does not reflect severity of impairment, nor does it provide a score to follow a patient’s course over time.

To better quantify the subjective perceptions of cognition by patients and their families, we developed the Visual Analog Cognition Scale (VACS)—which we’ll describe in a bit—and added it to our protocol of neuropsychological tests for dementia. Visual analog scales are well-accepted measures for a variety of subjective phenomena,¹⁹ including pain,²⁰ treatment response,²¹ sleep,²² affective states,²³ and quality of life.²⁴ We designed this current study to delineate the degree to which patient or informant perspective could assist physicians in the identification process.

We examined VACS responses from a consecutive sample of patients seen in our practice from July through December 2010. Our goal was to quantify the perceptions of patients and their informants regarding patients’ cognitive states across 5 important areas and to determine the relationship between these ratings and the objective results of neuropsychological evaluation. We also wanted to measure the relative accuracy of such subjective ratings with that of 2 validated screening tools, the Folstein Mini-Mental State Exam (MMSE)²⁵ and the recently published Memory Orientation Screening Test (MOST), which we developed.²⁶

Methods

Subjects
We administered the VACS to 201 patients as part of a 4-hour comprehensive neuropsychological evaluation. Patients were referred by community-based physicians, typically in primary care, neurology, or psychiatry. The sample was 66% female (n=133), with an average age of 78.5 (±6.8) years and an average education of 13.2 (±3.2) years. Of the 201 patients, 7 could not complete the VACS because of confusion or visual impairment; 20 had no accompanying informant. Of the 181 accompanied patients, 89 informants were grown children (49%), 64 were spouses (35%), 12 were siblings (7%), and 16 were friends or paid caregivers (9%).

Procedure
An administrative assistant handed each patient and informant the VACS as they checked in at the front desk. We asked them to fill out the questionnaire in the waiting room and advised them not to discuss their ratings with each other. We then conducted a comprehensive neuropsychological evaluation of the patient while another clinician separately interviewed the informant regarding the patient’s current health, cognitive and emotional symptoms, and daily function.

Instruments
The VACS is a 5-item, visual analog scale with parallel forms for patients (VACS-P) and informants (VACS-I). The form instructs the user to “Rate yourself (or the patient with whom you came) in each of these 5 areas by circling a number that best describes how you (they) are doing.” The 5 areas and their descriptions are:

• Attention: Keeping focused, avoiding being distracted, completing tasks
• Initiation: Starting tasks, following through, staying busy and active
• Judgment: Figuring things out and making good decisions
• Memory: Remembering new information and how to do things
• Self-care: Dressing, bathing, preparing food.

Each area has a visual analog scale of 1 to 10 below it, with each number occupying a box in a continuous sequence. Words appear above some of the numbers to help anchor the ratings in a systematic way: 1=very poor; 4=fair; 7=good; 10=very good.

The MMSE and its properties are well known. The MOST is a 29-point scale comprising 3-word recall, orientation to 6 date-and-time items, unforewarned recall of 12 pictured household items, and an 8-point clock drawing score. The validation study, using a total sample exceeding 1000 patients, demonstrated the MOST correlated highly and significantly (Pearson’s correlation coefficient [r]=0.81; P<.001) with dementia severity and 3 standardized memory tests. At a cutoff score of 18 points, it produced a 0.90 area under the curve (AUC) (95% confidence interval [CI], 0.87-0.94), with a sensitivity of 0.85 and specificity of 0.76, correctly classifying 83% of patients. Test-retest reliability was r≥0.90; P<.001 for both shorter (average 2-month) and longer (average 9-month) intervals.

With each patient, we conducted a diagnostic interview and administered a battery of standardized neuropsychological tests to assess intelligence, attention, executive function, language, and memory. The measures of primary interest for this investigation were the MOST, MMSE, delayed story memory (Wechsler Memory Scale-Revised [WMS-R] Logical Memory-II, or LM-II),²⁷ delayed visual memory (WMS-R Visual Recall-II, or VR-II), delayed recall of a 12-item repeated presentation list of common grocery store items (Shopping List Test-Recall, or SLT-R), and the 15-item Geriatric Depression Scale (GDS-15).²⁸ Additionally, each psychologist made a clinical diagnosis, according to Diagnostic and Statistical Manual of Mental Disorders [Fourth Edition] (DSM-IV)²⁹ criteria and rated the patient’s dementia severity (DS) on a 0-to-3 Clinical Dementia Rating-type scale.³⁰ We based diagnoses and severity ratings on age- and education-adjusted neuropsychological test scores, medical and psychiatric history, patient interview, and separate interview with a family informant.

Statistical methods
We calculated VACS totals for each patient and informant. Total VACS scores ranged from 5 to 50. MOST scores, comprising 3-word recall, 6-item orientation, 12-item list memory, and an 8-point clock drawing score, ranged from 0 to 29. We used the MMSE in the traditional method, counting the first error in spelling WORLD backwards, yielding a result of 0 to 30. The GDS score, 0 to 15, reflected the number of items indicating depression. We computed neuropsychological tests using standard scoring techniques. We rated dementia severity as: 0=normal cognition; 0.5=mild cognitive impairment; 1.0=mild dementia; 2.0=moderate dementia; and 3.0=severe dementia. We also assigned half-point ratings from 1 to 3.

We compared MOST, MMSE, VACS-P, and VACS-I scores with dementia severity and the 3 neuropsychological tests of delayed memory and the GDS-15. We computed Pearson’s correlation coefficients and their levels of significance vs 0. Tests of significant differences between correlations used Fisher’s z-transformation and tested the normalized difference vs 0.

Results

Diagnoses and dementia severity levels are listed in TABLE 1. TABLE 2 presents the mean scores for predictor and outcome variables. Correlations and significance ratings between the VACS-P, VACS-I, MOST, and MMSE with the criterion variables of Dementia Severity Rating, LM-II, VR-II, SLT-R, and GDS-15 are shown in TABLE 3.

Patients, on average, rated themselves as having “good” cognition overall. There was no difference in patient self-ratings between the top quartile of dementia severity (mean=34.6; SD= 8.6) and those in the lowest quartile (mean=36.4; SD=9.0). Informants rated the patients, on average, as having only “fair” cognition. Objective neuropsychological tests, however, found the patients, on average, to be mild to moderately demented and to have mild to moderate impairment on objective memory tests. Most patients were not depressed, with an average GDS score well below the clinical cutoff of 7 or more items. However, 30 of the 194 (15.5%) who completed the VACS-P fell into the clinical range for depression.

Patient self-ratings did not correlate (r=0.02) with dementia severity or with any of the 3 standardized memory tests. Informant scores correlated modestly with dementia severity and memory tests, but were significantly higher (P<.001) than those of the patients. Both the MOST (r=–0.86) and the MMSE (r=–0.76) had much stronger and highly significant (P<.001) correlations with dementia severity and with the memory measures (r=0.49–0.70). In addition, the MOST and MMSE were significantly (P<.001) better correlated with dementia severity and objective memory scores than were the informant ratings. Only the MMSE correlation with visual recall (P=.06) did not surpass that of the informant.

The MOST had a significantly higher correlation than the MMSE with dementia severity (P<.01) and with each of the 3 memory tests (P<.05). The MOST and MMSE scores were not related to level of depression (r=–0.01 and –0.03). Patient reports correlated significantly with depression level (r=–0.40; P<.001) as did those of the informants (r=–0.22; P<.01). Nevertheless, depression did not appear to be responsible for the limited relationship between patient self-ratings and objective test scores for cognition. When clinically depressed (GDS≥7) patients were removed from the analysis (remaining n=166), there was no significant improvement in the correlation between subjective ratings and objective scores.

We conducted a secondary analysis of patients whose cognition ranged between normal and mild-to-moderate dementia to see if more cognitively intact individuals would be more accurate at self-rating. In this subsample (n=127; mean age=77.3 years; 57% females), patient self-reports again did not correlate significantly (r=0.05) with dementia severity. Informant ratings remained modest, but significant (r=–0.25; P=.004) and statistically better (P<.05) than those of the patients. The MOST (r=–0.69; P<.001) and the MMSE (r=–0.54; P<.001) remained well-correlated with dementia severity and again outperformed the informant ratings (MOST, P<.001; MMSE, P<.05).

TABLE 1
Cognition diagnoses and severity levels in 201 consecutively evaluated elderly patients

TABLE 2
Mean test scores for predictor and outcome variables

TABLE 3
How the MOST, MMSE, and VACS predictor variables compared with outcome measures

DISCUSSION

Results of this study demonstrate that patients referred for specialized memory evaluation had virtually no idea of the degree of their cognitive impairment. Patients, on average, rated their function in 5 critical areas of cognition and behavior as “good.” While 80% of these patients demonstrated dementia on formal evaluation, more than 95% rated themselves as having good or very good cognition. Their ratings did not correlate with any objective memory measures or expert clinician opinion.

Patient and informant ratings are unreliable. Patients with better cognition, who might visit their doctor alone for the Annual Wellness Visit and would appear more intact, were no better at judging their cognition than the total patient sample. Both the patients with good cognition and those with dementia rated themselves equally unimpaired. This finding is not unique to the visual analog scale that we used in this study. When 148 self-nominated “cognitively healthy” community-dwelling elders took the MOST and a battery of neuropsychological tests as part of a norming study for the MOST,³¹ more than 20% would be classified as having dementia based on their memory and executive function test scores. These findings strongly suggest that patients cannot be relied on to inform their physician of cognitive impairment.

While informants possessed some knowledge about a patient’s cognitive status and were able to supply helpful anecdotal information, their ratings correlated only modestly with objectively measured cognition. This is not surprising given the volume of research demonstrating rater and observer bias.

Rely instead on an objective cognitive screening test. Of greatest relevance, these results indicate that an objective cognitive screening test is more accurate in identifying and measuring cognitive impairment than is the rating of a patient or an informant. Both the MOST and MMSE outperformed patients and informants in assessing patients’ severity of cognitive impairment, including those with milder problems. This last finding is particularly important given that less impaired patients are more likely to visit their doctor without an informant and to appear relatively intact when interviewed or observed by the physician.¹⁷ Without an objective test, their cognitive impairment would likely be missed.³²

The MOST outperformed the MMSE in detecting dementia and determining disease severity on a sample of 700 patients, and demonstrated twice the sensitivity for disease detection in those who were mildly impaired.²⁶ The current study confirms that the MOST has a significantly higher correlation with dementia severity than does the MMSE, and significantly higher correlations with longer standardized memory tests.

MOST, MMSE test-taking time varies, too. Time constraints are an important consideration in a medical office. The average time to administer the MOST on cognitively impaired patients (a group that is slower to perform than patients with normal cognition) is 4.5 minutes.²⁶ The MMSE, by comparison, takes 10 minutes or more.^33,34

Cognition is as measurable as body mass index, blood pressure, height, weight, and level of depression, also mandated in the Annual Wellness Visit. Numbers are easily recorded and compared, while impressions or even a positive (>2) AD8 score are less precise. Provider observation, even if informed by family report, is not as sound a basis for risk analysis, treatment planning, or future monitoring as is an objective measure. Because several current screening tests for dementia possess known reliabilities over time,^26,33,35 the physician can periodically repeat such a test to assess treatment response and ongoing risk.

Is there a place for a subjective rating scale? Possibly. A waiting room tool such as the VACS, combined with an objective test, may alert the clinician to a patient with anosognosia. These patients require different management strategies if treatment is to be effective. The care team faces an even greater challenge if an informant shares the patient’s lack of awareness. Conversely, a favorable cognitive screening result and a high score from the informant would give all parties assurance that cognition was normal.

Study limitations. The primary limitation of this study is that it was conducted in a tertiary memory center, where most patients have either suspected or demonstrated cognitive deficits. The relative proportion of normal to impaired patients is, consequently, different from that found in the primary care office, in which about 15% would have mild cognitive impairment³⁶ and a similar percentage would have dementia.³⁷ A replication of this study in such an environment would be helpful. On the other hand, without a companion neuropsychological evaluation as a criterion, the accuracy of self- or informant-report is more difficult to measure. As noted above, 20% of elders volunteering for a study on “normal cognitive functioning” showed significant objective deficits.³¹

Assessment of cognitive impairment in the primary care physician’s office is uniquely challenging. Physicians are taught to respond to the complaints of patients. But when a patient has dementia, that approach does not work. Family reports are helpful, but not sufficiently accurate. The recent Alzheimer’s Association report³⁷ notes that “Medicare’s new Annual Wellness Visit includes assessment for possible cognitive impairment,” but also points out that “many existing barriers affect the ability or willingness of individuals and their caregivers to recognize cognitive impairment and to discuss it with their physician.” We agree, and we believe that a sound approach to this problem would be for primary care physicians to consistently use an objective tool to measure cognitive functioning in the Annual Wellness Visit and in follow-up visits. A score that reflects the current level of cognition, provides diagnostic information, and reflects change in cognitive status over time will optimize this unique opportunity for earlier detection and potentially earlier treatment of dementia.

CORRESPONDENCE
Mitchell Clionsky, PhD, ABPP (CN), Clionsky Neuro Systems, 155 Maple Street, Suite 203, Springfield, MA 01105; [email protected]

As of January 2011, physicians are required to include detection of cognitive impairment as part of their health risk assessment in the Medicare Annual Wellness Visit.¹ The Centers for Medicare and Medicaid Services (CMS) specifically mandate an “assessment of an individual’s cognitive function by direct observation, with due consideration of information obtained by way of patient report, concerns raised by family members, friends, caretakers, or others.”² Unfortunately, these means of assessment may be unreliable.

Why observation alone won’t work. Physicians often fail to identify cognitive impairment^3-5 until it becomes quite severe.^6-8 This failure to diagnose may be due to time constraints,⁹,¹⁰ a focus on other health measures,¹¹ or the lack of appropriate and usable tools.^11-14 Reliance on patient self-report is also likely to be a flawed approach.¹⁵ A recent study found that most patients with dementia in a community sample denied they had memory problems.¹⁶ This is consistent with our clinical experience of 30 years in a tertiary memory assessment practice. These patients believe they are no worse off than their contemporaries and minimize or rationalize even demonstrable memory and functional problems. “I remember everything I need to remember” is a common response to the question, “How is your memory?”

During the comment period preceding implementation of the CMS regulation, 38 national organizations comprising the Partnership to Fight Chronic Disease¹⁷ argued that reliance on subjective measures alone is inadequate to achieve the stated goal of the legislation. We share this concern.

Improving cognition assessment. Although family complaints have been viewed as valid in at least 1 commonly used screening instrument, the AD8 (with more than 2 of 8 complaints likely to aid in dementia detection)¹⁸ does not reflect severity of impairment, nor does it provide a score to follow a patient’s course over time.

To better quantify the subjective perceptions of cognition by patients and their families, we developed the Visual Analog Cognition Scale (VACS)—which we’ll describe in a bit—and added it to our protocol of neuropsychological tests for dementia. Visual analog scales are well-accepted measures for a variety of subjective phenomena,¹⁹ including pain,²⁰ treatment response,²¹ sleep,²² affective states,²³ and quality of life.²⁴ We designed this current study to delineate the degree to which patient or informant perspective could assist physicians in the identification process.

We examined VACS responses from a consecutive sample of patients seen in our practice from July through December 2010. Our goal was to quantify the perceptions of patients and their informants regarding patients’ cognitive states across 5 important areas and to determine the relationship between these ratings and the objective results of neuropsychological evaluation. We also wanted to measure the relative accuracy of such subjective ratings with that of 2 validated screening tools, the Folstein Mini-Mental State Exam (MMSE)²⁵ and the recently published Memory Orientation Screening Test (MOST), which we developed.²⁶

Methods

Subjects
We administered the VACS to 201 patients as part of a 4-hour comprehensive neuropsychological evaluation. Patients were referred by community-based physicians, typically in primary care, neurology, or psychiatry. The sample was 66% female (n=133), with an average age of 78.5 (±6.8) years and an average education of 13.2 (±3.2) years. Of the 201 patients, 7 could not complete the VACS because of confusion or visual impairment; 20 had no accompanying informant. Of the 181 accompanied patients, 89 informants were grown children (49%), 64 were spouses (35%), 12 were siblings (7%), and 16 were friends or paid caregivers (9%).

Procedure
An administrative assistant handed each patient and informant the VACS as they checked in at the front desk. We asked them to fill out the questionnaire in the waiting room and advised them not to discuss their ratings with each other. We then conducted a comprehensive neuropsychological evaluation of the patient while another clinician separately interviewed the informant regarding the patient’s current health, cognitive and emotional symptoms, and daily function.

Instruments
The VACS is a 5-item, visual analog scale with parallel forms for patients (VACS-P) and informants (VACS-I). The form instructs the user to “Rate yourself (or the patient with whom you came) in each of these 5 areas by circling a number that best describes how you (they) are doing.” The 5 areas and their descriptions are:

• Attention: Keeping focused, avoiding being distracted, completing tasks
• Initiation: Starting tasks, following through, staying busy and active
• Judgment: Figuring things out and making good decisions
• Memory: Remembering new information and how to do things
• Self-care: Dressing, bathing, preparing food.

Each area has a visual analog scale of 1 to 10 below it, with each number occupying a box in a continuous sequence. Words appear above some of the numbers to help anchor the ratings in a systematic way: 1=very poor; 4=fair; 7=good; 10=very good.

The MMSE and its properties are well known. The MOST is a 29-point scale comprising 3-word recall, orientation to 6 date-and-time items, unforewarned recall of 12 pictured household items, and an 8-point clock drawing score. The validation study, using a total sample exceeding 1000 patients, demonstrated the MOST correlated highly and significantly (Pearson’s correlation coefficient [r]=0.81; P<.001) with dementia severity and 3 standardized memory tests. At a cutoff score of 18 points, it produced a 0.90 area under the curve (AUC) (95% confidence interval [CI], 0.87-0.94), with a sensitivity of 0.85 and specificity of 0.76, correctly classifying 83% of patients. Test-retest reliability was r≥0.90; P<.001 for both shorter (average 2-month) and longer (average 9-month) intervals.

With each patient, we conducted a diagnostic interview and administered a battery of standardized neuropsychological tests to assess intelligence, attention, executive function, language, and memory. The measures of primary interest for this investigation were the MOST, MMSE, delayed story memory (Wechsler Memory Scale-Revised [WMS-R] Logical Memory-II, or LM-II),²⁷ delayed visual memory (WMS-R Visual Recall-II, or VR-II), delayed recall of a 12-item repeated presentation list of common grocery store items (Shopping List Test-Recall, or SLT-R), and the 15-item Geriatric Depression Scale (GDS-15).²⁸ Additionally, each psychologist made a clinical diagnosis, according to Diagnostic and Statistical Manual of Mental Disorders [Fourth Edition] (DSM-IV)²⁹ criteria and rated the patient’s dementia severity (DS) on a 0-to-3 Clinical Dementia Rating-type scale.³⁰ We based diagnoses and severity ratings on age- and education-adjusted neuropsychological test scores, medical and psychiatric history, patient interview, and separate interview with a family informant.

Statistical methods
We calculated VACS totals for each patient and informant. Total VACS scores ranged from 5 to 50. MOST scores, comprising 3-word recall, 6-item orientation, 12-item list memory, and an 8-point clock drawing score, ranged from 0 to 29. We used the MMSE in the traditional method, counting the first error in spelling WORLD backwards, yielding a result of 0 to 30. The GDS score, 0 to 15, reflected the number of items indicating depression. We computed neuropsychological tests using standard scoring techniques. We rated dementia severity as: 0=normal cognition; 0.5=mild cognitive impairment; 1.0=mild dementia; 2.0=moderate dementia; and 3.0=severe dementia. We also assigned half-point ratings from 1 to 3.

We compared MOST, MMSE, VACS-P, and VACS-I scores with dementia severity and the 3 neuropsychological tests of delayed memory and the GDS-15. We computed Pearson’s correlation coefficients and their levels of significance vs 0. Tests of significant differences between correlations used Fisher’s z-transformation and tested the normalized difference vs 0.

Results

Diagnoses and dementia severity levels are listed in TABLE 1. TABLE 2 presents the mean scores for predictor and outcome variables. Correlations and significance ratings between the VACS-P, VACS-I, MOST, and MMSE with the criterion variables of Dementia Severity Rating, LM-II, VR-II, SLT-R, and GDS-15 are shown in TABLE 3.

Patients, on average, rated themselves as having “good” cognition overall. There was no difference in patient self-ratings between the top quartile of dementia severity (mean=34.6; SD= 8.6) and those in the lowest quartile (mean=36.4; SD=9.0). Informants rated the patients, on average, as having only “fair” cognition. Objective neuropsychological tests, however, found the patients, on average, to be mild to moderately demented and to have mild to moderate impairment on objective memory tests. Most patients were not depressed, with an average GDS score well below the clinical cutoff of 7 or more items. However, 30 of the 194 (15.5%) who completed the VACS-P fell into the clinical range for depression.

Patient self-ratings did not correlate (r=0.02) with dementia severity or with any of the 3 standardized memory tests. Informant scores correlated modestly with dementia severity and memory tests, but were significantly higher (P<.001) than those of the patients. Both the MOST (r=–0.86) and the MMSE (r=–0.76) had much stronger and highly significant (P<.001) correlations with dementia severity and with the memory measures (r=0.49–0.70). In addition, the MOST and MMSE were significantly (P<.001) better correlated with dementia severity and objective memory scores than were the informant ratings. Only the MMSE correlation with visual recall (P=.06) did not surpass that of the informant.

The MOST had a significantly higher correlation than the MMSE with dementia severity (P<.01) and with each of the 3 memory tests (P<.05). The MOST and MMSE scores were not related to level of depression (r=–0.01 and –0.03). Patient reports correlated significantly with depression level (r=–0.40; P<.001) as did those of the informants (r=–0.22; P<.01). Nevertheless, depression did not appear to be responsible for the limited relationship between patient self-ratings and objective test scores for cognition. When clinically depressed (GDS≥7) patients were removed from the analysis (remaining n=166), there was no significant improvement in the correlation between subjective ratings and objective scores.

We conducted a secondary analysis of patients whose cognition ranged between normal and mild-to-moderate dementia to see if more cognitively intact individuals would be more accurate at self-rating. In this subsample (n=127; mean age=77.3 years; 57% females), patient self-reports again did not correlate significantly (r=0.05) with dementia severity. Informant ratings remained modest, but significant (r=–0.25; P=.004) and statistically better (P<.05) than those of the patients. The MOST (r=–0.69; P<.001) and the MMSE (r=–0.54; P<.001) remained well-correlated with dementia severity and again outperformed the informant ratings (MOST, P<.001; MMSE, P<.05).

TABLE 1
Cognition diagnoses and severity levels in 201 consecutively evaluated elderly patients

TABLE 2
Mean test scores for predictor and outcome variables

TABLE 3
How the MOST, MMSE, and VACS predictor variables compared with outcome measures

DISCUSSION

Results of this study demonstrate that patients referred for specialized memory evaluation had virtually no idea of the degree of their cognitive impairment. Patients, on average, rated their function in 5 critical areas of cognition and behavior as “good.” While 80% of these patients demonstrated dementia on formal evaluation, more than 95% rated themselves as having good or very good cognition. Their ratings did not correlate with any objective memory measures or expert clinician opinion.

Patient and informant ratings are unreliable. Patients with better cognition, who might visit their doctor alone for the Annual Wellness Visit and would appear more intact, were no better at judging their cognition than the total patient sample. Both the patients with good cognition and those with dementia rated themselves equally unimpaired. This finding is not unique to the visual analog scale that we used in this study. When 148 self-nominated “cognitively healthy” community-dwelling elders took the MOST and a battery of neuropsychological tests as part of a norming study for the MOST,³¹ more than 20% would be classified as having dementia based on their memory and executive function test scores. These findings strongly suggest that patients cannot be relied on to inform their physician of cognitive impairment.

While informants possessed some knowledge about a patient’s cognitive status and were able to supply helpful anecdotal information, their ratings correlated only modestly with objectively measured cognition. This is not surprising given the volume of research demonstrating rater and observer bias.

Rely instead on an objective cognitive screening test. Of greatest relevance, these results indicate that an objective cognitive screening test is more accurate in identifying and measuring cognitive impairment than is the rating of a patient or an informant. Both the MOST and MMSE outperformed patients and informants in assessing patients’ severity of cognitive impairment, including those with milder problems. This last finding is particularly important given that less impaired patients are more likely to visit their doctor without an informant and to appear relatively intact when interviewed or observed by the physician.¹⁷ Without an objective test, their cognitive impairment would likely be missed.³²

The MOST outperformed the MMSE in detecting dementia and determining disease severity on a sample of 700 patients, and demonstrated twice the sensitivity for disease detection in those who were mildly impaired.²⁶ The current study confirms that the MOST has a significantly higher correlation with dementia severity than does the MMSE, and significantly higher correlations with longer standardized memory tests.

MOST, MMSE test-taking time varies, too. Time constraints are an important consideration in a medical office. The average time to administer the MOST on cognitively impaired patients (a group that is slower to perform than patients with normal cognition) is 4.5 minutes.²⁶ The MMSE, by comparison, takes 10 minutes or more.^33,34

Cognition is as measurable as body mass index, blood pressure, height, weight, and level of depression, also mandated in the Annual Wellness Visit. Numbers are easily recorded and compared, while impressions or even a positive (>2) AD8 score are less precise. Provider observation, even if informed by family report, is not as sound a basis for risk analysis, treatment planning, or future monitoring as is an objective measure. Because several current screening tests for dementia possess known reliabilities over time,^26,33,35 the physician can periodically repeat such a test to assess treatment response and ongoing risk.

Is there a place for a subjective rating scale? Possibly. A waiting room tool such as the VACS, combined with an objective test, may alert the clinician to a patient with anosognosia. These patients require different management strategies if treatment is to be effective. The care team faces an even greater challenge if an informant shares the patient’s lack of awareness. Conversely, a favorable cognitive screening result and a high score from the informant would give all parties assurance that cognition was normal.

Study limitations. The primary limitation of this study is that it was conducted in a tertiary memory center, where most patients have either suspected or demonstrated cognitive deficits. The relative proportion of normal to impaired patients is, consequently, different from that found in the primary care office, in which about 15% would have mild cognitive impairment³⁶ and a similar percentage would have dementia.³⁷ A replication of this study in such an environment would be helpful. On the other hand, without a companion neuropsychological evaluation as a criterion, the accuracy of self- or informant-report is more difficult to measure. As noted above, 20% of elders volunteering for a study on “normal cognitive functioning” showed significant objective deficits.³¹

Assessment of cognitive impairment in the primary care physician’s office is uniquely challenging. Physicians are taught to respond to the complaints of patients. But when a patient has dementia, that approach does not work. Family reports are helpful, but not sufficiently accurate. The recent Alzheimer’s Association report³⁷ notes that “Medicare’s new Annual Wellness Visit includes assessment for possible cognitive impairment,” but also points out that “many existing barriers affect the ability or willingness of individuals and their caregivers to recognize cognitive impairment and to discuss it with their physician.” We agree, and we believe that a sound approach to this problem would be for primary care physicians to consistently use an objective tool to measure cognitive functioning in the Annual Wellness Visit and in follow-up visits. A score that reflects the current level of cognition, provides diagnostic information, and reflects change in cognitive status over time will optimize this unique opportunity for earlier detection and potentially earlier treatment of dementia.

CORRESPONDENCE
Mitchell Clionsky, PhD, ABPP (CN), Clionsky Neuro Systems, 155 Maple Street, Suite 203, Springfield, MA 01105; [email protected]

As of January 2011, physicians are required to include detection of cognitive impairment as part of their health risk assessment in the Medicare Annual Wellness Visit.¹ The Centers for Medicare and Medicaid Services (CMS) specifically mandate an “assessment of an individual’s cognitive function by direct observation, with due consideration of information obtained by way of patient report, concerns raised by family members, friends, caretakers, or others.”² Unfortunately, these means of assessment may be unreliable.

Why observation alone won’t work. Physicians often fail to identify cognitive impairment^3-5 until it becomes quite severe.^6-8 This failure to diagnose may be due to time constraints,⁹,¹⁰ a focus on other health measures,¹¹ or the lack of appropriate and usable tools.^11-14 Reliance on patient self-report is also likely to be a flawed approach.¹⁵ A recent study found that most patients with dementia in a community sample denied they had memory problems.¹⁶ This is consistent with our clinical experience of 30 years in a tertiary memory assessment practice. These patients believe they are no worse off than their contemporaries and minimize or rationalize even demonstrable memory and functional problems. “I remember everything I need to remember” is a common response to the question, “How is your memory?”

During the comment period preceding implementation of the CMS regulation, 38 national organizations comprising the Partnership to Fight Chronic Disease¹⁷ argued that reliance on subjective measures alone is inadequate to achieve the stated goal of the legislation. We share this concern.

Improving cognition assessment. Although family complaints have been viewed as valid in at least 1 commonly used screening instrument, the AD8 (with more than 2 of 8 complaints likely to aid in dementia detection)¹⁸ does not reflect severity of impairment, nor does it provide a score to follow a patient’s course over time.

To better quantify the subjective perceptions of cognition by patients and their families, we developed the Visual Analog Cognition Scale (VACS)—which we’ll describe in a bit—and added it to our protocol of neuropsychological tests for dementia. Visual analog scales are well-accepted measures for a variety of subjective phenomena,¹⁹ including pain,²⁰ treatment response,²¹ sleep,²² affective states,²³ and quality of life.²⁴ We designed this current study to delineate the degree to which patient or informant perspective could assist physicians in the identification process.

We examined VACS responses from a consecutive sample of patients seen in our practice from July through December 2010. Our goal was to quantify the perceptions of patients and their informants regarding patients’ cognitive states across 5 important areas and to determine the relationship between these ratings and the objective results of neuropsychological evaluation. We also wanted to measure the relative accuracy of such subjective ratings with that of 2 validated screening tools, the Folstein Mini-Mental State Exam (MMSE)²⁵ and the recently published Memory Orientation Screening Test (MOST), which we developed.²⁶

Methods

Subjects
We administered the VACS to 201 patients as part of a 4-hour comprehensive neuropsychological evaluation. Patients were referred by community-based physicians, typically in primary care, neurology, or psychiatry. The sample was 66% female (n=133), with an average age of 78.5 (±6.8) years and an average education of 13.2 (±3.2) years. Of the 201 patients, 7 could not complete the VACS because of confusion or visual impairment; 20 had no accompanying informant. Of the 181 accompanied patients, 89 informants were grown children (49%), 64 were spouses (35%), 12 were siblings (7%), and 16 were friends or paid caregivers (9%).

Procedure
An administrative assistant handed each patient and informant the VACS as they checked in at the front desk. We asked them to fill out the questionnaire in the waiting room and advised them not to discuss their ratings with each other. We then conducted a comprehensive neuropsychological evaluation of the patient while another clinician separately interviewed the informant regarding the patient’s current health, cognitive and emotional symptoms, and daily function.

Instruments
The VACS is a 5-item, visual analog scale with parallel forms for patients (VACS-P) and informants (VACS-I). The form instructs the user to “Rate yourself (or the patient with whom you came) in each of these 5 areas by circling a number that best describes how you (they) are doing.” The 5 areas and their descriptions are:

• Attention: Keeping focused, avoiding being distracted, completing tasks
• Initiation: Starting tasks, following through, staying busy and active
• Judgment: Figuring things out and making good decisions
• Memory: Remembering new information and how to do things
• Self-care: Dressing, bathing, preparing food.

Each area has a visual analog scale of 1 to 10 below it, with each number occupying a box in a continuous sequence. Words appear above some of the numbers to help anchor the ratings in a systematic way: 1=very poor; 4=fair; 7=good; 10=very good.

The MMSE and its properties are well known. The MOST is a 29-point scale comprising 3-word recall, orientation to 6 date-and-time items, unforewarned recall of 12 pictured household items, and an 8-point clock drawing score. The validation study, using a total sample exceeding 1000 patients, demonstrated the MOST correlated highly and significantly (Pearson’s correlation coefficient [r]=0.81; P<.001) with dementia severity and 3 standardized memory tests. At a cutoff score of 18 points, it produced a 0.90 area under the curve (AUC) (95% confidence interval [CI], 0.87-0.94), with a sensitivity of 0.85 and specificity of 0.76, correctly classifying 83% of patients. Test-retest reliability was r≥0.90; P<.001 for both shorter (average 2-month) and longer (average 9-month) intervals.

With each patient, we conducted a diagnostic interview and administered a battery of standardized neuropsychological tests to assess intelligence, attention, executive function, language, and memory. The measures of primary interest for this investigation were the MOST, MMSE, delayed story memory (Wechsler Memory Scale-Revised [WMS-R] Logical Memory-II, or LM-II),²⁷ delayed visual memory (WMS-R Visual Recall-II, or VR-II), delayed recall of a 12-item repeated presentation list of common grocery store items (Shopping List Test-Recall, or SLT-R), and the 15-item Geriatric Depression Scale (GDS-15).²⁸ Additionally, each psychologist made a clinical diagnosis, according to Diagnostic and Statistical Manual of Mental Disorders [Fourth Edition] (DSM-IV)²⁹ criteria and rated the patient’s dementia severity (DS) on a 0-to-3 Clinical Dementia Rating-type scale.³⁰ We based diagnoses and severity ratings on age- and education-adjusted neuropsychological test scores, medical and psychiatric history, patient interview, and separate interview with a family informant.

Statistical methods
We calculated VACS totals for each patient and informant. Total VACS scores ranged from 5 to 50. MOST scores, comprising 3-word recall, 6-item orientation, 12-item list memory, and an 8-point clock drawing score, ranged from 0 to 29. We used the MMSE in the traditional method, counting the first error in spelling WORLD backwards, yielding a result of 0 to 30. The GDS score, 0 to 15, reflected the number of items indicating depression. We computed neuropsychological tests using standard scoring techniques. We rated dementia severity as: 0=normal cognition; 0.5=mild cognitive impairment; 1.0=mild dementia; 2.0=moderate dementia; and 3.0=severe dementia. We also assigned half-point ratings from 1 to 3.

We compared MOST, MMSE, VACS-P, and VACS-I scores with dementia severity and the 3 neuropsychological tests of delayed memory and the GDS-15. We computed Pearson’s correlation coefficients and their levels of significance vs 0. Tests of significant differences between correlations used Fisher’s z-transformation and tested the normalized difference vs 0.

Results

Diagnoses and dementia severity levels are listed in TABLE 1. TABLE 2 presents the mean scores for predictor and outcome variables. Correlations and significance ratings between the VACS-P, VACS-I, MOST, and MMSE with the criterion variables of Dementia Severity Rating, LM-II, VR-II, SLT-R, and GDS-15 are shown in TABLE 3.

Patients, on average, rated themselves as having “good” cognition overall. There was no difference in patient self-ratings between the top quartile of dementia severity (mean=34.6; SD= 8.6) and those in the lowest quartile (mean=36.4; SD=9.0). Informants rated the patients, on average, as having only “fair” cognition. Objective neuropsychological tests, however, found the patients, on average, to be mild to moderately demented and to have mild to moderate impairment on objective memory tests. Most patients were not depressed, with an average GDS score well below the clinical cutoff of 7 or more items. However, 30 of the 194 (15.5%) who completed the VACS-P fell into the clinical range for depression.

Patient self-ratings did not correlate (r=0.02) with dementia severity or with any of the 3 standardized memory tests. Informant scores correlated modestly with dementia severity and memory tests, but were significantly higher (P<.001) than those of the patients. Both the MOST (r=–0.86) and the MMSE (r=–0.76) had much stronger and highly significant (P<.001) correlations with dementia severity and with the memory measures (r=0.49–0.70). In addition, the MOST and MMSE were significantly (P<.001) better correlated with dementia severity and objective memory scores than were the informant ratings. Only the MMSE correlation with visual recall (P=.06) did not surpass that of the informant.

The MOST had a significantly higher correlation than the MMSE with dementia severity (P<.01) and with each of the 3 memory tests (P<.05). The MOST and MMSE scores were not related to level of depression (r=–0.01 and –0.03). Patient reports correlated significantly with depression level (r=–0.40; P<.001) as did those of the informants (r=–0.22; P<.01). Nevertheless, depression did not appear to be responsible for the limited relationship between patient self-ratings and objective test scores for cognition. When clinically depressed (GDS≥7) patients were removed from the analysis (remaining n=166), there was no significant improvement in the correlation between subjective ratings and objective scores.

We conducted a secondary analysis of patients whose cognition ranged between normal and mild-to-moderate dementia to see if more cognitively intact individuals would be more accurate at self-rating. In this subsample (n=127; mean age=77.3 years; 57% females), patient self-reports again did not correlate significantly (r=0.05) with dementia severity. Informant ratings remained modest, but significant (r=–0.25; P=.004) and statistically better (P<.05) than those of the patients. The MOST (r=–0.69; P<.001) and the MMSE (r=–0.54; P<.001) remained well-correlated with dementia severity and again outperformed the informant ratings (MOST, P<.001; MMSE, P<.05).

TABLE 1
Cognition diagnoses and severity levels in 201 consecutively evaluated elderly patients

TABLE 2
Mean test scores for predictor and outcome variables

TABLE 3
How the MOST, MMSE, and VACS predictor variables compared with outcome measures

DISCUSSION

Results of this study demonstrate that patients referred for specialized memory evaluation had virtually no idea of the degree of their cognitive impairment. Patients, on average, rated their function in 5 critical areas of cognition and behavior as “good.” While 80% of these patients demonstrated dementia on formal evaluation, more than 95% rated themselves as having good or very good cognition. Their ratings did not correlate with any objective memory measures or expert clinician opinion.

Patient and informant ratings are unreliable. Patients with better cognition, who might visit their doctor alone for the Annual Wellness Visit and would appear more intact, were no better at judging their cognition than the total patient sample. Both the patients with good cognition and those with dementia rated themselves equally unimpaired. This finding is not unique to the visual analog scale that we used in this study. When 148 self-nominated “cognitively healthy” community-dwelling elders took the MOST and a battery of neuropsychological tests as part of a norming study for the MOST,³¹ more than 20% would be classified as having dementia based on their memory and executive function test scores. These findings strongly suggest that patients cannot be relied on to inform their physician of cognitive impairment.

While informants possessed some knowledge about a patient’s cognitive status and were able to supply helpful anecdotal information, their ratings correlated only modestly with objectively measured cognition. This is not surprising given the volume of research demonstrating rater and observer bias.

Rely instead on an objective cognitive screening test. Of greatest relevance, these results indicate that an objective cognitive screening test is more accurate in identifying and measuring cognitive impairment than is the rating of a patient or an informant. Both the MOST and MMSE outperformed patients and informants in assessing patients’ severity of cognitive impairment, including those with milder problems. This last finding is particularly important given that less impaired patients are more likely to visit their doctor without an informant and to appear relatively intact when interviewed or observed by the physician.¹⁷ Without an objective test, their cognitive impairment would likely be missed.³²

The MOST outperformed the MMSE in detecting dementia and determining disease severity on a sample of 700 patients, and demonstrated twice the sensitivity for disease detection in those who were mildly impaired.²⁶ The current study confirms that the MOST has a significantly higher correlation with dementia severity than does the MMSE, and significantly higher correlations with longer standardized memory tests.

MOST, MMSE test-taking time varies, too. Time constraints are an important consideration in a medical office. The average time to administer the MOST on cognitively impaired patients (a group that is slower to perform than patients with normal cognition) is 4.5 minutes.²⁶ The MMSE, by comparison, takes 10 minutes or more.^33,34

Cognition is as measurable as body mass index, blood pressure, height, weight, and level of depression, also mandated in the Annual Wellness Visit. Numbers are easily recorded and compared, while impressions or even a positive (>2) AD8 score are less precise. Provider observation, even if informed by family report, is not as sound a basis for risk analysis, treatment planning, or future monitoring as is an objective measure. Because several current screening tests for dementia possess known reliabilities over time,^26,33,35 the physician can periodically repeat such a test to assess treatment response and ongoing risk.

Is there a place for a subjective rating scale? Possibly. A waiting room tool such as the VACS, combined with an objective test, may alert the clinician to a patient with anosognosia. These patients require different management strategies if treatment is to be effective. The care team faces an even greater challenge if an informant shares the patient’s lack of awareness. Conversely, a favorable cognitive screening result and a high score from the informant would give all parties assurance that cognition was normal.

Study limitations. The primary limitation of this study is that it was conducted in a tertiary memory center, where most patients have either suspected or demonstrated cognitive deficits. The relative proportion of normal to impaired patients is, consequently, different from that found in the primary care office, in which about 15% would have mild cognitive impairment³⁶ and a similar percentage would have dementia.³⁷ A replication of this study in such an environment would be helpful. On the other hand, without a companion neuropsychological evaluation as a criterion, the accuracy of self- or informant-report is more difficult to measure. As noted above, 20% of elders volunteering for a study on “normal cognitive functioning” showed significant objective deficits.³¹

Assessment of cognitive impairment in the primary care physician’s office is uniquely challenging. Physicians are taught to respond to the complaints of patients. But when a patient has dementia, that approach does not work. Family reports are helpful, but not sufficiently accurate. The recent Alzheimer’s Association report³⁷ notes that “Medicare’s new Annual Wellness Visit includes assessment for possible cognitive impairment,” but also points out that “many existing barriers affect the ability or willingness of individuals and their caregivers to recognize cognitive impairment and to discuss it with their physician.” We agree, and we believe that a sound approach to this problem would be for primary care physicians to consistently use an objective tool to measure cognitive functioning in the Annual Wellness Visit and in follow-up visits. A score that reflects the current level of cognition, provides diagnostic information, and reflects change in cognitive status over time will optimize this unique opportunity for earlier detection and potentially earlier treatment of dementia.

CORRESPONDENCE
Mitchell Clionsky, PhD, ABPP (CN), Clionsky Neuro Systems, 155 Maple Street, Suite 203, Springfield, MA 01105; [email protected]

CASE Jim F, 40 years old and overweight (BMI=28 kg/m²), has come to see you because of foot pain that began shortly after he took up running. Jim tells you that turning 40 was “an eye opener” that prompted him to “get healthy.” He says that while he was a competitive athlete in high school, he never ran regularly—until he embarked on a running program 3 months ago.

Jim denies acute injury, bruising, swelling, redness, fever, or chills, but states that the pain, which he describes as dull and achy, is gradually getting worse. It hurts the most when he stands for long periods of time. He says that he occasionally takes ibuprofen for the foot pain, but has not tried icing or stretching. When you ask him what kind of sneakers he wears during his runs, Jim reports that his running shoes—purchased at a discount store—are about 5 years old.

Participation in running has grown by more than 40% in the United States in the past decade.¹ As a result, patients like Jim are bound to have their share of aches, pains, and injuries that prompt them to visit their family physician. And that’s where this review can help. This rundown of the most common foot pain diagnoses, as well as the at-a-glance summaries of the differential diagnosis (TABLE 1)^2-5 and treatment options (TABLE 2),^3,6-25 can help you quickly get patients the relief they need to return to running.

TABLE 1
Differential diagnosis for runners’ foot pain^2-5

TABLE 2
Diagnosing and treating common runners’ injuries

Metatarsalgia: Pain on the plantar surface

Typically associated with a recent increase in activity or change in footwear, metatarsalgia is defined by pain on the plantar surface of the forefoot in the area of the metatarsal heads. The second, third, and fourth metatarsals are the most common offenders, and the pain may or may not be accompanied by swelling, bruising, or deformity.

Mechanical irregularities in the foot are thought to contribute to the development of metatarsalgia, which is typically inflammatory in nature. Physical exam often reveals tenderness at the affected metatarsal heads, with or without pain in the corresponding metatarsophalangeal joint, and occasionally, with overlying edema or hyperkeratosis.

Tuning fork test. Commonly used but weakly supported, this diagnostic test is performed by applying a vibrating tuning fork to a site of possible fracture. If the maneuver produces focal pain, the test is positive and may be helpful in ruling in metatarsal stress fractures.²⁶

Treatment: Change shoes, consider NSAIDs. Treatment for metatarsalgia begins conservatively, with a change in footwear. High heels or pointy-toed shoes should be avoided, and metatarsal pads (FIGURE 1) can be placed inside the shoes to help off-load the metatarsal head.⁶ The pads come prefabricated or can be custom made, and are typically placed by physical therapists to ensure proper placement. Orthotics should also be considered, as they can help normalize abnormal foot mechanics that may contribute to metatarsalgia.^7,8 (See “A word about runners’ footwear”.^9,27-31)

Metatarsalgia is believed to be an inflammatory process, and NSAIDs may be helpful. Contrast baths—alternately submerging the affected foot in a basin of hot (but not scalding) water for 1 to 2 minutes, then immersing it in cold water for 30 to 60 seconds and repeating the process for about 20 minutes once or twice daily—may be helpful. Magnetic insoles are not recommended, as they have been found to be no better than sham insoles.³² Rarely, surgical repair of underlying mechanical abnormalities is indicated for treatment of refractory metatarsalgia.

CASE On examination, Jim F has no swelling, but some hyperkeratosis overlying the second and third metatarsal heads. He has tenderness to palpation at these heads as well as the corresponding metatarsophalangeal joints, and a negative tuning fork test.

You advise Jim that he has metatarsalgia, educate him about the pathophysiology of this condition, and give him a prescription for a nonsteroidal anti-inflammatory drug. You suggest he use contrast baths—and explain how this is done—once or twice a day and refer him to physical therapy for proper placement of metatarsal pads in his shoes, and schedule an appointment for a 6-week follow-up.

Return to running. There is no firm recommendation regarding abstaining from running with metatarsalgia. Advise patients to use pain as a guide in determining the intensity and duration of activity.

FIGURE 1
Treatment for metatarsalgia is conservative

Stress fracture: Tenderness and pain of insidious onset

Stress fractures of the foot (SFF)—overuse injuries also known as fatigue fractures—are common in recreational runners. They are thought to result from microtraumas, which alone are not sufficient to break bone but together overwhelm the bone’s natural ability to remodel and recover over time. SFF are characterized by tenderness and pain of insidious onset, and typically occur when more than one training variable (eg, frequency, duration, and intensity) is changed simultaneously. SFF can also result from a change in exercise mechanics, such as foot strike.

Stress fractures can occur in any bone in the foot, but are most common in the metatarsal bones, specifically the mid or distal portion of the second or third metatarsal, or the tarsal navicular.^2,33 On examination, the patient will have tenderness to palpation, often well localized. A positive tuning fork test (see page 647) is highly suggestive of a stress fracture.

FAST TRACK

Some studies suggest that barefoot running or barefoot running shoes improve running mechanics; other studies have had unfavorable or inconsistent results.

In female runners, stress fractures may be associated with the female athlete triad—osteoporosis or osteopenia, disordered eating (specifically caloric deficiency and low BMI), and amenorrhea. In addition to the major long-term health problems that may result from even one component of the triad, SFF may be a short-term consequence.³⁴

Although SFF is a clinical diagnosis, x-rays—including 3-view plain films of the foot, with the area of concern clearly noted on the order—are recommended. Magnetic resonance imaging may be used for secondary imaging if doubt about the source of the pain remains.³⁵

Of note: Occasionally, a metatarsal stress fracture progresses to a frank fracture, specifically of the metaphyseal-diaphyseal junction of the fifth metatarsal—known as a Jones fracture. This type of fracture has a high rate of malunion or nonunion.³⁶ If there is any suspicion of a fracture in this area, consider a referral to a sports medicine specialist or orthopedic surgeon.

Treatment: Icing, analgesics, and a boot. Standard treatment for SFF includes icing for 15 to 20 minutes up to 3 times a day for a minimum of 72 hours after injury, but may be continued throughout the healing period. Analgesics such as acetaminophen and a walking boot for 3 to 4 weeks, with follow-up at 3 weeks, should also be implemented. Recent evidence suggests that NSAIDs may hinder the bone healing process, and their use in treating SFF is controversial.^10-12

Weaning from the boot can begin when the patient is pain free with the boot on, usually by 3 to 4 weeks. Patients often progress quickly from wearing the boot at all times to wearing it only outside of the house, to not wearing it at all. Advise patients who need to walk long distances for a good portion of the day to keep the boot nearby and to put it on if the pain returns.

Once weaning from the boot begins, physical therapy (PT) should be considered to help the patient regain foot and ankle range of motion (ROM), proprioception, and strength. Once he or she learns the exercises, rehabilitation can be accomplished with a home exercise program. Foot deformities, such as pes planus or pes cavus, may indicate a need for orthotics. A well-structured athletic shoe may help to prevent future injury.^7,8

Return to running. Once adequate ROM and strength in the foot and ankle are recovered, the patient can begin to resume activity, starting with a low-impact cross-training exercise, such as a stationary bike or elliptical, for a week or 2. A patient who remains pain free can progress from cross-training to running on a treadmill for another week or 2, then gradually switch to outdoor running.

Plantar fasciitis: Heel pain with an insidious onset

Plantar fasciitis is one of the most common causes of heel pain in athletes (primarily runners) and nonathletes alike. Plantar fasciitis may be associated with acute trauma, but is more commonly insidious in onset. The diagnosis is clinical and rarely requires imaging.

Pain associated with plantar fasciitis may be described as sharp and stabbing or dull and aching. It is on the plantar surface of the heel, sometimes radiating to the arch, and may localize to the insertion of the plantar fascia on the medial calcaneal tubercle (FIGURE 2). The pain is typically most severe with the first few steps in the morning or after other periods of prolonged rest. It usually improves after a few steps, but may return later in the day. Plantar fasciitis does not cause paresthesias or other neurologic symptoms, so their presence is suggestive of a different diagnosis, such as nerve entrapment, compartment syndrome, or tarsal tunnel syndrome.^3,5

Treatment: It’s multifactorial. NSAIDs are commonly used. Relative rest is recommended, but cross training may be considered to maintain fitness.³⁷ Short-term PT is also recommended to teach the patient proper stretching and strengthening techniques in the form of a home exercise plan. Modalities such as iontophoresis (a system of transdermal delivery of medication with the use of electrical currents), Graston (a form of instrument-assisted soft tissue mobilization), and taping may be incorporated into PT, as well.¹³

Night splinting may also be used to keep the foot in a dorsiflexed position. A splint can be purchased without a prescription and prevents the plantar fascia from shortening overnight by providing a continuous passive stretch, thus reducing pain with first steps.¹⁴

Orthotics may also help to reduce symptom severity and duration, and studies have found no difference in outcomes with prefabricated vs custom-made devices.¹⁵ Another treatment to consider, particularly for recalcitrant cases of plantar fasciitis, is extracorporeal shock wave therapy, which has been studied for more than a decade with conflicting results.¹⁶ Corticosteroid injection may also be used for treatment-refractory plantar fasciitis, but caution is required, as the injection may increase the risk of rupture of the plantar fascia.^17,18

Return to running. There are no set guidelines for when an athlete with plantar fasciitis can return to running. Typically, after 2 to 4 weeks of relative rest and other treatments, the runner can begin to transition from cross-training to treadmill running.

FIGURE 2
Severe pain with first steps of the day

Achilles tendinopathy: An overuse injury

Achilles tendinopathy (AT) is typically an overuse injury incurred by athletes, although it is sometimes seen in patients who are sedentary and overweight. With a prevalence among runners of approximately 11%, AT is sometimes called the “runners’ disease.”⁴

Tendinopathy is a more accurate description than tendonitis, as histologic studies of affected Achilles tendons suggest that AT is a degenerative, rather than an inflammatory, condition.³⁸ A diagnosis of AT can be further classified as midportion or insertional.

Midportion Achilles tendinopathy (MAT), characterized by pain that occurs in the body of the Achilles tendon and worsens with activity, is often a clinical diagnosis. Physical findings suggestive of MAT are tenderness to palpation of the midportion of the Achilles tendon, with thickening of the tendon, warmth, crepitus, or palpable nodules in the tendon body. Onset is insidious and is commonly associated with an increase in activity.

Treatment: Orthotics or a heel lift. Like that of plantar fasciitis, treatment of midportion Achilles tendinopathy is primarily conservative. The use of orthotics, or a heel lift, is one of the most cost-effective interventions, and they are widely used, despite limited evidence of efficacy.³⁹ Custom orthotics are costly, and patients often benefit from trying prefabricated orthotics first to determine whether they will help.

Eccentric exercises. One of the most studied interventions for MAT is eccentric exercise training. Studies of eccentric exercises have been very favorable, and the exercises can be taught during routine PT sessions.^19-22 Modalities such as ultrasound therapy and extracorporeal shock wave therapy (ESWT) have also been studied. But because results have been inconsistent, they are generally reserved for treatment-refractory cases.²³

In patients with no contraindications, NSAIDs may be a good choice for pain management with relatively favorable results in the literature.²⁴ Corticosteroid injections should not be used, as they have been directly linked to rupture of the Achilles tendon.²³

Other interventions, such as plasma-rich protein injections and prolotherapy—a technique in which an irritant is injected into the tendon in an attempt to create an inflammatory reaction, thus increasing local blood flow and healing—are being studied for the treatment of AT, but are not routinely used or covered by insurance for this purpose. Surgical intervention may be considered for patients whose symptoms last for more than 3 to 6 months despite conservative treatment.

Insertional Achilles tendinopathy (IAT) can be clinically differentiated from MAT by the location of symptoms and tenderness to palpation at the insertion site of the Achilles into the calcaneous. Like MAT, IAT is exacerbated by activity. Other conditions that may contribute to, or be mistaken for, IAT are a Haglund deformity and retrocalcaneal bursitis.

Treatment: Footwear modification. Treatment of IAT, like that of MAT, is primarily conservative. Orthotics or heel lifts are commonly used. However, there is greater emphasis on footwear modification due to the mechanical irritation and resultant posterior heel swelling often associated with IAT. While eccentric exercises play a role in IAT treatment, the benefits are limited.²⁵

As with MAT, corticosteroid injections are contraindicated due to the risk of tendon rupture. Modalities such as ultrasound, ESWT, plasma-rich protein, and prolotherapy lack sufficient evidence to be widely recommended.

For refractory cases of IAT, surgical intervention often relieves the pain.

Return to running. After an initial rest of 2 to 4 weeks, patients may return to running while completing therapy. It’s not necessary to wait until the patient is completely pain free, but pain should be used to guide decisions about intensity and duration of activity.

CASE When Jim returns 6 weeks later, he reports that he took 3 weeks off from running because of the pain. Initially, he used contrast baths daily, Jim says, but now he uses them only when he is symptomatic, and he discontinued the NSAID a few weeks ago. Jim tells you he went to the local running store for a new pair of running shoes and that he is now able to run at his previous pace while remaining relatively pain free.

CORRESPONDENCE Jessica Favero Butts, MD, One American Square, Suite 185, Indianapolis, IN 46282; [email protected]

CASE Jim F, 40 years old and overweight (BMI=28 kg/m²), has come to see you because of foot pain that began shortly after he took up running. Jim tells you that turning 40 was “an eye opener” that prompted him to “get healthy.” He says that while he was a competitive athlete in high school, he never ran regularly—until he embarked on a running program 3 months ago.

Jim denies acute injury, bruising, swelling, redness, fever, or chills, but states that the pain, which he describes as dull and achy, is gradually getting worse. It hurts the most when he stands for long periods of time. He says that he occasionally takes ibuprofen for the foot pain, but has not tried icing or stretching. When you ask him what kind of sneakers he wears during his runs, Jim reports that his running shoes—purchased at a discount store—are about 5 years old.

Participation in running has grown by more than 40% in the United States in the past decade.¹ As a result, patients like Jim are bound to have their share of aches, pains, and injuries that prompt them to visit their family physician. And that’s where this review can help. This rundown of the most common foot pain diagnoses, as well as the at-a-glance summaries of the differential diagnosis (TABLE 1)^2-5 and treatment options (TABLE 2),^3,6-25 can help you quickly get patients the relief they need to return to running.

TABLE 1
Differential diagnosis for runners’ foot pain^2-5

TABLE 2
Diagnosing and treating common runners’ injuries

Metatarsalgia: Pain on the plantar surface

Typically associated with a recent increase in activity or change in footwear, metatarsalgia is defined by pain on the plantar surface of the forefoot in the area of the metatarsal heads. The second, third, and fourth metatarsals are the most common offenders, and the pain may or may not be accompanied by swelling, bruising, or deformity.

Mechanical irregularities in the foot are thought to contribute to the development of metatarsalgia, which is typically inflammatory in nature. Physical exam often reveals tenderness at the affected metatarsal heads, with or without pain in the corresponding metatarsophalangeal joint, and occasionally, with overlying edema or hyperkeratosis.

Tuning fork test. Commonly used but weakly supported, this diagnostic test is performed by applying a vibrating tuning fork to a site of possible fracture. If the maneuver produces focal pain, the test is positive and may be helpful in ruling in metatarsal stress fractures.²⁶

Treatment: Change shoes, consider NSAIDs. Treatment for metatarsalgia begins conservatively, with a change in footwear. High heels or pointy-toed shoes should be avoided, and metatarsal pads (FIGURE 1) can be placed inside the shoes to help off-load the metatarsal head.⁶ The pads come prefabricated or can be custom made, and are typically placed by physical therapists to ensure proper placement. Orthotics should also be considered, as they can help normalize abnormal foot mechanics that may contribute to metatarsalgia.^7,8 (See “A word about runners’ footwear”.^9,27-31)

Metatarsalgia is believed to be an inflammatory process, and NSAIDs may be helpful. Contrast baths—alternately submerging the affected foot in a basin of hot (but not scalding) water for 1 to 2 minutes, then immersing it in cold water for 30 to 60 seconds and repeating the process for about 20 minutes once or twice daily—may be helpful. Magnetic insoles are not recommended, as they have been found to be no better than sham insoles.³² Rarely, surgical repair of underlying mechanical abnormalities is indicated for treatment of refractory metatarsalgia.

CASE On examination, Jim F has no swelling, but some hyperkeratosis overlying the second and third metatarsal heads. He has tenderness to palpation at these heads as well as the corresponding metatarsophalangeal joints, and a negative tuning fork test.

You advise Jim that he has metatarsalgia, educate him about the pathophysiology of this condition, and give him a prescription for a nonsteroidal anti-inflammatory drug. You suggest he use contrast baths—and explain how this is done—once or twice a day and refer him to physical therapy for proper placement of metatarsal pads in his shoes, and schedule an appointment for a 6-week follow-up.

Return to running. There is no firm recommendation regarding abstaining from running with metatarsalgia. Advise patients to use pain as a guide in determining the intensity and duration of activity.

FIGURE 1
Treatment for metatarsalgia is conservative

Stress fracture: Tenderness and pain of insidious onset

Stress fractures of the foot (SFF)—overuse injuries also known as fatigue fractures—are common in recreational runners. They are thought to result from microtraumas, which alone are not sufficient to break bone but together overwhelm the bone’s natural ability to remodel and recover over time. SFF are characterized by tenderness and pain of insidious onset, and typically occur when more than one training variable (eg, frequency, duration, and intensity) is changed simultaneously. SFF can also result from a change in exercise mechanics, such as foot strike.

Stress fractures can occur in any bone in the foot, but are most common in the metatarsal bones, specifically the mid or distal portion of the second or third metatarsal, or the tarsal navicular.^2,33 On examination, the patient will have tenderness to palpation, often well localized. A positive tuning fork test (see page 647) is highly suggestive of a stress fracture.

FAST TRACK

Some studies suggest that barefoot running or barefoot running shoes improve running mechanics; other studies have had unfavorable or inconsistent results.

In female runners, stress fractures may be associated with the female athlete triad—osteoporosis or osteopenia, disordered eating (specifically caloric deficiency and low BMI), and amenorrhea. In addition to the major long-term health problems that may result from even one component of the triad, SFF may be a short-term consequence.³⁴

Although SFF is a clinical diagnosis, x-rays—including 3-view plain films of the foot, with the area of concern clearly noted on the order—are recommended. Magnetic resonance imaging may be used for secondary imaging if doubt about the source of the pain remains.³⁵

Of note: Occasionally, a metatarsal stress fracture progresses to a frank fracture, specifically of the metaphyseal-diaphyseal junction of the fifth metatarsal—known as a Jones fracture. This type of fracture has a high rate of malunion or nonunion.³⁶ If there is any suspicion of a fracture in this area, consider a referral to a sports medicine specialist or orthopedic surgeon.

Treatment: Icing, analgesics, and a boot. Standard treatment for SFF includes icing for 15 to 20 minutes up to 3 times a day for a minimum of 72 hours after injury, but may be continued throughout the healing period. Analgesics such as acetaminophen and a walking boot for 3 to 4 weeks, with follow-up at 3 weeks, should also be implemented. Recent evidence suggests that NSAIDs may hinder the bone healing process, and their use in treating SFF is controversial.^10-12

Weaning from the boot can begin when the patient is pain free with the boot on, usually by 3 to 4 weeks. Patients often progress quickly from wearing the boot at all times to wearing it only outside of the house, to not wearing it at all. Advise patients who need to walk long distances for a good portion of the day to keep the boot nearby and to put it on if the pain returns.

Once weaning from the boot begins, physical therapy (PT) should be considered to help the patient regain foot and ankle range of motion (ROM), proprioception, and strength. Once he or she learns the exercises, rehabilitation can be accomplished with a home exercise program. Foot deformities, such as pes planus or pes cavus, may indicate a need for orthotics. A well-structured athletic shoe may help to prevent future injury.^7,8

Return to running. Once adequate ROM and strength in the foot and ankle are recovered, the patient can begin to resume activity, starting with a low-impact cross-training exercise, such as a stationary bike or elliptical, for a week or 2. A patient who remains pain free can progress from cross-training to running on a treadmill for another week or 2, then gradually switch to outdoor running.

Plantar fasciitis: Heel pain with an insidious onset

Plantar fasciitis is one of the most common causes of heel pain in athletes (primarily runners) and nonathletes alike. Plantar fasciitis may be associated with acute trauma, but is more commonly insidious in onset. The diagnosis is clinical and rarely requires imaging.

Pain associated with plantar fasciitis may be described as sharp and stabbing or dull and aching. It is on the plantar surface of the heel, sometimes radiating to the arch, and may localize to the insertion of the plantar fascia on the medial calcaneal tubercle (FIGURE 2). The pain is typically most severe with the first few steps in the morning or after other periods of prolonged rest. It usually improves after a few steps, but may return later in the day. Plantar fasciitis does not cause paresthesias or other neurologic symptoms, so their presence is suggestive of a different diagnosis, such as nerve entrapment, compartment syndrome, or tarsal tunnel syndrome.^3,5

Treatment: It’s multifactorial. NSAIDs are commonly used. Relative rest is recommended, but cross training may be considered to maintain fitness.³⁷ Short-term PT is also recommended to teach the patient proper stretching and strengthening techniques in the form of a home exercise plan. Modalities such as iontophoresis (a system of transdermal delivery of medication with the use of electrical currents), Graston (a form of instrument-assisted soft tissue mobilization), and taping may be incorporated into PT, as well.¹³

Night splinting may also be used to keep the foot in a dorsiflexed position. A splint can be purchased without a prescription and prevents the plantar fascia from shortening overnight by providing a continuous passive stretch, thus reducing pain with first steps.¹⁴

Orthotics may also help to reduce symptom severity and duration, and studies have found no difference in outcomes with prefabricated vs custom-made devices.¹⁵ Another treatment to consider, particularly for recalcitrant cases of plantar fasciitis, is extracorporeal shock wave therapy, which has been studied for more than a decade with conflicting results.¹⁶ Corticosteroid injection may also be used for treatment-refractory plantar fasciitis, but caution is required, as the injection may increase the risk of rupture of the plantar fascia.^17,18

Return to running. There are no set guidelines for when an athlete with plantar fasciitis can return to running. Typically, after 2 to 4 weeks of relative rest and other treatments, the runner can begin to transition from cross-training to treadmill running.

FIGURE 2
Severe pain with first steps of the day

Achilles tendinopathy: An overuse injury

Achilles tendinopathy (AT) is typically an overuse injury incurred by athletes, although it is sometimes seen in patients who are sedentary and overweight. With a prevalence among runners of approximately 11%, AT is sometimes called the “runners’ disease.”⁴

Tendinopathy is a more accurate description than tendonitis, as histologic studies of affected Achilles tendons suggest that AT is a degenerative, rather than an inflammatory, condition.³⁸ A diagnosis of AT can be further classified as midportion or insertional.

Midportion Achilles tendinopathy (MAT), characterized by pain that occurs in the body of the Achilles tendon and worsens with activity, is often a clinical diagnosis. Physical findings suggestive of MAT are tenderness to palpation of the midportion of the Achilles tendon, with thickening of the tendon, warmth, crepitus, or palpable nodules in the tendon body. Onset is insidious and is commonly associated with an increase in activity.

Treatment: Orthotics or a heel lift. Like that of plantar fasciitis, treatment of midportion Achilles tendinopathy is primarily conservative. The use of orthotics, or a heel lift, is one of the most cost-effective interventions, and they are widely used, despite limited evidence of efficacy.³⁹ Custom orthotics are costly, and patients often benefit from trying prefabricated orthotics first to determine whether they will help.

Eccentric exercises. One of the most studied interventions for MAT is eccentric exercise training. Studies of eccentric exercises have been very favorable, and the exercises can be taught during routine PT sessions.^19-22 Modalities such as ultrasound therapy and extracorporeal shock wave therapy (ESWT) have also been studied. But because results have been inconsistent, they are generally reserved for treatment-refractory cases.²³

In patients with no contraindications, NSAIDs may be a good choice for pain management with relatively favorable results in the literature.²⁴ Corticosteroid injections should not be used, as they have been directly linked to rupture of the Achilles tendon.²³

Other interventions, such as plasma-rich protein injections and prolotherapy—a technique in which an irritant is injected into the tendon in an attempt to create an inflammatory reaction, thus increasing local blood flow and healing—are being studied for the treatment of AT, but are not routinely used or covered by insurance for this purpose. Surgical intervention may be considered for patients whose symptoms last for more than 3 to 6 months despite conservative treatment.

Insertional Achilles tendinopathy (IAT) can be clinically differentiated from MAT by the location of symptoms and tenderness to palpation at the insertion site of the Achilles into the calcaneous. Like MAT, IAT is exacerbated by activity. Other conditions that may contribute to, or be mistaken for, IAT are a Haglund deformity and retrocalcaneal bursitis.

Treatment: Footwear modification. Treatment of IAT, like that of MAT, is primarily conservative. Orthotics or heel lifts are commonly used. However, there is greater emphasis on footwear modification due to the mechanical irritation and resultant posterior heel swelling often associated with IAT. While eccentric exercises play a role in IAT treatment, the benefits are limited.²⁵

As with MAT, corticosteroid injections are contraindicated due to the risk of tendon rupture. Modalities such as ultrasound, ESWT, plasma-rich protein, and prolotherapy lack sufficient evidence to be widely recommended.

For refractory cases of IAT, surgical intervention often relieves the pain.

Return to running. After an initial rest of 2 to 4 weeks, patients may return to running while completing therapy. It’s not necessary to wait until the patient is completely pain free, but pain should be used to guide decisions about intensity and duration of activity.

CASE When Jim returns 6 weeks later, he reports that he took 3 weeks off from running because of the pain. Initially, he used contrast baths daily, Jim says, but now he uses them only when he is symptomatic, and he discontinued the NSAID a few weeks ago. Jim tells you he went to the local running store for a new pair of running shoes and that he is now able to run at his previous pace while remaining relatively pain free.

CORRESPONDENCE Jessica Favero Butts, MD, One American Square, Suite 185, Indianapolis, IN 46282; [email protected]

CASE Jim F, 40 years old and overweight (BMI=28 kg/m²), has come to see you because of foot pain that began shortly after he took up running. Jim tells you that turning 40 was “an eye opener” that prompted him to “get healthy.” He says that while he was a competitive athlete in high school, he never ran regularly—until he embarked on a running program 3 months ago.

Jim denies acute injury, bruising, swelling, redness, fever, or chills, but states that the pain, which he describes as dull and achy, is gradually getting worse. It hurts the most when he stands for long periods of time. He says that he occasionally takes ibuprofen for the foot pain, but has not tried icing or stretching. When you ask him what kind of sneakers he wears during his runs, Jim reports that his running shoes—purchased at a discount store—are about 5 years old.

Participation in running has grown by more than 40% in the United States in the past decade.¹ As a result, patients like Jim are bound to have their share of aches, pains, and injuries that prompt them to visit their family physician. And that’s where this review can help. This rundown of the most common foot pain diagnoses, as well as the at-a-glance summaries of the differential diagnosis (TABLE 1)^2-5 and treatment options (TABLE 2),^3,6-25 can help you quickly get patients the relief they need to return to running.

TABLE 1
Differential diagnosis for runners’ foot pain^2-5

TABLE 2
Diagnosing and treating common runners’ injuries

Metatarsalgia: Pain on the plantar surface

Typically associated with a recent increase in activity or change in footwear, metatarsalgia is defined by pain on the plantar surface of the forefoot in the area of the metatarsal heads. The second, third, and fourth metatarsals are the most common offenders, and the pain may or may not be accompanied by swelling, bruising, or deformity.

Mechanical irregularities in the foot are thought to contribute to the development of metatarsalgia, which is typically inflammatory in nature. Physical exam often reveals tenderness at the affected metatarsal heads, with or without pain in the corresponding metatarsophalangeal joint, and occasionally, with overlying edema or hyperkeratosis.

Tuning fork test. Commonly used but weakly supported, this diagnostic test is performed by applying a vibrating tuning fork to a site of possible fracture. If the maneuver produces focal pain, the test is positive and may be helpful in ruling in metatarsal stress fractures.²⁶

Treatment: Change shoes, consider NSAIDs. Treatment for metatarsalgia begins conservatively, with a change in footwear. High heels or pointy-toed shoes should be avoided, and metatarsal pads (FIGURE 1) can be placed inside the shoes to help off-load the metatarsal head.⁶ The pads come prefabricated or can be custom made, and are typically placed by physical therapists to ensure proper placement. Orthotics should also be considered, as they can help normalize abnormal foot mechanics that may contribute to metatarsalgia.^7,8 (See “A word about runners’ footwear”.^9,27-31)

Metatarsalgia is believed to be an inflammatory process, and NSAIDs may be helpful. Contrast baths—alternately submerging the affected foot in a basin of hot (but not scalding) water for 1 to 2 minutes, then immersing it in cold water for 30 to 60 seconds and repeating the process for about 20 minutes once or twice daily—may be helpful. Magnetic insoles are not recommended, as they have been found to be no better than sham insoles.³² Rarely, surgical repair of underlying mechanical abnormalities is indicated for treatment of refractory metatarsalgia.

CASE On examination, Jim F has no swelling, but some hyperkeratosis overlying the second and third metatarsal heads. He has tenderness to palpation at these heads as well as the corresponding metatarsophalangeal joints, and a negative tuning fork test.

You advise Jim that he has metatarsalgia, educate him about the pathophysiology of this condition, and give him a prescription for a nonsteroidal anti-inflammatory drug. You suggest he use contrast baths—and explain how this is done—once or twice a day and refer him to physical therapy for proper placement of metatarsal pads in his shoes, and schedule an appointment for a 6-week follow-up.

Return to running. There is no firm recommendation regarding abstaining from running with metatarsalgia. Advise patients to use pain as a guide in determining the intensity and duration of activity.

FIGURE 1
Treatment for metatarsalgia is conservative

Stress fracture: Tenderness and pain of insidious onset

Stress fractures of the foot (SFF)—overuse injuries also known as fatigue fractures—are common in recreational runners. They are thought to result from microtraumas, which alone are not sufficient to break bone but together overwhelm the bone’s natural ability to remodel and recover over time. SFF are characterized by tenderness and pain of insidious onset, and typically occur when more than one training variable (eg, frequency, duration, and intensity) is changed simultaneously. SFF can also result from a change in exercise mechanics, such as foot strike.

Stress fractures can occur in any bone in the foot, but are most common in the metatarsal bones, specifically the mid or distal portion of the second or third metatarsal, or the tarsal navicular.^2,33 On examination, the patient will have tenderness to palpation, often well localized. A positive tuning fork test (see page 647) is highly suggestive of a stress fracture.

FAST TRACK

Some studies suggest that barefoot running or barefoot running shoes improve running mechanics; other studies have had unfavorable or inconsistent results.

In female runners, stress fractures may be associated with the female athlete triad—osteoporosis or osteopenia, disordered eating (specifically caloric deficiency and low BMI), and amenorrhea. In addition to the major long-term health problems that may result from even one component of the triad, SFF may be a short-term consequence.³⁴

Although SFF is a clinical diagnosis, x-rays—including 3-view plain films of the foot, with the area of concern clearly noted on the order—are recommended. Magnetic resonance imaging may be used for secondary imaging if doubt about the source of the pain remains.³⁵

Of note: Occasionally, a metatarsal stress fracture progresses to a frank fracture, specifically of the metaphyseal-diaphyseal junction of the fifth metatarsal—known as a Jones fracture. This type of fracture has a high rate of malunion or nonunion.³⁶ If there is any suspicion of a fracture in this area, consider a referral to a sports medicine specialist or orthopedic surgeon.

Treatment: Icing, analgesics, and a boot. Standard treatment for SFF includes icing for 15 to 20 minutes up to 3 times a day for a minimum of 72 hours after injury, but may be continued throughout the healing period. Analgesics such as acetaminophen and a walking boot for 3 to 4 weeks, with follow-up at 3 weeks, should also be implemented. Recent evidence suggests that NSAIDs may hinder the bone healing process, and their use in treating SFF is controversial.^10-12

Weaning from the boot can begin when the patient is pain free with the boot on, usually by 3 to 4 weeks. Patients often progress quickly from wearing the boot at all times to wearing it only outside of the house, to not wearing it at all. Advise patients who need to walk long distances for a good portion of the day to keep the boot nearby and to put it on if the pain returns.

Once weaning from the boot begins, physical therapy (PT) should be considered to help the patient regain foot and ankle range of motion (ROM), proprioception, and strength. Once he or she learns the exercises, rehabilitation can be accomplished with a home exercise program. Foot deformities, such as pes planus or pes cavus, may indicate a need for orthotics. A well-structured athletic shoe may help to prevent future injury.^7,8

Return to running. Once adequate ROM and strength in the foot and ankle are recovered, the patient can begin to resume activity, starting with a low-impact cross-training exercise, such as a stationary bike or elliptical, for a week or 2. A patient who remains pain free can progress from cross-training to running on a treadmill for another week or 2, then gradually switch to outdoor running.

Plantar fasciitis: Heel pain with an insidious onset

Plantar fasciitis is one of the most common causes of heel pain in athletes (primarily runners) and nonathletes alike. Plantar fasciitis may be associated with acute trauma, but is more commonly insidious in onset. The diagnosis is clinical and rarely requires imaging.

Pain associated with plantar fasciitis may be described as sharp and stabbing or dull and aching. It is on the plantar surface of the heel, sometimes radiating to the arch, and may localize to the insertion of the plantar fascia on the medial calcaneal tubercle (FIGURE 2). The pain is typically most severe with the first few steps in the morning or after other periods of prolonged rest. It usually improves after a few steps, but may return later in the day. Plantar fasciitis does not cause paresthesias or other neurologic symptoms, so their presence is suggestive of a different diagnosis, such as nerve entrapment, compartment syndrome, or tarsal tunnel syndrome.^3,5

Treatment: It’s multifactorial. NSAIDs are commonly used. Relative rest is recommended, but cross training may be considered to maintain fitness.³⁷ Short-term PT is also recommended to teach the patient proper stretching and strengthening techniques in the form of a home exercise plan. Modalities such as iontophoresis (a system of transdermal delivery of medication with the use of electrical currents), Graston (a form of instrument-assisted soft tissue mobilization), and taping may be incorporated into PT, as well.¹³

Night splinting may also be used to keep the foot in a dorsiflexed position. A splint can be purchased without a prescription and prevents the plantar fascia from shortening overnight by providing a continuous passive stretch, thus reducing pain with first steps.¹⁴

Orthotics may also help to reduce symptom severity and duration, and studies have found no difference in outcomes with prefabricated vs custom-made devices.¹⁵ Another treatment to consider, particularly for recalcitrant cases of plantar fasciitis, is extracorporeal shock wave therapy, which has been studied for more than a decade with conflicting results.¹⁶ Corticosteroid injection may also be used for treatment-refractory plantar fasciitis, but caution is required, as the injection may increase the risk of rupture of the plantar fascia.^17,18

Return to running. There are no set guidelines for when an athlete with plantar fasciitis can return to running. Typically, after 2 to 4 weeks of relative rest and other treatments, the runner can begin to transition from cross-training to treadmill running.

FIGURE 2
Severe pain with first steps of the day

Achilles tendinopathy: An overuse injury

Achilles tendinopathy (AT) is typically an overuse injury incurred by athletes, although it is sometimes seen in patients who are sedentary and overweight. With a prevalence among runners of approximately 11%, AT is sometimes called the “runners’ disease.”⁴

Tendinopathy is a more accurate description than tendonitis, as histologic studies of affected Achilles tendons suggest that AT is a degenerative, rather than an inflammatory, condition.³⁸ A diagnosis of AT can be further classified as midportion or insertional.

Midportion Achilles tendinopathy (MAT), characterized by pain that occurs in the body of the Achilles tendon and worsens with activity, is often a clinical diagnosis. Physical findings suggestive of MAT are tenderness to palpation of the midportion of the Achilles tendon, with thickening of the tendon, warmth, crepitus, or palpable nodules in the tendon body. Onset is insidious and is commonly associated with an increase in activity.

Treatment: Orthotics or a heel lift. Like that of plantar fasciitis, treatment of midportion Achilles tendinopathy is primarily conservative. The use of orthotics, or a heel lift, is one of the most cost-effective interventions, and they are widely used, despite limited evidence of efficacy.³⁹ Custom orthotics are costly, and patients often benefit from trying prefabricated orthotics first to determine whether they will help.

Eccentric exercises. One of the most studied interventions for MAT is eccentric exercise training. Studies of eccentric exercises have been very favorable, and the exercises can be taught during routine PT sessions.^19-22 Modalities such as ultrasound therapy and extracorporeal shock wave therapy (ESWT) have also been studied. But because results have been inconsistent, they are generally reserved for treatment-refractory cases.²³

In patients with no contraindications, NSAIDs may be a good choice for pain management with relatively favorable results in the literature.²⁴ Corticosteroid injections should not be used, as they have been directly linked to rupture of the Achilles tendon.²³

Other interventions, such as plasma-rich protein injections and prolotherapy—a technique in which an irritant is injected into the tendon in an attempt to create an inflammatory reaction, thus increasing local blood flow and healing—are being studied for the treatment of AT, but are not routinely used or covered by insurance for this purpose. Surgical intervention may be considered for patients whose symptoms last for more than 3 to 6 months despite conservative treatment.

Insertional Achilles tendinopathy (IAT) can be clinically differentiated from MAT by the location of symptoms and tenderness to palpation at the insertion site of the Achilles into the calcaneous. Like MAT, IAT is exacerbated by activity. Other conditions that may contribute to, or be mistaken for, IAT are a Haglund deformity and retrocalcaneal bursitis.

Treatment: Footwear modification. Treatment of IAT, like that of MAT, is primarily conservative. Orthotics or heel lifts are commonly used. However, there is greater emphasis on footwear modification due to the mechanical irritation and resultant posterior heel swelling often associated with IAT. While eccentric exercises play a role in IAT treatment, the benefits are limited.²⁵

As with MAT, corticosteroid injections are contraindicated due to the risk of tendon rupture. Modalities such as ultrasound, ESWT, plasma-rich protein, and prolotherapy lack sufficient evidence to be widely recommended.

For refractory cases of IAT, surgical intervention often relieves the pain.

Return to running. After an initial rest of 2 to 4 weeks, patients may return to running while completing therapy. It’s not necessary to wait until the patient is completely pain free, but pain should be used to guide decisions about intensity and duration of activity.

CASE When Jim returns 6 weeks later, he reports that he took 3 weeks off from running because of the pain. Initially, he used contrast baths daily, Jim says, but now he uses them only when he is symptomatic, and he discontinued the NSAID a few weeks ago. Jim tells you he went to the local running store for a new pair of running shoes and that he is now able to run at his previous pace while remaining relatively pain free.

CORRESPONDENCE Jessica Favero Butts, MD, One American Square, Suite 185, Indianapolis, IN 46282; [email protected]

Obsessive-compulsive disorder (OCD) is marked by recurrent and persistent anxiety-provoking thoughts (obsessions) accompanied by repetitive behaviors (compulsions) that focus on alleviating distress caused by obsessive thoughts. Although patients recognize the obsessions and compulsions are unreasonable, these thoughts and behaviors remain time-consuming and impair function. Even when they appropriately identify and treat OCD, clinicians often face “treatment-resistant” (or “treatment-refractory”) patients who do not respond adequately to standard therapies (Box).¹ Several factors contribute to treatment resistance, including those related to the patient, the environment, the clinician/health system, and pathology (Table 1).² An estimated 10% to 40% of patients with OCD are treatment-resistant.²

This article discusses the range of options for addressing resistant OCD, including augmenting first-line treatments with pharmacotherapy, psychotherapy, or reversible or irreversible forms of neuromodulation.

Table 1

Factors that contribute to treatment resistance in obsessive-compulsive disorder

First-line pharmacotherapy

Clomipramine or a selective serotonin reuptake inhibitor (SSRI) are considered first-line treatments for OCD. Although some evidence indicates that clomipramine may have greater efficacy than SSRIs, its poor tolerability and potential lethality in overdose make it a less practical first choice in treatment-naïve patients.^3,4 SSRIs generally are well tolerated and have a favorable safety profile. Nearly all SSRIs have randomized clinical trials (RCTs) and FDA indications that support their use in OCD. SSRI choice may be guided by patient or prescriber preference because no evidence suggests that 1 SSRI is superior to another for treating OCD.⁵ In contrast to major depressive disorder, in OCD there is a dose-response relationship for SSRI treatment; higher doses typically are required to achieve response or remission.^6,7

Augmentation and other options

Patients who have not responded to at least 2 adequate trials of first-line medications may benefit from an augmentation strategy or treatment with an unconventional agent. Such cases should be managed by a specialist who has experience in treating OCD and with careful consideration of potential risks of these interventions.

Evidence suggests the following pharmacotherapies may effectively treat OCD and may be warranted for treatment-resistant patients.

Serotonergic agents

Supratherapeutic SSRI doses. Evidence suggests that supratherapeutic doses of SSRIs may be effective, which may be a logical first step when treating patients already taking an SSRI who have not responded. In a multi-center, double-blind study comparing sertraline, 200 mg/d, to sertraline, 250 to 400 mg/d, the latter group showed significantly greater symptom improvement.⁸ Citalopram may not be suitable for this approach because of the recent FDA announcement regarding dose-dependent QTc prolongation associated with this medication.⁹

Serotonin-norepinephrine reuptake inhibitors (SNRIs). In the only double-blind, placebo-controlled study of venlafaxine for OCD, the drug was not significantly more effective than placebo.¹⁰ This study was small (N = 30). There are sufficient positive results from open-label and blinded comparator studies that venlafaxine generally is accepted as an effective and well-tolerated treatment for OCD at doses ≥225 mg/d.¹¹

Duloxetine also may be effective in treating OCD. One case series reported improvement in 3 of 4 SSRI nonresponders who were switched to this medication and rapidly titrated to 120 mg/d.¹²

Clomipramine/SSRI augmentation. For patients who have not responded to an SSRI, several open-label trials support adding clomipramine.¹³ Conversely, SSRI augmentation for patients who have not adequately responded to clomipramine may be effective.¹⁴ With any dual therapy with serotonergic agents, monitor patients for signs and symptoms of serotonin syndrome.

IV clomipramine. By bypassing first-pass metabolism, IV clomipramine rapidly achieves high plasma levels. In a double-blind, placebo-controlled study of 54 OCD patients who were nonresponsive to oral clomipramine, IV clomipramine was more effective than placebo.¹⁵ An additional study found IV clomipramine is more effective when pulse loaded than when titrated gradually.¹⁶

Pindolol. The beta blocker pindolol acts as an antagonist of presynaptic 5-HT1A autoreceptors, increasing serotonergic signaling. A small double-blind, placebo-controlled trial (N = 14) found a significant decrease in Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score with pindolol augmentation, 2.5 mg, 3 times daily, among patients who did not respond to ≥3 serotonin reuptake inhibitor (SRI) trials.¹⁷ Pindolol augmentation showed modest effects in 2 open-label studies.^18,19 However, another small double-blind, placebo-controlled study (N = 15) found no difference between placebo and fluvoxamine augmented with pindolol.²⁰

Ondansetron. A 5-HT3 receptor antagonist, ondansetron is used primarily as an antiemetic but has been shown to have anxiolytic properties in animal studies. In an open-label study of 8 patients with non–treatment refractory OCD, 3 achieved clinical response (at least 35% reduction in Y-BOCS score) with ondansetron monotherapy dosed at 1 mg, 3 times daily.²¹ In a subsequent single-blind trial with 14 treatment-resistant patients, 9 responded (at least 25% reduction in Y-BOCS score).²²

Other medications

Antipsychotics. Most studies examining antipsychotic monotherapy for OCD have been negative. One exception was a small, open-label trial of aripiprazole monotherapy (N = 8) that found modest efficacy among non–treatment refractory patients.²³ Augmentation with antipsychotics, however, has been well studied and there is good evidence of efficacy for this approach. Double-blind, placebo-controlled studies have supported the efficacy of augmenting SRIs with haloperidol, risperidone, olanzapine, quetiapine, and aripiprazole.^24-26 Several case reports suggest ziprasidone may be an effective SRI adjunct, but 1 retrospective study found it was inferior to quetiapine.²⁷

Benzodiazepines. Case reports present positive effects of clonazepam and alprazolam for OCD, but double-blind, placebo-controlled trials for monotherapy or adjunctive clonazepam have been negative.^28,29 Furthermore, cognitive impairment and potential for dependence associated with benzodiazepines weigh against their use in OCD.

Opioids. A double-blind, placebo controlled crossover study of 23 patients with treatment-refractory OCD found once-weekly oral morphine added to patients’ current regimen significantly reduced Y-BOCS score vs placebo. Patients received 30 mg the first week and 15 to 45 mg the next week, depending on response or side effects.³⁰ A case report and a small open-label trial support the efficacy of tramadol, a weak agonist of the μ opioid receptor and an inhibitor of serotonin and norepinephrine transporters, as monotherapy and as an adjunct to fluoxetine.^31,32 Because patients with OCD may be particularly vulnerable to dependence and intentional or accidental overdose via opioid/benzodiazepine combinations, evaluate the risks and benefits before initiating an opioid.

Psychostimulants. Sparse but good evidence supports the efficacy of dextroamphetamine monotherapy for OCD.^33,34 There are no positive studies of methylphenidate and several case reports of methylphenidate-induced OCD symptoms.³⁵

N-methyl-D-aspartate (NMDA) antagonists. Increased glutamatergic neurotransmission has been implicated in the pathophysiology of OCD, which suggests a possible role for glutamate receptor antagonists. In an open-label trial, memantine, an NMDA antagonist used primarily to treat dementia, was associated with clinical response (>25% reduction in Y-BOCS scores) in 6 of 14 patients with treatment-refractory OCD.³⁶ Several case reports and an open-label trial support the efficacy of riluzole—which is indicated for treating amyotrophic lateral sclerosis—as an adjunct for treatment-refractory OCD.³⁷ Although its exact mechanism of action is unclear, riluzole’s effects are thought to be mediated via reduction in glutamatergic neurotransmission. IV ketamine has reported anti-OCD effects in a case report of a woman with treatment-resistant OCD. These effects occurred almost immediately and persisted for several days.³⁸

Hallucinogens. Psilocybin, psilocin, and lysergic acid diethylamide have reported anti-OCD properties.³⁹ As schedule I substances, however, they are not available outside of sanctioned research protocols and may carry substantial risk. Nonetheless, their efficacy suggests that other compounds that share their mechanism of action—namely agonism of 5-HT2A and 5-HT2C receptors—may merit investigation as potential treatments for OCD.

Psychotherapy

Cognitive-behavioral therapy (CBT) has been shown to be effective for OCD as monotherapy and augmentation to pharmacotherapy. CBT consists of cognitive and behavioral components, typically involving some form of cognitive restructuring and exposure response prevention. Although these 2 types of interventions arise from independent traditions, in CBT they are frequently intertwined, particularly when the focus of OCD patients’ anxiety is ego-dystonic thoughts.

One benefit of CBT over pharmacotherapy is that effects persist after treatment is terminated. A recent prospective study found CBT was effective for treatment-refractory OCD, with 74% of patients demonstrating clinical response after 20 to 25 sessions over 2 months and 61% maintaining clinical response 1 year after treatment.⁴⁰ CBT administered remotely via teleconference, also known as “teletherapy,” has shown efficacy for OCD.⁴¹

Alternative medicine

Despite widespread use of herbal remedies for OCD, no trials have shown a strong positive effect. Both Hypericum perforatum (St. John’s wort) and Silybum marianum (milk thistle) have been used to treat obsessive and compulsive symptoms; however, placebo-controlled trials did not find any significant differences in symptoms or side effects between treatment groups.^42,43 Lower-quality studies have reported modest effects for mindfulness meditation, yoga, and acupuncture.⁴⁴

Because many patients continue to use complementary and alternative medicine therapies despite the lack of data on efficacy, it is important to monitor for potential interactions with prescription medications. St. John’s wort interacts with many medications because of induction of the cytochrome P450 (CYP) isoenzymes 3A4 and 2C9. This interaction may lower blood levels of alprazolam and clonazepam (3A4). Combining St. John’s wort with SSRIs increases the risk of serotonin syndrome. Milk thistle inhibits CYP450 isoenzyme 3A4, and may increase serum levels of other medications metabolized by this pathway.

Invasive therapies

Invasive options may be considered after several pharmacotherapeutic and psychotherapeutic approaches have not been effective or when significant functional impairment remains (Table 2). These therapies typically are reserved for patients whose treatment resistance is strongest.

Electroconvulsive therapy (ECT). Although ECT is an effective tool for treatment-resistant mood disorders or treatment-resistant anxiety complicated by severe depression, studies have not found ECT to be effective for OCD. One uncontrolled case series reported considerable improvements in OCD patients the year after ECT, although improvement was correlated with improved depression scores.⁴⁵

Vagal nerve stimulation (VNS). In an open-label study of 7 OCD patients who received VNS, 3 were acute responders—characterized by a ≥25% improvement on the Y-BOCS—and 2 received continued benefits at 4-year follow up (2 patients dropped out).⁴⁶

Repetitive transcranial magnetic stimulation (rTMS). A meta-analysis of 3 RCTs of rTMS for patients with OCD did not yield a large or statistically significant effect.⁴⁷ Limitations of these trials included asymmetric stimulation sites (eg, left vs right only), limited stimulation sites (dorsolateral prefrontal cortex), different stimulation frequencies between studies, and a lack of sham stimulation conditions. A more recent RCT and subsequent review described moderate efficacy (defined by ≥25% decrease in Y-BOCS scores) compared with sham stimulations in OCD patients at 4 weeks, using the supplementary motor area as a stimulation site.^48,49

The main limitation of rTMS is the inability to penetrate deeper brain structures implicated in OCD (eg, caudate nucleus, thalamus, anterior capsule fiber tracts), as well as a lack of specificity in stimulation site.

Surgical approaches. Cingulotomy is the most commonly employed surgical procedure for OCD in North America, likely because of a combination of clinical efficacy and low morbidity and mortality rates.⁵⁰ Of the >1,000 cingulotomies that have been performed at Massachusetts General Hospital, no deaths or postoperative infections have been reported and 2 subdural hematomas have occurred.⁵⁰ Common postsurgical side effects include transient headache, nausea, or difficulty urinating. The most serious common side effect—postoperative seizures—has been reported in 1% to 9% of cases.

Outcomes for these procedures cannot be fully assessed until at least 6 months to 2 years after the procedure, which suggests postoperative neural reorganization plays an important role in recovery. Direct comparisons of each lesion approach within studies are extremely rare. Overall, long-term outcomes of these approaches have demonstrated significant therapeutic effects of each of these procedures. Reported response rates vary between 30% to 70%, when applied to remission, response (≥35% Y-BOCS reduction), and functional improvements in quality of life.⁵⁰

Deep brain stimulation (DBS). With this approach, small electrodes are inserted under precise stereotactic MRI guidance. The advantage of DBS over ablative surgery is the ability to adjust and customize neurostimulation. Following implantation, modifiable parameters of electrode stimulation include electrode polarity, intensity, frequency, and laterality. A specially trained psychiatrist can conduct parameter optimization during long-term follow-up.

The first trial of DBS for OCD was reported in 1999 (N = 4), with the initial target selected based on the site of anterior capsulotomy. Three patients derived clinically observed benefit, although no validated questionnaires were administered.⁵¹ Since then, at least 7 studies with blinded stimulation have been conducted, totaling 62 patients.⁵²

In recent years, structures adjacent to the internal capsule also have been targeted based on the approach employed in ventral capsulotomy. Across all trials, response rates for this approach consistently have been in the 50% range, with average Y-BOCS score reductions ranging from 6.8 to 31 points.⁵³ Some patients have reported rapid improvements in anhedonia, and this approach is being employed in treatment-resistant depression.

Postoperative complications occur more often with DBS than with lesion approaches because of the prosthetic nature of the procedure (eg, increased risk of infection, lead malfunction, etc.). Additionally, batteries must be periodically explanted and replaced. Reported stimulation-related side effects include mood changes (transient sadness, anxiety, euphoria, and hypomania), sensory disturbances (olfactory, gustatory, and motor sensations), and cognitive changes (confusion and forgetfulness). These side effects typically are stimulation-dependent and disappear after altering stimulation parameters.

Table 2

Invasive therapies for treatment-resistant OCD

Related Resources

• American Psychiatric Association. Treatment of patients with obsessive-compulsive disorder. www.psychiatryonline.com/pracGuide/pracGuideTopic_10.aspx.
• Hyman BM, Pedrick C. The OCD workbook. Your guide to breaking free from obsessive compulsive disorder. 3rd ed. Oakland, CA: New Harbinger Publications Inc; 2010.
• Baer L. Getting control: overcoming your obsessions and compulsions. Revised ed. New York, NY: Plume; 2000.

Drug Brand Names

• Alprazolam • Xanax
• Aripiprazole • Abilify
• Citalopram • Celexa
• Clomipramine • Anafranil
• Clonazepam • Klonopin
• Dextroamphetamine • Adderall
• Duloxetine • Cymbalta
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Ketamine • Ketalar
• Memantine • Namenda
• Methylphenidate • Ritalin
• Morphine • MS Contin
• Olanzapine • Zyprexa
• Ondansetron • Zofran
• Pindolol • Visken
• Quetiapine • Seroquel
• Riluzole • Rilutek
• Risperidone • Risperdal
• Sertraline • Zoloft
• Tramadol • Ultram
• Venlafaxine • Effexor
• Ziprasidone • Geodon

Disclosures

Drs. Khalsa and Schiffman report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Bystritsky receives grant support from AstraZeneca, Brainways, Takeda, and Transcept and is a founder, stockholder, and consultant for BrainSonix.

Obsessive-compulsive disorder (OCD) is marked by recurrent and persistent anxiety-provoking thoughts (obsessions) accompanied by repetitive behaviors (compulsions) that focus on alleviating distress caused by obsessive thoughts. Although patients recognize the obsessions and compulsions are unreasonable, these thoughts and behaviors remain time-consuming and impair function. Even when they appropriately identify and treat OCD, clinicians often face “treatment-resistant” (or “treatment-refractory”) patients who do not respond adequately to standard therapies (Box).¹ Several factors contribute to treatment resistance, including those related to the patient, the environment, the clinician/health system, and pathology (Table 1).² An estimated 10% to 40% of patients with OCD are treatment-resistant.²

This article discusses the range of options for addressing resistant OCD, including augmenting first-line treatments with pharmacotherapy, psychotherapy, or reversible or irreversible forms of neuromodulation.

Table 1

Factors that contribute to treatment resistance in obsessive-compulsive disorder

First-line pharmacotherapy

Clomipramine or a selective serotonin reuptake inhibitor (SSRI) are considered first-line treatments for OCD. Although some evidence indicates that clomipramine may have greater efficacy than SSRIs, its poor tolerability and potential lethality in overdose make it a less practical first choice in treatment-naïve patients.^3,4 SSRIs generally are well tolerated and have a favorable safety profile. Nearly all SSRIs have randomized clinical trials (RCTs) and FDA indications that support their use in OCD. SSRI choice may be guided by patient or prescriber preference because no evidence suggests that 1 SSRI is superior to another for treating OCD.⁵ In contrast to major depressive disorder, in OCD there is a dose-response relationship for SSRI treatment; higher doses typically are required to achieve response or remission.^6,7

Augmentation and other options

Patients who have not responded to at least 2 adequate trials of first-line medications may benefit from an augmentation strategy or treatment with an unconventional agent. Such cases should be managed by a specialist who has experience in treating OCD and with careful consideration of potential risks of these interventions.

Evidence suggests the following pharmacotherapies may effectively treat OCD and may be warranted for treatment-resistant patients.

Serotonergic agents

Supratherapeutic SSRI doses. Evidence suggests that supratherapeutic doses of SSRIs may be effective, which may be a logical first step when treating patients already taking an SSRI who have not responded. In a multi-center, double-blind study comparing sertraline, 200 mg/d, to sertraline, 250 to 400 mg/d, the latter group showed significantly greater symptom improvement.⁸ Citalopram may not be suitable for this approach because of the recent FDA announcement regarding dose-dependent QTc prolongation associated with this medication.⁹

Serotonin-norepinephrine reuptake inhibitors (SNRIs). In the only double-blind, placebo-controlled study of venlafaxine for OCD, the drug was not significantly more effective than placebo.¹⁰ This study was small (N = 30). There are sufficient positive results from open-label and blinded comparator studies that venlafaxine generally is accepted as an effective and well-tolerated treatment for OCD at doses ≥225 mg/d.¹¹

Duloxetine also may be effective in treating OCD. One case series reported improvement in 3 of 4 SSRI nonresponders who were switched to this medication and rapidly titrated to 120 mg/d.¹²

Clomipramine/SSRI augmentation. For patients who have not responded to an SSRI, several open-label trials support adding clomipramine.¹³ Conversely, SSRI augmentation for patients who have not adequately responded to clomipramine may be effective.¹⁴ With any dual therapy with serotonergic agents, monitor patients for signs and symptoms of serotonin syndrome.

IV clomipramine. By bypassing first-pass metabolism, IV clomipramine rapidly achieves high plasma levels. In a double-blind, placebo-controlled study of 54 OCD patients who were nonresponsive to oral clomipramine, IV clomipramine was more effective than placebo.¹⁵ An additional study found IV clomipramine is more effective when pulse loaded than when titrated gradually.¹⁶

Pindolol. The beta blocker pindolol acts as an antagonist of presynaptic 5-HT1A autoreceptors, increasing serotonergic signaling. A small double-blind, placebo-controlled trial (N = 14) found a significant decrease in Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score with pindolol augmentation, 2.5 mg, 3 times daily, among patients who did not respond to ≥3 serotonin reuptake inhibitor (SRI) trials.¹⁷ Pindolol augmentation showed modest effects in 2 open-label studies.^18,19 However, another small double-blind, placebo-controlled study (N = 15) found no difference between placebo and fluvoxamine augmented with pindolol.²⁰

Ondansetron. A 5-HT3 receptor antagonist, ondansetron is used primarily as an antiemetic but has been shown to have anxiolytic properties in animal studies. In an open-label study of 8 patients with non–treatment refractory OCD, 3 achieved clinical response (at least 35% reduction in Y-BOCS score) with ondansetron monotherapy dosed at 1 mg, 3 times daily.²¹ In a subsequent single-blind trial with 14 treatment-resistant patients, 9 responded (at least 25% reduction in Y-BOCS score).²²

Other medications

Antipsychotics. Most studies examining antipsychotic monotherapy for OCD have been negative. One exception was a small, open-label trial of aripiprazole monotherapy (N = 8) that found modest efficacy among non–treatment refractory patients.²³ Augmentation with antipsychotics, however, has been well studied and there is good evidence of efficacy for this approach. Double-blind, placebo-controlled studies have supported the efficacy of augmenting SRIs with haloperidol, risperidone, olanzapine, quetiapine, and aripiprazole.^24-26 Several case reports suggest ziprasidone may be an effective SRI adjunct, but 1 retrospective study found it was inferior to quetiapine.²⁷

Benzodiazepines. Case reports present positive effects of clonazepam and alprazolam for OCD, but double-blind, placebo-controlled trials for monotherapy or adjunctive clonazepam have been negative.^28,29 Furthermore, cognitive impairment and potential for dependence associated with benzodiazepines weigh against their use in OCD.

Opioids. A double-blind, placebo controlled crossover study of 23 patients with treatment-refractory OCD found once-weekly oral morphine added to patients’ current regimen significantly reduced Y-BOCS score vs placebo. Patients received 30 mg the first week and 15 to 45 mg the next week, depending on response or side effects.³⁰ A case report and a small open-label trial support the efficacy of tramadol, a weak agonist of the μ opioid receptor and an inhibitor of serotonin and norepinephrine transporters, as monotherapy and as an adjunct to fluoxetine.^31,32 Because patients with OCD may be particularly vulnerable to dependence and intentional or accidental overdose via opioid/benzodiazepine combinations, evaluate the risks and benefits before initiating an opioid.

Psychostimulants. Sparse but good evidence supports the efficacy of dextroamphetamine monotherapy for OCD.^33,34 There are no positive studies of methylphenidate and several case reports of methylphenidate-induced OCD symptoms.³⁵

N-methyl-D-aspartate (NMDA) antagonists. Increased glutamatergic neurotransmission has been implicated in the pathophysiology of OCD, which suggests a possible role for glutamate receptor antagonists. In an open-label trial, memantine, an NMDA antagonist used primarily to treat dementia, was associated with clinical response (>25% reduction in Y-BOCS scores) in 6 of 14 patients with treatment-refractory OCD.³⁶ Several case reports and an open-label trial support the efficacy of riluzole—which is indicated for treating amyotrophic lateral sclerosis—as an adjunct for treatment-refractory OCD.³⁷ Although its exact mechanism of action is unclear, riluzole’s effects are thought to be mediated via reduction in glutamatergic neurotransmission. IV ketamine has reported anti-OCD effects in a case report of a woman with treatment-resistant OCD. These effects occurred almost immediately and persisted for several days.³⁸

Hallucinogens. Psilocybin, psilocin, and lysergic acid diethylamide have reported anti-OCD properties.³⁹ As schedule I substances, however, they are not available outside of sanctioned research protocols and may carry substantial risk. Nonetheless, their efficacy suggests that other compounds that share their mechanism of action—namely agonism of 5-HT2A and 5-HT2C receptors—may merit investigation as potential treatments for OCD.

Psychotherapy

Cognitive-behavioral therapy (CBT) has been shown to be effective for OCD as monotherapy and augmentation to pharmacotherapy. CBT consists of cognitive and behavioral components, typically involving some form of cognitive restructuring and exposure response prevention. Although these 2 types of interventions arise from independent traditions, in CBT they are frequently intertwined, particularly when the focus of OCD patients’ anxiety is ego-dystonic thoughts.

One benefit of CBT over pharmacotherapy is that effects persist after treatment is terminated. A recent prospective study found CBT was effective for treatment-refractory OCD, with 74% of patients demonstrating clinical response after 20 to 25 sessions over 2 months and 61% maintaining clinical response 1 year after treatment.⁴⁰ CBT administered remotely via teleconference, also known as “teletherapy,” has shown efficacy for OCD.⁴¹

Alternative medicine

Despite widespread use of herbal remedies for OCD, no trials have shown a strong positive effect. Both Hypericum perforatum (St. John’s wort) and Silybum marianum (milk thistle) have been used to treat obsessive and compulsive symptoms; however, placebo-controlled trials did not find any significant differences in symptoms or side effects between treatment groups.^42,43 Lower-quality studies have reported modest effects for mindfulness meditation, yoga, and acupuncture.⁴⁴

Because many patients continue to use complementary and alternative medicine therapies despite the lack of data on efficacy, it is important to monitor for potential interactions with prescription medications. St. John’s wort interacts with many medications because of induction of the cytochrome P450 (CYP) isoenzymes 3A4 and 2C9. This interaction may lower blood levels of alprazolam and clonazepam (3A4). Combining St. John’s wort with SSRIs increases the risk of serotonin syndrome. Milk thistle inhibits CYP450 isoenzyme 3A4, and may increase serum levels of other medications metabolized by this pathway.

Invasive therapies

Invasive options may be considered after several pharmacotherapeutic and psychotherapeutic approaches have not been effective or when significant functional impairment remains (Table 2). These therapies typically are reserved for patients whose treatment resistance is strongest.

Electroconvulsive therapy (ECT). Although ECT is an effective tool for treatment-resistant mood disorders or treatment-resistant anxiety complicated by severe depression, studies have not found ECT to be effective for OCD. One uncontrolled case series reported considerable improvements in OCD patients the year after ECT, although improvement was correlated with improved depression scores.⁴⁵

Vagal nerve stimulation (VNS). In an open-label study of 7 OCD patients who received VNS, 3 were acute responders—characterized by a ≥25% improvement on the Y-BOCS—and 2 received continued benefits at 4-year follow up (2 patients dropped out).⁴⁶

Repetitive transcranial magnetic stimulation (rTMS). A meta-analysis of 3 RCTs of rTMS for patients with OCD did not yield a large or statistically significant effect.⁴⁷ Limitations of these trials included asymmetric stimulation sites (eg, left vs right only), limited stimulation sites (dorsolateral prefrontal cortex), different stimulation frequencies between studies, and a lack of sham stimulation conditions. A more recent RCT and subsequent review described moderate efficacy (defined by ≥25% decrease in Y-BOCS scores) compared with sham stimulations in OCD patients at 4 weeks, using the supplementary motor area as a stimulation site.^48,49

The main limitation of rTMS is the inability to penetrate deeper brain structures implicated in OCD (eg, caudate nucleus, thalamus, anterior capsule fiber tracts), as well as a lack of specificity in stimulation site.

Surgical approaches. Cingulotomy is the most commonly employed surgical procedure for OCD in North America, likely because of a combination of clinical efficacy and low morbidity and mortality rates.⁵⁰ Of the >1,000 cingulotomies that have been performed at Massachusetts General Hospital, no deaths or postoperative infections have been reported and 2 subdural hematomas have occurred.⁵⁰ Common postsurgical side effects include transient headache, nausea, or difficulty urinating. The most serious common side effect—postoperative seizures—has been reported in 1% to 9% of cases.

Outcomes for these procedures cannot be fully assessed until at least 6 months to 2 years after the procedure, which suggests postoperative neural reorganization plays an important role in recovery. Direct comparisons of each lesion approach within studies are extremely rare. Overall, long-term outcomes of these approaches have demonstrated significant therapeutic effects of each of these procedures. Reported response rates vary between 30% to 70%, when applied to remission, response (≥35% Y-BOCS reduction), and functional improvements in quality of life.⁵⁰

Deep brain stimulation (DBS). With this approach, small electrodes are inserted under precise stereotactic MRI guidance. The advantage of DBS over ablative surgery is the ability to adjust and customize neurostimulation. Following implantation, modifiable parameters of electrode stimulation include electrode polarity, intensity, frequency, and laterality. A specially trained psychiatrist can conduct parameter optimization during long-term follow-up.

The first trial of DBS for OCD was reported in 1999 (N = 4), with the initial target selected based on the site of anterior capsulotomy. Three patients derived clinically observed benefit, although no validated questionnaires were administered.⁵¹ Since then, at least 7 studies with blinded stimulation have been conducted, totaling 62 patients.⁵²

In recent years, structures adjacent to the internal capsule also have been targeted based on the approach employed in ventral capsulotomy. Across all trials, response rates for this approach consistently have been in the 50% range, with average Y-BOCS score reductions ranging from 6.8 to 31 points.⁵³ Some patients have reported rapid improvements in anhedonia, and this approach is being employed in treatment-resistant depression.

Postoperative complications occur more often with DBS than with lesion approaches because of the prosthetic nature of the procedure (eg, increased risk of infection, lead malfunction, etc.). Additionally, batteries must be periodically explanted and replaced. Reported stimulation-related side effects include mood changes (transient sadness, anxiety, euphoria, and hypomania), sensory disturbances (olfactory, gustatory, and motor sensations), and cognitive changes (confusion and forgetfulness). These side effects typically are stimulation-dependent and disappear after altering stimulation parameters.

Table 2

Invasive therapies for treatment-resistant OCD

Related Resources

• American Psychiatric Association. Treatment of patients with obsessive-compulsive disorder. www.psychiatryonline.com/pracGuide/pracGuideTopic_10.aspx.
• Hyman BM, Pedrick C. The OCD workbook. Your guide to breaking free from obsessive compulsive disorder. 3rd ed. Oakland, CA: New Harbinger Publications Inc; 2010.
• Baer L. Getting control: overcoming your obsessions and compulsions. Revised ed. New York, NY: Plume; 2000.

Drug Brand Names

• Alprazolam • Xanax
• Aripiprazole • Abilify
• Citalopram • Celexa
• Clomipramine • Anafranil
• Clonazepam • Klonopin
• Dextroamphetamine • Adderall
• Duloxetine • Cymbalta
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Ketamine • Ketalar
• Memantine • Namenda
• Methylphenidate • Ritalin
• Morphine • MS Contin
• Olanzapine • Zyprexa
• Ondansetron • Zofran
• Pindolol • Visken
• Quetiapine • Seroquel
• Riluzole • Rilutek
• Risperidone • Risperdal
• Sertraline • Zoloft
• Tramadol • Ultram
• Venlafaxine • Effexor
• Ziprasidone • Geodon

Disclosures

Drs. Khalsa and Schiffman report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Bystritsky receives grant support from AstraZeneca, Brainways, Takeda, and Transcept and is a founder, stockholder, and consultant for BrainSonix.

Obsessive-compulsive disorder (OCD) is marked by recurrent and persistent anxiety-provoking thoughts (obsessions) accompanied by repetitive behaviors (compulsions) that focus on alleviating distress caused by obsessive thoughts. Although patients recognize the obsessions and compulsions are unreasonable, these thoughts and behaviors remain time-consuming and impair function. Even when they appropriately identify and treat OCD, clinicians often face “treatment-resistant” (or “treatment-refractory”) patients who do not respond adequately to standard therapies (Box).¹ Several factors contribute to treatment resistance, including those related to the patient, the environment, the clinician/health system, and pathology (Table 1).² An estimated 10% to 40% of patients with OCD are treatment-resistant.²

This article discusses the range of options for addressing resistant OCD, including augmenting first-line treatments with pharmacotherapy, psychotherapy, or reversible or irreversible forms of neuromodulation.

Table 1

Factors that contribute to treatment resistance in obsessive-compulsive disorder

First-line pharmacotherapy

Clomipramine or a selective serotonin reuptake inhibitor (SSRI) are considered first-line treatments for OCD. Although some evidence indicates that clomipramine may have greater efficacy than SSRIs, its poor tolerability and potential lethality in overdose make it a less practical first choice in treatment-naïve patients.^3,4 SSRIs generally are well tolerated and have a favorable safety profile. Nearly all SSRIs have randomized clinical trials (RCTs) and FDA indications that support their use in OCD. SSRI choice may be guided by patient or prescriber preference because no evidence suggests that 1 SSRI is superior to another for treating OCD.⁵ In contrast to major depressive disorder, in OCD there is a dose-response relationship for SSRI treatment; higher doses typically are required to achieve response or remission.^6,7

Augmentation and other options

Patients who have not responded to at least 2 adequate trials of first-line medications may benefit from an augmentation strategy or treatment with an unconventional agent. Such cases should be managed by a specialist who has experience in treating OCD and with careful consideration of potential risks of these interventions.

Evidence suggests the following pharmacotherapies may effectively treat OCD and may be warranted for treatment-resistant patients.

Serotonergic agents

Supratherapeutic SSRI doses. Evidence suggests that supratherapeutic doses of SSRIs may be effective, which may be a logical first step when treating patients already taking an SSRI who have not responded. In a multi-center, double-blind study comparing sertraline, 200 mg/d, to sertraline, 250 to 400 mg/d, the latter group showed significantly greater symptom improvement.⁸ Citalopram may not be suitable for this approach because of the recent FDA announcement regarding dose-dependent QTc prolongation associated with this medication.⁹

Serotonin-norepinephrine reuptake inhibitors (SNRIs). In the only double-blind, placebo-controlled study of venlafaxine for OCD, the drug was not significantly more effective than placebo.¹⁰ This study was small (N = 30). There are sufficient positive results from open-label and blinded comparator studies that venlafaxine generally is accepted as an effective and well-tolerated treatment for OCD at doses ≥225 mg/d.¹¹

Duloxetine also may be effective in treating OCD. One case series reported improvement in 3 of 4 SSRI nonresponders who were switched to this medication and rapidly titrated to 120 mg/d.¹²

Clomipramine/SSRI augmentation. For patients who have not responded to an SSRI, several open-label trials support adding clomipramine.¹³ Conversely, SSRI augmentation for patients who have not adequately responded to clomipramine may be effective.¹⁴ With any dual therapy with serotonergic agents, monitor patients for signs and symptoms of serotonin syndrome.

IV clomipramine. By bypassing first-pass metabolism, IV clomipramine rapidly achieves high plasma levels. In a double-blind, placebo-controlled study of 54 OCD patients who were nonresponsive to oral clomipramine, IV clomipramine was more effective than placebo.¹⁵ An additional study found IV clomipramine is more effective when pulse loaded than when titrated gradually.¹⁶

Pindolol. The beta blocker pindolol acts as an antagonist of presynaptic 5-HT1A autoreceptors, increasing serotonergic signaling. A small double-blind, placebo-controlled trial (N = 14) found a significant decrease in Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score with pindolol augmentation, 2.5 mg, 3 times daily, among patients who did not respond to ≥3 serotonin reuptake inhibitor (SRI) trials.¹⁷ Pindolol augmentation showed modest effects in 2 open-label studies.^18,19 However, another small double-blind, placebo-controlled study (N = 15) found no difference between placebo and fluvoxamine augmented with pindolol.²⁰

Ondansetron. A 5-HT3 receptor antagonist, ondansetron is used primarily as an antiemetic but has been shown to have anxiolytic properties in animal studies. In an open-label study of 8 patients with non–treatment refractory OCD, 3 achieved clinical response (at least 35% reduction in Y-BOCS score) with ondansetron monotherapy dosed at 1 mg, 3 times daily.²¹ In a subsequent single-blind trial with 14 treatment-resistant patients, 9 responded (at least 25% reduction in Y-BOCS score).²²

Other medications

Antipsychotics. Most studies examining antipsychotic monotherapy for OCD have been negative. One exception was a small, open-label trial of aripiprazole monotherapy (N = 8) that found modest efficacy among non–treatment refractory patients.²³ Augmentation with antipsychotics, however, has been well studied and there is good evidence of efficacy for this approach. Double-blind, placebo-controlled studies have supported the efficacy of augmenting SRIs with haloperidol, risperidone, olanzapine, quetiapine, and aripiprazole.^24-26 Several case reports suggest ziprasidone may be an effective SRI adjunct, but 1 retrospective study found it was inferior to quetiapine.²⁷

Benzodiazepines. Case reports present positive effects of clonazepam and alprazolam for OCD, but double-blind, placebo-controlled trials for monotherapy or adjunctive clonazepam have been negative.^28,29 Furthermore, cognitive impairment and potential for dependence associated with benzodiazepines weigh against their use in OCD.

Opioids. A double-blind, placebo controlled crossover study of 23 patients with treatment-refractory OCD found once-weekly oral morphine added to patients’ current regimen significantly reduced Y-BOCS score vs placebo. Patients received 30 mg the first week and 15 to 45 mg the next week, depending on response or side effects.³⁰ A case report and a small open-label trial support the efficacy of tramadol, a weak agonist of the μ opioid receptor and an inhibitor of serotonin and norepinephrine transporters, as monotherapy and as an adjunct to fluoxetine.^31,32 Because patients with OCD may be particularly vulnerable to dependence and intentional or accidental overdose via opioid/benzodiazepine combinations, evaluate the risks and benefits before initiating an opioid.

Psychostimulants. Sparse but good evidence supports the efficacy of dextroamphetamine monotherapy for OCD.^33,34 There are no positive studies of methylphenidate and several case reports of methylphenidate-induced OCD symptoms.³⁵

N-methyl-D-aspartate (NMDA) antagonists. Increased glutamatergic neurotransmission has been implicated in the pathophysiology of OCD, which suggests a possible role for glutamate receptor antagonists. In an open-label trial, memantine, an NMDA antagonist used primarily to treat dementia, was associated with clinical response (>25% reduction in Y-BOCS scores) in 6 of 14 patients with treatment-refractory OCD.³⁶ Several case reports and an open-label trial support the efficacy of riluzole—which is indicated for treating amyotrophic lateral sclerosis—as an adjunct for treatment-refractory OCD.³⁷ Although its exact mechanism of action is unclear, riluzole’s effects are thought to be mediated via reduction in glutamatergic neurotransmission. IV ketamine has reported anti-OCD effects in a case report of a woman with treatment-resistant OCD. These effects occurred almost immediately and persisted for several days.³⁸

Hallucinogens. Psilocybin, psilocin, and lysergic acid diethylamide have reported anti-OCD properties.³⁹ As schedule I substances, however, they are not available outside of sanctioned research protocols and may carry substantial risk. Nonetheless, their efficacy suggests that other compounds that share their mechanism of action—namely agonism of 5-HT2A and 5-HT2C receptors—may merit investigation as potential treatments for OCD.

Psychotherapy

Cognitive-behavioral therapy (CBT) has been shown to be effective for OCD as monotherapy and augmentation to pharmacotherapy. CBT consists of cognitive and behavioral components, typically involving some form of cognitive restructuring and exposure response prevention. Although these 2 types of interventions arise from independent traditions, in CBT they are frequently intertwined, particularly when the focus of OCD patients’ anxiety is ego-dystonic thoughts.

One benefit of CBT over pharmacotherapy is that effects persist after treatment is terminated. A recent prospective study found CBT was effective for treatment-refractory OCD, with 74% of patients demonstrating clinical response after 20 to 25 sessions over 2 months and 61% maintaining clinical response 1 year after treatment.⁴⁰ CBT administered remotely via teleconference, also known as “teletherapy,” has shown efficacy for OCD.⁴¹

Alternative medicine

Despite widespread use of herbal remedies for OCD, no trials have shown a strong positive effect. Both Hypericum perforatum (St. John’s wort) and Silybum marianum (milk thistle) have been used to treat obsessive and compulsive symptoms; however, placebo-controlled trials did not find any significant differences in symptoms or side effects between treatment groups.^42,43 Lower-quality studies have reported modest effects for mindfulness meditation, yoga, and acupuncture.⁴⁴

Because many patients continue to use complementary and alternative medicine therapies despite the lack of data on efficacy, it is important to monitor for potential interactions with prescription medications. St. John’s wort interacts with many medications because of induction of the cytochrome P450 (CYP) isoenzymes 3A4 and 2C9. This interaction may lower blood levels of alprazolam and clonazepam (3A4). Combining St. John’s wort with SSRIs increases the risk of serotonin syndrome. Milk thistle inhibits CYP450 isoenzyme 3A4, and may increase serum levels of other medications metabolized by this pathway.

Invasive therapies

Invasive options may be considered after several pharmacotherapeutic and psychotherapeutic approaches have not been effective or when significant functional impairment remains (Table 2). These therapies typically are reserved for patients whose treatment resistance is strongest.

Electroconvulsive therapy (ECT). Although ECT is an effective tool for treatment-resistant mood disorders or treatment-resistant anxiety complicated by severe depression, studies have not found ECT to be effective for OCD. One uncontrolled case series reported considerable improvements in OCD patients the year after ECT, although improvement was correlated with improved depression scores.⁴⁵

Vagal nerve stimulation (VNS). In an open-label study of 7 OCD patients who received VNS, 3 were acute responders—characterized by a ≥25% improvement on the Y-BOCS—and 2 received continued benefits at 4-year follow up (2 patients dropped out).⁴⁶

Repetitive transcranial magnetic stimulation (rTMS). A meta-analysis of 3 RCTs of rTMS for patients with OCD did not yield a large or statistically significant effect.⁴⁷ Limitations of these trials included asymmetric stimulation sites (eg, left vs right only), limited stimulation sites (dorsolateral prefrontal cortex), different stimulation frequencies between studies, and a lack of sham stimulation conditions. A more recent RCT and subsequent review described moderate efficacy (defined by ≥25% decrease in Y-BOCS scores) compared with sham stimulations in OCD patients at 4 weeks, using the supplementary motor area as a stimulation site.^48,49

The main limitation of rTMS is the inability to penetrate deeper brain structures implicated in OCD (eg, caudate nucleus, thalamus, anterior capsule fiber tracts), as well as a lack of specificity in stimulation site.

Surgical approaches. Cingulotomy is the most commonly employed surgical procedure for OCD in North America, likely because of a combination of clinical efficacy and low morbidity and mortality rates.⁵⁰ Of the >1,000 cingulotomies that have been performed at Massachusetts General Hospital, no deaths or postoperative infections have been reported and 2 subdural hematomas have occurred.⁵⁰ Common postsurgical side effects include transient headache, nausea, or difficulty urinating. The most serious common side effect—postoperative seizures—has been reported in 1% to 9% of cases.

Outcomes for these procedures cannot be fully assessed until at least 6 months to 2 years after the procedure, which suggests postoperative neural reorganization plays an important role in recovery. Direct comparisons of each lesion approach within studies are extremely rare. Overall, long-term outcomes of these approaches have demonstrated significant therapeutic effects of each of these procedures. Reported response rates vary between 30% to 70%, when applied to remission, response (≥35% Y-BOCS reduction), and functional improvements in quality of life.⁵⁰

Deep brain stimulation (DBS). With this approach, small electrodes are inserted under precise stereotactic MRI guidance. The advantage of DBS over ablative surgery is the ability to adjust and customize neurostimulation. Following implantation, modifiable parameters of electrode stimulation include electrode polarity, intensity, frequency, and laterality. A specially trained psychiatrist can conduct parameter optimization during long-term follow-up.

The first trial of DBS for OCD was reported in 1999 (N = 4), with the initial target selected based on the site of anterior capsulotomy. Three patients derived clinically observed benefit, although no validated questionnaires were administered.⁵¹ Since then, at least 7 studies with blinded stimulation have been conducted, totaling 62 patients.⁵²

In recent years, structures adjacent to the internal capsule also have been targeted based on the approach employed in ventral capsulotomy. Across all trials, response rates for this approach consistently have been in the 50% range, with average Y-BOCS score reductions ranging from 6.8 to 31 points.⁵³ Some patients have reported rapid improvements in anhedonia, and this approach is being employed in treatment-resistant depression.

Postoperative complications occur more often with DBS than with lesion approaches because of the prosthetic nature of the procedure (eg, increased risk of infection, lead malfunction, etc.). Additionally, batteries must be periodically explanted and replaced. Reported stimulation-related side effects include mood changes (transient sadness, anxiety, euphoria, and hypomania), sensory disturbances (olfactory, gustatory, and motor sensations), and cognitive changes (confusion and forgetfulness). These side effects typically are stimulation-dependent and disappear after altering stimulation parameters.

Table 2

Invasive therapies for treatment-resistant OCD

Related Resources

• American Psychiatric Association. Treatment of patients with obsessive-compulsive disorder. www.psychiatryonline.com/pracGuide/pracGuideTopic_10.aspx.
• Hyman BM, Pedrick C. The OCD workbook. Your guide to breaking free from obsessive compulsive disorder. 3rd ed. Oakland, CA: New Harbinger Publications Inc; 2010.
• Baer L. Getting control: overcoming your obsessions and compulsions. Revised ed. New York, NY: Plume; 2000.

Drug Brand Names

• Alprazolam • Xanax
• Aripiprazole • Abilify
• Citalopram • Celexa
• Clomipramine • Anafranil
• Clonazepam • Klonopin
• Dextroamphetamine • Adderall
• Duloxetine • Cymbalta
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Ketamine • Ketalar
• Memantine • Namenda
• Methylphenidate • Ritalin
• Morphine • MS Contin
• Olanzapine • Zyprexa
• Ondansetron • Zofran
• Pindolol • Visken
• Quetiapine • Seroquel
• Riluzole • Rilutek
• Risperidone • Risperdal
• Sertraline • Zoloft
• Tramadol • Ultram
• Venlafaxine • Effexor
• Ziprasidone • Geodon

Disclosures

Drs. Khalsa and Schiffman report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Bystritsky receives grant support from AstraZeneca, Brainways, Takeda, and Transcept and is a founder, stockholder, and consultant for BrainSonix.