Article

This friable vascular papule was most consistent with a lobular capillary hemangioma (LCH), also called a pyogenic granuloma. A shave biopsy was performed at the base of the tumor to confirm the diagnosis and rule out malignant pedunculated tumors, including nodular melanoma, angiosarcoma, and metastatic carcinoma.

LCHs are benign vascular growths that occur on the skin and mucosa, most often in children and young adults. Growth may occur rapidly over days to weeks and tumors may grow to several centimeters in size. Although LCHs are often painless, they do tend to bleed easily with minor trauma.

While the triggering mechanism is unknown, LCHs have been associated with infection, trauma, hormonal factors (especially in the second and third trimesters of pregnancy), and therapy with retinoids. About 5% of pregnancies are associated with the development of an LCH on the oral mucosa, usually in the second or third trimester.¹

Treatment of LCHs is based on small case series and case reports. Individual tumors have a high likelihood of recurrence after a single treatment, so multiple visits for treatment are often recommended. Electrocautery is safe and effective with complete cure occurring after 2 sessions. Similarly, cryotherapy is safe and effective with excellent results after 3 treatment sessions. Cryotherapy may cause depigmentation in patients with darker skin types, so this should be discussed with patients with skin of color. Excision of small lesions is also safe and effective in a single session.²

This patient was treated with light electrodessication and curettage in 2 sessions with complete clearance.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME.

This friable vascular papule was most consistent with a lobular capillary hemangioma (LCH), also called a pyogenic granuloma. A shave biopsy was performed at the base of the tumor to confirm the diagnosis and rule out malignant pedunculated tumors, including nodular melanoma, angiosarcoma, and metastatic carcinoma.

LCHs are benign vascular growths that occur on the skin and mucosa, most often in children and young adults. Growth may occur rapidly over days to weeks and tumors may grow to several centimeters in size. Although LCHs are often painless, they do tend to bleed easily with minor trauma.

While the triggering mechanism is unknown, LCHs have been associated with infection, trauma, hormonal factors (especially in the second and third trimesters of pregnancy), and therapy with retinoids. About 5% of pregnancies are associated with the development of an LCH on the oral mucosa, usually in the second or third trimester.¹

Treatment of LCHs is based on small case series and case reports. Individual tumors have a high likelihood of recurrence after a single treatment, so multiple visits for treatment are often recommended. Electrocautery is safe and effective with complete cure occurring after 2 sessions. Similarly, cryotherapy is safe and effective with excellent results after 3 treatment sessions. Cryotherapy may cause depigmentation in patients with darker skin types, so this should be discussed with patients with skin of color. Excision of small lesions is also safe and effective in a single session.²

This patient was treated with light electrodessication and curettage in 2 sessions with complete clearance.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME.

This friable vascular papule was most consistent with a lobular capillary hemangioma (LCH), also called a pyogenic granuloma. A shave biopsy was performed at the base of the tumor to confirm the diagnosis and rule out malignant pedunculated tumors, including nodular melanoma, angiosarcoma, and metastatic carcinoma.

LCHs are benign vascular growths that occur on the skin and mucosa, most often in children and young adults. Growth may occur rapidly over days to weeks and tumors may grow to several centimeters in size. Although LCHs are often painless, they do tend to bleed easily with minor trauma.

While the triggering mechanism is unknown, LCHs have been associated with infection, trauma, hormonal factors (especially in the second and third trimesters of pregnancy), and therapy with retinoids. About 5% of pregnancies are associated with the development of an LCH on the oral mucosa, usually in the second or third trimester.¹

Treatment of LCHs is based on small case series and case reports. Individual tumors have a high likelihood of recurrence after a single treatment, so multiple visits for treatment are often recommended. Electrocautery is safe and effective with complete cure occurring after 2 sessions. Similarly, cryotherapy is safe and effective with excellent results after 3 treatment sessions. Cryotherapy may cause depigmentation in patients with darker skin types, so this should be discussed with patients with skin of color. Excision of small lesions is also safe and effective in a single session.²

This patient was treated with light electrodessication and curettage in 2 sessions with complete clearance.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME.

The calcitonin gene-related peptide (CGRP) antagonist class of medications has changed the face of migraine treatment — and there are now both acute and preventive options that are available in oral and injectable formulations. The gepant subclass of CGRP antagonists are small-molecule medications, in contrast to the CGRP monoclonal antibodies. Atogepant was developed as the first oral migraine-specific preventive medication, and the initial trials allowed for an initial approval by the US Food and Drug Administration for episodic migraine alone. The study by Pozo-Rosich and colleagues extended the patient population to patients with chronic migraine.

This was an international, multicenter, randomized controlled study of two dosages of atogepant (30 mg twice daily and 60 mg daily) compared with placebo over 12 weeks. The primary endpoint was change in mean monthly migraine days. There was a safety population as well that received a single dose of medication. Nearly 800 participants were enrolled equally into these three groups, and the authors used a modified intention-to-treat format that included all participants with at least 1 month of e-diary data and took at least one dose of the study medication.

The baseline number of mean monthly migraine days in this chronic migraine population was 18.6 days per month. After 12 weeks, the three groups showed decreases of 7.5, 6.1, and 5.1 days per month, which was statistically significant for the two intervention groups. The most common side effects were constipation and nausea, with up to 10% of the study population experiencing some gastrointestinal symptoms. Weight loss of 7% of body weight was also noticed in the two intervention groups.

This study describes the benefit of atogepant extending beyond the indication of episodic migraine. This chronic migraine population showed significant benefit in the decrease of mean monthly migraine days per month after 12 weeks. One additional benefit is weight loss even after 12 weeks. Compared with the monoclonal antibody class of CGRP antagonist, this medication appears to be approximately equally effective, with the additional benefit of weight loss. Because many preventive medications for migraine may be associated with weight gain — particularly the antidepressant and potentially the antihypertensive classes of medications — this can be a differentiating factor when choosing an appropriate preventive medication for your patients with chronic migraine.

CGRP is a known inflammatory modulator that also plays a significant role in the propagation of migraine. CGRP blockade has been associated, in some studies, with upper respiratory tract infection symptoms, raising the question of whether blocking CGRP chronically may increase the risk for infection. A prior study revealed that CGRP levels were decreased in patients with severe COVID-19, and another study did not find significant differences in COVID-19 disease, progression, or severity among migraine patients on CGRP antagonists. Wang and colleagues specifically sought to determine any potential association or risk between the use of CGRP antagonist medications and COVID.

This retrospective cohort study was performed in the US Veterans Affairs (VA) hospital system. It analyzed the electronic medical records of veterans diagnosed with migraine between January and May 2022. The participants' exposure to CGRP medications and the 30-day odds of hospitalization, as well as use of mechanical ventilation, were calculated. CGRP prescriptions were identified using outpatient pharmacy records for erenumab, fremanezumab (225 mg/1.5 mL), and galcanezumab (120 mg/mL), which were the only CGRP medications available at that point in the VA system. The primary outcome was cumulative incidence of SARS-CoV-2 infection; occurrences of SARS-CoV-2 infection were obtained from the VA COVID-19 Shared Data Resource. Secondary analysis of the clinical outcomes was performed among patients with a positive SARS-CoV-2 test result.

This analysis revealed that CGRP monoclonal antibody use was not associated with risk for COVID-19, and among participants who tested positive for COVID-19, there were no significant differences in hospitalization, oxygen supplementation, mechanical ventilation, or COVID-19–related death between those who were receiving CGRP medications and those who were not. Although another prior study implied that CGRP blockade may decrease the risk for severe disease related to a cytokine storm, those results were only in vitro, and no results from human or animal trials have replicated these data. There is, therefore, no contraindication to using CGRP antagonist medications in people at high risk for development of COVID-19.

Many patients with migraine are recommended specific treatments for the prevention of migraine attacks and for the acute treatment of their attacks. Very few studies have investigated specific combinations of acute and preventive treatments. Although logically, there should be no contraindication to most treatment combinations, there may be some additional synergistic benefit to the combination of specific classes of medications. We have previously discussed a synergy between the CGRP antagonist class and onabotulinumtoxinA (Botox) for the prevention of chronic migraine; Manack Adams and colleagues sought to quantify the efficacy of ubrogepant when the patients were also administered botulinum toxin.

The joint American Academy of Neurology/American Headache Society consensus statement recommends starting preventive medication for anyone with migraine who experiences > 4-5 days of headache per month. It also recommends a migraine-specific acute treatment for anyone who experiences migraine attacks. Botulinum toxin is approved by the US Food and Drug Administration for the prevention of chronic migraine at a dose of 155 units injected every 3 months; ubrogepant is a CGRP oral small-molecule antagonist that is approved for the acute treatment of migraine.

This study investigated the effectiveness of ubrogepant, with a primary endpoint of meaningful pain relief and return to normal function 2 and 4 hours after an initial dose of 50 or 100 mg. Meaningful pain relief was defined as answering "yes" to a question about whether the patient experienced meaningful pain relief. This has been a pre-reported endpoint in other acute migraine treatment trials. Return to normal function was defined as the time point where the patient could perform their daily activities on the basis of a functional disability scale. Achieving normal function was classified as either remaining free of disability or by reporting functional disability before taking ubrogepant and then indicating a return to normal function at 2 and 4 hours post-dose.

A total of 134 patients were enrolled, taking both ubrogepant and botulinum toxin; patients were included if they were treated with ubrogepant at least once. Meaningful pain relief was achieved in 53.3% of patients at 2 hours and in 76.2% of patients at 4 hours post-dose. Return to normal function was achieved by 30.1% of patients at 2 hours and by 52.1% of patients at 4 hours post-dose. Both meaningful pain relief and return to normal function were seen to be statistically significant and stable across up to 10 attacks per person.

Headache treatment providers typically need to consider different classes of medications for prevention and acute treatment. A growing body of evidence describes a synergy between the CGRP class of medications and botulinum toxin. This appears to be true both when CGRP antagonists are used preventively and, in this case, when they are used for acute events. This certainly would be a safe and effective choice in many instances for many patients.

The calcitonin gene-related peptide (CGRP) antagonist class of medications has changed the face of migraine treatment — and there are now both acute and preventive options that are available in oral and injectable formulations. The gepant subclass of CGRP antagonists are small-molecule medications, in contrast to the CGRP monoclonal antibodies. Atogepant was developed as the first oral migraine-specific preventive medication, and the initial trials allowed for an initial approval by the US Food and Drug Administration for episodic migraine alone. The study by Pozo-Rosich and colleagues extended the patient population to patients with chronic migraine.

This was an international, multicenter, randomized controlled study of two dosages of atogepant (30 mg twice daily and 60 mg daily) compared with placebo over 12 weeks. The primary endpoint was change in mean monthly migraine days. There was a safety population as well that received a single dose of medication. Nearly 800 participants were enrolled equally into these three groups, and the authors used a modified intention-to-treat format that included all participants with at least 1 month of e-diary data and took at least one dose of the study medication.

The baseline number of mean monthly migraine days in this chronic migraine population was 18.6 days per month. After 12 weeks, the three groups showed decreases of 7.5, 6.1, and 5.1 days per month, which was statistically significant for the two intervention groups. The most common side effects were constipation and nausea, with up to 10% of the study population experiencing some gastrointestinal symptoms. Weight loss of 7% of body weight was also noticed in the two intervention groups.

This study describes the benefit of atogepant extending beyond the indication of episodic migraine. This chronic migraine population showed significant benefit in the decrease of mean monthly migraine days per month after 12 weeks. One additional benefit is weight loss even after 12 weeks. Compared with the monoclonal antibody class of CGRP antagonist, this medication appears to be approximately equally effective, with the additional benefit of weight loss. Because many preventive medications for migraine may be associated with weight gain — particularly the antidepressant and potentially the antihypertensive classes of medications — this can be a differentiating factor when choosing an appropriate preventive medication for your patients with chronic migraine.

CGRP is a known inflammatory modulator that also plays a significant role in the propagation of migraine. CGRP blockade has been associated, in some studies, with upper respiratory tract infection symptoms, raising the question of whether blocking CGRP chronically may increase the risk for infection. A prior study revealed that CGRP levels were decreased in patients with severe COVID-19, and another study did not find significant differences in COVID-19 disease, progression, or severity among migraine patients on CGRP antagonists. Wang and colleagues specifically sought to determine any potential association or risk between the use of CGRP antagonist medications and COVID.

This retrospective cohort study was performed in the US Veterans Affairs (VA) hospital system. It analyzed the electronic medical records of veterans diagnosed with migraine between January and May 2022. The participants' exposure to CGRP medications and the 30-day odds of hospitalization, as well as use of mechanical ventilation, were calculated. CGRP prescriptions were identified using outpatient pharmacy records for erenumab, fremanezumab (225 mg/1.5 mL), and galcanezumab (120 mg/mL), which were the only CGRP medications available at that point in the VA system. The primary outcome was cumulative incidence of SARS-CoV-2 infection; occurrences of SARS-CoV-2 infection were obtained from the VA COVID-19 Shared Data Resource. Secondary analysis of the clinical outcomes was performed among patients with a positive SARS-CoV-2 test result.

This analysis revealed that CGRP monoclonal antibody use was not associated with risk for COVID-19, and among participants who tested positive for COVID-19, there were no significant differences in hospitalization, oxygen supplementation, mechanical ventilation, or COVID-19–related death between those who were receiving CGRP medications and those who were not. Although another prior study implied that CGRP blockade may decrease the risk for severe disease related to a cytokine storm, those results were only in vitro, and no results from human or animal trials have replicated these data. There is, therefore, no contraindication to using CGRP antagonist medications in people at high risk for development of COVID-19.

Many patients with migraine are recommended specific treatments for the prevention of migraine attacks and for the acute treatment of their attacks. Very few studies have investigated specific combinations of acute and preventive treatments. Although logically, there should be no contraindication to most treatment combinations, there may be some additional synergistic benefit to the combination of specific classes of medications. We have previously discussed a synergy between the CGRP antagonist class and onabotulinumtoxinA (Botox) for the prevention of chronic migraine; Manack Adams and colleagues sought to quantify the efficacy of ubrogepant when the patients were also administered botulinum toxin.

The joint American Academy of Neurology/American Headache Society consensus statement recommends starting preventive medication for anyone with migraine who experiences > 4-5 days of headache per month. It also recommends a migraine-specific acute treatment for anyone who experiences migraine attacks. Botulinum toxin is approved by the US Food and Drug Administration for the prevention of chronic migraine at a dose of 155 units injected every 3 months; ubrogepant is a CGRP oral small-molecule antagonist that is approved for the acute treatment of migraine.

This study investigated the effectiveness of ubrogepant, with a primary endpoint of meaningful pain relief and return to normal function 2 and 4 hours after an initial dose of 50 or 100 mg. Meaningful pain relief was defined as answering "yes" to a question about whether the patient experienced meaningful pain relief. This has been a pre-reported endpoint in other acute migraine treatment trials. Return to normal function was defined as the time point where the patient could perform their daily activities on the basis of a functional disability scale. Achieving normal function was classified as either remaining free of disability or by reporting functional disability before taking ubrogepant and then indicating a return to normal function at 2 and 4 hours post-dose.

A total of 134 patients were enrolled, taking both ubrogepant and botulinum toxin; patients were included if they were treated with ubrogepant at least once. Meaningful pain relief was achieved in 53.3% of patients at 2 hours and in 76.2% of patients at 4 hours post-dose. Return to normal function was achieved by 30.1% of patients at 2 hours and by 52.1% of patients at 4 hours post-dose. Both meaningful pain relief and return to normal function were seen to be statistically significant and stable across up to 10 attacks per person.

Headache treatment providers typically need to consider different classes of medications for prevention and acute treatment. A growing body of evidence describes a synergy between the CGRP class of medications and botulinum toxin. This appears to be true both when CGRP antagonists are used preventively and, in this case, when they are used for acute events. This certainly would be a safe and effective choice in many instances for many patients.

The calcitonin gene-related peptide (CGRP) antagonist class of medications has changed the face of migraine treatment — and there are now both acute and preventive options that are available in oral and injectable formulations. The gepant subclass of CGRP antagonists are small-molecule medications, in contrast to the CGRP monoclonal antibodies. Atogepant was developed as the first oral migraine-specific preventive medication, and the initial trials allowed for an initial approval by the US Food and Drug Administration for episodic migraine alone. The study by Pozo-Rosich and colleagues extended the patient population to patients with chronic migraine.

This was an international, multicenter, randomized controlled study of two dosages of atogepant (30 mg twice daily and 60 mg daily) compared with placebo over 12 weeks. The primary endpoint was change in mean monthly migraine days. There was a safety population as well that received a single dose of medication. Nearly 800 participants were enrolled equally into these three groups, and the authors used a modified intention-to-treat format that included all participants with at least 1 month of e-diary data and took at least one dose of the study medication.

The baseline number of mean monthly migraine days in this chronic migraine population was 18.6 days per month. After 12 weeks, the three groups showed decreases of 7.5, 6.1, and 5.1 days per month, which was statistically significant for the two intervention groups. The most common side effects were constipation and nausea, with up to 10% of the study population experiencing some gastrointestinal symptoms. Weight loss of 7% of body weight was also noticed in the two intervention groups.

This study describes the benefit of atogepant extending beyond the indication of episodic migraine. This chronic migraine population showed significant benefit in the decrease of mean monthly migraine days per month after 12 weeks. One additional benefit is weight loss even after 12 weeks. Compared with the monoclonal antibody class of CGRP antagonist, this medication appears to be approximately equally effective, with the additional benefit of weight loss. Because many preventive medications for migraine may be associated with weight gain — particularly the antidepressant and potentially the antihypertensive classes of medications — this can be a differentiating factor when choosing an appropriate preventive medication for your patients with chronic migraine.

CGRP is a known inflammatory modulator that also plays a significant role in the propagation of migraine. CGRP blockade has been associated, in some studies, with upper respiratory tract infection symptoms, raising the question of whether blocking CGRP chronically may increase the risk for infection. A prior study revealed that CGRP levels were decreased in patients with severe COVID-19, and another study did not find significant differences in COVID-19 disease, progression, or severity among migraine patients on CGRP antagonists. Wang and colleagues specifically sought to determine any potential association or risk between the use of CGRP antagonist medications and COVID.

This retrospective cohort study was performed in the US Veterans Affairs (VA) hospital system. It analyzed the electronic medical records of veterans diagnosed with migraine between January and May 2022. The participants' exposure to CGRP medications and the 30-day odds of hospitalization, as well as use of mechanical ventilation, were calculated. CGRP prescriptions were identified using outpatient pharmacy records for erenumab, fremanezumab (225 mg/1.5 mL), and galcanezumab (120 mg/mL), which were the only CGRP medications available at that point in the VA system. The primary outcome was cumulative incidence of SARS-CoV-2 infection; occurrences of SARS-CoV-2 infection were obtained from the VA COVID-19 Shared Data Resource. Secondary analysis of the clinical outcomes was performed among patients with a positive SARS-CoV-2 test result.

This analysis revealed that CGRP monoclonal antibody use was not associated with risk for COVID-19, and among participants who tested positive for COVID-19, there were no significant differences in hospitalization, oxygen supplementation, mechanical ventilation, or COVID-19–related death between those who were receiving CGRP medications and those who were not. Although another prior study implied that CGRP blockade may decrease the risk for severe disease related to a cytokine storm, those results were only in vitro, and no results from human or animal trials have replicated these data. There is, therefore, no contraindication to using CGRP antagonist medications in people at high risk for development of COVID-19.

Many patients with migraine are recommended specific treatments for the prevention of migraine attacks and for the acute treatment of their attacks. Very few studies have investigated specific combinations of acute and preventive treatments. Although logically, there should be no contraindication to most treatment combinations, there may be some additional synergistic benefit to the combination of specific classes of medications. We have previously discussed a synergy between the CGRP antagonist class and onabotulinumtoxinA (Botox) for the prevention of chronic migraine; Manack Adams and colleagues sought to quantify the efficacy of ubrogepant when the patients were also administered botulinum toxin.

The joint American Academy of Neurology/American Headache Society consensus statement recommends starting preventive medication for anyone with migraine who experiences > 4-5 days of headache per month. It also recommends a migraine-specific acute treatment for anyone who experiences migraine attacks. Botulinum toxin is approved by the US Food and Drug Administration for the prevention of chronic migraine at a dose of 155 units injected every 3 months; ubrogepant is a CGRP oral small-molecule antagonist that is approved for the acute treatment of migraine.

This study investigated the effectiveness of ubrogepant, with a primary endpoint of meaningful pain relief and return to normal function 2 and 4 hours after an initial dose of 50 or 100 mg. Meaningful pain relief was defined as answering "yes" to a question about whether the patient experienced meaningful pain relief. This has been a pre-reported endpoint in other acute migraine treatment trials. Return to normal function was defined as the time point where the patient could perform their daily activities on the basis of a functional disability scale. Achieving normal function was classified as either remaining free of disability or by reporting functional disability before taking ubrogepant and then indicating a return to normal function at 2 and 4 hours post-dose.

A total of 134 patients were enrolled, taking both ubrogepant and botulinum toxin; patients were included if they were treated with ubrogepant at least once. Meaningful pain relief was achieved in 53.3% of patients at 2 hours and in 76.2% of patients at 4 hours post-dose. Return to normal function was achieved by 30.1% of patients at 2 hours and by 52.1% of patients at 4 hours post-dose. Both meaningful pain relief and return to normal function were seen to be statistically significant and stable across up to 10 attacks per person.

Headache treatment providers typically need to consider different classes of medications for prevention and acute treatment. A growing body of evidence describes a synergy between the CGRP class of medications and botulinum toxin. This appears to be true both when CGRP antagonists are used preventively and, in this case, when they are used for acute events. This certainly would be a safe and effective choice in many instances for many patients.

The Diagnosis: Infantile Transient Smooth Muscle Contraction of the Skin

A diagnosis of infantile transient smooth muscle contraction of the skin (ITSMC) was made based on our patient’s clinical presentation and eliminating the diagnoses in the differential. No treatment ultimately was indicated, as episodes became less frequent over time.

The term infantile transient smooth muscle contraction of the skin was first proposed in 2013 by Torrelo et al,¹ who described 9 newborns with episodic skin rippling occasionally associated with exposure to cold or friction. The authors postulated that ITSMC was the result of a transient contraction of the arrector pili smooth muscle fibers of the skin, secondary to autonomic immaturity, primitive reflexes, or smooth muscle hypersensitivity.¹ Since this first description, ITSMC has remained a rarely reported and poorly understood phenomenon with rare identified cases in the literature.^2,3 Clinical history and examination of infants with intermittent transient skin rippling help to distinguish ITSMC from other diagnoses without the need for biopsy, which is particularly undesirable in the pediatric population.

Congenital smooth muscle hamartoma is a benign proliferation of mature smooth muscle that also can arise from the arrector pili muscles.⁴ In contrast to ITSMC, a hamartoma does not clear; rather, it persists and grows proportionally with the child and is associated with overlying hyperpigmentation and hypertrichosis. The transient nature of ITSMC may be worrisome for mastocytoma; however, this condition presents as erythematous, yellow, red, or brown macules, papules, plaques, or nodules with a positive Darier sign.⁵ Although the differential diagnosis includes the shagreen patch characteristic of tuberous sclerosis, this irregular plaque typically is located on the lower back with overlying peau d’orange skin changes, and our patient lacked other features indicative of this condition.⁶ Becker nevus also remains a consideration in patients with rippled skin, but this entity typically becomes more notable at puberty and is associated with hyperpigmentation and hypertrichosis and is a type of smooth muscle hamartoma.⁴

Our case highlighted the unusual presentation of ITSMC, a condition that can easily go unrecognized, leading to unnecessary referrals and concern. Familiarity with this benign diagnosis is essential to inform prognosis and guide management.

The Diagnosis: Infantile Transient Smooth Muscle Contraction of the Skin

A diagnosis of infantile transient smooth muscle contraction of the skin (ITSMC) was made based on our patient’s clinical presentation and eliminating the diagnoses in the differential. No treatment ultimately was indicated, as episodes became less frequent over time.

The term infantile transient smooth muscle contraction of the skin was first proposed in 2013 by Torrelo et al,¹ who described 9 newborns with episodic skin rippling occasionally associated with exposure to cold or friction. The authors postulated that ITSMC was the result of a transient contraction of the arrector pili smooth muscle fibers of the skin, secondary to autonomic immaturity, primitive reflexes, or smooth muscle hypersensitivity.¹ Since this first description, ITSMC has remained a rarely reported and poorly understood phenomenon with rare identified cases in the literature.^2,3 Clinical history and examination of infants with intermittent transient skin rippling help to distinguish ITSMC from other diagnoses without the need for biopsy, which is particularly undesirable in the pediatric population.

Congenital smooth muscle hamartoma is a benign proliferation of mature smooth muscle that also can arise from the arrector pili muscles.⁴ In contrast to ITSMC, a hamartoma does not clear; rather, it persists and grows proportionally with the child and is associated with overlying hyperpigmentation and hypertrichosis. The transient nature of ITSMC may be worrisome for mastocytoma; however, this condition presents as erythematous, yellow, red, or brown macules, papules, plaques, or nodules with a positive Darier sign.⁵ Although the differential diagnosis includes the shagreen patch characteristic of tuberous sclerosis, this irregular plaque typically is located on the lower back with overlying peau d’orange skin changes, and our patient lacked other features indicative of this condition.⁶ Becker nevus also remains a consideration in patients with rippled skin, but this entity typically becomes more notable at puberty and is associated with hyperpigmentation and hypertrichosis and is a type of smooth muscle hamartoma.⁴

Our case highlighted the unusual presentation of ITSMC, a condition that can easily go unrecognized, leading to unnecessary referrals and concern. Familiarity with this benign diagnosis is essential to inform prognosis and guide management.

The Diagnosis: Infantile Transient Smooth Muscle Contraction of the Skin

A diagnosis of infantile transient smooth muscle contraction of the skin (ITSMC) was made based on our patient’s clinical presentation and eliminating the diagnoses in the differential. No treatment ultimately was indicated, as episodes became less frequent over time.

The term infantile transient smooth muscle contraction of the skin was first proposed in 2013 by Torrelo et al,¹ who described 9 newborns with episodic skin rippling occasionally associated with exposure to cold or friction. The authors postulated that ITSMC was the result of a transient contraction of the arrector pili smooth muscle fibers of the skin, secondary to autonomic immaturity, primitive reflexes, or smooth muscle hypersensitivity.¹ Since this first description, ITSMC has remained a rarely reported and poorly understood phenomenon with rare identified cases in the literature.^2,3 Clinical history and examination of infants with intermittent transient skin rippling help to distinguish ITSMC from other diagnoses without the need for biopsy, which is particularly undesirable in the pediatric population.

Congenital smooth muscle hamartoma is a benign proliferation of mature smooth muscle that also can arise from the arrector pili muscles.⁴ In contrast to ITSMC, a hamartoma does not clear; rather, it persists and grows proportionally with the child and is associated with overlying hyperpigmentation and hypertrichosis. The transient nature of ITSMC may be worrisome for mastocytoma; however, this condition presents as erythematous, yellow, red, or brown macules, papules, plaques, or nodules with a positive Darier sign.⁵ Although the differential diagnosis includes the shagreen patch characteristic of tuberous sclerosis, this irregular plaque typically is located on the lower back with overlying peau d’orange skin changes, and our patient lacked other features indicative of this condition.⁶ Becker nevus also remains a consideration in patients with rippled skin, but this entity typically becomes more notable at puberty and is associated with hyperpigmentation and hypertrichosis and is a type of smooth muscle hamartoma.⁴

Our case highlighted the unusual presentation of ITSMC, a condition that can easily go unrecognized, leading to unnecessary referrals and concern. Familiarity with this benign diagnosis is essential to inform prognosis and guide management.

THE CASE

A 24-year-old woman with a history of type 1 diabetes, seizure disorder, and migraines presented to a rural Federally Qualified Health Center (FQHC) with progressive and severe symmetric large joint arthralgias of several weeks’ duration. The patient’s existing medications included etonogestrel 68 mg subdermal implant, levetiracetam 1500 mg bid, insulin glargine 26 units subcutaneously nightly, and insulin lispro 20 units subcutaneously tid (before meals).

An examination revealed symmetrically edematous elbows, wrists, and fingers. Subsequent serologic analyses and a telemedicine consultation with a rheumatologist confirmed a diagnosis of rheumatoid arthritis (RA). The patient’s lab work was positive for antinuclear antibody titers (1:40), rheumatoid factor (513 IU/mL), and anticyclic citrullinated peptide antibodies (248 units/mL). Treatment was started with prednisone 60 mg PO daily, methotrexate 20 mg PO weekly, and hydroxychloroquine 400 mg PO daily. (The benefits of prednisone in treating this patient’s severe arthralgias outweighed concerns over its use in a patient with diabetes.)

After 2 months of receiving RA therapy, the patient underwent further work-up to assess its effectiveness. Liver function testing was performed, and she tested positive for hepatitis C virus (HCV) antibodies. Viral polymerase chain reaction confirmed active HCV infection. Lab work revealed a viral load of 15,000,000 IU/mL; transaminase, 173 U/L (normal range, 4-36 U/L); and aspartate aminotransferase, 246 U/L (normal range, 8-33 U/L). A liver sonogram demonstrated no findings of cirrhosis or fibrosis.

Upon receiving a diagnosis of active hepatitis C, the patient acknowledged that she’d had unprotected heterosexual intercourse and shared used insulin syringes with friends.

THE DIAGNOSIS

Consideration was given to a diagnosis of HCV arthropathy, which can present as an RA-like arthritis in HCV-infected individuals, in the differential diagnosis.¹ A cohort study found HCV-associated arthropathy occurred in 6.8% of those with chronic HCV infection.²

However, the symmetrical involvement of shoulders and knees as the patient’s primary arthralgias, and a rheumatologic work-up showing the presence of anticyclic citrullinated peptide antibody levels, confirmed the diagnosis of RA with coexisting HCV.

DISCUSSION

Delivering interdisciplinary care in a rural area

Although evidence-based guidelines and online HCV Treatment Path programs guided the initial evaluation of potential treatments for this patient, her multiple comorbidities prompted us to seek out additional, interdisciplinary advice through a resource for underserved communities called Project Extension for Community Healthcare Outcomes (ECHO; see “What is Project ECHO?^3,4”). The patient’s case was presented virtually, without identifying information, to a multidisciplinary HCV team. Two treatment options were suggested:

• sofosbuvir/velpatasvir (400 mg/100 mg) for 12 weeks or
• glecaprevir/pibrentasvir (100 mg/40 mg) for 8 weeks.

Both are evidence-based and recommended treatment options according to the HCV treatment guidelines issued jointly by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America.⁵

In most patients with HCV, treatment is guided by a number of factors, including pill burden, access to care, duration of therapy, drug interactions, and patient-specific needs. After analyzing all aspects of this patient’s case, 2 major concerns guided our shared decision-making process on treatment.

The best treatment is what works for the patient

Owing to the patient’s multiple comorbidities and prescribed medications for chronic diseases, concerns about possible medication interactions with the HCV treatment options were a factor in her HCV treatment plan. Additionally, the patient had significant social determinants of health barriers that made continued treatment and follow-up challenging.

The potential interaction of HCV infection treatment with the patient’s current methotrexate therapy for her RA was a primary concern. To determine the risk for interactions, the team used the University of Liverpool HEP/HIV Drug Interactions Checker, which helps identify possible interactions with these disease-specific medication therapies.⁶

Both sofosbuvir/velpatasvir and glecaprevir/­pibrentasvir have a potential interaction with methotrexate and are driven by a similar mechanism. Methotrexate is a substrate of the Breast Cancer Resistance Protein efflux transporter (BCRP), and the components of both sofosbuvir/velpatasvir and glecaprevir/pibrentasvir are inhibitors of BCRP.⁷ The inhibition of this efflux transporter can lead to an increased concentration of methotrexate, increasing the risk for methotrexate toxicity.⁷

Since no quantitative data exist regarding the degree of inhibition that these HCV drugs exert on BCRP, the team considered ­sofosbuvir/velpatasvir and glecaprevir/­pibrentasvir to have equal risk with regard to potential for drug interactions.

The patient’s barriers to treatment were another area of concern that directed our therapy decision. The patient had multiple barriers, including poor access to health care because of transportation issues, multiple children requiring care, a variety of chronic diseases, and other life stressors. Shared decision­-making ensured our patient’s autonomy in choosing a specific treatment.

This case shines a light on the multiple challenges that could have come between our patient and proper treatment—but ultimately, did not.

The patient’s social situation and preference narrowed the team’s basis for medication choice primarily down to the duration of therapy: 8 weeks of glecaprevir/pibrentasvir vs 12 weeks of sofosbuvir/velpatasvir. The patient mentioned multiple transportation challenges for follow-up visits to the clinic and therefore wanted to utilize the shorter treatment duration. Follow-up is needed every 4 weeks, so the patient was able to go from 3 to 2 visits.

For problems, there are solutions. Following careful consideration of these patient-specific factors and preferences, the team decided to begin therapy with glecaprevir/pibrentasvir. The patient worked with an outreach specialist at the FQHC to coordinate care and complete paperwork for the Project ECHO consultation. The outreach specialist also assisted the patient in completing paperwork for the Patient Assistance Program for HCV treatment. Because the patient is being cared for at an FQHC, the clinic’s in-house pharmacy was able to utilize the 340B Federal Drug Pricing Program, which makes otherwise out-of-reach medicines affordable for patients such as ours.

Our patient has had no issues with treatment adherence, adverse effects, or follow­-up appointments. The patient’s RA symptoms have improved significantly without any discernable worsening of her HCV infection.

THE TAKEAWAY

This case shines a light on the multiple challenges (clinical, geographic, and financial) that could have come between our patient and proper treatment—but ultimately, did not. The Project ECHO model of care remains a viable way to provide patients who live in rural and underserved communities and who have active HCV and other underlying chronic conditions with interdisciplinary care that can improve health outcomes.

THE CASE

A 24-year-old woman with a history of type 1 diabetes, seizure disorder, and migraines presented to a rural Federally Qualified Health Center (FQHC) with progressive and severe symmetric large joint arthralgias of several weeks’ duration. The patient’s existing medications included etonogestrel 68 mg subdermal implant, levetiracetam 1500 mg bid, insulin glargine 26 units subcutaneously nightly, and insulin lispro 20 units subcutaneously tid (before meals).

An examination revealed symmetrically edematous elbows, wrists, and fingers. Subsequent serologic analyses and a telemedicine consultation with a rheumatologist confirmed a diagnosis of rheumatoid arthritis (RA). The patient’s lab work was positive for antinuclear antibody titers (1:40), rheumatoid factor (513 IU/mL), and anticyclic citrullinated peptide antibodies (248 units/mL). Treatment was started with prednisone 60 mg PO daily, methotrexate 20 mg PO weekly, and hydroxychloroquine 400 mg PO daily. (The benefits of prednisone in treating this patient’s severe arthralgias outweighed concerns over its use in a patient with diabetes.)

After 2 months of receiving RA therapy, the patient underwent further work-up to assess its effectiveness. Liver function testing was performed, and she tested positive for hepatitis C virus (HCV) antibodies. Viral polymerase chain reaction confirmed active HCV infection. Lab work revealed a viral load of 15,000,000 IU/mL; transaminase, 173 U/L (normal range, 4-36 U/L); and aspartate aminotransferase, 246 U/L (normal range, 8-33 U/L). A liver sonogram demonstrated no findings of cirrhosis or fibrosis.

Upon receiving a diagnosis of active hepatitis C, the patient acknowledged that she’d had unprotected heterosexual intercourse and shared used insulin syringes with friends.

THE DIAGNOSIS

Consideration was given to a diagnosis of HCV arthropathy, which can present as an RA-like arthritis in HCV-infected individuals, in the differential diagnosis.¹ A cohort study found HCV-associated arthropathy occurred in 6.8% of those with chronic HCV infection.²

However, the symmetrical involvement of shoulders and knees as the patient’s primary arthralgias, and a rheumatologic work-up showing the presence of anticyclic citrullinated peptide antibody levels, confirmed the diagnosis of RA with coexisting HCV.

DISCUSSION

Delivering interdisciplinary care in a rural area

Although evidence-based guidelines and online HCV Treatment Path programs guided the initial evaluation of potential treatments for this patient, her multiple comorbidities prompted us to seek out additional, interdisciplinary advice through a resource for underserved communities called Project Extension for Community Healthcare Outcomes (ECHO; see “What is Project ECHO?^3,4”). The patient’s case was presented virtually, without identifying information, to a multidisciplinary HCV team. Two treatment options were suggested:

• sofosbuvir/velpatasvir (400 mg/100 mg) for 12 weeks or
• glecaprevir/pibrentasvir (100 mg/40 mg) for 8 weeks.

Both are evidence-based and recommended treatment options according to the HCV treatment guidelines issued jointly by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America.⁵

In most patients with HCV, treatment is guided by a number of factors, including pill burden, access to care, duration of therapy, drug interactions, and patient-specific needs. After analyzing all aspects of this patient’s case, 2 major concerns guided our shared decision-making process on treatment.

The best treatment is what works for the patient

Owing to the patient’s multiple comorbidities and prescribed medications for chronic diseases, concerns about possible medication interactions with the HCV treatment options were a factor in her HCV treatment plan. Additionally, the patient had significant social determinants of health barriers that made continued treatment and follow-up challenging.

The potential interaction of HCV infection treatment with the patient’s current methotrexate therapy for her RA was a primary concern. To determine the risk for interactions, the team used the University of Liverpool HEP/HIV Drug Interactions Checker, which helps identify possible interactions with these disease-specific medication therapies.⁶

Both sofosbuvir/velpatasvir and glecaprevir/­pibrentasvir have a potential interaction with methotrexate and are driven by a similar mechanism. Methotrexate is a substrate of the Breast Cancer Resistance Protein efflux transporter (BCRP), and the components of both sofosbuvir/velpatasvir and glecaprevir/pibrentasvir are inhibitors of BCRP.⁷ The inhibition of this efflux transporter can lead to an increased concentration of methotrexate, increasing the risk for methotrexate toxicity.⁷

Since no quantitative data exist regarding the degree of inhibition that these HCV drugs exert on BCRP, the team considered ­sofosbuvir/velpatasvir and glecaprevir/­pibrentasvir to have equal risk with regard to potential for drug interactions.

The patient’s barriers to treatment were another area of concern that directed our therapy decision. The patient had multiple barriers, including poor access to health care because of transportation issues, multiple children requiring care, a variety of chronic diseases, and other life stressors. Shared decision­-making ensured our patient’s autonomy in choosing a specific treatment.

This case shines a light on the multiple challenges that could have come between our patient and proper treatment—but ultimately, did not.

The patient’s social situation and preference narrowed the team’s basis for medication choice primarily down to the duration of therapy: 8 weeks of glecaprevir/pibrentasvir vs 12 weeks of sofosbuvir/velpatasvir. The patient mentioned multiple transportation challenges for follow-up visits to the clinic and therefore wanted to utilize the shorter treatment duration. Follow-up is needed every 4 weeks, so the patient was able to go from 3 to 2 visits.

For problems, there are solutions. Following careful consideration of these patient-specific factors and preferences, the team decided to begin therapy with glecaprevir/pibrentasvir. The patient worked with an outreach specialist at the FQHC to coordinate care and complete paperwork for the Project ECHO consultation. The outreach specialist also assisted the patient in completing paperwork for the Patient Assistance Program for HCV treatment. Because the patient is being cared for at an FQHC, the clinic’s in-house pharmacy was able to utilize the 340B Federal Drug Pricing Program, which makes otherwise out-of-reach medicines affordable for patients such as ours.

Our patient has had no issues with treatment adherence, adverse effects, or follow­-up appointments. The patient’s RA symptoms have improved significantly without any discernable worsening of her HCV infection.

THE TAKEAWAY

This case shines a light on the multiple challenges (clinical, geographic, and financial) that could have come between our patient and proper treatment—but ultimately, did not. The Project ECHO model of care remains a viable way to provide patients who live in rural and underserved communities and who have active HCV and other underlying chronic conditions with interdisciplinary care that can improve health outcomes.

THE CASE

A 24-year-old woman with a history of type 1 diabetes, seizure disorder, and migraines presented to a rural Federally Qualified Health Center (FQHC) with progressive and severe symmetric large joint arthralgias of several weeks’ duration. The patient’s existing medications included etonogestrel 68 mg subdermal implant, levetiracetam 1500 mg bid, insulin glargine 26 units subcutaneously nightly, and insulin lispro 20 units subcutaneously tid (before meals).

An examination revealed symmetrically edematous elbows, wrists, and fingers. Subsequent serologic analyses and a telemedicine consultation with a rheumatologist confirmed a diagnosis of rheumatoid arthritis (RA). The patient’s lab work was positive for antinuclear antibody titers (1:40), rheumatoid factor (513 IU/mL), and anticyclic citrullinated peptide antibodies (248 units/mL). Treatment was started with prednisone 60 mg PO daily, methotrexate 20 mg PO weekly, and hydroxychloroquine 400 mg PO daily. (The benefits of prednisone in treating this patient’s severe arthralgias outweighed concerns over its use in a patient with diabetes.)

After 2 months of receiving RA therapy, the patient underwent further work-up to assess its effectiveness. Liver function testing was performed, and she tested positive for hepatitis C virus (HCV) antibodies. Viral polymerase chain reaction confirmed active HCV infection. Lab work revealed a viral load of 15,000,000 IU/mL; transaminase, 173 U/L (normal range, 4-36 U/L); and aspartate aminotransferase, 246 U/L (normal range, 8-33 U/L). A liver sonogram demonstrated no findings of cirrhosis or fibrosis.

Upon receiving a diagnosis of active hepatitis C, the patient acknowledged that she’d had unprotected heterosexual intercourse and shared used insulin syringes with friends.

THE DIAGNOSIS

Consideration was given to a diagnosis of HCV arthropathy, which can present as an RA-like arthritis in HCV-infected individuals, in the differential diagnosis.¹ A cohort study found HCV-associated arthropathy occurred in 6.8% of those with chronic HCV infection.²

However, the symmetrical involvement of shoulders and knees as the patient’s primary arthralgias, and a rheumatologic work-up showing the presence of anticyclic citrullinated peptide antibody levels, confirmed the diagnosis of RA with coexisting HCV.

DISCUSSION

Delivering interdisciplinary care in a rural area

Although evidence-based guidelines and online HCV Treatment Path programs guided the initial evaluation of potential treatments for this patient, her multiple comorbidities prompted us to seek out additional, interdisciplinary advice through a resource for underserved communities called Project Extension for Community Healthcare Outcomes (ECHO; see “What is Project ECHO?^3,4”). The patient’s case was presented virtually, without identifying information, to a multidisciplinary HCV team. Two treatment options were suggested:

• sofosbuvir/velpatasvir (400 mg/100 mg) for 12 weeks or
• glecaprevir/pibrentasvir (100 mg/40 mg) for 8 weeks.

Both are evidence-based and recommended treatment options according to the HCV treatment guidelines issued jointly by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America.⁵

In most patients with HCV, treatment is guided by a number of factors, including pill burden, access to care, duration of therapy, drug interactions, and patient-specific needs. After analyzing all aspects of this patient’s case, 2 major concerns guided our shared decision-making process on treatment.

The best treatment is what works for the patient

Owing to the patient’s multiple comorbidities and prescribed medications for chronic diseases, concerns about possible medication interactions with the HCV treatment options were a factor in her HCV treatment plan. Additionally, the patient had significant social determinants of health barriers that made continued treatment and follow-up challenging.

The potential interaction of HCV infection treatment with the patient’s current methotrexate therapy for her RA was a primary concern. To determine the risk for interactions, the team used the University of Liverpool HEP/HIV Drug Interactions Checker, which helps identify possible interactions with these disease-specific medication therapies.⁶

Both sofosbuvir/velpatasvir and glecaprevir/­pibrentasvir have a potential interaction with methotrexate and are driven by a similar mechanism. Methotrexate is a substrate of the Breast Cancer Resistance Protein efflux transporter (BCRP), and the components of both sofosbuvir/velpatasvir and glecaprevir/pibrentasvir are inhibitors of BCRP.⁷ The inhibition of this efflux transporter can lead to an increased concentration of methotrexate, increasing the risk for methotrexate toxicity.⁷

Since no quantitative data exist regarding the degree of inhibition that these HCV drugs exert on BCRP, the team considered ­sofosbuvir/velpatasvir and glecaprevir/­pibrentasvir to have equal risk with regard to potential for drug interactions.

The patient’s barriers to treatment were another area of concern that directed our therapy decision. The patient had multiple barriers, including poor access to health care because of transportation issues, multiple children requiring care, a variety of chronic diseases, and other life stressors. Shared decision­-making ensured our patient’s autonomy in choosing a specific treatment.

This case shines a light on the multiple challenges that could have come between our patient and proper treatment—but ultimately, did not.

The patient’s social situation and preference narrowed the team’s basis for medication choice primarily down to the duration of therapy: 8 weeks of glecaprevir/pibrentasvir vs 12 weeks of sofosbuvir/velpatasvir. The patient mentioned multiple transportation challenges for follow-up visits to the clinic and therefore wanted to utilize the shorter treatment duration. Follow-up is needed every 4 weeks, so the patient was able to go from 3 to 2 visits.

For problems, there are solutions. Following careful consideration of these patient-specific factors and preferences, the team decided to begin therapy with glecaprevir/pibrentasvir. The patient worked with an outreach specialist at the FQHC to coordinate care and complete paperwork for the Project ECHO consultation. The outreach specialist also assisted the patient in completing paperwork for the Patient Assistance Program for HCV treatment. Because the patient is being cared for at an FQHC, the clinic’s in-house pharmacy was able to utilize the 340B Federal Drug Pricing Program, which makes otherwise out-of-reach medicines affordable for patients such as ours.

Our patient has had no issues with treatment adherence, adverse effects, or follow­-up appointments. The patient’s RA symptoms have improved significantly without any discernable worsening of her HCV infection.

THE TAKEAWAY

This case shines a light on the multiple challenges (clinical, geographic, and financial) that could have come between our patient and proper treatment—but ultimately, did not. The Project ECHO model of care remains a viable way to provide patients who live in rural and underserved communities and who have active HCV and other underlying chronic conditions with interdisciplinary care that can improve health outcomes.

THE CASE

A 49-year-old woman was hospitalized with a headache and neck pain that radiated to her ears and eyes in the context of severe hypertension (270/150 mm Hg). Her medical history was significant for heterozygous factor V Leiden mutation, longstanding untreated hypertension, and multiple severe episodes of HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome during pregnancy.

After receiving antihypertensive treatment at a community hospital, her blood pressure gradually improved to 160/100 mm Hg with the addition of a third medication. However, on Day 3 of her stay, her systolic blood pressure rose to more than 200 mm Hg and was accompanied by somnolence, emesis, and paleness. She was transferred to a tertiary care center.

THE DIAGNOSIS

On admission, the patient had left-side hemiparesis and facial droop with dysarthria, resulting in a National Institutes of Health Stroke Scale (NIHSS) score of 7 (out of 42) and a Glasgow Coma Scale (GCS) score of 13 (out of 15). Noncontrast computed tomography (CT) and CT angiography of the head and neck were ordered and showed occlusion of both intracranial vertebral arteries. There were also signs of multifocal infarction in her occipital lobes, thus systemic recombinant human-tissue plasminogen activator (tPA) could not be administered.

The patient was next taken to the angiography suite, where a digital subtraction angiography confirmed the presence of bilateral vertebral artery occlusions (FIGURE 1A). A thrombectomy was performed to open the left occluded segment, resulting in recanalization; however, a high-grade stenosis remained in the intracranial left vertebral artery (FIGURE 1B). The right vertebral artery had a severe extracranial origin stenosis, and balloon angioplasty was performed in order to reach the intracranial circulation; however, the occlusion of the intracranial right vertebral artery segment could not be catheterized. Subsequent magnetic resonance imaging (MRI) with a time-of-flight magnetic resonance angiography showed that the intracranial left vertebral artery with high-grade stenosis had closed down again; thus, there was occlusion of both intracranial vertebral arteries and absent flow signal in the basilar artery (FIGURE 2). There were scattered small acute strokes within the cerebellum, brainstem, and occipital lobes.

Unfortunately, within 48 hours, the patient’s NIHSS score increased from 7 to 29. She developed tetraplegia, was significantly less responsive (GCS score, 3/15), and required intubation and mechanical ventilation. Reopening the stenosis and keeping it open with a stent would be an aggressive procedure with poor odds for success and would require antithrombotic medications with the associated risk for intracranial hemorrhage in the setting of demarcated strokes. Thus, no further intervention was pursued.

Further standard stroke work-up (echocardiography, extracranial ultrasound of the cerebral circulation, and vasculitis screening) was unremarkable. In the intensive care unit, intravenous therapeutic heparin was initiated because of the potential prothrombotic effect of the factor V Leiden mutation but was subsequently switched to dual anti-­aggregation therapy (aspirin 100 mg/d and clopidogrel 75 mg/d) as secondary stroke prevention given the final diagnosis of severe atherosclerosis. Nevertheless, the patient remained tetraplegic with a partial locked-in syndrome when she was discharged, after 2 weeks in the tertiary care center, to a rehabilitation center.

DISCUSSION

Posterior circulation strokes account for 20% to 25% of all ischemic strokes^1,2 and are associated with infarction within the vertebrobasilar arterial system. Common etiologies of these infarctions include atherosclerosis (as seen in our patient), embolism, small-artery penetrating disease, and arterial dissection.² Although the estimated overall mortality of these strokes is low (3.6% to 11%),² basilar occlusion syndrome, in particular, is a life-threatening condition with a high mortality rate of 80% to 90%.³

Continue to: Diagnosis can be particularly challenging...

Diagnosis can be particularly challenging due to the anatomic variations of posterior arterial circulation, as well as the fluctuating nonfocal or multifocal symptoms.² Specific symptoms include vertigo, ataxia, unilateral motor weakness, dysarthria, and oculomotor dysfunction. However, nonspecific symptoms such as headache, nausea, dizziness, hoarseness, falls, and Horner syndrome may be the only presenting signs of a posterior circulation stroke—as was the case with our patient.² Her radiating neck pain could have been interpreted as a pointer to vertebral artery dissection within the context of severe hypertension.⁴ Unfortunately, the diagnosis was delayed and head imaging was obtained only after her mental status deteriorated.

Immediate neuroimaging is necessary to guide treatment in patients with suspected acute posterior circulation stroke,^1,5,6 although it is not always definitive. While CT is pivotal in stroke work-up and may reliably exclude intracranial hemorrhage, its ability to detect acute posterior circulation ischemic strokes is limited given its poor visualization of the posterior fossa (as low as 16% sensitivity).⁵ Fortunately, CT angiography has a high sensitivity (nearing 100%) for large-vessel occlusion and high predictive values for dissection (65%-100% positive predictive value and 70%-98% negative predictive value).^5,7 ­Diffusion-weighted MRI (when available in the emergency setting) has the highest sensitivity for detecting acute infarcts, although posterior circulation infarcts still can be missed (19% false-negative rate).^5,8 Thus, correlative vessel imaging with magnetic resonance or CT angiography is very important, along with a high index of suspicion. In some instances, repeat MRI may be necessary to detect small strokes.

A patient-specific approach to management is key for individuals with suspected posterior circulation stroke.⁵ Because specific data for the appropriate management of posterior circulation ischemic stroke are lacking, current American Heart ­Association/American Stroke Association (AHA/ASA) guidelines apply to anterior and ­posterior circulation strokes.⁶ For eligible ­patients without multifocal disease, intravenous tPA is the first-line therapy and should be initiated according to guidelines within 4.5 hours of stroke onset⁹; it is important to note that these guidelines are based on studies that ­focused more on anterior circulation strokes than posterior circulation strokes.^6,9-13 This can be done in combination with ­endovascular therapy, which consists of ­mechanical thrombectomy, intra-arterial thrombolysis, or a combination of revascularization ­techniques.^3,5,6

Nonspecific symptoms such as headache, nausea, and dizziness may be the only presenting signs of a posterior circulation stroke.

Mechanical thrombectomy specifically has high proven recanalization rates for all target vessels.^3-6 The latest AHA/ASA guidelines recommend mechanical thrombectomy be performed within 6 hours of stroke onset.⁶ However, there is emerging evidence that suggests this timeframe should be ­extended—even beyond 24 hours—given the poor prognosis of posterior circulation strokes.^5,6,14 More data on the management of posterior circulation strokes are urgently needed to better understand which therapeutic approach is most efficient.

In patients such as ours, who have evidence of multifocal disease, treatment may be limited to endovascular therapy. Intracranial stenting of symptomatic lesions in particular has been controversial since the publication of the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis trial, which found that aggressive medical management was superior to stenting in patients who recently had a transient ischemic attack or stroke attributed to stenosis.¹⁵ Although additional studies have been performed, there are no definitive data on the topic—and certainly no data in the emergency setting.¹⁶ Further challenges are raised in patients with bilateral disease, as was the case with this patient.

When our patient was admitted to the rehabilitation clinic, she had a GCS score of 10 to 11/15. After 9 months of rehabilitation, she was discharged home with a GCS score of 15/15 and persistent left-side hemiparesis.

THE TAKEAWAY

Posterior circulation stroke is a life-­threatening disease that may manifest with a variety of symptoms and be difficult to identify on emergent imaging. Thus, a high degree of clinical suspicion and additional follow-up are paramount to ensure prompt diagnosis and a patient-tailored treatment strategy.

CORRESPONDENCE
Kristine A. Blackham, MD, Associate Professor, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland; [email protected] Orcid no: 0000-0002-1620-1144 (Dr. Blackham); 0000-0002- 5225-5414 (Dr. Saleh)

THE CASE

A 49-year-old woman was hospitalized with a headache and neck pain that radiated to her ears and eyes in the context of severe hypertension (270/150 mm Hg). Her medical history was significant for heterozygous factor V Leiden mutation, longstanding untreated hypertension, and multiple severe episodes of HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome during pregnancy.

After receiving antihypertensive treatment at a community hospital, her blood pressure gradually improved to 160/100 mm Hg with the addition of a third medication. However, on Day 3 of her stay, her systolic blood pressure rose to more than 200 mm Hg and was accompanied by somnolence, emesis, and paleness. She was transferred to a tertiary care center.

THE DIAGNOSIS

On admission, the patient had left-side hemiparesis and facial droop with dysarthria, resulting in a National Institutes of Health Stroke Scale (NIHSS) score of 7 (out of 42) and a Glasgow Coma Scale (GCS) score of 13 (out of 15). Noncontrast computed tomography (CT) and CT angiography of the head and neck were ordered and showed occlusion of both intracranial vertebral arteries. There were also signs of multifocal infarction in her occipital lobes, thus systemic recombinant human-tissue plasminogen activator (tPA) could not be administered.

The patient was next taken to the angiography suite, where a digital subtraction angiography confirmed the presence of bilateral vertebral artery occlusions (FIGURE 1A). A thrombectomy was performed to open the left occluded segment, resulting in recanalization; however, a high-grade stenosis remained in the intracranial left vertebral artery (FIGURE 1B). The right vertebral artery had a severe extracranial origin stenosis, and balloon angioplasty was performed in order to reach the intracranial circulation; however, the occlusion of the intracranial right vertebral artery segment could not be catheterized. Subsequent magnetic resonance imaging (MRI) with a time-of-flight magnetic resonance angiography showed that the intracranial left vertebral artery with high-grade stenosis had closed down again; thus, there was occlusion of both intracranial vertebral arteries and absent flow signal in the basilar artery (FIGURE 2). There were scattered small acute strokes within the cerebellum, brainstem, and occipital lobes.

Unfortunately, within 48 hours, the patient’s NIHSS score increased from 7 to 29. She developed tetraplegia, was significantly less responsive (GCS score, 3/15), and required intubation and mechanical ventilation. Reopening the stenosis and keeping it open with a stent would be an aggressive procedure with poor odds for success and would require antithrombotic medications with the associated risk for intracranial hemorrhage in the setting of demarcated strokes. Thus, no further intervention was pursued.

Further standard stroke work-up (echocardiography, extracranial ultrasound of the cerebral circulation, and vasculitis screening) was unremarkable. In the intensive care unit, intravenous therapeutic heparin was initiated because of the potential prothrombotic effect of the factor V Leiden mutation but was subsequently switched to dual anti-­aggregation therapy (aspirin 100 mg/d and clopidogrel 75 mg/d) as secondary stroke prevention given the final diagnosis of severe atherosclerosis. Nevertheless, the patient remained tetraplegic with a partial locked-in syndrome when she was discharged, after 2 weeks in the tertiary care center, to a rehabilitation center.

DISCUSSION

Posterior circulation strokes account for 20% to 25% of all ischemic strokes^1,2 and are associated with infarction within the vertebrobasilar arterial system. Common etiologies of these infarctions include atherosclerosis (as seen in our patient), embolism, small-artery penetrating disease, and arterial dissection.² Although the estimated overall mortality of these strokes is low (3.6% to 11%),² basilar occlusion syndrome, in particular, is a life-threatening condition with a high mortality rate of 80% to 90%.³

Continue to: Diagnosis can be particularly challenging...

Diagnosis can be particularly challenging due to the anatomic variations of posterior arterial circulation, as well as the fluctuating nonfocal or multifocal symptoms.² Specific symptoms include vertigo, ataxia, unilateral motor weakness, dysarthria, and oculomotor dysfunction. However, nonspecific symptoms such as headache, nausea, dizziness, hoarseness, falls, and Horner syndrome may be the only presenting signs of a posterior circulation stroke—as was the case with our patient.² Her radiating neck pain could have been interpreted as a pointer to vertebral artery dissection within the context of severe hypertension.⁴ Unfortunately, the diagnosis was delayed and head imaging was obtained only after her mental status deteriorated.

Immediate neuroimaging is necessary to guide treatment in patients with suspected acute posterior circulation stroke,^1,5,6 although it is not always definitive. While CT is pivotal in stroke work-up and may reliably exclude intracranial hemorrhage, its ability to detect acute posterior circulation ischemic strokes is limited given its poor visualization of the posterior fossa (as low as 16% sensitivity).⁵ Fortunately, CT angiography has a high sensitivity (nearing 100%) for large-vessel occlusion and high predictive values for dissection (65%-100% positive predictive value and 70%-98% negative predictive value).^5,7 ­Diffusion-weighted MRI (when available in the emergency setting) has the highest sensitivity for detecting acute infarcts, although posterior circulation infarcts still can be missed (19% false-negative rate).^5,8 Thus, correlative vessel imaging with magnetic resonance or CT angiography is very important, along with a high index of suspicion. In some instances, repeat MRI may be necessary to detect small strokes.

A patient-specific approach to management is key for individuals with suspected posterior circulation stroke.⁵ Because specific data for the appropriate management of posterior circulation ischemic stroke are lacking, current American Heart ­Association/American Stroke Association (AHA/ASA) guidelines apply to anterior and ­posterior circulation strokes.⁶ For eligible ­patients without multifocal disease, intravenous tPA is the first-line therapy and should be initiated according to guidelines within 4.5 hours of stroke onset⁹; it is important to note that these guidelines are based on studies that ­focused more on anterior circulation strokes than posterior circulation strokes.^6,9-13 This can be done in combination with ­endovascular therapy, which consists of ­mechanical thrombectomy, intra-arterial thrombolysis, or a combination of revascularization ­techniques.^3,5,6

Nonspecific symptoms such as headache, nausea, and dizziness may be the only presenting signs of a posterior circulation stroke.

Mechanical thrombectomy specifically has high proven recanalization rates for all target vessels.^3-6 The latest AHA/ASA guidelines recommend mechanical thrombectomy be performed within 6 hours of stroke onset.⁶ However, there is emerging evidence that suggests this timeframe should be ­extended—even beyond 24 hours—given the poor prognosis of posterior circulation strokes.^5,6,14 More data on the management of posterior circulation strokes are urgently needed to better understand which therapeutic approach is most efficient.

In patients such as ours, who have evidence of multifocal disease, treatment may be limited to endovascular therapy. Intracranial stenting of symptomatic lesions in particular has been controversial since the publication of the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis trial, which found that aggressive medical management was superior to stenting in patients who recently had a transient ischemic attack or stroke attributed to stenosis.¹⁵ Although additional studies have been performed, there are no definitive data on the topic—and certainly no data in the emergency setting.¹⁶ Further challenges are raised in patients with bilateral disease, as was the case with this patient.

When our patient was admitted to the rehabilitation clinic, she had a GCS score of 10 to 11/15. After 9 months of rehabilitation, she was discharged home with a GCS score of 15/15 and persistent left-side hemiparesis.

THE TAKEAWAY

Posterior circulation stroke is a life-­threatening disease that may manifest with a variety of symptoms and be difficult to identify on emergent imaging. Thus, a high degree of clinical suspicion and additional follow-up are paramount to ensure prompt diagnosis and a patient-tailored treatment strategy.

CORRESPONDENCE
Kristine A. Blackham, MD, Associate Professor, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland; [email protected] Orcid no: 0000-0002-1620-1144 (Dr. Blackham); 0000-0002- 5225-5414 (Dr. Saleh)

THE CASE

A 49-year-old woman was hospitalized with a headache and neck pain that radiated to her ears and eyes in the context of severe hypertension (270/150 mm Hg). Her medical history was significant for heterozygous factor V Leiden mutation, longstanding untreated hypertension, and multiple severe episodes of HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome during pregnancy.

After receiving antihypertensive treatment at a community hospital, her blood pressure gradually improved to 160/100 mm Hg with the addition of a third medication. However, on Day 3 of her stay, her systolic blood pressure rose to more than 200 mm Hg and was accompanied by somnolence, emesis, and paleness. She was transferred to a tertiary care center.

THE DIAGNOSIS

On admission, the patient had left-side hemiparesis and facial droop with dysarthria, resulting in a National Institutes of Health Stroke Scale (NIHSS) score of 7 (out of 42) and a Glasgow Coma Scale (GCS) score of 13 (out of 15). Noncontrast computed tomography (CT) and CT angiography of the head and neck were ordered and showed occlusion of both intracranial vertebral arteries. There were also signs of multifocal infarction in her occipital lobes, thus systemic recombinant human-tissue plasminogen activator (tPA) could not be administered.

The patient was next taken to the angiography suite, where a digital subtraction angiography confirmed the presence of bilateral vertebral artery occlusions (FIGURE 1A). A thrombectomy was performed to open the left occluded segment, resulting in recanalization; however, a high-grade stenosis remained in the intracranial left vertebral artery (FIGURE 1B). The right vertebral artery had a severe extracranial origin stenosis, and balloon angioplasty was performed in order to reach the intracranial circulation; however, the occlusion of the intracranial right vertebral artery segment could not be catheterized. Subsequent magnetic resonance imaging (MRI) with a time-of-flight magnetic resonance angiography showed that the intracranial left vertebral artery with high-grade stenosis had closed down again; thus, there was occlusion of both intracranial vertebral arteries and absent flow signal in the basilar artery (FIGURE 2). There were scattered small acute strokes within the cerebellum, brainstem, and occipital lobes.

Unfortunately, within 48 hours, the patient’s NIHSS score increased from 7 to 29. She developed tetraplegia, was significantly less responsive (GCS score, 3/15), and required intubation and mechanical ventilation. Reopening the stenosis and keeping it open with a stent would be an aggressive procedure with poor odds for success and would require antithrombotic medications with the associated risk for intracranial hemorrhage in the setting of demarcated strokes. Thus, no further intervention was pursued.

Further standard stroke work-up (echocardiography, extracranial ultrasound of the cerebral circulation, and vasculitis screening) was unremarkable. In the intensive care unit, intravenous therapeutic heparin was initiated because of the potential prothrombotic effect of the factor V Leiden mutation but was subsequently switched to dual anti-­aggregation therapy (aspirin 100 mg/d and clopidogrel 75 mg/d) as secondary stroke prevention given the final diagnosis of severe atherosclerosis. Nevertheless, the patient remained tetraplegic with a partial locked-in syndrome when she was discharged, after 2 weeks in the tertiary care center, to a rehabilitation center.

DISCUSSION

Posterior circulation strokes account for 20% to 25% of all ischemic strokes^1,2 and are associated with infarction within the vertebrobasilar arterial system. Common etiologies of these infarctions include atherosclerosis (as seen in our patient), embolism, small-artery penetrating disease, and arterial dissection.² Although the estimated overall mortality of these strokes is low (3.6% to 11%),² basilar occlusion syndrome, in particular, is a life-threatening condition with a high mortality rate of 80% to 90%.³

Continue to: Diagnosis can be particularly challenging...

Diagnosis can be particularly challenging due to the anatomic variations of posterior arterial circulation, as well as the fluctuating nonfocal or multifocal symptoms.² Specific symptoms include vertigo, ataxia, unilateral motor weakness, dysarthria, and oculomotor dysfunction. However, nonspecific symptoms such as headache, nausea, dizziness, hoarseness, falls, and Horner syndrome may be the only presenting signs of a posterior circulation stroke—as was the case with our patient.² Her radiating neck pain could have been interpreted as a pointer to vertebral artery dissection within the context of severe hypertension.⁴ Unfortunately, the diagnosis was delayed and head imaging was obtained only after her mental status deteriorated.

Immediate neuroimaging is necessary to guide treatment in patients with suspected acute posterior circulation stroke,^1,5,6 although it is not always definitive. While CT is pivotal in stroke work-up and may reliably exclude intracranial hemorrhage, its ability to detect acute posterior circulation ischemic strokes is limited given its poor visualization of the posterior fossa (as low as 16% sensitivity).⁵ Fortunately, CT angiography has a high sensitivity (nearing 100%) for large-vessel occlusion and high predictive values for dissection (65%-100% positive predictive value and 70%-98% negative predictive value).^5,7 ­Diffusion-weighted MRI (when available in the emergency setting) has the highest sensitivity for detecting acute infarcts, although posterior circulation infarcts still can be missed (19% false-negative rate).^5,8 Thus, correlative vessel imaging with magnetic resonance or CT angiography is very important, along with a high index of suspicion. In some instances, repeat MRI may be necessary to detect small strokes.

A patient-specific approach to management is key for individuals with suspected posterior circulation stroke.⁵ Because specific data for the appropriate management of posterior circulation ischemic stroke are lacking, current American Heart ­Association/American Stroke Association (AHA/ASA) guidelines apply to anterior and ­posterior circulation strokes.⁶ For eligible ­patients without multifocal disease, intravenous tPA is the first-line therapy and should be initiated according to guidelines within 4.5 hours of stroke onset⁹; it is important to note that these guidelines are based on studies that ­focused more on anterior circulation strokes than posterior circulation strokes.^6,9-13 This can be done in combination with ­endovascular therapy, which consists of ­mechanical thrombectomy, intra-arterial thrombolysis, or a combination of revascularization ­techniques.^3,5,6

Nonspecific symptoms such as headache, nausea, and dizziness may be the only presenting signs of a posterior circulation stroke.

Mechanical thrombectomy specifically has high proven recanalization rates for all target vessels.^3-6 The latest AHA/ASA guidelines recommend mechanical thrombectomy be performed within 6 hours of stroke onset.⁶ However, there is emerging evidence that suggests this timeframe should be ­extended—even beyond 24 hours—given the poor prognosis of posterior circulation strokes.^5,6,14 More data on the management of posterior circulation strokes are urgently needed to better understand which therapeutic approach is most efficient.

In patients such as ours, who have evidence of multifocal disease, treatment may be limited to endovascular therapy. Intracranial stenting of symptomatic lesions in particular has been controversial since the publication of the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis trial, which found that aggressive medical management was superior to stenting in patients who recently had a transient ischemic attack or stroke attributed to stenosis.¹⁵ Although additional studies have been performed, there are no definitive data on the topic—and certainly no data in the emergency setting.¹⁶ Further challenges are raised in patients with bilateral disease, as was the case with this patient.

When our patient was admitted to the rehabilitation clinic, she had a GCS score of 10 to 11/15. After 9 months of rehabilitation, she was discharged home with a GCS score of 15/15 and persistent left-side hemiparesis.

THE TAKEAWAY

Posterior circulation stroke is a life-­threatening disease that may manifest with a variety of symptoms and be difficult to identify on emergent imaging. Thus, a high degree of clinical suspicion and additional follow-up are paramount to ensure prompt diagnosis and a patient-tailored treatment strategy.

CORRESPONDENCE
Kristine A. Blackham, MD, Associate Professor, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland; [email protected] Orcid no: 0000-0002-1620-1144 (Dr. Blackham); 0000-0002- 5225-5414 (Dr. Saleh)

ILLUSTRATIVE CASE

A 51-year-old woman with a history of elevated cholesterol and a body mass index (BMI) of 31 presents to your clinic for a scheduled follow-up visit to review recent blood test results. Her A1C was elevated at 5.9%. She wants to know if she should start medication now.

Prediabetes is a high-risk state that ­confers increased risk for type 2 ­diabetes (T2D). It is identified by impaired fasting glucose (fasting plasma glucose [FPG], 100-125 mg/dL), impaired glucose tolerance (2-hour oral glucose tolerance test, 140-199 mg/dL), or an elevated A1C (between 5.7% and 6.4%).²

An estimated 96 million ­Americans—38% of the US adult population—have prediabetes, according to the Centers for Disease Control and Prevention.³ Family physicians frequently encounter this condition when screening for T2D in asymptomatic adults (ages 35 to 70 years) with overweight or obesity, as recommended by the US Preventive Services Task Force (grade “B”).⁴

To treat, or not? Studies have shown that interventions such as lifestyle modification and use of metformin by patients with prediabetes can decrease their risk for T2D.^5,6 In the Diabetes Prevention Program (DPP) study, progression from prediabetes to T2D was reduced to 14% with lifestyle modification and 22% with metformin use, vs 29% with placebo.⁷

However, there is disagreement about whether to treat prediabetes, particularly with medication. Some argue that metformin is a safe, effective, and cost-saving treatment to prevent T2D and its associated health consequences.⁸ The current American Diabetes Association (ADA) guidelines suggest that metformin be considered in certain patients with prediabetes and high-risk factors, especially younger age, obesity or hyperglycemia, or a history of gestational diabetes.⁹ However, only an estimated 1% to 4% of adults with prediabetes are prescribed metformin.¹⁰

Others argue that treating a preclinical condition is not a patient-centered approach, especially since not all patients with prediabetes progress to T2D and the risk for development or progression of retinopathy and microalbuminuria is extremely low if A1C levels remain < 7.0%.¹¹ By this standard, pharmacologic treatment should be initiated only if, or when, a patient develops T2D, with a focus on intensive lifestyle intervention for high-risk patients in the interim.¹¹

Given the conflicting viewpoints, ongoing long-term studies on T2D prevention will help guide treatment decisions for patients with prediabetes. The study by Lee et al¹ was the first to evaluate the effect of metformin or intensive lifestyle modification on all-cause and cause-specific mortality in patients at high risk for T2D.

Continue to: STUDY SUMMARY

No mortality benefit from metformin or lifestyle modification

This secondary analysis evaluated mortality outcomes for patients at risk for T2D who were part of the DPP trial and then were ­followed long term in the Diabetes Prevention Program Outcomes Study (DPPOS).¹ The initial DPP trial included 3234 adult patients at high risk for T2D (defined as having a BMI ≥ 24; an FPG of 95-125 mg/dL; and a 2-hour glucose level of 140-199 mg/dL). Participants were randomized into groups receiving either intensive lifestyle intervention (which focused on achieving ≥ 150 min/wk of exercise and ≥ 7% body weight loss), metformin 850 mg twice daily, or placebo twice daily; the latter 2 groups also received standard exercise and diet recommendations. Mean age was 51 years, mean BMI was 34, and 68% of participants were female.

Both the metformin and lifestyle intervention groups experienced decreases in weight and cardiovascular risk factors but not in mortality.

At the conclusion of the initial 5-year trial, treatment was unmasked and 86% of the patients continued to be followed for long-term outcomes. Patients in the lifestyle group were offered semiannual lifestyle reinforcement, while the metformin group continued to receive the twice-daily 850-mg dose unless a contraindication developed. If FPG levels increased to ≥ 140 mg/dL in the DPP study, or A1C increased to ≥ 7% in the DPPOS, study metformin was discontinued and management of the patient’s diabetes was transferred to their health care provider. By the end of the DPPOS, 53% of patients in the lifestyle group and 55% in the metformin group had progressed to T2D, compared with 60% in the placebo group (P = 0.003).

After a median 21-year follow-up interval, the investigators collected data on cause of death for patients and evaluated hazard ratios (HRs) for overall and cause-specific mortality. In total, 14% of the participants died, with no statistically significant difference in rates between the 3 groups. Cancer (37%) was the leading cause of death in all groups, followed by cardiovascular disease (CVD; 29%).

Compared with the placebo group, patients taking metformin did not have a decreased rate of overall mortality (HR = 0.99; 95% CI, 0.79-1.25), mortality from cancer (HR = 1.04; 95% CI, 0.72-1.52), or mortality due to CVD (HR = 1.08; 95% CI, 0.70-1.66). Similarly, compared with the placebo group, lifestyle intervention did not decrease overall mortality (HR = 1.02; 95% CI, 0.81-1.28), mortality from cancer (HR = 1.07; 95% CI, 0.74-1.55), or mortality due to CVD (HR = 1.18; 95% CI, 0.77-1.81). Results were similar when adjusted for other factors, including out-of-study metformin use, T2D status and duration, BMI change, and other cardiovascular risk factors.

WHAT’S NEW

Long-term data clarifylimits to interventions’ utility

This study looked at long-term follow-up data on mortality outcomes for patients with prediabetes treated with metformin or lifestyle intervention. Although these interventions did support weight loss, reduce the incidence of T2D, and lower cardiovascular risk factors (eg, hypertension, dyslipidemia), the comorbidity benefits did not affect risk for all-cause or cause-specific mortality, which were similar between the treatment and placebo groups.

Continue to: CAVEATS

Exclusion criteria, residual confounding may limit the findings

Patients with significant cardiovascular or renal disease were excluded, so results may not apply to patients with these comorbidities. Additionally, there was a high amount of “drop-in” use of metformin prescribed by physicians once patients developed T2D, which may not have been controlled for completely. And while the intensive lifestyle intervention group had specific goals, the metformin and placebo groups also were encouraged to follow standard diet and lifestyle recommendations—and during a bridge period, all participants were offered a modified group lifestyle intervention. However, multivariable adjustment did not change the study conclusion.

CHALLENGES TO IMPLEMENTATION

Physicians may be unwilling to change their current prescribing habits

Physicians may not be willing to change their practice of prescribing metformin in prediabetes based on a singular study (with residual confounding) that showed no long-term mortality differences between the study groups. However, there may be long-term morbidity differences of interest to patients that were not specifically evaluated in this study—such as quality-of-life benefits from weight loss that may outweigh the risks (eg, gastrointestinal adverse effects such as diarrhea, nausea, and abdominal pain) of metformin for some patients. Therefore, a discussion of the risks and benefits of treatment for prediabetes should be had with patients at high risk who would prefer a pharmacologic intervention.

ILLUSTRATIVE CASE

A 51-year-old woman with a history of elevated cholesterol and a body mass index (BMI) of 31 presents to your clinic for a scheduled follow-up visit to review recent blood test results. Her A1C was elevated at 5.9%. She wants to know if she should start medication now.

Prediabetes is a high-risk state that ­confers increased risk for type 2 ­diabetes (T2D). It is identified by impaired fasting glucose (fasting plasma glucose [FPG], 100-125 mg/dL), impaired glucose tolerance (2-hour oral glucose tolerance test, 140-199 mg/dL), or an elevated A1C (between 5.7% and 6.4%).²

An estimated 96 million ­Americans—38% of the US adult population—have prediabetes, according to the Centers for Disease Control and Prevention.³ Family physicians frequently encounter this condition when screening for T2D in asymptomatic adults (ages 35 to 70 years) with overweight or obesity, as recommended by the US Preventive Services Task Force (grade “B”).⁴

To treat, or not? Studies have shown that interventions such as lifestyle modification and use of metformin by patients with prediabetes can decrease their risk for T2D.^5,6 In the Diabetes Prevention Program (DPP) study, progression from prediabetes to T2D was reduced to 14% with lifestyle modification and 22% with metformin use, vs 29% with placebo.⁷

However, there is disagreement about whether to treat prediabetes, particularly with medication. Some argue that metformin is a safe, effective, and cost-saving treatment to prevent T2D and its associated health consequences.⁸ The current American Diabetes Association (ADA) guidelines suggest that metformin be considered in certain patients with prediabetes and high-risk factors, especially younger age, obesity or hyperglycemia, or a history of gestational diabetes.⁹ However, only an estimated 1% to 4% of adults with prediabetes are prescribed metformin.¹⁰

Others argue that treating a preclinical condition is not a patient-centered approach, especially since not all patients with prediabetes progress to T2D and the risk for development or progression of retinopathy and microalbuminuria is extremely low if A1C levels remain < 7.0%.¹¹ By this standard, pharmacologic treatment should be initiated only if, or when, a patient develops T2D, with a focus on intensive lifestyle intervention for high-risk patients in the interim.¹¹

Given the conflicting viewpoints, ongoing long-term studies on T2D prevention will help guide treatment decisions for patients with prediabetes. The study by Lee et al¹ was the first to evaluate the effect of metformin or intensive lifestyle modification on all-cause and cause-specific mortality in patients at high risk for T2D.

Continue to: STUDY SUMMARY

No mortality benefit from metformin or lifestyle modification

This secondary analysis evaluated mortality outcomes for patients at risk for T2D who were part of the DPP trial and then were ­followed long term in the Diabetes Prevention Program Outcomes Study (DPPOS).¹ The initial DPP trial included 3234 adult patients at high risk for T2D (defined as having a BMI ≥ 24; an FPG of 95-125 mg/dL; and a 2-hour glucose level of 140-199 mg/dL). Participants were randomized into groups receiving either intensive lifestyle intervention (which focused on achieving ≥ 150 min/wk of exercise and ≥ 7% body weight loss), metformin 850 mg twice daily, or placebo twice daily; the latter 2 groups also received standard exercise and diet recommendations. Mean age was 51 years, mean BMI was 34, and 68% of participants were female.

Both the metformin and lifestyle intervention groups experienced decreases in weight and cardiovascular risk factors but not in mortality.

At the conclusion of the initial 5-year trial, treatment was unmasked and 86% of the patients continued to be followed for long-term outcomes. Patients in the lifestyle group were offered semiannual lifestyle reinforcement, while the metformin group continued to receive the twice-daily 850-mg dose unless a contraindication developed. If FPG levels increased to ≥ 140 mg/dL in the DPP study, or A1C increased to ≥ 7% in the DPPOS, study metformin was discontinued and management of the patient’s diabetes was transferred to their health care provider. By the end of the DPPOS, 53% of patients in the lifestyle group and 55% in the metformin group had progressed to T2D, compared with 60% in the placebo group (P = 0.003).

After a median 21-year follow-up interval, the investigators collected data on cause of death for patients and evaluated hazard ratios (HRs) for overall and cause-specific mortality. In total, 14% of the participants died, with no statistically significant difference in rates between the 3 groups. Cancer (37%) was the leading cause of death in all groups, followed by cardiovascular disease (CVD; 29%).

Compared with the placebo group, patients taking metformin did not have a decreased rate of overall mortality (HR = 0.99; 95% CI, 0.79-1.25), mortality from cancer (HR = 1.04; 95% CI, 0.72-1.52), or mortality due to CVD (HR = 1.08; 95% CI, 0.70-1.66). Similarly, compared with the placebo group, lifestyle intervention did not decrease overall mortality (HR = 1.02; 95% CI, 0.81-1.28), mortality from cancer (HR = 1.07; 95% CI, 0.74-1.55), or mortality due to CVD (HR = 1.18; 95% CI, 0.77-1.81). Results were similar when adjusted for other factors, including out-of-study metformin use, T2D status and duration, BMI change, and other cardiovascular risk factors.

WHAT’S NEW

Long-term data clarifylimits to interventions’ utility

This study looked at long-term follow-up data on mortality outcomes for patients with prediabetes treated with metformin or lifestyle intervention. Although these interventions did support weight loss, reduce the incidence of T2D, and lower cardiovascular risk factors (eg, hypertension, dyslipidemia), the comorbidity benefits did not affect risk for all-cause or cause-specific mortality, which were similar between the treatment and placebo groups.

Continue to: CAVEATS

Exclusion criteria, residual confounding may limit the findings

Patients with significant cardiovascular or renal disease were excluded, so results may not apply to patients with these comorbidities. Additionally, there was a high amount of “drop-in” use of metformin prescribed by physicians once patients developed T2D, which may not have been controlled for completely. And while the intensive lifestyle intervention group had specific goals, the metformin and placebo groups also were encouraged to follow standard diet and lifestyle recommendations—and during a bridge period, all participants were offered a modified group lifestyle intervention. However, multivariable adjustment did not change the study conclusion.

CHALLENGES TO IMPLEMENTATION

Physicians may be unwilling to change their current prescribing habits

Physicians may not be willing to change their practice of prescribing metformin in prediabetes based on a singular study (with residual confounding) that showed no long-term mortality differences between the study groups. However, there may be long-term morbidity differences of interest to patients that were not specifically evaluated in this study—such as quality-of-life benefits from weight loss that may outweigh the risks (eg, gastrointestinal adverse effects such as diarrhea, nausea, and abdominal pain) of metformin for some patients. Therefore, a discussion of the risks and benefits of treatment for prediabetes should be had with patients at high risk who would prefer a pharmacologic intervention.

ILLUSTRATIVE CASE

A 51-year-old woman with a history of elevated cholesterol and a body mass index (BMI) of 31 presents to your clinic for a scheduled follow-up visit to review recent blood test results. Her A1C was elevated at 5.9%. She wants to know if she should start medication now.

Prediabetes is a high-risk state that ­confers increased risk for type 2 ­diabetes (T2D). It is identified by impaired fasting glucose (fasting plasma glucose [FPG], 100-125 mg/dL), impaired glucose tolerance (2-hour oral glucose tolerance test, 140-199 mg/dL), or an elevated A1C (between 5.7% and 6.4%).²

An estimated 96 million ­Americans—38% of the US adult population—have prediabetes, according to the Centers for Disease Control and Prevention.³ Family physicians frequently encounter this condition when screening for T2D in asymptomatic adults (ages 35 to 70 years) with overweight or obesity, as recommended by the US Preventive Services Task Force (grade “B”).⁴

To treat, or not? Studies have shown that interventions such as lifestyle modification and use of metformin by patients with prediabetes can decrease their risk for T2D.^5,6 In the Diabetes Prevention Program (DPP) study, progression from prediabetes to T2D was reduced to 14% with lifestyle modification and 22% with metformin use, vs 29% with placebo.⁷

However, there is disagreement about whether to treat prediabetes, particularly with medication. Some argue that metformin is a safe, effective, and cost-saving treatment to prevent T2D and its associated health consequences.⁸ The current American Diabetes Association (ADA) guidelines suggest that metformin be considered in certain patients with prediabetes and high-risk factors, especially younger age, obesity or hyperglycemia, or a history of gestational diabetes.⁹ However, only an estimated 1% to 4% of adults with prediabetes are prescribed metformin.¹⁰

Others argue that treating a preclinical condition is not a patient-centered approach, especially since not all patients with prediabetes progress to T2D and the risk for development or progression of retinopathy and microalbuminuria is extremely low if A1C levels remain < 7.0%.¹¹ By this standard, pharmacologic treatment should be initiated only if, or when, a patient develops T2D, with a focus on intensive lifestyle intervention for high-risk patients in the interim.¹¹

Given the conflicting viewpoints, ongoing long-term studies on T2D prevention will help guide treatment decisions for patients with prediabetes. The study by Lee et al¹ was the first to evaluate the effect of metformin or intensive lifestyle modification on all-cause and cause-specific mortality in patients at high risk for T2D.

Continue to: STUDY SUMMARY

No mortality benefit from metformin or lifestyle modification

This secondary analysis evaluated mortality outcomes for patients at risk for T2D who were part of the DPP trial and then were ­followed long term in the Diabetes Prevention Program Outcomes Study (DPPOS).¹ The initial DPP trial included 3234 adult patients at high risk for T2D (defined as having a BMI ≥ 24; an FPG of 95-125 mg/dL; and a 2-hour glucose level of 140-199 mg/dL). Participants were randomized into groups receiving either intensive lifestyle intervention (which focused on achieving ≥ 150 min/wk of exercise and ≥ 7% body weight loss), metformin 850 mg twice daily, or placebo twice daily; the latter 2 groups also received standard exercise and diet recommendations. Mean age was 51 years, mean BMI was 34, and 68% of participants were female.

Both the metformin and lifestyle intervention groups experienced decreases in weight and cardiovascular risk factors but not in mortality.

At the conclusion of the initial 5-year trial, treatment was unmasked and 86% of the patients continued to be followed for long-term outcomes. Patients in the lifestyle group were offered semiannual lifestyle reinforcement, while the metformin group continued to receive the twice-daily 850-mg dose unless a contraindication developed. If FPG levels increased to ≥ 140 mg/dL in the DPP study, or A1C increased to ≥ 7% in the DPPOS, study metformin was discontinued and management of the patient’s diabetes was transferred to their health care provider. By the end of the DPPOS, 53% of patients in the lifestyle group and 55% in the metformin group had progressed to T2D, compared with 60% in the placebo group (P = 0.003).

After a median 21-year follow-up interval, the investigators collected data on cause of death for patients and evaluated hazard ratios (HRs) for overall and cause-specific mortality. In total, 14% of the participants died, with no statistically significant difference in rates between the 3 groups. Cancer (37%) was the leading cause of death in all groups, followed by cardiovascular disease (CVD; 29%).

Compared with the placebo group, patients taking metformin did not have a decreased rate of overall mortality (HR = 0.99; 95% CI, 0.79-1.25), mortality from cancer (HR = 1.04; 95% CI, 0.72-1.52), or mortality due to CVD (HR = 1.08; 95% CI, 0.70-1.66). Similarly, compared with the placebo group, lifestyle intervention did not decrease overall mortality (HR = 1.02; 95% CI, 0.81-1.28), mortality from cancer (HR = 1.07; 95% CI, 0.74-1.55), or mortality due to CVD (HR = 1.18; 95% CI, 0.77-1.81). Results were similar when adjusted for other factors, including out-of-study metformin use, T2D status and duration, BMI change, and other cardiovascular risk factors.

WHAT’S NEW

Long-term data clarifylimits to interventions’ utility

This study looked at long-term follow-up data on mortality outcomes for patients with prediabetes treated with metformin or lifestyle intervention. Although these interventions did support weight loss, reduce the incidence of T2D, and lower cardiovascular risk factors (eg, hypertension, dyslipidemia), the comorbidity benefits did not affect risk for all-cause or cause-specific mortality, which were similar between the treatment and placebo groups.

Continue to: CAVEATS

Exclusion criteria, residual confounding may limit the findings

Patients with significant cardiovascular or renal disease were excluded, so results may not apply to patients with these comorbidities. Additionally, there was a high amount of “drop-in” use of metformin prescribed by physicians once patients developed T2D, which may not have been controlled for completely. And while the intensive lifestyle intervention group had specific goals, the metformin and placebo groups also were encouraged to follow standard diet and lifestyle recommendations—and during a bridge period, all participants were offered a modified group lifestyle intervention. However, multivariable adjustment did not change the study conclusion.

CHALLENGES TO IMPLEMENTATION

Physicians may be unwilling to change their current prescribing habits

Physicians may not be willing to change their practice of prescribing metformin in prediabetes based on a singular study (with residual confounding) that showed no long-term mortality differences between the study groups. However, there may be long-term morbidity differences of interest to patients that were not specifically evaluated in this study—such as quality-of-life benefits from weight loss that may outweigh the risks (eg, gastrointestinal adverse effects such as diarrhea, nausea, and abdominal pain) of metformin for some patients. Therefore, a discussion of the risks and benefits of treatment for prediabetes should be had with patients at high risk who would prefer a pharmacologic intervention.

ABSTRACT

Background: We sought to examine whether electrical impedance spectroscopy (EIS), a diagnostic tool approved by the US Food and Drug Administration for the evaluation of pigmented skin lesions (PSLs), is beneficial to primary care providers (PCPs) by comparing the accuracy of PCPs’ management decisions for PSLs based on visual examination alone with those based on concurrent visual and EIS evaluation.

Methods: Physicians and nurse practitioners (NPs) participated in an anonymous online survey in which they viewed clinical images of PSLs and were asked to make 2 clinical decisions before and after being provided an EIS score that indicated the likelihood that the lesion was a melanoma. They were asked (1) if they would biopsy the lesion/refer the patient out and (2) what they expected the pathology results would show.

Results: Forty-four physicians and 17 NPs participated, making clinical decisions for 1354 presented lesions. Overall, with the addition of EIS to visual inspection of clinical images, the sensitivity of biopsy/referral decisions for melanomas and severely dysplastic nevi (SDN) increased from 69.2% to 90.0% (P < .001), while specificity increased from 44.0% to 72.6% (P < .001). Physicians and NPs, regardless of years of experience, each saw significant improvements in sensitivity, specificity, and diagnostic accuracy with the addition of EIS scores.

Conclusions: The incorporation of EIS data into clinical decision-making by PCPs significantly increased the sensitivity and specificity of biopsy/referral decisions for melanomas and SDN and overall diagnostic accuracy compared with visual inspection alone. The results of this study suggest that diagnostic accuracy for PSLs by PCPs may be improved with adjunctive use of EIS with visual inspection.

Primary care providers (PCPs) are often the first line of defense in detecting skin cancers. For patients with concerning skin lesions, PCPs may choose to perform a biopsy or facilitate access to specialty services (eg, Dermatology). Consequently, PCPs play a critical role in the timely detection of skin cancers, and it is paramount to employ continually improving detection methods, such as the application of technologic advances.¹

Differentiating benign nevi from melanoma and severely dysplastic nevi (SDN), both of which warrant excision, poses a unique challenge to clinicians examining pigmented skin lesions (PSLs). PCPs often rely on visual inspection to differentiate benign skin lesions from malignant skin cancers. In some primary care practices, dermoscopy, which involves using a handheld device to evaluate lesions with polarized light and magnification, is used to improve melanoma detection. However, while visual inspection and dermoscopy are valid, effective techniques for the diagnosis of melanocytic lesions, in many instances they still can lead to missed cancers or unnecessary biopsies and specialty referrals. Adjunctive use of dermoscopy with visual inspection has been shown to increase the probability of skin cancer detection, but it fails to achieve a near-100% success rate.² Furthermore, dermoscopy is heavily user-dependent, requiring significant training and experience for appropriate use.³

Another option is an electrical impedance spectroscopy (EIS) device (Nevisense, Scibase, Stockholm, Sweden), which has been approved by the US Food and Drug Administration (FDA) to assist in the detection of melanoma and differentiation from benign PSLs.⁴ EIS is a noninvasive, rapidly applied technology designed to accompany the visual examination of melanocytic lesions in office, with or without dermoscopy. Still relatively new, the technology is employed today by many dermatologists, increasing diagnostic accuracy for PSLs.⁵ The lightweight and portable instrument features a handheld probe, which is held against a lesion to obtain a reading. EIS uses a low-voltage electrode to apply a harmless electrical current to the skin at various frequencies.⁶ As benign and malignant tissues vary in cell shape, size, and composition, EIS distinguishes differential electrical resistance of the tissue to aid in diagnosis.⁷

Continue to: EIS provides high-sensitivity...

EIS provides high-sensitivity melanoma diagnosis vs histopathologic confirmation from biopsies, with 1 study showing a 96.6% sensitivity rating, detecting 256 of 265 melanomas.⁴ The EIS device, by measuring differences in electrical resistance between benign and cancerous cells, outputs a simple integer score ranging from 0 to 10 associated with the likelihood of the lesion being a melanoma.⁸ Based on data from the Nevisense pivotal trial,⁴ Nevisense reports that scores of 0 to 3 carry a negative predictive value of 99% for melanoma, whereas scores of 4 to 10 signify increasingly greater positive predictive values from 7% to 61%.

Findings suggest that the use of electrical impedance spectroscopy is particularly advantageous to clinicians who are less proficient in assessing melanocytic lesions.

We aimed to assess whether EIS may be beneficial to PCPs by comparing the accuracy of clinical decision-making for PSLs based on visual examination alone with that based on concurrent visual and EIS evaluation.

METHODS

A questionnaire was distributed via email to 142 clinicians at clinics affiliated with either of 2 organizations delivering care to the New York City area through a network of community health centers: the Institute for Family Health (IFH) and the Community Healthcare Network (CHN). Of these recipients, 72 were affiliated with IFH across 27 community health centers and 70 were affiliated with CHN across 14 community health centers. Recipients were physicians and nurse practitioners (NPs) practicing at primary health care facilities.

Survey instrument. The first section of the survey instrument (APPENDIX) solicited demographic information and explained how to apply the EIS scores for diagnostic ­decision-making. The second featured images of 12 randomly selected, histologically confirmed, and EIS-evaluated PSLs from a previously published prospective blinded trial of 2416 lesions.⁴ The Institutional Review Board of the Icahn School of Medicine at Mount Sinai reviewed and approved the study and survey instrument.

Clinical images of these lesions, comprising 4 melanocytic nevi, 4 dysplastic nevi (including 3 mild-moderately dysplastic and 1 severely dysplastic nevus), and 4 melanomas, were first presented to respondents with 2 tasks: (1) rate on a scale of 1 to 5 their likelihood to biopsy or refer this lesion to a dermatologist (1: not likely; 5: extremely likely); and (2) select what they expect the pathology results to be: melanocytic nevus, dysplastic nevus, or malignant melanoma. Subsequently, respondents repeated the assessments after being presented with the EIS score for the same lesion in conjunction with the clinical image.

Continue to: Analysis

Analysis. A biopsy or referral rating of 4 or 5 was considered a decision to biopsy or refer (ie, a diagnostic decision consistent with melanoma or SDN warranting excision), whereas a selection of 1 to 3 was considered a decision not to biopsy or refer (ie, a diagnostic decision consistent with a benign PSL). The sensitivity and specificity of biopsy/­referral decisions for melanomas and SDN, the proportion of missed melanomas and SDN, and the proportion of biopsy/referral decisions for benign lesions were separately determined for visual inspection alone and visual inspection with EIS score. Similarly, diagnostic accuracy was calculated for these clinical scenarios. These metrics were further stratified among different subsets of the respondent population. Differences in sensitivity, specificity, biopsy/referral decision proportions, and diagnostic accuracy were calculated using McNemar’s test for paired proportions.

RESULTS

Sixty-one respondents, comprising 44 physicians and 17 NPs, completed the survey, yielding a response rate of 43% (TABLE 1). In total, 1354 clinical decisions (677 based on visual inspection alone and 677 based on visual inspection plus EIS) were made. A biopsy/­referral decision was made after assessing 416 of 677 cases (61%) with visual inspection alone and 360 of 677 cases (53%) when relying on visual inspection plus EIS. None of the respondents reported any prior experience with EIS.

When incorporating EIS scores, respondents’ mean sensitivity for melanomas and SDN increased from 69.2% to 90.0% (P < .001) and specificity from 44.0% to 72.6% (P < .001; TABLE 2). At baseline, physicians demonstrated a sensitivity and specificity of 74.6% and 46.5%, respectively, while NPs demonstrated a sensitivity and specificity of 56.1% and 37.9%, respectively.

All respondent subgroups stratified by occupation and years of experience saw significant increases in both sensitivity and specificity upon the incorporation of EIS scores, with NPs seeing a greater increase in sensitivity (56.1% vs 85.4%; P < .001) and specificity (37.9% vs 69.0%; P < .001) than physicians (sensitivity: 74.6% vs 91.9%; P < .001; specificity: 46.5% vs 74.1%; P < .001). The only difference in diagnostic performance based on years of experience was a greater pre-EIS sensitivity by clinicians who had been in practice for ≥ 15 years, compared with those in practice for shorter periods (TABLE 2).

The improvements, seen in clinicians of varying training and experience, suggest that the learning curve of EIS may not be as steep as that of dermoscopy.

Diagnostic accuracy increased significantly from 48% when based on visual inspection alone to 73% with the addition of EIS scores (P < .001; TABLE 3). Physicians and NPs each significantly increased their diagnostic accuracy upon the incorporation of EIS, with NPs exhibiting the greatest increase (from 36.9% to 65.7%; P < .001). PCPs with 6 to 14 years of experience saw the greatest increase in diagnostic accuracy when adding EIS (45.9% vs 76.4%; P < .001). Overall, the addition of EIS scores resulted in 58 fewer missed melanomas and SDN and 114 fewer benign referrals or biopsies (TABLE 4).

Continue to: DISCUSSION

DISCUSSION

Primary care evaluation plays a significant role in the diagnosis and management of PSLs, ultimately shaping outcomes for patients with melanoma. Improved accuracy of PSL classification could yield greater sensitivity for the diagnosis of melanomas and high-risk melanocytic lesions at earlier stages, while also reducing the number of unnecessary biopsies and referrals—leading to decreased patient morbidity and mortality and reduced health care spending.⁹

Diagnostic tools are valuable insofar as they can improve accuracy and positively impact clinical management and patient outcomes.¹⁰ In this case, increased sensitivity reduced missed melanoma diagnoses, while increased specificity avoided the additional costs and patient toll associated with a biopsy or referral for a benign lesion.

Dermoscopy has been shown to improve the sensitivity and specificity of PSL diagnosis compared with visual inspection alone; however, without substantial training and experience, accuracy with dermoscopy can be no better than examination with the naked eye.^3,11,12 The dropout rates are high for training PCPs in its use, given that several months of training may be needed for competent use.^13,14 To improve the clinical management of PSLs broadly in primary care, a need exists for easy-to-use adjunctive tools that increase diagnostic accuracy.¹⁵

In this study, with only a brief explanation of how to interpret EIS scores, clinicians without any prior experience using EIS demonstrated significantly improved accuracy in deciding appropriate management and classifying melanocytic lesions with the addition of EIS to visual inspection. These improvements, seen in clinicians of varying training and experience, suggest that the learning curve of EIS may not be as steep as that of dermoscopy.

The greater baseline sensitivity, specificity, and diagnostic accuracy of physicians’ clinical decision-making compared with NPs before the incorporation of EIS in the study may be a product of comparatively more extensive medical training. In addition, EIS yielded a greater benefit to NPs than to physicians, with greater increases in sensitivity and specificity noted. This suggests that the use of EIS is particularly advantageous to clinicians who are less proficient in assessing melanocytic lesions. Using visual inspection alone, more experienced respondents made biopsy/referral decisions with greater sensitivity but similar specificity to those with less experience. With the incorporation of EIS scores, the sensitivity and specificity of respondents’ clinical decision-making rose to comparable levels across all experience groups, providing further indication of EIS’s particular value to clinicians who are less proficient in PSL evaluation.

Continue to: This technology holds the potential...

This technology holds the potential to be seamlessly implemented into primary care practice, given that dermatology expertise training is not required to use the EIS device; this could allow for EIS measurement of lesions to be delegated to office staff (eg, nurses, medical assistants).¹⁶ Future studies are needed to assess EIS use among PCPs in a real-world setting, where factors such as its application on nonmelanocytic lesions (eg, seborrheic keratoses) and its pairing with patient historical data could produce varying results.

Limitations. While revealing, this study had its limitations. Respondents did not have access to additional pertinent clinical information, such as patients’ histories and risk factors. Clinical decisions in this survey were made based on digital images rather than in vivo examination. This may not represent a real-life evaluation; there is the potential for minimization of the true consequences of a missed melanoma or unnecessary biopsy in the minds of participants, and this does not factor in the operation of the actual EIS device. The Hawthorne effect may also have influenced PCPs’ diagnostic selections. Also, the limited sample size constitutes another limitation.

The results of this preliminary study suggest that diagnostic accuracy for pigmented skin lesions by PCPs may be improved with the adjunctive use of electrical impedance spectroscopy with visual inspection.

Of note, in this survey format, respondents rated their inclination to biopsy or refer each lesion from 1 to 5. For statistical analyses, lesions rated 1 to 3 were considered as not biopsied/referred and those rated 4 to 5 as biopsied/referred. The sensitivity and specificity values observed, for both visual examination and concurrent visual and EIS evaluation, are therefore based on this classification system of participants’ provided ratings. It is conceivable that differing sensitivity and specificity values might have been detected if clinicians were instead given a binary choice for referral/biopsy decisions.

CONCLUSIONS

Among PCPs tasked with evaluating melanocytic lesions, the incorporation of EIS data into clinical decision-making in this study significantly increased the sensitivity, specificity, and overall diagnostic accuracy of biopsy or referral decisions for melanomas and SDN compared with visual inspection alone. Overall, the results of this preliminary study suggest that diagnostic accuracy for PSLs by PCPs may be improved with the adjunctive use of EIS with visual inspection. This would ultimately improve patient care and reduce the morbidity and mortality of a melanoma diagnosis.

CORRESPONDENCE
Jonathan Ungar, MD, Kimberly and Eric J. Waldman Department of Dermatology, Icahn School of Medicine at Mount Sinai, 5 East 98th Street, 5th Floor, New York, NY 10029; [email protected]

ABSTRACT

Background: We sought to examine whether electrical impedance spectroscopy (EIS), a diagnostic tool approved by the US Food and Drug Administration for the evaluation of pigmented skin lesions (PSLs), is beneficial to primary care providers (PCPs) by comparing the accuracy of PCPs’ management decisions for PSLs based on visual examination alone with those based on concurrent visual and EIS evaluation.

Methods: Physicians and nurse practitioners (NPs) participated in an anonymous online survey in which they viewed clinical images of PSLs and were asked to make 2 clinical decisions before and after being provided an EIS score that indicated the likelihood that the lesion was a melanoma. They were asked (1) if they would biopsy the lesion/refer the patient out and (2) what they expected the pathology results would show.

Results: Forty-four physicians and 17 NPs participated, making clinical decisions for 1354 presented lesions. Overall, with the addition of EIS to visual inspection of clinical images, the sensitivity of biopsy/referral decisions for melanomas and severely dysplastic nevi (SDN) increased from 69.2% to 90.0% (P < .001), while specificity increased from 44.0% to 72.6% (P < .001). Physicians and NPs, regardless of years of experience, each saw significant improvements in sensitivity, specificity, and diagnostic accuracy with the addition of EIS scores.

Conclusions: The incorporation of EIS data into clinical decision-making by PCPs significantly increased the sensitivity and specificity of biopsy/referral decisions for melanomas and SDN and overall diagnostic accuracy compared with visual inspection alone. The results of this study suggest that diagnostic accuracy for PSLs by PCPs may be improved with adjunctive use of EIS with visual inspection.

Primary care providers (PCPs) are often the first line of defense in detecting skin cancers. For patients with concerning skin lesions, PCPs may choose to perform a biopsy or facilitate access to specialty services (eg, Dermatology). Consequently, PCPs play a critical role in the timely detection of skin cancers, and it is paramount to employ continually improving detection methods, such as the application of technologic advances.¹

Differentiating benign nevi from melanoma and severely dysplastic nevi (SDN), both of which warrant excision, poses a unique challenge to clinicians examining pigmented skin lesions (PSLs). PCPs often rely on visual inspection to differentiate benign skin lesions from malignant skin cancers. In some primary care practices, dermoscopy, which involves using a handheld device to evaluate lesions with polarized light and magnification, is used to improve melanoma detection. However, while visual inspection and dermoscopy are valid, effective techniques for the diagnosis of melanocytic lesions, in many instances they still can lead to missed cancers or unnecessary biopsies and specialty referrals. Adjunctive use of dermoscopy with visual inspection has been shown to increase the probability of skin cancer detection, but it fails to achieve a near-100% success rate.² Furthermore, dermoscopy is heavily user-dependent, requiring significant training and experience for appropriate use.³

Another option is an electrical impedance spectroscopy (EIS) device (Nevisense, Scibase, Stockholm, Sweden), which has been approved by the US Food and Drug Administration (FDA) to assist in the detection of melanoma and differentiation from benign PSLs.⁴ EIS is a noninvasive, rapidly applied technology designed to accompany the visual examination of melanocytic lesions in office, with or without dermoscopy. Still relatively new, the technology is employed today by many dermatologists, increasing diagnostic accuracy for PSLs.⁵ The lightweight and portable instrument features a handheld probe, which is held against a lesion to obtain a reading. EIS uses a low-voltage electrode to apply a harmless electrical current to the skin at various frequencies.⁶ As benign and malignant tissues vary in cell shape, size, and composition, EIS distinguishes differential electrical resistance of the tissue to aid in diagnosis.⁷

Continue to: EIS provides high-sensitivity...

EIS provides high-sensitivity melanoma diagnosis vs histopathologic confirmation from biopsies, with 1 study showing a 96.6% sensitivity rating, detecting 256 of 265 melanomas.⁴ The EIS device, by measuring differences in electrical resistance between benign and cancerous cells, outputs a simple integer score ranging from 0 to 10 associated with the likelihood of the lesion being a melanoma.⁸ Based on data from the Nevisense pivotal trial,⁴ Nevisense reports that scores of 0 to 3 carry a negative predictive value of 99% for melanoma, whereas scores of 4 to 10 signify increasingly greater positive predictive values from 7% to 61%.

Findings suggest that the use of electrical impedance spectroscopy is particularly advantageous to clinicians who are less proficient in assessing melanocytic lesions.

We aimed to assess whether EIS may be beneficial to PCPs by comparing the accuracy of clinical decision-making for PSLs based on visual examination alone with that based on concurrent visual and EIS evaluation.

METHODS

A questionnaire was distributed via email to 142 clinicians at clinics affiliated with either of 2 organizations delivering care to the New York City area through a network of community health centers: the Institute for Family Health (IFH) and the Community Healthcare Network (CHN). Of these recipients, 72 were affiliated with IFH across 27 community health centers and 70 were affiliated with CHN across 14 community health centers. Recipients were physicians and nurse practitioners (NPs) practicing at primary health care facilities.

Survey instrument. The first section of the survey instrument (APPENDIX) solicited demographic information and explained how to apply the EIS scores for diagnostic ­decision-making. The second featured images of 12 randomly selected, histologically confirmed, and EIS-evaluated PSLs from a previously published prospective blinded trial of 2416 lesions.⁴ The Institutional Review Board of the Icahn School of Medicine at Mount Sinai reviewed and approved the study and survey instrument.

Clinical images of these lesions, comprising 4 melanocytic nevi, 4 dysplastic nevi (including 3 mild-moderately dysplastic and 1 severely dysplastic nevus), and 4 melanomas, were first presented to respondents with 2 tasks: (1) rate on a scale of 1 to 5 their likelihood to biopsy or refer this lesion to a dermatologist (1: not likely; 5: extremely likely); and (2) select what they expect the pathology results to be: melanocytic nevus, dysplastic nevus, or malignant melanoma. Subsequently, respondents repeated the assessments after being presented with the EIS score for the same lesion in conjunction with the clinical image.

Continue to: Analysis

Analysis. A biopsy or referral rating of 4 or 5 was considered a decision to biopsy or refer (ie, a diagnostic decision consistent with melanoma or SDN warranting excision), whereas a selection of 1 to 3 was considered a decision not to biopsy or refer (ie, a diagnostic decision consistent with a benign PSL). The sensitivity and specificity of biopsy/­referral decisions for melanomas and SDN, the proportion of missed melanomas and SDN, and the proportion of biopsy/referral decisions for benign lesions were separately determined for visual inspection alone and visual inspection with EIS score. Similarly, diagnostic accuracy was calculated for these clinical scenarios. These metrics were further stratified among different subsets of the respondent population. Differences in sensitivity, specificity, biopsy/referral decision proportions, and diagnostic accuracy were calculated using McNemar’s test for paired proportions.

RESULTS

Sixty-one respondents, comprising 44 physicians and 17 NPs, completed the survey, yielding a response rate of 43% (TABLE 1). In total, 1354 clinical decisions (677 based on visual inspection alone and 677 based on visual inspection plus EIS) were made. A biopsy/­referral decision was made after assessing 416 of 677 cases (61%) with visual inspection alone and 360 of 677 cases (53%) when relying on visual inspection plus EIS. None of the respondents reported any prior experience with EIS.

When incorporating EIS scores, respondents’ mean sensitivity for melanomas and SDN increased from 69.2% to 90.0% (P < .001) and specificity from 44.0% to 72.6% (P < .001; TABLE 2). At baseline, physicians demonstrated a sensitivity and specificity of 74.6% and 46.5%, respectively, while NPs demonstrated a sensitivity and specificity of 56.1% and 37.9%, respectively.

All respondent subgroups stratified by occupation and years of experience saw significant increases in both sensitivity and specificity upon the incorporation of EIS scores, with NPs seeing a greater increase in sensitivity (56.1% vs 85.4%; P < .001) and specificity (37.9% vs 69.0%; P < .001) than physicians (sensitivity: 74.6% vs 91.9%; P < .001; specificity: 46.5% vs 74.1%; P < .001). The only difference in diagnostic performance based on years of experience was a greater pre-EIS sensitivity by clinicians who had been in practice for ≥ 15 years, compared with those in practice for shorter periods (TABLE 2).

The improvements, seen in clinicians of varying training and experience, suggest that the learning curve of EIS may not be as steep as that of dermoscopy.

Diagnostic accuracy increased significantly from 48% when based on visual inspection alone to 73% with the addition of EIS scores (P < .001; TABLE 3). Physicians and NPs each significantly increased their diagnostic accuracy upon the incorporation of EIS, with NPs exhibiting the greatest increase (from 36.9% to 65.7%; P < .001). PCPs with 6 to 14 years of experience saw the greatest increase in diagnostic accuracy when adding EIS (45.9% vs 76.4%; P < .001). Overall, the addition of EIS scores resulted in 58 fewer missed melanomas and SDN and 114 fewer benign referrals or biopsies (TABLE 4).

Continue to: DISCUSSION

DISCUSSION

Primary care evaluation plays a significant role in the diagnosis and management of PSLs, ultimately shaping outcomes for patients with melanoma. Improved accuracy of PSL classification could yield greater sensitivity for the diagnosis of melanomas and high-risk melanocytic lesions at earlier stages, while also reducing the number of unnecessary biopsies and referrals—leading to decreased patient morbidity and mortality and reduced health care spending.⁹

Diagnostic tools are valuable insofar as they can improve accuracy and positively impact clinical management and patient outcomes.¹⁰ In this case, increased sensitivity reduced missed melanoma diagnoses, while increased specificity avoided the additional costs and patient toll associated with a biopsy or referral for a benign lesion.

Dermoscopy has been shown to improve the sensitivity and specificity of PSL diagnosis compared with visual inspection alone; however, without substantial training and experience, accuracy with dermoscopy can be no better than examination with the naked eye.^3,11,12 The dropout rates are high for training PCPs in its use, given that several months of training may be needed for competent use.^13,14 To improve the clinical management of PSLs broadly in primary care, a need exists for easy-to-use adjunctive tools that increase diagnostic accuracy.¹⁵

In this study, with only a brief explanation of how to interpret EIS scores, clinicians without any prior experience using EIS demonstrated significantly improved accuracy in deciding appropriate management and classifying melanocytic lesions with the addition of EIS to visual inspection. These improvements, seen in clinicians of varying training and experience, suggest that the learning curve of EIS may not be as steep as that of dermoscopy.

The greater baseline sensitivity, specificity, and diagnostic accuracy of physicians’ clinical decision-making compared with NPs before the incorporation of EIS in the study may be a product of comparatively more extensive medical training. In addition, EIS yielded a greater benefit to NPs than to physicians, with greater increases in sensitivity and specificity noted. This suggests that the use of EIS is particularly advantageous to clinicians who are less proficient in assessing melanocytic lesions. Using visual inspection alone, more experienced respondents made biopsy/referral decisions with greater sensitivity but similar specificity to those with less experience. With the incorporation of EIS scores, the sensitivity and specificity of respondents’ clinical decision-making rose to comparable levels across all experience groups, providing further indication of EIS’s particular value to clinicians who are less proficient in PSL evaluation.

Continue to: This technology holds the potential...

This technology holds the potential to be seamlessly implemented into primary care practice, given that dermatology expertise training is not required to use the EIS device; this could allow for EIS measurement of lesions to be delegated to office staff (eg, nurses, medical assistants).¹⁶ Future studies are needed to assess EIS use among PCPs in a real-world setting, where factors such as its application on nonmelanocytic lesions (eg, seborrheic keratoses) and its pairing with patient historical data could produce varying results.

Limitations. While revealing, this study had its limitations. Respondents did not have access to additional pertinent clinical information, such as patients’ histories and risk factors. Clinical decisions in this survey were made based on digital images rather than in vivo examination. This may not represent a real-life evaluation; there is the potential for minimization of the true consequences of a missed melanoma or unnecessary biopsy in the minds of participants, and this does not factor in the operation of the actual EIS device. The Hawthorne effect may also have influenced PCPs’ diagnostic selections. Also, the limited sample size constitutes another limitation.

The results of this preliminary study suggest that diagnostic accuracy for pigmented skin lesions by PCPs may be improved with the adjunctive use of electrical impedance spectroscopy with visual inspection.

Of note, in this survey format, respondents rated their inclination to biopsy or refer each lesion from 1 to 5. For statistical analyses, lesions rated 1 to 3 were considered as not biopsied/referred and those rated 4 to 5 as biopsied/referred. The sensitivity and specificity values observed, for both visual examination and concurrent visual and EIS evaluation, are therefore based on this classification system of participants’ provided ratings. It is conceivable that differing sensitivity and specificity values might have been detected if clinicians were instead given a binary choice for referral/biopsy decisions.

CONCLUSIONS

Among PCPs tasked with evaluating melanocytic lesions, the incorporation of EIS data into clinical decision-making in this study significantly increased the sensitivity, specificity, and overall diagnostic accuracy of biopsy or referral decisions for melanomas and SDN compared with visual inspection alone. Overall, the results of this preliminary study suggest that diagnostic accuracy for PSLs by PCPs may be improved with the adjunctive use of EIS with visual inspection. This would ultimately improve patient care and reduce the morbidity and mortality of a melanoma diagnosis.

CORRESPONDENCE
Jonathan Ungar, MD, Kimberly and Eric J. Waldman Department of Dermatology, Icahn School of Medicine at Mount Sinai, 5 East 98th Street, 5th Floor, New York, NY 10029; [email protected]

ABSTRACT

Background: We sought to examine whether electrical impedance spectroscopy (EIS), a diagnostic tool approved by the US Food and Drug Administration for the evaluation of pigmented skin lesions (PSLs), is beneficial to primary care providers (PCPs) by comparing the accuracy of PCPs’ management decisions for PSLs based on visual examination alone with those based on concurrent visual and EIS evaluation.

Methods: Physicians and nurse practitioners (NPs) participated in an anonymous online survey in which they viewed clinical images of PSLs and were asked to make 2 clinical decisions before and after being provided an EIS score that indicated the likelihood that the lesion was a melanoma. They were asked (1) if they would biopsy the lesion/refer the patient out and (2) what they expected the pathology results would show.

Results: Forty-four physicians and 17 NPs participated, making clinical decisions for 1354 presented lesions. Overall, with the addition of EIS to visual inspection of clinical images, the sensitivity of biopsy/referral decisions for melanomas and severely dysplastic nevi (SDN) increased from 69.2% to 90.0% (P < .001), while specificity increased from 44.0% to 72.6% (P < .001). Physicians and NPs, regardless of years of experience, each saw significant improvements in sensitivity, specificity, and diagnostic accuracy with the addition of EIS scores.

Conclusions: The incorporation of EIS data into clinical decision-making by PCPs significantly increased the sensitivity and specificity of biopsy/referral decisions for melanomas and SDN and overall diagnostic accuracy compared with visual inspection alone. The results of this study suggest that diagnostic accuracy for PSLs by PCPs may be improved with adjunctive use of EIS with visual inspection.

Primary care providers (PCPs) are often the first line of defense in detecting skin cancers. For patients with concerning skin lesions, PCPs may choose to perform a biopsy or facilitate access to specialty services (eg, Dermatology). Consequently, PCPs play a critical role in the timely detection of skin cancers, and it is paramount to employ continually improving detection methods, such as the application of technologic advances.¹

Differentiating benign nevi from melanoma and severely dysplastic nevi (SDN), both of which warrant excision, poses a unique challenge to clinicians examining pigmented skin lesions (PSLs). PCPs often rely on visual inspection to differentiate benign skin lesions from malignant skin cancers. In some primary care practices, dermoscopy, which involves using a handheld device to evaluate lesions with polarized light and magnification, is used to improve melanoma detection. However, while visual inspection and dermoscopy are valid, effective techniques for the diagnosis of melanocytic lesions, in many instances they still can lead to missed cancers or unnecessary biopsies and specialty referrals. Adjunctive use of dermoscopy with visual inspection has been shown to increase the probability of skin cancer detection, but it fails to achieve a near-100% success rate.² Furthermore, dermoscopy is heavily user-dependent, requiring significant training and experience for appropriate use.³

Another option is an electrical impedance spectroscopy (EIS) device (Nevisense, Scibase, Stockholm, Sweden), which has been approved by the US Food and Drug Administration (FDA) to assist in the detection of melanoma and differentiation from benign PSLs.⁴ EIS is a noninvasive, rapidly applied technology designed to accompany the visual examination of melanocytic lesions in office, with or without dermoscopy. Still relatively new, the technology is employed today by many dermatologists, increasing diagnostic accuracy for PSLs.⁵ The lightweight and portable instrument features a handheld probe, which is held against a lesion to obtain a reading. EIS uses a low-voltage electrode to apply a harmless electrical current to the skin at various frequencies.⁶ As benign and malignant tissues vary in cell shape, size, and composition, EIS distinguishes differential electrical resistance of the tissue to aid in diagnosis.⁷

Continue to: EIS provides high-sensitivity...

EIS provides high-sensitivity melanoma diagnosis vs histopathologic confirmation from biopsies, with 1 study showing a 96.6% sensitivity rating, detecting 256 of 265 melanomas.⁴ The EIS device, by measuring differences in electrical resistance between benign and cancerous cells, outputs a simple integer score ranging from 0 to 10 associated with the likelihood of the lesion being a melanoma.⁸ Based on data from the Nevisense pivotal trial,⁴ Nevisense reports that scores of 0 to 3 carry a negative predictive value of 99% for melanoma, whereas scores of 4 to 10 signify increasingly greater positive predictive values from 7% to 61%.

Findings suggest that the use of electrical impedance spectroscopy is particularly advantageous to clinicians who are less proficient in assessing melanocytic lesions.

We aimed to assess whether EIS may be beneficial to PCPs by comparing the accuracy of clinical decision-making for PSLs based on visual examination alone with that based on concurrent visual and EIS evaluation.

METHODS

A questionnaire was distributed via email to 142 clinicians at clinics affiliated with either of 2 organizations delivering care to the New York City area through a network of community health centers: the Institute for Family Health (IFH) and the Community Healthcare Network (CHN). Of these recipients, 72 were affiliated with IFH across 27 community health centers and 70 were affiliated with CHN across 14 community health centers. Recipients were physicians and nurse practitioners (NPs) practicing at primary health care facilities.

Survey instrument. The first section of the survey instrument (APPENDIX) solicited demographic information and explained how to apply the EIS scores for diagnostic ­decision-making. The second featured images of 12 randomly selected, histologically confirmed, and EIS-evaluated PSLs from a previously published prospective blinded trial of 2416 lesions.⁴ The Institutional Review Board of the Icahn School of Medicine at Mount Sinai reviewed and approved the study and survey instrument.

Clinical images of these lesions, comprising 4 melanocytic nevi, 4 dysplastic nevi (including 3 mild-moderately dysplastic and 1 severely dysplastic nevus), and 4 melanomas, were first presented to respondents with 2 tasks: (1) rate on a scale of 1 to 5 their likelihood to biopsy or refer this lesion to a dermatologist (1: not likely; 5: extremely likely); and (2) select what they expect the pathology results to be: melanocytic nevus, dysplastic nevus, or malignant melanoma. Subsequently, respondents repeated the assessments after being presented with the EIS score for the same lesion in conjunction with the clinical image.

Continue to: Analysis

Analysis. A biopsy or referral rating of 4 or 5 was considered a decision to biopsy or refer (ie, a diagnostic decision consistent with melanoma or SDN warranting excision), whereas a selection of 1 to 3 was considered a decision not to biopsy or refer (ie, a diagnostic decision consistent with a benign PSL). The sensitivity and specificity of biopsy/­referral decisions for melanomas and SDN, the proportion of missed melanomas and SDN, and the proportion of biopsy/referral decisions for benign lesions were separately determined for visual inspection alone and visual inspection with EIS score. Similarly, diagnostic accuracy was calculated for these clinical scenarios. These metrics were further stratified among different subsets of the respondent population. Differences in sensitivity, specificity, biopsy/referral decision proportions, and diagnostic accuracy were calculated using McNemar’s test for paired proportions.

RESULTS

Sixty-one respondents, comprising 44 physicians and 17 NPs, completed the survey, yielding a response rate of 43% (TABLE 1). In total, 1354 clinical decisions (677 based on visual inspection alone and 677 based on visual inspection plus EIS) were made. A biopsy/­referral decision was made after assessing 416 of 677 cases (61%) with visual inspection alone and 360 of 677 cases (53%) when relying on visual inspection plus EIS. None of the respondents reported any prior experience with EIS.

When incorporating EIS scores, respondents’ mean sensitivity for melanomas and SDN increased from 69.2% to 90.0% (P < .001) and specificity from 44.0% to 72.6% (P < .001; TABLE 2). At baseline, physicians demonstrated a sensitivity and specificity of 74.6% and 46.5%, respectively, while NPs demonstrated a sensitivity and specificity of 56.1% and 37.9%, respectively.

All respondent subgroups stratified by occupation and years of experience saw significant increases in both sensitivity and specificity upon the incorporation of EIS scores, with NPs seeing a greater increase in sensitivity (56.1% vs 85.4%; P < .001) and specificity (37.9% vs 69.0%; P < .001) than physicians (sensitivity: 74.6% vs 91.9%; P < .001; specificity: 46.5% vs 74.1%; P < .001). The only difference in diagnostic performance based on years of experience was a greater pre-EIS sensitivity by clinicians who had been in practice for ≥ 15 years, compared with those in practice for shorter periods (TABLE 2).

The improvements, seen in clinicians of varying training and experience, suggest that the learning curve of EIS may not be as steep as that of dermoscopy.

Diagnostic accuracy increased significantly from 48% when based on visual inspection alone to 73% with the addition of EIS scores (P < .001; TABLE 3). Physicians and NPs each significantly increased their diagnostic accuracy upon the incorporation of EIS, with NPs exhibiting the greatest increase (from 36.9% to 65.7%; P < .001). PCPs with 6 to 14 years of experience saw the greatest increase in diagnostic accuracy when adding EIS (45.9% vs 76.4%; P < .001). Overall, the addition of EIS scores resulted in 58 fewer missed melanomas and SDN and 114 fewer benign referrals or biopsies (TABLE 4).

Continue to: DISCUSSION

DISCUSSION

Primary care evaluation plays a significant role in the diagnosis and management of PSLs, ultimately shaping outcomes for patients with melanoma. Improved accuracy of PSL classification could yield greater sensitivity for the diagnosis of melanomas and high-risk melanocytic lesions at earlier stages, while also reducing the number of unnecessary biopsies and referrals—leading to decreased patient morbidity and mortality and reduced health care spending.⁹

Diagnostic tools are valuable insofar as they can improve accuracy and positively impact clinical management and patient outcomes.¹⁰ In this case, increased sensitivity reduced missed melanoma diagnoses, while increased specificity avoided the additional costs and patient toll associated with a biopsy or referral for a benign lesion.

Dermoscopy has been shown to improve the sensitivity and specificity of PSL diagnosis compared with visual inspection alone; however, without substantial training and experience, accuracy with dermoscopy can be no better than examination with the naked eye.^3,11,12 The dropout rates are high for training PCPs in its use, given that several months of training may be needed for competent use.^13,14 To improve the clinical management of PSLs broadly in primary care, a need exists for easy-to-use adjunctive tools that increase diagnostic accuracy.¹⁵

In this study, with only a brief explanation of how to interpret EIS scores, clinicians without any prior experience using EIS demonstrated significantly improved accuracy in deciding appropriate management and classifying melanocytic lesions with the addition of EIS to visual inspection. These improvements, seen in clinicians of varying training and experience, suggest that the learning curve of EIS may not be as steep as that of dermoscopy.

The greater baseline sensitivity, specificity, and diagnostic accuracy of physicians’ clinical decision-making compared with NPs before the incorporation of EIS in the study may be a product of comparatively more extensive medical training. In addition, EIS yielded a greater benefit to NPs than to physicians, with greater increases in sensitivity and specificity noted. This suggests that the use of EIS is particularly advantageous to clinicians who are less proficient in assessing melanocytic lesions. Using visual inspection alone, more experienced respondents made biopsy/referral decisions with greater sensitivity but similar specificity to those with less experience. With the incorporation of EIS scores, the sensitivity and specificity of respondents’ clinical decision-making rose to comparable levels across all experience groups, providing further indication of EIS’s particular value to clinicians who are less proficient in PSL evaluation.

Continue to: This technology holds the potential...

This technology holds the potential to be seamlessly implemented into primary care practice, given that dermatology expertise training is not required to use the EIS device; this could allow for EIS measurement of lesions to be delegated to office staff (eg, nurses, medical assistants).¹⁶ Future studies are needed to assess EIS use among PCPs in a real-world setting, where factors such as its application on nonmelanocytic lesions (eg, seborrheic keratoses) and its pairing with patient historical data could produce varying results.

Limitations. While revealing, this study had its limitations. Respondents did not have access to additional pertinent clinical information, such as patients’ histories and risk factors. Clinical decisions in this survey were made based on digital images rather than in vivo examination. This may not represent a real-life evaluation; there is the potential for minimization of the true consequences of a missed melanoma or unnecessary biopsy in the minds of participants, and this does not factor in the operation of the actual EIS device. The Hawthorne effect may also have influenced PCPs’ diagnostic selections. Also, the limited sample size constitutes another limitation.

The results of this preliminary study suggest that diagnostic accuracy for pigmented skin lesions by PCPs may be improved with the adjunctive use of electrical impedance spectroscopy with visual inspection.

Of note, in this survey format, respondents rated their inclination to biopsy or refer each lesion from 1 to 5. For statistical analyses, lesions rated 1 to 3 were considered as not biopsied/referred and those rated 4 to 5 as biopsied/referred. The sensitivity and specificity values observed, for both visual examination and concurrent visual and EIS evaluation, are therefore based on this classification system of participants’ provided ratings. It is conceivable that differing sensitivity and specificity values might have been detected if clinicians were instead given a binary choice for referral/biopsy decisions.

CONCLUSIONS

Among PCPs tasked with evaluating melanocytic lesions, the incorporation of EIS data into clinical decision-making in this study significantly increased the sensitivity, specificity, and overall diagnostic accuracy of biopsy or referral decisions for melanomas and SDN compared with visual inspection alone. Overall, the results of this preliminary study suggest that diagnostic accuracy for PSLs by PCPs may be improved with the adjunctive use of EIS with visual inspection. This would ultimately improve patient care and reduce the morbidity and mortality of a melanoma diagnosis.

CORRESPONDENCE
Jonathan Ungar, MD, Kimberly and Eric J. Waldman Department of Dermatology, Icahn School of Medicine at Mount Sinai, 5 East 98th Street, 5th Floor, New York, NY 10029; [email protected]

Changing behavior is hard. And at nearly every clinical encounter, we counsel/encourage/remind/help (choose a verb) our patients to make a change—to do something hard. We tell them they need to increase their physical activity, get more sleep, or alter their eating habits. We know that if they make the needed changes, they can improve their health and possibly lengthen their lives. But we also know (from the systematic reviews the US Preventive Services Task Force [USPSTF] uses to make its recommendations) that brief counseling in our offices is largely ineffective unless we connect patients to resources to support the recommended change.

As examples, the USPSTF currently recommends the following (both grade “B”):

• offer or refer adults with cardiovascular disease risk factors to behavioral counseling interventions to promote a healthy diet and physical activity.¹
• offer or refer adults with a body mass index of 30 or higher to intensive, multicomponent behavioral interventions.²

This 2-step rule is tech-free and can be applied by patients in a few seconds to make healthier food choices.

To support our patients when making recommendations such as these, we might refer them to a dietitian for intensive counseling and meal-planning guidance. The American Diabetes Association says that patients seeking to manage their diabetes and prediabetes “can start by working with a registered dietitian nutritionist … to make an eating plan that works for [them].”³ However, this kind of resource is unavailable to many of our patients.

So what else can we do?

We can help patients decide what to buy in the grocery aisle. Nutrition labels are useful, but they are limited by their complexity and requisite level of health literacy.⁴ Even the concept of “calories” is not so intuitive. This challenge with interpreting calories led me (in some of my prior work) to explore a potentially more useful approach: conveying calorie information as physical activity equivalents.⁵

In this issue of The Journal of Family Practice, Dong and colleagues present their findings on whether a simple equation (the Altman Rule) that uses information on nutrition labels may be a reasonable proxy for an even more difficult concept—­glycemic load.⁶ The idea is that consumers (eg, patients with diabetes) can use this rule to help them in their decision-making at the grocery store (or the convenience store or gas station, for that matter, where the high-glycemic-load carbohydrates may be even more tempting). The 2-step rule is tech-free and can be applied in a few seconds. Their research demonstrated that the rule is a reasonable proxy for glycemic load for packaged carbohydrates (eg, chips, cereals, crackers, granola bars). Caveats acknowledged, foods that meet the rule are likely to be healthier choices.

Looking ahead, I would like to see whether counseling patients about the Altman Rule leads to their use of it, and how that translates into healthier eating, lower A1C, and ideally better health. For now, the Altman Rule is worth learning about. It may serve as another tool that you can use to support your patients when you ask them to do the hard work of making healthier food choices. 

Changing behavior is hard. And at nearly every clinical encounter, we counsel/encourage/remind/help (choose a verb) our patients to make a change—to do something hard. We tell them they need to increase their physical activity, get more sleep, or alter their eating habits. We know that if they make the needed changes, they can improve their health and possibly lengthen their lives. But we also know (from the systematic reviews the US Preventive Services Task Force [USPSTF] uses to make its recommendations) that brief counseling in our offices is largely ineffective unless we connect patients to resources to support the recommended change.

As examples, the USPSTF currently recommends the following (both grade “B”):

• offer or refer adults with cardiovascular disease risk factors to behavioral counseling interventions to promote a healthy diet and physical activity.¹
• offer or refer adults with a body mass index of 30 or higher to intensive, multicomponent behavioral interventions.²

This 2-step rule is tech-free and can be applied by patients in a few seconds to make healthier food choices.

To support our patients when making recommendations such as these, we might refer them to a dietitian for intensive counseling and meal-planning guidance. The American Diabetes Association says that patients seeking to manage their diabetes and prediabetes “can start by working with a registered dietitian nutritionist … to make an eating plan that works for [them].”³ However, this kind of resource is unavailable to many of our patients.

So what else can we do?

We can help patients decide what to buy in the grocery aisle. Nutrition labels are useful, but they are limited by their complexity and requisite level of health literacy.⁴ Even the concept of “calories” is not so intuitive. This challenge with interpreting calories led me (in some of my prior work) to explore a potentially more useful approach: conveying calorie information as physical activity equivalents.⁵

In this issue of The Journal of Family Practice, Dong and colleagues present their findings on whether a simple equation (the Altman Rule) that uses information on nutrition labels may be a reasonable proxy for an even more difficult concept—­glycemic load.⁶ The idea is that consumers (eg, patients with diabetes) can use this rule to help them in their decision-making at the grocery store (or the convenience store or gas station, for that matter, where the high-glycemic-load carbohydrates may be even more tempting). The 2-step rule is tech-free and can be applied in a few seconds. Their research demonstrated that the rule is a reasonable proxy for glycemic load for packaged carbohydrates (eg, chips, cereals, crackers, granola bars). Caveats acknowledged, foods that meet the rule are likely to be healthier choices.

Looking ahead, I would like to see whether counseling patients about the Altman Rule leads to their use of it, and how that translates into healthier eating, lower A1C, and ideally better health. For now, the Altman Rule is worth learning about. It may serve as another tool that you can use to support your patients when you ask them to do the hard work of making healthier food choices. 

Changing behavior is hard. And at nearly every clinical encounter, we counsel/encourage/remind/help (choose a verb) our patients to make a change—to do something hard. We tell them they need to increase their physical activity, get more sleep, or alter their eating habits. We know that if they make the needed changes, they can improve their health and possibly lengthen their lives. But we also know (from the systematic reviews the US Preventive Services Task Force [USPSTF] uses to make its recommendations) that brief counseling in our offices is largely ineffective unless we connect patients to resources to support the recommended change.

As examples, the USPSTF currently recommends the following (both grade “B”):

• offer or refer adults with cardiovascular disease risk factors to behavioral counseling interventions to promote a healthy diet and physical activity.¹
• offer or refer adults with a body mass index of 30 or higher to intensive, multicomponent behavioral interventions.²

This 2-step rule is tech-free and can be applied by patients in a few seconds to make healthier food choices.

To support our patients when making recommendations such as these, we might refer them to a dietitian for intensive counseling and meal-planning guidance. The American Diabetes Association says that patients seeking to manage their diabetes and prediabetes “can start by working with a registered dietitian nutritionist … to make an eating plan that works for [them].”³ However, this kind of resource is unavailable to many of our patients.

So what else can we do?

We can help patients decide what to buy in the grocery aisle. Nutrition labels are useful, but they are limited by their complexity and requisite level of health literacy.⁴ Even the concept of “calories” is not so intuitive. This challenge with interpreting calories led me (in some of my prior work) to explore a potentially more useful approach: conveying calorie information as physical activity equivalents.⁵

In this issue of The Journal of Family Practice, Dong and colleagues present their findings on whether a simple equation (the Altman Rule) that uses information on nutrition labels may be a reasonable proxy for an even more difficult concept—­glycemic load.⁶ The idea is that consumers (eg, patients with diabetes) can use this rule to help them in their decision-making at the grocery store (or the convenience store or gas station, for that matter, where the high-glycemic-load carbohydrates may be even more tempting). The 2-step rule is tech-free and can be applied in a few seconds. Their research demonstrated that the rule is a reasonable proxy for glycemic load for packaged carbohydrates (eg, chips, cereals, crackers, granola bars). Caveats acknowledged, foods that meet the rule are likely to be healthier choices.

Looking ahead, I would like to see whether counseling patients about the Altman Rule leads to their use of it, and how that translates into healthier eating, lower A1C, and ideally better health. For now, the Altman Rule is worth learning about. It may serve as another tool that you can use to support your patients when you ask them to do the hard work of making healthier food choices. 

A 75-YEAR-OLD MAN presented to the dermatology clinic for evaluation of localized, persistent burning pain and discomfort attributed to shingles and postherpetic neuralgia. He had received a diagnosis of shingles on his left upper back about 3 years prior to this presentation.

In the ensuing years, the patient had been evaluated and treated by his primary care physician, a pain management team, and a neurologist. These clinicians treated the symptoms as postherpetic neuralgia, with no consensus explanation for the skin findings. The patient reported that his symptoms were unresponsive to trials of gabapentin 800 mg tid, duloxetine 60 mg PO qd, and acetaminophen 1 to 3 g/d PO. He also had undergone several rounds of acupuncture, thoracic and cervical spine steroid injections, and epidurals, without resolution of symptoms. The patient believed the only treatment that helped was a lidocaine 4% patch, which he had used nearly every day for the previous 3 years.

Physical exam by the dermatologist revealed a lidocaine patch applied to the patient’s left upper back. Upon its removal, skin examination showed a well-demarcated, erythematous, hyperpigmented, lichenified plaque with excoriations and erosions where the patch had been (FIGURE).

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

The patient’s history and skin exam provided enough information to diagnose contact dermatitis. The pruritus, burning, and pain the patient had experienced were due to continuous application of the lidocaine patch to the area rather than postherpetic neuralgia.

There are 2 types of contact dermatitis: irritant and allergic. Irritant contact dermatitis is an inflammatory reaction caused directly by a substance, while allergic contact dermatitis is a delayed hypersensitivity reaction to specific allergens.¹ While data to elucidate the incidence and prevalence of allergic contact dermatitis are unknown, common causes include latex, dyes, oils, resins, and compounds in textiles, rubber, cosmetics, and other products used in daily life.¹

The pruritus, burning, and pain the patient had experienced were due to continuous application of the lidocaine patch to the area rather than postherpetic neuralgia.

Allergic contact dermatitis due to ­lidocaine is becoming more prevalent with increased use and availability of over-the-counter products.² A retrospective chart review of 1819 patch-tested patients from the University of British Columbia Contact Dermatitis Clinic showed a significant proportion of patients (2.4%) were found to have an allergic contact dermatitis to local anesthetics—most commonly benzocaine (45%), followed by lidocaine (32%).³ Therefore, it is important to consider contact dermatitis in patients using topical anesthetics for pain relief.

The differential varies by area affected

The differential diagnosis for contact dermatitis varies by area affected and the distribution of rash. Atopic dermatitis, lichen planus, and psoriasis are a few dermatologic conditions to consider in the differential diagnosis. They can look similar to contact dermatitis, but the patient’s history can help to discern the most likely diagnosis.¹

Atopic dermatitis is a complex dysfunction of the skin barrier and immune factors that often begins in childhood and persists in some patients throughout their lifetime. Atopic dermatitis is associated with other forms of atopy including asthma, allergic rhinitis, and food and contact allergies. Atopic dermatitis in the absence of contact allergies may manifest with chronic, diffuse, scaly patches with poorly defined borders. The patches appear in a symmetrical distribution and favor the flexural surfaces, such as the antecubital fossa, wrists, and neck.

Continue to: Lichen planus

Lichen planus most often manifests in the fourth through sixth decade of life as flat-topped itchy pink-to-purple polygonal papules to plaques. Lesions range from 2 to 10 mm and favor the volar wrists, shins, and lower back, although they may be widespread. Oral lesions manifesting as ulcers or white lacy patches in the buccal mucosa are common and may be a clue to the diagnosis. Unlike more generalized contact dermatitis, lichen planus lesions are discrete.

Psoriasis manifests as well-demarcated scaly plaques distributed symmetrically over extensor surfaces. The plaques commonly are found on the elbows, knees, and scalp. When psoriasis manifests in a very limited form (as just a single plaque or limited number of plaques), it can be hard to confidently exclude other etiologies. In these circumstances, look for psoriasis signs in more unique locations (eg, pitting in the nails or plaques on the scalp or in the gluteal cleft). Adding those findings to an otherwise solitary plaque significantly adds to diagnostic certainty.

Diagnosis entails getting the shape of things

Diagnosis is based on history of exposure to irritating or allergic substances, as well as a clinical exam. Skin examination of contact dermatitis can vary based on how long it has been present: Acute manifestations include erythema, oozing, scale, vesicles, and bullae, while chronic contact dermatitis tends to demonstrate lichenification and scale.¹

Distinctive findings. The most distinctive physical exam findings in patients with contact dermatitis are often shape and distribution of the rash, which reflect points of contact with the offending agent. This clue helped to elucidate the diagnosis in our patient: his rash was perfectly demarcated within the precise area where the patch was applied daily.

Irritant vs allergic. Patch testing can be performed to differentiate irritant vs allergic contact dermatitis.¹ Irritant contact dermatitis usually is apparent when removing a patch and will resolve over a day, whereas allergic contact dermatitis forms over time and the skin rash is most prominent several days after the patch has been removed.¹

Continue to: Treatment

Treatment of both variants of contact dermatitis includes avoidance of the causative substance and symptomatic treatment with topical steroids, antihistamines, and possibly oral steroids depending on the severity.¹

For our patient, a viral swab was taken and submitted for varicella zoster virus polymerase chain reaction testing to rule out persistent herpes zoster infection; the result was negative. The patient was counseled to discontinue use of the lidocaine patch.

Given the severity and protracted duration of the patient’s symptoms, he also was started on high-potency topical steroids (clobetasol 0.05% ointment to be applied twice daily under occlusion for 2 months), a 4-week prednisone taper (60 mg × 1 week, 40 mg × 1 week, 20 mg × 1 week, 10 mg × 1 week, then stop), and hydroxyzine (25 mg nightly as needed for pruritus). The patient’s rash and symptoms improved dramatically within the first few doses of prednisone and completely cleared by Week 4 of the prednisone taper. At his follow-up appointment 1 month after completing the prednisone taper, he stated that the pain on his back had resolved.

A 75-YEAR-OLD MAN presented to the dermatology clinic for evaluation of localized, persistent burning pain and discomfort attributed to shingles and postherpetic neuralgia. He had received a diagnosis of shingles on his left upper back about 3 years prior to this presentation.

In the ensuing years, the patient had been evaluated and treated by his primary care physician, a pain management team, and a neurologist. These clinicians treated the symptoms as postherpetic neuralgia, with no consensus explanation for the skin findings. The patient reported that his symptoms were unresponsive to trials of gabapentin 800 mg tid, duloxetine 60 mg PO qd, and acetaminophen 1 to 3 g/d PO. He also had undergone several rounds of acupuncture, thoracic and cervical spine steroid injections, and epidurals, without resolution of symptoms. The patient believed the only treatment that helped was a lidocaine 4% patch, which he had used nearly every day for the previous 3 years.

Physical exam by the dermatologist revealed a lidocaine patch applied to the patient’s left upper back. Upon its removal, skin examination showed a well-demarcated, erythematous, hyperpigmented, lichenified plaque with excoriations and erosions where the patch had been (FIGURE).

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

The patient’s history and skin exam provided enough information to diagnose contact dermatitis. The pruritus, burning, and pain the patient had experienced were due to continuous application of the lidocaine patch to the area rather than postherpetic neuralgia.

There are 2 types of contact dermatitis: irritant and allergic. Irritant contact dermatitis is an inflammatory reaction caused directly by a substance, while allergic contact dermatitis is a delayed hypersensitivity reaction to specific allergens.¹ While data to elucidate the incidence and prevalence of allergic contact dermatitis are unknown, common causes include latex, dyes, oils, resins, and compounds in textiles, rubber, cosmetics, and other products used in daily life.¹

The pruritus, burning, and pain the patient had experienced were due to continuous application of the lidocaine patch to the area rather than postherpetic neuralgia.

Allergic contact dermatitis due to ­lidocaine is becoming more prevalent with increased use and availability of over-the-counter products.² A retrospective chart review of 1819 patch-tested patients from the University of British Columbia Contact Dermatitis Clinic showed a significant proportion of patients (2.4%) were found to have an allergic contact dermatitis to local anesthetics—most commonly benzocaine (45%), followed by lidocaine (32%).³ Therefore, it is important to consider contact dermatitis in patients using topical anesthetics for pain relief.

The differential varies by area affected

The differential diagnosis for contact dermatitis varies by area affected and the distribution of rash. Atopic dermatitis, lichen planus, and psoriasis are a few dermatologic conditions to consider in the differential diagnosis. They can look similar to contact dermatitis, but the patient’s history can help to discern the most likely diagnosis.¹

Atopic dermatitis is a complex dysfunction of the skin barrier and immune factors that often begins in childhood and persists in some patients throughout their lifetime. Atopic dermatitis is associated with other forms of atopy including asthma, allergic rhinitis, and food and contact allergies. Atopic dermatitis in the absence of contact allergies may manifest with chronic, diffuse, scaly patches with poorly defined borders. The patches appear in a symmetrical distribution and favor the flexural surfaces, such as the antecubital fossa, wrists, and neck.

Continue to: Lichen planus

Lichen planus most often manifests in the fourth through sixth decade of life as flat-topped itchy pink-to-purple polygonal papules to plaques. Lesions range from 2 to 10 mm and favor the volar wrists, shins, and lower back, although they may be widespread. Oral lesions manifesting as ulcers or white lacy patches in the buccal mucosa are common and may be a clue to the diagnosis. Unlike more generalized contact dermatitis, lichen planus lesions are discrete.

Psoriasis manifests as well-demarcated scaly plaques distributed symmetrically over extensor surfaces. The plaques commonly are found on the elbows, knees, and scalp. When psoriasis manifests in a very limited form (as just a single plaque or limited number of plaques), it can be hard to confidently exclude other etiologies. In these circumstances, look for psoriasis signs in more unique locations (eg, pitting in the nails or plaques on the scalp or in the gluteal cleft). Adding those findings to an otherwise solitary plaque significantly adds to diagnostic certainty.

Diagnosis entails getting the shape of things

Diagnosis is based on history of exposure to irritating or allergic substances, as well as a clinical exam. Skin examination of contact dermatitis can vary based on how long it has been present: Acute manifestations include erythema, oozing, scale, vesicles, and bullae, while chronic contact dermatitis tends to demonstrate lichenification and scale.¹

Distinctive findings. The most distinctive physical exam findings in patients with contact dermatitis are often shape and distribution of the rash, which reflect points of contact with the offending agent. This clue helped to elucidate the diagnosis in our patient: his rash was perfectly demarcated within the precise area where the patch was applied daily.

Irritant vs allergic. Patch testing can be performed to differentiate irritant vs allergic contact dermatitis.¹ Irritant contact dermatitis usually is apparent when removing a patch and will resolve over a day, whereas allergic contact dermatitis forms over time and the skin rash is most prominent several days after the patch has been removed.¹

Continue to: Treatment

Treatment of both variants of contact dermatitis includes avoidance of the causative substance and symptomatic treatment with topical steroids, antihistamines, and possibly oral steroids depending on the severity.¹

For our patient, a viral swab was taken and submitted for varicella zoster virus polymerase chain reaction testing to rule out persistent herpes zoster infection; the result was negative. The patient was counseled to discontinue use of the lidocaine patch.

Given the severity and protracted duration of the patient’s symptoms, he also was started on high-potency topical steroids (clobetasol 0.05% ointment to be applied twice daily under occlusion for 2 months), a 4-week prednisone taper (60 mg × 1 week, 40 mg × 1 week, 20 mg × 1 week, 10 mg × 1 week, then stop), and hydroxyzine (25 mg nightly as needed for pruritus). The patient’s rash and symptoms improved dramatically within the first few doses of prednisone and completely cleared by Week 4 of the prednisone taper. At his follow-up appointment 1 month after completing the prednisone taper, he stated that the pain on his back had resolved.

A 75-YEAR-OLD MAN presented to the dermatology clinic for evaluation of localized, persistent burning pain and discomfort attributed to shingles and postherpetic neuralgia. He had received a diagnosis of shingles on his left upper back about 3 years prior to this presentation.

In the ensuing years, the patient had been evaluated and treated by his primary care physician, a pain management team, and a neurologist. These clinicians treated the symptoms as postherpetic neuralgia, with no consensus explanation for the skin findings. The patient reported that his symptoms were unresponsive to trials of gabapentin 800 mg tid, duloxetine 60 mg PO qd, and acetaminophen 1 to 3 g/d PO. He also had undergone several rounds of acupuncture, thoracic and cervical spine steroid injections, and epidurals, without resolution of symptoms. The patient believed the only treatment that helped was a lidocaine 4% patch, which he had used nearly every day for the previous 3 years.

Physical exam by the dermatologist revealed a lidocaine patch applied to the patient’s left upper back. Upon its removal, skin examination showed a well-demarcated, erythematous, hyperpigmented, lichenified plaque with excoriations and erosions where the patch had been (FIGURE).

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

The patient’s history and skin exam provided enough information to diagnose contact dermatitis. The pruritus, burning, and pain the patient had experienced were due to continuous application of the lidocaine patch to the area rather than postherpetic neuralgia.

There are 2 types of contact dermatitis: irritant and allergic. Irritant contact dermatitis is an inflammatory reaction caused directly by a substance, while allergic contact dermatitis is a delayed hypersensitivity reaction to specific allergens.¹ While data to elucidate the incidence and prevalence of allergic contact dermatitis are unknown, common causes include latex, dyes, oils, resins, and compounds in textiles, rubber, cosmetics, and other products used in daily life.¹

The pruritus, burning, and pain the patient had experienced were due to continuous application of the lidocaine patch to the area rather than postherpetic neuralgia.

Allergic contact dermatitis due to ­lidocaine is becoming more prevalent with increased use and availability of over-the-counter products.² A retrospective chart review of 1819 patch-tested patients from the University of British Columbia Contact Dermatitis Clinic showed a significant proportion of patients (2.4%) were found to have an allergic contact dermatitis to local anesthetics—most commonly benzocaine (45%), followed by lidocaine (32%).³ Therefore, it is important to consider contact dermatitis in patients using topical anesthetics for pain relief.

The differential varies by area affected

The differential diagnosis for contact dermatitis varies by area affected and the distribution of rash. Atopic dermatitis, lichen planus, and psoriasis are a few dermatologic conditions to consider in the differential diagnosis. They can look similar to contact dermatitis, but the patient’s history can help to discern the most likely diagnosis.¹

Atopic dermatitis is a complex dysfunction of the skin barrier and immune factors that often begins in childhood and persists in some patients throughout their lifetime. Atopic dermatitis is associated with other forms of atopy including asthma, allergic rhinitis, and food and contact allergies. Atopic dermatitis in the absence of contact allergies may manifest with chronic, diffuse, scaly patches with poorly defined borders. The patches appear in a symmetrical distribution and favor the flexural surfaces, such as the antecubital fossa, wrists, and neck.

Continue to: Lichen planus

Lichen planus most often manifests in the fourth through sixth decade of life as flat-topped itchy pink-to-purple polygonal papules to plaques. Lesions range from 2 to 10 mm and favor the volar wrists, shins, and lower back, although they may be widespread. Oral lesions manifesting as ulcers or white lacy patches in the buccal mucosa are common and may be a clue to the diagnosis. Unlike more generalized contact dermatitis, lichen planus lesions are discrete.

Psoriasis manifests as well-demarcated scaly plaques distributed symmetrically over extensor surfaces. The plaques commonly are found on the elbows, knees, and scalp. When psoriasis manifests in a very limited form (as just a single plaque or limited number of plaques), it can be hard to confidently exclude other etiologies. In these circumstances, look for psoriasis signs in more unique locations (eg, pitting in the nails or plaques on the scalp or in the gluteal cleft). Adding those findings to an otherwise solitary plaque significantly adds to diagnostic certainty.

Diagnosis entails getting the shape of things

Diagnosis is based on history of exposure to irritating or allergic substances, as well as a clinical exam. Skin examination of contact dermatitis can vary based on how long it has been present: Acute manifestations include erythema, oozing, scale, vesicles, and bullae, while chronic contact dermatitis tends to demonstrate lichenification and scale.¹

Distinctive findings. The most distinctive physical exam findings in patients with contact dermatitis are often shape and distribution of the rash, which reflect points of contact with the offending agent. This clue helped to elucidate the diagnosis in our patient: his rash was perfectly demarcated within the precise area where the patch was applied daily.

Irritant vs allergic. Patch testing can be performed to differentiate irritant vs allergic contact dermatitis.¹ Irritant contact dermatitis usually is apparent when removing a patch and will resolve over a day, whereas allergic contact dermatitis forms over time and the skin rash is most prominent several days after the patch has been removed.¹

Continue to: Treatment

Treatment of both variants of contact dermatitis includes avoidance of the causative substance and symptomatic treatment with topical steroids, antihistamines, and possibly oral steroids depending on the severity.¹

For our patient, a viral swab was taken and submitted for varicella zoster virus polymerase chain reaction testing to rule out persistent herpes zoster infection; the result was negative. The patient was counseled to discontinue use of the lidocaine patch.

Given the severity and protracted duration of the patient’s symptoms, he also was started on high-potency topical steroids (clobetasol 0.05% ointment to be applied twice daily under occlusion for 2 months), a 4-week prednisone taper (60 mg × 1 week, 40 mg × 1 week, 20 mg × 1 week, 10 mg × 1 week, then stop), and hydroxyzine (25 mg nightly as needed for pruritus). The patient’s rash and symptoms improved dramatically within the first few doses of prednisone and completely cleared by Week 4 of the prednisone taper. At his follow-up appointment 1 month after completing the prednisone taper, he stated that the pain on his back had resolved.

Evidence summary

Naltrexone is comparable to amitriptyline for diabetic neuropathy pain

A 2021 randomized, double-blind, active-comparator, crossover clinical trial conducted in India examined the efficacy of low-dose naltrexone vs standard-of-care amitriptyline in patients (N = 67) with painful diabetic neuropathy. Participants were adults (ages 18 to 75 years) with painful diabetic neuropathy who had been on a stable dose of nonopioid pain medication for at least 1 month.¹

Patients were randomly assigned to start receiving naltrexone 2 mg (n = 33) or amitriptyline 10 mg (n = 34). They received their starting medication for 6 weeks (with follow-up every 2 weeks), then completed a 2-week washout period, and then switched to the other study medication for 6 weeks (same follow-up schedule). If patients reported < 20% pain reduction on the Visual Analog Scale (VAS; 0-100 scoring system with 0 = no pain and 100 = worst pain) at a follow-up visit, their medication dose was titrated up, to a maximum of 4 mg of naltrexone or 25 to 50 mg of amitriptyline.¹

The primary outcome of interest was the mean change in VAS pain score following 6 weeks of treatment. There was no statistically different change from baseline VAS pain score between the amitriptyline and nal­trexone groups (mean difference [MD] = 1.6; 95% CI, –0.9 to 4.2; P = 0.21). These findings were consistent across the secondary endpoints (Likert 5-point pain scale and McGill Pain Questionnaire scores). There was no statistically significant difference in Hamilton Depression Rating Scale scores (13 in the naltrexone group vs 11 in the amitriptyline group; P = .81), no reports of decreased sleep quality in either group, and no significant difference in Patients’ Global Impression of Change scores at 6-week evaluation.¹

The naltrexone cohort experienced 8 adverse events (most commonly, mild diarrhea), while the amitriptyline cohort experienced 52 adverse events (most commonly, somnolence) (P < .001). The limitations of the study include the lack of a placebo arm and a relatively small sample size.¹

Greater reduction in pain scores with naltrexone

A 2022 retrospective cohort study evaluated the effectiveness of naltrexone for patients treated at a single outpatient integrative pain management practice in Alaska between 2014 and 2019. The exposure group (n = 36) included patients who had completed at least a 2-month continuous regimen of oral naltrexone 4.5 mg. Controls (n = 42) were selected from the remaining practice population receiving standard care and were primarily matched by diagnosis code, followed by gender, then age +/– 5 years. Patients were divided into subgroups for inflammatory and neuropathic pain.²

The primary outcome measured was the mean change in VAS score or numeric rating score (NRS; both used a 1-10 rating system), which was assessed during a patient’s appointment from initiation of treatment to the most recent visit or at the termination of therapy (intervention interquartile range, 12-14 months). There was no statistically significant difference in VAS/NRS between the low-dose naltrexone and control groups at baseline (6.09 vs 6.38; P = .454). The low-dose naltrexone group experienced a greater reduction in VAS/NRS pain scores compared to the control group (–37.8% vs –4.3%; P < .001).²

Compared with control patients in each group, patients in the inflammatory pain subgroup and the neuropathic pain subgroup who received low-dose naltrexone reported reductions in pain scores of 32% (P < .001) and 44% (P = .048), respectively. There was no statistically significant difference in mean change in VAS/NRS scores between the inflammatory and neuropathic subgroups (P = .763). A multivariate linear regression analysis did not identify significant variables other than low-dose naltrexone that correlated with pain improvement. The number needed to treat to observe a ≥ 50% reduction in pain scores was 3.2.²

Continue to: Limitations for this study...

Limitations for this study include its small sample size and open-label design.²

Low-dose naltrexone is effective for fibromyalgia pain

A 2020 single-blind prospective dose-­response study utilized the up-and-down method to identify effective naltrexone dose for patients in a Danish university hospital pain clinic. Patients were White women ages 18 to 60 years (N = 25) who had a diagnosis of fibromyalgia unresponsive to traditional pharmacologic treatment. All patients received treatment with low-dose naltrexone (ranging from 0.75 mg to 6.0 mg) but were blinded to dose.³

Studies show that low-dose naltrexone has some effectiveness in a variety of pain conditions—including diabetic neuropathy and fibromyalgia—with few adverse effects.

Patients were evaluated for improvement in fibromyalgia symptoms using the Patient Global Impression of Improvement (PGI-I) scale—which ranges from 1 (very much improved) to 7 (very much worse), with 4 being “no change”—at baseline and after 2 to 3 weeks of treatment with low-dose naltrexone. A patient was considered a responder if they scored 1 to 3 on the follow-up PGI-I scale or if they experienced a > 30% pain reduction on the VAS. If a patient did not respond to their dose, the next patient began treatment at a dose 0.75 mg higher than the previous patient’s ending dose. If a patient did respond to low-dose naltrexone treatment, the next patient’s starting dose was 0.75 mg less than the previous patient’s. Eleven of 25 patients were considered responders.³

The primary outcomes were effective dose for 50% of fibromyalgia patients (3.88 mg; 95% CI, 3.39-4.35) and effective dose for 95% of fibromyalgia patients (5.4 mg; 95% CI, 4.66-6.13). Secondary outcomes were fibromyalgia symptoms as evaluated on the Fibromyalgia Impact Questionnaire Revised. Five of the 11 responders reported a > 30% improvement in tenderness and 8 of the 11 responders reported a > 30% decrease in waking unrefreshed.³

Limitations of the study include the short time period of treatment before response was assessed and the decision to use low test ­doses, which may have hindered detection of effective doses > 6 mg in fibromyalgia.³

Editor’s takeaway

Low-dose naltrexone, a less-often-used form of pain management, is a welcome option. Studies show some effectiveness in a variety of pain conditions with few adverse effects. The small number of studies, the small sample sizes, and the limited follow-up duration should encourage more investigation into how to best use this intervention.

Evidence summary

Naltrexone is comparable to amitriptyline for diabetic neuropathy pain

A 2021 randomized, double-blind, active-comparator, crossover clinical trial conducted in India examined the efficacy of low-dose naltrexone vs standard-of-care amitriptyline in patients (N = 67) with painful diabetic neuropathy. Participants were adults (ages 18 to 75 years) with painful diabetic neuropathy who had been on a stable dose of nonopioid pain medication for at least 1 month.¹

Patients were randomly assigned to start receiving naltrexone 2 mg (n = 33) or amitriptyline 10 mg (n = 34). They received their starting medication for 6 weeks (with follow-up every 2 weeks), then completed a 2-week washout period, and then switched to the other study medication for 6 weeks (same follow-up schedule). If patients reported < 20% pain reduction on the Visual Analog Scale (VAS; 0-100 scoring system with 0 = no pain and 100 = worst pain) at a follow-up visit, their medication dose was titrated up, to a maximum of 4 mg of naltrexone or 25 to 50 mg of amitriptyline.¹

The primary outcome of interest was the mean change in VAS pain score following 6 weeks of treatment. There was no statistically different change from baseline VAS pain score between the amitriptyline and nal­trexone groups (mean difference [MD] = 1.6; 95% CI, –0.9 to 4.2; P = 0.21). These findings were consistent across the secondary endpoints (Likert 5-point pain scale and McGill Pain Questionnaire scores). There was no statistically significant difference in Hamilton Depression Rating Scale scores (13 in the naltrexone group vs 11 in the amitriptyline group; P = .81), no reports of decreased sleep quality in either group, and no significant difference in Patients’ Global Impression of Change scores at 6-week evaluation.¹

The naltrexone cohort experienced 8 adverse events (most commonly, mild diarrhea), while the amitriptyline cohort experienced 52 adverse events (most commonly, somnolence) (P < .001). The limitations of the study include the lack of a placebo arm and a relatively small sample size.¹

Greater reduction in pain scores with naltrexone

A 2022 retrospective cohort study evaluated the effectiveness of naltrexone for patients treated at a single outpatient integrative pain management practice in Alaska between 2014 and 2019. The exposure group (n = 36) included patients who had completed at least a 2-month continuous regimen of oral naltrexone 4.5 mg. Controls (n = 42) were selected from the remaining practice population receiving standard care and were primarily matched by diagnosis code, followed by gender, then age +/– 5 years. Patients were divided into subgroups for inflammatory and neuropathic pain.²

The primary outcome measured was the mean change in VAS score or numeric rating score (NRS; both used a 1-10 rating system), which was assessed during a patient’s appointment from initiation of treatment to the most recent visit or at the termination of therapy (intervention interquartile range, 12-14 months). There was no statistically significant difference in VAS/NRS between the low-dose naltrexone and control groups at baseline (6.09 vs 6.38; P = .454). The low-dose naltrexone group experienced a greater reduction in VAS/NRS pain scores compared to the control group (–37.8% vs –4.3%; P < .001).²

Compared with control patients in each group, patients in the inflammatory pain subgroup and the neuropathic pain subgroup who received low-dose naltrexone reported reductions in pain scores of 32% (P < .001) and 44% (P = .048), respectively. There was no statistically significant difference in mean change in VAS/NRS scores between the inflammatory and neuropathic subgroups (P = .763). A multivariate linear regression analysis did not identify significant variables other than low-dose naltrexone that correlated with pain improvement. The number needed to treat to observe a ≥ 50% reduction in pain scores was 3.2.²

Continue to: Limitations for this study...

Limitations for this study include its small sample size and open-label design.²

Low-dose naltrexone is effective for fibromyalgia pain

A 2020 single-blind prospective dose-­response study utilized the up-and-down method to identify effective naltrexone dose for patients in a Danish university hospital pain clinic. Patients were White women ages 18 to 60 years (N = 25) who had a diagnosis of fibromyalgia unresponsive to traditional pharmacologic treatment. All patients received treatment with low-dose naltrexone (ranging from 0.75 mg to 6.0 mg) but were blinded to dose.³

Studies show that low-dose naltrexone has some effectiveness in a variety of pain conditions—including diabetic neuropathy and fibromyalgia—with few adverse effects.

Patients were evaluated for improvement in fibromyalgia symptoms using the Patient Global Impression of Improvement (PGI-I) scale—which ranges from 1 (very much improved) to 7 (very much worse), with 4 being “no change”—at baseline and after 2 to 3 weeks of treatment with low-dose naltrexone. A patient was considered a responder if they scored 1 to 3 on the follow-up PGI-I scale or if they experienced a > 30% pain reduction on the VAS. If a patient did not respond to their dose, the next patient began treatment at a dose 0.75 mg higher than the previous patient’s ending dose. If a patient did respond to low-dose naltrexone treatment, the next patient’s starting dose was 0.75 mg less than the previous patient’s. Eleven of 25 patients were considered responders.³

The primary outcomes were effective dose for 50% of fibromyalgia patients (3.88 mg; 95% CI, 3.39-4.35) and effective dose for 95% of fibromyalgia patients (5.4 mg; 95% CI, 4.66-6.13). Secondary outcomes were fibromyalgia symptoms as evaluated on the Fibromyalgia Impact Questionnaire Revised. Five of the 11 responders reported a > 30% improvement in tenderness and 8 of the 11 responders reported a > 30% decrease in waking unrefreshed.³

Limitations of the study include the short time period of treatment before response was assessed and the decision to use low test ­doses, which may have hindered detection of effective doses > 6 mg in fibromyalgia.³

Editor’s takeaway

Low-dose naltrexone, a less-often-used form of pain management, is a welcome option. Studies show some effectiveness in a variety of pain conditions with few adverse effects. The small number of studies, the small sample sizes, and the limited follow-up duration should encourage more investigation into how to best use this intervention.

Evidence summary

Naltrexone is comparable to amitriptyline for diabetic neuropathy pain

A 2021 randomized, double-blind, active-comparator, crossover clinical trial conducted in India examined the efficacy of low-dose naltrexone vs standard-of-care amitriptyline in patients (N = 67) with painful diabetic neuropathy. Participants were adults (ages 18 to 75 years) with painful diabetic neuropathy who had been on a stable dose of nonopioid pain medication for at least 1 month.¹

Patients were randomly assigned to start receiving naltrexone 2 mg (n = 33) or amitriptyline 10 mg (n = 34). They received their starting medication for 6 weeks (with follow-up every 2 weeks), then completed a 2-week washout period, and then switched to the other study medication for 6 weeks (same follow-up schedule). If patients reported < 20% pain reduction on the Visual Analog Scale (VAS; 0-100 scoring system with 0 = no pain and 100 = worst pain) at a follow-up visit, their medication dose was titrated up, to a maximum of 4 mg of naltrexone or 25 to 50 mg of amitriptyline.¹

The primary outcome of interest was the mean change in VAS pain score following 6 weeks of treatment. There was no statistically different change from baseline VAS pain score between the amitriptyline and nal­trexone groups (mean difference [MD] = 1.6; 95% CI, –0.9 to 4.2; P = 0.21). These findings were consistent across the secondary endpoints (Likert 5-point pain scale and McGill Pain Questionnaire scores). There was no statistically significant difference in Hamilton Depression Rating Scale scores (13 in the naltrexone group vs 11 in the amitriptyline group; P = .81), no reports of decreased sleep quality in either group, and no significant difference in Patients’ Global Impression of Change scores at 6-week evaluation.¹

The naltrexone cohort experienced 8 adverse events (most commonly, mild diarrhea), while the amitriptyline cohort experienced 52 adverse events (most commonly, somnolence) (P < .001). The limitations of the study include the lack of a placebo arm and a relatively small sample size.¹

Greater reduction in pain scores with naltrexone

A 2022 retrospective cohort study evaluated the effectiveness of naltrexone for patients treated at a single outpatient integrative pain management practice in Alaska between 2014 and 2019. The exposure group (n = 36) included patients who had completed at least a 2-month continuous regimen of oral naltrexone 4.5 mg. Controls (n = 42) were selected from the remaining practice population receiving standard care and were primarily matched by diagnosis code, followed by gender, then age +/– 5 years. Patients were divided into subgroups for inflammatory and neuropathic pain.²

The primary outcome measured was the mean change in VAS score or numeric rating score (NRS; both used a 1-10 rating system), which was assessed during a patient’s appointment from initiation of treatment to the most recent visit or at the termination of therapy (intervention interquartile range, 12-14 months). There was no statistically significant difference in VAS/NRS between the low-dose naltrexone and control groups at baseline (6.09 vs 6.38; P = .454). The low-dose naltrexone group experienced a greater reduction in VAS/NRS pain scores compared to the control group (–37.8% vs –4.3%; P < .001).²

Compared with control patients in each group, patients in the inflammatory pain subgroup and the neuropathic pain subgroup who received low-dose naltrexone reported reductions in pain scores of 32% (P < .001) and 44% (P = .048), respectively. There was no statistically significant difference in mean change in VAS/NRS scores between the inflammatory and neuropathic subgroups (P = .763). A multivariate linear regression analysis did not identify significant variables other than low-dose naltrexone that correlated with pain improvement. The number needed to treat to observe a ≥ 50% reduction in pain scores was 3.2.²

Continue to: Limitations for this study...

Limitations for this study include its small sample size and open-label design.²

Low-dose naltrexone is effective for fibromyalgia pain

A 2020 single-blind prospective dose-­response study utilized the up-and-down method to identify effective naltrexone dose for patients in a Danish university hospital pain clinic. Patients were White women ages 18 to 60 years (N = 25) who had a diagnosis of fibromyalgia unresponsive to traditional pharmacologic treatment. All patients received treatment with low-dose naltrexone (ranging from 0.75 mg to 6.0 mg) but were blinded to dose.³

Studies show that low-dose naltrexone has some effectiveness in a variety of pain conditions—including diabetic neuropathy and fibromyalgia—with few adverse effects.

Patients were evaluated for improvement in fibromyalgia symptoms using the Patient Global Impression of Improvement (PGI-I) scale—which ranges from 1 (very much improved) to 7 (very much worse), with 4 being “no change”—at baseline and after 2 to 3 weeks of treatment with low-dose naltrexone. A patient was considered a responder if they scored 1 to 3 on the follow-up PGI-I scale or if they experienced a > 30% pain reduction on the VAS. If a patient did not respond to their dose, the next patient began treatment at a dose 0.75 mg higher than the previous patient’s ending dose. If a patient did respond to low-dose naltrexone treatment, the next patient’s starting dose was 0.75 mg less than the previous patient’s. Eleven of 25 patients were considered responders.³

The primary outcomes were effective dose for 50% of fibromyalgia patients (3.88 mg; 95% CI, 3.39-4.35) and effective dose for 95% of fibromyalgia patients (5.4 mg; 95% CI, 4.66-6.13). Secondary outcomes were fibromyalgia symptoms as evaluated on the Fibromyalgia Impact Questionnaire Revised. Five of the 11 responders reported a > 30% improvement in tenderness and 8 of the 11 responders reported a > 30% decrease in waking unrefreshed.³

Limitations of the study include the short time period of treatment before response was assessed and the decision to use low test ­doses, which may have hindered detection of effective doses > 6 mg in fibromyalgia.³

Editor’s takeaway

Low-dose naltrexone, a less-often-used form of pain management, is a welcome option. Studies show some effectiveness in a variety of pain conditions with few adverse effects. The small number of studies, the small sample sizes, and the limited follow-up duration should encourage more investigation into how to best use this intervention.