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Novel NSAID–triptan drug effectively relieves migraine pain
, new research suggests. Results from the phase 3 INTERCEPT trial show that the treatment, known as AXS-07 (Axsome Therapeutics), also provided greater relief from the patients’ most bothersome symptom (MBS) compared with placebo.
In addition, about 74% of patients who received AXS-07 experienced no progression of pain from 2 to 24 hours after dosing and were less than half as likely to use rescue medication through 24 hours than those who received placebo.
Similar to a previous formulation combining naproxen sodium and sumatriptan, AXS-07 combines a nonsteroidal anti-inflammatory drug with a triptan. The combination is synergistic, investigators note, because one drug addresses pain mechanisms that the other does not.
“Rizatriptan’s primary mechanism is peripheral, and NSAIDs have both peripheral and central benefit,” said study investigator Stewart J. Tepper, MD, professor of neurology, Geisel School of Medicine at Dartmouth, Hanover, N.H. “That is why the whole is greater than the sum of the parts,” Dr. Tepper added.
The findings were presented at the American Headache Society’s 2021 annual meeting.
Acute treatments needed
For many patients, current migraine treatments are inadequate. In addition, suboptimal acute treatment can increase risk for progression from episodic migraine to chronic migraine. It also increases the risk for medication-overuse headache.
The search for optimal acute treatments is therefore “really important for patients,” Dr. Tepper noted.
Because it contains rizatriptan, AXS-07 is believed to inhibit the release of calcitonin gene-related peptide, reverse the vasodilation that it causes, and decrease the transmission of pain signals. Meloxicam, on the other hand, is thought to reduce neuroinflammation and reverse central sensitization, which maintains chronic pain.
In the phase 3, double-blind INTERCEPT trial, the investigators examined AXS-07 for early treatment of migraine. Eligible patients were aged 18 to 65 years, had been diagnosed with migraine in accordance with ICHD-3 criteria, and averaged two to eight migraines per month.
The researchers randomly assigned a single dose of AXS-07 (n = 152) or placebo (n = 150). Participants were asked to administer treatment to themselves at the earliest sign of migraine pain.
The trial’s two primary endpoints were pain freedom and freedom from the MBS 2 hours after dosing. Secondary endpoints included sustained pain freedom and freedom from pain progression, functional disability, and use of rescue medication.
Demographic characteristics of the study population reflected those of the general population of people with migraine, according to the researchers. More than 85% of participants were women, and the study group’s mean age was 41 years. There were no demographic differences between the two treatment groups.
Reduced pain progression
Results showed that 2 hours after treatment, rate of pain freedom was 32.6% in the AXS-07 group and 16.3% in the placebo group (P = .002). At the same time point, rate of freedom from MBS was 43.9% and 26.7%, respectively (P = .003).
Approximately 64% of patients who received AXS-07 were pain free at 12 hours, and 69% were pain free at 24 hours. In contrast, 42% of the placebo group were pain free at 12 hours, and 47% were pain free at 24 hours (P < .001 for both comparisons).
The benefits AXS-07 provided were sustained; 22.7% of the active-treatment group achieved sustained pain freedom from 2 to 24 hours after treatment, compared with 12.6% of the placebo group (P = .03). Results were similar for sustained pain freedom from 2 to 48 hours after treatment (20.5% vs. 9.6%; P = .013).
In addition, 73.5% of patients who received AXS-07 had freedom from pain progression from 2 to 24 hours after treatment, versus 47.4% of those who received placebo (P < .001). The rate of rescue medication use through 24 hours was 15.3% and 42.2%, respectively (P < .001).
AXS-07 was also linked to significant reductions in functional disability. About 74% of patients who received it reported no disability at 24 hours, compared with 47% of patients who received placebo (P < .001). Scores on the Patient Global Impression of Change scale were very much improved or much improved 2 hours after dosing for 52.4% of the AXS-07 group, versus 27.7% of the placebo group (P < .001).
The overall rate of treatment-emergent adverse events (AEs) was 17.9% in the active group and 7.7% among the control group. The rate of somnolence was 4.3%, versus 2.1%; the rate of dizziness was 2.9%, versus 1.4%; and the rate of paresthesia was 2.1%, versus 0%. There were no serious AEs.
“Unexpectedly, and it’s hard to interpret this, but the nausea associated with the use of AXS-07 is less than with either of the active components or the placebo,” said Dr. Tepper. “It’s not dramatically different for dizziness.”
Improved adherence?
Meloxicam is generally used not as an acute medication but for prevention, Dr. Tepper noted. The drug is often administered to reduce inflammation in conditions such as chronic arthritis.
AXS-07 incorporates an altered pharmacokinetic delivery system to provide a quicker onset of effect for meloxicam.
“Most headache specialists would say that of all the oral triptans, rizatriptan is the fastest,” said Dr. Tepper.
The idea for the new agent was to hasten the onset of meloxicam’s effect so that both active components would work rapidly. “We know that there is a synergy between NSAIDs and triptans, in terms of complete headache response,” Dr. Tepper said.
Data indicate that when neurologists recommend that patients take an NSAID and triptan together at the beginning of an attack, patients rarely comply. “It’s a big adherence issue,” said Dr. Tepper. “They’re more likely to get a complete response if they take them together, especially if the tablet is designed to deliver the two products together in an optimal way.”
Uncertain therapeutic advantage
Commenting on the findings, Robert Shapiro, MD, PhD, professor of neurologic science at the University of Vermont, Burlington, noted that because of favorable data from past studies for the combination of 85 mg of sumatriptan with 500 mg of naproxen sodium, the coadministration of a triptan with an NSAID has been a standard of care for the past decade.
“It’s therefore unsurprising that a combination of rizatriptan 10 mg plus meloxicam 20 mg in a proprietary MoSEIC formulation might also prove to be more effective than either individual medication taken alone for acute migraine attacks,” said Dr. Shapiro, who was not involved with the research.
It is not possible to compare the efficacy and tolerability of AXS-07 with those of sumatriptan–naproxen sodium without head-to-head trials. However, the available data suggest that the latter formulation is superior, he added.
In 2008, researchers conducted two parallel-group, placebo-controlled trials of sumatriptan–naproxen sodium taken early in a migraine attack. These trials had protocols comparable to that of the current INTERCEPT trial for AXS-07, said Dr. Shapiro.
For the key primary endpoint of 2-hour pain freedom, the two sumatriptan–naproxen sodium trials found therapeutic gains of 35% and 36%, respectively, versus 16.3% for the AXS-07 trial. The placebo response rates (17% and 15% for sumatriptan–naproxen sodium, vs. 16.3% for the AXS-07 trial) were comparable.
Similarly, for the endpoint of 2- to 24-hour pain freedom, the sumatriptan–naproxen sodium trials found therapeutic gains of 33% and 26%, respectively, versus 15.1% for the AXS-07 trial. Again, response rates for placebo were comparable (12% and 14% for sumatriptan–naproxen sodium, vs. 12.6% for AXS-07).
The placebo-adjusted differences for reporting any treatment-emergent AE, otherwise known as “therapeutic penalty,” was 10.2% for AXS-07 in the INTERCEPT trial, versus 7% and 5%, respectively for participants in the two sumatriptan–naproxen sodium trials.
“In light of these data, it’s not immediately apparent what advantage AXS-07 might offer over sumatriptan–naproxen sodium,” said Dr. Shapiro.
“Furthermore, sumatriptan–naproxen sodium is currently available in generic form,” he added.
The study was funded by Axsome Therapeutics. Dr. Tepper is a consultant to Axsome Therapeutics. Dr. Shapiro has previously performed research consulting for Lilly and Lundbeck.
A version of this article first appeared on Medscape.com.
, new research suggests. Results from the phase 3 INTERCEPT trial show that the treatment, known as AXS-07 (Axsome Therapeutics), also provided greater relief from the patients’ most bothersome symptom (MBS) compared with placebo.
In addition, about 74% of patients who received AXS-07 experienced no progression of pain from 2 to 24 hours after dosing and were less than half as likely to use rescue medication through 24 hours than those who received placebo.
Similar to a previous formulation combining naproxen sodium and sumatriptan, AXS-07 combines a nonsteroidal anti-inflammatory drug with a triptan. The combination is synergistic, investigators note, because one drug addresses pain mechanisms that the other does not.
“Rizatriptan’s primary mechanism is peripheral, and NSAIDs have both peripheral and central benefit,” said study investigator Stewart J. Tepper, MD, professor of neurology, Geisel School of Medicine at Dartmouth, Hanover, N.H. “That is why the whole is greater than the sum of the parts,” Dr. Tepper added.
The findings were presented at the American Headache Society’s 2021 annual meeting.
Acute treatments needed
For many patients, current migraine treatments are inadequate. In addition, suboptimal acute treatment can increase risk for progression from episodic migraine to chronic migraine. It also increases the risk for medication-overuse headache.
The search for optimal acute treatments is therefore “really important for patients,” Dr. Tepper noted.
Because it contains rizatriptan, AXS-07 is believed to inhibit the release of calcitonin gene-related peptide, reverse the vasodilation that it causes, and decrease the transmission of pain signals. Meloxicam, on the other hand, is thought to reduce neuroinflammation and reverse central sensitization, which maintains chronic pain.
In the phase 3, double-blind INTERCEPT trial, the investigators examined AXS-07 for early treatment of migraine. Eligible patients were aged 18 to 65 years, had been diagnosed with migraine in accordance with ICHD-3 criteria, and averaged two to eight migraines per month.
The researchers randomly assigned a single dose of AXS-07 (n = 152) or placebo (n = 150). Participants were asked to administer treatment to themselves at the earliest sign of migraine pain.
The trial’s two primary endpoints were pain freedom and freedom from the MBS 2 hours after dosing. Secondary endpoints included sustained pain freedom and freedom from pain progression, functional disability, and use of rescue medication.
Demographic characteristics of the study population reflected those of the general population of people with migraine, according to the researchers. More than 85% of participants were women, and the study group’s mean age was 41 years. There were no demographic differences between the two treatment groups.
Reduced pain progression
Results showed that 2 hours after treatment, rate of pain freedom was 32.6% in the AXS-07 group and 16.3% in the placebo group (P = .002). At the same time point, rate of freedom from MBS was 43.9% and 26.7%, respectively (P = .003).
Approximately 64% of patients who received AXS-07 were pain free at 12 hours, and 69% were pain free at 24 hours. In contrast, 42% of the placebo group were pain free at 12 hours, and 47% were pain free at 24 hours (P < .001 for both comparisons).
The benefits AXS-07 provided were sustained; 22.7% of the active-treatment group achieved sustained pain freedom from 2 to 24 hours after treatment, compared with 12.6% of the placebo group (P = .03). Results were similar for sustained pain freedom from 2 to 48 hours after treatment (20.5% vs. 9.6%; P = .013).
In addition, 73.5% of patients who received AXS-07 had freedom from pain progression from 2 to 24 hours after treatment, versus 47.4% of those who received placebo (P < .001). The rate of rescue medication use through 24 hours was 15.3% and 42.2%, respectively (P < .001).
AXS-07 was also linked to significant reductions in functional disability. About 74% of patients who received it reported no disability at 24 hours, compared with 47% of patients who received placebo (P < .001). Scores on the Patient Global Impression of Change scale were very much improved or much improved 2 hours after dosing for 52.4% of the AXS-07 group, versus 27.7% of the placebo group (P < .001).
The overall rate of treatment-emergent adverse events (AEs) was 17.9% in the active group and 7.7% among the control group. The rate of somnolence was 4.3%, versus 2.1%; the rate of dizziness was 2.9%, versus 1.4%; and the rate of paresthesia was 2.1%, versus 0%. There were no serious AEs.
“Unexpectedly, and it’s hard to interpret this, but the nausea associated with the use of AXS-07 is less than with either of the active components or the placebo,” said Dr. Tepper. “It’s not dramatically different for dizziness.”
Improved adherence?
Meloxicam is generally used not as an acute medication but for prevention, Dr. Tepper noted. The drug is often administered to reduce inflammation in conditions such as chronic arthritis.
AXS-07 incorporates an altered pharmacokinetic delivery system to provide a quicker onset of effect for meloxicam.
“Most headache specialists would say that of all the oral triptans, rizatriptan is the fastest,” said Dr. Tepper.
The idea for the new agent was to hasten the onset of meloxicam’s effect so that both active components would work rapidly. “We know that there is a synergy between NSAIDs and triptans, in terms of complete headache response,” Dr. Tepper said.
Data indicate that when neurologists recommend that patients take an NSAID and triptan together at the beginning of an attack, patients rarely comply. “It’s a big adherence issue,” said Dr. Tepper. “They’re more likely to get a complete response if they take them together, especially if the tablet is designed to deliver the two products together in an optimal way.”
Uncertain therapeutic advantage
Commenting on the findings, Robert Shapiro, MD, PhD, professor of neurologic science at the University of Vermont, Burlington, noted that because of favorable data from past studies for the combination of 85 mg of sumatriptan with 500 mg of naproxen sodium, the coadministration of a triptan with an NSAID has been a standard of care for the past decade.
“It’s therefore unsurprising that a combination of rizatriptan 10 mg plus meloxicam 20 mg in a proprietary MoSEIC formulation might also prove to be more effective than either individual medication taken alone for acute migraine attacks,” said Dr. Shapiro, who was not involved with the research.
It is not possible to compare the efficacy and tolerability of AXS-07 with those of sumatriptan–naproxen sodium without head-to-head trials. However, the available data suggest that the latter formulation is superior, he added.
In 2008, researchers conducted two parallel-group, placebo-controlled trials of sumatriptan–naproxen sodium taken early in a migraine attack. These trials had protocols comparable to that of the current INTERCEPT trial for AXS-07, said Dr. Shapiro.
For the key primary endpoint of 2-hour pain freedom, the two sumatriptan–naproxen sodium trials found therapeutic gains of 35% and 36%, respectively, versus 16.3% for the AXS-07 trial. The placebo response rates (17% and 15% for sumatriptan–naproxen sodium, vs. 16.3% for the AXS-07 trial) were comparable.
Similarly, for the endpoint of 2- to 24-hour pain freedom, the sumatriptan–naproxen sodium trials found therapeutic gains of 33% and 26%, respectively, versus 15.1% for the AXS-07 trial. Again, response rates for placebo were comparable (12% and 14% for sumatriptan–naproxen sodium, vs. 12.6% for AXS-07).
The placebo-adjusted differences for reporting any treatment-emergent AE, otherwise known as “therapeutic penalty,” was 10.2% for AXS-07 in the INTERCEPT trial, versus 7% and 5%, respectively for participants in the two sumatriptan–naproxen sodium trials.
“In light of these data, it’s not immediately apparent what advantage AXS-07 might offer over sumatriptan–naproxen sodium,” said Dr. Shapiro.
“Furthermore, sumatriptan–naproxen sodium is currently available in generic form,” he added.
The study was funded by Axsome Therapeutics. Dr. Tepper is a consultant to Axsome Therapeutics. Dr. Shapiro has previously performed research consulting for Lilly and Lundbeck.
A version of this article first appeared on Medscape.com.
, new research suggests. Results from the phase 3 INTERCEPT trial show that the treatment, known as AXS-07 (Axsome Therapeutics), also provided greater relief from the patients’ most bothersome symptom (MBS) compared with placebo.
In addition, about 74% of patients who received AXS-07 experienced no progression of pain from 2 to 24 hours after dosing and were less than half as likely to use rescue medication through 24 hours than those who received placebo.
Similar to a previous formulation combining naproxen sodium and sumatriptan, AXS-07 combines a nonsteroidal anti-inflammatory drug with a triptan. The combination is synergistic, investigators note, because one drug addresses pain mechanisms that the other does not.
“Rizatriptan’s primary mechanism is peripheral, and NSAIDs have both peripheral and central benefit,” said study investigator Stewart J. Tepper, MD, professor of neurology, Geisel School of Medicine at Dartmouth, Hanover, N.H. “That is why the whole is greater than the sum of the parts,” Dr. Tepper added.
The findings were presented at the American Headache Society’s 2021 annual meeting.
Acute treatments needed
For many patients, current migraine treatments are inadequate. In addition, suboptimal acute treatment can increase risk for progression from episodic migraine to chronic migraine. It also increases the risk for medication-overuse headache.
The search for optimal acute treatments is therefore “really important for patients,” Dr. Tepper noted.
Because it contains rizatriptan, AXS-07 is believed to inhibit the release of calcitonin gene-related peptide, reverse the vasodilation that it causes, and decrease the transmission of pain signals. Meloxicam, on the other hand, is thought to reduce neuroinflammation and reverse central sensitization, which maintains chronic pain.
In the phase 3, double-blind INTERCEPT trial, the investigators examined AXS-07 for early treatment of migraine. Eligible patients were aged 18 to 65 years, had been diagnosed with migraine in accordance with ICHD-3 criteria, and averaged two to eight migraines per month.
The researchers randomly assigned a single dose of AXS-07 (n = 152) or placebo (n = 150). Participants were asked to administer treatment to themselves at the earliest sign of migraine pain.
The trial’s two primary endpoints were pain freedom and freedom from the MBS 2 hours after dosing. Secondary endpoints included sustained pain freedom and freedom from pain progression, functional disability, and use of rescue medication.
Demographic characteristics of the study population reflected those of the general population of people with migraine, according to the researchers. More than 85% of participants were women, and the study group’s mean age was 41 years. There were no demographic differences between the two treatment groups.
Reduced pain progression
Results showed that 2 hours after treatment, rate of pain freedom was 32.6% in the AXS-07 group and 16.3% in the placebo group (P = .002). At the same time point, rate of freedom from MBS was 43.9% and 26.7%, respectively (P = .003).
Approximately 64% of patients who received AXS-07 were pain free at 12 hours, and 69% were pain free at 24 hours. In contrast, 42% of the placebo group were pain free at 12 hours, and 47% were pain free at 24 hours (P < .001 for both comparisons).
The benefits AXS-07 provided were sustained; 22.7% of the active-treatment group achieved sustained pain freedom from 2 to 24 hours after treatment, compared with 12.6% of the placebo group (P = .03). Results were similar for sustained pain freedom from 2 to 48 hours after treatment (20.5% vs. 9.6%; P = .013).
In addition, 73.5% of patients who received AXS-07 had freedom from pain progression from 2 to 24 hours after treatment, versus 47.4% of those who received placebo (P < .001). The rate of rescue medication use through 24 hours was 15.3% and 42.2%, respectively (P < .001).
AXS-07 was also linked to significant reductions in functional disability. About 74% of patients who received it reported no disability at 24 hours, compared with 47% of patients who received placebo (P < .001). Scores on the Patient Global Impression of Change scale were very much improved or much improved 2 hours after dosing for 52.4% of the AXS-07 group, versus 27.7% of the placebo group (P < .001).
The overall rate of treatment-emergent adverse events (AEs) was 17.9% in the active group and 7.7% among the control group. The rate of somnolence was 4.3%, versus 2.1%; the rate of dizziness was 2.9%, versus 1.4%; and the rate of paresthesia was 2.1%, versus 0%. There were no serious AEs.
“Unexpectedly, and it’s hard to interpret this, but the nausea associated with the use of AXS-07 is less than with either of the active components or the placebo,” said Dr. Tepper. “It’s not dramatically different for dizziness.”
Improved adherence?
Meloxicam is generally used not as an acute medication but for prevention, Dr. Tepper noted. The drug is often administered to reduce inflammation in conditions such as chronic arthritis.
AXS-07 incorporates an altered pharmacokinetic delivery system to provide a quicker onset of effect for meloxicam.
“Most headache specialists would say that of all the oral triptans, rizatriptan is the fastest,” said Dr. Tepper.
The idea for the new agent was to hasten the onset of meloxicam’s effect so that both active components would work rapidly. “We know that there is a synergy between NSAIDs and triptans, in terms of complete headache response,” Dr. Tepper said.
Data indicate that when neurologists recommend that patients take an NSAID and triptan together at the beginning of an attack, patients rarely comply. “It’s a big adherence issue,” said Dr. Tepper. “They’re more likely to get a complete response if they take them together, especially if the tablet is designed to deliver the two products together in an optimal way.”
Uncertain therapeutic advantage
Commenting on the findings, Robert Shapiro, MD, PhD, professor of neurologic science at the University of Vermont, Burlington, noted that because of favorable data from past studies for the combination of 85 mg of sumatriptan with 500 mg of naproxen sodium, the coadministration of a triptan with an NSAID has been a standard of care for the past decade.
“It’s therefore unsurprising that a combination of rizatriptan 10 mg plus meloxicam 20 mg in a proprietary MoSEIC formulation might also prove to be more effective than either individual medication taken alone for acute migraine attacks,” said Dr. Shapiro, who was not involved with the research.
It is not possible to compare the efficacy and tolerability of AXS-07 with those of sumatriptan–naproxen sodium without head-to-head trials. However, the available data suggest that the latter formulation is superior, he added.
In 2008, researchers conducted two parallel-group, placebo-controlled trials of sumatriptan–naproxen sodium taken early in a migraine attack. These trials had protocols comparable to that of the current INTERCEPT trial for AXS-07, said Dr. Shapiro.
For the key primary endpoint of 2-hour pain freedom, the two sumatriptan–naproxen sodium trials found therapeutic gains of 35% and 36%, respectively, versus 16.3% for the AXS-07 trial. The placebo response rates (17% and 15% for sumatriptan–naproxen sodium, vs. 16.3% for the AXS-07 trial) were comparable.
Similarly, for the endpoint of 2- to 24-hour pain freedom, the sumatriptan–naproxen sodium trials found therapeutic gains of 33% and 26%, respectively, versus 15.1% for the AXS-07 trial. Again, response rates for placebo were comparable (12% and 14% for sumatriptan–naproxen sodium, vs. 12.6% for AXS-07).
The placebo-adjusted differences for reporting any treatment-emergent AE, otherwise known as “therapeutic penalty,” was 10.2% for AXS-07 in the INTERCEPT trial, versus 7% and 5%, respectively for participants in the two sumatriptan–naproxen sodium trials.
“In light of these data, it’s not immediately apparent what advantage AXS-07 might offer over sumatriptan–naproxen sodium,” said Dr. Shapiro.
“Furthermore, sumatriptan–naproxen sodium is currently available in generic form,” he added.
The study was funded by Axsome Therapeutics. Dr. Tepper is a consultant to Axsome Therapeutics. Dr. Shapiro has previously performed research consulting for Lilly and Lundbeck.
A version of this article first appeared on Medscape.com.
From AHS 2021
Diaphragmatic endometriosis diagnosed many years after symptom onset
Diaphragmatic endometriosis is often diagnosed several years after the start of symptoms – mainly moderate to severe pain – and this is potentially because of general lack of awareness of diaphragmatic endometriosis among the general population and medical professionals.
Findings of the international survey that explored the diagnosis and treatment of diaphragmatic endometriosis were presented at this year’s Royal College of Obstetricians and Gynecologists 2021 Virtual World Congress by medical student Rachel Piccus, MSc, based at the University of Birmingham (England). Robert Sutcliffe, MD, consultant in hepatobiliary and pancreatic surgery, at Queen Elizabeth Hospital Birmingham was senior author. Results were also published in the May 2021 issue of the European Journal of Obstetrics and Gynaecology and Reproductive Biology.
The study found that it took an average of five visits to a primary physician before referral to a gynecologist.
“Late diagnosis could also be due to the idea that diaphragmatic endometriosis symptoms often present before pelvic symptoms and therefore the site of pain is considered atypical for pelvic endometriosis,” Ms. Piccus said, adding that “clinicians are screening for cyclical pain, which is typical of endometriosis, but our study has shown that pain can in fact be more frequent – daily and weekly.”
These significant diagnostic delays, seen from the time of the initial primary care and gynecology consultation has the potential to significantly affect quality of life as seen in pelvic endometriosis, said Ms. Piccus. “These delays are partly due to a lack of awareness among gynecologists, but could also be due to pelvic laparoscopy being insufficient to examine the diaphragm behind the liver.”
Justin Clark, MD, consultant gynaecologist, Birmingham (England) Women’s and Children Hospital, moderated the session and agreed that the study highlights the need for greater awareness of this variant of endometriosis. “Whilst endometriosis affecting the diaphragm, subdiaphragm, and thorax is rare, the condition causes substantial morbidity.”
“Greater knowledge of thoracic endometriosis amongst clinicians in both primary and secondary care is needed to ensure accurate and timely diagnosis,” he added.
Diaphragmatic endometriosis is estimated to affect 1%-1.5% of all endometriosis patients and presents as cyclical pain in the chest, abdomen, and shoulder tip, as well as other respiratory symptoms such as catamenial pneumothorax and difficulty breathing.
“Cross-sectional imaging has shown low sensitivity so upper abdominal laparoscopy is the gold standard; however, this has implications for diagnostic delay because a strong clinical suspicion is required to refer for this invasive procedure,” explained Ms. Piccus referring to one of the reasons underpinning the need for the study.
When successfully diagnosed, treatment requires excision or ablation surgery and studies show symptomatic relief in 75%-100% of cases.
To gauge the extent of delayed diagnosis as well as treatment outcomes from a patient perspective, Ms. Piccus circulated an anonymous online survey among women with a previous history of surgery for diaphragmatic endometriosis.
Diaphragmatic endometriosis pain – daily and weekly as well as cyclical
A total of 137 participants responded to the survey, with a median age of 34 years (range, 19-53). Median age of diaphragmatic endometriosis onset was 27 years (range, 11-50), and importantly, diaphragmatic endometriosis symptoms started before pelvic symptoms in 90 respondents (66%).
The dominant symptom was pain. A total of 38% reported cyclical pain (related to endometrial shedding during menstruation), 15% weekly pain, and 47% daily pain, both of which were worse during the menstrual cycle. Furthermore, 14% reported other symptoms including catamenial pneumothorax, difficulty breathing, and hemoptysis.
“Whilst this cyclical pain is typical of endometriosis, we see that diagnostic delays may be due to misdiagnosis because clinicians are screening for this cyclical pain whilst our study has shown that pain can in fact be more frequent, being daily and weekly,” noted Ms. Piccus. Moderate to severe pain was reported in 67% of respondents and moderate in 31%, only 2% reported pain as mild.
Location of pain comprised moderate to severe pain in the upper abdomen (68%), chest (64%) and shoulder (54%). Pain was right-sided in 54%, left-sided in 11% and bilateral in 35%. Upper back and neck were also reported as sites of pain.
Indirectly providing a measure of the lack of awareness of diaphragmatic endometriosis on behalf of primary care, 122 participants reported initially visiting their primary care physician for help and 65 were given a diagnosis – in only 14 cases was that diaphragmatic endometriosis. There were a range of other gynecologic (e.g. ovarian cyst, two), respiratory (spontaneous pneumothorax, seven), gastrointestinal (gastritis/reflux, eight), musculoskeletal (six), and psychological (anxiety/stress, four) diagnoses.
A median of 5 primary care consultations (range, 1-100) were required before referral to a gynecologist, with 30% seeing a primary care physician over 10 times. A further 14 patients self-referred to gynecologist.
“These findings have implications for diagnostic delay, added Ms. Piccus. “While the majority of respondents were diagnosed less than a year from the first GP visit, the median delay was 2 years, with 31% diagnosed after 5 or more years. One took 23 years for an initial diagnosis.”
Most cases were diagnosed at the time of surgery – 93%, with 52% at pelvic laparoscopy, 35% upper abdominal laparoscopy, with 30% requiring two or more laparoscopies before they were diagnosed with diaphragmatic endometriosis. A total of 7% were diagnosed via cross-sectional imaging prior to surgery.
Treatment outcomes for diaphragmatic endometriosis
Reflecting the literature, surgery to remove the endometriosis lesions was mainly laparoscopic with 47% abdominal excisions, and 29% abdominal ablations; 6% received open abdominal procedures, and 18% received open thoracotomy or video-assisted thoracoscopic surgery.
The survey asked about postoperative symptoms 6 months after surgery and at the time of survey. Symptoms at 6 months post surgery had completely resolved in 18%, shown significant improvement in 48%, and no improvement in 20%. Worsening of symptoms was seen in 14%. Long-term pain was reported by 21% as severe, 27% as moderate, 35% as mild, and 17% had no symptoms.
Further findings included that 23% underwent additional procedures to treat their diaphragmatic endometriosis, and that there was no significant difference between excision and ablation, nor between age of onset of symptoms or length of diagnostic delay.
“Surgical treatment to remove these extra pelvic deposits of endometriosis will depend upon the type and distribution of thoracic endometriosis and a variety of surgical specialties may need to be involved including gynecologists, cardiothoracic, and upper gastrointestinal/liver surgeons,” Dr. Clark said.
He added that familiar hormonal medical treatments for more typical pelvic endometriosis should also be considered for primary and maintenance treatment. “These data suggest a high symptomatic recurrence rate after surgical treatment and so medical treatments should be considered to try and minimize the risks of endometriosis symptoms returning.”
Dr. Clark also pointed out that multidisciplinary clinical teams should be established in specialized centers to plan surgical and medical management to enhance clinical outcomes and collect data to better understand this enigmatic condition.
Ms. Piccus and Dr. Clark have no relevant conflicts of interest.
Diaphragmatic endometriosis is often diagnosed several years after the start of symptoms – mainly moderate to severe pain – and this is potentially because of general lack of awareness of diaphragmatic endometriosis among the general population and medical professionals.
Findings of the international survey that explored the diagnosis and treatment of diaphragmatic endometriosis were presented at this year’s Royal College of Obstetricians and Gynecologists 2021 Virtual World Congress by medical student Rachel Piccus, MSc, based at the University of Birmingham (England). Robert Sutcliffe, MD, consultant in hepatobiliary and pancreatic surgery, at Queen Elizabeth Hospital Birmingham was senior author. Results were also published in the May 2021 issue of the European Journal of Obstetrics and Gynaecology and Reproductive Biology.
The study found that it took an average of five visits to a primary physician before referral to a gynecologist.
“Late diagnosis could also be due to the idea that diaphragmatic endometriosis symptoms often present before pelvic symptoms and therefore the site of pain is considered atypical for pelvic endometriosis,” Ms. Piccus said, adding that “clinicians are screening for cyclical pain, which is typical of endometriosis, but our study has shown that pain can in fact be more frequent – daily and weekly.”
These significant diagnostic delays, seen from the time of the initial primary care and gynecology consultation has the potential to significantly affect quality of life as seen in pelvic endometriosis, said Ms. Piccus. “These delays are partly due to a lack of awareness among gynecologists, but could also be due to pelvic laparoscopy being insufficient to examine the diaphragm behind the liver.”
Justin Clark, MD, consultant gynaecologist, Birmingham (England) Women’s and Children Hospital, moderated the session and agreed that the study highlights the need for greater awareness of this variant of endometriosis. “Whilst endometriosis affecting the diaphragm, subdiaphragm, and thorax is rare, the condition causes substantial morbidity.”
“Greater knowledge of thoracic endometriosis amongst clinicians in both primary and secondary care is needed to ensure accurate and timely diagnosis,” he added.
Diaphragmatic endometriosis is estimated to affect 1%-1.5% of all endometriosis patients and presents as cyclical pain in the chest, abdomen, and shoulder tip, as well as other respiratory symptoms such as catamenial pneumothorax and difficulty breathing.
“Cross-sectional imaging has shown low sensitivity so upper abdominal laparoscopy is the gold standard; however, this has implications for diagnostic delay because a strong clinical suspicion is required to refer for this invasive procedure,” explained Ms. Piccus referring to one of the reasons underpinning the need for the study.
When successfully diagnosed, treatment requires excision or ablation surgery and studies show symptomatic relief in 75%-100% of cases.
To gauge the extent of delayed diagnosis as well as treatment outcomes from a patient perspective, Ms. Piccus circulated an anonymous online survey among women with a previous history of surgery for diaphragmatic endometriosis.
Diaphragmatic endometriosis pain – daily and weekly as well as cyclical
A total of 137 participants responded to the survey, with a median age of 34 years (range, 19-53). Median age of diaphragmatic endometriosis onset was 27 years (range, 11-50), and importantly, diaphragmatic endometriosis symptoms started before pelvic symptoms in 90 respondents (66%).
The dominant symptom was pain. A total of 38% reported cyclical pain (related to endometrial shedding during menstruation), 15% weekly pain, and 47% daily pain, both of which were worse during the menstrual cycle. Furthermore, 14% reported other symptoms including catamenial pneumothorax, difficulty breathing, and hemoptysis.
“Whilst this cyclical pain is typical of endometriosis, we see that diagnostic delays may be due to misdiagnosis because clinicians are screening for this cyclical pain whilst our study has shown that pain can in fact be more frequent, being daily and weekly,” noted Ms. Piccus. Moderate to severe pain was reported in 67% of respondents and moderate in 31%, only 2% reported pain as mild.
Location of pain comprised moderate to severe pain in the upper abdomen (68%), chest (64%) and shoulder (54%). Pain was right-sided in 54%, left-sided in 11% and bilateral in 35%. Upper back and neck were also reported as sites of pain.
Indirectly providing a measure of the lack of awareness of diaphragmatic endometriosis on behalf of primary care, 122 participants reported initially visiting their primary care physician for help and 65 were given a diagnosis – in only 14 cases was that diaphragmatic endometriosis. There were a range of other gynecologic (e.g. ovarian cyst, two), respiratory (spontaneous pneumothorax, seven), gastrointestinal (gastritis/reflux, eight), musculoskeletal (six), and psychological (anxiety/stress, four) diagnoses.
A median of 5 primary care consultations (range, 1-100) were required before referral to a gynecologist, with 30% seeing a primary care physician over 10 times. A further 14 patients self-referred to gynecologist.
“These findings have implications for diagnostic delay, added Ms. Piccus. “While the majority of respondents were diagnosed less than a year from the first GP visit, the median delay was 2 years, with 31% diagnosed after 5 or more years. One took 23 years for an initial diagnosis.”
Most cases were diagnosed at the time of surgery – 93%, with 52% at pelvic laparoscopy, 35% upper abdominal laparoscopy, with 30% requiring two or more laparoscopies before they were diagnosed with diaphragmatic endometriosis. A total of 7% were diagnosed via cross-sectional imaging prior to surgery.
Treatment outcomes for diaphragmatic endometriosis
Reflecting the literature, surgery to remove the endometriosis lesions was mainly laparoscopic with 47% abdominal excisions, and 29% abdominal ablations; 6% received open abdominal procedures, and 18% received open thoracotomy or video-assisted thoracoscopic surgery.
The survey asked about postoperative symptoms 6 months after surgery and at the time of survey. Symptoms at 6 months post surgery had completely resolved in 18%, shown significant improvement in 48%, and no improvement in 20%. Worsening of symptoms was seen in 14%. Long-term pain was reported by 21% as severe, 27% as moderate, 35% as mild, and 17% had no symptoms.
Further findings included that 23% underwent additional procedures to treat their diaphragmatic endometriosis, and that there was no significant difference between excision and ablation, nor between age of onset of symptoms or length of diagnostic delay.
“Surgical treatment to remove these extra pelvic deposits of endometriosis will depend upon the type and distribution of thoracic endometriosis and a variety of surgical specialties may need to be involved including gynecologists, cardiothoracic, and upper gastrointestinal/liver surgeons,” Dr. Clark said.
He added that familiar hormonal medical treatments for more typical pelvic endometriosis should also be considered for primary and maintenance treatment. “These data suggest a high symptomatic recurrence rate after surgical treatment and so medical treatments should be considered to try and minimize the risks of endometriosis symptoms returning.”
Dr. Clark also pointed out that multidisciplinary clinical teams should be established in specialized centers to plan surgical and medical management to enhance clinical outcomes and collect data to better understand this enigmatic condition.
Ms. Piccus and Dr. Clark have no relevant conflicts of interest.
Diaphragmatic endometriosis is often diagnosed several years after the start of symptoms – mainly moderate to severe pain – and this is potentially because of general lack of awareness of diaphragmatic endometriosis among the general population and medical professionals.
Findings of the international survey that explored the diagnosis and treatment of diaphragmatic endometriosis were presented at this year’s Royal College of Obstetricians and Gynecologists 2021 Virtual World Congress by medical student Rachel Piccus, MSc, based at the University of Birmingham (England). Robert Sutcliffe, MD, consultant in hepatobiliary and pancreatic surgery, at Queen Elizabeth Hospital Birmingham was senior author. Results were also published in the May 2021 issue of the European Journal of Obstetrics and Gynaecology and Reproductive Biology.
The study found that it took an average of five visits to a primary physician before referral to a gynecologist.
“Late diagnosis could also be due to the idea that diaphragmatic endometriosis symptoms often present before pelvic symptoms and therefore the site of pain is considered atypical for pelvic endometriosis,” Ms. Piccus said, adding that “clinicians are screening for cyclical pain, which is typical of endometriosis, but our study has shown that pain can in fact be more frequent – daily and weekly.”
These significant diagnostic delays, seen from the time of the initial primary care and gynecology consultation has the potential to significantly affect quality of life as seen in pelvic endometriosis, said Ms. Piccus. “These delays are partly due to a lack of awareness among gynecologists, but could also be due to pelvic laparoscopy being insufficient to examine the diaphragm behind the liver.”
Justin Clark, MD, consultant gynaecologist, Birmingham (England) Women’s and Children Hospital, moderated the session and agreed that the study highlights the need for greater awareness of this variant of endometriosis. “Whilst endometriosis affecting the diaphragm, subdiaphragm, and thorax is rare, the condition causes substantial morbidity.”
“Greater knowledge of thoracic endometriosis amongst clinicians in both primary and secondary care is needed to ensure accurate and timely diagnosis,” he added.
Diaphragmatic endometriosis is estimated to affect 1%-1.5% of all endometriosis patients and presents as cyclical pain in the chest, abdomen, and shoulder tip, as well as other respiratory symptoms such as catamenial pneumothorax and difficulty breathing.
“Cross-sectional imaging has shown low sensitivity so upper abdominal laparoscopy is the gold standard; however, this has implications for diagnostic delay because a strong clinical suspicion is required to refer for this invasive procedure,” explained Ms. Piccus referring to one of the reasons underpinning the need for the study.
When successfully diagnosed, treatment requires excision or ablation surgery and studies show symptomatic relief in 75%-100% of cases.
To gauge the extent of delayed diagnosis as well as treatment outcomes from a patient perspective, Ms. Piccus circulated an anonymous online survey among women with a previous history of surgery for diaphragmatic endometriosis.
Diaphragmatic endometriosis pain – daily and weekly as well as cyclical
A total of 137 participants responded to the survey, with a median age of 34 years (range, 19-53). Median age of diaphragmatic endometriosis onset was 27 years (range, 11-50), and importantly, diaphragmatic endometriosis symptoms started before pelvic symptoms in 90 respondents (66%).
The dominant symptom was pain. A total of 38% reported cyclical pain (related to endometrial shedding during menstruation), 15% weekly pain, and 47% daily pain, both of which were worse during the menstrual cycle. Furthermore, 14% reported other symptoms including catamenial pneumothorax, difficulty breathing, and hemoptysis.
“Whilst this cyclical pain is typical of endometriosis, we see that diagnostic delays may be due to misdiagnosis because clinicians are screening for this cyclical pain whilst our study has shown that pain can in fact be more frequent, being daily and weekly,” noted Ms. Piccus. Moderate to severe pain was reported in 67% of respondents and moderate in 31%, only 2% reported pain as mild.
Location of pain comprised moderate to severe pain in the upper abdomen (68%), chest (64%) and shoulder (54%). Pain was right-sided in 54%, left-sided in 11% and bilateral in 35%. Upper back and neck were also reported as sites of pain.
Indirectly providing a measure of the lack of awareness of diaphragmatic endometriosis on behalf of primary care, 122 participants reported initially visiting their primary care physician for help and 65 were given a diagnosis – in only 14 cases was that diaphragmatic endometriosis. There were a range of other gynecologic (e.g. ovarian cyst, two), respiratory (spontaneous pneumothorax, seven), gastrointestinal (gastritis/reflux, eight), musculoskeletal (six), and psychological (anxiety/stress, four) diagnoses.
A median of 5 primary care consultations (range, 1-100) were required before referral to a gynecologist, with 30% seeing a primary care physician over 10 times. A further 14 patients self-referred to gynecologist.
“These findings have implications for diagnostic delay, added Ms. Piccus. “While the majority of respondents were diagnosed less than a year from the first GP visit, the median delay was 2 years, with 31% diagnosed after 5 or more years. One took 23 years for an initial diagnosis.”
Most cases were diagnosed at the time of surgery – 93%, with 52% at pelvic laparoscopy, 35% upper abdominal laparoscopy, with 30% requiring two or more laparoscopies before they were diagnosed with diaphragmatic endometriosis. A total of 7% were diagnosed via cross-sectional imaging prior to surgery.
Treatment outcomes for diaphragmatic endometriosis
Reflecting the literature, surgery to remove the endometriosis lesions was mainly laparoscopic with 47% abdominal excisions, and 29% abdominal ablations; 6% received open abdominal procedures, and 18% received open thoracotomy or video-assisted thoracoscopic surgery.
The survey asked about postoperative symptoms 6 months after surgery and at the time of survey. Symptoms at 6 months post surgery had completely resolved in 18%, shown significant improvement in 48%, and no improvement in 20%. Worsening of symptoms was seen in 14%. Long-term pain was reported by 21% as severe, 27% as moderate, 35% as mild, and 17% had no symptoms.
Further findings included that 23% underwent additional procedures to treat their diaphragmatic endometriosis, and that there was no significant difference between excision and ablation, nor between age of onset of symptoms or length of diagnostic delay.
“Surgical treatment to remove these extra pelvic deposits of endometriosis will depend upon the type and distribution of thoracic endometriosis and a variety of surgical specialties may need to be involved including gynecologists, cardiothoracic, and upper gastrointestinal/liver surgeons,” Dr. Clark said.
He added that familiar hormonal medical treatments for more typical pelvic endometriosis should also be considered for primary and maintenance treatment. “These data suggest a high symptomatic recurrence rate after surgical treatment and so medical treatments should be considered to try and minimize the risks of endometriosis symptoms returning.”
Dr. Clark also pointed out that multidisciplinary clinical teams should be established in specialized centers to plan surgical and medical management to enhance clinical outcomes and collect data to better understand this enigmatic condition.
Ms. Piccus and Dr. Clark have no relevant conflicts of interest.
Foot rash and joint pain
A 21-year-old man presented to the emergency department (ED) with a 2-month history of joint pain, swelling, and difficulty walking that began with swelling of his right knee (FIGURE 1A). The patient said that over the course of several weeks, the swelling and joint pain spread to his left knee, followed by bilateral elbows and ankles. Nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin produced only modest improvement.
Two weeks prior to presentation, the patient also experienced widespread pruritus and conjunctivitis. His past medical history was significant for a sexual encounter that resulted in urinary tract infection (UTI)–like symptoms approximately 1 month prior to the onset of his joint symptoms. He did not seek care for the UTI-like symptoms.
In the ED, the patient was febrile (102.1 °F) and tachycardic. Skin examination revealed erythematous papules, intact vesicles, and pustules with background hyperkeratosis and desquamation on his right foot (FIGURE 1B). The patient had spotty erythema on his palate and a 4-mm superficial erosion on the right penile shaft. Swelling and tenderness were noted over the elbows, knees, hands, and ankles. No inguinal lymphadenopathy was noted.
An arthrocentesis was performed on the right knee that demonstrated no organisms on Gram stain and a normal joint fluid cell count. A complete blood count (CBC), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and urinalysis were ordered. A punch biopsy was performed on a scaly patch on the right elbow.
WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?
Dx: Keratoderma blenorrhagicum
The patient’s history, clinical findings, and lab results, including a positive Chlamydia trachomatis polymerase chain reaction (PCR) test from a urethral swab, pointed to a diagnosis of keratoderma blenorrhagicum in association with reactive arthritis (following infection with C trachomatis).
Relevant diagnostic findings included an elevated CRP of 26.5 mg/L (normal range, < 10 mg/L), an elevated ESR of 116 mm/h (normal range, < 15 mm/h) and as noted, a positive C trachomatis PCR test. The patient’s white blood cell count was 9.7/μL (normal range, 4.5-11 μL) and the rest of the CBC was within normal limits. Urinalysis was positive for leukocytes and rare bacteria. A treponemal antibody test was negative.
Additionally, the punch biopsy from the right elbow revealed acanthosis, intercellular spongiosis, and subcorneal pustules consistent with localized pustular psoriasis or keratoderma blenorrhagicum. After the diagnosis was made, human leukocyte antigen B27 allele (HLA-B27) testing was conducted and was positive.
A predisposition exacerbates the infection
Reactive arthritis, a type of spondyloarthropathy, features a triad of conjunctivitis, urethritis, and arthritis that follows either gastrointestinal or urogenital infection.1 Reactive arthritis occurs with a male predominance of 3:1, and the worldwide prevalence is 1 in 3000.1 Causative bacteria include C trachomatis, Yersinia, Salmonella, Shigella, and Campylobacter, Escherichia coli, Clostridioides (formerly Clostridium) difficile, and C pneumoniae.2 Patients with the HLA-B27 allele are 50 times more likely to develop reactive arthritis following infection with the aforementioned bacteria.1
Findings consistent with a diagnosis of reactive arthritis include a recent history of gastrointestinal or urogenital illness, joint pain, conjunctivitis, oral lesions, cutaneous changes, and genital lesions.3 Diagnostic tests should include arthrocentesis with cultures or PCR and cell count, ESR, CRP, CBC, and urinalysis. HLA-B27 can be used to support the diagnosis but is not routinely recommended.2
Pustules and psoriasiform scaling characterize this diagnosis
The differential diagnosis for the signs and symptoms seen in this patient include disseminated gonococcal arthritis, psoriatic arthritis, rheumatoid arthritis, and secondary syphilis.
Gonococcal arthritis manifests with painful, sterile joints as well as pustules on the palms and soles, but not with the psoriasiform scaling and desquamation that was seen in this case. A culture or PCR from urethral discharge or pustules on the palms and soles could be used to confirm this diagnosis.3
Continue to: Psoriasis in association with psoriatic arthritis
Psoriasis in association with psoriatic arthritis and the psoriasiform rashing of reactive arthritis (keratoderma blenorrhagicum) show similar histopathology; however, patients with psoriatic arthritis generally exhibit fewer constitutional symptoms.4
Rheumatoid arthritis also manifests with joint pain and swelling, especially in the hands, wrists, and knees. This diagnosis was unlikely in this patient, where small joints were largely uninvolved.4
Secondary syphilis also manifests with papular, scaly, erythematous lesions on the palms and soles along with pityriasis rosea–like rashing on the trunk. However, it rarely produces pustules or hyperkeratotic keratoderma.5 As noted earlier, a treponemal antibody test in this patient was negative.
Drug therapy is the best option
First-line therapy for reactive arthritis consists of NSAIDs. If the patient exhibits an inadequate response after a 2-week trial, intra-articular or systemic glucocorticoids may be considered.3 If the patient fails to respond to the steroids, disease-modifying antirheumatic drugs (DMARDs) may be considered. Reactive arthritis is considered chronic if the disease lasts longer than 6 months, at which point, DMARDs or tumor necrosis factor-α inhibitors may be utilized.3 For cutaneous manifestations, such as keratoderma blenorrhagicum, topical glucocorticoids twice daily may be used along with keratolytic agents.
Our patient received 2 doses of azithromycin (500 mg IV) and 1 dose of ceftriaxone (2 g IV) to treat his infection while in the ED. Over the course of his hospital stay, he received ceftriaxone (1 g IV daily) for 6 days and naproxen (500 mg tid po) which was tapered. Additionally, he received a week of methylprednisolone (60 mg IM daily) before tapering to oral prednisone. His taper consisted of 40 mg po for 1 week and was decreased by 10 mg each week. Augmented betamethasone dipropionate 0.05% cream and urea 20% cream were prescribed for twice-daily application for the hyperkeratotic scale on both of his feet.
1. Hayes KM, Hayes RJP, Turk MA, et al. Evolving patterns of reactive arthritis. Clin Rheumatol. 2019;38:2083-2088. doi: 10.1007/s10067-019-04522-4
2. Duba AS, Mathew SD. The seronegative spondyloarthropathies. Prim Care. 2018;45:271-287. doi: 10.1016/j.pop.2018.02.005
3. Yu DT, van Tubergen A. Reactive arthritis. In: Joachim S, Romain PL, eds. UpToDate. Updated April 28, 2021. Accessed June 3, 2021. https://www.uptodate.com/contents/reactive-arthritis?search=reactive%20arthritis&topicRef=5571&source=see_link#H9
4. Barth WF, Segal K. Reactive arthritis (Reiter’s Syndrome). Am Fam Physician. 1999;60:499-503, 507.
5. Coleman E, Fiahlo A, Brateanu A. Secondary syphilis. Cleve Clin J Med. 2017;84:510-511. doi: 10.3949/ccjm.84a.16089
A 21-year-old man presented to the emergency department (ED) with a 2-month history of joint pain, swelling, and difficulty walking that began with swelling of his right knee (FIGURE 1A). The patient said that over the course of several weeks, the swelling and joint pain spread to his left knee, followed by bilateral elbows and ankles. Nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin produced only modest improvement.
Two weeks prior to presentation, the patient also experienced widespread pruritus and conjunctivitis. His past medical history was significant for a sexual encounter that resulted in urinary tract infection (UTI)–like symptoms approximately 1 month prior to the onset of his joint symptoms. He did not seek care for the UTI-like symptoms.
In the ED, the patient was febrile (102.1 °F) and tachycardic. Skin examination revealed erythematous papules, intact vesicles, and pustules with background hyperkeratosis and desquamation on his right foot (FIGURE 1B). The patient had spotty erythema on his palate and a 4-mm superficial erosion on the right penile shaft. Swelling and tenderness were noted over the elbows, knees, hands, and ankles. No inguinal lymphadenopathy was noted.
An arthrocentesis was performed on the right knee that demonstrated no organisms on Gram stain and a normal joint fluid cell count. A complete blood count (CBC), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and urinalysis were ordered. A punch biopsy was performed on a scaly patch on the right elbow.
WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?
Dx: Keratoderma blenorrhagicum
The patient’s history, clinical findings, and lab results, including a positive Chlamydia trachomatis polymerase chain reaction (PCR) test from a urethral swab, pointed to a diagnosis of keratoderma blenorrhagicum in association with reactive arthritis (following infection with C trachomatis).
Relevant diagnostic findings included an elevated CRP of 26.5 mg/L (normal range, < 10 mg/L), an elevated ESR of 116 mm/h (normal range, < 15 mm/h) and as noted, a positive C trachomatis PCR test. The patient’s white blood cell count was 9.7/μL (normal range, 4.5-11 μL) and the rest of the CBC was within normal limits. Urinalysis was positive for leukocytes and rare bacteria. A treponemal antibody test was negative.
Additionally, the punch biopsy from the right elbow revealed acanthosis, intercellular spongiosis, and subcorneal pustules consistent with localized pustular psoriasis or keratoderma blenorrhagicum. After the diagnosis was made, human leukocyte antigen B27 allele (HLA-B27) testing was conducted and was positive.
A predisposition exacerbates the infection
Reactive arthritis, a type of spondyloarthropathy, features a triad of conjunctivitis, urethritis, and arthritis that follows either gastrointestinal or urogenital infection.1 Reactive arthritis occurs with a male predominance of 3:1, and the worldwide prevalence is 1 in 3000.1 Causative bacteria include C trachomatis, Yersinia, Salmonella, Shigella, and Campylobacter, Escherichia coli, Clostridioides (formerly Clostridium) difficile, and C pneumoniae.2 Patients with the HLA-B27 allele are 50 times more likely to develop reactive arthritis following infection with the aforementioned bacteria.1
Findings consistent with a diagnosis of reactive arthritis include a recent history of gastrointestinal or urogenital illness, joint pain, conjunctivitis, oral lesions, cutaneous changes, and genital lesions.3 Diagnostic tests should include arthrocentesis with cultures or PCR and cell count, ESR, CRP, CBC, and urinalysis. HLA-B27 can be used to support the diagnosis but is not routinely recommended.2
Pustules and psoriasiform scaling characterize this diagnosis
The differential diagnosis for the signs and symptoms seen in this patient include disseminated gonococcal arthritis, psoriatic arthritis, rheumatoid arthritis, and secondary syphilis.
Gonococcal arthritis manifests with painful, sterile joints as well as pustules on the palms and soles, but not with the psoriasiform scaling and desquamation that was seen in this case. A culture or PCR from urethral discharge or pustules on the palms and soles could be used to confirm this diagnosis.3
Continue to: Psoriasis in association with psoriatic arthritis
Psoriasis in association with psoriatic arthritis and the psoriasiform rashing of reactive arthritis (keratoderma blenorrhagicum) show similar histopathology; however, patients with psoriatic arthritis generally exhibit fewer constitutional symptoms.4
Rheumatoid arthritis also manifests with joint pain and swelling, especially in the hands, wrists, and knees. This diagnosis was unlikely in this patient, where small joints were largely uninvolved.4
Secondary syphilis also manifests with papular, scaly, erythematous lesions on the palms and soles along with pityriasis rosea–like rashing on the trunk. However, it rarely produces pustules or hyperkeratotic keratoderma.5 As noted earlier, a treponemal antibody test in this patient was negative.
Drug therapy is the best option
First-line therapy for reactive arthritis consists of NSAIDs. If the patient exhibits an inadequate response after a 2-week trial, intra-articular or systemic glucocorticoids may be considered.3 If the patient fails to respond to the steroids, disease-modifying antirheumatic drugs (DMARDs) may be considered. Reactive arthritis is considered chronic if the disease lasts longer than 6 months, at which point, DMARDs or tumor necrosis factor-α inhibitors may be utilized.3 For cutaneous manifestations, such as keratoderma blenorrhagicum, topical glucocorticoids twice daily may be used along with keratolytic agents.
Our patient received 2 doses of azithromycin (500 mg IV) and 1 dose of ceftriaxone (2 g IV) to treat his infection while in the ED. Over the course of his hospital stay, he received ceftriaxone (1 g IV daily) for 6 days and naproxen (500 mg tid po) which was tapered. Additionally, he received a week of methylprednisolone (60 mg IM daily) before tapering to oral prednisone. His taper consisted of 40 mg po for 1 week and was decreased by 10 mg each week. Augmented betamethasone dipropionate 0.05% cream and urea 20% cream were prescribed for twice-daily application for the hyperkeratotic scale on both of his feet.
A 21-year-old man presented to the emergency department (ED) with a 2-month history of joint pain, swelling, and difficulty walking that began with swelling of his right knee (FIGURE 1A). The patient said that over the course of several weeks, the swelling and joint pain spread to his left knee, followed by bilateral elbows and ankles. Nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin produced only modest improvement.
Two weeks prior to presentation, the patient also experienced widespread pruritus and conjunctivitis. His past medical history was significant for a sexual encounter that resulted in urinary tract infection (UTI)–like symptoms approximately 1 month prior to the onset of his joint symptoms. He did not seek care for the UTI-like symptoms.
In the ED, the patient was febrile (102.1 °F) and tachycardic. Skin examination revealed erythematous papules, intact vesicles, and pustules with background hyperkeratosis and desquamation on his right foot (FIGURE 1B). The patient had spotty erythema on his palate and a 4-mm superficial erosion on the right penile shaft. Swelling and tenderness were noted over the elbows, knees, hands, and ankles. No inguinal lymphadenopathy was noted.
An arthrocentesis was performed on the right knee that demonstrated no organisms on Gram stain and a normal joint fluid cell count. A complete blood count (CBC), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and urinalysis were ordered. A punch biopsy was performed on a scaly patch on the right elbow.
WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?
Dx: Keratoderma blenorrhagicum
The patient’s history, clinical findings, and lab results, including a positive Chlamydia trachomatis polymerase chain reaction (PCR) test from a urethral swab, pointed to a diagnosis of keratoderma blenorrhagicum in association with reactive arthritis (following infection with C trachomatis).
Relevant diagnostic findings included an elevated CRP of 26.5 mg/L (normal range, < 10 mg/L), an elevated ESR of 116 mm/h (normal range, < 15 mm/h) and as noted, a positive C trachomatis PCR test. The patient’s white blood cell count was 9.7/μL (normal range, 4.5-11 μL) and the rest of the CBC was within normal limits. Urinalysis was positive for leukocytes and rare bacteria. A treponemal antibody test was negative.
Additionally, the punch biopsy from the right elbow revealed acanthosis, intercellular spongiosis, and subcorneal pustules consistent with localized pustular psoriasis or keratoderma blenorrhagicum. After the diagnosis was made, human leukocyte antigen B27 allele (HLA-B27) testing was conducted and was positive.
A predisposition exacerbates the infection
Reactive arthritis, a type of spondyloarthropathy, features a triad of conjunctivitis, urethritis, and arthritis that follows either gastrointestinal or urogenital infection.1 Reactive arthritis occurs with a male predominance of 3:1, and the worldwide prevalence is 1 in 3000.1 Causative bacteria include C trachomatis, Yersinia, Salmonella, Shigella, and Campylobacter, Escherichia coli, Clostridioides (formerly Clostridium) difficile, and C pneumoniae.2 Patients with the HLA-B27 allele are 50 times more likely to develop reactive arthritis following infection with the aforementioned bacteria.1
Findings consistent with a diagnosis of reactive arthritis include a recent history of gastrointestinal or urogenital illness, joint pain, conjunctivitis, oral lesions, cutaneous changes, and genital lesions.3 Diagnostic tests should include arthrocentesis with cultures or PCR and cell count, ESR, CRP, CBC, and urinalysis. HLA-B27 can be used to support the diagnosis but is not routinely recommended.2
Pustules and psoriasiform scaling characterize this diagnosis
The differential diagnosis for the signs and symptoms seen in this patient include disseminated gonococcal arthritis, psoriatic arthritis, rheumatoid arthritis, and secondary syphilis.
Gonococcal arthritis manifests with painful, sterile joints as well as pustules on the palms and soles, but not with the psoriasiform scaling and desquamation that was seen in this case. A culture or PCR from urethral discharge or pustules on the palms and soles could be used to confirm this diagnosis.3
Continue to: Psoriasis in association with psoriatic arthritis
Psoriasis in association with psoriatic arthritis and the psoriasiform rashing of reactive arthritis (keratoderma blenorrhagicum) show similar histopathology; however, patients with psoriatic arthritis generally exhibit fewer constitutional symptoms.4
Rheumatoid arthritis also manifests with joint pain and swelling, especially in the hands, wrists, and knees. This diagnosis was unlikely in this patient, where small joints were largely uninvolved.4
Secondary syphilis also manifests with papular, scaly, erythematous lesions on the palms and soles along with pityriasis rosea–like rashing on the trunk. However, it rarely produces pustules or hyperkeratotic keratoderma.5 As noted earlier, a treponemal antibody test in this patient was negative.
Drug therapy is the best option
First-line therapy for reactive arthritis consists of NSAIDs. If the patient exhibits an inadequate response after a 2-week trial, intra-articular or systemic glucocorticoids may be considered.3 If the patient fails to respond to the steroids, disease-modifying antirheumatic drugs (DMARDs) may be considered. Reactive arthritis is considered chronic if the disease lasts longer than 6 months, at which point, DMARDs or tumor necrosis factor-α inhibitors may be utilized.3 For cutaneous manifestations, such as keratoderma blenorrhagicum, topical glucocorticoids twice daily may be used along with keratolytic agents.
Our patient received 2 doses of azithromycin (500 mg IV) and 1 dose of ceftriaxone (2 g IV) to treat his infection while in the ED. Over the course of his hospital stay, he received ceftriaxone (1 g IV daily) for 6 days and naproxen (500 mg tid po) which was tapered. Additionally, he received a week of methylprednisolone (60 mg IM daily) before tapering to oral prednisone. His taper consisted of 40 mg po for 1 week and was decreased by 10 mg each week. Augmented betamethasone dipropionate 0.05% cream and urea 20% cream were prescribed for twice-daily application for the hyperkeratotic scale on both of his feet.
1. Hayes KM, Hayes RJP, Turk MA, et al. Evolving patterns of reactive arthritis. Clin Rheumatol. 2019;38:2083-2088. doi: 10.1007/s10067-019-04522-4
2. Duba AS, Mathew SD. The seronegative spondyloarthropathies. Prim Care. 2018;45:271-287. doi: 10.1016/j.pop.2018.02.005
3. Yu DT, van Tubergen A. Reactive arthritis. In: Joachim S, Romain PL, eds. UpToDate. Updated April 28, 2021. Accessed June 3, 2021. https://www.uptodate.com/contents/reactive-arthritis?search=reactive%20arthritis&topicRef=5571&source=see_link#H9
4. Barth WF, Segal K. Reactive arthritis (Reiter’s Syndrome). Am Fam Physician. 1999;60:499-503, 507.
5. Coleman E, Fiahlo A, Brateanu A. Secondary syphilis. Cleve Clin J Med. 2017;84:510-511. doi: 10.3949/ccjm.84a.16089
1. Hayes KM, Hayes RJP, Turk MA, et al. Evolving patterns of reactive arthritis. Clin Rheumatol. 2019;38:2083-2088. doi: 10.1007/s10067-019-04522-4
2. Duba AS, Mathew SD. The seronegative spondyloarthropathies. Prim Care. 2018;45:271-287. doi: 10.1016/j.pop.2018.02.005
3. Yu DT, van Tubergen A. Reactive arthritis. In: Joachim S, Romain PL, eds. UpToDate. Updated April 28, 2021. Accessed June 3, 2021. https://www.uptodate.com/contents/reactive-arthritis?search=reactive%20arthritis&topicRef=5571&source=see_link#H9
4. Barth WF, Segal K. Reactive arthritis (Reiter’s Syndrome). Am Fam Physician. 1999;60:499-503, 507.
5. Coleman E, Fiahlo A, Brateanu A. Secondary syphilis. Cleve Clin J Med. 2017;84:510-511. doi: 10.3949/ccjm.84a.16089
Photobiomodulation: Evaluation in a wide range of medical specialties underway
according to Juanita J. Anders, PhD.
During the annual conference of the American Society for Laser Medicine and Surgery, Dr. Anders, professor of anatomy, physiology, and genetics at the Uniformed Services University of the Health Sciences, Bethesda, Md., defined photobiomodulation (PBM) as the mechanism by which nonionizing optical radiation in the visible and near-infrared spectral range is absorbed by endogenous chromophores to elicit photophysical and photochemical events at various biological scales. Photobiomodulation therapy (PBMT) involves the use of light sources including lasers, LEDs, and broadband light, that emit visible and/or near-infrared light to cause physiological changes in cells and tissues and result in therapeutic benefits.
In dermatology, LED light therapy devices are commonly used for PBMT in wavelengths that range from blue (415 nm) and red (633 nm) to near infrared (830 nm). “Often, when PBMT is referred to by dermatologists it’s called LED therapy or LED light therapy,” Dr. Anders noted. “Some people are under the impression that this is different from PBMT. But remember: It’s not the device that’s producing the photons that is clinically relevant, but it’s the photons themselves. In both cases, the same radiances and fluence ranges are being used and the mechanisms are the same, so it’s all PBMT.”
The therapy is used to treat a wide variety of medical and aesthetic disorders including acne vulgaris, psoriasis, burns, and wound healing. It has also been used in conjunction with surgical aesthetic and resurfacing procedures and has been reported to reduce erythema, edema, bruising, and days to healing. It’s been shown that PBMT stimulates fibroblast proliferation, collagen synthesis, and extracellular matrix resulting in lifting and tightening lax skin.
According to Dr. Anders, French dermatologists Linda Fouque, MD, and Michele Pelletier, MD, performed a series of in vivo and in vitro studies in which they tested the effects of yellow and red light for skin rejuvenation when used individually or in combination. “They found that fibroblasts and keratinocytes in vitro had great improvement in their morphology both with the yellow and red light, but the best improvement was seen with combination therapy,” Dr. Anders said. “This held true in their work looking at epidermal and dermal markers in the skin, where they found the best up-regulation in protein synthesis of such markers as collagens and fibronectin were produced when a combination wavelength light was used.”
Oral mucositis and pain
PBMT is also being used to treat oral mucositis (OM), a common adverse response to chemotherapy and/or radiation therapy, which causes pain, difficulty in swallowing and eating, and oral ulceration, and often interrupts the course of treatments. Authors of a recently published review on the risks and benefits of PBMT concluded that there is consistent evidence from a small number of high-quality studies that PBMT can help prevent the development of cancer therapy–induced OM, reduce pain intensity, as well as promote healing, and enhance patient quality of life.
“They also cautioned that, due to the limited long-term follow-up of patients, there is still concern for the potential long-term risks of PBMT in cancer cell mutation and amplification,” Dr. Anders said. “They advised that PBMT should be used carefully when the irradiation beam is in the direction of the tumor zone.”
Using PBMT for modulation of pain is another area of active research. Based on work from the laboratory of Dr. Anders and others, there are two methods to modulate pain. The first is to target tissue at irradiances below 100 mW/cm2.
“In my laboratory, based on in vivo preclinical animal models of neuropathic pain, we used a 980-nm wavelength laser at 43.25 mW/cm2 transcutaneously delivered to the level of the nerve for 20 seconds,” said Dr. Anders, who is a past president of the ASLMS. “Essentially, we found that the pain was modulated by reducing sensitivity to mechanical stimulation and also by causing an anti-inflammatory shift in microglial and macrophage phenotype in the dorsal root ganglion and spinal cord of affected segments.”
The second way to modulate pain, she continued, is to target tissue at irradiances above 250 mW/cm2. She and her colleagues have conducted in vitro and in vivo studies, which indicate that treatment with an irradiance/fluence rate at 270 mW/cm2 or higher at the nerve can rapidly block pain transmission.
“In vitro, we found that if we used an 810-nm wavelength light at 300 mW/cm2, we got a disruption of microtubules in the DRG neurons in culture, specifically the small neurons, the nociceptive fibers, but we did not affect the proprioceptive fibers unless we increased the length of the treatment,” she said. “We essentially found the same thing in vivo in a rodent model of neuropathic pain.”
In a pilot study, Dr. Anders and coauthors examined the efficacy of laser irradiation of the dorsal root ganglion of the second lumbar spinal nerve for patients with chronic back pain.
They found that PBMT effectively reduced back pain equal to the effects of lidocaine.
Based on these two irradiation approaches of targeting tissue, Dr. Anders recommends that a combination therapy be used to modulate neuropathic pain going forward. “This approach would involve the initial use of a high-irradiance treatment [at least 250 mW/cm2] at the nerve to block the pain transmission,” she said. “That treatment would be followed by a series of low-irradiance treatments [10-100 mW/cm2] along the course of the involved nerve to alter chronic pathology and inflammation.”
Potential applications in neurology
Dr. Anders also discussed research efforts under way involving transcranial PBMT: the delivery of near-infrared light through the tissues of the scalp and skull to targeted brain regions to treat neurologic injuries and disorders. “There have been some exciting results in preclinical animal work and in small clinical pilot work that show that there could be possible beneficial effects in Parkinson’s disease, Alzheimer’s disease, depression, and improvement in cognition and memory after a brain injury, such as a TBI,” she said.
“Initially, though, there were a lot of questions about whether you could really deliver light to the brain through the scalp. In my laboratory, we used slices of nonfixed brain and found that the sulci within the human brain act as light-wave guides. We used an 808-nm near-infrared wavelength of light, so that the light could penetrate more deeply.” Using nonfixed cadaver heads, where the light was applied at the scalp surface, Dr. Anders and colleagues were able to measure photons down to the depth of 4 cm. “It’s generally agreed now, though, that it’s to a maximum depth of 2.5-3 cm that enough photons are delivered that would cause a beneficial therapeutic effect,” she said.
Dr. Anders disclosed that she has received equipment from LiteCure, grant funding from the Department of Defense, and that she holds advisory board roles with LiteCure and Neurothera. She has also served in leadership roles for the Optical Society and holds intellectual property rights for the Henry M. Jackson Foundation for the Advancement of Military Medicine.
according to Juanita J. Anders, PhD.
During the annual conference of the American Society for Laser Medicine and Surgery, Dr. Anders, professor of anatomy, physiology, and genetics at the Uniformed Services University of the Health Sciences, Bethesda, Md., defined photobiomodulation (PBM) as the mechanism by which nonionizing optical radiation in the visible and near-infrared spectral range is absorbed by endogenous chromophores to elicit photophysical and photochemical events at various biological scales. Photobiomodulation therapy (PBMT) involves the use of light sources including lasers, LEDs, and broadband light, that emit visible and/or near-infrared light to cause physiological changes in cells and tissues and result in therapeutic benefits.
In dermatology, LED light therapy devices are commonly used for PBMT in wavelengths that range from blue (415 nm) and red (633 nm) to near infrared (830 nm). “Often, when PBMT is referred to by dermatologists it’s called LED therapy or LED light therapy,” Dr. Anders noted. “Some people are under the impression that this is different from PBMT. But remember: It’s not the device that’s producing the photons that is clinically relevant, but it’s the photons themselves. In both cases, the same radiances and fluence ranges are being used and the mechanisms are the same, so it’s all PBMT.”
The therapy is used to treat a wide variety of medical and aesthetic disorders including acne vulgaris, psoriasis, burns, and wound healing. It has also been used in conjunction with surgical aesthetic and resurfacing procedures and has been reported to reduce erythema, edema, bruising, and days to healing. It’s been shown that PBMT stimulates fibroblast proliferation, collagen synthesis, and extracellular matrix resulting in lifting and tightening lax skin.
According to Dr. Anders, French dermatologists Linda Fouque, MD, and Michele Pelletier, MD, performed a series of in vivo and in vitro studies in which they tested the effects of yellow and red light for skin rejuvenation when used individually or in combination. “They found that fibroblasts and keratinocytes in vitro had great improvement in their morphology both with the yellow and red light, but the best improvement was seen with combination therapy,” Dr. Anders said. “This held true in their work looking at epidermal and dermal markers in the skin, where they found the best up-regulation in protein synthesis of such markers as collagens and fibronectin were produced when a combination wavelength light was used.”
Oral mucositis and pain
PBMT is also being used to treat oral mucositis (OM), a common adverse response to chemotherapy and/or radiation therapy, which causes pain, difficulty in swallowing and eating, and oral ulceration, and often interrupts the course of treatments. Authors of a recently published review on the risks and benefits of PBMT concluded that there is consistent evidence from a small number of high-quality studies that PBMT can help prevent the development of cancer therapy–induced OM, reduce pain intensity, as well as promote healing, and enhance patient quality of life.
“They also cautioned that, due to the limited long-term follow-up of patients, there is still concern for the potential long-term risks of PBMT in cancer cell mutation and amplification,” Dr. Anders said. “They advised that PBMT should be used carefully when the irradiation beam is in the direction of the tumor zone.”
Using PBMT for modulation of pain is another area of active research. Based on work from the laboratory of Dr. Anders and others, there are two methods to modulate pain. The first is to target tissue at irradiances below 100 mW/cm2.
“In my laboratory, based on in vivo preclinical animal models of neuropathic pain, we used a 980-nm wavelength laser at 43.25 mW/cm2 transcutaneously delivered to the level of the nerve for 20 seconds,” said Dr. Anders, who is a past president of the ASLMS. “Essentially, we found that the pain was modulated by reducing sensitivity to mechanical stimulation and also by causing an anti-inflammatory shift in microglial and macrophage phenotype in the dorsal root ganglion and spinal cord of affected segments.”
The second way to modulate pain, she continued, is to target tissue at irradiances above 250 mW/cm2. She and her colleagues have conducted in vitro and in vivo studies, which indicate that treatment with an irradiance/fluence rate at 270 mW/cm2 or higher at the nerve can rapidly block pain transmission.
“In vitro, we found that if we used an 810-nm wavelength light at 300 mW/cm2, we got a disruption of microtubules in the DRG neurons in culture, specifically the small neurons, the nociceptive fibers, but we did not affect the proprioceptive fibers unless we increased the length of the treatment,” she said. “We essentially found the same thing in vivo in a rodent model of neuropathic pain.”
In a pilot study, Dr. Anders and coauthors examined the efficacy of laser irradiation of the dorsal root ganglion of the second lumbar spinal nerve for patients with chronic back pain.
They found that PBMT effectively reduced back pain equal to the effects of lidocaine.
Based on these two irradiation approaches of targeting tissue, Dr. Anders recommends that a combination therapy be used to modulate neuropathic pain going forward. “This approach would involve the initial use of a high-irradiance treatment [at least 250 mW/cm2] at the nerve to block the pain transmission,” she said. “That treatment would be followed by a series of low-irradiance treatments [10-100 mW/cm2] along the course of the involved nerve to alter chronic pathology and inflammation.”
Potential applications in neurology
Dr. Anders also discussed research efforts under way involving transcranial PBMT: the delivery of near-infrared light through the tissues of the scalp and skull to targeted brain regions to treat neurologic injuries and disorders. “There have been some exciting results in preclinical animal work and in small clinical pilot work that show that there could be possible beneficial effects in Parkinson’s disease, Alzheimer’s disease, depression, and improvement in cognition and memory after a brain injury, such as a TBI,” she said.
“Initially, though, there were a lot of questions about whether you could really deliver light to the brain through the scalp. In my laboratory, we used slices of nonfixed brain and found that the sulci within the human brain act as light-wave guides. We used an 808-nm near-infrared wavelength of light, so that the light could penetrate more deeply.” Using nonfixed cadaver heads, where the light was applied at the scalp surface, Dr. Anders and colleagues were able to measure photons down to the depth of 4 cm. “It’s generally agreed now, though, that it’s to a maximum depth of 2.5-3 cm that enough photons are delivered that would cause a beneficial therapeutic effect,” she said.
Dr. Anders disclosed that she has received equipment from LiteCure, grant funding from the Department of Defense, and that she holds advisory board roles with LiteCure and Neurothera. She has also served in leadership roles for the Optical Society and holds intellectual property rights for the Henry M. Jackson Foundation for the Advancement of Military Medicine.
according to Juanita J. Anders, PhD.
During the annual conference of the American Society for Laser Medicine and Surgery, Dr. Anders, professor of anatomy, physiology, and genetics at the Uniformed Services University of the Health Sciences, Bethesda, Md., defined photobiomodulation (PBM) as the mechanism by which nonionizing optical radiation in the visible and near-infrared spectral range is absorbed by endogenous chromophores to elicit photophysical and photochemical events at various biological scales. Photobiomodulation therapy (PBMT) involves the use of light sources including lasers, LEDs, and broadband light, that emit visible and/or near-infrared light to cause physiological changes in cells and tissues and result in therapeutic benefits.
In dermatology, LED light therapy devices are commonly used for PBMT in wavelengths that range from blue (415 nm) and red (633 nm) to near infrared (830 nm). “Often, when PBMT is referred to by dermatologists it’s called LED therapy or LED light therapy,” Dr. Anders noted. “Some people are under the impression that this is different from PBMT. But remember: It’s not the device that’s producing the photons that is clinically relevant, but it’s the photons themselves. In both cases, the same radiances and fluence ranges are being used and the mechanisms are the same, so it’s all PBMT.”
The therapy is used to treat a wide variety of medical and aesthetic disorders including acne vulgaris, psoriasis, burns, and wound healing. It has also been used in conjunction with surgical aesthetic and resurfacing procedures and has been reported to reduce erythema, edema, bruising, and days to healing. It’s been shown that PBMT stimulates fibroblast proliferation, collagen synthesis, and extracellular matrix resulting in lifting and tightening lax skin.
According to Dr. Anders, French dermatologists Linda Fouque, MD, and Michele Pelletier, MD, performed a series of in vivo and in vitro studies in which they tested the effects of yellow and red light for skin rejuvenation when used individually or in combination. “They found that fibroblasts and keratinocytes in vitro had great improvement in their morphology both with the yellow and red light, but the best improvement was seen with combination therapy,” Dr. Anders said. “This held true in their work looking at epidermal and dermal markers in the skin, where they found the best up-regulation in protein synthesis of such markers as collagens and fibronectin were produced when a combination wavelength light was used.”
Oral mucositis and pain
PBMT is also being used to treat oral mucositis (OM), a common adverse response to chemotherapy and/or radiation therapy, which causes pain, difficulty in swallowing and eating, and oral ulceration, and often interrupts the course of treatments. Authors of a recently published review on the risks and benefits of PBMT concluded that there is consistent evidence from a small number of high-quality studies that PBMT can help prevent the development of cancer therapy–induced OM, reduce pain intensity, as well as promote healing, and enhance patient quality of life.
“They also cautioned that, due to the limited long-term follow-up of patients, there is still concern for the potential long-term risks of PBMT in cancer cell mutation and amplification,” Dr. Anders said. “They advised that PBMT should be used carefully when the irradiation beam is in the direction of the tumor zone.”
Using PBMT for modulation of pain is another area of active research. Based on work from the laboratory of Dr. Anders and others, there are two methods to modulate pain. The first is to target tissue at irradiances below 100 mW/cm2.
“In my laboratory, based on in vivo preclinical animal models of neuropathic pain, we used a 980-nm wavelength laser at 43.25 mW/cm2 transcutaneously delivered to the level of the nerve for 20 seconds,” said Dr. Anders, who is a past president of the ASLMS. “Essentially, we found that the pain was modulated by reducing sensitivity to mechanical stimulation and also by causing an anti-inflammatory shift in microglial and macrophage phenotype in the dorsal root ganglion and spinal cord of affected segments.”
The second way to modulate pain, she continued, is to target tissue at irradiances above 250 mW/cm2. She and her colleagues have conducted in vitro and in vivo studies, which indicate that treatment with an irradiance/fluence rate at 270 mW/cm2 or higher at the nerve can rapidly block pain transmission.
“In vitro, we found that if we used an 810-nm wavelength light at 300 mW/cm2, we got a disruption of microtubules in the DRG neurons in culture, specifically the small neurons, the nociceptive fibers, but we did not affect the proprioceptive fibers unless we increased the length of the treatment,” she said. “We essentially found the same thing in vivo in a rodent model of neuropathic pain.”
In a pilot study, Dr. Anders and coauthors examined the efficacy of laser irradiation of the dorsal root ganglion of the second lumbar spinal nerve for patients with chronic back pain.
They found that PBMT effectively reduced back pain equal to the effects of lidocaine.
Based on these two irradiation approaches of targeting tissue, Dr. Anders recommends that a combination therapy be used to modulate neuropathic pain going forward. “This approach would involve the initial use of a high-irradiance treatment [at least 250 mW/cm2] at the nerve to block the pain transmission,” she said. “That treatment would be followed by a series of low-irradiance treatments [10-100 mW/cm2] along the course of the involved nerve to alter chronic pathology and inflammation.”
Potential applications in neurology
Dr. Anders also discussed research efforts under way involving transcranial PBMT: the delivery of near-infrared light through the tissues of the scalp and skull to targeted brain regions to treat neurologic injuries and disorders. “There have been some exciting results in preclinical animal work and in small clinical pilot work that show that there could be possible beneficial effects in Parkinson’s disease, Alzheimer’s disease, depression, and improvement in cognition and memory after a brain injury, such as a TBI,” she said.
“Initially, though, there were a lot of questions about whether you could really deliver light to the brain through the scalp. In my laboratory, we used slices of nonfixed brain and found that the sulci within the human brain act as light-wave guides. We used an 808-nm near-infrared wavelength of light, so that the light could penetrate more deeply.” Using nonfixed cadaver heads, where the light was applied at the scalp surface, Dr. Anders and colleagues were able to measure photons down to the depth of 4 cm. “It’s generally agreed now, though, that it’s to a maximum depth of 2.5-3 cm that enough photons are delivered that would cause a beneficial therapeutic effect,” she said.
Dr. Anders disclosed that she has received equipment from LiteCure, grant funding from the Department of Defense, and that she holds advisory board roles with LiteCure and Neurothera. She has also served in leadership roles for the Optical Society and holds intellectual property rights for the Henry M. Jackson Foundation for the Advancement of Military Medicine.
FROM ASLMS 2021
Chronic headache pain in veterans linked to suicide attempts
, according to findings presented at the American Headache Society’s 2021 annual meeting. Risk rose even more in those with chronic headache pain and a comorbid traumatic brain injury (TBI).
“In addition, as expected, veterans with psychiatric conditions have increased risk of suicide attempt with the exception of anxiety in men and dependent personality in women,” said X. Michelle Androulakis, MD, associate professor of neurology at the University of South Carolina, Columbia.
‘Surprising’ findings
“These findings are eye-opening but not surprising since we know that veterans in general and people with chronic pain are at higher risk for suicidal behaviors compared with their civilian counterparts,” said Amy. S Grinberg, PhD, a clinical health psychologist who practices in New Rochelle, N.Y. Dr. Grinberg, who also works at VA Connecticut Healthcare System, was not involved in the study.
“It is, however, very interesting that suicidal attempts are higher in veterans with chronic headache compared with other chronic pain disorders, such as chronic neck and back pain,” Dr Grinberg said. “This really highlights the impact of living with a chronic headache disorder, and emphasizes the continued efforts that should be put into place to support veterans with chronic headache, including improved access to a range of treatment options and continued funding for future research.”
Veterans with chronic pain
The researchers retrospectively analyzed Veterans Health Administration electronic health records of 3,252,704 veterans, predominantly male and White, who had been diagnosed with any type of chronic pain from 2000 to 2010.
The researchers looked at overall headache diagnoses instead of specific diagnoses, such as migraine, cluster headache, or posttraumatic headache, since specific headache disorders are frequently underdiagnosed.
The population included 14.7% of patients with chronic headache, 14.9% with chronic neck pain, 59.2% with chronic back pain, and 60.2% with other types of chronic pain, including arthritis, fibromyalgia, joint pain, and reflex sympathetic dystrophy.
Traumatic brain injury occurred in 11.2% of those with chronic headaches, compared with 6.8% of those with chronic back pain, 8.5% of those with chronic neck pain, and 5.9% of those with other chronic pain.
More than half (56.4%) of those with chronic headache had depression, the most common comorbidity in the group, followed by 31.5% who had posttraumatic stress disorder (PTSD), and 21.8% who had adjustment disorder. Other rates of psychiatric disorders were all below 10%. Prevalence of depression occurred in 44.5% of those with back pain, 52.4% of those with neck pain, and 39% of those with other chronic pain. PTSD rates were also lower in those with back (22%), neck (27.2%), or other chronic pain (18.6%).
“Interestingly, this study found that those veterans with a history of traumatic brain injury and psychiatric comorbidities, such as depression, are at greater risk for suicide attempts,” said Dr. Grinberg. “The good news is that these are modifiable risk factors, and evidence-based treatments for depression, PTSD, and headache, for example, are widely disseminated within the VA.”
The majority of headache diagnoses were not otherwise specified (80.1%). Half (50.2%) were migraine headaches while rates were much lower for tension-type headache (8.8%), trigeminal neuralgia (5%), cluster headache (0.8%), and posttraumatic headache (0.7%).
The highest incidence of suicide attempts occurred among those with chronic headaches, ranging from 329 to 396 per 100,000, aside from a peak of 482 per 100,000 in 2005. Suicide attempts peaked among all patients with chronic pain in 2005, “likely related to the deployment and policy changes in the Veterans Health Administration,” Dr. Androulakis said.
Those with neck pain had the next highest rate of suicide attempts, ranging from 263 to 314 per 100,000, excluding the peak of 398 per 100,000 in 2005.
Male veterans with chronic headaches had a 1.5 times greater likelihood of a suicide attempt than did those with back or neck pain (relative risk [RR] = 1.5), which increased to a relative risk of 2.8 greater for those with concurrent TBI. Among female veterans, chronic headache was associated with a 1.6 times greater risk of a suicide attempt, which rose to 2.15 times greater with concurrent TBI.
“Knowing that veterans with chronic headache disorders have an elevated rate of suicide, it is imperative that doctors and other clinical providers continue to conduct in-depth risk assessments and implement strategies to support those veterans who are at risk,” said Dr. Grinberg. “Clinical providers should continue in their efforts to reduce stigma associated with headache disorders and mental health treatment in order to effectively engage veterans in evidence-based treatments that are likely a step towards reducing symptoms and suicidal attempts.”
No external funding was noted. Dr. Androulakis and Dr. Grinberg had no disclosures.
, according to findings presented at the American Headache Society’s 2021 annual meeting. Risk rose even more in those with chronic headache pain and a comorbid traumatic brain injury (TBI).
“In addition, as expected, veterans with psychiatric conditions have increased risk of suicide attempt with the exception of anxiety in men and dependent personality in women,” said X. Michelle Androulakis, MD, associate professor of neurology at the University of South Carolina, Columbia.
‘Surprising’ findings
“These findings are eye-opening but not surprising since we know that veterans in general and people with chronic pain are at higher risk for suicidal behaviors compared with their civilian counterparts,” said Amy. S Grinberg, PhD, a clinical health psychologist who practices in New Rochelle, N.Y. Dr. Grinberg, who also works at VA Connecticut Healthcare System, was not involved in the study.
“It is, however, very interesting that suicidal attempts are higher in veterans with chronic headache compared with other chronic pain disorders, such as chronic neck and back pain,” Dr Grinberg said. “This really highlights the impact of living with a chronic headache disorder, and emphasizes the continued efforts that should be put into place to support veterans with chronic headache, including improved access to a range of treatment options and continued funding for future research.”
Veterans with chronic pain
The researchers retrospectively analyzed Veterans Health Administration electronic health records of 3,252,704 veterans, predominantly male and White, who had been diagnosed with any type of chronic pain from 2000 to 2010.
The researchers looked at overall headache diagnoses instead of specific diagnoses, such as migraine, cluster headache, or posttraumatic headache, since specific headache disorders are frequently underdiagnosed.
The population included 14.7% of patients with chronic headache, 14.9% with chronic neck pain, 59.2% with chronic back pain, and 60.2% with other types of chronic pain, including arthritis, fibromyalgia, joint pain, and reflex sympathetic dystrophy.
Traumatic brain injury occurred in 11.2% of those with chronic headaches, compared with 6.8% of those with chronic back pain, 8.5% of those with chronic neck pain, and 5.9% of those with other chronic pain.
More than half (56.4%) of those with chronic headache had depression, the most common comorbidity in the group, followed by 31.5% who had posttraumatic stress disorder (PTSD), and 21.8% who had adjustment disorder. Other rates of psychiatric disorders were all below 10%. Prevalence of depression occurred in 44.5% of those with back pain, 52.4% of those with neck pain, and 39% of those with other chronic pain. PTSD rates were also lower in those with back (22%), neck (27.2%), or other chronic pain (18.6%).
“Interestingly, this study found that those veterans with a history of traumatic brain injury and psychiatric comorbidities, such as depression, are at greater risk for suicide attempts,” said Dr. Grinberg. “The good news is that these are modifiable risk factors, and evidence-based treatments for depression, PTSD, and headache, for example, are widely disseminated within the VA.”
The majority of headache diagnoses were not otherwise specified (80.1%). Half (50.2%) were migraine headaches while rates were much lower for tension-type headache (8.8%), trigeminal neuralgia (5%), cluster headache (0.8%), and posttraumatic headache (0.7%).
The highest incidence of suicide attempts occurred among those with chronic headaches, ranging from 329 to 396 per 100,000, aside from a peak of 482 per 100,000 in 2005. Suicide attempts peaked among all patients with chronic pain in 2005, “likely related to the deployment and policy changes in the Veterans Health Administration,” Dr. Androulakis said.
Those with neck pain had the next highest rate of suicide attempts, ranging from 263 to 314 per 100,000, excluding the peak of 398 per 100,000 in 2005.
Male veterans with chronic headaches had a 1.5 times greater likelihood of a suicide attempt than did those with back or neck pain (relative risk [RR] = 1.5), which increased to a relative risk of 2.8 greater for those with concurrent TBI. Among female veterans, chronic headache was associated with a 1.6 times greater risk of a suicide attempt, which rose to 2.15 times greater with concurrent TBI.
“Knowing that veterans with chronic headache disorders have an elevated rate of suicide, it is imperative that doctors and other clinical providers continue to conduct in-depth risk assessments and implement strategies to support those veterans who are at risk,” said Dr. Grinberg. “Clinical providers should continue in their efforts to reduce stigma associated with headache disorders and mental health treatment in order to effectively engage veterans in evidence-based treatments that are likely a step towards reducing symptoms and suicidal attempts.”
No external funding was noted. Dr. Androulakis and Dr. Grinberg had no disclosures.
, according to findings presented at the American Headache Society’s 2021 annual meeting. Risk rose even more in those with chronic headache pain and a comorbid traumatic brain injury (TBI).
“In addition, as expected, veterans with psychiatric conditions have increased risk of suicide attempt with the exception of anxiety in men and dependent personality in women,” said X. Michelle Androulakis, MD, associate professor of neurology at the University of South Carolina, Columbia.
‘Surprising’ findings
“These findings are eye-opening but not surprising since we know that veterans in general and people with chronic pain are at higher risk for suicidal behaviors compared with their civilian counterparts,” said Amy. S Grinberg, PhD, a clinical health psychologist who practices in New Rochelle, N.Y. Dr. Grinberg, who also works at VA Connecticut Healthcare System, was not involved in the study.
“It is, however, very interesting that suicidal attempts are higher in veterans with chronic headache compared with other chronic pain disorders, such as chronic neck and back pain,” Dr Grinberg said. “This really highlights the impact of living with a chronic headache disorder, and emphasizes the continued efforts that should be put into place to support veterans with chronic headache, including improved access to a range of treatment options and continued funding for future research.”
Veterans with chronic pain
The researchers retrospectively analyzed Veterans Health Administration electronic health records of 3,252,704 veterans, predominantly male and White, who had been diagnosed with any type of chronic pain from 2000 to 2010.
The researchers looked at overall headache diagnoses instead of specific diagnoses, such as migraine, cluster headache, or posttraumatic headache, since specific headache disorders are frequently underdiagnosed.
The population included 14.7% of patients with chronic headache, 14.9% with chronic neck pain, 59.2% with chronic back pain, and 60.2% with other types of chronic pain, including arthritis, fibromyalgia, joint pain, and reflex sympathetic dystrophy.
Traumatic brain injury occurred in 11.2% of those with chronic headaches, compared with 6.8% of those with chronic back pain, 8.5% of those with chronic neck pain, and 5.9% of those with other chronic pain.
More than half (56.4%) of those with chronic headache had depression, the most common comorbidity in the group, followed by 31.5% who had posttraumatic stress disorder (PTSD), and 21.8% who had adjustment disorder. Other rates of psychiatric disorders were all below 10%. Prevalence of depression occurred in 44.5% of those with back pain, 52.4% of those with neck pain, and 39% of those with other chronic pain. PTSD rates were also lower in those with back (22%), neck (27.2%), or other chronic pain (18.6%).
“Interestingly, this study found that those veterans with a history of traumatic brain injury and psychiatric comorbidities, such as depression, are at greater risk for suicide attempts,” said Dr. Grinberg. “The good news is that these are modifiable risk factors, and evidence-based treatments for depression, PTSD, and headache, for example, are widely disseminated within the VA.”
The majority of headache diagnoses were not otherwise specified (80.1%). Half (50.2%) were migraine headaches while rates were much lower for tension-type headache (8.8%), trigeminal neuralgia (5%), cluster headache (0.8%), and posttraumatic headache (0.7%).
The highest incidence of suicide attempts occurred among those with chronic headaches, ranging from 329 to 396 per 100,000, aside from a peak of 482 per 100,000 in 2005. Suicide attempts peaked among all patients with chronic pain in 2005, “likely related to the deployment and policy changes in the Veterans Health Administration,” Dr. Androulakis said.
Those with neck pain had the next highest rate of suicide attempts, ranging from 263 to 314 per 100,000, excluding the peak of 398 per 100,000 in 2005.
Male veterans with chronic headaches had a 1.5 times greater likelihood of a suicide attempt than did those with back or neck pain (relative risk [RR] = 1.5), which increased to a relative risk of 2.8 greater for those with concurrent TBI. Among female veterans, chronic headache was associated with a 1.6 times greater risk of a suicide attempt, which rose to 2.15 times greater with concurrent TBI.
“Knowing that veterans with chronic headache disorders have an elevated rate of suicide, it is imperative that doctors and other clinical providers continue to conduct in-depth risk assessments and implement strategies to support those veterans who are at risk,” said Dr. Grinberg. “Clinical providers should continue in their efforts to reduce stigma associated with headache disorders and mental health treatment in order to effectively engage veterans in evidence-based treatments that are likely a step towards reducing symptoms and suicidal attempts.”
No external funding was noted. Dr. Androulakis and Dr. Grinberg had no disclosures.
FROM AHS 2021
e-TNS device passes at-home test
The study also demonstrated that the device, manufactured by Cefaly and cleared in 2020 by the Food and Drug Administration for over-the-counter use, can be safely and effectively used at home.
The study also explored the benefits of 2 hours of use, rather than the 1 hour of use tested in a previous study. “The programming on the device is currently [set to] turn off at 1 hour. As a result of this study, I tell patients if they don’t have adequate relief, and they’re tolerating it, that they can activate it again for a second hour,” Stewart Tepper, MD, said in an interview. Dr. Tepper is a professor of neurology at Geisel School of Medicine at Dartmouth, Hanover, N.H., and a coauthor of the study that was presented by Deena Kuruvilla, MD, at the American Headache Society’s 2021 annual meeting. Dr. Kuruvilla is a neurologist and director of the Westport (Conn.) Headache Institute.
The improvements seen over the sham were significant but not overwhelming, according to Deborah Friedman, MD, MPH, professor of neurology and ophthalmology at the University of Texas, Dallas.
“The numbers are not super impressive when you compare them with other devices. I thought it was interesting that the most bothersome symptom went away in a much higher percentage of people than the headache. That was actually pretty impressive,” said Dr. Friedman, who was asked to comment on the study. She also wondered if the sham device may have inadvertently provided a small amount of stimulation, which could explain the smaller than expected efficacy difference. “It just kind of makes me wonder because I would expect to see a larger separation, even though it was statistically significant.”
The study was an overall success according to Dr. Tepper, who noted that the efficacy of pain freedom was comparable with what has been seen with calcitonin gene-related peptide receptor antagonists (gepants), as well as relieving the most bothersome symptom at 2 hours. The device failed to reduce the usage of rescue medication, suggesting that it might be a candidate to combine with rescue medications. “I think the main thing is it works. It works in a sham-controlled trial, it works at home, and it works comparably to acute medication. And it is further evidence that the lack of access is something that needs to be addressed,” said Dr. Tepper.
Access will depend on insurance companies, who have so far been reluctant to pay for the device. Dr. Tepper is not optimistic they will come around on their own. “My feeling about it is that the only way that payers will finally start to cover this is with a concerted, organized advocacy campaign by patients. The analogy is that when the disease-modifying therapies became available for multiple sclerosis, the National MS Society organized the MS patients and they demanded that the payers cover the disease modifying therapies. That’s the kind of intense focus of advocacy that needs to be done for these noninvasive neuromodulation devices,” said Dr. Tepper.
The TEAM study was a double blind, randomized, sham-controlled trial of 538 patients who were asked to use neurostimulation for a 2-hour, continuous session within 4 hours of a moderate to severe migraine accompanied by at least one migraine-associated symptom. At 2 hours, 25.5% of those using the device achieved pain freedom, compared with 18.3% of those using the sham (P < .05). Among those using the device, 56.4% had freedom from most bothersome symptom, compared with 42.3% of those using the sham (P < .01).
Pain relief at 2 hours was more common in the device group (69.5% vs. 55.2%; P < .01), as was absence of all migraine-associated symptoms at 2 hours (42.5% vs. 34.1%; P < .05), sustained pain freedom at 24 hours (22.8% vs. 15.8%; P < .05), and sustained pain relief at 24 hours (45.9% vs. 34.4%; P < .01). There was no statistically significant between-group difference in use of rescue medications.
In the device group, 8.5% of patients experienced an adverse event, versus 2.9% in the sham group (P = .004). The only adverse reaction that occurred more frequently in the device group was forehead paresthesia, discomfort, and burning (3.5% vs. 0.4%; P = .009).
The study was funded by Cefaly. Dr. Tepper and Dr. Friedman have no relevant financial disclosures.
The study also demonstrated that the device, manufactured by Cefaly and cleared in 2020 by the Food and Drug Administration for over-the-counter use, can be safely and effectively used at home.
The study also explored the benefits of 2 hours of use, rather than the 1 hour of use tested in a previous study. “The programming on the device is currently [set to] turn off at 1 hour. As a result of this study, I tell patients if they don’t have adequate relief, and they’re tolerating it, that they can activate it again for a second hour,” Stewart Tepper, MD, said in an interview. Dr. Tepper is a professor of neurology at Geisel School of Medicine at Dartmouth, Hanover, N.H., and a coauthor of the study that was presented by Deena Kuruvilla, MD, at the American Headache Society’s 2021 annual meeting. Dr. Kuruvilla is a neurologist and director of the Westport (Conn.) Headache Institute.
The improvements seen over the sham were significant but not overwhelming, according to Deborah Friedman, MD, MPH, professor of neurology and ophthalmology at the University of Texas, Dallas.
“The numbers are not super impressive when you compare them with other devices. I thought it was interesting that the most bothersome symptom went away in a much higher percentage of people than the headache. That was actually pretty impressive,” said Dr. Friedman, who was asked to comment on the study. She also wondered if the sham device may have inadvertently provided a small amount of stimulation, which could explain the smaller than expected efficacy difference. “It just kind of makes me wonder because I would expect to see a larger separation, even though it was statistically significant.”
The study was an overall success according to Dr. Tepper, who noted that the efficacy of pain freedom was comparable with what has been seen with calcitonin gene-related peptide receptor antagonists (gepants), as well as relieving the most bothersome symptom at 2 hours. The device failed to reduce the usage of rescue medication, suggesting that it might be a candidate to combine with rescue medications. “I think the main thing is it works. It works in a sham-controlled trial, it works at home, and it works comparably to acute medication. And it is further evidence that the lack of access is something that needs to be addressed,” said Dr. Tepper.
Access will depend on insurance companies, who have so far been reluctant to pay for the device. Dr. Tepper is not optimistic they will come around on their own. “My feeling about it is that the only way that payers will finally start to cover this is with a concerted, organized advocacy campaign by patients. The analogy is that when the disease-modifying therapies became available for multiple sclerosis, the National MS Society organized the MS patients and they demanded that the payers cover the disease modifying therapies. That’s the kind of intense focus of advocacy that needs to be done for these noninvasive neuromodulation devices,” said Dr. Tepper.
The TEAM study was a double blind, randomized, sham-controlled trial of 538 patients who were asked to use neurostimulation for a 2-hour, continuous session within 4 hours of a moderate to severe migraine accompanied by at least one migraine-associated symptom. At 2 hours, 25.5% of those using the device achieved pain freedom, compared with 18.3% of those using the sham (P < .05). Among those using the device, 56.4% had freedom from most bothersome symptom, compared with 42.3% of those using the sham (P < .01).
Pain relief at 2 hours was more common in the device group (69.5% vs. 55.2%; P < .01), as was absence of all migraine-associated symptoms at 2 hours (42.5% vs. 34.1%; P < .05), sustained pain freedom at 24 hours (22.8% vs. 15.8%; P < .05), and sustained pain relief at 24 hours (45.9% vs. 34.4%; P < .01). There was no statistically significant between-group difference in use of rescue medications.
In the device group, 8.5% of patients experienced an adverse event, versus 2.9% in the sham group (P = .004). The only adverse reaction that occurred more frequently in the device group was forehead paresthesia, discomfort, and burning (3.5% vs. 0.4%; P = .009).
The study was funded by Cefaly. Dr. Tepper and Dr. Friedman have no relevant financial disclosures.
The study also demonstrated that the device, manufactured by Cefaly and cleared in 2020 by the Food and Drug Administration for over-the-counter use, can be safely and effectively used at home.
The study also explored the benefits of 2 hours of use, rather than the 1 hour of use tested in a previous study. “The programming on the device is currently [set to] turn off at 1 hour. As a result of this study, I tell patients if they don’t have adequate relief, and they’re tolerating it, that they can activate it again for a second hour,” Stewart Tepper, MD, said in an interview. Dr. Tepper is a professor of neurology at Geisel School of Medicine at Dartmouth, Hanover, N.H., and a coauthor of the study that was presented by Deena Kuruvilla, MD, at the American Headache Society’s 2021 annual meeting. Dr. Kuruvilla is a neurologist and director of the Westport (Conn.) Headache Institute.
The improvements seen over the sham were significant but not overwhelming, according to Deborah Friedman, MD, MPH, professor of neurology and ophthalmology at the University of Texas, Dallas.
“The numbers are not super impressive when you compare them with other devices. I thought it was interesting that the most bothersome symptom went away in a much higher percentage of people than the headache. That was actually pretty impressive,” said Dr. Friedman, who was asked to comment on the study. She also wondered if the sham device may have inadvertently provided a small amount of stimulation, which could explain the smaller than expected efficacy difference. “It just kind of makes me wonder because I would expect to see a larger separation, even though it was statistically significant.”
The study was an overall success according to Dr. Tepper, who noted that the efficacy of pain freedom was comparable with what has been seen with calcitonin gene-related peptide receptor antagonists (gepants), as well as relieving the most bothersome symptom at 2 hours. The device failed to reduce the usage of rescue medication, suggesting that it might be a candidate to combine with rescue medications. “I think the main thing is it works. It works in a sham-controlled trial, it works at home, and it works comparably to acute medication. And it is further evidence that the lack of access is something that needs to be addressed,” said Dr. Tepper.
Access will depend on insurance companies, who have so far been reluctant to pay for the device. Dr. Tepper is not optimistic they will come around on their own. “My feeling about it is that the only way that payers will finally start to cover this is with a concerted, organized advocacy campaign by patients. The analogy is that when the disease-modifying therapies became available for multiple sclerosis, the National MS Society organized the MS patients and they demanded that the payers cover the disease modifying therapies. That’s the kind of intense focus of advocacy that needs to be done for these noninvasive neuromodulation devices,” said Dr. Tepper.
The TEAM study was a double blind, randomized, sham-controlled trial of 538 patients who were asked to use neurostimulation for a 2-hour, continuous session within 4 hours of a moderate to severe migraine accompanied by at least one migraine-associated symptom. At 2 hours, 25.5% of those using the device achieved pain freedom, compared with 18.3% of those using the sham (P < .05). Among those using the device, 56.4% had freedom from most bothersome symptom, compared with 42.3% of those using the sham (P < .01).
Pain relief at 2 hours was more common in the device group (69.5% vs. 55.2%; P < .01), as was absence of all migraine-associated symptoms at 2 hours (42.5% vs. 34.1%; P < .05), sustained pain freedom at 24 hours (22.8% vs. 15.8%; P < .05), and sustained pain relief at 24 hours (45.9% vs. 34.4%; P < .01). There was no statistically significant between-group difference in use of rescue medications.
In the device group, 8.5% of patients experienced an adverse event, versus 2.9% in the sham group (P = .004). The only adverse reaction that occurred more frequently in the device group was forehead paresthesia, discomfort, and burning (3.5% vs. 0.4%; P = .009).
The study was funded by Cefaly. Dr. Tepper and Dr. Friedman have no relevant financial disclosures.
FROM AHS 2021
A large proportion of migraine patients are not offered preventive treatment
, new research suggests. Investigators found that among patients with migraine who are eligible for preventive therapy, more than a third were not offered this option. In addition, fewer than 10% were currently taking preventive medication, and an additional 10% had discontinued preventive therapy.
“We confirmed that as of 2012 to 2013 – the years these data were collected from a large, comprehensive survey – gaps in care remained,” said study investigator Stephanie J. Nahas, MD, director of the headache medicine fellowship program, Thomas Jefferson University, Philadelphia. “In this preventive-eligible population, 35% reported never even being offered preventive medication.”
Furthermore, only 28% of patients taking preventive medication experienced a reduction in headache frequency to less than 4 days per month, which is a primary goal of treatment, said Dr. Nahas. Disease burden, as measured with scales of disability and affective comorbidities, remained substantial.
The findings were presented at the American Headache Society’s 2021 annual meeting.
Lack of efficacy?
In 2019, the American Headache Society published a position statement recommending that preventive treatment be considered for patients who have migraine and four or more monthly headache days (MHDs), regardless of their level of associated disability. However, previous data suggest few patients who are eligible for preventive treatment receive it. In addition, many who have used preventive medications do not adhere to their regimens because of problems with tolerability, efficacy, or both.
To identify treatment gaps and characterize self-reported use of preventive medications for migraine, the investigators examined data from the Chronic Migraine Epidemiology and Outcomes (CaMEO) study, a web-based survey conducted in a representative U.S. sample from September 2012 through November 2013.
The survey identified and characterized patients who met modified criteria for migraine consistent with those in ICHD-3. The researchers classified respondents who had migraine and four or more MHDs as potentially eligible for migraine preventive treatment.
The investigators assessed the study population’s use of oral preventive medications, migraine-related disability and burden, willingness to take preventive treatment, and reasons for discontinuation.
Assessments included the Migraine Disability Assessment Questionnaire, the Patient Health Questionnaire–9 for depression, the Generalized Anxiety Disorder 7-Item Scale, the Migraine Specific Quality of Life questionnaire, and the Migraine Symptom Severity Scale.
In all, 16,789 respondents met criteria for migraine, and 6,579 (39.2%) reported having at least four MHDs. The median age of this subgroup that was eligible for preventive treatment was 40.3 years, and approximately 79% were women.
Only 9.8% of respondents who were eligible for preventive medications were currently using an oral preventive medication. Among those who had ever tried an oral preventive medication, 53.6% discontinued it. Efficacy for patients who used medications appeared to be inadequate. Among all current users of preventive treatment, 68.4% continued to have at least four MHDs.
The researchers assessed treatment eligibility among patients not taking preventive medication. Among respondents who had never used a preventive treatment, 35.7% were eligible to receive it. Among all users who had discontinued preventive medication, 61.0% were still eligible to receive it.
Attitudes toward injectables
Among respondents who had never used a preventive treatment, 64.3% had zero to three MHDs. The remaining 35.7% had 4-7, 8-14, or 15 or more MHDs. Among current users of preventive treatments, 68.4% had four or more MHDs. Among those who had discontinued preventive treatment, 61.0% had four or more MHDs.
Patients who have never used preventive medication “have substantial management gaps,” said Dr. Nahas. High proportions of these patients have moderate or severe disability (64.7%), depression (43%), and anxiety (39%). The rates of these outcomes are higher in users who discontinued treatment, likely because of confounding by indication, she added.
The prevalence of anxiety was similar between those who currently used, formerly used, or never used preventive medications. However, there were differences between never-users and current or former users with respect to moderate to severe depression (never-users, 43%; current users, 49.4%; discontinued users, 46.5%) and moderate to severe disability (never-users, 64.7%; current users, 80.4%; discontinued users, 78.9%).
In all, 44.6% of those who discontinued preventive therapy reported safety and tolerability problems as reasons for stopping treatment. In addition, 39.7% reported that these medications did not prevent enough headaches. Some patients reported partial or temporary efficacy as a reason for discontinuation. Other reasons were related to health care costs and access and personal preferences. Only 9.2% of patients who discontinued treatment said that their headaches improved enough to stop medication.
The investigators also analyzed respondents’ interest in preventive therapies. Among respondents who had never used preventive therapies, 61.8% of those who were eligible to use them were somewhat or very interested in trying an oral prescription medication for migraine prevention. However, 59.1% of never-users who were eligible for preventive medications were not at all interested, not sure, or needed more information about trying an injectable preventive medication. About 40% were not at all interested in injectables. In general, current users and those who had discontinued medication were more interested in preventive medication, including injectables.
‘Disheartening’ discontinuation rates
There are likely multiple reasons for the low rate of migraine prevention treatment, said Dr. Nahas. Many people with migraine never consult a clinician, owing to factors such as stigma, cost, lack of access, and lack of awareness. In addition, patients with migraine are frequently misdiagnosed, she added.
“Other data suggest that only about a quarter of people with episodic migraine and under 5% of people with chronic migraine consult a clinician, receive an accurate diagnosis, and are prescribed appropriate therapy,” said Dr. Nahas.
When the data in this analysis were gathered, public awareness of migraine was much lower than it is today, and injectable migraine therapies had not gained broad acceptance, she noted. Dr. Nahas added it is possible that attitudes toward injectable preventive medications have changed.
“Would people still prefer daily oral medications? We can’t know for sure until we start asking,” she said. In addition, scientific advances and educational outreach have increased clinicians’ awareness, interest, and skill regarding injectable medications, she said.
“I would certainly hope to see that a much greater proportion of preventive-eligible persons with migraine were at least offered, if not currently taking, preventive medication,” said Dr. Nahas. “But there’s no pleasing everyone, so I think we would still see somewhat disheartening discontinuation rates. The reasons for discontinuation, however, might be less typified by concerns about safety and tolerability.”
Still relevant
Commenting on the study, Mia Tova Minen, MD, chief of headache research and associate professor of neurology and population health at NYU Langone Health, New York, noted that although CaMEO is an older study, its results are still highly relevant.
“Unfortunately, primary care providers are still uncomfortable prescribing migraine preventive medications, and this accounts for the large percentage [of patients] with migraine who, while eligible for migraine preventive therapy, are not offered it,” she said.
Although the public and primary care physicians are now more aware of preventive treatments for migraine, “the number of people offered migraine preventive medication still needs to increase dramatically,” said Dr. Minen.
The American Academy of Neurology’s guidelines for migraine prevention were published in 2012 and are currently being updated. The updated guidelines may include new evidence for candesartan and emerging treatments, such as melatonin and aerobic exercise.
“It is my hope that primary care providers will become more comfortable prescribing migraine preventive medications sooner,” said Dr. Minen.
The current findings suggest a need for additional ways of educating patients with migraine who are eligible for preventive therapies so that they can advocate for themselves, she added. They also suggest the idea of demanding more insurance coverage of behavioral therapies for migraine, because data indicate that these treatments have long-term efficacy and good safety profiles, said Dr. Minen.
An ‘invisible’ disorder
Also commenting on the study, Barbara L. Nye, MD, director of the headache fellowship and codirector of the headache clinic at Dartmouth-Hitchcock Medical Center, Lebanon, N.H., said the CaMEO cohort likely is representative of the general population of patients with migraine.
She noted that a significant weakness of the current study is that it examined data collected before the Food and Drug Administration approved monoclonal antibodies and therefore does not reflect patients’ current experience with medications.
“I believe that the attitudes and fears surrounding the use of injectable medication are now likely far less than previously reported, given the positive track record the new generation of once-a-month injectable medications has,” said Dr. Nye.
The findings reinforce the idea that either patients are not talking to their primary care physicians about their headaches and disability or that clinicians are not asking about them, she added. “Both issues are likely linked to the stigma that this disease state has surrounding it. This is an invisible neurological disorder to most,” Dr. Nye said.
The study was sponsored by Allergan before it was acquired by AbbVie. Dr. Nahas has served as a consultant, advisory board member, or speaker for AbbVie/Allergan, Alder/Lundbeck, Amgen/Novartis, Biohaven, Eli Lilly, Impel, Nesos Corp, Supernus, Teva, Theranica, and Zosano. She has not received and will not receive monetary compensation for this research. Dr. Minen has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, new research suggests. Investigators found that among patients with migraine who are eligible for preventive therapy, more than a third were not offered this option. In addition, fewer than 10% were currently taking preventive medication, and an additional 10% had discontinued preventive therapy.
“We confirmed that as of 2012 to 2013 – the years these data were collected from a large, comprehensive survey – gaps in care remained,” said study investigator Stephanie J. Nahas, MD, director of the headache medicine fellowship program, Thomas Jefferson University, Philadelphia. “In this preventive-eligible population, 35% reported never even being offered preventive medication.”
Furthermore, only 28% of patients taking preventive medication experienced a reduction in headache frequency to less than 4 days per month, which is a primary goal of treatment, said Dr. Nahas. Disease burden, as measured with scales of disability and affective comorbidities, remained substantial.
The findings were presented at the American Headache Society’s 2021 annual meeting.
Lack of efficacy?
In 2019, the American Headache Society published a position statement recommending that preventive treatment be considered for patients who have migraine and four or more monthly headache days (MHDs), regardless of their level of associated disability. However, previous data suggest few patients who are eligible for preventive treatment receive it. In addition, many who have used preventive medications do not adhere to their regimens because of problems with tolerability, efficacy, or both.
To identify treatment gaps and characterize self-reported use of preventive medications for migraine, the investigators examined data from the Chronic Migraine Epidemiology and Outcomes (CaMEO) study, a web-based survey conducted in a representative U.S. sample from September 2012 through November 2013.
The survey identified and characterized patients who met modified criteria for migraine consistent with those in ICHD-3. The researchers classified respondents who had migraine and four or more MHDs as potentially eligible for migraine preventive treatment.
The investigators assessed the study population’s use of oral preventive medications, migraine-related disability and burden, willingness to take preventive treatment, and reasons for discontinuation.
Assessments included the Migraine Disability Assessment Questionnaire, the Patient Health Questionnaire–9 for depression, the Generalized Anxiety Disorder 7-Item Scale, the Migraine Specific Quality of Life questionnaire, and the Migraine Symptom Severity Scale.
In all, 16,789 respondents met criteria for migraine, and 6,579 (39.2%) reported having at least four MHDs. The median age of this subgroup that was eligible for preventive treatment was 40.3 years, and approximately 79% were women.
Only 9.8% of respondents who were eligible for preventive medications were currently using an oral preventive medication. Among those who had ever tried an oral preventive medication, 53.6% discontinued it. Efficacy for patients who used medications appeared to be inadequate. Among all current users of preventive treatment, 68.4% continued to have at least four MHDs.
The researchers assessed treatment eligibility among patients not taking preventive medication. Among respondents who had never used a preventive treatment, 35.7% were eligible to receive it. Among all users who had discontinued preventive medication, 61.0% were still eligible to receive it.
Attitudes toward injectables
Among respondents who had never used a preventive treatment, 64.3% had zero to three MHDs. The remaining 35.7% had 4-7, 8-14, or 15 or more MHDs. Among current users of preventive treatments, 68.4% had four or more MHDs. Among those who had discontinued preventive treatment, 61.0% had four or more MHDs.
Patients who have never used preventive medication “have substantial management gaps,” said Dr. Nahas. High proportions of these patients have moderate or severe disability (64.7%), depression (43%), and anxiety (39%). The rates of these outcomes are higher in users who discontinued treatment, likely because of confounding by indication, she added.
The prevalence of anxiety was similar between those who currently used, formerly used, or never used preventive medications. However, there were differences between never-users and current or former users with respect to moderate to severe depression (never-users, 43%; current users, 49.4%; discontinued users, 46.5%) and moderate to severe disability (never-users, 64.7%; current users, 80.4%; discontinued users, 78.9%).
In all, 44.6% of those who discontinued preventive therapy reported safety and tolerability problems as reasons for stopping treatment. In addition, 39.7% reported that these medications did not prevent enough headaches. Some patients reported partial or temporary efficacy as a reason for discontinuation. Other reasons were related to health care costs and access and personal preferences. Only 9.2% of patients who discontinued treatment said that their headaches improved enough to stop medication.
The investigators also analyzed respondents’ interest in preventive therapies. Among respondents who had never used preventive therapies, 61.8% of those who were eligible to use them were somewhat or very interested in trying an oral prescription medication for migraine prevention. However, 59.1% of never-users who were eligible for preventive medications were not at all interested, not sure, or needed more information about trying an injectable preventive medication. About 40% were not at all interested in injectables. In general, current users and those who had discontinued medication were more interested in preventive medication, including injectables.
‘Disheartening’ discontinuation rates
There are likely multiple reasons for the low rate of migraine prevention treatment, said Dr. Nahas. Many people with migraine never consult a clinician, owing to factors such as stigma, cost, lack of access, and lack of awareness. In addition, patients with migraine are frequently misdiagnosed, she added.
“Other data suggest that only about a quarter of people with episodic migraine and under 5% of people with chronic migraine consult a clinician, receive an accurate diagnosis, and are prescribed appropriate therapy,” said Dr. Nahas.
When the data in this analysis were gathered, public awareness of migraine was much lower than it is today, and injectable migraine therapies had not gained broad acceptance, she noted. Dr. Nahas added it is possible that attitudes toward injectable preventive medications have changed.
“Would people still prefer daily oral medications? We can’t know for sure until we start asking,” she said. In addition, scientific advances and educational outreach have increased clinicians’ awareness, interest, and skill regarding injectable medications, she said.
“I would certainly hope to see that a much greater proportion of preventive-eligible persons with migraine were at least offered, if not currently taking, preventive medication,” said Dr. Nahas. “But there’s no pleasing everyone, so I think we would still see somewhat disheartening discontinuation rates. The reasons for discontinuation, however, might be less typified by concerns about safety and tolerability.”
Still relevant
Commenting on the study, Mia Tova Minen, MD, chief of headache research and associate professor of neurology and population health at NYU Langone Health, New York, noted that although CaMEO is an older study, its results are still highly relevant.
“Unfortunately, primary care providers are still uncomfortable prescribing migraine preventive medications, and this accounts for the large percentage [of patients] with migraine who, while eligible for migraine preventive therapy, are not offered it,” she said.
Although the public and primary care physicians are now more aware of preventive treatments for migraine, “the number of people offered migraine preventive medication still needs to increase dramatically,” said Dr. Minen.
The American Academy of Neurology’s guidelines for migraine prevention were published in 2012 and are currently being updated. The updated guidelines may include new evidence for candesartan and emerging treatments, such as melatonin and aerobic exercise.
“It is my hope that primary care providers will become more comfortable prescribing migraine preventive medications sooner,” said Dr. Minen.
The current findings suggest a need for additional ways of educating patients with migraine who are eligible for preventive therapies so that they can advocate for themselves, she added. They also suggest the idea of demanding more insurance coverage of behavioral therapies for migraine, because data indicate that these treatments have long-term efficacy and good safety profiles, said Dr. Minen.
An ‘invisible’ disorder
Also commenting on the study, Barbara L. Nye, MD, director of the headache fellowship and codirector of the headache clinic at Dartmouth-Hitchcock Medical Center, Lebanon, N.H., said the CaMEO cohort likely is representative of the general population of patients with migraine.
She noted that a significant weakness of the current study is that it examined data collected before the Food and Drug Administration approved monoclonal antibodies and therefore does not reflect patients’ current experience with medications.
“I believe that the attitudes and fears surrounding the use of injectable medication are now likely far less than previously reported, given the positive track record the new generation of once-a-month injectable medications has,” said Dr. Nye.
The findings reinforce the idea that either patients are not talking to their primary care physicians about their headaches and disability or that clinicians are not asking about them, she added. “Both issues are likely linked to the stigma that this disease state has surrounding it. This is an invisible neurological disorder to most,” Dr. Nye said.
The study was sponsored by Allergan before it was acquired by AbbVie. Dr. Nahas has served as a consultant, advisory board member, or speaker for AbbVie/Allergan, Alder/Lundbeck, Amgen/Novartis, Biohaven, Eli Lilly, Impel, Nesos Corp, Supernus, Teva, Theranica, and Zosano. She has not received and will not receive monetary compensation for this research. Dr. Minen has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, new research suggests. Investigators found that among patients with migraine who are eligible for preventive therapy, more than a third were not offered this option. In addition, fewer than 10% were currently taking preventive medication, and an additional 10% had discontinued preventive therapy.
“We confirmed that as of 2012 to 2013 – the years these data were collected from a large, comprehensive survey – gaps in care remained,” said study investigator Stephanie J. Nahas, MD, director of the headache medicine fellowship program, Thomas Jefferson University, Philadelphia. “In this preventive-eligible population, 35% reported never even being offered preventive medication.”
Furthermore, only 28% of patients taking preventive medication experienced a reduction in headache frequency to less than 4 days per month, which is a primary goal of treatment, said Dr. Nahas. Disease burden, as measured with scales of disability and affective comorbidities, remained substantial.
The findings were presented at the American Headache Society’s 2021 annual meeting.
Lack of efficacy?
In 2019, the American Headache Society published a position statement recommending that preventive treatment be considered for patients who have migraine and four or more monthly headache days (MHDs), regardless of their level of associated disability. However, previous data suggest few patients who are eligible for preventive treatment receive it. In addition, many who have used preventive medications do not adhere to their regimens because of problems with tolerability, efficacy, or both.
To identify treatment gaps and characterize self-reported use of preventive medications for migraine, the investigators examined data from the Chronic Migraine Epidemiology and Outcomes (CaMEO) study, a web-based survey conducted in a representative U.S. sample from September 2012 through November 2013.
The survey identified and characterized patients who met modified criteria for migraine consistent with those in ICHD-3. The researchers classified respondents who had migraine and four or more MHDs as potentially eligible for migraine preventive treatment.
The investigators assessed the study population’s use of oral preventive medications, migraine-related disability and burden, willingness to take preventive treatment, and reasons for discontinuation.
Assessments included the Migraine Disability Assessment Questionnaire, the Patient Health Questionnaire–9 for depression, the Generalized Anxiety Disorder 7-Item Scale, the Migraine Specific Quality of Life questionnaire, and the Migraine Symptom Severity Scale.
In all, 16,789 respondents met criteria for migraine, and 6,579 (39.2%) reported having at least four MHDs. The median age of this subgroup that was eligible for preventive treatment was 40.3 years, and approximately 79% were women.
Only 9.8% of respondents who were eligible for preventive medications were currently using an oral preventive medication. Among those who had ever tried an oral preventive medication, 53.6% discontinued it. Efficacy for patients who used medications appeared to be inadequate. Among all current users of preventive treatment, 68.4% continued to have at least four MHDs.
The researchers assessed treatment eligibility among patients not taking preventive medication. Among respondents who had never used a preventive treatment, 35.7% were eligible to receive it. Among all users who had discontinued preventive medication, 61.0% were still eligible to receive it.
Attitudes toward injectables
Among respondents who had never used a preventive treatment, 64.3% had zero to three MHDs. The remaining 35.7% had 4-7, 8-14, or 15 or more MHDs. Among current users of preventive treatments, 68.4% had four or more MHDs. Among those who had discontinued preventive treatment, 61.0% had four or more MHDs.
Patients who have never used preventive medication “have substantial management gaps,” said Dr. Nahas. High proportions of these patients have moderate or severe disability (64.7%), depression (43%), and anxiety (39%). The rates of these outcomes are higher in users who discontinued treatment, likely because of confounding by indication, she added.
The prevalence of anxiety was similar between those who currently used, formerly used, or never used preventive medications. However, there were differences between never-users and current or former users with respect to moderate to severe depression (never-users, 43%; current users, 49.4%; discontinued users, 46.5%) and moderate to severe disability (never-users, 64.7%; current users, 80.4%; discontinued users, 78.9%).
In all, 44.6% of those who discontinued preventive therapy reported safety and tolerability problems as reasons for stopping treatment. In addition, 39.7% reported that these medications did not prevent enough headaches. Some patients reported partial or temporary efficacy as a reason for discontinuation. Other reasons were related to health care costs and access and personal preferences. Only 9.2% of patients who discontinued treatment said that their headaches improved enough to stop medication.
The investigators also analyzed respondents’ interest in preventive therapies. Among respondents who had never used preventive therapies, 61.8% of those who were eligible to use them were somewhat or very interested in trying an oral prescription medication for migraine prevention. However, 59.1% of never-users who were eligible for preventive medications were not at all interested, not sure, or needed more information about trying an injectable preventive medication. About 40% were not at all interested in injectables. In general, current users and those who had discontinued medication were more interested in preventive medication, including injectables.
‘Disheartening’ discontinuation rates
There are likely multiple reasons for the low rate of migraine prevention treatment, said Dr. Nahas. Many people with migraine never consult a clinician, owing to factors such as stigma, cost, lack of access, and lack of awareness. In addition, patients with migraine are frequently misdiagnosed, she added.
“Other data suggest that only about a quarter of people with episodic migraine and under 5% of people with chronic migraine consult a clinician, receive an accurate diagnosis, and are prescribed appropriate therapy,” said Dr. Nahas.
When the data in this analysis were gathered, public awareness of migraine was much lower than it is today, and injectable migraine therapies had not gained broad acceptance, she noted. Dr. Nahas added it is possible that attitudes toward injectable preventive medications have changed.
“Would people still prefer daily oral medications? We can’t know for sure until we start asking,” she said. In addition, scientific advances and educational outreach have increased clinicians’ awareness, interest, and skill regarding injectable medications, she said.
“I would certainly hope to see that a much greater proportion of preventive-eligible persons with migraine were at least offered, if not currently taking, preventive medication,” said Dr. Nahas. “But there’s no pleasing everyone, so I think we would still see somewhat disheartening discontinuation rates. The reasons for discontinuation, however, might be less typified by concerns about safety and tolerability.”
Still relevant
Commenting on the study, Mia Tova Minen, MD, chief of headache research and associate professor of neurology and population health at NYU Langone Health, New York, noted that although CaMEO is an older study, its results are still highly relevant.
“Unfortunately, primary care providers are still uncomfortable prescribing migraine preventive medications, and this accounts for the large percentage [of patients] with migraine who, while eligible for migraine preventive therapy, are not offered it,” she said.
Although the public and primary care physicians are now more aware of preventive treatments for migraine, “the number of people offered migraine preventive medication still needs to increase dramatically,” said Dr. Minen.
The American Academy of Neurology’s guidelines for migraine prevention were published in 2012 and are currently being updated. The updated guidelines may include new evidence for candesartan and emerging treatments, such as melatonin and aerobic exercise.
“It is my hope that primary care providers will become more comfortable prescribing migraine preventive medications sooner,” said Dr. Minen.
The current findings suggest a need for additional ways of educating patients with migraine who are eligible for preventive therapies so that they can advocate for themselves, she added. They also suggest the idea of demanding more insurance coverage of behavioral therapies for migraine, because data indicate that these treatments have long-term efficacy and good safety profiles, said Dr. Minen.
An ‘invisible’ disorder
Also commenting on the study, Barbara L. Nye, MD, director of the headache fellowship and codirector of the headache clinic at Dartmouth-Hitchcock Medical Center, Lebanon, N.H., said the CaMEO cohort likely is representative of the general population of patients with migraine.
She noted that a significant weakness of the current study is that it examined data collected before the Food and Drug Administration approved monoclonal antibodies and therefore does not reflect patients’ current experience with medications.
“I believe that the attitudes and fears surrounding the use of injectable medication are now likely far less than previously reported, given the positive track record the new generation of once-a-month injectable medications has,” said Dr. Nye.
The findings reinforce the idea that either patients are not talking to their primary care physicians about their headaches and disability or that clinicians are not asking about them, she added. “Both issues are likely linked to the stigma that this disease state has surrounding it. This is an invisible neurological disorder to most,” Dr. Nye said.
The study was sponsored by Allergan before it was acquired by AbbVie. Dr. Nahas has served as a consultant, advisory board member, or speaker for AbbVie/Allergan, Alder/Lundbeck, Amgen/Novartis, Biohaven, Eli Lilly, Impel, Nesos Corp, Supernus, Teva, Theranica, and Zosano. She has not received and will not receive monetary compensation for this research. Dr. Minen has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM AHS 2021
Physician convicted in buprenorphine scheme faces up to 20 years in prison
A West Virginia physician faces up to 20 years in prison in the wake of his conviction by a federal jury for illegally distributing buprenorphine.
The jury convicted Sriramloo Kesari, MD, 78, of Charleston, for distributing buprenorphine outside the scope of medical practice, according to a U.S. Department of Justice statement.
Investigators from the Drug Enforcement Administration presented evidence at the trial that Dr. Kesari, a general practitioner, operated a cash-only business selling buprenorphine prescriptions.
Federal prosecutors said that the physician signed prescriptions, which were then distributed by an employee in exchange for cash. Dr. Kesari was often absent, at times physically located in California, according to the federal government.
Prosecutors indicted the West Virginia physician in September 2019 as part of an “opioid strikeforce takedown” in Ohio, Virginia, and West Virginia that resulted in charges against 13 individuals, including 11 physicians.
Dr. Kesari’s attorneys filed motions during the course of the lengthy case showing that psychiatric and neurological exams indicated that the physician was cognitively impaired.
Based on that evidence and the federal indictment, the West Virginia Board of Medicine suspended Dr. Kesari’s license in February 2020, stating that he is not “mentally and/or physically fit to practice medicine and surgery with reasonable skill and safety.”
Dr. Kesari was first licensed in West Virginia in 1979. In 1987, the Board of Medicine placed Dr. Kesari on a 3-year probation because of his failure to keep records for patients for whom he was prescribing controlled substances.
However, within a few months, the Board changed the probation order to allow Dr. Kesari to write prescriptions for schedule II and III substances in the Boone Hospital emergency room where he continued to work.
The physician had no other disciplinary actions until his license suspension, but the Board lists settlement of four malpractice cases and the dismissal of a fifth between 1986 and 2001.
A version of this article first appeared on Medscape.com.
A West Virginia physician faces up to 20 years in prison in the wake of his conviction by a federal jury for illegally distributing buprenorphine.
The jury convicted Sriramloo Kesari, MD, 78, of Charleston, for distributing buprenorphine outside the scope of medical practice, according to a U.S. Department of Justice statement.
Investigators from the Drug Enforcement Administration presented evidence at the trial that Dr. Kesari, a general practitioner, operated a cash-only business selling buprenorphine prescriptions.
Federal prosecutors said that the physician signed prescriptions, which were then distributed by an employee in exchange for cash. Dr. Kesari was often absent, at times physically located in California, according to the federal government.
Prosecutors indicted the West Virginia physician in September 2019 as part of an “opioid strikeforce takedown” in Ohio, Virginia, and West Virginia that resulted in charges against 13 individuals, including 11 physicians.
Dr. Kesari’s attorneys filed motions during the course of the lengthy case showing that psychiatric and neurological exams indicated that the physician was cognitively impaired.
Based on that evidence and the federal indictment, the West Virginia Board of Medicine suspended Dr. Kesari’s license in February 2020, stating that he is not “mentally and/or physically fit to practice medicine and surgery with reasonable skill and safety.”
Dr. Kesari was first licensed in West Virginia in 1979. In 1987, the Board of Medicine placed Dr. Kesari on a 3-year probation because of his failure to keep records for patients for whom he was prescribing controlled substances.
However, within a few months, the Board changed the probation order to allow Dr. Kesari to write prescriptions for schedule II and III substances in the Boone Hospital emergency room where he continued to work.
The physician had no other disciplinary actions until his license suspension, but the Board lists settlement of four malpractice cases and the dismissal of a fifth between 1986 and 2001.
A version of this article first appeared on Medscape.com.
A West Virginia physician faces up to 20 years in prison in the wake of his conviction by a federal jury for illegally distributing buprenorphine.
The jury convicted Sriramloo Kesari, MD, 78, of Charleston, for distributing buprenorphine outside the scope of medical practice, according to a U.S. Department of Justice statement.
Investigators from the Drug Enforcement Administration presented evidence at the trial that Dr. Kesari, a general practitioner, operated a cash-only business selling buprenorphine prescriptions.
Federal prosecutors said that the physician signed prescriptions, which were then distributed by an employee in exchange for cash. Dr. Kesari was often absent, at times physically located in California, according to the federal government.
Prosecutors indicted the West Virginia physician in September 2019 as part of an “opioid strikeforce takedown” in Ohio, Virginia, and West Virginia that resulted in charges against 13 individuals, including 11 physicians.
Dr. Kesari’s attorneys filed motions during the course of the lengthy case showing that psychiatric and neurological exams indicated that the physician was cognitively impaired.
Based on that evidence and the federal indictment, the West Virginia Board of Medicine suspended Dr. Kesari’s license in February 2020, stating that he is not “mentally and/or physically fit to practice medicine and surgery with reasonable skill and safety.”
Dr. Kesari was first licensed in West Virginia in 1979. In 1987, the Board of Medicine placed Dr. Kesari on a 3-year probation because of his failure to keep records for patients for whom he was prescribing controlled substances.
However, within a few months, the Board changed the probation order to allow Dr. Kesari to write prescriptions for schedule II and III substances in the Boone Hospital emergency room where he continued to work.
The physician had no other disciplinary actions until his license suspension, but the Board lists settlement of four malpractice cases and the dismissal of a fifth between 1986 and 2001.
A version of this article first appeared on Medscape.com.
Combination therapy may benefit patients with migraine
, according to a large retrospective analysis. The results lend hope that the combination may be synergistic, according to Andrew Blumenfeld, MD, director of the Headache Center of Southern California in Carlsbad. Dr. Blumenfeld presented at the American Headache Society’s 2021 annual meeting. The study was published online April 21 in Pain Therapy.
The retrospective analysis showed a 4-day reduction in headache days per month. In contrast, in the pivotal study for erenumab, the most commonly used anti-CGRP antibody among subjects in the study, showed a 2-day benefit in a subanalysis of patients who had failed at least two oral preventives.
There is mechanistic evidence to suggest the two therapies could be synergistic. OnabotulinumtoxinA is believed to inhibit the release of CGRP, and antibodies reduce CGRP levels. OnabotulinumtoxinA prevents activation of C-fibers in the trigeminal sensory afferents, but does not affect A-delta fibers.
On the other hand, most data indicate that the anti-CGRP antibody fremanezumab prevents activation of A-delta but not C-fibers, and a recent review argues that CGRP antibody nonresponders may have migraines driven by C-fibers or other pathways. “Thus, concomitant use of medications blocking the activation of meningeal C-fibers may provide a synergistic effect on the trigeminal nociceptive pathway,” the authors wrote.
Study finding match clinical practice
The results of the new study strengthen the case that the combination is effective, though proof would require prospective, randomized trials. “I think that it really gives credibility to what we are seeing in practice, which is that combined therapy often is much better than therapy with onabotulinumtoxinA alone, said Deborah Friedman, MD, MPH, who was asked to comment on the findings. Dr. Friedman is professor of neurology and ophthalmology at the University of Texas, Dallas.
The extra 4 migraine-free days per month is a significant benefit, said Stewart Tepper, MD, professor of neurology at the Geisel School of Medicine at Dartmouth, Hanover, N.H. “It’s an extra month and a half of no disability per year, and that’s on top of what onabotulinumtoxinA does. So it’s really a very important clinical finding,” Dr. Tepper said in an interview.
Many insurance companies refuse to pay for the combination therapy, despite the fact that relatively few migraine patients would likely seek it out, according to Dr. Friedman. “It’s just kind of a shame,” she said.
Insurance companies often object that the combination therapy is experimental, despite the widespread use of combination therapies in migraine. “It’s no more experimental in my opinion than any other combination of medications that we use. For people that have severe migraine, we use combination therapy all the time,” said Dr. Friedman.
Improvements with combination therapy
The study was a chart review of 257 patients who started on onabotulinumtoxinA and later initiated anti-CGRP antibody therapy. A total of 104 completed four visits after initiation of anti-CGRP antibody therapy (completers). Before starting any therapy, patients reported an average of 21 headache days per month in the overall group, and 22 among completers. That frequency dropped to 12 in both groups after onabotulinumtoxinA therapy (overall group difference, –9 days; 95% confidence interval, –8 to –11 days; completers group difference, –10; 95% CI, –7 to –12 days).
A total of 77.8% of subjects in the overall cohort took erenumab, 16.3% took galcanezumab, and 5.8% took fremanezumab. In the completers cohort, the percentages were 84.5%, 10.7%, and 4.9%, respectively.
Compared with baseline, both completers and noncompleters had clinically significant improvements in disability, as measured by at least a 5-point improvement in Migraine Disability Assessment (MIDAS) score at the 3-month visit (–5.8 for completers and –6.3 for the overall cohort group), the 6-month visit (–6.6 and –11.1), the 9-month visit (–8.3 and –6.1), and 1 year (–12.7 and –8.4).
At the first visit, 33.0% of completers had at least a 5-point reduction in MIDAS, as did 36.0% of the overall cohort group, and the trend continued at 6 months (39.8% and 45.1%), 9 months (43.7% and 43.7%), and at 1 year (45.3% and 44.8%).
The study was funded by Allergan. Dr. Blumenfeld has served on advisory boards for Aeon, AbbVie, Amgen, Alder, Biohaven, Teva, Supernus, Promius, Eaglet, and Lilly, and has received funding for speaking from AbbVie, Amgen, Pernix, Supernus, Depomed, Avanir, Promius, Teva, Eli Lilly, Lundbeck, Novartis, and Theranica. Dr. Tepper has consulted for Teva. Dr. Friedman has been on the advisory board for Allergan, Amgen, Lundbeck, Eli Lilly, and Teva Pharmaceuticals, and has received grant support from Allergan and Eli Lilly.
, according to a large retrospective analysis. The results lend hope that the combination may be synergistic, according to Andrew Blumenfeld, MD, director of the Headache Center of Southern California in Carlsbad. Dr. Blumenfeld presented at the American Headache Society’s 2021 annual meeting. The study was published online April 21 in Pain Therapy.
The retrospective analysis showed a 4-day reduction in headache days per month. In contrast, in the pivotal study for erenumab, the most commonly used anti-CGRP antibody among subjects in the study, showed a 2-day benefit in a subanalysis of patients who had failed at least two oral preventives.
There is mechanistic evidence to suggest the two therapies could be synergistic. OnabotulinumtoxinA is believed to inhibit the release of CGRP, and antibodies reduce CGRP levels. OnabotulinumtoxinA prevents activation of C-fibers in the trigeminal sensory afferents, but does not affect A-delta fibers.
On the other hand, most data indicate that the anti-CGRP antibody fremanezumab prevents activation of A-delta but not C-fibers, and a recent review argues that CGRP antibody nonresponders may have migraines driven by C-fibers or other pathways. “Thus, concomitant use of medications blocking the activation of meningeal C-fibers may provide a synergistic effect on the trigeminal nociceptive pathway,” the authors wrote.
Study finding match clinical practice
The results of the new study strengthen the case that the combination is effective, though proof would require prospective, randomized trials. “I think that it really gives credibility to what we are seeing in practice, which is that combined therapy often is much better than therapy with onabotulinumtoxinA alone, said Deborah Friedman, MD, MPH, who was asked to comment on the findings. Dr. Friedman is professor of neurology and ophthalmology at the University of Texas, Dallas.
The extra 4 migraine-free days per month is a significant benefit, said Stewart Tepper, MD, professor of neurology at the Geisel School of Medicine at Dartmouth, Hanover, N.H. “It’s an extra month and a half of no disability per year, and that’s on top of what onabotulinumtoxinA does. So it’s really a very important clinical finding,” Dr. Tepper said in an interview.
Many insurance companies refuse to pay for the combination therapy, despite the fact that relatively few migraine patients would likely seek it out, according to Dr. Friedman. “It’s just kind of a shame,” she said.
Insurance companies often object that the combination therapy is experimental, despite the widespread use of combination therapies in migraine. “It’s no more experimental in my opinion than any other combination of medications that we use. For people that have severe migraine, we use combination therapy all the time,” said Dr. Friedman.
Improvements with combination therapy
The study was a chart review of 257 patients who started on onabotulinumtoxinA and later initiated anti-CGRP antibody therapy. A total of 104 completed four visits after initiation of anti-CGRP antibody therapy (completers). Before starting any therapy, patients reported an average of 21 headache days per month in the overall group, and 22 among completers. That frequency dropped to 12 in both groups after onabotulinumtoxinA therapy (overall group difference, –9 days; 95% confidence interval, –8 to –11 days; completers group difference, –10; 95% CI, –7 to –12 days).
A total of 77.8% of subjects in the overall cohort took erenumab, 16.3% took galcanezumab, and 5.8% took fremanezumab. In the completers cohort, the percentages were 84.5%, 10.7%, and 4.9%, respectively.
Compared with baseline, both completers and noncompleters had clinically significant improvements in disability, as measured by at least a 5-point improvement in Migraine Disability Assessment (MIDAS) score at the 3-month visit (–5.8 for completers and –6.3 for the overall cohort group), the 6-month visit (–6.6 and –11.1), the 9-month visit (–8.3 and –6.1), and 1 year (–12.7 and –8.4).
At the first visit, 33.0% of completers had at least a 5-point reduction in MIDAS, as did 36.0% of the overall cohort group, and the trend continued at 6 months (39.8% and 45.1%), 9 months (43.7% and 43.7%), and at 1 year (45.3% and 44.8%).
The study was funded by Allergan. Dr. Blumenfeld has served on advisory boards for Aeon, AbbVie, Amgen, Alder, Biohaven, Teva, Supernus, Promius, Eaglet, and Lilly, and has received funding for speaking from AbbVie, Amgen, Pernix, Supernus, Depomed, Avanir, Promius, Teva, Eli Lilly, Lundbeck, Novartis, and Theranica. Dr. Tepper has consulted for Teva. Dr. Friedman has been on the advisory board for Allergan, Amgen, Lundbeck, Eli Lilly, and Teva Pharmaceuticals, and has received grant support from Allergan and Eli Lilly.
, according to a large retrospective analysis. The results lend hope that the combination may be synergistic, according to Andrew Blumenfeld, MD, director of the Headache Center of Southern California in Carlsbad. Dr. Blumenfeld presented at the American Headache Society’s 2021 annual meeting. The study was published online April 21 in Pain Therapy.
The retrospective analysis showed a 4-day reduction in headache days per month. In contrast, in the pivotal study for erenumab, the most commonly used anti-CGRP antibody among subjects in the study, showed a 2-day benefit in a subanalysis of patients who had failed at least two oral preventives.
There is mechanistic evidence to suggest the two therapies could be synergistic. OnabotulinumtoxinA is believed to inhibit the release of CGRP, and antibodies reduce CGRP levels. OnabotulinumtoxinA prevents activation of C-fibers in the trigeminal sensory afferents, but does not affect A-delta fibers.
On the other hand, most data indicate that the anti-CGRP antibody fremanezumab prevents activation of A-delta but not C-fibers, and a recent review argues that CGRP antibody nonresponders may have migraines driven by C-fibers or other pathways. “Thus, concomitant use of medications blocking the activation of meningeal C-fibers may provide a synergistic effect on the trigeminal nociceptive pathway,” the authors wrote.
Study finding match clinical practice
The results of the new study strengthen the case that the combination is effective, though proof would require prospective, randomized trials. “I think that it really gives credibility to what we are seeing in practice, which is that combined therapy often is much better than therapy with onabotulinumtoxinA alone, said Deborah Friedman, MD, MPH, who was asked to comment on the findings. Dr. Friedman is professor of neurology and ophthalmology at the University of Texas, Dallas.
The extra 4 migraine-free days per month is a significant benefit, said Stewart Tepper, MD, professor of neurology at the Geisel School of Medicine at Dartmouth, Hanover, N.H. “It’s an extra month and a half of no disability per year, and that’s on top of what onabotulinumtoxinA does. So it’s really a very important clinical finding,” Dr. Tepper said in an interview.
Many insurance companies refuse to pay for the combination therapy, despite the fact that relatively few migraine patients would likely seek it out, according to Dr. Friedman. “It’s just kind of a shame,” she said.
Insurance companies often object that the combination therapy is experimental, despite the widespread use of combination therapies in migraine. “It’s no more experimental in my opinion than any other combination of medications that we use. For people that have severe migraine, we use combination therapy all the time,” said Dr. Friedman.
Improvements with combination therapy
The study was a chart review of 257 patients who started on onabotulinumtoxinA and later initiated anti-CGRP antibody therapy. A total of 104 completed four visits after initiation of anti-CGRP antibody therapy (completers). Before starting any therapy, patients reported an average of 21 headache days per month in the overall group, and 22 among completers. That frequency dropped to 12 in both groups after onabotulinumtoxinA therapy (overall group difference, –9 days; 95% confidence interval, –8 to –11 days; completers group difference, –10; 95% CI, –7 to –12 days).
A total of 77.8% of subjects in the overall cohort took erenumab, 16.3% took galcanezumab, and 5.8% took fremanezumab. In the completers cohort, the percentages were 84.5%, 10.7%, and 4.9%, respectively.
Compared with baseline, both completers and noncompleters had clinically significant improvements in disability, as measured by at least a 5-point improvement in Migraine Disability Assessment (MIDAS) score at the 3-month visit (–5.8 for completers and –6.3 for the overall cohort group), the 6-month visit (–6.6 and –11.1), the 9-month visit (–8.3 and –6.1), and 1 year (–12.7 and –8.4).
At the first visit, 33.0% of completers had at least a 5-point reduction in MIDAS, as did 36.0% of the overall cohort group, and the trend continued at 6 months (39.8% and 45.1%), 9 months (43.7% and 43.7%), and at 1 year (45.3% and 44.8%).
The study was funded by Allergan. Dr. Blumenfeld has served on advisory boards for Aeon, AbbVie, Amgen, Alder, Biohaven, Teva, Supernus, Promius, Eaglet, and Lilly, and has received funding for speaking from AbbVie, Amgen, Pernix, Supernus, Depomed, Avanir, Promius, Teva, Eli Lilly, Lundbeck, Novartis, and Theranica. Dr. Tepper has consulted for Teva. Dr. Friedman has been on the advisory board for Allergan, Amgen, Lundbeck, Eli Lilly, and Teva Pharmaceuticals, and has received grant support from Allergan and Eli Lilly.
FROM AHS 2021
Not your ordinary neuropathy
She has had a diagnosis of type 2 diabetes for the past 4 years. She initially presented with polyuria/polydipsia and a hemoglobin A1c level of 9.5. She has previously not tolerated metformin, and did not want to take any subsequent medications. She was seen 4 months ago and at that time had an A1c level of 12.5. She decided she wanted to really treat her diabetes as well as she could. She started consuming a low carbohydrate diet, restarted metformin and began using a continuous glucose monitor. She also started taking nighttime glargine insulin, and mealtime insulin apart. She reports she lost 20 pounds over the past 4 months, her blood sugars now run between 100-120 fasting, and up to 180 before meals. She has had a severe, sharp pain in both of her feet over the past month that is interfering with sleep and makes walking painful for her. An exam reveals hyperesthesia of both feet, and her A1c level is 7.5. What is the most likely cause of her neuropathic symptoms?
A. Vitamin B12 deficiency
B. Diabetic neuropathy
C. Insulin neuritis
D. Charcot-Marie-Tooth disease
The most likely cause
In this case, certainly considering vitamin B12 deficiency is reasonable. It is highly unlikely though, given the rapidity of onset of symptoms, and that the patient has been on metformin for a very short period of time. Chronic metformin use is associated with low B12 levels, and the American Diabetes Association has advised that regular monitoring of vitamin B12 levels should be done on patients who are on long-term metformin.1
Diabetic neuropathy is also unlikely, given the rapidity of symptoms in this patient. What is most likely in this patient is treatment-induced neuropathy (TIN), first described with the name “insulin neuritis”.
Research on TIN
Gibbons and colleagues evaluated 16 patients with diabetes with recent marked, rapid improvement in glycemic control who developed a sudden, painful neuropathy.2 All developed symptoms within 8 weeks of intensive glucose control, with 69% having autonomic dysfunction as well, and all developing worsening retinopathy.
Gibbons and Freeman did a retrospective study of patients referred to a diabetic neuropathy clinic over a 5-year period to try to understand how prevalent TIN is.3
A total of 954 patients were evaluated for diabetic neuropathy. Treatment induced neuropathy was defined as a painful neuropathy and/or autonomic dysfunction occurring within 8 weeks of intensified treatment and a drop of the A1c level greater than 2 over a 3-month period.
A total of 104 patients (10.9%) met the criteria for treatment induced neuropathy. Patients who had a decrease in A1c had a much greater chance of developing a painful or autonomic neuropathy than patients who had no change in A1c (P < .0001). The same patients had a much higher risk of developing retinopathy (P < .001). The greater the reduction in A1c, the greater the risk. Patients whose A1c decreased by 2%-3% over 3 months had an absolute risk of 20%, whereas those with a A1c decease of greater than 4% had an 80% absolute risk.
Siddique and colleagues reported on three cases with very different clinical presentations of TIN.4 One patient had an acute third nerve palsy, another patient had a lumbosacral radiculoplexus neuropathy, and the third patient presented with a diffuse painful sensory neuropathy and postural hypotension.
Most patients improve over time from their neuropathic symptoms, with better recovery in patients with type 1 diabetes.2
Pearl
Strongly consider treatment induced neuropathy in your patients with diabetes who present with acute painful neuropathy and/or autonomic dysfunction in the setting of rapid improvement of glucose control.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].
References
1. American Diabetes Association. Diabetes Care. 2019 Jan;42(Suppl 1):S90-102.
2. Gibbons CH and Freeman R. Ann Neurol 2010; 67:534–41.
3. Gibbons CH and Freeman R. Brain. 2015;138:43-52.
4. Siddique N et al. Endocrinol Diabetes Metab Case Rep. 2020 Feb 26;2020:19-0140.
She has had a diagnosis of type 2 diabetes for the past 4 years. She initially presented with polyuria/polydipsia and a hemoglobin A1c level of 9.5. She has previously not tolerated metformin, and did not want to take any subsequent medications. She was seen 4 months ago and at that time had an A1c level of 12.5. She decided she wanted to really treat her diabetes as well as she could. She started consuming a low carbohydrate diet, restarted metformin and began using a continuous glucose monitor. She also started taking nighttime glargine insulin, and mealtime insulin apart. She reports she lost 20 pounds over the past 4 months, her blood sugars now run between 100-120 fasting, and up to 180 before meals. She has had a severe, sharp pain in both of her feet over the past month that is interfering with sleep and makes walking painful for her. An exam reveals hyperesthesia of both feet, and her A1c level is 7.5. What is the most likely cause of her neuropathic symptoms?
A. Vitamin B12 deficiency
B. Diabetic neuropathy
C. Insulin neuritis
D. Charcot-Marie-Tooth disease
The most likely cause
In this case, certainly considering vitamin B12 deficiency is reasonable. It is highly unlikely though, given the rapidity of onset of symptoms, and that the patient has been on metformin for a very short period of time. Chronic metformin use is associated with low B12 levels, and the American Diabetes Association has advised that regular monitoring of vitamin B12 levels should be done on patients who are on long-term metformin.1
Diabetic neuropathy is also unlikely, given the rapidity of symptoms in this patient. What is most likely in this patient is treatment-induced neuropathy (TIN), first described with the name “insulin neuritis”.
Research on TIN
Gibbons and colleagues evaluated 16 patients with diabetes with recent marked, rapid improvement in glycemic control who developed a sudden, painful neuropathy.2 All developed symptoms within 8 weeks of intensive glucose control, with 69% having autonomic dysfunction as well, and all developing worsening retinopathy.
Gibbons and Freeman did a retrospective study of patients referred to a diabetic neuropathy clinic over a 5-year period to try to understand how prevalent TIN is.3
A total of 954 patients were evaluated for diabetic neuropathy. Treatment induced neuropathy was defined as a painful neuropathy and/or autonomic dysfunction occurring within 8 weeks of intensified treatment and a drop of the A1c level greater than 2 over a 3-month period.
A total of 104 patients (10.9%) met the criteria for treatment induced neuropathy. Patients who had a decrease in A1c had a much greater chance of developing a painful or autonomic neuropathy than patients who had no change in A1c (P < .0001). The same patients had a much higher risk of developing retinopathy (P < .001). The greater the reduction in A1c, the greater the risk. Patients whose A1c decreased by 2%-3% over 3 months had an absolute risk of 20%, whereas those with a A1c decease of greater than 4% had an 80% absolute risk.
Siddique and colleagues reported on three cases with very different clinical presentations of TIN.4 One patient had an acute third nerve palsy, another patient had a lumbosacral radiculoplexus neuropathy, and the third patient presented with a diffuse painful sensory neuropathy and postural hypotension.
Most patients improve over time from their neuropathic symptoms, with better recovery in patients with type 1 diabetes.2
Pearl
Strongly consider treatment induced neuropathy in your patients with diabetes who present with acute painful neuropathy and/or autonomic dysfunction in the setting of rapid improvement of glucose control.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].
References
1. American Diabetes Association. Diabetes Care. 2019 Jan;42(Suppl 1):S90-102.
2. Gibbons CH and Freeman R. Ann Neurol 2010; 67:534–41.
3. Gibbons CH and Freeman R. Brain. 2015;138:43-52.
4. Siddique N et al. Endocrinol Diabetes Metab Case Rep. 2020 Feb 26;2020:19-0140.
She has had a diagnosis of type 2 diabetes for the past 4 years. She initially presented with polyuria/polydipsia and a hemoglobin A1c level of 9.5. She has previously not tolerated metformin, and did not want to take any subsequent medications. She was seen 4 months ago and at that time had an A1c level of 12.5. She decided she wanted to really treat her diabetes as well as she could. She started consuming a low carbohydrate diet, restarted metformin and began using a continuous glucose monitor. She also started taking nighttime glargine insulin, and mealtime insulin apart. She reports she lost 20 pounds over the past 4 months, her blood sugars now run between 100-120 fasting, and up to 180 before meals. She has had a severe, sharp pain in both of her feet over the past month that is interfering with sleep and makes walking painful for her. An exam reveals hyperesthesia of both feet, and her A1c level is 7.5. What is the most likely cause of her neuropathic symptoms?
A. Vitamin B12 deficiency
B. Diabetic neuropathy
C. Insulin neuritis
D. Charcot-Marie-Tooth disease
The most likely cause
In this case, certainly considering vitamin B12 deficiency is reasonable. It is highly unlikely though, given the rapidity of onset of symptoms, and that the patient has been on metformin for a very short period of time. Chronic metformin use is associated with low B12 levels, and the American Diabetes Association has advised that regular monitoring of vitamin B12 levels should be done on patients who are on long-term metformin.1
Diabetic neuropathy is also unlikely, given the rapidity of symptoms in this patient. What is most likely in this patient is treatment-induced neuropathy (TIN), first described with the name “insulin neuritis”.
Research on TIN
Gibbons and colleagues evaluated 16 patients with diabetes with recent marked, rapid improvement in glycemic control who developed a sudden, painful neuropathy.2 All developed symptoms within 8 weeks of intensive glucose control, with 69% having autonomic dysfunction as well, and all developing worsening retinopathy.
Gibbons and Freeman did a retrospective study of patients referred to a diabetic neuropathy clinic over a 5-year period to try to understand how prevalent TIN is.3
A total of 954 patients were evaluated for diabetic neuropathy. Treatment induced neuropathy was defined as a painful neuropathy and/or autonomic dysfunction occurring within 8 weeks of intensified treatment and a drop of the A1c level greater than 2 over a 3-month period.
A total of 104 patients (10.9%) met the criteria for treatment induced neuropathy. Patients who had a decrease in A1c had a much greater chance of developing a painful or autonomic neuropathy than patients who had no change in A1c (P < .0001). The same patients had a much higher risk of developing retinopathy (P < .001). The greater the reduction in A1c, the greater the risk. Patients whose A1c decreased by 2%-3% over 3 months had an absolute risk of 20%, whereas those with a A1c decease of greater than 4% had an 80% absolute risk.
Siddique and colleagues reported on three cases with very different clinical presentations of TIN.4 One patient had an acute third nerve palsy, another patient had a lumbosacral radiculoplexus neuropathy, and the third patient presented with a diffuse painful sensory neuropathy and postural hypotension.
Most patients improve over time from their neuropathic symptoms, with better recovery in patients with type 1 diabetes.2
Pearl
Strongly consider treatment induced neuropathy in your patients with diabetes who present with acute painful neuropathy and/or autonomic dysfunction in the setting of rapid improvement of glucose control.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].
References
1. American Diabetes Association. Diabetes Care. 2019 Jan;42(Suppl 1):S90-102.
2. Gibbons CH and Freeman R. Ann Neurol 2010; 67:534–41.
3. Gibbons CH and Freeman R. Brain. 2015;138:43-52.
4. Siddique N et al. Endocrinol Diabetes Metab Case Rep. 2020 Feb 26;2020:19-0140.