AAN Annual Meeting

VANCOUVER – An investigational antibody that targets the calcitonin gene-related peptide (CGRP) receptor may be efficacious and safe in the longer term for preventing episodic migraine, data from an ongoing extension of a phase II trial showed.

Among the 483 adults studied, the benefit seen with Amgen’s 334 antibody (AMG 334) at the highest dose at 12 weeks persisted out to a year, according to interim results reported at the annual meeting of the American Academy of Neurology.

Susan London/Frontline Medical News

At that time, patients on average were having roughly 5 fewer migraine days each month. Nearly two-thirds had experienced at least a halving of monthly migraine days, and nearly one-fifth had become totally migraine free. In addition, the antibody’s good safety profile also held up.

“These data strongly support the further investigation of AMG 334 as a potential preventive medication,” commented presenting author Dr. Stephen Silberstein, professor and director of the headache center at Thomas Jefferson University, Philadelphia.

“If you give a monoclonal antibody to someone with migraine and it takes away the associated features, then you just wind up with a headache day,” Dr. Silberstein noted. “But analysis clearly shows the reduction in migraine days with a concomitant reduction in headache days, showing you are not just removing the associated symptoms.”

It is too early to say whether the antibody is actually modifying the underlying disease, according to Dr. Silberstein. That will require a randomized withdrawal trial, assessing whether patients who stop treatment have a recurrence.

In any event, on the basis of the favorable findings from the phase II trial and its extension, a phase III trial, the Study to Evaluate the Efficacy and Safety of AMG 334 in Migraine Prevention (STRIVE), is now underway.

Four antibodies targeting CGRP signaling are now being investigated for migraine prevention, but AMG 334 is the only one targeting the receptor, noted session attendee Dr. Denise E. Chou of the department of neurology at Columbia University and director of the Columbia University headache center, New York.

“Particularly striking is the almost 20% rate of 100% remission. That’s remarkable, because it’s unheard of for any of the current existing migraine therapies,” she noted. The antibody’s longer half-life (translating to greater convenience for patients) and good safety profile are also pluses.

“With the four different antibodies out there, it’s kind of a race,” Dr. Chou commented. “We’ll have to see which have the best efficacy rates and side effect profiles, and which are going to be the best in terms of patient compliance and dosing scheme.”

Compared with some other trials, the AMG 334 trial enrolled a population that had episodic migraine, which is relatively easier to treat, Dr. Chou noted.

“We know, in general, that chronic refractory patients tend to have lower response rates to therapies,” she said. “But it is nice that there are different studies looking at different populations, because that’s what we see, a very heterogeneous clinic population. To be able to reflect the real-world setting is important.”

Patients were eligible for the Amgen-sponsored trial if they had 4-14 migraine days and fewer than 15 headache days per month. They could have experienced failure of up to two previous prophylactic therapies. Rescue medications were allowed, but medication overuse was not.

The patients were randomized 2:2:2:3 to monthly subcutaneous injections of AMG 334 at doses of 7 mg, 21 mg, or 70 mg, or to placebo, on a double-blind basis.

At baseline, the patients had about 9 migraine days and 10 headache days each month so that migraine accounted for most of the total, Dr. Silberstein noted.

At 12 weeks, the change in monthly migraine days – the trial’s primary outcome – was greater with the 70-mg dose than with placebo, with a reduction of 3.40 days vs. 2.28 days each month (P = .021) (Lancet Neurol. 2016 Apr.;15[4]:382-90).

A post hoc analysis suggested that this difference was already significant merely 2 weeks into treatment, Dr. Silberstein reported. The reductions seen with the lower doses were not significant.

All patients were then switched to the 70-mg dose of AMG 334 on the open-label extension, which is planned to continue for up to 5 years. The results showed that both lower-dose groups and the placebo group quickly caught up to their peers on the higher dose when it came to the reduction in monthly migraine days.

“In contrast to both the topiramate and botulinum [toxin] studies, at 16 weeks, there was no difference between patients who had started on the higher dose of [AMG 334] or who were transferred over,” Dr. Silberstein commented. “If one does an individual analysis of patients who were before on placebo or the lower doses, each of them caught up, which suggests a difference in the [mechanism of] … botulinum toxin or topiramate – because with those drugs, they never caught up at the end of 6 months.”

At 52 weeks, the patients as a whole were having about 5 fewer migraine days each month, compared with baseline. Overall, 62.3% of patients had achieved a reduction of at least 50% in monthly migraine days; 38.4%, a reduction of at least 75%; and 18.5%, a reduction of 100%.

The pattern was similar when it came to monthly migraine-specific medication days, monthly headache days, and monthly migraine attacks, according to Dr. Silberstein.

“The safety and tolerability during the open-label phase were similar to that in the double-blind phase,” he noted. “One of the reasons this is important is that, unlike small molecules, the monoclonal antibodies are not metabolized in the liver, but are metabolized in the reticuloendothelial system. So, the concept of small-molecule toxicity does not exist.”

Amgen sponsored the trial. Dr. Silberstein disclosed that he receives consulting fees from Amgen.

VANCOUVER – An investigational antibody that targets the calcitonin gene-related peptide (CGRP) receptor may be efficacious and safe in the longer term for preventing episodic migraine, data from an ongoing extension of a phase II trial showed.

Among the 483 adults studied, the benefit seen with Amgen’s 334 antibody (AMG 334) at the highest dose at 12 weeks persisted out to a year, according to interim results reported at the annual meeting of the American Academy of Neurology.

Susan London/Frontline Medical News

At that time, patients on average were having roughly 5 fewer migraine days each month. Nearly two-thirds had experienced at least a halving of monthly migraine days, and nearly one-fifth had become totally migraine free. In addition, the antibody’s good safety profile also held up.

“These data strongly support the further investigation of AMG 334 as a potential preventive medication,” commented presenting author Dr. Stephen Silberstein, professor and director of the headache center at Thomas Jefferson University, Philadelphia.

“If you give a monoclonal antibody to someone with migraine and it takes away the associated features, then you just wind up with a headache day,” Dr. Silberstein noted. “But analysis clearly shows the reduction in migraine days with a concomitant reduction in headache days, showing you are not just removing the associated symptoms.”

It is too early to say whether the antibody is actually modifying the underlying disease, according to Dr. Silberstein. That will require a randomized withdrawal trial, assessing whether patients who stop treatment have a recurrence.

In any event, on the basis of the favorable findings from the phase II trial and its extension, a phase III trial, the Study to Evaluate the Efficacy and Safety of AMG 334 in Migraine Prevention (STRIVE), is now underway.

Four antibodies targeting CGRP signaling are now being investigated for migraine prevention, but AMG 334 is the only one targeting the receptor, noted session attendee Dr. Denise E. Chou of the department of neurology at Columbia University and director of the Columbia University headache center, New York.

“Particularly striking is the almost 20% rate of 100% remission. That’s remarkable, because it’s unheard of for any of the current existing migraine therapies,” she noted. The antibody’s longer half-life (translating to greater convenience for patients) and good safety profile are also pluses.

“With the four different antibodies out there, it’s kind of a race,” Dr. Chou commented. “We’ll have to see which have the best efficacy rates and side effect profiles, and which are going to be the best in terms of patient compliance and dosing scheme.”

Compared with some other trials, the AMG 334 trial enrolled a population that had episodic migraine, which is relatively easier to treat, Dr. Chou noted.

“We know, in general, that chronic refractory patients tend to have lower response rates to therapies,” she said. “But it is nice that there are different studies looking at different populations, because that’s what we see, a very heterogeneous clinic population. To be able to reflect the real-world setting is important.”

Patients were eligible for the Amgen-sponsored trial if they had 4-14 migraine days and fewer than 15 headache days per month. They could have experienced failure of up to two previous prophylactic therapies. Rescue medications were allowed, but medication overuse was not.

The patients were randomized 2:2:2:3 to monthly subcutaneous injections of AMG 334 at doses of 7 mg, 21 mg, or 70 mg, or to placebo, on a double-blind basis.

At baseline, the patients had about 9 migraine days and 10 headache days each month so that migraine accounted for most of the total, Dr. Silberstein noted.

At 12 weeks, the change in monthly migraine days – the trial’s primary outcome – was greater with the 70-mg dose than with placebo, with a reduction of 3.40 days vs. 2.28 days each month (P = .021) (Lancet Neurol. 2016 Apr.;15[4]:382-90).

A post hoc analysis suggested that this difference was already significant merely 2 weeks into treatment, Dr. Silberstein reported. The reductions seen with the lower doses were not significant.

All patients were then switched to the 70-mg dose of AMG 334 on the open-label extension, which is planned to continue for up to 5 years. The results showed that both lower-dose groups and the placebo group quickly caught up to their peers on the higher dose when it came to the reduction in monthly migraine days.

“In contrast to both the topiramate and botulinum [toxin] studies, at 16 weeks, there was no difference between patients who had started on the higher dose of [AMG 334] or who were transferred over,” Dr. Silberstein commented. “If one does an individual analysis of patients who were before on placebo or the lower doses, each of them caught up, which suggests a difference in the [mechanism of] … botulinum toxin or topiramate – because with those drugs, they never caught up at the end of 6 months.”

At 52 weeks, the patients as a whole were having about 5 fewer migraine days each month, compared with baseline. Overall, 62.3% of patients had achieved a reduction of at least 50% in monthly migraine days; 38.4%, a reduction of at least 75%; and 18.5%, a reduction of 100%.

The pattern was similar when it came to monthly migraine-specific medication days, monthly headache days, and monthly migraine attacks, according to Dr. Silberstein.

“The safety and tolerability during the open-label phase were similar to that in the double-blind phase,” he noted. “One of the reasons this is important is that, unlike small molecules, the monoclonal antibodies are not metabolized in the liver, but are metabolized in the reticuloendothelial system. So, the concept of small-molecule toxicity does not exist.”

Amgen sponsored the trial. Dr. Silberstein disclosed that he receives consulting fees from Amgen.

VANCOUVER – An investigational antibody that targets the calcitonin gene-related peptide (CGRP) receptor may be efficacious and safe in the longer term for preventing episodic migraine, data from an ongoing extension of a phase II trial showed.

Among the 483 adults studied, the benefit seen with Amgen’s 334 antibody (AMG 334) at the highest dose at 12 weeks persisted out to a year, according to interim results reported at the annual meeting of the American Academy of Neurology.

Susan London/Frontline Medical News

At that time, patients on average were having roughly 5 fewer migraine days each month. Nearly two-thirds had experienced at least a halving of monthly migraine days, and nearly one-fifth had become totally migraine free. In addition, the antibody’s good safety profile also held up.

“These data strongly support the further investigation of AMG 334 as a potential preventive medication,” commented presenting author Dr. Stephen Silberstein, professor and director of the headache center at Thomas Jefferson University, Philadelphia.

“If you give a monoclonal antibody to someone with migraine and it takes away the associated features, then you just wind up with a headache day,” Dr. Silberstein noted. “But analysis clearly shows the reduction in migraine days with a concomitant reduction in headache days, showing you are not just removing the associated symptoms.”

It is too early to say whether the antibody is actually modifying the underlying disease, according to Dr. Silberstein. That will require a randomized withdrawal trial, assessing whether patients who stop treatment have a recurrence.

In any event, on the basis of the favorable findings from the phase II trial and its extension, a phase III trial, the Study to Evaluate the Efficacy and Safety of AMG 334 in Migraine Prevention (STRIVE), is now underway.

Four antibodies targeting CGRP signaling are now being investigated for migraine prevention, but AMG 334 is the only one targeting the receptor, noted session attendee Dr. Denise E. Chou of the department of neurology at Columbia University and director of the Columbia University headache center, New York.

“Particularly striking is the almost 20% rate of 100% remission. That’s remarkable, because it’s unheard of for any of the current existing migraine therapies,” she noted. The antibody’s longer half-life (translating to greater convenience for patients) and good safety profile are also pluses.

“With the four different antibodies out there, it’s kind of a race,” Dr. Chou commented. “We’ll have to see which have the best efficacy rates and side effect profiles, and which are going to be the best in terms of patient compliance and dosing scheme.”

Compared with some other trials, the AMG 334 trial enrolled a population that had episodic migraine, which is relatively easier to treat, Dr. Chou noted.

“We know, in general, that chronic refractory patients tend to have lower response rates to therapies,” she said. “But it is nice that there are different studies looking at different populations, because that’s what we see, a very heterogeneous clinic population. To be able to reflect the real-world setting is important.”

Patients were eligible for the Amgen-sponsored trial if they had 4-14 migraine days and fewer than 15 headache days per month. They could have experienced failure of up to two previous prophylactic therapies. Rescue medications were allowed, but medication overuse was not.

The patients were randomized 2:2:2:3 to monthly subcutaneous injections of AMG 334 at doses of 7 mg, 21 mg, or 70 mg, or to placebo, on a double-blind basis.

At baseline, the patients had about 9 migraine days and 10 headache days each month so that migraine accounted for most of the total, Dr. Silberstein noted.

At 12 weeks, the change in monthly migraine days – the trial’s primary outcome – was greater with the 70-mg dose than with placebo, with a reduction of 3.40 days vs. 2.28 days each month (P = .021) (Lancet Neurol. 2016 Apr.;15[4]:382-90).

A post hoc analysis suggested that this difference was already significant merely 2 weeks into treatment, Dr. Silberstein reported. The reductions seen with the lower doses were not significant.

All patients were then switched to the 70-mg dose of AMG 334 on the open-label extension, which is planned to continue for up to 5 years. The results showed that both lower-dose groups and the placebo group quickly caught up to their peers on the higher dose when it came to the reduction in monthly migraine days.

“In contrast to both the topiramate and botulinum [toxin] studies, at 16 weeks, there was no difference between patients who had started on the higher dose of [AMG 334] or who were transferred over,” Dr. Silberstein commented. “If one does an individual analysis of patients who were before on placebo or the lower doses, each of them caught up, which suggests a difference in the [mechanism of] … botulinum toxin or topiramate – because with those drugs, they never caught up at the end of 6 months.”

At 52 weeks, the patients as a whole were having about 5 fewer migraine days each month, compared with baseline. Overall, 62.3% of patients had achieved a reduction of at least 50% in monthly migraine days; 38.4%, a reduction of at least 75%; and 18.5%, a reduction of 100%.

The pattern was similar when it came to monthly migraine-specific medication days, monthly headache days, and monthly migraine attacks, according to Dr. Silberstein.

“The safety and tolerability during the open-label phase were similar to that in the double-blind phase,” he noted. “One of the reasons this is important is that, unlike small molecules, the monoclonal antibodies are not metabolized in the liver, but are metabolized in the reticuloendothelial system. So, the concept of small-molecule toxicity does not exist.”

Amgen sponsored the trial. Dr. Silberstein disclosed that he receives consulting fees from Amgen.

VANCOUVER – More than two-thirds of patients with definite or probable misdiagnosis of multiple sclerosis took unnecessary disease-modifying therapy and nearly one-third experienced unnecessary morbidity in a prospective pilot study.

The findings highlight a problem that has been noted before in the medical literature, but since many instances are case reports of unusual cases or were published about 20 or more years ago, they may not reflect the current spectrum of misdiagnosis, Dr. Andrew J. Solomon said at the annual meeting of the American Academy of Neurology.

During a 13-month period, neurologists at four U.S. academic multiple sclerosis centers reported that 51 (46%) of 110 misdiagnosed patients had “definite” misdiagnosis because an alternate diagnosis was identified after assessing clinical, laboratory, and neuroimaging data, while 59 had “probable” misdiagnoses.

Participating neurologists felt that the misdiagnoses were based in part on inappropriately attributing symptoms to demyelinating disease in 65% of cases. MS diagnostic criteria were not rigorously validated for use in patients with atypical presentations, suggesting that the misuse of the criteria could represent a misunderstanding of what constitutes a typical demyelinating attack, said Dr. Solomon of the department of neurological sciences at the University of Vermont, Burlington.

In 48% of cases, the participating neurologists said that objective evidence of a lesion was not used to corroborate historical symptoms.

Many instances also were seen in which the neurologists felt magnetic resonance imaging criteria were misinterpreted or misapplied. In 60%, the MS misdiagnosis relied too heavily on MRI abnormalities to meet the MS diagnostic criteria for dissemination in space when the patient had nonspecific neurologic symptoms, and in another 33% there was an incorrect determination of juxtacortical or periventricular lesion location to fulfill the diagnostic criteria for dissemination in space. Dr. Solomon said that the MRI criteria for MS were not developed to differentiate MS from other conditions, but instead to identify patients at high risk for MS after initial typical presentations of demyelination.

“Overreliance on MRI abnormalities in the setting of atypical symptoms and unverified prior symptoms may be a major cause of misdiagnosis,” he said.

Many earlier patient visits contained red flags that could have led to a correct diagnosis, according to the neurologists who participated in the study. There was evidence for this opportunity being missed in 79 (72%) patients.

“We don’t know how frequent this problem is in practice. I think it’s pretty frequent just based on my own clinical experience, but no one’s done a population-based study, as you can imagine that would be kind of difficult to do,” said Dr. Jonathan Carter, an MS specialist at the Mayo Clinic in Scottsdale, Ariz., who was part of the study.

Study patients were previously diagnosed with MS; none were allowed to have MS as one of several potential diagnoses. Patients were mostly female (85%) and had a mean age of 49 years. They were referred to the Mayo Clinic (55%), the University of Vermont (25%), Washington University (11%), and Oregon Health and Science University (9%). The high highest percentage of misdiagnoses were from physicians with an unknown level of specific training in neurology or (42%), followed by neurologists without MS fellowship training (34%), neurologists with MS fellowship training or a practice focus on MS (24%), and nonneurologists (3%).

It was no surprise to see MS fellowship–trained neurologists among those making misdiagnoses, Dr. Carter said in an interview. “The criteria are somewhat subjective and interpretation of test results are somewhat subjective, then it’s quite possible to have another MS specialist diagnose somebody and then have them come to a different center and have that diagnosis questioned. I think it happens probably less frequently with MS fellowship–trained physicians than with general neurologists, but it still happens.”

All but three patients were informed that their MS diagnosis was incorrect: one who had died and was determined on autopsy to have neuromyelitis optica spectrum disorder, one who had been informed already of a possible alternate diagnosis, and one who had an upcoming follow-up visit.

Many of the patients had a longstanding MS misdiagnosis. A total of 29% had been misdiagnosed for 3-9 years, and 33% for 10 or more years.

The patients received a variety of primary diagnoses following reevaluation at the centers. The most common, accounting for two-thirds of all diagnoses, were migraine alone or in combination with other diagnoses in 24 (22%), fibromyalgia in 16 (15%), nonspecific or nonlocalizing neurological symptoms with abnormal MRI in 13 (12%), conversion or psychogenic disorder in 12 (11%), and neuromyelitis optica spectrum disorder in 7 (6%). Twenty six additional diagnoses were made.

The most common primary diagnoses, except for neuromyelitis spectrum disorder, all share the lack a specific biomarker, Dr. Solomon noted. Most of them require clinical skills and critical thinking to make the diagnosis, he said.

Most (70%) patients had received immunomodulatory treatment for MS, including 36% with more than one disease-modifying therapy. The treatments included natalizumab (Tysabri) in 13%, dimethyl fumarate (Tecfidera) in 6%, and fingolimod (Gilenya) in 5% – all of which have known risk for progressive multifocal leukoencephalopathy – as well as mitoxantrone in two patients and cyclophosphamide in one. Overall, 29% of those who received immunomodulatory therapy used it for 3-9 years, and another 29% used it for 10 or more years.

Dr. Solomon acknowledged selection and referral bias as limitations to the study, as well as possibly incorrect alternate diagnoses. The disease duration and hindshight bias also may have allowed a correct diagnosis to come to light. The study could not provide information on the frequency of misdiagnosis but “provides rationale for such data in the future,” he said.

jevans@frontlinemedcom.com

VANCOUVER – More than two-thirds of patients with definite or probable misdiagnosis of multiple sclerosis took unnecessary disease-modifying therapy and nearly one-third experienced unnecessary morbidity in a prospective pilot study.

The findings highlight a problem that has been noted before in the medical literature, but since many instances are case reports of unusual cases or were published about 20 or more years ago, they may not reflect the current spectrum of misdiagnosis, Dr. Andrew J. Solomon said at the annual meeting of the American Academy of Neurology.

During a 13-month period, neurologists at four U.S. academic multiple sclerosis centers reported that 51 (46%) of 110 misdiagnosed patients had “definite” misdiagnosis because an alternate diagnosis was identified after assessing clinical, laboratory, and neuroimaging data, while 59 had “probable” misdiagnoses.

Participating neurologists felt that the misdiagnoses were based in part on inappropriately attributing symptoms to demyelinating disease in 65% of cases. MS diagnostic criteria were not rigorously validated for use in patients with atypical presentations, suggesting that the misuse of the criteria could represent a misunderstanding of what constitutes a typical demyelinating attack, said Dr. Solomon of the department of neurological sciences at the University of Vermont, Burlington.

In 48% of cases, the participating neurologists said that objective evidence of a lesion was not used to corroborate historical symptoms.

Many instances also were seen in which the neurologists felt magnetic resonance imaging criteria were misinterpreted or misapplied. In 60%, the MS misdiagnosis relied too heavily on MRI abnormalities to meet the MS diagnostic criteria for dissemination in space when the patient had nonspecific neurologic symptoms, and in another 33% there was an incorrect determination of juxtacortical or periventricular lesion location to fulfill the diagnostic criteria for dissemination in space. Dr. Solomon said that the MRI criteria for MS were not developed to differentiate MS from other conditions, but instead to identify patients at high risk for MS after initial typical presentations of demyelination.

“Overreliance on MRI abnormalities in the setting of atypical symptoms and unverified prior symptoms may be a major cause of misdiagnosis,” he said.

Many earlier patient visits contained red flags that could have led to a correct diagnosis, according to the neurologists who participated in the study. There was evidence for this opportunity being missed in 79 (72%) patients.

“We don’t know how frequent this problem is in practice. I think it’s pretty frequent just based on my own clinical experience, but no one’s done a population-based study, as you can imagine that would be kind of difficult to do,” said Dr. Jonathan Carter, an MS specialist at the Mayo Clinic in Scottsdale, Ariz., who was part of the study.

Study patients were previously diagnosed with MS; none were allowed to have MS as one of several potential diagnoses. Patients were mostly female (85%) and had a mean age of 49 years. They were referred to the Mayo Clinic (55%), the University of Vermont (25%), Washington University (11%), and Oregon Health and Science University (9%). The high highest percentage of misdiagnoses were from physicians with an unknown level of specific training in neurology or (42%), followed by neurologists without MS fellowship training (34%), neurologists with MS fellowship training or a practice focus on MS (24%), and nonneurologists (3%).

It was no surprise to see MS fellowship–trained neurologists among those making misdiagnoses, Dr. Carter said in an interview. “The criteria are somewhat subjective and interpretation of test results are somewhat subjective, then it’s quite possible to have another MS specialist diagnose somebody and then have them come to a different center and have that diagnosis questioned. I think it happens probably less frequently with MS fellowship–trained physicians than with general neurologists, but it still happens.”

All but three patients were informed that their MS diagnosis was incorrect: one who had died and was determined on autopsy to have neuromyelitis optica spectrum disorder, one who had been informed already of a possible alternate diagnosis, and one who had an upcoming follow-up visit.

Many of the patients had a longstanding MS misdiagnosis. A total of 29% had been misdiagnosed for 3-9 years, and 33% for 10 or more years.

The patients received a variety of primary diagnoses following reevaluation at the centers. The most common, accounting for two-thirds of all diagnoses, were migraine alone or in combination with other diagnoses in 24 (22%), fibromyalgia in 16 (15%), nonspecific or nonlocalizing neurological symptoms with abnormal MRI in 13 (12%), conversion or psychogenic disorder in 12 (11%), and neuromyelitis optica spectrum disorder in 7 (6%). Twenty six additional diagnoses were made.

The most common primary diagnoses, except for neuromyelitis spectrum disorder, all share the lack a specific biomarker, Dr. Solomon noted. Most of them require clinical skills and critical thinking to make the diagnosis, he said.

Most (70%) patients had received immunomodulatory treatment for MS, including 36% with more than one disease-modifying therapy. The treatments included natalizumab (Tysabri) in 13%, dimethyl fumarate (Tecfidera) in 6%, and fingolimod (Gilenya) in 5% – all of which have known risk for progressive multifocal leukoencephalopathy – as well as mitoxantrone in two patients and cyclophosphamide in one. Overall, 29% of those who received immunomodulatory therapy used it for 3-9 years, and another 29% used it for 10 or more years.

Dr. Solomon acknowledged selection and referral bias as limitations to the study, as well as possibly incorrect alternate diagnoses. The disease duration and hindshight bias also may have allowed a correct diagnosis to come to light. The study could not provide information on the frequency of misdiagnosis but “provides rationale for such data in the future,” he said.

jevans@frontlinemedcom.com

VANCOUVER – More than two-thirds of patients with definite or probable misdiagnosis of multiple sclerosis took unnecessary disease-modifying therapy and nearly one-third experienced unnecessary morbidity in a prospective pilot study.

The findings highlight a problem that has been noted before in the medical literature, but since many instances are case reports of unusual cases or were published about 20 or more years ago, they may not reflect the current spectrum of misdiagnosis, Dr. Andrew J. Solomon said at the annual meeting of the American Academy of Neurology.

During a 13-month period, neurologists at four U.S. academic multiple sclerosis centers reported that 51 (46%) of 110 misdiagnosed patients had “definite” misdiagnosis because an alternate diagnosis was identified after assessing clinical, laboratory, and neuroimaging data, while 59 had “probable” misdiagnoses.

Participating neurologists felt that the misdiagnoses were based in part on inappropriately attributing symptoms to demyelinating disease in 65% of cases. MS diagnostic criteria were not rigorously validated for use in patients with atypical presentations, suggesting that the misuse of the criteria could represent a misunderstanding of what constitutes a typical demyelinating attack, said Dr. Solomon of the department of neurological sciences at the University of Vermont, Burlington.

In 48% of cases, the participating neurologists said that objective evidence of a lesion was not used to corroborate historical symptoms.

Many instances also were seen in which the neurologists felt magnetic resonance imaging criteria were misinterpreted or misapplied. In 60%, the MS misdiagnosis relied too heavily on MRI abnormalities to meet the MS diagnostic criteria for dissemination in space when the patient had nonspecific neurologic symptoms, and in another 33% there was an incorrect determination of juxtacortical or periventricular lesion location to fulfill the diagnostic criteria for dissemination in space. Dr. Solomon said that the MRI criteria for MS were not developed to differentiate MS from other conditions, but instead to identify patients at high risk for MS after initial typical presentations of demyelination.

“Overreliance on MRI abnormalities in the setting of atypical symptoms and unverified prior symptoms may be a major cause of misdiagnosis,” he said.

Many earlier patient visits contained red flags that could have led to a correct diagnosis, according to the neurologists who participated in the study. There was evidence for this opportunity being missed in 79 (72%) patients.

“We don’t know how frequent this problem is in practice. I think it’s pretty frequent just based on my own clinical experience, but no one’s done a population-based study, as you can imagine that would be kind of difficult to do,” said Dr. Jonathan Carter, an MS specialist at the Mayo Clinic in Scottsdale, Ariz., who was part of the study.

Study patients were previously diagnosed with MS; none were allowed to have MS as one of several potential diagnoses. Patients were mostly female (85%) and had a mean age of 49 years. They were referred to the Mayo Clinic (55%), the University of Vermont (25%), Washington University (11%), and Oregon Health and Science University (9%). The high highest percentage of misdiagnoses were from physicians with an unknown level of specific training in neurology or (42%), followed by neurologists without MS fellowship training (34%), neurologists with MS fellowship training or a practice focus on MS (24%), and nonneurologists (3%).

It was no surprise to see MS fellowship–trained neurologists among those making misdiagnoses, Dr. Carter said in an interview. “The criteria are somewhat subjective and interpretation of test results are somewhat subjective, then it’s quite possible to have another MS specialist diagnose somebody and then have them come to a different center and have that diagnosis questioned. I think it happens probably less frequently with MS fellowship–trained physicians than with general neurologists, but it still happens.”

All but three patients were informed that their MS diagnosis was incorrect: one who had died and was determined on autopsy to have neuromyelitis optica spectrum disorder, one who had been informed already of a possible alternate diagnosis, and one who had an upcoming follow-up visit.

Many of the patients had a longstanding MS misdiagnosis. A total of 29% had been misdiagnosed for 3-9 years, and 33% for 10 or more years.

The patients received a variety of primary diagnoses following reevaluation at the centers. The most common, accounting for two-thirds of all diagnoses, were migraine alone or in combination with other diagnoses in 24 (22%), fibromyalgia in 16 (15%), nonspecific or nonlocalizing neurological symptoms with abnormal MRI in 13 (12%), conversion or psychogenic disorder in 12 (11%), and neuromyelitis optica spectrum disorder in 7 (6%). Twenty six additional diagnoses were made.

The most common primary diagnoses, except for neuromyelitis spectrum disorder, all share the lack a specific biomarker, Dr. Solomon noted. Most of them require clinical skills and critical thinking to make the diagnosis, he said.

Most (70%) patients had received immunomodulatory treatment for MS, including 36% with more than one disease-modifying therapy. The treatments included natalizumab (Tysabri) in 13%, dimethyl fumarate (Tecfidera) in 6%, and fingolimod (Gilenya) in 5% – all of which have known risk for progressive multifocal leukoencephalopathy – as well as mitoxantrone in two patients and cyclophosphamide in one. Overall, 29% of those who received immunomodulatory therapy used it for 3-9 years, and another 29% used it for 10 or more years.

Dr. Solomon acknowledged selection and referral bias as limitations to the study, as well as possibly incorrect alternate diagnoses. The disease duration and hindshight bias also may have allowed a correct diagnosis to come to light. The study could not provide information on the frequency of misdiagnosis but “provides rationale for such data in the future,” he said.

jevans@frontlinemedcom.com

Emotionally abused children are 52% more likely to develop migraine in young adulthood than are those who were never abused, based on longitudinal survey data from nearly 15,000 individuals.

“Childhood maltreatment, and especially emotional abuse, is a common, likely under-recognized occurrence, which has enduring consequences for health throughout life. The association of emotional abuse with migraine has not heretofore been well studied, being the subject of only population-based study,” lead author Dr. Gretchen E. Tietjen of the University of Toledo (Ohio) said in an interview in advance of the presentation of the study at the annual meeting of the American Academy of Neurology in Vancouver in April.

Dr. Tietjen and her colleagues assessed data from 14,484 adults aged 24-32 years who took part in wave four of the National Longitudinal Study of Adolescent to Adult Health. Of these, 2,061 (14%) reported a migraine diagnosis, and 1,246 (60%) of those diagnosed with migraines reported some type of childhood abuse. A total of 6,088 (49%) individuals without migraine reported some type of childhood abuse.

Overall, the odds of migraine in adulthood was 55% higher in children who reported emotional abuse, physical abuse, or sexual abuse, compared with those who reported no childhood abuse, after controlling for age, race, sex, and income (odds ratio, 1.55; 95% confidence interval, 1.35-1.77). However, only emotional abuse remained significantly associated with increased odds for migraine after controlling for other types of abuse (OR, 1.52; 95% CI, 1.34-1.73).

Emotional abuse was assessed by asking, “How often did a parent or other adult caregiver say things that really hurt your feelings or made you feel like you were not wanted or loved?” Physical abuse was defined as being hit with a fist, kicked, or thrown down on the floor, into a wall, or down stairs. Sexual abuse included forced sexual touching or sexual relations.

Controlling for depression and anxiety weakened the associations between childhood abuse overall and likelihood of migraine in young adulthood, as well as for emotional abuse in particular, but the relationships remained statistically significant (OR, 1.32 and 1.33, respectively).

Dr. Tietjen said she was surprised by the absence of an association between migraine and physical and sexual abuse after controlling for other types of abuse.

“Sexual and physical abuse may be less frequent, occur over a briefer duration, and if limited, lead in some cases to resilience,” Dr. Tietjen noted. “Emotional abuse is likely more insidious, being ingrained in the fabric of the family dynamic. It may occur over years without recognition or intervention,” she said. “This type of abuse may cause more cumulative stress, with subsequent dysregulation of the HPA axis, immune, autonomic, and metabolic systems,” she added. 

The study does not show cause and effect, the researchers noted, and more research is needed. But the findings suggest that clinicians might consider childhood abuse when counseling adult migraine patients.

“In migraineurs, childhood abuse, particularly emotional abuse, is common and possibly causally related,” Dr. Tietjen said. “Knowledge of adverse childhood experiences allows physicians to identify migraineurs at higher risk for psychiatric disease, pain comorbidities, and conditions associated with inflammation. These patients would likely benefit from exposure to cognitive behavioral therapy strategies, in order to decrease neurophysiological responses to stress,” she noted.

“There are currently therapies which reverse stress-induced epigenetic changes, which might be particularly useful in the subset of migraineurs who have been abused,” said Dr. Tietjen. Her next steps for research involve studying the effect of early life stress on factors such as pain sensitivity, anxiety, and depression.

The University of Toledo and the Clair Martig Endowment funded the study.

Emotionally abused children are 52% more likely to develop migraine in young adulthood than are those who were never abused, based on longitudinal survey data from nearly 15,000 individuals.

“Childhood maltreatment, and especially emotional abuse, is a common, likely under-recognized occurrence, which has enduring consequences for health throughout life. The association of emotional abuse with migraine has not heretofore been well studied, being the subject of only population-based study,” lead author Dr. Gretchen E. Tietjen of the University of Toledo (Ohio) said in an interview in advance of the presentation of the study at the annual meeting of the American Academy of Neurology in Vancouver in April.

Dr. Tietjen and her colleagues assessed data from 14,484 adults aged 24-32 years who took part in wave four of the National Longitudinal Study of Adolescent to Adult Health. Of these, 2,061 (14%) reported a migraine diagnosis, and 1,246 (60%) of those diagnosed with migraines reported some type of childhood abuse. A total of 6,088 (49%) individuals without migraine reported some type of childhood abuse.

Overall, the odds of migraine in adulthood was 55% higher in children who reported emotional abuse, physical abuse, or sexual abuse, compared with those who reported no childhood abuse, after controlling for age, race, sex, and income (odds ratio, 1.55; 95% confidence interval, 1.35-1.77). However, only emotional abuse remained significantly associated with increased odds for migraine after controlling for other types of abuse (OR, 1.52; 95% CI, 1.34-1.73).

Emotional abuse was assessed by asking, “How often did a parent or other adult caregiver say things that really hurt your feelings or made you feel like you were not wanted or loved?” Physical abuse was defined as being hit with a fist, kicked, or thrown down on the floor, into a wall, or down stairs. Sexual abuse included forced sexual touching or sexual relations.

Controlling for depression and anxiety weakened the associations between childhood abuse overall and likelihood of migraine in young adulthood, as well as for emotional abuse in particular, but the relationships remained statistically significant (OR, 1.32 and 1.33, respectively).

Dr. Tietjen said she was surprised by the absence of an association between migraine and physical and sexual abuse after controlling for other types of abuse.

“Sexual and physical abuse may be less frequent, occur over a briefer duration, and if limited, lead in some cases to resilience,” Dr. Tietjen noted. “Emotional abuse is likely more insidious, being ingrained in the fabric of the family dynamic. It may occur over years without recognition or intervention,” she said. “This type of abuse may cause more cumulative stress, with subsequent dysregulation of the HPA axis, immune, autonomic, and metabolic systems,” she added. 

The study does not show cause and effect, the researchers noted, and more research is needed. But the findings suggest that clinicians might consider childhood abuse when counseling adult migraine patients.

“In migraineurs, childhood abuse, particularly emotional abuse, is common and possibly causally related,” Dr. Tietjen said. “Knowledge of adverse childhood experiences allows physicians to identify migraineurs at higher risk for psychiatric disease, pain comorbidities, and conditions associated with inflammation. These patients would likely benefit from exposure to cognitive behavioral therapy strategies, in order to decrease neurophysiological responses to stress,” she noted.

“There are currently therapies which reverse stress-induced epigenetic changes, which might be particularly useful in the subset of migraineurs who have been abused,” said Dr. Tietjen. Her next steps for research involve studying the effect of early life stress on factors such as pain sensitivity, anxiety, and depression.

The University of Toledo and the Clair Martig Endowment funded the study.

Emotionally abused children are 52% more likely to develop migraine in young adulthood than are those who were never abused, based on longitudinal survey data from nearly 15,000 individuals.

“Childhood maltreatment, and especially emotional abuse, is a common, likely under-recognized occurrence, which has enduring consequences for health throughout life. The association of emotional abuse with migraine has not heretofore been well studied, being the subject of only population-based study,” lead author Dr. Gretchen E. Tietjen of the University of Toledo (Ohio) said in an interview in advance of the presentation of the study at the annual meeting of the American Academy of Neurology in Vancouver in April.

Dr. Tietjen and her colleagues assessed data from 14,484 adults aged 24-32 years who took part in wave four of the National Longitudinal Study of Adolescent to Adult Health. Of these, 2,061 (14%) reported a migraine diagnosis, and 1,246 (60%) of those diagnosed with migraines reported some type of childhood abuse. A total of 6,088 (49%) individuals without migraine reported some type of childhood abuse.

Overall, the odds of migraine in adulthood was 55% higher in children who reported emotional abuse, physical abuse, or sexual abuse, compared with those who reported no childhood abuse, after controlling for age, race, sex, and income (odds ratio, 1.55; 95% confidence interval, 1.35-1.77). However, only emotional abuse remained significantly associated with increased odds for migraine after controlling for other types of abuse (OR, 1.52; 95% CI, 1.34-1.73).

Emotional abuse was assessed by asking, “How often did a parent or other adult caregiver say things that really hurt your feelings or made you feel like you were not wanted or loved?” Physical abuse was defined as being hit with a fist, kicked, or thrown down on the floor, into a wall, or down stairs. Sexual abuse included forced sexual touching or sexual relations.

Controlling for depression and anxiety weakened the associations between childhood abuse overall and likelihood of migraine in young adulthood, as well as for emotional abuse in particular, but the relationships remained statistically significant (OR, 1.32 and 1.33, respectively).

Dr. Tietjen said she was surprised by the absence of an association between migraine and physical and sexual abuse after controlling for other types of abuse.

“Sexual and physical abuse may be less frequent, occur over a briefer duration, and if limited, lead in some cases to resilience,” Dr. Tietjen noted. “Emotional abuse is likely more insidious, being ingrained in the fabric of the family dynamic. It may occur over years without recognition or intervention,” she said. “This type of abuse may cause more cumulative stress, with subsequent dysregulation of the HPA axis, immune, autonomic, and metabolic systems,” she added. 

The study does not show cause and effect, the researchers noted, and more research is needed. But the findings suggest that clinicians might consider childhood abuse when counseling adult migraine patients.

“In migraineurs, childhood abuse, particularly emotional abuse, is common and possibly causally related,” Dr. Tietjen said. “Knowledge of adverse childhood experiences allows physicians to identify migraineurs at higher risk for psychiatric disease, pain comorbidities, and conditions associated with inflammation. These patients would likely benefit from exposure to cognitive behavioral therapy strategies, in order to decrease neurophysiological responses to stress,” she noted.

“There are currently therapies which reverse stress-induced epigenetic changes, which might be particularly useful in the subset of migraineurs who have been abused,” said Dr. Tietjen. Her next steps for research involve studying the effect of early life stress on factors such as pain sensitivity, anxiety, and depression.

The University of Toledo and the Clair Martig Endowment funded the study.

A drug that was found to have no dose-limiting side effects in nonhuman primates is being evaluated in a clinical trial for its ability to reduce production of the protein that causes Huntington’s disease (HD).

The new drug, which is an antisense oligonucleotide, was formerly known as ISIS-HTTRx and was renamed IONIS-HTTRx, because its developer changed its name in December 2015 to Ionis Pharmaceuticals from Isis Pharmaceuticals. IONIS-HTTRx acts as a gene silencer to inhibit the production of huntington protein in people with HD. The clinical trial now underway is a randomized, double-blind, placebo-controlled study aimed at evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple ascending doses of IONIS-HTTRx in up to 36 patients with early manifest HD. If the trial is successful, IONIS-HTTRx would be the first drug to modify HD progression in patients, according to an abstract to be presented at the annual meeting of the American Academy of Neurology in Vancouver in April.

©Jezperklauzen/ThinkStock

Ionis found the drug to be well tolerated in rodents and nonhuman primates in investigational new drug-enabling toxicology studies, with nonhuman primates having received doses up to 20 mg of the drug intrathecally, according to the trial’s principal investigator Dr. Blair R. Leavitt of the University of British Columbia, Vancouver, and colleagues.

“It is very exciting to have the possibility of a treatment that could alter the course of this devastating disease. Right now we only have treatments that work on the symptoms of the disease.” Dr. Leavitt said in a written statement.

The study is supported by Ionis Pharmaceuticals and is part of Ionis’ collaboration with Roche to develop antisense drugs to treat HD, according to the investigators.

klennon@frontlinemedcom.com

A drug that was found to have no dose-limiting side effects in nonhuman primates is being evaluated in a clinical trial for its ability to reduce production of the protein that causes Huntington’s disease (HD).

The new drug, which is an antisense oligonucleotide, was formerly known as ISIS-HTTRx and was renamed IONIS-HTTRx, because its developer changed its name in December 2015 to Ionis Pharmaceuticals from Isis Pharmaceuticals. IONIS-HTTRx acts as a gene silencer to inhibit the production of huntington protein in people with HD. The clinical trial now underway is a randomized, double-blind, placebo-controlled study aimed at evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple ascending doses of IONIS-HTTRx in up to 36 patients with early manifest HD. If the trial is successful, IONIS-HTTRx would be the first drug to modify HD progression in patients, according to an abstract to be presented at the annual meeting of the American Academy of Neurology in Vancouver in April.

©Jezperklauzen/ThinkStock

Ionis found the drug to be well tolerated in rodents and nonhuman primates in investigational new drug-enabling toxicology studies, with nonhuman primates having received doses up to 20 mg of the drug intrathecally, according to the trial’s principal investigator Dr. Blair R. Leavitt of the University of British Columbia, Vancouver, and colleagues.

“It is very exciting to have the possibility of a treatment that could alter the course of this devastating disease. Right now we only have treatments that work on the symptoms of the disease.” Dr. Leavitt said in a written statement.

The study is supported by Ionis Pharmaceuticals and is part of Ionis’ collaboration with Roche to develop antisense drugs to treat HD, according to the investigators.

klennon@frontlinemedcom.com

A drug that was found to have no dose-limiting side effects in nonhuman primates is being evaluated in a clinical trial for its ability to reduce production of the protein that causes Huntington’s disease (HD).

The new drug, which is an antisense oligonucleotide, was formerly known as ISIS-HTTRx and was renamed IONIS-HTTRx, because its developer changed its name in December 2015 to Ionis Pharmaceuticals from Isis Pharmaceuticals. IONIS-HTTRx acts as a gene silencer to inhibit the production of huntington protein in people with HD. The clinical trial now underway is a randomized, double-blind, placebo-controlled study aimed at evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple ascending doses of IONIS-HTTRx in up to 36 patients with early manifest HD. If the trial is successful, IONIS-HTTRx would be the first drug to modify HD progression in patients, according to an abstract to be presented at the annual meeting of the American Academy of Neurology in Vancouver in April.

©Jezperklauzen/ThinkStock

Ionis found the drug to be well tolerated in rodents and nonhuman primates in investigational new drug-enabling toxicology studies, with nonhuman primates having received doses up to 20 mg of the drug intrathecally, according to the trial’s principal investigator Dr. Blair R. Leavitt of the University of British Columbia, Vancouver, and colleagues.

“It is very exciting to have the possibility of a treatment that could alter the course of this devastating disease. Right now we only have treatments that work on the symptoms of the disease.” Dr. Leavitt said in a written statement.

The study is supported by Ionis Pharmaceuticals and is part of Ionis’ collaboration with Roche to develop antisense drugs to treat HD, according to the investigators.

klennon@frontlinemedcom.com