A patient with an aggressive form of squamous cell carcinoma (SCC) experienced complete resolution of tumors following administration of human papillomavirus (HPV) vaccine, a recent case report shows.

The patient, an immunocompetent woman, aged in her 90s, with multiple inoperable cutaneous basaloid SCCs, was treated with a combination of systemic and intratumoral delivery of 9-valent HPV vaccine, authors of the case report wrote in JAMA Dermatology.

All tumors resolved within 11 months of the first intratumoral injection, according to Anna J. Nichols, MD, PhD, department of dermatology and cutaneous surgery, University of Miami, and her coauthors.

‘These findings suggest that the 9-valent HPV vaccine can provide a therapeutic option for inoperable cutaneous SCCs, in addition to its approved use to prevent anogenital HPV infection,” they wrote.

Previously, Dr. Nichols and her coinvestigators reported a reduction in SCCs and basal cell carcinoma in 2 immunocompetent patients who had received quadrivalent HPV vaccine. Those results suggested development of these keratinocyte carcinomas in immunocompetent patients may be driven in part by HPV, the investigators said at the time.

The patient in the current report was treated with 9-valent HPV vaccine in a university-based outpatient clinic between March 2016 and February 2017.

She initially received two doses of intramuscular vaccine 6 weeks apart; 3 weeks later, she received intratumoral administration of the vaccine diluted with sterile saline, followed by three additional intratumoral doses over the next 8 months.

“The marked regression of numerous SCCs after initiation of the intratumoral injections eliminated the need for additional treatment,” Dr. Nichols and her coauthors said in the report.

A reduction in tumor size and number was seen 2 weeks after the second intratumoral dose of the 9-valent HPV vaccine, and within 11 months of the first intratumoral dose, there was no clinical or histologic evidence of SCC, they said.

The patient was left with small, violet-colored scars, along with a small pink papule, histopathologic analysis of which showed mild cellular atypia of basal keratinocytes with hyperkeratosis, according to published details of the case report.

The patient experienced mild pain in some of the tumors on days of intratumoral treatment, but no other side effects were seen, according to the authors.

The patient remained tumor free at the end of follow-up in May 2018, and there was no clinical evidence of SCC recurrence at the patient’s most recent follow-up visit, 24 months after the first intratumoral HPV dose, the researchers wrote.

It’s not clear what role the systemic vaccine doses played in the therapeutic benefit the patient experienced, authors said, noting that tumors not injected directly may have regressed because of either local vaccine dispersion or systemic, immune-mediated mechanisms.

“The potent therapeutic benefit may reflect a combination of immunologic, antiviral, and antitumor effects of 9-valent HPV vaccine,” they concluded.

Dr. Nichols had no disclosures. Study coauthors Tim Ioannides, MD, and Evangelos V. Badiavas, MD, PhD, have a patent pending for the application of human papillomavirus vaccine described in the study.

SOURCE: Nichols AJ et al. JAMA Dermatol. 2018 Jul 3. doi: 10.1001/jamadermatol.2016.5703.

A patient with an aggressive form of squamous cell carcinoma (SCC) experienced complete resolution of tumors following administration of human papillomavirus (HPV) vaccine, a recent case report shows.

The patient, an immunocompetent woman, aged in her 90s, with multiple inoperable cutaneous basaloid SCCs, was treated with a combination of systemic and intratumoral delivery of 9-valent HPV vaccine, authors of the case report wrote in JAMA Dermatology.

All tumors resolved within 11 months of the first intratumoral injection, according to Anna J. Nichols, MD, PhD, department of dermatology and cutaneous surgery, University of Miami, and her coauthors.

‘These findings suggest that the 9-valent HPV vaccine can provide a therapeutic option for inoperable cutaneous SCCs, in addition to its approved use to prevent anogenital HPV infection,” they wrote.

Previously, Dr. Nichols and her coinvestigators reported a reduction in SCCs and basal cell carcinoma in 2 immunocompetent patients who had received quadrivalent HPV vaccine. Those results suggested development of these keratinocyte carcinomas in immunocompetent patients may be driven in part by HPV, the investigators said at the time.

The patient in the current report was treated with 9-valent HPV vaccine in a university-based outpatient clinic between March 2016 and February 2017.

She initially received two doses of intramuscular vaccine 6 weeks apart; 3 weeks later, she received intratumoral administration of the vaccine diluted with sterile saline, followed by three additional intratumoral doses over the next 8 months.

“The marked regression of numerous SCCs after initiation of the intratumoral injections eliminated the need for additional treatment,” Dr. Nichols and her coauthors said in the report.

A reduction in tumor size and number was seen 2 weeks after the second intratumoral dose of the 9-valent HPV vaccine, and within 11 months of the first intratumoral dose, there was no clinical or histologic evidence of SCC, they said.

The patient was left with small, violet-colored scars, along with a small pink papule, histopathologic analysis of which showed mild cellular atypia of basal keratinocytes with hyperkeratosis, according to published details of the case report.

The patient experienced mild pain in some of the tumors on days of intratumoral treatment, but no other side effects were seen, according to the authors.

The patient remained tumor free at the end of follow-up in May 2018, and there was no clinical evidence of SCC recurrence at the patient’s most recent follow-up visit, 24 months after the first intratumoral HPV dose, the researchers wrote.

It’s not clear what role the systemic vaccine doses played in the therapeutic benefit the patient experienced, authors said, noting that tumors not injected directly may have regressed because of either local vaccine dispersion or systemic, immune-mediated mechanisms.

“The potent therapeutic benefit may reflect a combination of immunologic, antiviral, and antitumor effects of 9-valent HPV vaccine,” they concluded.

Dr. Nichols had no disclosures. Study coauthors Tim Ioannides, MD, and Evangelos V. Badiavas, MD, PhD, have a patent pending for the application of human papillomavirus vaccine described in the study.

SOURCE: Nichols AJ et al. JAMA Dermatol. 2018 Jul 3. doi: 10.1001/jamadermatol.2016.5703.

A patient with an aggressive form of squamous cell carcinoma (SCC) experienced complete resolution of tumors following administration of human papillomavirus (HPV) vaccine, a recent case report shows.

The patient, an immunocompetent woman, aged in her 90s, with multiple inoperable cutaneous basaloid SCCs, was treated with a combination of systemic and intratumoral delivery of 9-valent HPV vaccine, authors of the case report wrote in JAMA Dermatology.

All tumors resolved within 11 months of the first intratumoral injection, according to Anna J. Nichols, MD, PhD, department of dermatology and cutaneous surgery, University of Miami, and her coauthors.

‘These findings suggest that the 9-valent HPV vaccine can provide a therapeutic option for inoperable cutaneous SCCs, in addition to its approved use to prevent anogenital HPV infection,” they wrote.

Previously, Dr. Nichols and her coinvestigators reported a reduction in SCCs and basal cell carcinoma in 2 immunocompetent patients who had received quadrivalent HPV vaccine. Those results suggested development of these keratinocyte carcinomas in immunocompetent patients may be driven in part by HPV, the investigators said at the time.

The patient in the current report was treated with 9-valent HPV vaccine in a university-based outpatient clinic between March 2016 and February 2017.

She initially received two doses of intramuscular vaccine 6 weeks apart; 3 weeks later, she received intratumoral administration of the vaccine diluted with sterile saline, followed by three additional intratumoral doses over the next 8 months.

“The marked regression of numerous SCCs after initiation of the intratumoral injections eliminated the need for additional treatment,” Dr. Nichols and her coauthors said in the report.

A reduction in tumor size and number was seen 2 weeks after the second intratumoral dose of the 9-valent HPV vaccine, and within 11 months of the first intratumoral dose, there was no clinical or histologic evidence of SCC, they said.

The patient was left with small, violet-colored scars, along with a small pink papule, histopathologic analysis of which showed mild cellular atypia of basal keratinocytes with hyperkeratosis, according to published details of the case report.

The patient experienced mild pain in some of the tumors on days of intratumoral treatment, but no other side effects were seen, according to the authors.

The patient remained tumor free at the end of follow-up in May 2018, and there was no clinical evidence of SCC recurrence at the patient’s most recent follow-up visit, 24 months after the first intratumoral HPV dose, the researchers wrote.

It’s not clear what role the systemic vaccine doses played in the therapeutic benefit the patient experienced, authors said, noting that tumors not injected directly may have regressed because of either local vaccine dispersion or systemic, immune-mediated mechanisms.

“The potent therapeutic benefit may reflect a combination of immunologic, antiviral, and antitumor effects of 9-valent HPV vaccine,” they concluded.

Dr. Nichols had no disclosures. Study coauthors Tim Ioannides, MD, and Evangelos V. Badiavas, MD, PhD, have a patent pending for the application of human papillomavirus vaccine described in the study.

SOURCE: Nichols AJ et al. JAMA Dermatol. 2018 Jul 3. doi: 10.1001/jamadermatol.2016.5703.

NASHVILLE—Two doses of ozanimod provide greater benefits on annualized relapse rate and MRI end points than interferon beta-1a does, according to research described at the 2018 CMSC Annual Meeting. Together with safety and tolerability results, the data indicate that oral ozanimod has a favorable risk–benefit profile in patients with relapsing-remitting multiple sclerosis (MS), said the investigators.

Ozanimod is an oral immunomodulator that selectively targets sphingosine 1-phosphate receptors 1 and 5. The drug is administered once daily. Bruce A. C. Cree, MD, PhD, Associate Professor of Neurology at the University of California, San Francisco, and colleagues examined data for patients with relapsing-remitting MS in the SUNBEAM and RADIANCE Part B trials to compare the efficacy and safety of ozanimod with those of interferon beta-1a. Patients received 1 mg or 0.5 mg of ozanimod HCl (with a seven-day dose escalation) or 30 μg of interferon beta-1a.

Ozanimod Decreased Annualized Relapse Rate

Dr. Cree and colleagues analyzed 12-month efficacy data from SUNBEAM, 24-month efficacy data from RADIANCE, and pooled safety data.

In all, 1,346 patients were treated in SUNBEAM, and 1,313 patients were treated in RADIANCE. Ozanimod 1 mg and 0.5 mg reduced participants’ adjusted annualized relapse rate by 48% (0.181) and 31% (0.241), respectively, versus interferon beta-1a (0.350) in SUNBEAM, and by 38% (0.172) and 21% (0.218), respectively, versus interferon beta-1a (0.276) in RADIANCE.

The adjusted mean number of new or enlarging T2 lesions was reduced by 48% and 25% versus interferon beta-1a for ozanimod 1 mg and 0.5 mg, respectively, in SUNBEAM, and by 42% and 34%, respectively, in RADIANCE. The adjusted mean number of gadolinium-enhancing lesions was reduced by 63% for the 1-mg dose of ozanimod and by 34% for the 0.5-mg dose of ozanimod versus interferon beta-1a in SUNBEAM. In RADIANCE, ozanimod 1 mg reduced this outcome by 53% and ozanimod 0.5 mg reduced this outcome by 47%, compared with interferon beta-1a.

Fewer Adverse Events With Ozanimod

Confirmed three-month pooled disability progression was low in the ozanimod 1 mg (0.102), ozanimod 0.5 mg (0.080), and interferon beta-1a (0.099) groups. In SUNBEAM, whole brain volume loss was 33% lower with ozanimod 1 mg and 12% lower with ozanimod 0.5 mg, compared with interferon beta-1a. In RADIANCE, whole brain volume loss was 27% lower with ozanimod 1 mg and 25% lower with ozanimod 0.5 mg, compared with interferon beta-1a. Ozanimod was associated with greater slowing of cortical gray matter and thalamic volume loss in both studies, compared with interferon beta-1a.

Compared with interferon beta-1a, ozanimod-treated patients had fewer adverse events (ozanimod 1 mg, 67.1%; ozanimod 0.5 mg, 65.6%; interferon beta-1a, 79.2%) and adverse events leading to study drug discontinuation (ozanimod 1 mg, 2.9%; ozanimod 0.5 mg, 2.4%; interferon beta-1a, 3.8%). Serious adverse events, including infections, were balanced and infrequent across groups (ozanimod 1 mg, 4.6%; ozanimod 0.5 mg, 5.3%; interferon beta-1a, 4.4%); no serious opportunistic infections were reported.

No second degree or higher atrioventricular block was observed. Researchers observed one death due to drowning (ozanimod 0.5 mg) deemed unrelated to the study drug.

NASHVILLE—Two doses of ozanimod provide greater benefits on annualized relapse rate and MRI end points than interferon beta-1a does, according to research described at the 2018 CMSC Annual Meeting. Together with safety and tolerability results, the data indicate that oral ozanimod has a favorable risk–benefit profile in patients with relapsing-remitting multiple sclerosis (MS), said the investigators.

Ozanimod is an oral immunomodulator that selectively targets sphingosine 1-phosphate receptors 1 and 5. The drug is administered once daily. Bruce A. C. Cree, MD, PhD, Associate Professor of Neurology at the University of California, San Francisco, and colleagues examined data for patients with relapsing-remitting MS in the SUNBEAM and RADIANCE Part B trials to compare the efficacy and safety of ozanimod with those of interferon beta-1a. Patients received 1 mg or 0.5 mg of ozanimod HCl (with a seven-day dose escalation) or 30 μg of interferon beta-1a.

Ozanimod Decreased Annualized Relapse Rate

Dr. Cree and colleagues analyzed 12-month efficacy data from SUNBEAM, 24-month efficacy data from RADIANCE, and pooled safety data.

In all, 1,346 patients were treated in SUNBEAM, and 1,313 patients were treated in RADIANCE. Ozanimod 1 mg and 0.5 mg reduced participants’ adjusted annualized relapse rate by 48% (0.181) and 31% (0.241), respectively, versus interferon beta-1a (0.350) in SUNBEAM, and by 38% (0.172) and 21% (0.218), respectively, versus interferon beta-1a (0.276) in RADIANCE.

The adjusted mean number of new or enlarging T2 lesions was reduced by 48% and 25% versus interferon beta-1a for ozanimod 1 mg and 0.5 mg, respectively, in SUNBEAM, and by 42% and 34%, respectively, in RADIANCE. The adjusted mean number of gadolinium-enhancing lesions was reduced by 63% for the 1-mg dose of ozanimod and by 34% for the 0.5-mg dose of ozanimod versus interferon beta-1a in SUNBEAM. In RADIANCE, ozanimod 1 mg reduced this outcome by 53% and ozanimod 0.5 mg reduced this outcome by 47%, compared with interferon beta-1a.

Fewer Adverse Events With Ozanimod

Confirmed three-month pooled disability progression was low in the ozanimod 1 mg (0.102), ozanimod 0.5 mg (0.080), and interferon beta-1a (0.099) groups. In SUNBEAM, whole brain volume loss was 33% lower with ozanimod 1 mg and 12% lower with ozanimod 0.5 mg, compared with interferon beta-1a. In RADIANCE, whole brain volume loss was 27% lower with ozanimod 1 mg and 25% lower with ozanimod 0.5 mg, compared with interferon beta-1a. Ozanimod was associated with greater slowing of cortical gray matter and thalamic volume loss in both studies, compared with interferon beta-1a.

Compared with interferon beta-1a, ozanimod-treated patients had fewer adverse events (ozanimod 1 mg, 67.1%; ozanimod 0.5 mg, 65.6%; interferon beta-1a, 79.2%) and adverse events leading to study drug discontinuation (ozanimod 1 mg, 2.9%; ozanimod 0.5 mg, 2.4%; interferon beta-1a, 3.8%). Serious adverse events, including infections, were balanced and infrequent across groups (ozanimod 1 mg, 4.6%; ozanimod 0.5 mg, 5.3%; interferon beta-1a, 4.4%); no serious opportunistic infections were reported.

No second degree or higher atrioventricular block was observed. Researchers observed one death due to drowning (ozanimod 0.5 mg) deemed unrelated to the study drug.

NASHVILLE—Two doses of ozanimod provide greater benefits on annualized relapse rate and MRI end points than interferon beta-1a does, according to research described at the 2018 CMSC Annual Meeting. Together with safety and tolerability results, the data indicate that oral ozanimod has a favorable risk–benefit profile in patients with relapsing-remitting multiple sclerosis (MS), said the investigators.

Ozanimod is an oral immunomodulator that selectively targets sphingosine 1-phosphate receptors 1 and 5. The drug is administered once daily. Bruce A. C. Cree, MD, PhD, Associate Professor of Neurology at the University of California, San Francisco, and colleagues examined data for patients with relapsing-remitting MS in the SUNBEAM and RADIANCE Part B trials to compare the efficacy and safety of ozanimod with those of interferon beta-1a. Patients received 1 mg or 0.5 mg of ozanimod HCl (with a seven-day dose escalation) or 30 μg of interferon beta-1a.

Ozanimod Decreased Annualized Relapse Rate

Dr. Cree and colleagues analyzed 12-month efficacy data from SUNBEAM, 24-month efficacy data from RADIANCE, and pooled safety data.

In all, 1,346 patients were treated in SUNBEAM, and 1,313 patients were treated in RADIANCE. Ozanimod 1 mg and 0.5 mg reduced participants’ adjusted annualized relapse rate by 48% (0.181) and 31% (0.241), respectively, versus interferon beta-1a (0.350) in SUNBEAM, and by 38% (0.172) and 21% (0.218), respectively, versus interferon beta-1a (0.276) in RADIANCE.

The adjusted mean number of new or enlarging T2 lesions was reduced by 48% and 25% versus interferon beta-1a for ozanimod 1 mg and 0.5 mg, respectively, in SUNBEAM, and by 42% and 34%, respectively, in RADIANCE. The adjusted mean number of gadolinium-enhancing lesions was reduced by 63% for the 1-mg dose of ozanimod and by 34% for the 0.5-mg dose of ozanimod versus interferon beta-1a in SUNBEAM. In RADIANCE, ozanimod 1 mg reduced this outcome by 53% and ozanimod 0.5 mg reduced this outcome by 47%, compared with interferon beta-1a.

Fewer Adverse Events With Ozanimod

Confirmed three-month pooled disability progression was low in the ozanimod 1 mg (0.102), ozanimod 0.5 mg (0.080), and interferon beta-1a (0.099) groups. In SUNBEAM, whole brain volume loss was 33% lower with ozanimod 1 mg and 12% lower with ozanimod 0.5 mg, compared with interferon beta-1a. In RADIANCE, whole brain volume loss was 27% lower with ozanimod 1 mg and 25% lower with ozanimod 0.5 mg, compared with interferon beta-1a. Ozanimod was associated with greater slowing of cortical gray matter and thalamic volume loss in both studies, compared with interferon beta-1a.

Compared with interferon beta-1a, ozanimod-treated patients had fewer adverse events (ozanimod 1 mg, 67.1%; ozanimod 0.5 mg, 65.6%; interferon beta-1a, 79.2%) and adverse events leading to study drug discontinuation (ozanimod 1 mg, 2.9%; ozanimod 0.5 mg, 2.4%; interferon beta-1a, 3.8%). Serious adverse events, including infections, were balanced and infrequent across groups (ozanimod 1 mg, 4.6%; ozanimod 0.5 mg, 5.3%; interferon beta-1a, 4.4%); no serious opportunistic infections were reported.

No second degree or higher atrioventricular block was observed. Researchers observed one death due to drowning (ozanimod 0.5 mg) deemed unrelated to the study drug.

LOS ANGELES—Amyloid PET scans may play an important role in neurologists’ management of patients with cognitive impairment. For the moment, clinical use should be restricted to cases that can be summarized with the mnemonic MAY—Mild, Atypical, and Young, said Gil D. Rabinovici, MD. “Those are the people who are most likely to benefit,” he said.

Although amyloid PET scans may affect diagnostic certainty and influence treatment in these scenarios, most patients do not get the scans. “They cost thousands of dollars, and most insurance will not pay for them,” Dr. Rabinovici said in a lecture at the 70th Annual Meeting of the American Academy of Neurology.

Three FDA-Approved Tracers

Three amyloid-beta tracers are FDA approved for clinical use in cognitively impaired patients—18F-florbetapir (Amyvid, approved in 2012), 18F-flutemetamol (Vizamyl, approved in 2013), and 18F-florbetaben (Neuraceq, approved in 2014).

The agents were approved on the basis of studies that found that blinded visual reads of amyloid PET scans during life accurately predicted postmortem burden of amyloid pathology in the same individuals. The scans distinguish patients with moderate or frequent neuritic plaques from those with absent or sparse neuritic plaques with a sensitivity and specificity of 80% or greater. Many scans can be categorized as positive or negative, and neurologists can quickly learn to read them, Dr. Rabinovici said.

Scans have the potential to improve the accuracy of Alzheimer’s disease diagnosis. Compared with postmortem findings, the clinical diagnosis of probable Alzheimer’s disease was accurate only 70% of the time in one study. Conversely, another study found that approximately 40% of patients with a diagnosis of non-Alzheimer’s disease dementia turned out to have Alzheimer’s disease as the primary causative pathology at autopsy.

Real-Life Ramifications

To illustrate amyloid PET’s potential usefulness in clinical practice, Dr. Rabinovici described a case of a 57-year-old internist. The patient had progressive trouble finding words, but otherwise did not have major symptoms or concerns. He did poorly on repeating sentences, but the rest of his examination was normal. MRI revealed nothing remarkable.

“That is the typical standard of care that is meant for someone with a cognitive complaint,” Dr. Rabinovici said. An FDG-PET scan was suspicious but not definitive. The patient’s amyloid PET scan, however, was clearly positive and showed amyloid throughout the neocortex. “With the scans, I could diagnose him. He had mild cognitive impairment, but I thought with high likelihood due to Alzheimer’s disease.”

As a result, Dr. Rabinovici started the patient on a cholinesterase inhibitor, and the patient decided to retire early due to medical disability. In addition, the patient enrolled in a clinical trial of an investigational antiamyloid therapy.

“I was not able to cure or modify the course of his Alzheimer’s disease, but amyloid PET did have real ramifications for his life,” he said.

Consider the Clinical Context

As with any diagnostic agent, clinical context is critical for interpreting the significance of positive and negative amyloid scans, Dr. Rabinovici said.

Among patients with dementia, amyloid PET can distinguish Alzheimer’s disease from conditions that do not involve amyloid-beta deposition, such as frontotemporal dementia or pure vascular dementia. It is not useful, however, in distinguishing Alzheimer’s disease from other conditions in which amyloid is deposited in the brain, such as cerebral amyloid angiopathy or dementia with Lewy bodies.

“It is important to consider the patient’s age when you think about the meaning of a positive scan,” he said. “A negative scan is always helpful in ruling out Alzheimer’s disease,” but a positive scan is less meaningful in older patients. Approximately 25% of cognitively normal older individuals have positive amyloid PET scans. The prevalence of amyloid positivity is about 10% at age 60 and more than 50% at age 90.

Not everyone with amyloid deposition has or develops Alzheimer’s disease dementia or mild cognitive impairment, but amyloid is a risk factor, said Dr. Rabinovici. “To summarize 15 years of research in one bullet point, it is not good to have amyloid in your brain even if you are cognitively normal,” he said. “Amyloid-positive normal controls are already showing Alzheimer’s-disease-like structural and functional changes in their brains. Over time, they are likely to decline cognitively. And they have an increased risk of cognitive impairment,” compared with people who are amyloid negative.

Research indicates that the deposition of amyloid plaques begins at least 15 years before the onset of cognitive symptoms, which may represent a window for early intervention, Dr. Rabinovici said.

When to Scan and When Not To

To guide clinicians in the appropriate use of amyloid PET, the Society for Nuclear Medicine and Molecular Imaging and the Alzheimer’s Association in 2013 published appropriate use criteria for the technology. Given amyloid PET’s cost and need for nuanced interpretation, the authors determined that it should not be a first-line test in the evaluation of cognitive complaints, Dr. Rabinovici said. Rather, it should be an ancillary test ordered by subspecialists in patients who meet the following criteria:

• Have a cognitive complaint with objectively confirmed impairment.
• Have an uncertain diagnosis, with Alzheimer’s disease as a possibility, after comprehensive evaluation by a dementia expert.
• Knowledge of their amyloid-beta status is expected to increase diagnostic certainty and alter management.

The three main clinical scenarios in which amyloid imaging may be most useful include the following:

• Cases with persistent and progressive unexplained mild cognitive impairment.
• Cases with possible (rather than probable) Alzheimer’s disease who have an atypical or mixed course or significant comorbidities (eg, vascular, psychiatric, or substance abuse disorders).
• Cases with an atypically early age of onset (ie, younger than 65).

The appropriate use criteria also highlight the following scenarios in which clinical amyloid PET is considered inappropriate:

• For the initial evaluation of cognitive complaints.
• To screen cognitively normal individuals outside the context of research or clinical trials.
• When requested solely based on a family history of dementia or the presence of other Alzheimer’s disease risk factors, such as the ApoE4 gene.
• As a substitute for genetic testing for mutations that cause Alzheimer’s disease.
• For nonmedical reasons, such as insurance, legal, or employment decisions.

Finally, the criteria identify scenarios where amyloid imaging is unlikely to be useful, including as a means of determining the severity of dementia, straightforward clinical cases, and to differentiate Alzheimer’s disease from other diseases that involve the deposition of amyloid-beta.

Effects on Management and Outcomes

Relatively few studies have assessed amyloid PET’s impact on clinical decision making and patient outcomes, Dr. Rabinovici said. In 2013, the US Centers for Medicare and Medicaid Services (CMS) determined that there was insufficient evidence to justify reimbursement of amyloid PET and said that it would reimburse the scans for patients who enroll in studies to assess amyloid PET’s clinical utility, under a mechanism called coverage with evidence development. For CMS to reconsider its coverage decision, studies must demonstrate that amyloid PET changes patient management in the short term and improves dementia outcomes long term. The Imaging Dementia—Evidence for Amyloid Scanning (IDEAS) study, which Dr. Rabinovici chairs, is a multisite study to assess the utility of amyloid PET in Medicare beneficiaries age 65 and older who meet appropriate use criteria for amyloid imaging.

The IDEAS study enrolled more than 18,000 participants and finished recruiting patients this year. It aims to examine how the scans affect patient management plans at three months and medical outcomes at 12 months. “The primary hypothesis is that, in these diagnostically uncertain cases, knowing the amyloid result will change management, and that will translate into better outcomes,” Dr. Rabinovici said.

Results regarding amyloid PET’s influence on patient management at three months will be presented soon, and 12-month outcome data are expected to be presented in 2019.

An interim analysis of the first 3,979 patients found that, three months after the amyloid PET scans, patients’ management plans had changed from the pre-PET management plan in about 67% of cases. Changes included starting or stopping Alzheimer’s-disease-specific medications and other neurologic therapies and changes in patient counseling.

Matched With Controls

To assess 12-month outcomes, investigators plan to use Medicare claims data to compare medical outcomes for patients enrolled in the study with those for matched controls who did not undergo amyloid PET. The primary objective is to determine whether amyloid PET is associated with a 10% or greater reduction in hospitalizations and emergency room visits. The researchers plan to use an algorithm to match each IDEAS study participant with a control with a similar dementia diagnosis, pre-scan dementia-related resource utilization, age, race, gender, ethnicity, geographic location, and comorbid chronic conditions.

Further imaging advances, such as tau PET tracers, are in development but have not yet received regulatory approval from the FDA, Dr. Rabinovici said. Tau PET has the potential to detect pathology in tauopathies such as progressive supranuclear palsy, corticobasal degeneration, chronic traumatic encephalopathy, and subtypes of frontotemporal dementia, as well as Alzheimer’s disease, he said.

—Jake Remaly

Suggested Reading

Jack CR Jr, Bennett DA, Blennow K, et al. NIA-AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14(4):535-562.

Johnson KA, Minoshima S, Bohnen NI, et al. Appropriate use criteria for amyloid PET: a report of the Amyloid Imaging Task Force, the Society of Nuclear Medicine and Molecular Imaging, and the Alzheimer’s Association. Alzheimers Dement. 2013;9(1):e1-e16.

LOS ANGELES—Amyloid PET scans may play an important role in neurologists’ management of patients with cognitive impairment. For the moment, clinical use should be restricted to cases that can be summarized with the mnemonic MAY—Mild, Atypical, and Young, said Gil D. Rabinovici, MD. “Those are the people who are most likely to benefit,” he said.

Although amyloid PET scans may affect diagnostic certainty and influence treatment in these scenarios, most patients do not get the scans. “They cost thousands of dollars, and most insurance will not pay for them,” Dr. Rabinovici said in a lecture at the 70th Annual Meeting of the American Academy of Neurology.

Three FDA-Approved Tracers

Three amyloid-beta tracers are FDA approved for clinical use in cognitively impaired patients—18F-florbetapir (Amyvid, approved in 2012), 18F-flutemetamol (Vizamyl, approved in 2013), and 18F-florbetaben (Neuraceq, approved in 2014).

The agents were approved on the basis of studies that found that blinded visual reads of amyloid PET scans during life accurately predicted postmortem burden of amyloid pathology in the same individuals. The scans distinguish patients with moderate or frequent neuritic plaques from those with absent or sparse neuritic plaques with a sensitivity and specificity of 80% or greater. Many scans can be categorized as positive or negative, and neurologists can quickly learn to read them, Dr. Rabinovici said.

Scans have the potential to improve the accuracy of Alzheimer’s disease diagnosis. Compared with postmortem findings, the clinical diagnosis of probable Alzheimer’s disease was accurate only 70% of the time in one study. Conversely, another study found that approximately 40% of patients with a diagnosis of non-Alzheimer’s disease dementia turned out to have Alzheimer’s disease as the primary causative pathology at autopsy.

Real-Life Ramifications

To illustrate amyloid PET’s potential usefulness in clinical practice, Dr. Rabinovici described a case of a 57-year-old internist. The patient had progressive trouble finding words, but otherwise did not have major symptoms or concerns. He did poorly on repeating sentences, but the rest of his examination was normal. MRI revealed nothing remarkable.

“That is the typical standard of care that is meant for someone with a cognitive complaint,” Dr. Rabinovici said. An FDG-PET scan was suspicious but not definitive. The patient’s amyloid PET scan, however, was clearly positive and showed amyloid throughout the neocortex. “With the scans, I could diagnose him. He had mild cognitive impairment, but I thought with high likelihood due to Alzheimer’s disease.”

As a result, Dr. Rabinovici started the patient on a cholinesterase inhibitor, and the patient decided to retire early due to medical disability. In addition, the patient enrolled in a clinical trial of an investigational antiamyloid therapy.

“I was not able to cure or modify the course of his Alzheimer’s disease, but amyloid PET did have real ramifications for his life,” he said.

Consider the Clinical Context

As with any diagnostic agent, clinical context is critical for interpreting the significance of positive and negative amyloid scans, Dr. Rabinovici said.

Among patients with dementia, amyloid PET can distinguish Alzheimer’s disease from conditions that do not involve amyloid-beta deposition, such as frontotemporal dementia or pure vascular dementia. It is not useful, however, in distinguishing Alzheimer’s disease from other conditions in which amyloid is deposited in the brain, such as cerebral amyloid angiopathy or dementia with Lewy bodies.

“It is important to consider the patient’s age when you think about the meaning of a positive scan,” he said. “A negative scan is always helpful in ruling out Alzheimer’s disease,” but a positive scan is less meaningful in older patients. Approximately 25% of cognitively normal older individuals have positive amyloid PET scans. The prevalence of amyloid positivity is about 10% at age 60 and more than 50% at age 90.

Not everyone with amyloid deposition has or develops Alzheimer’s disease dementia or mild cognitive impairment, but amyloid is a risk factor, said Dr. Rabinovici. “To summarize 15 years of research in one bullet point, it is not good to have amyloid in your brain even if you are cognitively normal,” he said. “Amyloid-positive normal controls are already showing Alzheimer’s-disease-like structural and functional changes in their brains. Over time, they are likely to decline cognitively. And they have an increased risk of cognitive impairment,” compared with people who are amyloid negative.

Research indicates that the deposition of amyloid plaques begins at least 15 years before the onset of cognitive symptoms, which may represent a window for early intervention, Dr. Rabinovici said.

When to Scan and When Not To

To guide clinicians in the appropriate use of amyloid PET, the Society for Nuclear Medicine and Molecular Imaging and the Alzheimer’s Association in 2013 published appropriate use criteria for the technology. Given amyloid PET’s cost and need for nuanced interpretation, the authors determined that it should not be a first-line test in the evaluation of cognitive complaints, Dr. Rabinovici said. Rather, it should be an ancillary test ordered by subspecialists in patients who meet the following criteria:

• Have a cognitive complaint with objectively confirmed impairment.
• Have an uncertain diagnosis, with Alzheimer’s disease as a possibility, after comprehensive evaluation by a dementia expert.
• Knowledge of their amyloid-beta status is expected to increase diagnostic certainty and alter management.

The three main clinical scenarios in which amyloid imaging may be most useful include the following:

• Cases with persistent and progressive unexplained mild cognitive impairment.
• Cases with possible (rather than probable) Alzheimer’s disease who have an atypical or mixed course or significant comorbidities (eg, vascular, psychiatric, or substance abuse disorders).
• Cases with an atypically early age of onset (ie, younger than 65).

The appropriate use criteria also highlight the following scenarios in which clinical amyloid PET is considered inappropriate:

• For the initial evaluation of cognitive complaints.
• To screen cognitively normal individuals outside the context of research or clinical trials.
• When requested solely based on a family history of dementia or the presence of other Alzheimer’s disease risk factors, such as the ApoE4 gene.
• As a substitute for genetic testing for mutations that cause Alzheimer’s disease.
• For nonmedical reasons, such as insurance, legal, or employment decisions.

Finally, the criteria identify scenarios where amyloid imaging is unlikely to be useful, including as a means of determining the severity of dementia, straightforward clinical cases, and to differentiate Alzheimer’s disease from other diseases that involve the deposition of amyloid-beta.

Effects on Management and Outcomes

Relatively few studies have assessed amyloid PET’s impact on clinical decision making and patient outcomes, Dr. Rabinovici said. In 2013, the US Centers for Medicare and Medicaid Services (CMS) determined that there was insufficient evidence to justify reimbursement of amyloid PET and said that it would reimburse the scans for patients who enroll in studies to assess amyloid PET’s clinical utility, under a mechanism called coverage with evidence development. For CMS to reconsider its coverage decision, studies must demonstrate that amyloid PET changes patient management in the short term and improves dementia outcomes long term. The Imaging Dementia—Evidence for Amyloid Scanning (IDEAS) study, which Dr. Rabinovici chairs, is a multisite study to assess the utility of amyloid PET in Medicare beneficiaries age 65 and older who meet appropriate use criteria for amyloid imaging.

The IDEAS study enrolled more than 18,000 participants and finished recruiting patients this year. It aims to examine how the scans affect patient management plans at three months and medical outcomes at 12 months. “The primary hypothesis is that, in these diagnostically uncertain cases, knowing the amyloid result will change management, and that will translate into better outcomes,” Dr. Rabinovici said.

Results regarding amyloid PET’s influence on patient management at three months will be presented soon, and 12-month outcome data are expected to be presented in 2019.

An interim analysis of the first 3,979 patients found that, three months after the amyloid PET scans, patients’ management plans had changed from the pre-PET management plan in about 67% of cases. Changes included starting or stopping Alzheimer’s-disease-specific medications and other neurologic therapies and changes in patient counseling.

Matched With Controls

To assess 12-month outcomes, investigators plan to use Medicare claims data to compare medical outcomes for patients enrolled in the study with those for matched controls who did not undergo amyloid PET. The primary objective is to determine whether amyloid PET is associated with a 10% or greater reduction in hospitalizations and emergency room visits. The researchers plan to use an algorithm to match each IDEAS study participant with a control with a similar dementia diagnosis, pre-scan dementia-related resource utilization, age, race, gender, ethnicity, geographic location, and comorbid chronic conditions.

Further imaging advances, such as tau PET tracers, are in development but have not yet received regulatory approval from the FDA, Dr. Rabinovici said. Tau PET has the potential to detect pathology in tauopathies such as progressive supranuclear palsy, corticobasal degeneration, chronic traumatic encephalopathy, and subtypes of frontotemporal dementia, as well as Alzheimer’s disease, he said.

—Jake Remaly

Suggested Reading

Jack CR Jr, Bennett DA, Blennow K, et al. NIA-AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14(4):535-562.

Johnson KA, Minoshima S, Bohnen NI, et al. Appropriate use criteria for amyloid PET: a report of the Amyloid Imaging Task Force, the Society of Nuclear Medicine and Molecular Imaging, and the Alzheimer’s Association. Alzheimers Dement. 2013;9(1):e1-e16.

LOS ANGELES—Amyloid PET scans may play an important role in neurologists’ management of patients with cognitive impairment. For the moment, clinical use should be restricted to cases that can be summarized with the mnemonic MAY—Mild, Atypical, and Young, said Gil D. Rabinovici, MD. “Those are the people who are most likely to benefit,” he said.

Although amyloid PET scans may affect diagnostic certainty and influence treatment in these scenarios, most patients do not get the scans. “They cost thousands of dollars, and most insurance will not pay for them,” Dr. Rabinovici said in a lecture at the 70th Annual Meeting of the American Academy of Neurology.

Three FDA-Approved Tracers

Three amyloid-beta tracers are FDA approved for clinical use in cognitively impaired patients—18F-florbetapir (Amyvid, approved in 2012), 18F-flutemetamol (Vizamyl, approved in 2013), and 18F-florbetaben (Neuraceq, approved in 2014).

The agents were approved on the basis of studies that found that blinded visual reads of amyloid PET scans during life accurately predicted postmortem burden of amyloid pathology in the same individuals. The scans distinguish patients with moderate or frequent neuritic plaques from those with absent or sparse neuritic plaques with a sensitivity and specificity of 80% or greater. Many scans can be categorized as positive or negative, and neurologists can quickly learn to read them, Dr. Rabinovici said.

Scans have the potential to improve the accuracy of Alzheimer’s disease diagnosis. Compared with postmortem findings, the clinical diagnosis of probable Alzheimer’s disease was accurate only 70% of the time in one study. Conversely, another study found that approximately 40% of patients with a diagnosis of non-Alzheimer’s disease dementia turned out to have Alzheimer’s disease as the primary causative pathology at autopsy.

Real-Life Ramifications

To illustrate amyloid PET’s potential usefulness in clinical practice, Dr. Rabinovici described a case of a 57-year-old internist. The patient had progressive trouble finding words, but otherwise did not have major symptoms or concerns. He did poorly on repeating sentences, but the rest of his examination was normal. MRI revealed nothing remarkable.

“That is the typical standard of care that is meant for someone with a cognitive complaint,” Dr. Rabinovici said. An FDG-PET scan was suspicious but not definitive. The patient’s amyloid PET scan, however, was clearly positive and showed amyloid throughout the neocortex. “With the scans, I could diagnose him. He had mild cognitive impairment, but I thought with high likelihood due to Alzheimer’s disease.”

As a result, Dr. Rabinovici started the patient on a cholinesterase inhibitor, and the patient decided to retire early due to medical disability. In addition, the patient enrolled in a clinical trial of an investigational antiamyloid therapy.

“I was not able to cure or modify the course of his Alzheimer’s disease, but amyloid PET did have real ramifications for his life,” he said.

Consider the Clinical Context

As with any diagnostic agent, clinical context is critical for interpreting the significance of positive and negative amyloid scans, Dr. Rabinovici said.

Among patients with dementia, amyloid PET can distinguish Alzheimer’s disease from conditions that do not involve amyloid-beta deposition, such as frontotemporal dementia or pure vascular dementia. It is not useful, however, in distinguishing Alzheimer’s disease from other conditions in which amyloid is deposited in the brain, such as cerebral amyloid angiopathy or dementia with Lewy bodies.

“It is important to consider the patient’s age when you think about the meaning of a positive scan,” he said. “A negative scan is always helpful in ruling out Alzheimer’s disease,” but a positive scan is less meaningful in older patients. Approximately 25% of cognitively normal older individuals have positive amyloid PET scans. The prevalence of amyloid positivity is about 10% at age 60 and more than 50% at age 90.

Not everyone with amyloid deposition has or develops Alzheimer’s disease dementia or mild cognitive impairment, but amyloid is a risk factor, said Dr. Rabinovici. “To summarize 15 years of research in one bullet point, it is not good to have amyloid in your brain even if you are cognitively normal,” he said. “Amyloid-positive normal controls are already showing Alzheimer’s-disease-like structural and functional changes in their brains. Over time, they are likely to decline cognitively. And they have an increased risk of cognitive impairment,” compared with people who are amyloid negative.

Research indicates that the deposition of amyloid plaques begins at least 15 years before the onset of cognitive symptoms, which may represent a window for early intervention, Dr. Rabinovici said.

When to Scan and When Not To

To guide clinicians in the appropriate use of amyloid PET, the Society for Nuclear Medicine and Molecular Imaging and the Alzheimer’s Association in 2013 published appropriate use criteria for the technology. Given amyloid PET’s cost and need for nuanced interpretation, the authors determined that it should not be a first-line test in the evaluation of cognitive complaints, Dr. Rabinovici said. Rather, it should be an ancillary test ordered by subspecialists in patients who meet the following criteria:

• Have a cognitive complaint with objectively confirmed impairment.
• Have an uncertain diagnosis, with Alzheimer’s disease as a possibility, after comprehensive evaluation by a dementia expert.
• Knowledge of their amyloid-beta status is expected to increase diagnostic certainty and alter management.

The three main clinical scenarios in which amyloid imaging may be most useful include the following:

• Cases with persistent and progressive unexplained mild cognitive impairment.
• Cases with possible (rather than probable) Alzheimer’s disease who have an atypical or mixed course or significant comorbidities (eg, vascular, psychiatric, or substance abuse disorders).
• Cases with an atypically early age of onset (ie, younger than 65).

The appropriate use criteria also highlight the following scenarios in which clinical amyloid PET is considered inappropriate:

• For the initial evaluation of cognitive complaints.
• To screen cognitively normal individuals outside the context of research or clinical trials.
• When requested solely based on a family history of dementia or the presence of other Alzheimer’s disease risk factors, such as the ApoE4 gene.
• As a substitute for genetic testing for mutations that cause Alzheimer’s disease.
• For nonmedical reasons, such as insurance, legal, or employment decisions.

Finally, the criteria identify scenarios where amyloid imaging is unlikely to be useful, including as a means of determining the severity of dementia, straightforward clinical cases, and to differentiate Alzheimer’s disease from other diseases that involve the deposition of amyloid-beta.

Effects on Management and Outcomes

Relatively few studies have assessed amyloid PET’s impact on clinical decision making and patient outcomes, Dr. Rabinovici said. In 2013, the US Centers for Medicare and Medicaid Services (CMS) determined that there was insufficient evidence to justify reimbursement of amyloid PET and said that it would reimburse the scans for patients who enroll in studies to assess amyloid PET’s clinical utility, under a mechanism called coverage with evidence development. For CMS to reconsider its coverage decision, studies must demonstrate that amyloid PET changes patient management in the short term and improves dementia outcomes long term. The Imaging Dementia—Evidence for Amyloid Scanning (IDEAS) study, which Dr. Rabinovici chairs, is a multisite study to assess the utility of amyloid PET in Medicare beneficiaries age 65 and older who meet appropriate use criteria for amyloid imaging.

The IDEAS study enrolled more than 18,000 participants and finished recruiting patients this year. It aims to examine how the scans affect patient management plans at three months and medical outcomes at 12 months. “The primary hypothesis is that, in these diagnostically uncertain cases, knowing the amyloid result will change management, and that will translate into better outcomes,” Dr. Rabinovici said.

Results regarding amyloid PET’s influence on patient management at three months will be presented soon, and 12-month outcome data are expected to be presented in 2019.

An interim analysis of the first 3,979 patients found that, three months after the amyloid PET scans, patients’ management plans had changed from the pre-PET management plan in about 67% of cases. Changes included starting or stopping Alzheimer’s-disease-specific medications and other neurologic therapies and changes in patient counseling.

Matched With Controls

To assess 12-month outcomes, investigators plan to use Medicare claims data to compare medical outcomes for patients enrolled in the study with those for matched controls who did not undergo amyloid PET. The primary objective is to determine whether amyloid PET is associated with a 10% or greater reduction in hospitalizations and emergency room visits. The researchers plan to use an algorithm to match each IDEAS study participant with a control with a similar dementia diagnosis, pre-scan dementia-related resource utilization, age, race, gender, ethnicity, geographic location, and comorbid chronic conditions.

Further imaging advances, such as tau PET tracers, are in development but have not yet received regulatory approval from the FDA, Dr. Rabinovici said. Tau PET has the potential to detect pathology in tauopathies such as progressive supranuclear palsy, corticobasal degeneration, chronic traumatic encephalopathy, and subtypes of frontotemporal dementia, as well as Alzheimer’s disease, he said.

—Jake Remaly

Suggested Reading

Jack CR Jr, Bennett DA, Blennow K, et al. NIA-AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14(4):535-562.

Johnson KA, Minoshima S, Bohnen NI, et al. Appropriate use criteria for amyloid PET: a report of the Amyloid Imaging Task Force, the Society of Nuclear Medicine and Molecular Imaging, and the Alzheimer’s Association. Alzheimers Dement. 2013;9(1):e1-e16.

NASHVILLE—Gadolinium-based contrast agents (GBCAs) are necessary for the accurate initial diagnosis of patients experiencing a first clinical attack of symptoms consistent with multiple sclerosis (MS) and for following patients with highly active disease or sudden, unexpected declines, according to a guideline issued by the Consortium of MS Centers (CMSC).

GBCAs are optional, although helpful, in many other clinical scenarios, especially when noncontrast MRI can provide answers.

“The key is that there is an optional role for gadolinium,” said David Li, MD, Professor of Radiology and Associate Member in Neurology at the University of British Columbia in Vancouver, at the 2018 CMSC Annual Meeting.

—Michele G. Sullivan

NASHVILLE—Gadolinium-based contrast agents (GBCAs) are necessary for the accurate initial diagnosis of patients experiencing a first clinical attack of symptoms consistent with multiple sclerosis (MS) and for following patients with highly active disease or sudden, unexpected declines, according to a guideline issued by the Consortium of MS Centers (CMSC).

GBCAs are optional, although helpful, in many other clinical scenarios, especially when noncontrast MRI can provide answers.

“The key is that there is an optional role for gadolinium,” said David Li, MD, Professor of Radiology and Associate Member in Neurology at the University of British Columbia in Vancouver, at the 2018 CMSC Annual Meeting.

—Michele G. Sullivan

NASHVILLE—Gadolinium-based contrast agents (GBCAs) are necessary for the accurate initial diagnosis of patients experiencing a first clinical attack of symptoms consistent with multiple sclerosis (MS) and for following patients with highly active disease or sudden, unexpected declines, according to a guideline issued by the Consortium of MS Centers (CMSC).

GBCAs are optional, although helpful, in many other clinical scenarios, especially when noncontrast MRI can provide answers.

“The key is that there is an optional role for gadolinium,” said David Li, MD, Professor of Radiology and Associate Member in Neurology at the University of British Columbia in Vancouver, at the 2018 CMSC Annual Meeting.

—Michele G. Sullivan

LOS ANGELES—Surgical intervention for epilepsy is often seen as a last resort, even among patients with drug-resistant focal epilepsies, said Gregory D. Cascino, MD, a neurologist at Mayo Clinic in Rochester, Minnesota. One reason for this phenomenon may be concern about potential adverse effects. Research indicates, however, that clinical and functional outcomes of surgery significantly surpass those of treatment with antiepileptic drugs (AEDs) in selected patients with drug-resistant focal epilepsy.

“The three important goals of epilepsy treatment are no seizures, no adverse effects, and no lifestyle limitations. This is what patients want when they seek neurologic care,” said Dr. Cascino at the 70th Annual Meeting of the American Academy of Neurology. “Seizure freedom is important because of its beneficial effects on quality of life, which include the ability to drive, pursue an education, have a career, and live independently with no need for a caregiver. We need to consider the risk of any intervention, whether it is medical or surgical, against the natural history of the disease.” All patients with epilepsy, not just those with drug-resistant focal epilepsy, are at significant risk of mortality due to seizure complications, progressive cognitive disorder, mood disorders, and even sudden unexpected death in epilepsy, he noted.

Identifying Surgical Candidates

“As soon as a patient is diagnosed with drug-resistant focal epilepsy, the neurologist probably should begin to triage for alternative forms of treatment,” Dr. Cascino said. “That doesn’t mean that patients need surgery on the first visit. But perhaps physicians should consider them for inpatient epilepsy monitoring and carefully review a high-resolution MRI head seizure protocol.”

Research suggests that patients who tend to have the best outcomes are those who have neuroimaging abnormalities resulting from substrate-directed pathology (eg, tumor, vascular anomaly, malformation of cortical development, or mesial temporal sclerosis) and undergo a complete resection of the epileptogenic lesion and the site of seizure onset. “These patients have the highest likelihood of being seizure-free after surgery, although some will have to continue taking AEDs to remain seizure-free,” Dr. Cascino said. Approximately 75% of patients with a surgically remediable epileptic syndrome who undergo epilepsy surgery become seizure-free.

Surgery Versus Medication

“When you compare best pharmaceutical treatment with best surgical practice, the numbers are strongly in favor of surgery, both in terms of efficacy and quality of life, for selected patients,” Dr. Cascino said. In one randomized controlled trial, 80 patients with temporal lobe epilepsy were randomly assigned 1:1 to surgery or optimal medical therapy with AEDs for one year. At one year, 58% of surgical patients were seizure-free versus 8% of the AED group. Quality of life was significantly higher among surgical patients. Four patients had adverse effects of surgery, and one patient in the AED group died.

Another randomized trial compared early referral to surgery of patients with drug-resistant mesial temporal lobe epilepsy with continued AED treatment for controlling seizures and improving quality of life. Although the study was halted prematurely due to slow accrual, none of the 23 patients in the AED group were seizure-free during year two of follow-up versus 11 of 15 surgery patients. Surgery had a significantly favorable treatment effect on quality of life. One person in the surgery group had a transient neurologic deficit attributed to postoperative stroke, and three participants in the medication group had status epilepticus.

Surgery in Patients With Normal MRI

One study followed 87 consecutive patients with normal MRI for one year after epilepsy surgery. “They all had temporal lobe epilepsy. Most of them had nonspecific gliosis, a few met the criteria for mesial temporal sclerosis, and none of them had tumors or lesions,” Dr. Cascino said. “About 55% were seizure-free, which compares quite favorably with neuromodulation and other treatments.” The best predictor of seizure freedom was unilateral interictal epileptiform discharge (IED) on scalp EEG and complete resection of brain regions generating IEDs on baseline intraoperative electrocorticography.

Another study demonstrated that the addition of PET to the diagnostic workup may improve outcomes. Among adults with PET-positive and MRI-negative temporal lobe epilepsy, three out of four were seizure-free postoperatively.

Trends in the Rate of Surgery

“Although there are high-quality clinical trials and major epilepsy surgical centers throughout the United States, the number of operative procedures for drug-resistant focal epilepsy has remained stable over the past 20 years,” Dr. Cascino said. “The patient population and surgical techniques have changed. The number of anterior temporal lobectomies may be decreasing, but more patients are being considered for surgery with MRI-negative extratemporal seizures or multifocal seizures.”

In one study, researchers examined epilepsy surgeries performed between 1991 and 2011 on 1,346 patients in nine major surgery centers in the US, Germany, and Australia. In eight centers, the highest number of surgeries for mesial temporal sclerosis occurred in 1991 or 2001, the researchers found. In 2011, the nine centers performed 48% fewer such surgeries, compared with 1991 or 2001, with a parallel increase in the performance of surgery for nonlesional epilepsy. In addition, the number of intracranial EEG implantations that did not lead to subsequent brain resections rose by 0.6% per year.

The study authors called for future research to improve the use of epilepsy surgery, to assess the effectiveness of various surgical procedures and presurgical evaluation tools, and to study extratemporal epilepsy, given its growing contribution to the surgical epilepsy burden.

—Adriene Marshall

Suggested Reading

Burkholder DB, Sulc V, Hoffman EM, et al. Interictal scalp electroencephalography and intraoperative electrocorticography in magnetic resonance imaging-negative temporal lobe epilepsy surgery. JAMA Neurol. 2014;71(6):702-709.

de Tisi J, Bell GS, Peacock JL, et al. The long-term outcome of adult epilepsy surgery, patterns of seizure remission, and relapse: a cohort study. Lancet. 2011;378(9800):1388-1395.

Engel J Jr, McDermott MP, Wiebe S, et al. Early surgical therapy for drug-resistant temporal lobe epilepsy: a randomized trial. JAMA. 2012;307(9):922-930.

Jehi L, Friedman D, Carlson C, et al. The evolution of epilepsy surgery between 1991 and 2011 in nine major epilepsy centers across the United States, Germany, and Australia. Epilepsia. 2015;56(10):1526-1533.

Jobst BC, Cascino GD. Resective epilepsy surgery for drug-resistant focal epilepsy: a review. JAMA. 2015;313(3):285-293.

LoPinto-Khoury C, Sperling MR, Skidmore C, et al. Surgical outcome in PET-positive, MRI-negative patients with temporal lobe epilepsy. Epilepsia. 2012;53(2):342-348.

Mohammed HS, Kaufman CB, Limbrick DD, et al. Impact of epilepsy surgery on seizure control and quality of life: a 26-year follow-up study. Epilepsia. 2012;53(4):712-720.

Wiebe S, Blume WT, Girvin JP, et al. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med. 2001;345(5):311-318.

Zhang J, Liu W, Chen H, et al. Identification of common predictors of surgical outcomes for epilepsy surgery. Neuropsychiatr Dis Treat. 2013;9:1673-1682.

LOS ANGELES—Surgical intervention for epilepsy is often seen as a last resort, even among patients with drug-resistant focal epilepsies, said Gregory D. Cascino, MD, a neurologist at Mayo Clinic in Rochester, Minnesota. One reason for this phenomenon may be concern about potential adverse effects. Research indicates, however, that clinical and functional outcomes of surgery significantly surpass those of treatment with antiepileptic drugs (AEDs) in selected patients with drug-resistant focal epilepsy.

“The three important goals of epilepsy treatment are no seizures, no adverse effects, and no lifestyle limitations. This is what patients want when they seek neurologic care,” said Dr. Cascino at the 70th Annual Meeting of the American Academy of Neurology. “Seizure freedom is important because of its beneficial effects on quality of life, which include the ability to drive, pursue an education, have a career, and live independently with no need for a caregiver. We need to consider the risk of any intervention, whether it is medical or surgical, against the natural history of the disease.” All patients with epilepsy, not just those with drug-resistant focal epilepsy, are at significant risk of mortality due to seizure complications, progressive cognitive disorder, mood disorders, and even sudden unexpected death in epilepsy, he noted.

Identifying Surgical Candidates

“As soon as a patient is diagnosed with drug-resistant focal epilepsy, the neurologist probably should begin to triage for alternative forms of treatment,” Dr. Cascino said. “That doesn’t mean that patients need surgery on the first visit. But perhaps physicians should consider them for inpatient epilepsy monitoring and carefully review a high-resolution MRI head seizure protocol.”

Research suggests that patients who tend to have the best outcomes are those who have neuroimaging abnormalities resulting from substrate-directed pathology (eg, tumor, vascular anomaly, malformation of cortical development, or mesial temporal sclerosis) and undergo a complete resection of the epileptogenic lesion and the site of seizure onset. “These patients have the highest likelihood of being seizure-free after surgery, although some will have to continue taking AEDs to remain seizure-free,” Dr. Cascino said. Approximately 75% of patients with a surgically remediable epileptic syndrome who undergo epilepsy surgery become seizure-free.

Surgery Versus Medication

“When you compare best pharmaceutical treatment with best surgical practice, the numbers are strongly in favor of surgery, both in terms of efficacy and quality of life, for selected patients,” Dr. Cascino said. In one randomized controlled trial, 80 patients with temporal lobe epilepsy were randomly assigned 1:1 to surgery or optimal medical therapy with AEDs for one year. At one year, 58% of surgical patients were seizure-free versus 8% of the AED group. Quality of life was significantly higher among surgical patients. Four patients had adverse effects of surgery, and one patient in the AED group died.

Another randomized trial compared early referral to surgery of patients with drug-resistant mesial temporal lobe epilepsy with continued AED treatment for controlling seizures and improving quality of life. Although the study was halted prematurely due to slow accrual, none of the 23 patients in the AED group were seizure-free during year two of follow-up versus 11 of 15 surgery patients. Surgery had a significantly favorable treatment effect on quality of life. One person in the surgery group had a transient neurologic deficit attributed to postoperative stroke, and three participants in the medication group had status epilepticus.

Surgery in Patients With Normal MRI

One study followed 87 consecutive patients with normal MRI for one year after epilepsy surgery. “They all had temporal lobe epilepsy. Most of them had nonspecific gliosis, a few met the criteria for mesial temporal sclerosis, and none of them had tumors or lesions,” Dr. Cascino said. “About 55% were seizure-free, which compares quite favorably with neuromodulation and other treatments.” The best predictor of seizure freedom was unilateral interictal epileptiform discharge (IED) on scalp EEG and complete resection of brain regions generating IEDs on baseline intraoperative electrocorticography.

Another study demonstrated that the addition of PET to the diagnostic workup may improve outcomes. Among adults with PET-positive and MRI-negative temporal lobe epilepsy, three out of four were seizure-free postoperatively.

Trends in the Rate of Surgery

“Although there are high-quality clinical trials and major epilepsy surgical centers throughout the United States, the number of operative procedures for drug-resistant focal epilepsy has remained stable over the past 20 years,” Dr. Cascino said. “The patient population and surgical techniques have changed. The number of anterior temporal lobectomies may be decreasing, but more patients are being considered for surgery with MRI-negative extratemporal seizures or multifocal seizures.”

In one study, researchers examined epilepsy surgeries performed between 1991 and 2011 on 1,346 patients in nine major surgery centers in the US, Germany, and Australia. In eight centers, the highest number of surgeries for mesial temporal sclerosis occurred in 1991 or 2001, the researchers found. In 2011, the nine centers performed 48% fewer such surgeries, compared with 1991 or 2001, with a parallel increase in the performance of surgery for nonlesional epilepsy. In addition, the number of intracranial EEG implantations that did not lead to subsequent brain resections rose by 0.6% per year.

The study authors called for future research to improve the use of epilepsy surgery, to assess the effectiveness of various surgical procedures and presurgical evaluation tools, and to study extratemporal epilepsy, given its growing contribution to the surgical epilepsy burden.

—Adriene Marshall

Suggested Reading

Burkholder DB, Sulc V, Hoffman EM, et al. Interictal scalp electroencephalography and intraoperative electrocorticography in magnetic resonance imaging-negative temporal lobe epilepsy surgery. JAMA Neurol. 2014;71(6):702-709.

de Tisi J, Bell GS, Peacock JL, et al. The long-term outcome of adult epilepsy surgery, patterns of seizure remission, and relapse: a cohort study. Lancet. 2011;378(9800):1388-1395.

Engel J Jr, McDermott MP, Wiebe S, et al. Early surgical therapy for drug-resistant temporal lobe epilepsy: a randomized trial. JAMA. 2012;307(9):922-930.

Jehi L, Friedman D, Carlson C, et al. The evolution of epilepsy surgery between 1991 and 2011 in nine major epilepsy centers across the United States, Germany, and Australia. Epilepsia. 2015;56(10):1526-1533.

Jobst BC, Cascino GD. Resective epilepsy surgery for drug-resistant focal epilepsy: a review. JAMA. 2015;313(3):285-293.

LoPinto-Khoury C, Sperling MR, Skidmore C, et al. Surgical outcome in PET-positive, MRI-negative patients with temporal lobe epilepsy. Epilepsia. 2012;53(2):342-348.

Mohammed HS, Kaufman CB, Limbrick DD, et al. Impact of epilepsy surgery on seizure control and quality of life: a 26-year follow-up study. Epilepsia. 2012;53(4):712-720.

Wiebe S, Blume WT, Girvin JP, et al. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med. 2001;345(5):311-318.

Zhang J, Liu W, Chen H, et al. Identification of common predictors of surgical outcomes for epilepsy surgery. Neuropsychiatr Dis Treat. 2013;9:1673-1682.

LOS ANGELES—Surgical intervention for epilepsy is often seen as a last resort, even among patients with drug-resistant focal epilepsies, said Gregory D. Cascino, MD, a neurologist at Mayo Clinic in Rochester, Minnesota. One reason for this phenomenon may be concern about potential adverse effects. Research indicates, however, that clinical and functional outcomes of surgery significantly surpass those of treatment with antiepileptic drugs (AEDs) in selected patients with drug-resistant focal epilepsy.

“The three important goals of epilepsy treatment are no seizures, no adverse effects, and no lifestyle limitations. This is what patients want when they seek neurologic care,” said Dr. Cascino at the 70th Annual Meeting of the American Academy of Neurology. “Seizure freedom is important because of its beneficial effects on quality of life, which include the ability to drive, pursue an education, have a career, and live independently with no need for a caregiver. We need to consider the risk of any intervention, whether it is medical or surgical, against the natural history of the disease.” All patients with epilepsy, not just those with drug-resistant focal epilepsy, are at significant risk of mortality due to seizure complications, progressive cognitive disorder, mood disorders, and even sudden unexpected death in epilepsy, he noted.

Identifying Surgical Candidates

“As soon as a patient is diagnosed with drug-resistant focal epilepsy, the neurologist probably should begin to triage for alternative forms of treatment,” Dr. Cascino said. “That doesn’t mean that patients need surgery on the first visit. But perhaps physicians should consider them for inpatient epilepsy monitoring and carefully review a high-resolution MRI head seizure protocol.”

Research suggests that patients who tend to have the best outcomes are those who have neuroimaging abnormalities resulting from substrate-directed pathology (eg, tumor, vascular anomaly, malformation of cortical development, or mesial temporal sclerosis) and undergo a complete resection of the epileptogenic lesion and the site of seizure onset. “These patients have the highest likelihood of being seizure-free after surgery, although some will have to continue taking AEDs to remain seizure-free,” Dr. Cascino said. Approximately 75% of patients with a surgically remediable epileptic syndrome who undergo epilepsy surgery become seizure-free.

Surgery Versus Medication

“When you compare best pharmaceutical treatment with best surgical practice, the numbers are strongly in favor of surgery, both in terms of efficacy and quality of life, for selected patients,” Dr. Cascino said. In one randomized controlled trial, 80 patients with temporal lobe epilepsy were randomly assigned 1:1 to surgery or optimal medical therapy with AEDs for one year. At one year, 58% of surgical patients were seizure-free versus 8% of the AED group. Quality of life was significantly higher among surgical patients. Four patients had adverse effects of surgery, and one patient in the AED group died.

Another randomized trial compared early referral to surgery of patients with drug-resistant mesial temporal lobe epilepsy with continued AED treatment for controlling seizures and improving quality of life. Although the study was halted prematurely due to slow accrual, none of the 23 patients in the AED group were seizure-free during year two of follow-up versus 11 of 15 surgery patients. Surgery had a significantly favorable treatment effect on quality of life. One person in the surgery group had a transient neurologic deficit attributed to postoperative stroke, and three participants in the medication group had status epilepticus.

Surgery in Patients With Normal MRI

One study followed 87 consecutive patients with normal MRI for one year after epilepsy surgery. “They all had temporal lobe epilepsy. Most of them had nonspecific gliosis, a few met the criteria for mesial temporal sclerosis, and none of them had tumors or lesions,” Dr. Cascino said. “About 55% were seizure-free, which compares quite favorably with neuromodulation and other treatments.” The best predictor of seizure freedom was unilateral interictal epileptiform discharge (IED) on scalp EEG and complete resection of brain regions generating IEDs on baseline intraoperative electrocorticography.

Another study demonstrated that the addition of PET to the diagnostic workup may improve outcomes. Among adults with PET-positive and MRI-negative temporal lobe epilepsy, three out of four were seizure-free postoperatively.

Trends in the Rate of Surgery

“Although there are high-quality clinical trials and major epilepsy surgical centers throughout the United States, the number of operative procedures for drug-resistant focal epilepsy has remained stable over the past 20 years,” Dr. Cascino said. “The patient population and surgical techniques have changed. The number of anterior temporal lobectomies may be decreasing, but more patients are being considered for surgery with MRI-negative extratemporal seizures or multifocal seizures.”

In one study, researchers examined epilepsy surgeries performed between 1991 and 2011 on 1,346 patients in nine major surgery centers in the US, Germany, and Australia. In eight centers, the highest number of surgeries for mesial temporal sclerosis occurred in 1991 or 2001, the researchers found. In 2011, the nine centers performed 48% fewer such surgeries, compared with 1991 or 2001, with a parallel increase in the performance of surgery for nonlesional epilepsy. In addition, the number of intracranial EEG implantations that did not lead to subsequent brain resections rose by 0.6% per year.

The study authors called for future research to improve the use of epilepsy surgery, to assess the effectiveness of various surgical procedures and presurgical evaluation tools, and to study extratemporal epilepsy, given its growing contribution to the surgical epilepsy burden.

—Adriene Marshall

Suggested Reading

Burkholder DB, Sulc V, Hoffman EM, et al. Interictal scalp electroencephalography and intraoperative electrocorticography in magnetic resonance imaging-negative temporal lobe epilepsy surgery. JAMA Neurol. 2014;71(6):702-709.

de Tisi J, Bell GS, Peacock JL, et al. The long-term outcome of adult epilepsy surgery, patterns of seizure remission, and relapse: a cohort study. Lancet. 2011;378(9800):1388-1395.

Engel J Jr, McDermott MP, Wiebe S, et al. Early surgical therapy for drug-resistant temporal lobe epilepsy: a randomized trial. JAMA. 2012;307(9):922-930.

Jehi L, Friedman D, Carlson C, et al. The evolution of epilepsy surgery between 1991 and 2011 in nine major epilepsy centers across the United States, Germany, and Australia. Epilepsia. 2015;56(10):1526-1533.

Jobst BC, Cascino GD. Resective epilepsy surgery for drug-resistant focal epilepsy: a review. JAMA. 2015;313(3):285-293.

LoPinto-Khoury C, Sperling MR, Skidmore C, et al. Surgical outcome in PET-positive, MRI-negative patients with temporal lobe epilepsy. Epilepsia. 2012;53(2):342-348.

Mohammed HS, Kaufman CB, Limbrick DD, et al. Impact of epilepsy surgery on seizure control and quality of life: a 26-year follow-up study. Epilepsia. 2012;53(4):712-720.

Wiebe S, Blume WT, Girvin JP, et al. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med. 2001;345(5):311-318.

Zhang J, Liu W, Chen H, et al. Identification of common predictors of surgical outcomes for epilepsy surgery. Neuropsychiatr Dis Treat. 2013;9:1673-1682.

LOS ANGELES—Fremanezumab, a fully humanized monoclonal antibody, is a safe and effective therapy for the preventive treatment of chronic migraine, according to phase III data presented at the 70th Annual Meeting of the American Academy of Neurology. The treatment also has a flexible dosing profile.

Monthly and Quarterly Dosing Regimens

Fremanezumab selectively targets the calcitonin gene-related peptide ligand and is administered through subcutaneous injections. Stephen Silberstein, MD, Director of the Headache Center at Thomas Jefferson University Hospital in Philadelphia, and colleagues conducted a multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate two subcutaneous dose regimens of fremanezumab for the prevention of chronic migraine. Eligible patients were between ages 18 and 70. Exclusion criteria included use of onabotulinumtoxinA in the four months before screening, use of opioids or barbiturates for more than four days during the pretreatment period, and failure of two or more prior preventive medicines.

The investigators assigned 1,130 participants to one of three treatment arms. The first (monthly dosing) arm received 675 mg of fremanuzemab during the first month, followed by 225 mg of fremanezumab at months two and three. The second (quarterly dosing) arm received 675 mg of fremanezumab at month one, followed by placebo injections at months two and three. The third arm received monthly administration of matching placebo. The study’s primary efficacy end point was the mean change in the monthly average number of headache days of at least moderate severity from baseline (ie, a 28-day pretreatment period) to the 12-week double-blind treatment period. Dr. Silberstein and colleagues evaluated this end point using an analysis of covariance method or the Wilcoxon rank sum test.

During the 28-day baseline period, participants’ mean number of headache days of at least moderate severity was 13.1. During the 12-week period after the first dose, the number of monthly headache days of at least moderate severity decreased by 2.5 in the placebo arm, 4.6 in the monthly dosing arm, and 4.3 in the quarterly arm. The differences between the fremanezumab and placebo arms were statistically significant.

Secondary End Points Favored Fremanezumab

In addition, the number of monthly migraine days decreased significantly during the 12-week period after the first dose in the monthly dosing arm (by 5.0 from 16.0) and the quarterly dosing arm (by 4.9 from 16.2), compared with the placebo arm (by 3.2 from 16.3). The number of monthly migraine days also decreased significantly for both dosing regimens during the four weeks after the first dose.

Furthermore, 37.6% of patients in the quarterly dosing arm and 40.8% of patients in the monthly dosing arm had at least a 50% reduction in headache days of at least moderate severity, compared with 18.1% of the placebo arm. Similarly, 7.5% of patients in the quarterly dosing arm and 9.1% of patients in the monthly dosing arm had at least a 75% reduction in headache days of at least moderate severity, compared with 2.7% of the placebo arm.

Fremanezumab was associated with reductions in work productivity loss, compared with placebo. The change from baseline on the Work Productivity and Activity Impairment Questionnaire was −16.6 days in the quarterly dosing arm, −15.9 in the monthly dosing arm, and −9.1 in the placebo arm. In addition, mean score on the Headache Impact Test-6 decreased by 6.4 in the quarterly dosing arm, 6.8 in the monthly dosing arm, and 4.5 in the placebo arm.

The most common adverse event in the study was injection-site reaction. Discontinuation for adverse events was infrequent. Similar proportions of patients in each treatment group had at least one adverse event, and the frequency of these events was lower among controls.

“These results are consistent with [those of] the prior phase II trials in chronic migraine, with similar efficacy and similar treatment effects,” said Dr. Silberstein. Fremanezumab’s safety, tolerability, early onset of efficacy, and flexible dosing “may increase adherence and improve clinical outcomes for patients with migraine,” he concluded.

LOS ANGELES—Fremanezumab, a fully humanized monoclonal antibody, is a safe and effective therapy for the preventive treatment of chronic migraine, according to phase III data presented at the 70th Annual Meeting of the American Academy of Neurology. The treatment also has a flexible dosing profile.

Monthly and Quarterly Dosing Regimens

Fremanezumab selectively targets the calcitonin gene-related peptide ligand and is administered through subcutaneous injections. Stephen Silberstein, MD, Director of the Headache Center at Thomas Jefferson University Hospital in Philadelphia, and colleagues conducted a multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate two subcutaneous dose regimens of fremanezumab for the prevention of chronic migraine. Eligible patients were between ages 18 and 70. Exclusion criteria included use of onabotulinumtoxinA in the four months before screening, use of opioids or barbiturates for more than four days during the pretreatment period, and failure of two or more prior preventive medicines.

The investigators assigned 1,130 participants to one of three treatment arms. The first (monthly dosing) arm received 675 mg of fremanuzemab during the first month, followed by 225 mg of fremanezumab at months two and three. The second (quarterly dosing) arm received 675 mg of fremanezumab at month one, followed by placebo injections at months two and three. The third arm received monthly administration of matching placebo. The study’s primary efficacy end point was the mean change in the monthly average number of headache days of at least moderate severity from baseline (ie, a 28-day pretreatment period) to the 12-week double-blind treatment period. Dr. Silberstein and colleagues evaluated this end point using an analysis of covariance method or the Wilcoxon rank sum test.

During the 28-day baseline period, participants’ mean number of headache days of at least moderate severity was 13.1. During the 12-week period after the first dose, the number of monthly headache days of at least moderate severity decreased by 2.5 in the placebo arm, 4.6 in the monthly dosing arm, and 4.3 in the quarterly arm. The differences between the fremanezumab and placebo arms were statistically significant.

Secondary End Points Favored Fremanezumab

In addition, the number of monthly migraine days decreased significantly during the 12-week period after the first dose in the monthly dosing arm (by 5.0 from 16.0) and the quarterly dosing arm (by 4.9 from 16.2), compared with the placebo arm (by 3.2 from 16.3). The number of monthly migraine days also decreased significantly for both dosing regimens during the four weeks after the first dose.

Furthermore, 37.6% of patients in the quarterly dosing arm and 40.8% of patients in the monthly dosing arm had at least a 50% reduction in headache days of at least moderate severity, compared with 18.1% of the placebo arm. Similarly, 7.5% of patients in the quarterly dosing arm and 9.1% of patients in the monthly dosing arm had at least a 75% reduction in headache days of at least moderate severity, compared with 2.7% of the placebo arm.

Fremanezumab was associated with reductions in work productivity loss, compared with placebo. The change from baseline on the Work Productivity and Activity Impairment Questionnaire was −16.6 days in the quarterly dosing arm, −15.9 in the monthly dosing arm, and −9.1 in the placebo arm. In addition, mean score on the Headache Impact Test-6 decreased by 6.4 in the quarterly dosing arm, 6.8 in the monthly dosing arm, and 4.5 in the placebo arm.

The most common adverse event in the study was injection-site reaction. Discontinuation for adverse events was infrequent. Similar proportions of patients in each treatment group had at least one adverse event, and the frequency of these events was lower among controls.

“These results are consistent with [those of] the prior phase II trials in chronic migraine, with similar efficacy and similar treatment effects,” said Dr. Silberstein. Fremanezumab’s safety, tolerability, early onset of efficacy, and flexible dosing “may increase adherence and improve clinical outcomes for patients with migraine,” he concluded.

LOS ANGELES—Fremanezumab, a fully humanized monoclonal antibody, is a safe and effective therapy for the preventive treatment of chronic migraine, according to phase III data presented at the 70th Annual Meeting of the American Academy of Neurology. The treatment also has a flexible dosing profile.

Monthly and Quarterly Dosing Regimens

Fremanezumab selectively targets the calcitonin gene-related peptide ligand and is administered through subcutaneous injections. Stephen Silberstein, MD, Director of the Headache Center at Thomas Jefferson University Hospital in Philadelphia, and colleagues conducted a multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate two subcutaneous dose regimens of fremanezumab for the prevention of chronic migraine. Eligible patients were between ages 18 and 70. Exclusion criteria included use of onabotulinumtoxinA in the four months before screening, use of opioids or barbiturates for more than four days during the pretreatment period, and failure of two or more prior preventive medicines.

The investigators assigned 1,130 participants to one of three treatment arms. The first (monthly dosing) arm received 675 mg of fremanuzemab during the first month, followed by 225 mg of fremanezumab at months two and three. The second (quarterly dosing) arm received 675 mg of fremanezumab at month one, followed by placebo injections at months two and three. The third arm received monthly administration of matching placebo. The study’s primary efficacy end point was the mean change in the monthly average number of headache days of at least moderate severity from baseline (ie, a 28-day pretreatment period) to the 12-week double-blind treatment period. Dr. Silberstein and colleagues evaluated this end point using an analysis of covariance method or the Wilcoxon rank sum test.

During the 28-day baseline period, participants’ mean number of headache days of at least moderate severity was 13.1. During the 12-week period after the first dose, the number of monthly headache days of at least moderate severity decreased by 2.5 in the placebo arm, 4.6 in the monthly dosing arm, and 4.3 in the quarterly arm. The differences between the fremanezumab and placebo arms were statistically significant.

Secondary End Points Favored Fremanezumab

In addition, the number of monthly migraine days decreased significantly during the 12-week period after the first dose in the monthly dosing arm (by 5.0 from 16.0) and the quarterly dosing arm (by 4.9 from 16.2), compared with the placebo arm (by 3.2 from 16.3). The number of monthly migraine days also decreased significantly for both dosing regimens during the four weeks after the first dose.

Furthermore, 37.6% of patients in the quarterly dosing arm and 40.8% of patients in the monthly dosing arm had at least a 50% reduction in headache days of at least moderate severity, compared with 18.1% of the placebo arm. Similarly, 7.5% of patients in the quarterly dosing arm and 9.1% of patients in the monthly dosing arm had at least a 75% reduction in headache days of at least moderate severity, compared with 2.7% of the placebo arm.

Fremanezumab was associated with reductions in work productivity loss, compared with placebo. The change from baseline on the Work Productivity and Activity Impairment Questionnaire was −16.6 days in the quarterly dosing arm, −15.9 in the monthly dosing arm, and −9.1 in the placebo arm. In addition, mean score on the Headache Impact Test-6 decreased by 6.4 in the quarterly dosing arm, 6.8 in the monthly dosing arm, and 4.5 in the placebo arm.

The most common adverse event in the study was injection-site reaction. Discontinuation for adverse events was infrequent. Similar proportions of patients in each treatment group had at least one adverse event, and the frequency of these events was lower among controls.

“These results are consistent with [those of] the prior phase II trials in chronic migraine, with similar efficacy and similar treatment effects,” said Dr. Silberstein. Fremanezumab’s safety, tolerability, early onset of efficacy, and flexible dosing “may increase adherence and improve clinical outcomes for patients with migraine,” he concluded.

Is it me, or is anyone else worried about the online, pay-to-publish movement sweeping science?

I am being inundated with “please publish in our online journal for a fee” emails. I confess, I tried it once or twice and was pleased with the published outcome, as I communicated a concept that I thought was important to the practice of medicine. However, it was a bit disconcerting that the publishers of this online journal wanted an article within 3 weeks. Naturally, a scientific publication thrown together in 3 weeks could not be that good – unless it already had been on the drawing board for a while. Of note, the various editors of these journals often maintain that the articles are “peer reviewed.”

An article that I paid the Journal of Family Medicine and Disease Prevention to publish was one I coauthored, titled, “Prenatal vitamins deficient in recommended choline intake for pregnant women” (J Fam Med Dis Prev. 2016;2[4]1-3.)

That very straightforward article that surveyed the choline content in the top 75 prenatal vitamins showed that none of those vitamins contained the daily recommended dosage for pregnant women established by the Institute of Medicine in 1998. So, in many ways, the conclusions we drew in the article were a no-brainer and the result of simple, yet important observations that science had overlooked.

Despite the straightforward nature of that pay-to-publish article, the evidence it presented was sufficient to get the American Medical Association’s House of Delegates to pass a resolution calling for an increase in the choline content in prenatal vitamins.

So on the negative side of the ledger, I am concerned that some very “faulty science” could get published in the online, pay-to-publish journals, in light of what seems like their rush to publish. Of course, every now and then some of our prestigious journals publish information that is poorly interpreted, such as the recent article about the suicide rates among U.S. youth (JAMA Pediatr. 2018;172[7]:697-9).

Another separate, but related issue is what at least seems from a distance to be a rush by some of the tried and true medical journals (the New England Journal of Medicine, the various JAMA Network journals, The Lancet, and so on), to keep up with the trend of online journals by making their journals more accessible online.

I am concerned but not sure what to do about these new publishing trends in medicine and science. Accordingly, I will advocate that, as physicians and scientists, we learn how to read research reports critically and how to be clear when a research design is solid and leads to legitimate scientific conclusions. We must be able to discern when reports are poorly designed – and when they lead to “junk science.”

Like most things, Internet access to scientific articles is a blessing and a curse. The blessing is that more people around the world will be able to get access to scientific study and facts they can use to improve health care. The curse is that the “snake oil salespeople” may have better opportunities to convince the public that their “snake oil” works and the public should buy their “cure.”
 

Dr. Bell is staff psychiatrist at Jackson Park Hospital Surgical-Medical/Psychiatric Inpatient Unit; clinical professor emeritus, department of psychiatry, University of Illinois at Chicago; and former director of the Institute for Juvenile Research (the birthplace of child psychiatry), all in Chicago. He also serves as chair of psychiatry at Windsor University, St. Kitts.

Is it me, or is anyone else worried about the online, pay-to-publish movement sweeping science?

I am being inundated with “please publish in our online journal for a fee” emails. I confess, I tried it once or twice and was pleased with the published outcome, as I communicated a concept that I thought was important to the practice of medicine. However, it was a bit disconcerting that the publishers of this online journal wanted an article within 3 weeks. Naturally, a scientific publication thrown together in 3 weeks could not be that good – unless it already had been on the drawing board for a while. Of note, the various editors of these journals often maintain that the articles are “peer reviewed.”

An article that I paid the Journal of Family Medicine and Disease Prevention to publish was one I coauthored, titled, “Prenatal vitamins deficient in recommended choline intake for pregnant women” (J Fam Med Dis Prev. 2016;2[4]1-3.)

That very straightforward article that surveyed the choline content in the top 75 prenatal vitamins showed that none of those vitamins contained the daily recommended dosage for pregnant women established by the Institute of Medicine in 1998. So, in many ways, the conclusions we drew in the article were a no-brainer and the result of simple, yet important observations that science had overlooked.

Despite the straightforward nature of that pay-to-publish article, the evidence it presented was sufficient to get the American Medical Association’s House of Delegates to pass a resolution calling for an increase in the choline content in prenatal vitamins.

So on the negative side of the ledger, I am concerned that some very “faulty science” could get published in the online, pay-to-publish journals, in light of what seems like their rush to publish. Of course, every now and then some of our prestigious journals publish information that is poorly interpreted, such as the recent article about the suicide rates among U.S. youth (JAMA Pediatr. 2018;172[7]:697-9).

Another separate, but related issue is what at least seems from a distance to be a rush by some of the tried and true medical journals (the New England Journal of Medicine, the various JAMA Network journals, The Lancet, and so on), to keep up with the trend of online journals by making their journals more accessible online.

I am concerned but not sure what to do about these new publishing trends in medicine and science. Accordingly, I will advocate that, as physicians and scientists, we learn how to read research reports critically and how to be clear when a research design is solid and leads to legitimate scientific conclusions. We must be able to discern when reports are poorly designed – and when they lead to “junk science.”

Like most things, Internet access to scientific articles is a blessing and a curse. The blessing is that more people around the world will be able to get access to scientific study and facts they can use to improve health care. The curse is that the “snake oil salespeople” may have better opportunities to convince the public that their “snake oil” works and the public should buy their “cure.”
 

Dr. Bell is staff psychiatrist at Jackson Park Hospital Surgical-Medical/Psychiatric Inpatient Unit; clinical professor emeritus, department of psychiatry, University of Illinois at Chicago; and former director of the Institute for Juvenile Research (the birthplace of child psychiatry), all in Chicago. He also serves as chair of psychiatry at Windsor University, St. Kitts.

Is it me, or is anyone else worried about the online, pay-to-publish movement sweeping science?

I am being inundated with “please publish in our online journal for a fee” emails. I confess, I tried it once or twice and was pleased with the published outcome, as I communicated a concept that I thought was important to the practice of medicine. However, it was a bit disconcerting that the publishers of this online journal wanted an article within 3 weeks. Naturally, a scientific publication thrown together in 3 weeks could not be that good – unless it already had been on the drawing board for a while. Of note, the various editors of these journals often maintain that the articles are “peer reviewed.”

An article that I paid the Journal of Family Medicine and Disease Prevention to publish was one I coauthored, titled, “Prenatal vitamins deficient in recommended choline intake for pregnant women” (J Fam Med Dis Prev. 2016;2[4]1-3.)

That very straightforward article that surveyed the choline content in the top 75 prenatal vitamins showed that none of those vitamins contained the daily recommended dosage for pregnant women established by the Institute of Medicine in 1998. So, in many ways, the conclusions we drew in the article were a no-brainer and the result of simple, yet important observations that science had overlooked.

Despite the straightforward nature of that pay-to-publish article, the evidence it presented was sufficient to get the American Medical Association’s House of Delegates to pass a resolution calling for an increase in the choline content in prenatal vitamins.

So on the negative side of the ledger, I am concerned that some very “faulty science” could get published in the online, pay-to-publish journals, in light of what seems like their rush to publish. Of course, every now and then some of our prestigious journals publish information that is poorly interpreted, such as the recent article about the suicide rates among U.S. youth (JAMA Pediatr. 2018;172[7]:697-9).

Another separate, but related issue is what at least seems from a distance to be a rush by some of the tried and true medical journals (the New England Journal of Medicine, the various JAMA Network journals, The Lancet, and so on), to keep up with the trend of online journals by making their journals more accessible online.

I am concerned but not sure what to do about these new publishing trends in medicine and science. Accordingly, I will advocate that, as physicians and scientists, we learn how to read research reports critically and how to be clear when a research design is solid and leads to legitimate scientific conclusions. We must be able to discern when reports are poorly designed – and when they lead to “junk science.”

Like most things, Internet access to scientific articles is a blessing and a curse. The blessing is that more people around the world will be able to get access to scientific study and facts they can use to improve health care. The curse is that the “snake oil salespeople” may have better opportunities to convince the public that their “snake oil” works and the public should buy their “cure.”
 

Dr. Bell is staff psychiatrist at Jackson Park Hospital Surgical-Medical/Psychiatric Inpatient Unit; clinical professor emeritus, department of psychiatry, University of Illinois at Chicago; and former director of the Institute for Juvenile Research (the birthplace of child psychiatry), all in Chicago. He also serves as chair of psychiatry at Windsor University, St. Kitts.

BALTIMORE – Emerging developments for the treatment of obstructive sleep apnea have shown promise in providing options beyond continuous-positive airway pressure, investigators reported at the annual meeting of the Associated Professional Sleep Societies. These developments include a single-use nasopharyngeal airway stent, upper-airway stimulation using a pacemaker-like device, a negative-pressure device that opens the airway, and an artificial intelligence approach that can predict outcomes of oral appliance therapy.

Nasopharyngeal airway stent

Clete A. Kushida, MD, of Stanford (Calif.) University reported on recent results of a trial of the nasopharyngeal airway stent (NAS) single-use disposable insert (Seven Dreamers Laboratories, Tokyo). This device consists of a flexible semi-rigid silicone rubber tube 120-145 mm in length and coated with a hydrophilic gel. The patient inserts the distal end of the tube into the nostril, and it positions itself within the nasopharynx and retropalatal oropharynx to open the airway. A clip attaches to the exterior septum to keep the device in place. The patient removes the NAS in the morning. The device is commercially available in Japan and some European countries.

Dr. Kushida reported on two posters that were presented at Sleep 2018. The first by the Osaka University Graduate School of Dentistry in Japan investigated the predictability of NAS efficacy in patients with a velopharynx that was narrower than the hypopharynx (Sleep. 2018;41 (suppl 1):A207: doi.org/10.1093/sleep/zsy061.554). The study showed that 11 responders had a narrow velopharynx while 18 nonresponders had a narrow hypopharynx. Response was defined as 50% or greater reduction of apnea-hypopnea index (AHI) from baseline. “The success rate of NAS for the patients with narrowing of the velopharynx is 83.3%,” Dr. Kushida said.

He also reported on a study he led of NAS in patients with obstructive sleep apnea and healthy controls (Sleep. 2018;41 (suppl 1):A207: doi.org/10.1093/sleep/zsy061.555). The trial was conducted at Stanford and Tokyo sleep medical centers, with healthy controls at the Tokyo site only. AHI improved in all three obstructive sleep apnea (OSA) groups, but most significantly in those with moderate (n = 23) and severe (n = 21) OSA: 7.2 (P = .0038) and 11.7 (P = .0069), respectively. In the Stanford cohort, 2 of 32 patients originally enrolled dropped out because they found the NAS uncomfortable; none dropped out of the Tokyo cohort.

“NAS can be effective in treatment of snoring and OSA, in particular those with moderate/severe OSA, with significant improvement in mean obstructive apnea index,” Dr. Kushida said. He also noted the device is more effective in patients with narrowing of the oropharynx/velopharynx rather than the hypopharynx.

Dr. Kushida reported he had a financial relationship with the Seven Dreamers Laboratories.
 

Continuous negative external pressure

Jerrold A. Kram, MD, reported on a device that employs continuous negative external pressure – known as cNEP – that uses a silicone collar covering the front of the throat and a pump that applies suction to keep the airway open from the outside. He cited a small 2015 study out of Japan that found the device was effective in keeping the pharyngeal airway open in nonobese women (J Appl Physiol. 2015;118:912-20). Another small U.S. study found cNEP reduces respiratory impairment during screening colonoscopy (Endoscopy. 2016;48:584-7). Sommetrics, which has patented the technology, is developing a version of the product for obstructive sleep apnea, Dr. Kram said. The company already has a Food and Drug Administration–approved product to treat apneas that people experience when under mild to moderate sedation, such as a colonoscopy. It is approved for sale in Canada, but not in the United States.

“It gives us another tool in the box,” Dr. Kram said. “It’s very small and portable, easy to take on an airplane with you, and it reduces the chance for claustrophobia” that comes with continuous-positive airway pressure (CPAP), said Dr. Kram. There are no tubes or masks and no humidifier to deal with.

Dr. Kram conducted a small study of 15 OSA patients using cNEP last year. Among nine excellent responders, the lowest AHI was 1.5 on average, from an average baseline of 43.9; among four partial responders, the lowest observed AHI averaged 11.75 (J Clin Sleep Med. 2017;13:1009-12).

The cNEP device is also the subject of a home study of patients with OSA in Canada, Dr. Kram said. Unpublished results indicate that 46% (27/59) of patients had an initial response rate to either -25 or -30 characteristic moment waveform (cmw) of negative airway pressure. For those who completed 3 weeks of treatment, the response rate was 64% (16/25). “Seventy-six percent of subjects felt their overall experience with cNEP was better than with CPAP,” Dr. Kram said.

However, studies have noted some minor issues with cNEP, Dr. Kram said. They include mild skin irritation, choking sensation if not properly placed, limited size availability, and absence of efficacy data. Dr. Kram said a U.S. pivotal trial is scheduled to start soon.

Dr. Kram disclosed he is a paid adviser for Sommetrics.
 

Oral appliance therapy

Oral appliance therapy (OAT) has been very effective in some patients and has been endorsed by the American Academy of Sleep Medicine since 2006, but it has been underutilized predominantly for two reasons, noted John Remmers, MD, because fitting the device requires a trial-and-error approach that can discourage patients; and the therapeutic success rate is 50%-60%.

To predict which patients are likely to succeed with OAT, Dr. Remmers and his colleagues at Zephyr Sleep Technologies have developed an artificial intelligence (AI) platform that uses a feedback-controlled mandibular positioner, a mouthpiece-like device that opens the airway during sleep. Dr. Remmers is chief medical officer and cofounder of Zephyr Sleep Technologies, based in Calgary, Alta.

While imaging has been used in awake patients to fit OAT devices, Dr. Remmers noted a number of shortcomings with this modality. “Sleep apnea results from an anatomic problem – i.e., structural encroachment on the pharyngeal airway, which is neurally compensated when the patient is awake,” he said. “Because of this, we need to do the test when the patient is asleep.”

The AI platform with feedback-controlled mandibular positioner uses temporary dental trays to create impressions for the mouthpiece the patient uses during sleep. The mouthpiece connects to a remote-controlled device that makes real-time adjustments in the mandibular position without disturbing the patient’s sleep. “The computer identifies respiratory events all night long, adjusting the position of the mandible,” he said in explaining the AI component of the device. “Just think of it as similar to autotitration with CPAP.”

Dr. Remmers reported results of a phase 2 study of the platform presented as a poster reporting on a study of 101 patients with OSA participants. The study reported sensitivity of 86% and specificity of 92% in predicting success with the feedback-controlled mandibular positioner, he said.

“The sensitivity and overall predictive accuracy of the AI-based approach was greater than an intuitive approach using a pretreatment, temporary appliance, indicating that feedback-controlled mandibular positioning test outperformed the intuitive approach,” he said. The device has been approved by Health Canada and is awaiting clearance in the United States.
 

Upper airway stimulation

Upper airway stimulation (UAS) is emerging as a new class of therapy, said Patrick J. Strollo Jr., MD, of the University of Pittsburgh. The therapy involves an impulse generator (IPG) similar to a pacemaker that is implanted in the left side of the chest and connected to a stimulation lead secured to the distal hypoglossal nerve in the neck. The UAS system also incorporates a sensing lead that is implanted between the intercostal muscles and attached to the IPG allowing for phasic stimulation of the genioglossal muscle. The patient uses a remote control to turn the device on at night and off in the morning.

Dr. Strollo was lead author of the Stimulation Therapy for Apnea Reduction (STAR) trial (N Engl J Med. 2014:370;139-49), a prospective multicenter trial with a randomized therapy withdrawal arm. In 126 participants, he said, the median AHI score declined 68% in 12 months, from 29.3 at baseline to 9 (P less than .0001).

He provided updated results that showed 80% of patients continued to use the device after 5 years (Otolaryngol Head Neck Surg. 2018; doi: 10.1177/0194599818762383). Median AHI at 5 years was 6.9, Dr. Strollo said, and median Epworth Sleepiness Scale scores declined from 11.6 at baseline to 6.9 at 5 years.

Another postapproval study of UAS, the ADHERE registry, has enrolled 348 patients at 10 centers with a goal of 2,500, Dr. Strollo said (Otolaryngol Head Neck Surg. 2018: doi: 10.1177/0194599818764896). Twelve-month study results have shown reductions in AHI and Epworth Sleepiness Scale scores comparable to previous reports. ADHERE also reported that 92% of patients were satisfied with UAS.

The latest innovation for UAS is the ability to download data from the implant at office visits so the physician can review patient adherence patterns, along with energy levels and settings for sensing and stimulation, Dr. Strollo said.

“Upper airway stimulation is an additional tool in the management of properly selected, at-risk apnea patients who do not accept or adhere to positive pressure therapy,” Dr. Strollo said. “The STAR trial has provided robust evidence that upper airway stimulation is safe and effective in participants with moderate to severe OSA, and the treatment effect is maintained beyond the 12-month endpoint.”

Dr. Strollo disclosed a financial relationship with Inspire Medical Systems, manufacturer of the UAS device.

BALTIMORE – Emerging developments for the treatment of obstructive sleep apnea have shown promise in providing options beyond continuous-positive airway pressure, investigators reported at the annual meeting of the Associated Professional Sleep Societies. These developments include a single-use nasopharyngeal airway stent, upper-airway stimulation using a pacemaker-like device, a negative-pressure device that opens the airway, and an artificial intelligence approach that can predict outcomes of oral appliance therapy.

Nasopharyngeal airway stent

Clete A. Kushida, MD, of Stanford (Calif.) University reported on recent results of a trial of the nasopharyngeal airway stent (NAS) single-use disposable insert (Seven Dreamers Laboratories, Tokyo). This device consists of a flexible semi-rigid silicone rubber tube 120-145 mm in length and coated with a hydrophilic gel. The patient inserts the distal end of the tube into the nostril, and it positions itself within the nasopharynx and retropalatal oropharynx to open the airway. A clip attaches to the exterior septum to keep the device in place. The patient removes the NAS in the morning. The device is commercially available in Japan and some European countries.

Dr. Kushida reported on two posters that were presented at Sleep 2018. The first by the Osaka University Graduate School of Dentistry in Japan investigated the predictability of NAS efficacy in patients with a velopharynx that was narrower than the hypopharynx (Sleep. 2018;41 (suppl 1):A207: doi.org/10.1093/sleep/zsy061.554). The study showed that 11 responders had a narrow velopharynx while 18 nonresponders had a narrow hypopharynx. Response was defined as 50% or greater reduction of apnea-hypopnea index (AHI) from baseline. “The success rate of NAS for the patients with narrowing of the velopharynx is 83.3%,” Dr. Kushida said.

He also reported on a study he led of NAS in patients with obstructive sleep apnea and healthy controls (Sleep. 2018;41 (suppl 1):A207: doi.org/10.1093/sleep/zsy061.555). The trial was conducted at Stanford and Tokyo sleep medical centers, with healthy controls at the Tokyo site only. AHI improved in all three obstructive sleep apnea (OSA) groups, but most significantly in those with moderate (n = 23) and severe (n = 21) OSA: 7.2 (P = .0038) and 11.7 (P = .0069), respectively. In the Stanford cohort, 2 of 32 patients originally enrolled dropped out because they found the NAS uncomfortable; none dropped out of the Tokyo cohort.

“NAS can be effective in treatment of snoring and OSA, in particular those with moderate/severe OSA, with significant improvement in mean obstructive apnea index,” Dr. Kushida said. He also noted the device is more effective in patients with narrowing of the oropharynx/velopharynx rather than the hypopharynx.

Dr. Kushida reported he had a financial relationship with the Seven Dreamers Laboratories.
 

Continuous negative external pressure

Jerrold A. Kram, MD, reported on a device that employs continuous negative external pressure – known as cNEP – that uses a silicone collar covering the front of the throat and a pump that applies suction to keep the airway open from the outside. He cited a small 2015 study out of Japan that found the device was effective in keeping the pharyngeal airway open in nonobese women (J Appl Physiol. 2015;118:912-20). Another small U.S. study found cNEP reduces respiratory impairment during screening colonoscopy (Endoscopy. 2016;48:584-7). Sommetrics, which has patented the technology, is developing a version of the product for obstructive sleep apnea, Dr. Kram said. The company already has a Food and Drug Administration–approved product to treat apneas that people experience when under mild to moderate sedation, such as a colonoscopy. It is approved for sale in Canada, but not in the United States.

“It gives us another tool in the box,” Dr. Kram said. “It’s very small and portable, easy to take on an airplane with you, and it reduces the chance for claustrophobia” that comes with continuous-positive airway pressure (CPAP), said Dr. Kram. There are no tubes or masks and no humidifier to deal with.

Dr. Kram conducted a small study of 15 OSA patients using cNEP last year. Among nine excellent responders, the lowest AHI was 1.5 on average, from an average baseline of 43.9; among four partial responders, the lowest observed AHI averaged 11.75 (J Clin Sleep Med. 2017;13:1009-12).

The cNEP device is also the subject of a home study of patients with OSA in Canada, Dr. Kram said. Unpublished results indicate that 46% (27/59) of patients had an initial response rate to either -25 or -30 characteristic moment waveform (cmw) of negative airway pressure. For those who completed 3 weeks of treatment, the response rate was 64% (16/25). “Seventy-six percent of subjects felt their overall experience with cNEP was better than with CPAP,” Dr. Kram said.

However, studies have noted some minor issues with cNEP, Dr. Kram said. They include mild skin irritation, choking sensation if not properly placed, limited size availability, and absence of efficacy data. Dr. Kram said a U.S. pivotal trial is scheduled to start soon.

Dr. Kram disclosed he is a paid adviser for Sommetrics.
 

Oral appliance therapy

Oral appliance therapy (OAT) has been very effective in some patients and has been endorsed by the American Academy of Sleep Medicine since 2006, but it has been underutilized predominantly for two reasons, noted John Remmers, MD, because fitting the device requires a trial-and-error approach that can discourage patients; and the therapeutic success rate is 50%-60%.

To predict which patients are likely to succeed with OAT, Dr. Remmers and his colleagues at Zephyr Sleep Technologies have developed an artificial intelligence (AI) platform that uses a feedback-controlled mandibular positioner, a mouthpiece-like device that opens the airway during sleep. Dr. Remmers is chief medical officer and cofounder of Zephyr Sleep Technologies, based in Calgary, Alta.

While imaging has been used in awake patients to fit OAT devices, Dr. Remmers noted a number of shortcomings with this modality. “Sleep apnea results from an anatomic problem – i.e., structural encroachment on the pharyngeal airway, which is neurally compensated when the patient is awake,” he said. “Because of this, we need to do the test when the patient is asleep.”

The AI platform with feedback-controlled mandibular positioner uses temporary dental trays to create impressions for the mouthpiece the patient uses during sleep. The mouthpiece connects to a remote-controlled device that makes real-time adjustments in the mandibular position without disturbing the patient’s sleep. “The computer identifies respiratory events all night long, adjusting the position of the mandible,” he said in explaining the AI component of the device. “Just think of it as similar to autotitration with CPAP.”

Dr. Remmers reported results of a phase 2 study of the platform presented as a poster reporting on a study of 101 patients with OSA participants. The study reported sensitivity of 86% and specificity of 92% in predicting success with the feedback-controlled mandibular positioner, he said.

“The sensitivity and overall predictive accuracy of the AI-based approach was greater than an intuitive approach using a pretreatment, temporary appliance, indicating that feedback-controlled mandibular positioning test outperformed the intuitive approach,” he said. The device has been approved by Health Canada and is awaiting clearance in the United States.
 

Upper airway stimulation

Upper airway stimulation (UAS) is emerging as a new class of therapy, said Patrick J. Strollo Jr., MD, of the University of Pittsburgh. The therapy involves an impulse generator (IPG) similar to a pacemaker that is implanted in the left side of the chest and connected to a stimulation lead secured to the distal hypoglossal nerve in the neck. The UAS system also incorporates a sensing lead that is implanted between the intercostal muscles and attached to the IPG allowing for phasic stimulation of the genioglossal muscle. The patient uses a remote control to turn the device on at night and off in the morning.

Dr. Strollo was lead author of the Stimulation Therapy for Apnea Reduction (STAR) trial (N Engl J Med. 2014:370;139-49), a prospective multicenter trial with a randomized therapy withdrawal arm. In 126 participants, he said, the median AHI score declined 68% in 12 months, from 29.3 at baseline to 9 (P less than .0001).

He provided updated results that showed 80% of patients continued to use the device after 5 years (Otolaryngol Head Neck Surg. 2018; doi: 10.1177/0194599818762383). Median AHI at 5 years was 6.9, Dr. Strollo said, and median Epworth Sleepiness Scale scores declined from 11.6 at baseline to 6.9 at 5 years.

Another postapproval study of UAS, the ADHERE registry, has enrolled 348 patients at 10 centers with a goal of 2,500, Dr. Strollo said (Otolaryngol Head Neck Surg. 2018: doi: 10.1177/0194599818764896). Twelve-month study results have shown reductions in AHI and Epworth Sleepiness Scale scores comparable to previous reports. ADHERE also reported that 92% of patients were satisfied with UAS.

The latest innovation for UAS is the ability to download data from the implant at office visits so the physician can review patient adherence patterns, along with energy levels and settings for sensing and stimulation, Dr. Strollo said.

“Upper airway stimulation is an additional tool in the management of properly selected, at-risk apnea patients who do not accept or adhere to positive pressure therapy,” Dr. Strollo said. “The STAR trial has provided robust evidence that upper airway stimulation is safe and effective in participants with moderate to severe OSA, and the treatment effect is maintained beyond the 12-month endpoint.”

Dr. Strollo disclosed a financial relationship with Inspire Medical Systems, manufacturer of the UAS device.

BALTIMORE – Emerging developments for the treatment of obstructive sleep apnea have shown promise in providing options beyond continuous-positive airway pressure, investigators reported at the annual meeting of the Associated Professional Sleep Societies. These developments include a single-use nasopharyngeal airway stent, upper-airway stimulation using a pacemaker-like device, a negative-pressure device that opens the airway, and an artificial intelligence approach that can predict outcomes of oral appliance therapy.

Nasopharyngeal airway stent

Clete A. Kushida, MD, of Stanford (Calif.) University reported on recent results of a trial of the nasopharyngeal airway stent (NAS) single-use disposable insert (Seven Dreamers Laboratories, Tokyo). This device consists of a flexible semi-rigid silicone rubber tube 120-145 mm in length and coated with a hydrophilic gel. The patient inserts the distal end of the tube into the nostril, and it positions itself within the nasopharynx and retropalatal oropharynx to open the airway. A clip attaches to the exterior septum to keep the device in place. The patient removes the NAS in the morning. The device is commercially available in Japan and some European countries.

Dr. Kushida reported on two posters that were presented at Sleep 2018. The first by the Osaka University Graduate School of Dentistry in Japan investigated the predictability of NAS efficacy in patients with a velopharynx that was narrower than the hypopharynx (Sleep. 2018;41 (suppl 1):A207: doi.org/10.1093/sleep/zsy061.554). The study showed that 11 responders had a narrow velopharynx while 18 nonresponders had a narrow hypopharynx. Response was defined as 50% or greater reduction of apnea-hypopnea index (AHI) from baseline. “The success rate of NAS for the patients with narrowing of the velopharynx is 83.3%,” Dr. Kushida said.

He also reported on a study he led of NAS in patients with obstructive sleep apnea and healthy controls (Sleep. 2018;41 (suppl 1):A207: doi.org/10.1093/sleep/zsy061.555). The trial was conducted at Stanford and Tokyo sleep medical centers, with healthy controls at the Tokyo site only. AHI improved in all three obstructive sleep apnea (OSA) groups, but most significantly in those with moderate (n = 23) and severe (n = 21) OSA: 7.2 (P = .0038) and 11.7 (P = .0069), respectively. In the Stanford cohort, 2 of 32 patients originally enrolled dropped out because they found the NAS uncomfortable; none dropped out of the Tokyo cohort.

“NAS can be effective in treatment of snoring and OSA, in particular those with moderate/severe OSA, with significant improvement in mean obstructive apnea index,” Dr. Kushida said. He also noted the device is more effective in patients with narrowing of the oropharynx/velopharynx rather than the hypopharynx.

Dr. Kushida reported he had a financial relationship with the Seven Dreamers Laboratories.
 

Continuous negative external pressure

Jerrold A. Kram, MD, reported on a device that employs continuous negative external pressure – known as cNEP – that uses a silicone collar covering the front of the throat and a pump that applies suction to keep the airway open from the outside. He cited a small 2015 study out of Japan that found the device was effective in keeping the pharyngeal airway open in nonobese women (J Appl Physiol. 2015;118:912-20). Another small U.S. study found cNEP reduces respiratory impairment during screening colonoscopy (Endoscopy. 2016;48:584-7). Sommetrics, which has patented the technology, is developing a version of the product for obstructive sleep apnea, Dr. Kram said. The company already has a Food and Drug Administration–approved product to treat apneas that people experience when under mild to moderate sedation, such as a colonoscopy. It is approved for sale in Canada, but not in the United States.

“It gives us another tool in the box,” Dr. Kram said. “It’s very small and portable, easy to take on an airplane with you, and it reduces the chance for claustrophobia” that comes with continuous-positive airway pressure (CPAP), said Dr. Kram. There are no tubes or masks and no humidifier to deal with.

Dr. Kram conducted a small study of 15 OSA patients using cNEP last year. Among nine excellent responders, the lowest AHI was 1.5 on average, from an average baseline of 43.9; among four partial responders, the lowest observed AHI averaged 11.75 (J Clin Sleep Med. 2017;13:1009-12).

The cNEP device is also the subject of a home study of patients with OSA in Canada, Dr. Kram said. Unpublished results indicate that 46% (27/59) of patients had an initial response rate to either -25 or -30 characteristic moment waveform (cmw) of negative airway pressure. For those who completed 3 weeks of treatment, the response rate was 64% (16/25). “Seventy-six percent of subjects felt their overall experience with cNEP was better than with CPAP,” Dr. Kram said.

However, studies have noted some minor issues with cNEP, Dr. Kram said. They include mild skin irritation, choking sensation if not properly placed, limited size availability, and absence of efficacy data. Dr. Kram said a U.S. pivotal trial is scheduled to start soon.

Dr. Kram disclosed he is a paid adviser for Sommetrics.
 

Oral appliance therapy

Oral appliance therapy (OAT) has been very effective in some patients and has been endorsed by the American Academy of Sleep Medicine since 2006, but it has been underutilized predominantly for two reasons, noted John Remmers, MD, because fitting the device requires a trial-and-error approach that can discourage patients; and the therapeutic success rate is 50%-60%.

To predict which patients are likely to succeed with OAT, Dr. Remmers and his colleagues at Zephyr Sleep Technologies have developed an artificial intelligence (AI) platform that uses a feedback-controlled mandibular positioner, a mouthpiece-like device that opens the airway during sleep. Dr. Remmers is chief medical officer and cofounder of Zephyr Sleep Technologies, based in Calgary, Alta.

While imaging has been used in awake patients to fit OAT devices, Dr. Remmers noted a number of shortcomings with this modality. “Sleep apnea results from an anatomic problem – i.e., structural encroachment on the pharyngeal airway, which is neurally compensated when the patient is awake,” he said. “Because of this, we need to do the test when the patient is asleep.”

The AI platform with feedback-controlled mandibular positioner uses temporary dental trays to create impressions for the mouthpiece the patient uses during sleep. The mouthpiece connects to a remote-controlled device that makes real-time adjustments in the mandibular position without disturbing the patient’s sleep. “The computer identifies respiratory events all night long, adjusting the position of the mandible,” he said in explaining the AI component of the device. “Just think of it as similar to autotitration with CPAP.”

Dr. Remmers reported results of a phase 2 study of the platform presented as a poster reporting on a study of 101 patients with OSA participants. The study reported sensitivity of 86% and specificity of 92% in predicting success with the feedback-controlled mandibular positioner, he said.

“The sensitivity and overall predictive accuracy of the AI-based approach was greater than an intuitive approach using a pretreatment, temporary appliance, indicating that feedback-controlled mandibular positioning test outperformed the intuitive approach,” he said. The device has been approved by Health Canada and is awaiting clearance in the United States.
 

Upper airway stimulation

Upper airway stimulation (UAS) is emerging as a new class of therapy, said Patrick J. Strollo Jr., MD, of the University of Pittsburgh. The therapy involves an impulse generator (IPG) similar to a pacemaker that is implanted in the left side of the chest and connected to a stimulation lead secured to the distal hypoglossal nerve in the neck. The UAS system also incorporates a sensing lead that is implanted between the intercostal muscles and attached to the IPG allowing for phasic stimulation of the genioglossal muscle. The patient uses a remote control to turn the device on at night and off in the morning.

Dr. Strollo was lead author of the Stimulation Therapy for Apnea Reduction (STAR) trial (N Engl J Med. 2014:370;139-49), a prospective multicenter trial with a randomized therapy withdrawal arm. In 126 participants, he said, the median AHI score declined 68% in 12 months, from 29.3 at baseline to 9 (P less than .0001).

He provided updated results that showed 80% of patients continued to use the device after 5 years (Otolaryngol Head Neck Surg. 2018; doi: 10.1177/0194599818762383). Median AHI at 5 years was 6.9, Dr. Strollo said, and median Epworth Sleepiness Scale scores declined from 11.6 at baseline to 6.9 at 5 years.

Another postapproval study of UAS, the ADHERE registry, has enrolled 348 patients at 10 centers with a goal of 2,500, Dr. Strollo said (Otolaryngol Head Neck Surg. 2018: doi: 10.1177/0194599818764896). Twelve-month study results have shown reductions in AHI and Epworth Sleepiness Scale scores comparable to previous reports. ADHERE also reported that 92% of patients were satisfied with UAS.

The latest innovation for UAS is the ability to download data from the implant at office visits so the physician can review patient adherence patterns, along with energy levels and settings for sensing and stimulation, Dr. Strollo said.

“Upper airway stimulation is an additional tool in the management of properly selected, at-risk apnea patients who do not accept or adhere to positive pressure therapy,” Dr. Strollo said. “The STAR trial has provided robust evidence that upper airway stimulation is safe and effective in participants with moderate to severe OSA, and the treatment effect is maintained beyond the 12-month endpoint.”

Dr. Strollo disclosed a financial relationship with Inspire Medical Systems, manufacturer of the UAS device.

Hands-on surgical training is incomparable

I am not one to critique new technology or new technique. The article on use of virtual reality to not only teach technique but also to grade it caught my attention. I work in a small hospital without a million-dollar robot. Very complicated cases are sent out to larger hospitals. We have 2 new graduates who, like most new grads, have little experience with many surgical techniques. Dr. Lenihan and I were resident classmates, so I know he understands the rigors of a no-hour limit residency. Even with our residency, when we got out we relied on our partners to assist us until they knew we could do cases with a surgical assistant (SA) or a less experienced helper.

We are asking too much of our new graduates. It is up to us to provide the help and assistance with surgeries that they are not comfortable doing. While virtual reality training is great for teaching robotics and some laparoscopic techniques, it cannot teach things such as anterior and posterior repairs, tension-free vaginal tape procedures, and enterocoele repair. We can all watch YouTube tutorials, but actually doing surgery is very different. We owe it to our new graduates to provide mentoring and encouragement with their surgical cases. At our hospital, mentoring the first 10 cases performed by a new physician (new grad or otherwise) used to be required, but that requirement is gone. Our service is one of the few that still has 2 physicians at every major case. We have an SA available, but we prefer to assist each other. This makes our laparoscopic-assisted vaginal hysterectomy, bilateral salpingo-oophorectomy cases a 30- to 35-minute case. It allows us to teach anterior and posterior repair technique.

The involvement in surgical improvement is hands-on, and virtual reality training will never replace it.

Anthony J. Lemanski, MD
Kingman, Arizona

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Hands-on surgical training is incomparable

I am not one to critique new technology or new technique. The article on use of virtual reality to not only teach technique but also to grade it caught my attention. I work in a small hospital without a million-dollar robot. Very complicated cases are sent out to larger hospitals. We have 2 new graduates who, like most new grads, have little experience with many surgical techniques. Dr. Lenihan and I were resident classmates, so I know he understands the rigors of a no-hour limit residency. Even with our residency, when we got out we relied on our partners to assist us until they knew we could do cases with a surgical assistant (SA) or a less experienced helper.

We are asking too much of our new graduates. It is up to us to provide the help and assistance with surgeries that they are not comfortable doing. While virtual reality training is great for teaching robotics and some laparoscopic techniques, it cannot teach things such as anterior and posterior repairs, tension-free vaginal tape procedures, and enterocoele repair. We can all watch YouTube tutorials, but actually doing surgery is very different. We owe it to our new graduates to provide mentoring and encouragement with their surgical cases. At our hospital, mentoring the first 10 cases performed by a new physician (new grad or otherwise) used to be required, but that requirement is gone. Our service is one of the few that still has 2 physicians at every major case. We have an SA available, but we prefer to assist each other. This makes our laparoscopic-assisted vaginal hysterectomy, bilateral salpingo-oophorectomy cases a 30- to 35-minute case. It allows us to teach anterior and posterior repair technique.

The involvement in surgical improvement is hands-on, and virtual reality training will never replace it.

Anthony J. Lemanski, MD
Kingman, Arizona

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Hands-on surgical training is incomparable

I am not one to critique new technology or new technique. The article on use of virtual reality to not only teach technique but also to grade it caught my attention. I work in a small hospital without a million-dollar robot. Very complicated cases are sent out to larger hospitals. We have 2 new graduates who, like most new grads, have little experience with many surgical techniques. Dr. Lenihan and I were resident classmates, so I know he understands the rigors of a no-hour limit residency. Even with our residency, when we got out we relied on our partners to assist us until they knew we could do cases with a surgical assistant (SA) or a less experienced helper.

We are asking too much of our new graduates. It is up to us to provide the help and assistance with surgeries that they are not comfortable doing. While virtual reality training is great for teaching robotics and some laparoscopic techniques, it cannot teach things such as anterior and posterior repairs, tension-free vaginal tape procedures, and enterocoele repair. We can all watch YouTube tutorials, but actually doing surgery is very different. We owe it to our new graduates to provide mentoring and encouragement with their surgical cases. At our hospital, mentoring the first 10 cases performed by a new physician (new grad or otherwise) used to be required, but that requirement is gone. Our service is one of the few that still has 2 physicians at every major case. We have an SA available, but we prefer to assist each other. This makes our laparoscopic-assisted vaginal hysterectomy, bilateral salpingo-oophorectomy cases a 30- to 35-minute case. It allows us to teach anterior and posterior repair technique.

The involvement in surgical improvement is hands-on, and virtual reality training will never replace it.

Anthony J. Lemanski, MD
Kingman, Arizona

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Hypertensive crisis of pregnancy must be treated with all urgency

The following happened approximately 27 years ago when I worked as an attending at a regional level 2 hospital in Puerto Rico. One afternoon I received a call from the emergency department that they had been managing a patient (G4P3) at 33 weeks of gestation for about 4 hours. The patient was consulted for hypertension when she went into a hypertensive encephalopathic coma. The patient was brought back to the birth center. Apresoline was given but did not bring the blood pressure down. Magnesium sulfate also was started at that time. I called a colleague from internal medicine and started to give nitroprusside.

Every time the patient’s blood pressure dropped from 120 mm Hg diastolic, she would become conscious and speak with us. As soon as her blood pressure went up, she would go into a coma. The patient was then transferred to a tertiary center in as stable a condition as possible. Cesarean delivery was performed, and the baby did not survive. The mother had an intracerebral hemorrhage. She was transferred to the supra-tertiary center in San Juan where she later passed away from complications of the hypertensive crisis. If the emergency physician had called me earlier, more could have been done.

This event is always fresh I my mind when I manage my patients in Ohio. Thank God for the newer medications we have available and the protocols to manage hypertensive crisis in pregnancy. I hope this experience heightens awareness of how deadly this condition can be.

David A. Rosado, MD
Celina, Ohio

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Hypertensive crisis of pregnancy must be treated with all urgency

The following happened approximately 27 years ago when I worked as an attending at a regional level 2 hospital in Puerto Rico. One afternoon I received a call from the emergency department that they had been managing a patient (G4P3) at 33 weeks of gestation for about 4 hours. The patient was consulted for hypertension when she went into a hypertensive encephalopathic coma. The patient was brought back to the birth center. Apresoline was given but did not bring the blood pressure down. Magnesium sulfate also was started at that time. I called a colleague from internal medicine and started to give nitroprusside.

Every time the patient’s blood pressure dropped from 120 mm Hg diastolic, she would become conscious and speak with us. As soon as her blood pressure went up, she would go into a coma. The patient was then transferred to a tertiary center in as stable a condition as possible. Cesarean delivery was performed, and the baby did not survive. The mother had an intracerebral hemorrhage. She was transferred to the supra-tertiary center in San Juan where she later passed away from complications of the hypertensive crisis. If the emergency physician had called me earlier, more could have been done.

This event is always fresh I my mind when I manage my patients in Ohio. Thank God for the newer medications we have available and the protocols to manage hypertensive crisis in pregnancy. I hope this experience heightens awareness of how deadly this condition can be.

David A. Rosado, MD
Celina, Ohio

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Hypertensive crisis of pregnancy must be treated with all urgency

The following happened approximately 27 years ago when I worked as an attending at a regional level 2 hospital in Puerto Rico. One afternoon I received a call from the emergency department that they had been managing a patient (G4P3) at 33 weeks of gestation for about 4 hours. The patient was consulted for hypertension when she went into a hypertensive encephalopathic coma. The patient was brought back to the birth center. Apresoline was given but did not bring the blood pressure down. Magnesium sulfate also was started at that time. I called a colleague from internal medicine and started to give nitroprusside.

Every time the patient’s blood pressure dropped from 120 mm Hg diastolic, she would become conscious and speak with us. As soon as her blood pressure went up, she would go into a coma. The patient was then transferred to a tertiary center in as stable a condition as possible. Cesarean delivery was performed, and the baby did not survive. The mother had an intracerebral hemorrhage. She was transferred to the supra-tertiary center in San Juan where she later passed away from complications of the hypertensive crisis. If the emergency physician had called me earlier, more could have been done.

This event is always fresh I my mind when I manage my patients in Ohio. Thank God for the newer medications we have available and the protocols to manage hypertensive crisis in pregnancy. I hope this experience heightens awareness of how deadly this condition can be.

David A. Rosado, MD
Celina, Ohio

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.