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Cerliponase alfa continues to impress for CLN2 disease
BANGKOK – Biweekly cerliponase alfa continued to show durable and clinically important therapeutic benefit in children with neuronal ceroid lipofuscinosis type 2 (CLN2) disease at the 3-year mark in an ongoing international study, Marina Trivisano, MD, reported at the International Epilepsy Congress.
Cerliponase alfa, approved under the trade name Brineura by the Food and Drug Administration and European Commission, is a recombinant human tripeptidyl peptidase 1 designed as enzyme replacement therapy delivered by a surgically implanted intraventricular infusion device in children with this rare lysosomal storage disease, a form of Batten disease, she explained at the congress sponsored by the International League Against Epilepsy.
When both healthy parents carry one defective gene, each of their children has a one in four chance of inheriting this devastating disease that causes rapidly progressive dementia. CLN2 disease typically reveals itself when a child reaches about 3 years of age, with seizures, language delay, or loss of acquired language being the most common first indications.
Of 23 patients enrolled in the open-label study, 21 remained participants at 3 years of follow-up. The two dropouts weren’t caused by treatment-related adverse events, but rather by the formidable logistic challenges posed because the treatment – 300 mg of cerliponase alfa delivered by intraventricular infusion over a 4-hour period every 2 weeks – was available only at five medical centers located in Rome; London; New York; Hamburg, Germany; and Columbus, Ohio.
At 3 years of follow-up, 83% of patients met the primary study endpoint, defined as the absence of a 2-point or greater decline in the motor-language score on the 0-6 CLN2 Clinical Rating Scale. This was a success rate 12 times greater than in 42 historical controls. Indeed, at 3 years the cerliponase alfa–treated patients had an average CLN2 Clinical Rating Scale motor-language score 3.8 points better than the historical controls, reported Dr. Trivisano, a pediatric neurologist at Bambino Gesu Children’s Hospital in Rome.
Side effects included several cases of device failure, infection, and hypersensitivity reactions.
In an earlier report based upon 96 weeks of follow-up, the mean rate of decline in the motor-language score was 0.27 points per 48 weeks in treated patients, compared with 2.12 points in the historical controls (N Engl J Med. 2018 May 17;378[20]:1898-1907).
The study was funded by BioMarin Pharmaceutical, which markets Brineura. Dr. Trivisano was a subinvestigator in the trial.
SOURCE: Trivisano M et al. IEC 2019, Abstract P333.
BANGKOK – Biweekly cerliponase alfa continued to show durable and clinically important therapeutic benefit in children with neuronal ceroid lipofuscinosis type 2 (CLN2) disease at the 3-year mark in an ongoing international study, Marina Trivisano, MD, reported at the International Epilepsy Congress.
Cerliponase alfa, approved under the trade name Brineura by the Food and Drug Administration and European Commission, is a recombinant human tripeptidyl peptidase 1 designed as enzyme replacement therapy delivered by a surgically implanted intraventricular infusion device in children with this rare lysosomal storage disease, a form of Batten disease, she explained at the congress sponsored by the International League Against Epilepsy.
When both healthy parents carry one defective gene, each of their children has a one in four chance of inheriting this devastating disease that causes rapidly progressive dementia. CLN2 disease typically reveals itself when a child reaches about 3 years of age, with seizures, language delay, or loss of acquired language being the most common first indications.
Of 23 patients enrolled in the open-label study, 21 remained participants at 3 years of follow-up. The two dropouts weren’t caused by treatment-related adverse events, but rather by the formidable logistic challenges posed because the treatment – 300 mg of cerliponase alfa delivered by intraventricular infusion over a 4-hour period every 2 weeks – was available only at five medical centers located in Rome; London; New York; Hamburg, Germany; and Columbus, Ohio.
At 3 years of follow-up, 83% of patients met the primary study endpoint, defined as the absence of a 2-point or greater decline in the motor-language score on the 0-6 CLN2 Clinical Rating Scale. This was a success rate 12 times greater than in 42 historical controls. Indeed, at 3 years the cerliponase alfa–treated patients had an average CLN2 Clinical Rating Scale motor-language score 3.8 points better than the historical controls, reported Dr. Trivisano, a pediatric neurologist at Bambino Gesu Children’s Hospital in Rome.
Side effects included several cases of device failure, infection, and hypersensitivity reactions.
In an earlier report based upon 96 weeks of follow-up, the mean rate of decline in the motor-language score was 0.27 points per 48 weeks in treated patients, compared with 2.12 points in the historical controls (N Engl J Med. 2018 May 17;378[20]:1898-1907).
The study was funded by BioMarin Pharmaceutical, which markets Brineura. Dr. Trivisano was a subinvestigator in the trial.
SOURCE: Trivisano M et al. IEC 2019, Abstract P333.
BANGKOK – Biweekly cerliponase alfa continued to show durable and clinically important therapeutic benefit in children with neuronal ceroid lipofuscinosis type 2 (CLN2) disease at the 3-year mark in an ongoing international study, Marina Trivisano, MD, reported at the International Epilepsy Congress.
Cerliponase alfa, approved under the trade name Brineura by the Food and Drug Administration and European Commission, is a recombinant human tripeptidyl peptidase 1 designed as enzyme replacement therapy delivered by a surgically implanted intraventricular infusion device in children with this rare lysosomal storage disease, a form of Batten disease, she explained at the congress sponsored by the International League Against Epilepsy.
When both healthy parents carry one defective gene, each of their children has a one in four chance of inheriting this devastating disease that causes rapidly progressive dementia. CLN2 disease typically reveals itself when a child reaches about 3 years of age, with seizures, language delay, or loss of acquired language being the most common first indications.
Of 23 patients enrolled in the open-label study, 21 remained participants at 3 years of follow-up. The two dropouts weren’t caused by treatment-related adverse events, but rather by the formidable logistic challenges posed because the treatment – 300 mg of cerliponase alfa delivered by intraventricular infusion over a 4-hour period every 2 weeks – was available only at five medical centers located in Rome; London; New York; Hamburg, Germany; and Columbus, Ohio.
At 3 years of follow-up, 83% of patients met the primary study endpoint, defined as the absence of a 2-point or greater decline in the motor-language score on the 0-6 CLN2 Clinical Rating Scale. This was a success rate 12 times greater than in 42 historical controls. Indeed, at 3 years the cerliponase alfa–treated patients had an average CLN2 Clinical Rating Scale motor-language score 3.8 points better than the historical controls, reported Dr. Trivisano, a pediatric neurologist at Bambino Gesu Children’s Hospital in Rome.
Side effects included several cases of device failure, infection, and hypersensitivity reactions.
In an earlier report based upon 96 weeks of follow-up, the mean rate of decline in the motor-language score was 0.27 points per 48 weeks in treated patients, compared with 2.12 points in the historical controls (N Engl J Med. 2018 May 17;378[20]:1898-1907).
The study was funded by BioMarin Pharmaceutical, which markets Brineura. Dr. Trivisano was a subinvestigator in the trial.
SOURCE: Trivisano M et al. IEC 2019, Abstract P333.
REPORTING FROM IEC 2019
Combo therapy outcomes for West syndrome prove no better than monotherapy
BANGKOK – Hiroki Nariai, MD, declared at the International Epilepsy Congress.
West syndrome, or infantile spasms with a hypsarrhythmic EEG, is a severe infantile epileptic encephalopathy. It has high morbidity and mortality, and it’s challenging to treat. So neurologists and pediatricians were thrilled by an earlier preliminary report from an open-label, randomized, controlled trial conducted by the International Collaborative Infantile Spasms Study (ICISS) investigators. They reported that a hormonal therapy and vigabatrin (Sabril) combination provided significantly better seizure control between days 14 and 42 of treatment than hormonal therapy alone, albeit at the cost of more side effects (Lancet Neurol. 2017 Jan;16[1]:33-42).
However, a sobering update from the 377-infant study conducted in Australia, Switzerland, Germany, New Zealand, and the United Kingdom concluded that combination therapy didn’t result in improved developmental or epilepsy outcomes at 18 months, Dr. Nariai said at the congress sponsored by the International League Against Epilepsy.
“We still have inconclusive evidence to support the routine use of combination therapy. Clearly we need a better disease-modifying therapy because our best results with hormonal therapy or vigabatrin are only a 50%-70% response rate. And having a biomarker to guide early therapy and follow treatment response would help in establishing a better therapy,” commented Dr. Nariai, a pediatric neurologist at the University of California, Los Angeles.
He wasn’t involved in the international trial. He is, however, active in the search for a biomarker that would aid in speedier diagnosis of West syndrome, which in turn would allow for earlier treatment and, potentially, better outcomes. Indeed, Dr. Nariai has done pioneering work in identifying several EEG abnormalities readily measurable noninvasively using scalp electrodes that show considerable promise in this regard. These candidate biomarkers include ictal or interictal high-frequency oscillations at 80 Hz or more, along with cross-frequency coupling of high-frequency oscillations and delta-wave activity.
The primary endpoint in the ICISS study was developmental outcome at 18 months as evaluated using the Vineland Adaptive Behavior Scales composite score. The mean score was 73.9 in the combination therapy group and closely similar at 72.7 in the children on hormonal therapy alone. At 18 months, 30% of children in the combination therapy group carried a diagnosis of epilepsy, as did 29.2% of controls randomized to either high-dose oral steroids or intramuscular depot tetracosactide. About 15% of children randomized to combination therapy still had spasms at 18 months, as did 15.7% on hormonal therapy alone (Lancet Child Adolesc Health. 2018 Oct;2[10]:715-25).
The chief side effects of hormonal therapy included hypertension, hypoglycemia, and immunosuppression. Vigabatrin’s side effects included dose- and duration-dependent peripheral vision loss, movement disorders, and undesirable MRI signal changes.
Dr. Nariai observed that, even though hormonal therapy is widely used as first-line therapy in West syndrome, it remains surrounded by important unanswered questions.
“We don’t have head-to-head comparative studies of ACTH versus high-dose steroids, the optimal dosing protocol is not established, and we really don’t even know the mechanism of action for hormonal therapy and vigabatrin,” he said.
The study was sponsored by the U.K. National Institute of Health Research and other noncommercial entities. Dr. Nariai reported having no financial conflicts regarding his presentation.
BANGKOK – Hiroki Nariai, MD, declared at the International Epilepsy Congress.
West syndrome, or infantile spasms with a hypsarrhythmic EEG, is a severe infantile epileptic encephalopathy. It has high morbidity and mortality, and it’s challenging to treat. So neurologists and pediatricians were thrilled by an earlier preliminary report from an open-label, randomized, controlled trial conducted by the International Collaborative Infantile Spasms Study (ICISS) investigators. They reported that a hormonal therapy and vigabatrin (Sabril) combination provided significantly better seizure control between days 14 and 42 of treatment than hormonal therapy alone, albeit at the cost of more side effects (Lancet Neurol. 2017 Jan;16[1]:33-42).
However, a sobering update from the 377-infant study conducted in Australia, Switzerland, Germany, New Zealand, and the United Kingdom concluded that combination therapy didn’t result in improved developmental or epilepsy outcomes at 18 months, Dr. Nariai said at the congress sponsored by the International League Against Epilepsy.
“We still have inconclusive evidence to support the routine use of combination therapy. Clearly we need a better disease-modifying therapy because our best results with hormonal therapy or vigabatrin are only a 50%-70% response rate. And having a biomarker to guide early therapy and follow treatment response would help in establishing a better therapy,” commented Dr. Nariai, a pediatric neurologist at the University of California, Los Angeles.
He wasn’t involved in the international trial. He is, however, active in the search for a biomarker that would aid in speedier diagnosis of West syndrome, which in turn would allow for earlier treatment and, potentially, better outcomes. Indeed, Dr. Nariai has done pioneering work in identifying several EEG abnormalities readily measurable noninvasively using scalp electrodes that show considerable promise in this regard. These candidate biomarkers include ictal or interictal high-frequency oscillations at 80 Hz or more, along with cross-frequency coupling of high-frequency oscillations and delta-wave activity.
The primary endpoint in the ICISS study was developmental outcome at 18 months as evaluated using the Vineland Adaptive Behavior Scales composite score. The mean score was 73.9 in the combination therapy group and closely similar at 72.7 in the children on hormonal therapy alone. At 18 months, 30% of children in the combination therapy group carried a diagnosis of epilepsy, as did 29.2% of controls randomized to either high-dose oral steroids or intramuscular depot tetracosactide. About 15% of children randomized to combination therapy still had spasms at 18 months, as did 15.7% on hormonal therapy alone (Lancet Child Adolesc Health. 2018 Oct;2[10]:715-25).
The chief side effects of hormonal therapy included hypertension, hypoglycemia, and immunosuppression. Vigabatrin’s side effects included dose- and duration-dependent peripheral vision loss, movement disorders, and undesirable MRI signal changes.
Dr. Nariai observed that, even though hormonal therapy is widely used as first-line therapy in West syndrome, it remains surrounded by important unanswered questions.
“We don’t have head-to-head comparative studies of ACTH versus high-dose steroids, the optimal dosing protocol is not established, and we really don’t even know the mechanism of action for hormonal therapy and vigabatrin,” he said.
The study was sponsored by the U.K. National Institute of Health Research and other noncommercial entities. Dr. Nariai reported having no financial conflicts regarding his presentation.
BANGKOK – Hiroki Nariai, MD, declared at the International Epilepsy Congress.
West syndrome, or infantile spasms with a hypsarrhythmic EEG, is a severe infantile epileptic encephalopathy. It has high morbidity and mortality, and it’s challenging to treat. So neurologists and pediatricians were thrilled by an earlier preliminary report from an open-label, randomized, controlled trial conducted by the International Collaborative Infantile Spasms Study (ICISS) investigators. They reported that a hormonal therapy and vigabatrin (Sabril) combination provided significantly better seizure control between days 14 and 42 of treatment than hormonal therapy alone, albeit at the cost of more side effects (Lancet Neurol. 2017 Jan;16[1]:33-42).
However, a sobering update from the 377-infant study conducted in Australia, Switzerland, Germany, New Zealand, and the United Kingdom concluded that combination therapy didn’t result in improved developmental or epilepsy outcomes at 18 months, Dr. Nariai said at the congress sponsored by the International League Against Epilepsy.
“We still have inconclusive evidence to support the routine use of combination therapy. Clearly we need a better disease-modifying therapy because our best results with hormonal therapy or vigabatrin are only a 50%-70% response rate. And having a biomarker to guide early therapy and follow treatment response would help in establishing a better therapy,” commented Dr. Nariai, a pediatric neurologist at the University of California, Los Angeles.
He wasn’t involved in the international trial. He is, however, active in the search for a biomarker that would aid in speedier diagnosis of West syndrome, which in turn would allow for earlier treatment and, potentially, better outcomes. Indeed, Dr. Nariai has done pioneering work in identifying several EEG abnormalities readily measurable noninvasively using scalp electrodes that show considerable promise in this regard. These candidate biomarkers include ictal or interictal high-frequency oscillations at 80 Hz or more, along with cross-frequency coupling of high-frequency oscillations and delta-wave activity.
The primary endpoint in the ICISS study was developmental outcome at 18 months as evaluated using the Vineland Adaptive Behavior Scales composite score. The mean score was 73.9 in the combination therapy group and closely similar at 72.7 in the children on hormonal therapy alone. At 18 months, 30% of children in the combination therapy group carried a diagnosis of epilepsy, as did 29.2% of controls randomized to either high-dose oral steroids or intramuscular depot tetracosactide. About 15% of children randomized to combination therapy still had spasms at 18 months, as did 15.7% on hormonal therapy alone (Lancet Child Adolesc Health. 2018 Oct;2[10]:715-25).
The chief side effects of hormonal therapy included hypertension, hypoglycemia, and immunosuppression. Vigabatrin’s side effects included dose- and duration-dependent peripheral vision loss, movement disorders, and undesirable MRI signal changes.
Dr. Nariai observed that, even though hormonal therapy is widely used as first-line therapy in West syndrome, it remains surrounded by important unanswered questions.
“We don’t have head-to-head comparative studies of ACTH versus high-dose steroids, the optimal dosing protocol is not established, and we really don’t even know the mechanism of action for hormonal therapy and vigabatrin,” he said.
The study was sponsored by the U.K. National Institute of Health Research and other noncommercial entities. Dr. Nariai reported having no financial conflicts regarding his presentation.
EXPERT ANALYSIS FROM IEC 2019
FDA approves istradefylline for Parkinson’s disease
The Food and Drug Administration on Aug. 27 approved Nourianz (istradefylline) tablets as an add-on treatment to levodopa/carbidopa in adult patients with Parkinson’s disease experiencing off episodes. During off episodes, patients’ medications do not work well, and symptoms such as tremor and difficulty walking increase.
The effectiveness of Nourianz for this indication was shown in four 12-week placebo-controlled clinical studies that included 1,143 participants. In all four studies, patients treated with Nourianz experienced a statistically significant decrease from baseline in daily off time, compared with patients who received placebo.
The most common adverse reactions to istradefylline with an incidence of 5% or greater and occurring more frequently than with placebo were dyskinesia (15%, 17%, and 8%, for Nourianz 20 mg, 40 mg, and placebo, respectively), dizziness (3%, 6%, and 4%), constipation (5%, 6%, and 3%), nausea (4%, 6%, and 5%), hallucination (2%, 6%, and 3%), and insomnia (1%, 6%, and 4%). In clinical trials, 1% of patients treated with Nourianz 20 mg or 40 mg discontinued treatment because of dyskinesia, compared with no patients who received placebo.
In addition,one patient treated with Nourianz 40 mg experienced impulse control disorder, compared with no patients who received Nourianz 20 mg or placebo.
If hallucinations, psychotic behavior, or impulsive or compulsive behavior occurs, a dosage reduction or stoppage should be considered, according to the FDA. Use of Nourianz during pregnancy is not recommended, and women of childbearing potential should be advised to use contraception during treatment.
The maximum recommended dosage in patients taking strong CYP3A4 inhibitors is 20 mg once daily, and clinicians should avoid use of Nourianz with strong CYP3A4 inducers.
Istradefylline is the first adenosine A2A receptor antagonist for use in Parkinson’s disease in the United States, and the drug provides patients with a novel nondopaminergic daily oral treatment option, according to a news release from Kyowa Kirin, the company that markets the drug.
Since 2013, istradefylline has been marketed at Nouriast in Japan, where it is indicated for the wearing-off phenomenon in patients with Parkinson’s disease who take preparations containing levodopa.
The Food and Drug Administration on Aug. 27 approved Nourianz (istradefylline) tablets as an add-on treatment to levodopa/carbidopa in adult patients with Parkinson’s disease experiencing off episodes. During off episodes, patients’ medications do not work well, and symptoms such as tremor and difficulty walking increase.
The effectiveness of Nourianz for this indication was shown in four 12-week placebo-controlled clinical studies that included 1,143 participants. In all four studies, patients treated with Nourianz experienced a statistically significant decrease from baseline in daily off time, compared with patients who received placebo.
The most common adverse reactions to istradefylline with an incidence of 5% or greater and occurring more frequently than with placebo were dyskinesia (15%, 17%, and 8%, for Nourianz 20 mg, 40 mg, and placebo, respectively), dizziness (3%, 6%, and 4%), constipation (5%, 6%, and 3%), nausea (4%, 6%, and 5%), hallucination (2%, 6%, and 3%), and insomnia (1%, 6%, and 4%). In clinical trials, 1% of patients treated with Nourianz 20 mg or 40 mg discontinued treatment because of dyskinesia, compared with no patients who received placebo.
In addition,one patient treated with Nourianz 40 mg experienced impulse control disorder, compared with no patients who received Nourianz 20 mg or placebo.
If hallucinations, psychotic behavior, or impulsive or compulsive behavior occurs, a dosage reduction or stoppage should be considered, according to the FDA. Use of Nourianz during pregnancy is not recommended, and women of childbearing potential should be advised to use contraception during treatment.
The maximum recommended dosage in patients taking strong CYP3A4 inhibitors is 20 mg once daily, and clinicians should avoid use of Nourianz with strong CYP3A4 inducers.
Istradefylline is the first adenosine A2A receptor antagonist for use in Parkinson’s disease in the United States, and the drug provides patients with a novel nondopaminergic daily oral treatment option, according to a news release from Kyowa Kirin, the company that markets the drug.
Since 2013, istradefylline has been marketed at Nouriast in Japan, where it is indicated for the wearing-off phenomenon in patients with Parkinson’s disease who take preparations containing levodopa.
The Food and Drug Administration on Aug. 27 approved Nourianz (istradefylline) tablets as an add-on treatment to levodopa/carbidopa in adult patients with Parkinson’s disease experiencing off episodes. During off episodes, patients’ medications do not work well, and symptoms such as tremor and difficulty walking increase.
The effectiveness of Nourianz for this indication was shown in four 12-week placebo-controlled clinical studies that included 1,143 participants. In all four studies, patients treated with Nourianz experienced a statistically significant decrease from baseline in daily off time, compared with patients who received placebo.
The most common adverse reactions to istradefylline with an incidence of 5% or greater and occurring more frequently than with placebo were dyskinesia (15%, 17%, and 8%, for Nourianz 20 mg, 40 mg, and placebo, respectively), dizziness (3%, 6%, and 4%), constipation (5%, 6%, and 3%), nausea (4%, 6%, and 5%), hallucination (2%, 6%, and 3%), and insomnia (1%, 6%, and 4%). In clinical trials, 1% of patients treated with Nourianz 20 mg or 40 mg discontinued treatment because of dyskinesia, compared with no patients who received placebo.
In addition,one patient treated with Nourianz 40 mg experienced impulse control disorder, compared with no patients who received Nourianz 20 mg or placebo.
If hallucinations, psychotic behavior, or impulsive or compulsive behavior occurs, a dosage reduction or stoppage should be considered, according to the FDA. Use of Nourianz during pregnancy is not recommended, and women of childbearing potential should be advised to use contraception during treatment.
The maximum recommended dosage in patients taking strong CYP3A4 inhibitors is 20 mg once daily, and clinicians should avoid use of Nourianz with strong CYP3A4 inducers.
Istradefylline is the first adenosine A2A receptor antagonist for use in Parkinson’s disease in the United States, and the drug provides patients with a novel nondopaminergic daily oral treatment option, according to a news release from Kyowa Kirin, the company that markets the drug.
Since 2013, istradefylline has been marketed at Nouriast in Japan, where it is indicated for the wearing-off phenomenon in patients with Parkinson’s disease who take preparations containing levodopa.
AAN guideline encourages vaccinations for MS patients
according to an American Academy of Neurology practice guideline.
A summary of the guideline on vaccine-preventable infections and immunization in MS was published online Aug. 28 in Neurology. The new effort updates a 2002 guideline on this topic and incorporates new evidence, vaccines, and disease-modifying therapies (DMTs). The guideline was endorsed by the Consortium of Multiple Sclerosis Centers and by the Multiple Sclerosis Association of America.
To create the guideline, lead author Mauricio F. Farez, MD, of the Raúl Carrea Institute for Neurological Research (FLENI) in Buenos Aires and colleagues on the 17-member guideline panel performed a systematic review of the evidence and reached consensus on recommendations using a modified Delphi voting process. The review included randomized, controlled trials; cohort studies; and case-control studies published between 1990 and March 2018.
“Immunosuppressive or immunomodulating agents used to treat MS may suppress or modulate normal immune function. These drugs may increase susceptibility to infections and may reduce vaccine effectiveness because of a decreased ability to mount an immune response,” the authors said.
Based on its review of the evidence, principles of care, and inferences, the authors made the following eight recommendations:
- Clinicians should discuss with patients the evidence regarding immunization in MS (Level B). In addition, clinicians should examine patients’ opinions, preferences, and questions regarding immunizations (Level B).
- Clinicians should recommend that patients with MS follow all local vaccine standards in the absence of specific contraindications (Level B).
- Clinicians should consider local risks of vaccine-preventable diseases when counseling patients (Level B).
- Clinicians should recommend that patients with MS receive the influenza vaccination if there is no specific contraindication, such as a previous severe reaction (Level B).
- When treatment with an immunosuppressive or immunomodulating agent is considered, clinicians should counsel patients about infection risks associated with the specific medication and the treatment-specific vaccination guidance in the medication’s prescribing instructions (Level B). In addition, physicians should assess patients’ vaccination status before prescribing immunosuppressive or immunomodulating therapy and vaccinate patients according to local regulatory standards and treatment-specific infectious risks at least 4-6 weeks before initiating therapy, as advised by the prescribing information (Level B). Furthermore, clinicians may discuss the advantages of vaccination soon after MS diagnosis, regardless of initial therapeutic plans, to prevent delays should immunosuppressive or immunomodulating therapies be initiated in the future (Level C, based on variation in patient preferences).
- Clinicians must screen for certain infections (such as hepatitis, tuberculosis, and varicella zoster virus) according to a medication’s prescribing information before starting immunosuppressive or immunomodulating treatment (Level A) and should treat patients who have latent infections before MS treatment according to the medication prescribing information (Level B, based on feasibility and cost relative to benefit). Further, in high-risk populations or in countries with a high burden of infectious disease, clinicians must screen for latent infections before starting immunosuppressive or immunomodulating medications, even when such screening is not specifically mentioned in the prescribing information (Level A). Clinicians should consult infectious disease or other specialists about treating patients with latent infection before starting immunosuppressive or immunomodulating medications (Level B).
- Clinicians should recommend against live-attenuated vaccines in people with MS who receive immunosuppressive or immunomodulating therapies or have recently discontinued these therapies (Level B, based on importance of outcomes). When the risk of infection is high, clinicians may recommend live-attenuated vaccines if killed vaccines are unavailable (Level C, based on variation in patient preferences, benefit relative to harm, and importance of outcomes).
- If a patient with MS is experiencing a relapse, clinicians should delay vaccination until the relapse has clinically resolved or is no longer active, often many weeks after relapse onset (Level B).
Personal and population-level benefits
“There is no evidence that vaccination increases the risk of MS exacerbation, although the literature is sparse,” the authors said. “In addition to conferring personal benefits, vaccination of the MS patient population contributes to the well-established phenomenon of herd immunity for the communities in which patients with MS live,” the authors wrote.
Because influenza infection has known risks of exacerbation and morbidity, whereas influenza vaccine has no identified risks of exacerbation, “benefits of influenza vaccination outweigh the risks in most scenarios, although patients with MS receiving some [immunosuppressive or immunomodulating] treatments (fingolimod [Gilenya], glatiramer acetate [Copaxone], and mitoxantrone) may have a reduced response to influenza vaccination,” the authors said. Studies in patients with diseases other than MS suggest that rituximab (Rituxan) also may be associated with reduced influenza vaccine responsiveness.
Immunosuppressive or immunomodulatory medications including alemtuzumab (Lemtrada), dimethyl fumarate (Tecfidera), fingolimod, mitoxantrone, natalizumab (Tysabri), ocrelizumab (Ocrevus), rituximab, and teriflunomide (Aubagio) have been associated with severe occurrences or recurrences of vaccine-preventable infections, and many package inserts approved by the Food and Drug Administration provide guidance regarding immunization with live vaccines and treatment.
Prescribing information for alemtuzumab, fingolimod, ocrelizumab, and teriflunomide recommends against the use of live vaccines during and immediately preceding treatment. Furthermore, the prescribing information recommends waiting 2-6 months after treatment to immunize with live vaccines, depending on the half-life of the specific therapy.
“The guideline panel identified no evidence that vaccines increase the risk of relapse or worsen relapse severity, but studies are limited,” Dr. Farez and colleagues wrote. “Experts remain concerned that vaccines may worsen relapse severity if given to patients who are actively experiencing an MS relapse.” In addition, use of glucocorticoids may raise concerns about the safety of live-virus vaccines. “Immunization is not typically an urgent need and, in most cases, can be temporarily delayed without a marked increase in infection risk,” the guideline says.
Few high-quality studies
Data were lacking or insufficient to assess whether most vaccine-preventable diseases increase the risk of MS exacerbations. “It is probable that individuals with active MS exacerbations have higher odds of varicella zoster virus viral DNA present in peripheral blood mononuclear cells than individuals with MS in remission,” the guideline says.
Human papillomavirus, pertussis, and tetanus toxoid vaccinations probably are associated with a lower likelihood of a subsequent MS diagnosis, and smallpox vaccination is possibly associated with a lower likelihood of a subsequent MS diagnosis, the review found.
Studies included in the systematic review did not address whether live-attenuated vaccines are as effective in patients with MS as they are in the general population. With regard to the effectiveness of inactivated vaccines, patients with MS possibly are less likely to have a sufficient response to influenza vaccination, compared with controls.
The systematic review “found few high-quality studies to inform recommendations,” the authors said. “As more [immunosuppressive or immunomodulating] agents are developed to manage chronic diseases such as MS, long-term prospective cohort studies are required to evaluate both the safety and effectiveness of immunizations in MS.”
Dr. Farez has received funding for travel from Teva Argentina, Novartis Argentina, and Merck Serono Argentina and has received research support from Biogen. Coauthors’ disclosures included financial ties to pharmaceutical companies.
SOURCE: Farez M et al. Neurology. 2019 Aug 28. doi: 10.1212/WNL.0000000000008157.
according to an American Academy of Neurology practice guideline.
A summary of the guideline on vaccine-preventable infections and immunization in MS was published online Aug. 28 in Neurology. The new effort updates a 2002 guideline on this topic and incorporates new evidence, vaccines, and disease-modifying therapies (DMTs). The guideline was endorsed by the Consortium of Multiple Sclerosis Centers and by the Multiple Sclerosis Association of America.
To create the guideline, lead author Mauricio F. Farez, MD, of the Raúl Carrea Institute for Neurological Research (FLENI) in Buenos Aires and colleagues on the 17-member guideline panel performed a systematic review of the evidence and reached consensus on recommendations using a modified Delphi voting process. The review included randomized, controlled trials; cohort studies; and case-control studies published between 1990 and March 2018.
“Immunosuppressive or immunomodulating agents used to treat MS may suppress or modulate normal immune function. These drugs may increase susceptibility to infections and may reduce vaccine effectiveness because of a decreased ability to mount an immune response,” the authors said.
Based on its review of the evidence, principles of care, and inferences, the authors made the following eight recommendations:
- Clinicians should discuss with patients the evidence regarding immunization in MS (Level B). In addition, clinicians should examine patients’ opinions, preferences, and questions regarding immunizations (Level B).
- Clinicians should recommend that patients with MS follow all local vaccine standards in the absence of specific contraindications (Level B).
- Clinicians should consider local risks of vaccine-preventable diseases when counseling patients (Level B).
- Clinicians should recommend that patients with MS receive the influenza vaccination if there is no specific contraindication, such as a previous severe reaction (Level B).
- When treatment with an immunosuppressive or immunomodulating agent is considered, clinicians should counsel patients about infection risks associated with the specific medication and the treatment-specific vaccination guidance in the medication’s prescribing instructions (Level B). In addition, physicians should assess patients’ vaccination status before prescribing immunosuppressive or immunomodulating therapy and vaccinate patients according to local regulatory standards and treatment-specific infectious risks at least 4-6 weeks before initiating therapy, as advised by the prescribing information (Level B). Furthermore, clinicians may discuss the advantages of vaccination soon after MS diagnosis, regardless of initial therapeutic plans, to prevent delays should immunosuppressive or immunomodulating therapies be initiated in the future (Level C, based on variation in patient preferences).
- Clinicians must screen for certain infections (such as hepatitis, tuberculosis, and varicella zoster virus) according to a medication’s prescribing information before starting immunosuppressive or immunomodulating treatment (Level A) and should treat patients who have latent infections before MS treatment according to the medication prescribing information (Level B, based on feasibility and cost relative to benefit). Further, in high-risk populations or in countries with a high burden of infectious disease, clinicians must screen for latent infections before starting immunosuppressive or immunomodulating medications, even when such screening is not specifically mentioned in the prescribing information (Level A). Clinicians should consult infectious disease or other specialists about treating patients with latent infection before starting immunosuppressive or immunomodulating medications (Level B).
- Clinicians should recommend against live-attenuated vaccines in people with MS who receive immunosuppressive or immunomodulating therapies or have recently discontinued these therapies (Level B, based on importance of outcomes). When the risk of infection is high, clinicians may recommend live-attenuated vaccines if killed vaccines are unavailable (Level C, based on variation in patient preferences, benefit relative to harm, and importance of outcomes).
- If a patient with MS is experiencing a relapse, clinicians should delay vaccination until the relapse has clinically resolved or is no longer active, often many weeks after relapse onset (Level B).
Personal and population-level benefits
“There is no evidence that vaccination increases the risk of MS exacerbation, although the literature is sparse,” the authors said. “In addition to conferring personal benefits, vaccination of the MS patient population contributes to the well-established phenomenon of herd immunity for the communities in which patients with MS live,” the authors wrote.
Because influenza infection has known risks of exacerbation and morbidity, whereas influenza vaccine has no identified risks of exacerbation, “benefits of influenza vaccination outweigh the risks in most scenarios, although patients with MS receiving some [immunosuppressive or immunomodulating] treatments (fingolimod [Gilenya], glatiramer acetate [Copaxone], and mitoxantrone) may have a reduced response to influenza vaccination,” the authors said. Studies in patients with diseases other than MS suggest that rituximab (Rituxan) also may be associated with reduced influenza vaccine responsiveness.
Immunosuppressive or immunomodulatory medications including alemtuzumab (Lemtrada), dimethyl fumarate (Tecfidera), fingolimod, mitoxantrone, natalizumab (Tysabri), ocrelizumab (Ocrevus), rituximab, and teriflunomide (Aubagio) have been associated with severe occurrences or recurrences of vaccine-preventable infections, and many package inserts approved by the Food and Drug Administration provide guidance regarding immunization with live vaccines and treatment.
Prescribing information for alemtuzumab, fingolimod, ocrelizumab, and teriflunomide recommends against the use of live vaccines during and immediately preceding treatment. Furthermore, the prescribing information recommends waiting 2-6 months after treatment to immunize with live vaccines, depending on the half-life of the specific therapy.
“The guideline panel identified no evidence that vaccines increase the risk of relapse or worsen relapse severity, but studies are limited,” Dr. Farez and colleagues wrote. “Experts remain concerned that vaccines may worsen relapse severity if given to patients who are actively experiencing an MS relapse.” In addition, use of glucocorticoids may raise concerns about the safety of live-virus vaccines. “Immunization is not typically an urgent need and, in most cases, can be temporarily delayed without a marked increase in infection risk,” the guideline says.
Few high-quality studies
Data were lacking or insufficient to assess whether most vaccine-preventable diseases increase the risk of MS exacerbations. “It is probable that individuals with active MS exacerbations have higher odds of varicella zoster virus viral DNA present in peripheral blood mononuclear cells than individuals with MS in remission,” the guideline says.
Human papillomavirus, pertussis, and tetanus toxoid vaccinations probably are associated with a lower likelihood of a subsequent MS diagnosis, and smallpox vaccination is possibly associated with a lower likelihood of a subsequent MS diagnosis, the review found.
Studies included in the systematic review did not address whether live-attenuated vaccines are as effective in patients with MS as they are in the general population. With regard to the effectiveness of inactivated vaccines, patients with MS possibly are less likely to have a sufficient response to influenza vaccination, compared with controls.
The systematic review “found few high-quality studies to inform recommendations,” the authors said. “As more [immunosuppressive or immunomodulating] agents are developed to manage chronic diseases such as MS, long-term prospective cohort studies are required to evaluate both the safety and effectiveness of immunizations in MS.”
Dr. Farez has received funding for travel from Teva Argentina, Novartis Argentina, and Merck Serono Argentina and has received research support from Biogen. Coauthors’ disclosures included financial ties to pharmaceutical companies.
SOURCE: Farez M et al. Neurology. 2019 Aug 28. doi: 10.1212/WNL.0000000000008157.
according to an American Academy of Neurology practice guideline.
A summary of the guideline on vaccine-preventable infections and immunization in MS was published online Aug. 28 in Neurology. The new effort updates a 2002 guideline on this topic and incorporates new evidence, vaccines, and disease-modifying therapies (DMTs). The guideline was endorsed by the Consortium of Multiple Sclerosis Centers and by the Multiple Sclerosis Association of America.
To create the guideline, lead author Mauricio F. Farez, MD, of the Raúl Carrea Institute for Neurological Research (FLENI) in Buenos Aires and colleagues on the 17-member guideline panel performed a systematic review of the evidence and reached consensus on recommendations using a modified Delphi voting process. The review included randomized, controlled trials; cohort studies; and case-control studies published between 1990 and March 2018.
“Immunosuppressive or immunomodulating agents used to treat MS may suppress or modulate normal immune function. These drugs may increase susceptibility to infections and may reduce vaccine effectiveness because of a decreased ability to mount an immune response,” the authors said.
Based on its review of the evidence, principles of care, and inferences, the authors made the following eight recommendations:
- Clinicians should discuss with patients the evidence regarding immunization in MS (Level B). In addition, clinicians should examine patients’ opinions, preferences, and questions regarding immunizations (Level B).
- Clinicians should recommend that patients with MS follow all local vaccine standards in the absence of specific contraindications (Level B).
- Clinicians should consider local risks of vaccine-preventable diseases when counseling patients (Level B).
- Clinicians should recommend that patients with MS receive the influenza vaccination if there is no specific contraindication, such as a previous severe reaction (Level B).
- When treatment with an immunosuppressive or immunomodulating agent is considered, clinicians should counsel patients about infection risks associated with the specific medication and the treatment-specific vaccination guidance in the medication’s prescribing instructions (Level B). In addition, physicians should assess patients’ vaccination status before prescribing immunosuppressive or immunomodulating therapy and vaccinate patients according to local regulatory standards and treatment-specific infectious risks at least 4-6 weeks before initiating therapy, as advised by the prescribing information (Level B). Furthermore, clinicians may discuss the advantages of vaccination soon after MS diagnosis, regardless of initial therapeutic plans, to prevent delays should immunosuppressive or immunomodulating therapies be initiated in the future (Level C, based on variation in patient preferences).
- Clinicians must screen for certain infections (such as hepatitis, tuberculosis, and varicella zoster virus) according to a medication’s prescribing information before starting immunosuppressive or immunomodulating treatment (Level A) and should treat patients who have latent infections before MS treatment according to the medication prescribing information (Level B, based on feasibility and cost relative to benefit). Further, in high-risk populations or in countries with a high burden of infectious disease, clinicians must screen for latent infections before starting immunosuppressive or immunomodulating medications, even when such screening is not specifically mentioned in the prescribing information (Level A). Clinicians should consult infectious disease or other specialists about treating patients with latent infection before starting immunosuppressive or immunomodulating medications (Level B).
- Clinicians should recommend against live-attenuated vaccines in people with MS who receive immunosuppressive or immunomodulating therapies or have recently discontinued these therapies (Level B, based on importance of outcomes). When the risk of infection is high, clinicians may recommend live-attenuated vaccines if killed vaccines are unavailable (Level C, based on variation in patient preferences, benefit relative to harm, and importance of outcomes).
- If a patient with MS is experiencing a relapse, clinicians should delay vaccination until the relapse has clinically resolved or is no longer active, often many weeks after relapse onset (Level B).
Personal and population-level benefits
“There is no evidence that vaccination increases the risk of MS exacerbation, although the literature is sparse,” the authors said. “In addition to conferring personal benefits, vaccination of the MS patient population contributes to the well-established phenomenon of herd immunity for the communities in which patients with MS live,” the authors wrote.
Because influenza infection has known risks of exacerbation and morbidity, whereas influenza vaccine has no identified risks of exacerbation, “benefits of influenza vaccination outweigh the risks in most scenarios, although patients with MS receiving some [immunosuppressive or immunomodulating] treatments (fingolimod [Gilenya], glatiramer acetate [Copaxone], and mitoxantrone) may have a reduced response to influenza vaccination,” the authors said. Studies in patients with diseases other than MS suggest that rituximab (Rituxan) also may be associated with reduced influenza vaccine responsiveness.
Immunosuppressive or immunomodulatory medications including alemtuzumab (Lemtrada), dimethyl fumarate (Tecfidera), fingolimod, mitoxantrone, natalizumab (Tysabri), ocrelizumab (Ocrevus), rituximab, and teriflunomide (Aubagio) have been associated with severe occurrences or recurrences of vaccine-preventable infections, and many package inserts approved by the Food and Drug Administration provide guidance regarding immunization with live vaccines and treatment.
Prescribing information for alemtuzumab, fingolimod, ocrelizumab, and teriflunomide recommends against the use of live vaccines during and immediately preceding treatment. Furthermore, the prescribing information recommends waiting 2-6 months after treatment to immunize with live vaccines, depending on the half-life of the specific therapy.
“The guideline panel identified no evidence that vaccines increase the risk of relapse or worsen relapse severity, but studies are limited,” Dr. Farez and colleagues wrote. “Experts remain concerned that vaccines may worsen relapse severity if given to patients who are actively experiencing an MS relapse.” In addition, use of glucocorticoids may raise concerns about the safety of live-virus vaccines. “Immunization is not typically an urgent need and, in most cases, can be temporarily delayed without a marked increase in infection risk,” the guideline says.
Few high-quality studies
Data were lacking or insufficient to assess whether most vaccine-preventable diseases increase the risk of MS exacerbations. “It is probable that individuals with active MS exacerbations have higher odds of varicella zoster virus viral DNA present in peripheral blood mononuclear cells than individuals with MS in remission,” the guideline says.
Human papillomavirus, pertussis, and tetanus toxoid vaccinations probably are associated with a lower likelihood of a subsequent MS diagnosis, and smallpox vaccination is possibly associated with a lower likelihood of a subsequent MS diagnosis, the review found.
Studies included in the systematic review did not address whether live-attenuated vaccines are as effective in patients with MS as they are in the general population. With regard to the effectiveness of inactivated vaccines, patients with MS possibly are less likely to have a sufficient response to influenza vaccination, compared with controls.
The systematic review “found few high-quality studies to inform recommendations,” the authors said. “As more [immunosuppressive or immunomodulating] agents are developed to manage chronic diseases such as MS, long-term prospective cohort studies are required to evaluate both the safety and effectiveness of immunizations in MS.”
Dr. Farez has received funding for travel from Teva Argentina, Novartis Argentina, and Merck Serono Argentina and has received research support from Biogen. Coauthors’ disclosures included financial ties to pharmaceutical companies.
SOURCE: Farez M et al. Neurology. 2019 Aug 28. doi: 10.1212/WNL.0000000000008157.
FROM NEUROLOGY
A new beverage aims to make ketogenic diets more palatable
BANGKOK –
Chief among those shortcomings is the notoriously poor compliance with these highly restrictive diets, which, as defining features, emphasize high fat intake and scrupulous restriction of carbohydrates in an effort to mimic the metabolic effects of starvation, J. Helen Cross, MD, explained at the International Epilepsy Congress.
She was a coauthor of a study led by Natasha E. Schoeler, PhD, a research dietician at the University College London Great Ormond Street Institute of Child Health, which demonstrated that children and adults with epilepsy who experience a significant antiseizure effect in response to ketogenic diet therapies have higher baseline blood levels of acetyl carnitine (Epilepsia. 2017 May;58(5):893-900).
The importance of this novel observation is twofold: It indicates a potential role for baseline acetyl carnitine level as a predictor of differential response to ketogenic diet therapies, a predictor for which there is an unmet need, and it is consistent with the hypothesis that an important potential mechanism of ketogenic diet effectiveness in epilepsy involves altered mitochondrial energy metabolism. That is because acetyl carnitine plays an essential role in mitochondrial uptake of long-chain fatty acids, noted Dr. Cross, professor of pediatric neurology and head of the developmental neurosciences program at the University College London Great Ormond Street Institute of Child Health.
At the congress sponsored by the International League Against Epilepsy, Dr. Cross and Dr. Schoeler presented the results of the initial 12-week tolerability study of Betashot, a ready-to-use, palatable blend of specific medium-chain triglycerides designed to be consumed three to four times daily with normal meals, limiting only intake of foods high in refined sugar. The Betashot beverage was developed in conjunction with Vitaflo International, a nutritional products company.
“It actually tastes good. It tastes like a strawberry shake,” according to Dr. Schoeler.
The 12-week study included 35 children with genetically caused forms of epilepsy and 26 adults with drug-resistant epilepsy. This was primarily a tolerability and compliance study, and the main finding was that two-thirds of the children and 69% of adults who started the study were still using Betashot at the 12-week mark. Moreover, 91% of the children and 56% of adults who completed the study elected to stay on Betashot afterwards. By week 12, after titrating their daily dose of Betashot upward as tolerated, the pediatric patients averaged 18% of their total daily energy intake from Betashot, the adults 24%.
The most common reasons for discontinuation among both children and adults were gastrointestinal side effects: abdominal discomfort, diarrhea, and/or vomiting.
“What’s exciting is that, even though the study is not powered to look at seizure response – it’s a tolerability study – we can report that there was a statistically significant reduction in the number of seizures in the group overall after 3 months of treatment,” Dr. Cross said.
She declined to provide specific data on seizure frequency because the study was underpowered for that endpoint. However, she added that further larger studies looking at a possible antiseizure effect of Betashot are ongoing.
The Betashot study was funded by Vitaflo International.
BANGKOK –
Chief among those shortcomings is the notoriously poor compliance with these highly restrictive diets, which, as defining features, emphasize high fat intake and scrupulous restriction of carbohydrates in an effort to mimic the metabolic effects of starvation, J. Helen Cross, MD, explained at the International Epilepsy Congress.
She was a coauthor of a study led by Natasha E. Schoeler, PhD, a research dietician at the University College London Great Ormond Street Institute of Child Health, which demonstrated that children and adults with epilepsy who experience a significant antiseizure effect in response to ketogenic diet therapies have higher baseline blood levels of acetyl carnitine (Epilepsia. 2017 May;58(5):893-900).
The importance of this novel observation is twofold: It indicates a potential role for baseline acetyl carnitine level as a predictor of differential response to ketogenic diet therapies, a predictor for which there is an unmet need, and it is consistent with the hypothesis that an important potential mechanism of ketogenic diet effectiveness in epilepsy involves altered mitochondrial energy metabolism. That is because acetyl carnitine plays an essential role in mitochondrial uptake of long-chain fatty acids, noted Dr. Cross, professor of pediatric neurology and head of the developmental neurosciences program at the University College London Great Ormond Street Institute of Child Health.
At the congress sponsored by the International League Against Epilepsy, Dr. Cross and Dr. Schoeler presented the results of the initial 12-week tolerability study of Betashot, a ready-to-use, palatable blend of specific medium-chain triglycerides designed to be consumed three to four times daily with normal meals, limiting only intake of foods high in refined sugar. The Betashot beverage was developed in conjunction with Vitaflo International, a nutritional products company.
“It actually tastes good. It tastes like a strawberry shake,” according to Dr. Schoeler.
The 12-week study included 35 children with genetically caused forms of epilepsy and 26 adults with drug-resistant epilepsy. This was primarily a tolerability and compliance study, and the main finding was that two-thirds of the children and 69% of adults who started the study were still using Betashot at the 12-week mark. Moreover, 91% of the children and 56% of adults who completed the study elected to stay on Betashot afterwards. By week 12, after titrating their daily dose of Betashot upward as tolerated, the pediatric patients averaged 18% of their total daily energy intake from Betashot, the adults 24%.
The most common reasons for discontinuation among both children and adults were gastrointestinal side effects: abdominal discomfort, diarrhea, and/or vomiting.
“What’s exciting is that, even though the study is not powered to look at seizure response – it’s a tolerability study – we can report that there was a statistically significant reduction in the number of seizures in the group overall after 3 months of treatment,” Dr. Cross said.
She declined to provide specific data on seizure frequency because the study was underpowered for that endpoint. However, she added that further larger studies looking at a possible antiseizure effect of Betashot are ongoing.
The Betashot study was funded by Vitaflo International.
BANGKOK –
Chief among those shortcomings is the notoriously poor compliance with these highly restrictive diets, which, as defining features, emphasize high fat intake and scrupulous restriction of carbohydrates in an effort to mimic the metabolic effects of starvation, J. Helen Cross, MD, explained at the International Epilepsy Congress.
She was a coauthor of a study led by Natasha E. Schoeler, PhD, a research dietician at the University College London Great Ormond Street Institute of Child Health, which demonstrated that children and adults with epilepsy who experience a significant antiseizure effect in response to ketogenic diet therapies have higher baseline blood levels of acetyl carnitine (Epilepsia. 2017 May;58(5):893-900).
The importance of this novel observation is twofold: It indicates a potential role for baseline acetyl carnitine level as a predictor of differential response to ketogenic diet therapies, a predictor for which there is an unmet need, and it is consistent with the hypothesis that an important potential mechanism of ketogenic diet effectiveness in epilepsy involves altered mitochondrial energy metabolism. That is because acetyl carnitine plays an essential role in mitochondrial uptake of long-chain fatty acids, noted Dr. Cross, professor of pediatric neurology and head of the developmental neurosciences program at the University College London Great Ormond Street Institute of Child Health.
At the congress sponsored by the International League Against Epilepsy, Dr. Cross and Dr. Schoeler presented the results of the initial 12-week tolerability study of Betashot, a ready-to-use, palatable blend of specific medium-chain triglycerides designed to be consumed three to four times daily with normal meals, limiting only intake of foods high in refined sugar. The Betashot beverage was developed in conjunction with Vitaflo International, a nutritional products company.
“It actually tastes good. It tastes like a strawberry shake,” according to Dr. Schoeler.
The 12-week study included 35 children with genetically caused forms of epilepsy and 26 adults with drug-resistant epilepsy. This was primarily a tolerability and compliance study, and the main finding was that two-thirds of the children and 69% of adults who started the study were still using Betashot at the 12-week mark. Moreover, 91% of the children and 56% of adults who completed the study elected to stay on Betashot afterwards. By week 12, after titrating their daily dose of Betashot upward as tolerated, the pediatric patients averaged 18% of their total daily energy intake from Betashot, the adults 24%.
The most common reasons for discontinuation among both children and adults were gastrointestinal side effects: abdominal discomfort, diarrhea, and/or vomiting.
“What’s exciting is that, even though the study is not powered to look at seizure response – it’s a tolerability study – we can report that there was a statistically significant reduction in the number of seizures in the group overall after 3 months of treatment,” Dr. Cross said.
She declined to provide specific data on seizure frequency because the study was underpowered for that endpoint. However, she added that further larger studies looking at a possible antiseizure effect of Betashot are ongoing.
The Betashot study was funded by Vitaflo International.
REPORTING FROM IEC 2019
Prices, out-of-pocket costs for MS drugs rose despite competition
according to an analysis published in JAMA Neurology. The increased prices raise concern “because they demonstrate that the approval of new therapies did not ameliorate and could have even contributed to high inflation rates observed for incumbent drugs,” wrote the authors.
Four self-administered disease-modifying therapies (DMTs) for multiple sclerosis (MS) were available before 2009, and seven new branded DMTs were introduced after that year. Previous research indicated that the prices of DMTs for MS increased at higher rates than the prices of drugs for other disorders. How these price increases affected pharmaceutical spending during the past decade is uncertain, however.
A review of Medicare claims data
Alvaro San-Juan-Rodriguez, PharmD, a fellow in pharmacoeconomics, outcomes, and pharmacoanalytics research at the University of Pittsburgh, and colleagues examined claims data from 2006 to 2016 from a 5% random sample of Medicare beneficiaries. Information for a mean of 2.8 million Medicare beneficiaries per year was available. The researchers extracted all prescription claims for self-administered DMTs for MS (that is, glatiramer acetate, interferon beta-1a, interferon beta-1b, fingolimod, teriflunomide, dimethyl fumarate, and peginterferon beta-1a).
Dr. San-Juan-Rodriguez and associates chose three main outcomes. The first was the annual cost of treatment with each medication, which was based on Medicare Part D prescription claims gross costs and Food and Drug Administration–approved recommended dosing. The second was the market share of each medication, which the researchers defined as the proportion of pharmaceutical spending accounted for by each drug. The third was pharmaceutical spending per 1,000 Medicare beneficiaries for all drugs. The investigators also examined the relative contributions of Medicare Part D Plans’ payments, patients’ out-of-pocket costs, and other payments toward pharmaceutical spending.
Prices defied market expectations
The annual costs of treatment with self-administered DMTs for MS increased more than 300%. The mean annual cost was $18,660 in 2006 and $75,847 in 2016, and the mean annual rate of price increase was 12.8%. “Prices of most self-administered DMTs for MS increased in parallel, defying standard market expectations,” the investigators wrote.
Branded formulations of glatiramer acetate maintained the largest market share throughout the study period, ranging between 32.2% and 48.4%. However, the market share of platform therapies – glatiramer acetate, interferon beta-1a, and interferon beta-1b – decreased significantly from 2006 to 2016. Market shares for brand-name glatiramers declined from 36.7% to 32.2%, for intramuscular interferon beta-1a (30 mcg) from 32.3% to 14.2%, for interferon beta-1b from 18.7% to 4.5%, and for interferon beta-1a (8.8, 22, or 44 mcg) from 12.2% to 8.3%. The market shares of newer therapies, however, increased to 7.9% for fingolimod, 9.0% for teriflunomide, and 19.2% for dimethyl fumarate.
Pharmaceutical spending per 1,000 beneficiaries increased by a factor of 10.2 throughout the study period (from $7,794 to $79,411). Patients’ out-of-pocket spending per 1,000 beneficiaries increased by a factor of 7.2 (from $372 to $2,673). Furthermore, the relative contribution of federal payments toward pharmaceutical spending increased from 68.5% to 73.8%.
“Large increases in drug prices have not been specific to MS drugs,” said Dr. San-Juan-Rodriguez in an interview. “We previously described similar trends in other specialty medications used to treat severe disease states, such as tumor necrosis factor inhibitors [TNFi] for the treatment of rheumatoid arthritis. Yet these increases took place at a slower pace. For instance, list prices of TNFi increased at an average annual rate of 9.9% in the same time period, 2006-2016.
“It is important to acknowledge that rising list prices of drugs may partially reflect competition for rebates,” he added. “Yet the specific reasons behind the faster growth of prices of MS drugs, compared with the prices of drugs used in other disease states, remain uncertain.”
Neurologists should bear in mind that, although generic drugs are substantially cheaper than branded drugs, generic specialty medications do not always reduce costs for Medicare Part D beneficiaries. “On the contrary, due to incentive misalignments created by the Medicare Part D benefit design, beneficiaries using generic drugs such as Glatopa ... may pay more than those using the branded drug,” Dr. San-Juan-Rodriguez said.
What are neurologists’ responsibilities?
Although the original annual price of interferon beta-1b ($10,920) was stunning, physicians now recall it with nostalgia, wrote Daniel M. Hartung, PharmD, associate professor of biostatistics and epidemiology, and Dennis Bourdette, MD, professor of neurology, both at Oregon Health and Science University, Portland, in an accompanying editorial. “The prices for DMTs for MS have risen dramatically over the last 15 years, far outpacing inflation, and now have a mean price of more than $86,000 per year.”
Neurologists should be concerned about these rising prices, Dr. Hartung and Dr. Bourdette wrote. They should feel responsibility toward the health care system that pays for these medications, and toward patients who pay out of their own pockets. “Neurologists should be seeking to minimize the financial adverse effects of these therapies as much as they try to minimize physical adverse effects.”
One way for neurologists to address increasing prices is to urge state and federal lawmakers to pass legislation to curb them, they wrote. Neurologists also should reexamine their relationships with pharmaceutical and biotechnology companies. “Remaining silent should not be an option. ... Neurologists should not allow the unfettered increases in price for these drugs to hurt the health care system or patients.”
The Myers Family Foundation and the National Heart, Lung, and Blood Institute funded the research. Several authors are employees of health insurance companies such as the UPMC Health Plan Insurance Services Division and Humana. One author received personal fees from Pfizer that were unrelated to this study.
SOURCEs: San-Juan-Rodriguez A et al. JAMA Neurol. 2019 Aug 26. doi: 10.1001/jamaneurol.2019.2711; Hartung DM and Bourdette D. JAMA Neurol. 2019 Aug 26. doi: 10.1001/jamaneurol.2019.2445.
according to an analysis published in JAMA Neurology. The increased prices raise concern “because they demonstrate that the approval of new therapies did not ameliorate and could have even contributed to high inflation rates observed for incumbent drugs,” wrote the authors.
Four self-administered disease-modifying therapies (DMTs) for multiple sclerosis (MS) were available before 2009, and seven new branded DMTs were introduced after that year. Previous research indicated that the prices of DMTs for MS increased at higher rates than the prices of drugs for other disorders. How these price increases affected pharmaceutical spending during the past decade is uncertain, however.
A review of Medicare claims data
Alvaro San-Juan-Rodriguez, PharmD, a fellow in pharmacoeconomics, outcomes, and pharmacoanalytics research at the University of Pittsburgh, and colleagues examined claims data from 2006 to 2016 from a 5% random sample of Medicare beneficiaries. Information for a mean of 2.8 million Medicare beneficiaries per year was available. The researchers extracted all prescription claims for self-administered DMTs for MS (that is, glatiramer acetate, interferon beta-1a, interferon beta-1b, fingolimod, teriflunomide, dimethyl fumarate, and peginterferon beta-1a).
Dr. San-Juan-Rodriguez and associates chose three main outcomes. The first was the annual cost of treatment with each medication, which was based on Medicare Part D prescription claims gross costs and Food and Drug Administration–approved recommended dosing. The second was the market share of each medication, which the researchers defined as the proportion of pharmaceutical spending accounted for by each drug. The third was pharmaceutical spending per 1,000 Medicare beneficiaries for all drugs. The investigators also examined the relative contributions of Medicare Part D Plans’ payments, patients’ out-of-pocket costs, and other payments toward pharmaceutical spending.
Prices defied market expectations
The annual costs of treatment with self-administered DMTs for MS increased more than 300%. The mean annual cost was $18,660 in 2006 and $75,847 in 2016, and the mean annual rate of price increase was 12.8%. “Prices of most self-administered DMTs for MS increased in parallel, defying standard market expectations,” the investigators wrote.
Branded formulations of glatiramer acetate maintained the largest market share throughout the study period, ranging between 32.2% and 48.4%. However, the market share of platform therapies – glatiramer acetate, interferon beta-1a, and interferon beta-1b – decreased significantly from 2006 to 2016. Market shares for brand-name glatiramers declined from 36.7% to 32.2%, for intramuscular interferon beta-1a (30 mcg) from 32.3% to 14.2%, for interferon beta-1b from 18.7% to 4.5%, and for interferon beta-1a (8.8, 22, or 44 mcg) from 12.2% to 8.3%. The market shares of newer therapies, however, increased to 7.9% for fingolimod, 9.0% for teriflunomide, and 19.2% for dimethyl fumarate.
Pharmaceutical spending per 1,000 beneficiaries increased by a factor of 10.2 throughout the study period (from $7,794 to $79,411). Patients’ out-of-pocket spending per 1,000 beneficiaries increased by a factor of 7.2 (from $372 to $2,673). Furthermore, the relative contribution of federal payments toward pharmaceutical spending increased from 68.5% to 73.8%.
“Large increases in drug prices have not been specific to MS drugs,” said Dr. San-Juan-Rodriguez in an interview. “We previously described similar trends in other specialty medications used to treat severe disease states, such as tumor necrosis factor inhibitors [TNFi] for the treatment of rheumatoid arthritis. Yet these increases took place at a slower pace. For instance, list prices of TNFi increased at an average annual rate of 9.9% in the same time period, 2006-2016.
“It is important to acknowledge that rising list prices of drugs may partially reflect competition for rebates,” he added. “Yet the specific reasons behind the faster growth of prices of MS drugs, compared with the prices of drugs used in other disease states, remain uncertain.”
Neurologists should bear in mind that, although generic drugs are substantially cheaper than branded drugs, generic specialty medications do not always reduce costs for Medicare Part D beneficiaries. “On the contrary, due to incentive misalignments created by the Medicare Part D benefit design, beneficiaries using generic drugs such as Glatopa ... may pay more than those using the branded drug,” Dr. San-Juan-Rodriguez said.
What are neurologists’ responsibilities?
Although the original annual price of interferon beta-1b ($10,920) was stunning, physicians now recall it with nostalgia, wrote Daniel M. Hartung, PharmD, associate professor of biostatistics and epidemiology, and Dennis Bourdette, MD, professor of neurology, both at Oregon Health and Science University, Portland, in an accompanying editorial. “The prices for DMTs for MS have risen dramatically over the last 15 years, far outpacing inflation, and now have a mean price of more than $86,000 per year.”
Neurologists should be concerned about these rising prices, Dr. Hartung and Dr. Bourdette wrote. They should feel responsibility toward the health care system that pays for these medications, and toward patients who pay out of their own pockets. “Neurologists should be seeking to minimize the financial adverse effects of these therapies as much as they try to minimize physical adverse effects.”
One way for neurologists to address increasing prices is to urge state and federal lawmakers to pass legislation to curb them, they wrote. Neurologists also should reexamine their relationships with pharmaceutical and biotechnology companies. “Remaining silent should not be an option. ... Neurologists should not allow the unfettered increases in price for these drugs to hurt the health care system or patients.”
The Myers Family Foundation and the National Heart, Lung, and Blood Institute funded the research. Several authors are employees of health insurance companies such as the UPMC Health Plan Insurance Services Division and Humana. One author received personal fees from Pfizer that were unrelated to this study.
SOURCEs: San-Juan-Rodriguez A et al. JAMA Neurol. 2019 Aug 26. doi: 10.1001/jamaneurol.2019.2711; Hartung DM and Bourdette D. JAMA Neurol. 2019 Aug 26. doi: 10.1001/jamaneurol.2019.2445.
according to an analysis published in JAMA Neurology. The increased prices raise concern “because they demonstrate that the approval of new therapies did not ameliorate and could have even contributed to high inflation rates observed for incumbent drugs,” wrote the authors.
Four self-administered disease-modifying therapies (DMTs) for multiple sclerosis (MS) were available before 2009, and seven new branded DMTs were introduced after that year. Previous research indicated that the prices of DMTs for MS increased at higher rates than the prices of drugs for other disorders. How these price increases affected pharmaceutical spending during the past decade is uncertain, however.
A review of Medicare claims data
Alvaro San-Juan-Rodriguez, PharmD, a fellow in pharmacoeconomics, outcomes, and pharmacoanalytics research at the University of Pittsburgh, and colleagues examined claims data from 2006 to 2016 from a 5% random sample of Medicare beneficiaries. Information for a mean of 2.8 million Medicare beneficiaries per year was available. The researchers extracted all prescription claims for self-administered DMTs for MS (that is, glatiramer acetate, interferon beta-1a, interferon beta-1b, fingolimod, teriflunomide, dimethyl fumarate, and peginterferon beta-1a).
Dr. San-Juan-Rodriguez and associates chose three main outcomes. The first was the annual cost of treatment with each medication, which was based on Medicare Part D prescription claims gross costs and Food and Drug Administration–approved recommended dosing. The second was the market share of each medication, which the researchers defined as the proportion of pharmaceutical spending accounted for by each drug. The third was pharmaceutical spending per 1,000 Medicare beneficiaries for all drugs. The investigators also examined the relative contributions of Medicare Part D Plans’ payments, patients’ out-of-pocket costs, and other payments toward pharmaceutical spending.
Prices defied market expectations
The annual costs of treatment with self-administered DMTs for MS increased more than 300%. The mean annual cost was $18,660 in 2006 and $75,847 in 2016, and the mean annual rate of price increase was 12.8%. “Prices of most self-administered DMTs for MS increased in parallel, defying standard market expectations,” the investigators wrote.
Branded formulations of glatiramer acetate maintained the largest market share throughout the study period, ranging between 32.2% and 48.4%. However, the market share of platform therapies – glatiramer acetate, interferon beta-1a, and interferon beta-1b – decreased significantly from 2006 to 2016. Market shares for brand-name glatiramers declined from 36.7% to 32.2%, for intramuscular interferon beta-1a (30 mcg) from 32.3% to 14.2%, for interferon beta-1b from 18.7% to 4.5%, and for interferon beta-1a (8.8, 22, or 44 mcg) from 12.2% to 8.3%. The market shares of newer therapies, however, increased to 7.9% for fingolimod, 9.0% for teriflunomide, and 19.2% for dimethyl fumarate.
Pharmaceutical spending per 1,000 beneficiaries increased by a factor of 10.2 throughout the study period (from $7,794 to $79,411). Patients’ out-of-pocket spending per 1,000 beneficiaries increased by a factor of 7.2 (from $372 to $2,673). Furthermore, the relative contribution of federal payments toward pharmaceutical spending increased from 68.5% to 73.8%.
“Large increases in drug prices have not been specific to MS drugs,” said Dr. San-Juan-Rodriguez in an interview. “We previously described similar trends in other specialty medications used to treat severe disease states, such as tumor necrosis factor inhibitors [TNFi] for the treatment of rheumatoid arthritis. Yet these increases took place at a slower pace. For instance, list prices of TNFi increased at an average annual rate of 9.9% in the same time period, 2006-2016.
“It is important to acknowledge that rising list prices of drugs may partially reflect competition for rebates,” he added. “Yet the specific reasons behind the faster growth of prices of MS drugs, compared with the prices of drugs used in other disease states, remain uncertain.”
Neurologists should bear in mind that, although generic drugs are substantially cheaper than branded drugs, generic specialty medications do not always reduce costs for Medicare Part D beneficiaries. “On the contrary, due to incentive misalignments created by the Medicare Part D benefit design, beneficiaries using generic drugs such as Glatopa ... may pay more than those using the branded drug,” Dr. San-Juan-Rodriguez said.
What are neurologists’ responsibilities?
Although the original annual price of interferon beta-1b ($10,920) was stunning, physicians now recall it with nostalgia, wrote Daniel M. Hartung, PharmD, associate professor of biostatistics and epidemiology, and Dennis Bourdette, MD, professor of neurology, both at Oregon Health and Science University, Portland, in an accompanying editorial. “The prices for DMTs for MS have risen dramatically over the last 15 years, far outpacing inflation, and now have a mean price of more than $86,000 per year.”
Neurologists should be concerned about these rising prices, Dr. Hartung and Dr. Bourdette wrote. They should feel responsibility toward the health care system that pays for these medications, and toward patients who pay out of their own pockets. “Neurologists should be seeking to minimize the financial adverse effects of these therapies as much as they try to minimize physical adverse effects.”
One way for neurologists to address increasing prices is to urge state and federal lawmakers to pass legislation to curb them, they wrote. Neurologists also should reexamine their relationships with pharmaceutical and biotechnology companies. “Remaining silent should not be an option. ... Neurologists should not allow the unfettered increases in price for these drugs to hurt the health care system or patients.”
The Myers Family Foundation and the National Heart, Lung, and Blood Institute funded the research. Several authors are employees of health insurance companies such as the UPMC Health Plan Insurance Services Division and Humana. One author received personal fees from Pfizer that were unrelated to this study.
SOURCEs: San-Juan-Rodriguez A et al. JAMA Neurol. 2019 Aug 26. doi: 10.1001/jamaneurol.2019.2711; Hartung DM and Bourdette D. JAMA Neurol. 2019 Aug 26. doi: 10.1001/jamaneurol.2019.2445.
FROM JAMA NEUROLOGY
Blood test may reveal brain injury
researchers reported Aug. 26 in BMJ Paediatrics Open.
“GFAP outperformed UCH-L1 in detecting concussion in both children and adults within 4 hours of injury,” reported lead author Linda Papa, MD, and collaborators. Dr. Papa is an emergency medicine doctor at Orlando Health. “UCH-L1 was expressed at much higher levels than GFAP in those with nonconcussive trauma, particularly in children. Elevations of these biomarkers in nonconcussive head trauma suggest possible subconcussive brain injury. GFAP could be potentially useful to detect concussion for up to a week post injury.”
In 2018 the Food and Drug Administration approved the use of these biomarkers to guide CT scan ordering in adults with mild to moderate traumatic brain injury, but investigators have not established their ability to detect concussion in children or adults. Clinicians lack an objective measure to diagnose concussion acutely.
To assess the ability of GFAP and UCH-L1 to detect concussion, Dr. Papa and colleagues conducted a prospective cohort study. The researchers enrolled trauma patients of all ages at three level I trauma centers in the United States. They included patients with and without head trauma who had a Glasgow Coma Scale score of 15 and who presented within 4 hours of injury. Investigators screened for concussion symptoms, obtained biomarker data from 712 trauma patients, and conducted repeated blood sampling in adults.
They grouped patients by those with concussion (n = 371), those with head trauma without overt signs of concussion (n = 149), and those with peripheral trauma without head trauma or concussion (n = 192). The study included 175 children. Injury mechanisms included car crashes, falls, bicycle accidents, and sports injuries.
Patients with concussion had significantly higher GFAP concentrations, compared with patients with body trauma and patients with nonconcussive head trauma. UCH-L1 levels did not significantly differ between patients with concussion and head trauma controls, however.
“Based on these results, the potential utility of GFAP to distinguish concussion from body trauma controls over 7 days postinjury was fair to excellent,” with area under the receiver operating characteristics curves (AUCs) of 0.75-0.89, the researchers said. “UCH-L1’s ability was guarded and variable with AUCs from poor to good depending on timing of samples.” UCH-L1 demonstrated AUCs that ranged from 0.54 to 0.78; earlier samples performed better.
GFAP elevations in head trauma controls “may represent milder forms of concussion that do not elicit typical signs or symptoms associated with concussion,” the authors wrote. “These injuries may be irrelevant, or they may represent important trauma that is just below the level of clinical detection and referred to as subconcussive trauma. ... Biomarkers (such as GFAP and UCH-L1) could provide a more objective measure of injury and potentially identify those at risk for neurocognitive problems.”
The study was supported by the National Institute of Neurological Disorders and Stroke. Dr. Papa is an unpaid scientific consultant for Banyan Biomarkers, which developed kits to measure the biomarkers, and coauthors receive contract research funding from Banyan Biomarkers.
SOURCE: Papa L et al. BMJ Paediatr Open. 2019 Aug 26. doi: 10.1136/bmjpo-2019-000473.
researchers reported Aug. 26 in BMJ Paediatrics Open.
“GFAP outperformed UCH-L1 in detecting concussion in both children and adults within 4 hours of injury,” reported lead author Linda Papa, MD, and collaborators. Dr. Papa is an emergency medicine doctor at Orlando Health. “UCH-L1 was expressed at much higher levels than GFAP in those with nonconcussive trauma, particularly in children. Elevations of these biomarkers in nonconcussive head trauma suggest possible subconcussive brain injury. GFAP could be potentially useful to detect concussion for up to a week post injury.”
In 2018 the Food and Drug Administration approved the use of these biomarkers to guide CT scan ordering in adults with mild to moderate traumatic brain injury, but investigators have not established their ability to detect concussion in children or adults. Clinicians lack an objective measure to diagnose concussion acutely.
To assess the ability of GFAP and UCH-L1 to detect concussion, Dr. Papa and colleagues conducted a prospective cohort study. The researchers enrolled trauma patients of all ages at three level I trauma centers in the United States. They included patients with and without head trauma who had a Glasgow Coma Scale score of 15 and who presented within 4 hours of injury. Investigators screened for concussion symptoms, obtained biomarker data from 712 trauma patients, and conducted repeated blood sampling in adults.
They grouped patients by those with concussion (n = 371), those with head trauma without overt signs of concussion (n = 149), and those with peripheral trauma without head trauma or concussion (n = 192). The study included 175 children. Injury mechanisms included car crashes, falls, bicycle accidents, and sports injuries.
Patients with concussion had significantly higher GFAP concentrations, compared with patients with body trauma and patients with nonconcussive head trauma. UCH-L1 levels did not significantly differ between patients with concussion and head trauma controls, however.
“Based on these results, the potential utility of GFAP to distinguish concussion from body trauma controls over 7 days postinjury was fair to excellent,” with area under the receiver operating characteristics curves (AUCs) of 0.75-0.89, the researchers said. “UCH-L1’s ability was guarded and variable with AUCs from poor to good depending on timing of samples.” UCH-L1 demonstrated AUCs that ranged from 0.54 to 0.78; earlier samples performed better.
GFAP elevations in head trauma controls “may represent milder forms of concussion that do not elicit typical signs or symptoms associated with concussion,” the authors wrote. “These injuries may be irrelevant, or they may represent important trauma that is just below the level of clinical detection and referred to as subconcussive trauma. ... Biomarkers (such as GFAP and UCH-L1) could provide a more objective measure of injury and potentially identify those at risk for neurocognitive problems.”
The study was supported by the National Institute of Neurological Disorders and Stroke. Dr. Papa is an unpaid scientific consultant for Banyan Biomarkers, which developed kits to measure the biomarkers, and coauthors receive contract research funding from Banyan Biomarkers.
SOURCE: Papa L et al. BMJ Paediatr Open. 2019 Aug 26. doi: 10.1136/bmjpo-2019-000473.
researchers reported Aug. 26 in BMJ Paediatrics Open.
“GFAP outperformed UCH-L1 in detecting concussion in both children and adults within 4 hours of injury,” reported lead author Linda Papa, MD, and collaborators. Dr. Papa is an emergency medicine doctor at Orlando Health. “UCH-L1 was expressed at much higher levels than GFAP in those with nonconcussive trauma, particularly in children. Elevations of these biomarkers in nonconcussive head trauma suggest possible subconcussive brain injury. GFAP could be potentially useful to detect concussion for up to a week post injury.”
In 2018 the Food and Drug Administration approved the use of these biomarkers to guide CT scan ordering in adults with mild to moderate traumatic brain injury, but investigators have not established their ability to detect concussion in children or adults. Clinicians lack an objective measure to diagnose concussion acutely.
To assess the ability of GFAP and UCH-L1 to detect concussion, Dr. Papa and colleagues conducted a prospective cohort study. The researchers enrolled trauma patients of all ages at three level I trauma centers in the United States. They included patients with and without head trauma who had a Glasgow Coma Scale score of 15 and who presented within 4 hours of injury. Investigators screened for concussion symptoms, obtained biomarker data from 712 trauma patients, and conducted repeated blood sampling in adults.
They grouped patients by those with concussion (n = 371), those with head trauma without overt signs of concussion (n = 149), and those with peripheral trauma without head trauma or concussion (n = 192). The study included 175 children. Injury mechanisms included car crashes, falls, bicycle accidents, and sports injuries.
Patients with concussion had significantly higher GFAP concentrations, compared with patients with body trauma and patients with nonconcussive head trauma. UCH-L1 levels did not significantly differ between patients with concussion and head trauma controls, however.
“Based on these results, the potential utility of GFAP to distinguish concussion from body trauma controls over 7 days postinjury was fair to excellent,” with area under the receiver operating characteristics curves (AUCs) of 0.75-0.89, the researchers said. “UCH-L1’s ability was guarded and variable with AUCs from poor to good depending on timing of samples.” UCH-L1 demonstrated AUCs that ranged from 0.54 to 0.78; earlier samples performed better.
GFAP elevations in head trauma controls “may represent milder forms of concussion that do not elicit typical signs or symptoms associated with concussion,” the authors wrote. “These injuries may be irrelevant, or they may represent important trauma that is just below the level of clinical detection and referred to as subconcussive trauma. ... Biomarkers (such as GFAP and UCH-L1) could provide a more objective measure of injury and potentially identify those at risk for neurocognitive problems.”
The study was supported by the National Institute of Neurological Disorders and Stroke. Dr. Papa is an unpaid scientific consultant for Banyan Biomarkers, which developed kits to measure the biomarkers, and coauthors receive contract research funding from Banyan Biomarkers.
SOURCE: Papa L et al. BMJ Paediatr Open. 2019 Aug 26. doi: 10.1136/bmjpo-2019-000473.
FROM BMJ PAEDIATRICS OPEN
Key clinical point: Levels of glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase L1 (UCH-L1) are lowest in patients with nonconcussive body trauma, higher in patients with nonconcussive head trauma, and highest in patients with concussion.
Major finding: GFAP was fair to excellent at distinguishing concussion from body trauma, with area under the receiver operating characteristics curves of 0.75-0.89.
Study details: A prospective cohort study of 712 trauma patients of all ages at three level I trauma centers in the United States. The study included patients with and without head trauma who had a Glasgow Coma Scale score of 15 and presented within 4 hours of injury.
Disclosures: The study was supported by the National Institute of Neurological Disorders and Stroke. Dr. Papa is an unpaid scientific consultant for Banyan Biomarkers, which developed kits to measure the biomarkers. Coauthors receive contract research funding from Banyan Biomarkers.
Source: Papa L et al. BMJ Paediatr Open. 2019 Aug 26. doi: 10.1136/bmjpo-2019-000473.
Genotype may affect lifestyle’s influence on dementia risk
But among people at high genetic risk for dementia, these potentially modifiable factors – not smoking, not having depression or diabetes, getting regular physical activity, avoiding social isolation, and following a healthy diet – may not have protective associations, according to research published in Nature Medicine.
Recent analyses have indicated that eliminating known modifiable risk factors for dementia at a population level could prevent one-third of dementia cases, but prevention trials “have yielded inconsistent results so far,” wrote first author Silvan Licher, MD, of the department of epidemiology at Erasmus University Medical Center Rotterdam (the Netherlands) and his colleagues.
“Prior studies have mostly focused on the risk of dementia associated with an individual protective factor, yet the combination of multiple factors may yield more beneficial effects than the individual parts,” they wrote. “Combining data about a number of factors is also important because it takes into account the multifactorial nature of late-life dementia. We used data from the Rotterdam Study to determine to what extent a favorable profile based on modifiable risk factors is associated with a lower risk of dementia among individuals at low, intermediate, or high genetic risk.”
Grouped by APOE genotype
Patients who were apolipoprotein E epsilon-4 allele (APOE4) carriers (i.e., APOE2 and 4, APOE3 and 4, or two APOE4) were classified as having high genetic risk (n = 1,747). Other APOE genotypes were considered intermediate risk (n = 3,718 with two APOE3 alleles) or low risk (n = 887 with either two APOE2 alleles or APOE2 and 3).
The researchers measured six potentially modifiable lifestyle or health factors that “have been implicated in a lower risk of dementia.” Modifiable risk scores ranged from 0 to 6. Participants were classified as having an unfavorable profile (0-2 protective factors), an intermediate profile (3-4 protective factors), or a favorable profile (5-6 factors).
The researchers calculated the relative risk of developing dementia using a Cox proportional hazards model and the absolutely risk using competing risk models.
In all, 56.2% of the participants were women, the average age was about 69 years, and patient characteristics were similar across the categories of APOE risk. APOE4 carriers received dementia diagnoses at a younger age, more often had a parental history of dementia, and had higher total cholesterol levels, compared with noncarriers. In all, 915 people received a dementia diagnosis, of whom 739 received a diagnosis of Alzheimer’s disease. The other 2,644 participants died free from dementia. The median follow-up was 14.1 years.
“Dementia risk was significantly higher among participants at high or intermediate APOE risk, compared with those at low APOE risk,” the researchers said. In addition, the risk of dementia increased in participants who had fewer protective factors. Those with 0-2 protective factors had a 29% higher risk of dementia, compared with participants with 5 or 6 protective factors, after adjusting for age, sex, level of education, parental history of dementia, history of stroke, systolic blood pressure, and total and high-density lipoprotein cholesterol.
Lifestyle benefits tended to be greater in younger participants
“APOE genotype significantly modified the association between protective factors and dementia,” the authors said. Compared with participants with protective modifiable risk profiles, participants with unfavorable modifiable risk profiles had greater risk for dementia in the low–APOE risk group (hazard ratio, 2.51) and intermediate–APOE risk group (HR, 1.39), but not in the high–APOE risk group.
“Protective associations of favorable risk profiles against dementia tended to be stronger in younger individuals than in older individuals and were most pronounced for younger individuals at low APOE risk,” Dr. Licher and colleagues said. In a sensitivity analysis that used a polygenic risk score for Alzheimer’s disease based on 27 variants other than APOE to determine participants’ genetic risk, the patterns were “attenuated yet largely comparable,” they wrote. Patterns also remained consistent when the researchers used an ideal cardiovascular health score to indicate modifiable health profiles.
“Our results confirm that individuals with a favorable profile have a lower risk of dementia than those with intermediate or unfavorable profiles based on modifiable risk factors,” they said. Unlike in a subgroup analysis of data from the FINGER study, however, “this study found that a favorable profile could not offset high APOE risk.”
The findings may have implications for clinical trial design and suggest that APOE4 carriers may need to be targeted earlier in the disease process to influence their risk for dementia.
“On the positive side, results from this study show that avoiding an unhealthy lifestyle could potentially prevent or postpone the onset of dementia in most individuals in the population (73%), namely those at low and intermediate genetic risk,” the investigators wrote. “Among these, the majority were categorized has having a favorable profile (66%), yet room for improvement is still substantial.”
The study lacked data on hearing impairment and did not capture shifts to more adverse or optimal lifestyles during follow-up. In addition, the results are based on relatively small samples in each risk category, and the estimates had wide confidence intervals. The population was older and mostly of European descent, which limits the generalizability of the findings, the authors noted.
Lifestyle factors may benefit only people with low genetic risk
“The authors’ key finding was that modifiable lifestyle risk factors were able to reduce dementia risk only in people who did not have an APOE4 allele and hence were at lower genetic risk,” said Kenneth Rockwood, MD, professor of geriatric medicine and neurology at Dalhousie University in Halifax, N.S., and his coauthors, in an accompanying editorial.
The findings contrast with those of another recent population-based study using data from the UK Biobank (JAMA. 2019;322[5]:430-7. doi: 10.1001/jama.2019.9879), which suggested that modifiable factors affect dementia risk regardless of genetic risk.
Together, these studies “tell us that ... we must better understand outcomes in those most at risk,” they said. “We might begin by recognizing that aging is essential, rather than incidental, to dementia disease expression.” Future research should focus on people living with frailty, who often are excluded from trials and are at high risk for dementia. Older adults who develop delirium also may be an ideal target group of patients at increased risk for dementia.
“Reducing the extent of disease expression in people prone to developing dementia late in life is difficult. Studies investigating whether dementia can be prevented at all, such as the Rotterdam study, and then whether it can be prevented in the people at greatest risk, can be commended for their clear-eyed approach,” Dr. Rockwood and colleagues said.
The Rotterdam Study is funded by Erasmus Medical Center and University, as well as a variety of Dutch organizations, institutes, and government ministries, and the European Commission. The authors had no competing interests.
Dr. Rockwood is president and chief science officer of DGI Clinical, which has contracts with pharmaceutical and device manufacturers related to individualized outcome measurement.
SOURCES: Licher S et al. Nat Med. 2019 Aug 26. doi: 10.1038/s41591-019-0547-7; and Rockwood K et al. Nat Med. 2019 Aug 26. doi: 10.1038/s41591-019-0575-3.
The study by Dr. Licher and associates shows a clinically significant impact of a healthy lifestyle in reducing dementia. But what is surprising is that the effect was not seen in genetically higher-risk people.
If anything, the results strengthen our recommendations to people interested in lowering their risk for dementia with lifestyle modification. Bear in mind that APOE testing is not done routinely, so the vast majority of our patients do not know their APOE genotype. Since a healthy lifestyle can benefit the majority of the population (around 75%), even if it is less or ineffective in the APOE4 carrier group (about 25% of the population), it is certainly something to recommend. Of course, health care professionals already recommend heart healthy habits, which have an equivalent benefit, and sadly, adherence is relatively low. Adding that lifestyle modification may help prevent dementia might improve patient compliance. Starting healthy lifestyles as early in life as possible may be the key. It is less effective if we wait until we already have memory loss.
Finally, the study results regard relative risk, a concept that many fail to fully grasp. A person can still get dementia in any of the categories, including the “best one” (low genetic and lifestyle risk). It’s a matter of the odds being better or worse, but there is no guarantee of a positive or negative outcome.
Richard J. Caselli, MD, is professor of neurology at the Mayo Clinic Arizona in Scottsdale and associate director and clinical core director of the Arizona Alzheimer’s Disease Center, Phoenix. He made these comments in an interview.
The study by Dr. Licher and associates shows a clinically significant impact of a healthy lifestyle in reducing dementia. But what is surprising is that the effect was not seen in genetically higher-risk people.
If anything, the results strengthen our recommendations to people interested in lowering their risk for dementia with lifestyle modification. Bear in mind that APOE testing is not done routinely, so the vast majority of our patients do not know their APOE genotype. Since a healthy lifestyle can benefit the majority of the population (around 75%), even if it is less or ineffective in the APOE4 carrier group (about 25% of the population), it is certainly something to recommend. Of course, health care professionals already recommend heart healthy habits, which have an equivalent benefit, and sadly, adherence is relatively low. Adding that lifestyle modification may help prevent dementia might improve patient compliance. Starting healthy lifestyles as early in life as possible may be the key. It is less effective if we wait until we already have memory loss.
Finally, the study results regard relative risk, a concept that many fail to fully grasp. A person can still get dementia in any of the categories, including the “best one” (low genetic and lifestyle risk). It’s a matter of the odds being better or worse, but there is no guarantee of a positive or negative outcome.
Richard J. Caselli, MD, is professor of neurology at the Mayo Clinic Arizona in Scottsdale and associate director and clinical core director of the Arizona Alzheimer’s Disease Center, Phoenix. He made these comments in an interview.
The study by Dr. Licher and associates shows a clinically significant impact of a healthy lifestyle in reducing dementia. But what is surprising is that the effect was not seen in genetically higher-risk people.
If anything, the results strengthen our recommendations to people interested in lowering their risk for dementia with lifestyle modification. Bear in mind that APOE testing is not done routinely, so the vast majority of our patients do not know their APOE genotype. Since a healthy lifestyle can benefit the majority of the population (around 75%), even if it is less or ineffective in the APOE4 carrier group (about 25% of the population), it is certainly something to recommend. Of course, health care professionals already recommend heart healthy habits, which have an equivalent benefit, and sadly, adherence is relatively low. Adding that lifestyle modification may help prevent dementia might improve patient compliance. Starting healthy lifestyles as early in life as possible may be the key. It is less effective if we wait until we already have memory loss.
Finally, the study results regard relative risk, a concept that many fail to fully grasp. A person can still get dementia in any of the categories, including the “best one” (low genetic and lifestyle risk). It’s a matter of the odds being better or worse, but there is no guarantee of a positive or negative outcome.
Richard J. Caselli, MD, is professor of neurology at the Mayo Clinic Arizona in Scottsdale and associate director and clinical core director of the Arizona Alzheimer’s Disease Center, Phoenix. He made these comments in an interview.
But among people at high genetic risk for dementia, these potentially modifiable factors – not smoking, not having depression or diabetes, getting regular physical activity, avoiding social isolation, and following a healthy diet – may not have protective associations, according to research published in Nature Medicine.
Recent analyses have indicated that eliminating known modifiable risk factors for dementia at a population level could prevent one-third of dementia cases, but prevention trials “have yielded inconsistent results so far,” wrote first author Silvan Licher, MD, of the department of epidemiology at Erasmus University Medical Center Rotterdam (the Netherlands) and his colleagues.
“Prior studies have mostly focused on the risk of dementia associated with an individual protective factor, yet the combination of multiple factors may yield more beneficial effects than the individual parts,” they wrote. “Combining data about a number of factors is also important because it takes into account the multifactorial nature of late-life dementia. We used data from the Rotterdam Study to determine to what extent a favorable profile based on modifiable risk factors is associated with a lower risk of dementia among individuals at low, intermediate, or high genetic risk.”
Grouped by APOE genotype
Patients who were apolipoprotein E epsilon-4 allele (APOE4) carriers (i.e., APOE2 and 4, APOE3 and 4, or two APOE4) were classified as having high genetic risk (n = 1,747). Other APOE genotypes were considered intermediate risk (n = 3,718 with two APOE3 alleles) or low risk (n = 887 with either two APOE2 alleles or APOE2 and 3).
The researchers measured six potentially modifiable lifestyle or health factors that “have been implicated in a lower risk of dementia.” Modifiable risk scores ranged from 0 to 6. Participants were classified as having an unfavorable profile (0-2 protective factors), an intermediate profile (3-4 protective factors), or a favorable profile (5-6 factors).
The researchers calculated the relative risk of developing dementia using a Cox proportional hazards model and the absolutely risk using competing risk models.
In all, 56.2% of the participants were women, the average age was about 69 years, and patient characteristics were similar across the categories of APOE risk. APOE4 carriers received dementia diagnoses at a younger age, more often had a parental history of dementia, and had higher total cholesterol levels, compared with noncarriers. In all, 915 people received a dementia diagnosis, of whom 739 received a diagnosis of Alzheimer’s disease. The other 2,644 participants died free from dementia. The median follow-up was 14.1 years.
“Dementia risk was significantly higher among participants at high or intermediate APOE risk, compared with those at low APOE risk,” the researchers said. In addition, the risk of dementia increased in participants who had fewer protective factors. Those with 0-2 protective factors had a 29% higher risk of dementia, compared with participants with 5 or 6 protective factors, after adjusting for age, sex, level of education, parental history of dementia, history of stroke, systolic blood pressure, and total and high-density lipoprotein cholesterol.
Lifestyle benefits tended to be greater in younger participants
“APOE genotype significantly modified the association between protective factors and dementia,” the authors said. Compared with participants with protective modifiable risk profiles, participants with unfavorable modifiable risk profiles had greater risk for dementia in the low–APOE risk group (hazard ratio, 2.51) and intermediate–APOE risk group (HR, 1.39), but not in the high–APOE risk group.
“Protective associations of favorable risk profiles against dementia tended to be stronger in younger individuals than in older individuals and were most pronounced for younger individuals at low APOE risk,” Dr. Licher and colleagues said. In a sensitivity analysis that used a polygenic risk score for Alzheimer’s disease based on 27 variants other than APOE to determine participants’ genetic risk, the patterns were “attenuated yet largely comparable,” they wrote. Patterns also remained consistent when the researchers used an ideal cardiovascular health score to indicate modifiable health profiles.
“Our results confirm that individuals with a favorable profile have a lower risk of dementia than those with intermediate or unfavorable profiles based on modifiable risk factors,” they said. Unlike in a subgroup analysis of data from the FINGER study, however, “this study found that a favorable profile could not offset high APOE risk.”
The findings may have implications for clinical trial design and suggest that APOE4 carriers may need to be targeted earlier in the disease process to influence their risk for dementia.
“On the positive side, results from this study show that avoiding an unhealthy lifestyle could potentially prevent or postpone the onset of dementia in most individuals in the population (73%), namely those at low and intermediate genetic risk,” the investigators wrote. “Among these, the majority were categorized has having a favorable profile (66%), yet room for improvement is still substantial.”
The study lacked data on hearing impairment and did not capture shifts to more adverse or optimal lifestyles during follow-up. In addition, the results are based on relatively small samples in each risk category, and the estimates had wide confidence intervals. The population was older and mostly of European descent, which limits the generalizability of the findings, the authors noted.
Lifestyle factors may benefit only people with low genetic risk
“The authors’ key finding was that modifiable lifestyle risk factors were able to reduce dementia risk only in people who did not have an APOE4 allele and hence were at lower genetic risk,” said Kenneth Rockwood, MD, professor of geriatric medicine and neurology at Dalhousie University in Halifax, N.S., and his coauthors, in an accompanying editorial.
The findings contrast with those of another recent population-based study using data from the UK Biobank (JAMA. 2019;322[5]:430-7. doi: 10.1001/jama.2019.9879), which suggested that modifiable factors affect dementia risk regardless of genetic risk.
Together, these studies “tell us that ... we must better understand outcomes in those most at risk,” they said. “We might begin by recognizing that aging is essential, rather than incidental, to dementia disease expression.” Future research should focus on people living with frailty, who often are excluded from trials and are at high risk for dementia. Older adults who develop delirium also may be an ideal target group of patients at increased risk for dementia.
“Reducing the extent of disease expression in people prone to developing dementia late in life is difficult. Studies investigating whether dementia can be prevented at all, such as the Rotterdam study, and then whether it can be prevented in the people at greatest risk, can be commended for their clear-eyed approach,” Dr. Rockwood and colleagues said.
The Rotterdam Study is funded by Erasmus Medical Center and University, as well as a variety of Dutch organizations, institutes, and government ministries, and the European Commission. The authors had no competing interests.
Dr. Rockwood is president and chief science officer of DGI Clinical, which has contracts with pharmaceutical and device manufacturers related to individualized outcome measurement.
SOURCES: Licher S et al. Nat Med. 2019 Aug 26. doi: 10.1038/s41591-019-0547-7; and Rockwood K et al. Nat Med. 2019 Aug 26. doi: 10.1038/s41591-019-0575-3.
But among people at high genetic risk for dementia, these potentially modifiable factors – not smoking, not having depression or diabetes, getting regular physical activity, avoiding social isolation, and following a healthy diet – may not have protective associations, according to research published in Nature Medicine.
Recent analyses have indicated that eliminating known modifiable risk factors for dementia at a population level could prevent one-third of dementia cases, but prevention trials “have yielded inconsistent results so far,” wrote first author Silvan Licher, MD, of the department of epidemiology at Erasmus University Medical Center Rotterdam (the Netherlands) and his colleagues.
“Prior studies have mostly focused on the risk of dementia associated with an individual protective factor, yet the combination of multiple factors may yield more beneficial effects than the individual parts,” they wrote. “Combining data about a number of factors is also important because it takes into account the multifactorial nature of late-life dementia. We used data from the Rotterdam Study to determine to what extent a favorable profile based on modifiable risk factors is associated with a lower risk of dementia among individuals at low, intermediate, or high genetic risk.”
Grouped by APOE genotype
Patients who were apolipoprotein E epsilon-4 allele (APOE4) carriers (i.e., APOE2 and 4, APOE3 and 4, or two APOE4) were classified as having high genetic risk (n = 1,747). Other APOE genotypes were considered intermediate risk (n = 3,718 with two APOE3 alleles) or low risk (n = 887 with either two APOE2 alleles or APOE2 and 3).
The researchers measured six potentially modifiable lifestyle or health factors that “have been implicated in a lower risk of dementia.” Modifiable risk scores ranged from 0 to 6. Participants were classified as having an unfavorable profile (0-2 protective factors), an intermediate profile (3-4 protective factors), or a favorable profile (5-6 factors).
The researchers calculated the relative risk of developing dementia using a Cox proportional hazards model and the absolutely risk using competing risk models.
In all, 56.2% of the participants were women, the average age was about 69 years, and patient characteristics were similar across the categories of APOE risk. APOE4 carriers received dementia diagnoses at a younger age, more often had a parental history of dementia, and had higher total cholesterol levels, compared with noncarriers. In all, 915 people received a dementia diagnosis, of whom 739 received a diagnosis of Alzheimer’s disease. The other 2,644 participants died free from dementia. The median follow-up was 14.1 years.
“Dementia risk was significantly higher among participants at high or intermediate APOE risk, compared with those at low APOE risk,” the researchers said. In addition, the risk of dementia increased in participants who had fewer protective factors. Those with 0-2 protective factors had a 29% higher risk of dementia, compared with participants with 5 or 6 protective factors, after adjusting for age, sex, level of education, parental history of dementia, history of stroke, systolic blood pressure, and total and high-density lipoprotein cholesterol.
Lifestyle benefits tended to be greater in younger participants
“APOE genotype significantly modified the association between protective factors and dementia,” the authors said. Compared with participants with protective modifiable risk profiles, participants with unfavorable modifiable risk profiles had greater risk for dementia in the low–APOE risk group (hazard ratio, 2.51) and intermediate–APOE risk group (HR, 1.39), but not in the high–APOE risk group.
“Protective associations of favorable risk profiles against dementia tended to be stronger in younger individuals than in older individuals and were most pronounced for younger individuals at low APOE risk,” Dr. Licher and colleagues said. In a sensitivity analysis that used a polygenic risk score for Alzheimer’s disease based on 27 variants other than APOE to determine participants’ genetic risk, the patterns were “attenuated yet largely comparable,” they wrote. Patterns also remained consistent when the researchers used an ideal cardiovascular health score to indicate modifiable health profiles.
“Our results confirm that individuals with a favorable profile have a lower risk of dementia than those with intermediate or unfavorable profiles based on modifiable risk factors,” they said. Unlike in a subgroup analysis of data from the FINGER study, however, “this study found that a favorable profile could not offset high APOE risk.”
The findings may have implications for clinical trial design and suggest that APOE4 carriers may need to be targeted earlier in the disease process to influence their risk for dementia.
“On the positive side, results from this study show that avoiding an unhealthy lifestyle could potentially prevent or postpone the onset of dementia in most individuals in the population (73%), namely those at low and intermediate genetic risk,” the investigators wrote. “Among these, the majority were categorized has having a favorable profile (66%), yet room for improvement is still substantial.”
The study lacked data on hearing impairment and did not capture shifts to more adverse or optimal lifestyles during follow-up. In addition, the results are based on relatively small samples in each risk category, and the estimates had wide confidence intervals. The population was older and mostly of European descent, which limits the generalizability of the findings, the authors noted.
Lifestyle factors may benefit only people with low genetic risk
“The authors’ key finding was that modifiable lifestyle risk factors were able to reduce dementia risk only in people who did not have an APOE4 allele and hence were at lower genetic risk,” said Kenneth Rockwood, MD, professor of geriatric medicine and neurology at Dalhousie University in Halifax, N.S., and his coauthors, in an accompanying editorial.
The findings contrast with those of another recent population-based study using data from the UK Biobank (JAMA. 2019;322[5]:430-7. doi: 10.1001/jama.2019.9879), which suggested that modifiable factors affect dementia risk regardless of genetic risk.
Together, these studies “tell us that ... we must better understand outcomes in those most at risk,” they said. “We might begin by recognizing that aging is essential, rather than incidental, to dementia disease expression.” Future research should focus on people living with frailty, who often are excluded from trials and are at high risk for dementia. Older adults who develop delirium also may be an ideal target group of patients at increased risk for dementia.
“Reducing the extent of disease expression in people prone to developing dementia late in life is difficult. Studies investigating whether dementia can be prevented at all, such as the Rotterdam study, and then whether it can be prevented in the people at greatest risk, can be commended for their clear-eyed approach,” Dr. Rockwood and colleagues said.
The Rotterdam Study is funded by Erasmus Medical Center and University, as well as a variety of Dutch organizations, institutes, and government ministries, and the European Commission. The authors had no competing interests.
Dr. Rockwood is president and chief science officer of DGI Clinical, which has contracts with pharmaceutical and device manufacturers related to individualized outcome measurement.
SOURCES: Licher S et al. Nat Med. 2019 Aug 26. doi: 10.1038/s41591-019-0547-7; and Rockwood K et al. Nat Med. 2019 Aug 26. doi: 10.1038/s41591-019-0575-3.
FROM NATURE MEDICINE
Intranasal midazolam as first line for status epilepticus
BANGKOK – Lara Kay, MD, said at the International Epilepsy Congress.
Why? Because status epilepticus is a major medical emergency. It’s associated with substantial morbidity and mortality. And of the various factors that influence outcome in status epilepticus – including age, underlying etiology, and level of consciousness – only one is potentially within physician control: time to treatment, she noted at the congress sponsored by the International League Against Epilepsy.
“Time is brain,” observed Dr. Kay, a neurologist at the epilepsy center at University Hospital Frankfurt.
While intravenous benzodiazepines – for example, lorazepam at 2-4 mg – are widely accepted as the time-honored first-line treatment for status epilepticus, trying to place a line in a patient experiencing this emergency can be a tricky, time-consuming business. Multiple studies have demonstrated that various nonintravenous formulations of benzodiazepines, such as rectal diazepam or buccal or intramuscular midazolam, can be administered much faster and are as effective as intravenous benzodiazepines. But buccal midazolam is quite expensive in Germany, and the ready-to-use intramuscular midazolam applicator that’s available in the United States isn’t marketed in Germany. So several years ago Dr. Kay and her fellow neurologists started having their university hospital pharmacy manufacture intranasal midazolam.
Dr. Kay presented an observational study of 42 consecutive patients with status epilepticus who received intranasal midazolam as first-line treatment. The patients had a mean age of nearly 53 years and 23 were women. The starting dose was 2.5 mg per nostril, moving up to 5 mg per nostril after waiting 5 minutes in initial nonresponders.
Status epilepticus ceased both clinically and by EEG in 24 of the 42 patients, or 57%, in an average of 5 minutes after administration of the intranasal medication at a mean dose of 5.6 mg. Nonresponders received a mean dose of 7.5 mg. There were no significant differences between responders and nonresponders in terms of the proportion presenting with preexisting epilepsy or the epilepsy etiology. However, responders presented at a mean of 54 minutes in status epilepticus, while nonresponders had been in status for 17 minutes.
The 57% response rate with intranasal midazolam is comparable with other investigators’ reported success rates using other benzodiazepines and routes of administration, she noted.
Session cochair Gregory Krauss, MD, commented that he thought the Frankfurt neurologists may have been too cautious in their dosing of intranasal midazolam for status epilepticus.
“Often in the U.S. 5 mg is initially used in each nostril,” according to Dr. Krauss, professor of neurology at Johns Hopkins University, Baltimore.
Dr. Kay reported having no financial conflicts of interest regarding her study.
SOURCE: Kay L et al. IEC 2019, Abstract P029.
BANGKOK – Lara Kay, MD, said at the International Epilepsy Congress.
Why? Because status epilepticus is a major medical emergency. It’s associated with substantial morbidity and mortality. And of the various factors that influence outcome in status epilepticus – including age, underlying etiology, and level of consciousness – only one is potentially within physician control: time to treatment, she noted at the congress sponsored by the International League Against Epilepsy.
“Time is brain,” observed Dr. Kay, a neurologist at the epilepsy center at University Hospital Frankfurt.
While intravenous benzodiazepines – for example, lorazepam at 2-4 mg – are widely accepted as the time-honored first-line treatment for status epilepticus, trying to place a line in a patient experiencing this emergency can be a tricky, time-consuming business. Multiple studies have demonstrated that various nonintravenous formulations of benzodiazepines, such as rectal diazepam or buccal or intramuscular midazolam, can be administered much faster and are as effective as intravenous benzodiazepines. But buccal midazolam is quite expensive in Germany, and the ready-to-use intramuscular midazolam applicator that’s available in the United States isn’t marketed in Germany. So several years ago Dr. Kay and her fellow neurologists started having their university hospital pharmacy manufacture intranasal midazolam.
Dr. Kay presented an observational study of 42 consecutive patients with status epilepticus who received intranasal midazolam as first-line treatment. The patients had a mean age of nearly 53 years and 23 were women. The starting dose was 2.5 mg per nostril, moving up to 5 mg per nostril after waiting 5 minutes in initial nonresponders.
Status epilepticus ceased both clinically and by EEG in 24 of the 42 patients, or 57%, in an average of 5 minutes after administration of the intranasal medication at a mean dose of 5.6 mg. Nonresponders received a mean dose of 7.5 mg. There were no significant differences between responders and nonresponders in terms of the proportion presenting with preexisting epilepsy or the epilepsy etiology. However, responders presented at a mean of 54 minutes in status epilepticus, while nonresponders had been in status for 17 minutes.
The 57% response rate with intranasal midazolam is comparable with other investigators’ reported success rates using other benzodiazepines and routes of administration, she noted.
Session cochair Gregory Krauss, MD, commented that he thought the Frankfurt neurologists may have been too cautious in their dosing of intranasal midazolam for status epilepticus.
“Often in the U.S. 5 mg is initially used in each nostril,” according to Dr. Krauss, professor of neurology at Johns Hopkins University, Baltimore.
Dr. Kay reported having no financial conflicts of interest regarding her study.
SOURCE: Kay L et al. IEC 2019, Abstract P029.
BANGKOK – Lara Kay, MD, said at the International Epilepsy Congress.
Why? Because status epilepticus is a major medical emergency. It’s associated with substantial morbidity and mortality. And of the various factors that influence outcome in status epilepticus – including age, underlying etiology, and level of consciousness – only one is potentially within physician control: time to treatment, she noted at the congress sponsored by the International League Against Epilepsy.
“Time is brain,” observed Dr. Kay, a neurologist at the epilepsy center at University Hospital Frankfurt.
While intravenous benzodiazepines – for example, lorazepam at 2-4 mg – are widely accepted as the time-honored first-line treatment for status epilepticus, trying to place a line in a patient experiencing this emergency can be a tricky, time-consuming business. Multiple studies have demonstrated that various nonintravenous formulations of benzodiazepines, such as rectal diazepam or buccal or intramuscular midazolam, can be administered much faster and are as effective as intravenous benzodiazepines. But buccal midazolam is quite expensive in Germany, and the ready-to-use intramuscular midazolam applicator that’s available in the United States isn’t marketed in Germany. So several years ago Dr. Kay and her fellow neurologists started having their university hospital pharmacy manufacture intranasal midazolam.
Dr. Kay presented an observational study of 42 consecutive patients with status epilepticus who received intranasal midazolam as first-line treatment. The patients had a mean age of nearly 53 years and 23 were women. The starting dose was 2.5 mg per nostril, moving up to 5 mg per nostril after waiting 5 minutes in initial nonresponders.
Status epilepticus ceased both clinically and by EEG in 24 of the 42 patients, or 57%, in an average of 5 minutes after administration of the intranasal medication at a mean dose of 5.6 mg. Nonresponders received a mean dose of 7.5 mg. There were no significant differences between responders and nonresponders in terms of the proportion presenting with preexisting epilepsy or the epilepsy etiology. However, responders presented at a mean of 54 minutes in status epilepticus, while nonresponders had been in status for 17 minutes.
The 57% response rate with intranasal midazolam is comparable with other investigators’ reported success rates using other benzodiazepines and routes of administration, she noted.
Session cochair Gregory Krauss, MD, commented that he thought the Frankfurt neurologists may have been too cautious in their dosing of intranasal midazolam for status epilepticus.
“Often in the U.S. 5 mg is initially used in each nostril,” according to Dr. Krauss, professor of neurology at Johns Hopkins University, Baltimore.
Dr. Kay reported having no financial conflicts of interest regarding her study.
SOURCE: Kay L et al. IEC 2019, Abstract P029.
REPORTING FROM IEC 2019
A practical tool predicts childhood epilepsy diagnosis
BANGKOK – A prediction tool that determines the risk of a pediatric epilepsy diagnosis eventually being made in a child who has had one or more paroxysmal events of possible epileptic origin is now available, and the clarity it provides makes life considerably easier for physicians and worried parents, Kees P. Braun, MD, PhD, said at the International Epilepsy Congress.
This prediction tool is highly practical. It relies upon certain clinical characteristics and a first interictal EEG, all information readily available at the time of the family’s first consultation with a neurologist or pediatrician with access to EEG, noted Dr. Braun, professor of neurology at Utrecht (the Netherlands) University.
The tool is freely available online (http://epilepsypredictiontools.info/first-consultation). The details of how Dr. Braun and coinvestigators developed the prediction tool have been published (Pediatrics. 2018 Dec;142[6]:e20180931. doi: 10.1542/peds.2018-0931), he said at the congress sponsored by the International League Against Epilepsy.
Early and accurate diagnosis or exclusion of epilepsy following a suspicious paroxysmal event deserves to be a high priority. Diagnostic delay is common, with resultant unrecognized recurrent epileptic seizures that can cause cognitive and behavioral impairments. And overdiagnosis of pediatric epilepsy unnecessarily exposes a child to the risks of antiepileptic drug therapy, not to mention the potential social stigma.
The predictive tool was developed through retrospective, multidimensional analysis of detailed data on 451 children who visited the outpatient pediatric neurology clinic at University Medical Center Utrecht for a diagnostic work-up after one or more paroxysmal events that might have been seizures, all of whom were subsequently followed for a year or longer. The resultant predictive model was then independently validated in a separate cohort of 187 children seen for the same reason at another Dutch university.
The model had an area under the receiver operating characteristic curve of 0.86, which statisticians consider to be excellent discriminatory power. The tool’s sensitivity and specificity varied according to the diagnostic probability threshold selected by the parents and physicians. For example, the predictive tool had a sensitivity of 18%, specificity of 99%, positive predictive value of 94%, and negative predictive value of 80% for identification of individuals with a greater than 80% probability of being diagnosed with epilepsy. For identification of all patients with a greater than 20% likelihood of receiving the diagnosis, the sensitivity was 73%, specificity 82%, positive predictive value 76%, and negative predictive value 79%.
The clinical characteristics incorporated in the predictive model include age at first seizure, gender, details of the paroxysmal event, and specifics of the child’s medical history. The relevant features of the standard interictal EEG recorded at the time of consultation include the presence or absence of focal epileptiform abnormalities if focal spikes or spike-wave complexes were detected, generalized epileptiform abnormalities in the presence of generalized spikes or spike-wave complexes, and nonspecific nonepileptiform abnormalities.
Future predictive refinements are under study
Dr. Braun and coworkers have reported that examining EEG functional network characteristics – that is, the functional networks of correlated brain activity in an individual patient’s brain – improves the EEG’s predictive value for epilepsy (PLoS One. 2013;8[4]:e59764. doi: 10.1371/journal.pone.0059764), a conclusion further reinforced in their systematic review and meta-analysis incorporating 11 additional studies (PLoS One. 2014 Dec 10;9[12]:e114606. doi: 10.1371/journal.pone.0114606).
In addition, the Dutch investigators have shown that ripples superimposed on rolandic spikes seen in scalp EEG recordings have prognostic significance. An absence of ripples superimposed on rolandic spikes identified children without epilepsy. In contrast, more than five ripples predicted atypical and symptomatic rolandic epilepsy with a substantial seizure risk warranting consideration of antiepileptic drug therapy (Epilepsia. 2016 Jul;57[7]:1179-89).
A Boston group using a fully automated spike ripple detector subsequently confirmed that ripples occurring in conjunction with epileptiform discharges on scalp EEG constitute a noninvasive biomarker for seizure risk that outperforms analysis of spikes alone and could potentially be useful in guiding medication tapering decisions in children (Brain. 2019 May 1;142[5]:1296-1309).
Dr. Braun reported having no financial conflicts regarding his presentation.
BANGKOK – A prediction tool that determines the risk of a pediatric epilepsy diagnosis eventually being made in a child who has had one or more paroxysmal events of possible epileptic origin is now available, and the clarity it provides makes life considerably easier for physicians and worried parents, Kees P. Braun, MD, PhD, said at the International Epilepsy Congress.
This prediction tool is highly practical. It relies upon certain clinical characteristics and a first interictal EEG, all information readily available at the time of the family’s first consultation with a neurologist or pediatrician with access to EEG, noted Dr. Braun, professor of neurology at Utrecht (the Netherlands) University.
The tool is freely available online (http://epilepsypredictiontools.info/first-consultation). The details of how Dr. Braun and coinvestigators developed the prediction tool have been published (Pediatrics. 2018 Dec;142[6]:e20180931. doi: 10.1542/peds.2018-0931), he said at the congress sponsored by the International League Against Epilepsy.
Early and accurate diagnosis or exclusion of epilepsy following a suspicious paroxysmal event deserves to be a high priority. Diagnostic delay is common, with resultant unrecognized recurrent epileptic seizures that can cause cognitive and behavioral impairments. And overdiagnosis of pediatric epilepsy unnecessarily exposes a child to the risks of antiepileptic drug therapy, not to mention the potential social stigma.
The predictive tool was developed through retrospective, multidimensional analysis of detailed data on 451 children who visited the outpatient pediatric neurology clinic at University Medical Center Utrecht for a diagnostic work-up after one or more paroxysmal events that might have been seizures, all of whom were subsequently followed for a year or longer. The resultant predictive model was then independently validated in a separate cohort of 187 children seen for the same reason at another Dutch university.
The model had an area under the receiver operating characteristic curve of 0.86, which statisticians consider to be excellent discriminatory power. The tool’s sensitivity and specificity varied according to the diagnostic probability threshold selected by the parents and physicians. For example, the predictive tool had a sensitivity of 18%, specificity of 99%, positive predictive value of 94%, and negative predictive value of 80% for identification of individuals with a greater than 80% probability of being diagnosed with epilepsy. For identification of all patients with a greater than 20% likelihood of receiving the diagnosis, the sensitivity was 73%, specificity 82%, positive predictive value 76%, and negative predictive value 79%.
The clinical characteristics incorporated in the predictive model include age at first seizure, gender, details of the paroxysmal event, and specifics of the child’s medical history. The relevant features of the standard interictal EEG recorded at the time of consultation include the presence or absence of focal epileptiform abnormalities if focal spikes or spike-wave complexes were detected, generalized epileptiform abnormalities in the presence of generalized spikes or spike-wave complexes, and nonspecific nonepileptiform abnormalities.
Future predictive refinements are under study
Dr. Braun and coworkers have reported that examining EEG functional network characteristics – that is, the functional networks of correlated brain activity in an individual patient’s brain – improves the EEG’s predictive value for epilepsy (PLoS One. 2013;8[4]:e59764. doi: 10.1371/journal.pone.0059764), a conclusion further reinforced in their systematic review and meta-analysis incorporating 11 additional studies (PLoS One. 2014 Dec 10;9[12]:e114606. doi: 10.1371/journal.pone.0114606).
In addition, the Dutch investigators have shown that ripples superimposed on rolandic spikes seen in scalp EEG recordings have prognostic significance. An absence of ripples superimposed on rolandic spikes identified children without epilepsy. In contrast, more than five ripples predicted atypical and symptomatic rolandic epilepsy with a substantial seizure risk warranting consideration of antiepileptic drug therapy (Epilepsia. 2016 Jul;57[7]:1179-89).
A Boston group using a fully automated spike ripple detector subsequently confirmed that ripples occurring in conjunction with epileptiform discharges on scalp EEG constitute a noninvasive biomarker for seizure risk that outperforms analysis of spikes alone and could potentially be useful in guiding medication tapering decisions in children (Brain. 2019 May 1;142[5]:1296-1309).
Dr. Braun reported having no financial conflicts regarding his presentation.
BANGKOK – A prediction tool that determines the risk of a pediatric epilepsy diagnosis eventually being made in a child who has had one or more paroxysmal events of possible epileptic origin is now available, and the clarity it provides makes life considerably easier for physicians and worried parents, Kees P. Braun, MD, PhD, said at the International Epilepsy Congress.
This prediction tool is highly practical. It relies upon certain clinical characteristics and a first interictal EEG, all information readily available at the time of the family’s first consultation with a neurologist or pediatrician with access to EEG, noted Dr. Braun, professor of neurology at Utrecht (the Netherlands) University.
The tool is freely available online (http://epilepsypredictiontools.info/first-consultation). The details of how Dr. Braun and coinvestigators developed the prediction tool have been published (Pediatrics. 2018 Dec;142[6]:e20180931. doi: 10.1542/peds.2018-0931), he said at the congress sponsored by the International League Against Epilepsy.
Early and accurate diagnosis or exclusion of epilepsy following a suspicious paroxysmal event deserves to be a high priority. Diagnostic delay is common, with resultant unrecognized recurrent epileptic seizures that can cause cognitive and behavioral impairments. And overdiagnosis of pediatric epilepsy unnecessarily exposes a child to the risks of antiepileptic drug therapy, not to mention the potential social stigma.
The predictive tool was developed through retrospective, multidimensional analysis of detailed data on 451 children who visited the outpatient pediatric neurology clinic at University Medical Center Utrecht for a diagnostic work-up after one or more paroxysmal events that might have been seizures, all of whom were subsequently followed for a year or longer. The resultant predictive model was then independently validated in a separate cohort of 187 children seen for the same reason at another Dutch university.
The model had an area under the receiver operating characteristic curve of 0.86, which statisticians consider to be excellent discriminatory power. The tool’s sensitivity and specificity varied according to the diagnostic probability threshold selected by the parents and physicians. For example, the predictive tool had a sensitivity of 18%, specificity of 99%, positive predictive value of 94%, and negative predictive value of 80% for identification of individuals with a greater than 80% probability of being diagnosed with epilepsy. For identification of all patients with a greater than 20% likelihood of receiving the diagnosis, the sensitivity was 73%, specificity 82%, positive predictive value 76%, and negative predictive value 79%.
The clinical characteristics incorporated in the predictive model include age at first seizure, gender, details of the paroxysmal event, and specifics of the child’s medical history. The relevant features of the standard interictal EEG recorded at the time of consultation include the presence or absence of focal epileptiform abnormalities if focal spikes or spike-wave complexes were detected, generalized epileptiform abnormalities in the presence of generalized spikes or spike-wave complexes, and nonspecific nonepileptiform abnormalities.
Future predictive refinements are under study
Dr. Braun and coworkers have reported that examining EEG functional network characteristics – that is, the functional networks of correlated brain activity in an individual patient’s brain – improves the EEG’s predictive value for epilepsy (PLoS One. 2013;8[4]:e59764. doi: 10.1371/journal.pone.0059764), a conclusion further reinforced in their systematic review and meta-analysis incorporating 11 additional studies (PLoS One. 2014 Dec 10;9[12]:e114606. doi: 10.1371/journal.pone.0114606).
In addition, the Dutch investigators have shown that ripples superimposed on rolandic spikes seen in scalp EEG recordings have prognostic significance. An absence of ripples superimposed on rolandic spikes identified children without epilepsy. In contrast, more than five ripples predicted atypical and symptomatic rolandic epilepsy with a substantial seizure risk warranting consideration of antiepileptic drug therapy (Epilepsia. 2016 Jul;57[7]:1179-89).
A Boston group using a fully automated spike ripple detector subsequently confirmed that ripples occurring in conjunction with epileptiform discharges on scalp EEG constitute a noninvasive biomarker for seizure risk that outperforms analysis of spikes alone and could potentially be useful in guiding medication tapering decisions in children (Brain. 2019 May 1;142[5]:1296-1309).
Dr. Braun reported having no financial conflicts regarding his presentation.
REPORTING FROM IEC 2019