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Insomnia, major depressive episode linked in U.S. soldiers
Insomnia is prevalent among U.S. soldiers, and the highest prevalence rate is among those with current major depressive episode, according to a cross-sectional analysis.
“Psychiatric disorders moderated the relationship between insomnia and memory/concentration problems, suggesting the psychiatric disorders contribute unique variance to cognitive problems,” wrote Janeese A. Brownlow, PhD, of the University of Pennsylvania, Philadelphia, and her associates. “Results highlight the importance of considering both insomnia and psychiatric disorders in the diagnosis and treatment of cognitive deficits in military soldiers.”
The researchers used the All Army Study of the Army Study to Assess Risk and Resilience in Servicemembers as their data source. They used the Composite International Diagnostic Interview (CIDI) and the Posttraumatic Stress Disorder Checklist to assess psychiatric disorders; the CIDI also helped assess cognitive problems. One of the strengths of this study was its large sample size: It had an unweighted sample of 21,449 soldiers.
. The prevalence was 82.6% among soldiers with generalized anxiety disorder and 69.7% among those with PTSD. The likelihood of having insomnia grew with the number of comorbid psychiatric disorders.
One of the limitations of the study was that many of the measures were self-reported; for example, the psychiatric diagnoses and the determinations regarding insomnia were based on surveys and questionnaires rather than clinical interviews and assessments. Furthermore, the absence of a comprehensive neurocognitive battery might have limited the study’s ability to assess cognitive problems. Nevertheless, the researchers wrote, “addressing insomnia may increase resiliency and the ability to perform and cope with the complexities of active duty.”
Read more about the study in the Journal of Affective Disorders.
Insomnia is prevalent among U.S. soldiers, and the highest prevalence rate is among those with current major depressive episode, according to a cross-sectional analysis.
“Psychiatric disorders moderated the relationship between insomnia and memory/concentration problems, suggesting the psychiatric disorders contribute unique variance to cognitive problems,” wrote Janeese A. Brownlow, PhD, of the University of Pennsylvania, Philadelphia, and her associates. “Results highlight the importance of considering both insomnia and psychiatric disorders in the diagnosis and treatment of cognitive deficits in military soldiers.”
The researchers used the All Army Study of the Army Study to Assess Risk and Resilience in Servicemembers as their data source. They used the Composite International Diagnostic Interview (CIDI) and the Posttraumatic Stress Disorder Checklist to assess psychiatric disorders; the CIDI also helped assess cognitive problems. One of the strengths of this study was its large sample size: It had an unweighted sample of 21,449 soldiers.
. The prevalence was 82.6% among soldiers with generalized anxiety disorder and 69.7% among those with PTSD. The likelihood of having insomnia grew with the number of comorbid psychiatric disorders.
One of the limitations of the study was that many of the measures were self-reported; for example, the psychiatric diagnoses and the determinations regarding insomnia were based on surveys and questionnaires rather than clinical interviews and assessments. Furthermore, the absence of a comprehensive neurocognitive battery might have limited the study’s ability to assess cognitive problems. Nevertheless, the researchers wrote, “addressing insomnia may increase resiliency and the ability to perform and cope with the complexities of active duty.”
Read more about the study in the Journal of Affective Disorders.
Insomnia is prevalent among U.S. soldiers, and the highest prevalence rate is among those with current major depressive episode, according to a cross-sectional analysis.
“Psychiatric disorders moderated the relationship between insomnia and memory/concentration problems, suggesting the psychiatric disorders contribute unique variance to cognitive problems,” wrote Janeese A. Brownlow, PhD, of the University of Pennsylvania, Philadelphia, and her associates. “Results highlight the importance of considering both insomnia and psychiatric disorders in the diagnosis and treatment of cognitive deficits in military soldiers.”
The researchers used the All Army Study of the Army Study to Assess Risk and Resilience in Servicemembers as their data source. They used the Composite International Diagnostic Interview (CIDI) and the Posttraumatic Stress Disorder Checklist to assess psychiatric disorders; the CIDI also helped assess cognitive problems. One of the strengths of this study was its large sample size: It had an unweighted sample of 21,449 soldiers.
. The prevalence was 82.6% among soldiers with generalized anxiety disorder and 69.7% among those with PTSD. The likelihood of having insomnia grew with the number of comorbid psychiatric disorders.
One of the limitations of the study was that many of the measures were self-reported; for example, the psychiatric diagnoses and the determinations regarding insomnia were based on surveys and questionnaires rather than clinical interviews and assessments. Furthermore, the absence of a comprehensive neurocognitive battery might have limited the study’s ability to assess cognitive problems. Nevertheless, the researchers wrote, “addressing insomnia may increase resiliency and the ability to perform and cope with the complexities of active duty.”
Read more about the study in the Journal of Affective Disorders.
FROM JOURNAL OF AFFECTIVE DISORDERS
Mental health reporting laws: A false answer to gun violence
The tragic Feb. 14 massacre at Marjory Stoneman Douglas High School in Parkland, Fla., which left 17 people dead and 15 hospitalized, was the 34th1 U.S. mass shooting of 2018. Last year was a record year, with 346 mass shootings.2 In response to these tragedies, mental health providers are being looked at to help solve the problem. In fact, the day after the Florida shooting, President Trump tweeted: “So many signs that the Florida shooter was mentally disturbed ... Must always report such instances to authorities, again and again!”3
This response is reminiscent of how the state of New York reacted to the 2012 Sandy Hook massacre in Newtown, Conn. One month after the shooting, the NY SAFE (New York Secure Ammunition and Firearms Enforcement) Act was passed, which, among its measures, requires mental health providers to report individuals “likely” to engage in harm.4 The act represented an attempt to empower mental health providers to report high-risk, potentially violent individuals to the appropriate authorities.
However, we must acknowledge that some practical difficulties arise with such mandates. First is the reality that the overwhelming majority of patients in therapy who endorse violent impulses do not go on to commit harm toward themselves or others, nor do they break the law. Up to 25% of teenagers have thoughts of killing themselves6; 41% of depressed mothers have experienced thoughts of harming their children7; and up to 68% of individuals have homicidal fantasies.8 It would be difficult to argue that we would be doing our due diligence in reporting all patients who share such thoughts. Even if we agree that we ought to report only those who are at high risk for potential future violence, few guidelines are useful in stratifying risk for future violence outside of forensic settings. Prognostication is particularly difficult in cases where there is no history of previous criminal activity, as was the case with the confessed9 gunman in the Florida case. We also must acknowledge that evidence is scant suggesting that mental health treatment as a whole can reduce the incidence of mass murders. Evidence does suggest, however, that patients with serious mental illness are not involved in a majority of cases.10
Second, these types of mandates can perpetuate stigma in mental health, both potentially driving away patients who could benefit from therapy, and straining the relationships between patient and provider for those in treatment. Given the high degree of effort it takes for some populations to engage in mental health services, Indeed, it has been demonstrated many times that nothing matters more to the outcome of mental health treatment than the relationship between the providers and their patients,11 an effect that is true even for medication management.12 Being more wary of one’s treating provider may, therefore, limit the effect of treatment from the patient’s perspective. In the same vein, some therapists may rightly pause to consider whether they should be more vigilant and dutifully extract statements confirming a nonviolent mindset at every meeting, much in the way we perform suicide risk assessment to assess safety. Or, therapists could hesitate to probe for violent themes out of an underlying wish to avoid discovering something that they would have to report. Such tensions created within the therapist also may lend to suboptimal treatment.
Dr. Badre is a forensic psychiatrist in San Diego and an expert in correctional mental health. He holds teaching positions at the University of California, San Diego, and the University of San Diego. He teaches medical education, psychopharmacology, ethics in psychiatry, and correctional care. Dr. Joshi is a research track psychiatry resident at the University of California, San Diego. His current research focuses on developing novel therapeutic strategies to target cognitive impairment in schizophrenia. His interests include graduate medical education and applied bioethics.
References
1. Gun Violence Archive http://www.gunviolencearchive.org/reports/mass-shooting
2. https://www.abc15.com/news/data/mass-shootings-in-the-us-when-where-they-have-occurred-in-2018
3. https://twitter.com/realDonaldTrump/status/964110212885106689
4. http://www.nyspsych.org/index.php?option=com_content&view=article&id=73
5. https://www.politico.com/states/new-york/albany/story/2018/02/15/after-florida-school-shooting-cuomo-again-touts-safe-act-256104
6. MMWR 2004;53(2):1-96
7. J Affect Disord. 1999 Jul;54(1-2):21-8
8. Ethol Sociobiol. 1993;14(4):231-48
9. http://www.dcf.state.fl.us/newsroom/publicdocuments/Headquarters/Records20180219/Petition%20to%20Publically%20Release%20DCF%20Records.pdf
10. Ann Rev Clin Psychol. 2017 May 8;13:445-69
11. Psychotherapy Theory Res Prac. 2001;38(4):357-61
12. J Affect Disord. 2006 Jun;92(2-3):287-90
The tragic Feb. 14 massacre at Marjory Stoneman Douglas High School in Parkland, Fla., which left 17 people dead and 15 hospitalized, was the 34th1 U.S. mass shooting of 2018. Last year was a record year, with 346 mass shootings.2 In response to these tragedies, mental health providers are being looked at to help solve the problem. In fact, the day after the Florida shooting, President Trump tweeted: “So many signs that the Florida shooter was mentally disturbed ... Must always report such instances to authorities, again and again!”3
This response is reminiscent of how the state of New York reacted to the 2012 Sandy Hook massacre in Newtown, Conn. One month after the shooting, the NY SAFE (New York Secure Ammunition and Firearms Enforcement) Act was passed, which, among its measures, requires mental health providers to report individuals “likely” to engage in harm.4 The act represented an attempt to empower mental health providers to report high-risk, potentially violent individuals to the appropriate authorities.
However, we must acknowledge that some practical difficulties arise with such mandates. First is the reality that the overwhelming majority of patients in therapy who endorse violent impulses do not go on to commit harm toward themselves or others, nor do they break the law. Up to 25% of teenagers have thoughts of killing themselves6; 41% of depressed mothers have experienced thoughts of harming their children7; and up to 68% of individuals have homicidal fantasies.8 It would be difficult to argue that we would be doing our due diligence in reporting all patients who share such thoughts. Even if we agree that we ought to report only those who are at high risk for potential future violence, few guidelines are useful in stratifying risk for future violence outside of forensic settings. Prognostication is particularly difficult in cases where there is no history of previous criminal activity, as was the case with the confessed9 gunman in the Florida case. We also must acknowledge that evidence is scant suggesting that mental health treatment as a whole can reduce the incidence of mass murders. Evidence does suggest, however, that patients with serious mental illness are not involved in a majority of cases.10
Second, these types of mandates can perpetuate stigma in mental health, both potentially driving away patients who could benefit from therapy, and straining the relationships between patient and provider for those in treatment. Given the high degree of effort it takes for some populations to engage in mental health services, Indeed, it has been demonstrated many times that nothing matters more to the outcome of mental health treatment than the relationship between the providers and their patients,11 an effect that is true even for medication management.12 Being more wary of one’s treating provider may, therefore, limit the effect of treatment from the patient’s perspective. In the same vein, some therapists may rightly pause to consider whether they should be more vigilant and dutifully extract statements confirming a nonviolent mindset at every meeting, much in the way we perform suicide risk assessment to assess safety. Or, therapists could hesitate to probe for violent themes out of an underlying wish to avoid discovering something that they would have to report. Such tensions created within the therapist also may lend to suboptimal treatment.
Dr. Badre is a forensic psychiatrist in San Diego and an expert in correctional mental health. He holds teaching positions at the University of California, San Diego, and the University of San Diego. He teaches medical education, psychopharmacology, ethics in psychiatry, and correctional care. Dr. Joshi is a research track psychiatry resident at the University of California, San Diego. His current research focuses on developing novel therapeutic strategies to target cognitive impairment in schizophrenia. His interests include graduate medical education and applied bioethics.
References
1. Gun Violence Archive http://www.gunviolencearchive.org/reports/mass-shooting
2. https://www.abc15.com/news/data/mass-shootings-in-the-us-when-where-they-have-occurred-in-2018
3. https://twitter.com/realDonaldTrump/status/964110212885106689
4. http://www.nyspsych.org/index.php?option=com_content&view=article&id=73
5. https://www.politico.com/states/new-york/albany/story/2018/02/15/after-florida-school-shooting-cuomo-again-touts-safe-act-256104
6. MMWR 2004;53(2):1-96
7. J Affect Disord. 1999 Jul;54(1-2):21-8
8. Ethol Sociobiol. 1993;14(4):231-48
9. http://www.dcf.state.fl.us/newsroom/publicdocuments/Headquarters/Records20180219/Petition%20to%20Publically%20Release%20DCF%20Records.pdf
10. Ann Rev Clin Psychol. 2017 May 8;13:445-69
11. Psychotherapy Theory Res Prac. 2001;38(4):357-61
12. J Affect Disord. 2006 Jun;92(2-3):287-90
The tragic Feb. 14 massacre at Marjory Stoneman Douglas High School in Parkland, Fla., which left 17 people dead and 15 hospitalized, was the 34th1 U.S. mass shooting of 2018. Last year was a record year, with 346 mass shootings.2 In response to these tragedies, mental health providers are being looked at to help solve the problem. In fact, the day after the Florida shooting, President Trump tweeted: “So many signs that the Florida shooter was mentally disturbed ... Must always report such instances to authorities, again and again!”3
This response is reminiscent of how the state of New York reacted to the 2012 Sandy Hook massacre in Newtown, Conn. One month after the shooting, the NY SAFE (New York Secure Ammunition and Firearms Enforcement) Act was passed, which, among its measures, requires mental health providers to report individuals “likely” to engage in harm.4 The act represented an attempt to empower mental health providers to report high-risk, potentially violent individuals to the appropriate authorities.
However, we must acknowledge that some practical difficulties arise with such mandates. First is the reality that the overwhelming majority of patients in therapy who endorse violent impulses do not go on to commit harm toward themselves or others, nor do they break the law. Up to 25% of teenagers have thoughts of killing themselves6; 41% of depressed mothers have experienced thoughts of harming their children7; and up to 68% of individuals have homicidal fantasies.8 It would be difficult to argue that we would be doing our due diligence in reporting all patients who share such thoughts. Even if we agree that we ought to report only those who are at high risk for potential future violence, few guidelines are useful in stratifying risk for future violence outside of forensic settings. Prognostication is particularly difficult in cases where there is no history of previous criminal activity, as was the case with the confessed9 gunman in the Florida case. We also must acknowledge that evidence is scant suggesting that mental health treatment as a whole can reduce the incidence of mass murders. Evidence does suggest, however, that patients with serious mental illness are not involved in a majority of cases.10
Second, these types of mandates can perpetuate stigma in mental health, both potentially driving away patients who could benefit from therapy, and straining the relationships between patient and provider for those in treatment. Given the high degree of effort it takes for some populations to engage in mental health services, Indeed, it has been demonstrated many times that nothing matters more to the outcome of mental health treatment than the relationship between the providers and their patients,11 an effect that is true even for medication management.12 Being more wary of one’s treating provider may, therefore, limit the effect of treatment from the patient’s perspective. In the same vein, some therapists may rightly pause to consider whether they should be more vigilant and dutifully extract statements confirming a nonviolent mindset at every meeting, much in the way we perform suicide risk assessment to assess safety. Or, therapists could hesitate to probe for violent themes out of an underlying wish to avoid discovering something that they would have to report. Such tensions created within the therapist also may lend to suboptimal treatment.
Dr. Badre is a forensic psychiatrist in San Diego and an expert in correctional mental health. He holds teaching positions at the University of California, San Diego, and the University of San Diego. He teaches medical education, psychopharmacology, ethics in psychiatry, and correctional care. Dr. Joshi is a research track psychiatry resident at the University of California, San Diego. His current research focuses on developing novel therapeutic strategies to target cognitive impairment in schizophrenia. His interests include graduate medical education and applied bioethics.
References
1. Gun Violence Archive http://www.gunviolencearchive.org/reports/mass-shooting
2. https://www.abc15.com/news/data/mass-shootings-in-the-us-when-where-they-have-occurred-in-2018
3. https://twitter.com/realDonaldTrump/status/964110212885106689
4. http://www.nyspsych.org/index.php?option=com_content&view=article&id=73
5. https://www.politico.com/states/new-york/albany/story/2018/02/15/after-florida-school-shooting-cuomo-again-touts-safe-act-256104
6. MMWR 2004;53(2):1-96
7. J Affect Disord. 1999 Jul;54(1-2):21-8
8. Ethol Sociobiol. 1993;14(4):231-48
9. http://www.dcf.state.fl.us/newsroom/publicdocuments/Headquarters/Records20180219/Petition%20to%20Publically%20Release%20DCF%20Records.pdf
10. Ann Rev Clin Psychol. 2017 May 8;13:445-69
11. Psychotherapy Theory Res Prac. 2001;38(4):357-61
12. J Affect Disord. 2006 Jun;92(2-3):287-90
New Drug Technology Could Treat Huntington’s Disease
SAN DIEGO—Developments in strategies based on CRISPR and antisense oligonucleotides (ASOs) have raised the prospect that these therapies targeting genetically caused diseases could one day benefit patients with Huntington’s disease, according to an overview provided at the 142nd Annual Meeting of the American Neurological Association. Researchers aspire to conduct clinical trials in people who carry the risk gene for Huntington’s disease, but for whom disease onset is 20 or 30 years away. “If we can dose them early enough, we might be able to … delay or prevent onset,” said Sarah Tabrizi, MBChB, PhD, Joint Head of the Department of Neurodegenerative Disease at University College London. 
A Rare, Progressive Dementia
Huntington’s disease is the most common genetic dementia. Its prevalence is approximately one in 8,000. The disease is caused by a mutation in the first exon of HTT that influences the number of CAG trinucleotide repeats. A person with more than 40 CAG repeats will develop the disease. This number of repeats results in the production of an elongated version of the huntingtin protein, which subsequently is cleaved into toxic segments that accumulate in neurons. Disease onset typically occurs between the mid-30s and 40s.
Initial symptoms of Huntington’s disease include irritability, poor coordination, indecision, and chorea. Symptoms worsen as the disease progresses, and patients may develop personality changes and difficulty walking, swallowing, and thinking. Survival ranges from 15 to 20 years from symptom onset.
New Drug Modalities Have Many Potential Targets
Many pathogenic mechanisms contribute to the onset of Huntington’s disease and could be therapeutic targets. “Targeting DNA or RNA is absolutely critical,” said Dr. Tabrizi. “It does not matter what the downstream cellular pathway is. If you target proximally, you have more chance of achieving a therapeutic benefit in neurodegeneration.”
Many efforts to develop a therapy for Huntington’s disease focus on huntingtin transcription and translation. The aim is to lower the amount of mutant huntingtin in the brain. For example, studies of zinc finger proteins targeting DNA are in early preclinical development. Other investigators are using RNA interference to target huntingtin messenger RNA (mRNA) or ASOs to target huntingtin mRNA.
Data suggest that the CRISPR technique can remove the excess CAG repeats in cell lines. This technique is based on a naturally occurring genome-editing system that identifies viruses and cleaves their DNA, but it may be decades before this method is able to treat the whole human brain, said Dr. Tabrizi.
ASOs
She and her colleagues are studying an ASO as a therapy for Huntington’s disease. These molecules are short pieces of chemically modified DNA or RNA that can be diffused rapidly and easily enter cells in the CNS. They are stable, their effects are reversible, and they allow for dose titration. Dr. Tabrizi’s group is analyzing an ASO with 20 base pairs that recognizes and degrades the huntingtin mRNA transcript. The molecule’s chemical modifications give it high affinity, stability, and tolerability, and it is delivered intrathecally.
A preclinical study in nonhuman primates provided valuable pharmacokinetic and pharmacodynamic information that influenced the dosing of Dr. Tabrizi’s current, ongoing trial in humans. The investigators gave monkeys four intrathecal doses of therapy at monthly intervals before sacrificing them. They found that treatment significantly lowered huntingtin RNA levels in the frontal cortex and occipital cortex. The levels were about 50% lower in the caudate and thalamus after treatment, and approximately 75% lower in the hippocampus. Suppression of huntingtin RNA was sustained in the frontal cortex and the caudate for eight weeks, and the reduction was approximately 15% at that time. The ASO reached the deep structures of the brain, but had a predominantly cortical pharmacodynamic effect, said Dr. Tabrizi.
First-in-Man Study Is Complete
Dr. Tabrizi and colleagues have recently completed the first-in-man clinical trial. Their objective was primarily to evaluate the safety and tolerability of multiple intrathecal administrations of the therapy in ascending doses. They intended to obtain more information about the drug’s pharmacokinetics and to look at its effects on mutant huntingtin.
The trial was designed as a phase Ib–IIa study that could lead to a phase III clinical trial if enough data on dosing were obtained. Participants were randomized 3:1 to antisense drug or placebo. Including a placebo group in a first-in-man study was important for investigating drug effects, procedure effects, and the placebo effect, which is large in Huntington’s disease, said Dr. Tabrizi.
Patients received the ASO by a push bolus intrathecal injection through a small-gauge atraumatic needle. Each patient received four doses delivered at 28-day intervals. The follow-up period was 15 weeks.
The first participant received the first dose in September 2015, and enrollment was complete in June 2017. Dr. Tabrizi and colleagues enrolled 46 patients with early-stage Huntington’s disease into the study. Mean age at baseline was 47. Approximately 60% of participants were men. Participants’ mean number of CAG repeats was 44, and the baseline CSF level of mutant huntingtin, mean total functional capacity, and total motor score were consistent with early stage Huntington’s disease.
Intrathecal dosing was well tolerated. “We chose a small-gauge atraumatic needle because … we did not want to have to stop [the trial] because of headaches,” said Dr. Tabrizi. The researchers have not recorded any safety concerns to date, and the results seem to support further development of the therapy, she added.
The follow-up visits are complete, and patients are entering an open-label extension in which all participants will receive active treatment. The extension also will generate long-term safety data. In December 2017, Ionis Pharmaceuticals, which designed the ASO treatment and sponsored the first-in-man clinical study, announced that the study results provide clear evidence of target engagement and reduction in mutant huntingtin protein. Roche, Ionis’s partner in developing the treatment, licensed the drug and will be responsible for all future development
—Erik Greb
Suggested Reading
Aronin N, DiFiglia M. Huntingtin-lowering strategies in Huntington’s disease: antisense oligonucleotides, small RNAs, and gene editing. Mov Disord. 2014;29(11):1455-1461.
Skotte NH, Southwell AL, Østergaard ME, et al. Allele-specific suppression of mutant huntingtin using antisense oligonucleotides: providing a therapeutic option for all Huntington disease patients. PLoS One. 2014;9(9):e107434.
Wild EJ, Tabrizi SJ. Therapies targeting DNA and RNA in Huntington’s disease. Lancet Neurol. 2017;16(10):837-847.
SAN DIEGO—Developments in strategies based on CRISPR and antisense oligonucleotides (ASOs) have raised the prospect that these therapies targeting genetically caused diseases could one day benefit patients with Huntington’s disease, according to an overview provided at the 142nd Annual Meeting of the American Neurological Association. Researchers aspire to conduct clinical trials in people who carry the risk gene for Huntington’s disease, but for whom disease onset is 20 or 30 years away. “If we can dose them early enough, we might be able to … delay or prevent onset,” said Sarah Tabrizi, MBChB, PhD, Joint Head of the Department of Neurodegenerative Disease at University College London.
A Rare, Progressive Dementia
Huntington’s disease is the most common genetic dementia. Its prevalence is approximately one in 8,000. The disease is caused by a mutation in the first exon of HTT that influences the number of CAG trinucleotide repeats. A person with more than 40 CAG repeats will develop the disease. This number of repeats results in the production of an elongated version of the huntingtin protein, which subsequently is cleaved into toxic segments that accumulate in neurons. Disease onset typically occurs between the mid-30s and 40s.
Initial symptoms of Huntington’s disease include irritability, poor coordination, indecision, and chorea. Symptoms worsen as the disease progresses, and patients may develop personality changes and difficulty walking, swallowing, and thinking. Survival ranges from 15 to 20 years from symptom onset.
New Drug Modalities Have Many Potential Targets
Many pathogenic mechanisms contribute to the onset of Huntington’s disease and could be therapeutic targets. “Targeting DNA or RNA is absolutely critical,” said Dr. Tabrizi. “It does not matter what the downstream cellular pathway is. If you target proximally, you have more chance of achieving a therapeutic benefit in neurodegeneration.”
Many efforts to develop a therapy for Huntington’s disease focus on huntingtin transcription and translation. The aim is to lower the amount of mutant huntingtin in the brain. For example, studies of zinc finger proteins targeting DNA are in early preclinical development. Other investigators are using RNA interference to target huntingtin messenger RNA (mRNA) or ASOs to target huntingtin mRNA.
Data suggest that the CRISPR technique can remove the excess CAG repeats in cell lines. This technique is based on a naturally occurring genome-editing system that identifies viruses and cleaves their DNA, but it may be decades before this method is able to treat the whole human brain, said Dr. Tabrizi.
ASOs
She and her colleagues are studying an ASO as a therapy for Huntington’s disease. These molecules are short pieces of chemically modified DNA or RNA that can be diffused rapidly and easily enter cells in the CNS. They are stable, their effects are reversible, and they allow for dose titration. Dr. Tabrizi’s group is analyzing an ASO with 20 base pairs that recognizes and degrades the huntingtin mRNA transcript. The molecule’s chemical modifications give it high affinity, stability, and tolerability, and it is delivered intrathecally.
A preclinical study in nonhuman primates provided valuable pharmacokinetic and pharmacodynamic information that influenced the dosing of Dr. Tabrizi’s current, ongoing trial in humans. The investigators gave monkeys four intrathecal doses of therapy at monthly intervals before sacrificing them. They found that treatment significantly lowered huntingtin RNA levels in the frontal cortex and occipital cortex. The levels were about 50% lower in the caudate and thalamus after treatment, and approximately 75% lower in the hippocampus. Suppression of huntingtin RNA was sustained in the frontal cortex and the caudate for eight weeks, and the reduction was approximately 15% at that time. The ASO reached the deep structures of the brain, but had a predominantly cortical pharmacodynamic effect, said Dr. Tabrizi.
First-in-Man Study Is Complete
Dr. Tabrizi and colleagues have recently completed the first-in-man clinical trial. Their objective was primarily to evaluate the safety and tolerability of multiple intrathecal administrations of the therapy in ascending doses. They intended to obtain more information about the drug’s pharmacokinetics and to look at its effects on mutant huntingtin.
The trial was designed as a phase Ib–IIa study that could lead to a phase III clinical trial if enough data on dosing were obtained. Participants were randomized 3:1 to antisense drug or placebo. Including a placebo group in a first-in-man study was important for investigating drug effects, procedure effects, and the placebo effect, which is large in Huntington’s disease, said Dr. Tabrizi.
Patients received the ASO by a push bolus intrathecal injection through a small-gauge atraumatic needle. Each patient received four doses delivered at 28-day intervals. The follow-up period was 15 weeks.
The first participant received the first dose in September 2015, and enrollment was complete in June 2017. Dr. Tabrizi and colleagues enrolled 46 patients with early-stage Huntington’s disease into the study. Mean age at baseline was 47. Approximately 60% of participants were men. Participants’ mean number of CAG repeats was 44, and the baseline CSF level of mutant huntingtin, mean total functional capacity, and total motor score were consistent with early stage Huntington’s disease.
Intrathecal dosing was well tolerated. “We chose a small-gauge atraumatic needle because … we did not want to have to stop [the trial] because of headaches,” said Dr. Tabrizi. The researchers have not recorded any safety concerns to date, and the results seem to support further development of the therapy, she added.
The follow-up visits are complete, and patients are entering an open-label extension in which all participants will receive active treatment. The extension also will generate long-term safety data. In December 2017, Ionis Pharmaceuticals, which designed the ASO treatment and sponsored the first-in-man clinical study, announced that the study results provide clear evidence of target engagement and reduction in mutant huntingtin protein. Roche, Ionis’s partner in developing the treatment, licensed the drug and will be responsible for all future development
—Erik Greb
Suggested Reading
Aronin N, DiFiglia M. Huntingtin-lowering strategies in Huntington’s disease: antisense oligonucleotides, small RNAs, and gene editing. Mov Disord. 2014;29(11):1455-1461.
Skotte NH, Southwell AL, Østergaard ME, et al. Allele-specific suppression of mutant huntingtin using antisense oligonucleotides: providing a therapeutic option for all Huntington disease patients. PLoS One. 2014;9(9):e107434.
Wild EJ, Tabrizi SJ. Therapies targeting DNA and RNA in Huntington’s disease. Lancet Neurol. 2017;16(10):837-847.
SAN DIEGO—Developments in strategies based on CRISPR and antisense oligonucleotides (ASOs) have raised the prospect that these therapies targeting genetically caused diseases could one day benefit patients with Huntington’s disease, according to an overview provided at the 142nd Annual Meeting of the American Neurological Association. Researchers aspire to conduct clinical trials in people who carry the risk gene for Huntington’s disease, but for whom disease onset is 20 or 30 years away. “If we can dose them early enough, we might be able to … delay or prevent onset,” said Sarah Tabrizi, MBChB, PhD, Joint Head of the Department of Neurodegenerative Disease at University College London.
A Rare, Progressive Dementia
Huntington’s disease is the most common genetic dementia. Its prevalence is approximately one in 8,000. The disease is caused by a mutation in the first exon of HTT that influences the number of CAG trinucleotide repeats. A person with more than 40 CAG repeats will develop the disease. This number of repeats results in the production of an elongated version of the huntingtin protein, which subsequently is cleaved into toxic segments that accumulate in neurons. Disease onset typically occurs between the mid-30s and 40s.
Initial symptoms of Huntington’s disease include irritability, poor coordination, indecision, and chorea. Symptoms worsen as the disease progresses, and patients may develop personality changes and difficulty walking, swallowing, and thinking. Survival ranges from 15 to 20 years from symptom onset.
New Drug Modalities Have Many Potential Targets
Many pathogenic mechanisms contribute to the onset of Huntington’s disease and could be therapeutic targets. “Targeting DNA or RNA is absolutely critical,” said Dr. Tabrizi. “It does not matter what the downstream cellular pathway is. If you target proximally, you have more chance of achieving a therapeutic benefit in neurodegeneration.”
Many efforts to develop a therapy for Huntington’s disease focus on huntingtin transcription and translation. The aim is to lower the amount of mutant huntingtin in the brain. For example, studies of zinc finger proteins targeting DNA are in early preclinical development. Other investigators are using RNA interference to target huntingtin messenger RNA (mRNA) or ASOs to target huntingtin mRNA.
Data suggest that the CRISPR technique can remove the excess CAG repeats in cell lines. This technique is based on a naturally occurring genome-editing system that identifies viruses and cleaves their DNA, but it may be decades before this method is able to treat the whole human brain, said Dr. Tabrizi.
ASOs
She and her colleagues are studying an ASO as a therapy for Huntington’s disease. These molecules are short pieces of chemically modified DNA or RNA that can be diffused rapidly and easily enter cells in the CNS. They are stable, their effects are reversible, and they allow for dose titration. Dr. Tabrizi’s group is analyzing an ASO with 20 base pairs that recognizes and degrades the huntingtin mRNA transcript. The molecule’s chemical modifications give it high affinity, stability, and tolerability, and it is delivered intrathecally.
A preclinical study in nonhuman primates provided valuable pharmacokinetic and pharmacodynamic information that influenced the dosing of Dr. Tabrizi’s current, ongoing trial in humans. The investigators gave monkeys four intrathecal doses of therapy at monthly intervals before sacrificing them. They found that treatment significantly lowered huntingtin RNA levels in the frontal cortex and occipital cortex. The levels were about 50% lower in the caudate and thalamus after treatment, and approximately 75% lower in the hippocampus. Suppression of huntingtin RNA was sustained in the frontal cortex and the caudate for eight weeks, and the reduction was approximately 15% at that time. The ASO reached the deep structures of the brain, but had a predominantly cortical pharmacodynamic effect, said Dr. Tabrizi.
First-in-Man Study Is Complete
Dr. Tabrizi and colleagues have recently completed the first-in-man clinical trial. Their objective was primarily to evaluate the safety and tolerability of multiple intrathecal administrations of the therapy in ascending doses. They intended to obtain more information about the drug’s pharmacokinetics and to look at its effects on mutant huntingtin.
The trial was designed as a phase Ib–IIa study that could lead to a phase III clinical trial if enough data on dosing were obtained. Participants were randomized 3:1 to antisense drug or placebo. Including a placebo group in a first-in-man study was important for investigating drug effects, procedure effects, and the placebo effect, which is large in Huntington’s disease, said Dr. Tabrizi.
Patients received the ASO by a push bolus intrathecal injection through a small-gauge atraumatic needle. Each patient received four doses delivered at 28-day intervals. The follow-up period was 15 weeks.
The first participant received the first dose in September 2015, and enrollment was complete in June 2017. Dr. Tabrizi and colleagues enrolled 46 patients with early-stage Huntington’s disease into the study. Mean age at baseline was 47. Approximately 60% of participants were men. Participants’ mean number of CAG repeats was 44, and the baseline CSF level of mutant huntingtin, mean total functional capacity, and total motor score were consistent with early stage Huntington’s disease.
Intrathecal dosing was well tolerated. “We chose a small-gauge atraumatic needle because … we did not want to have to stop [the trial] because of headaches,” said Dr. Tabrizi. The researchers have not recorded any safety concerns to date, and the results seem to support further development of the therapy, she added.
The follow-up visits are complete, and patients are entering an open-label extension in which all participants will receive active treatment. The extension also will generate long-term safety data. In December 2017, Ionis Pharmaceuticals, which designed the ASO treatment and sponsored the first-in-man clinical study, announced that the study results provide clear evidence of target engagement and reduction in mutant huntingtin protein. Roche, Ionis’s partner in developing the treatment, licensed the drug and will be responsible for all future development
—Erik Greb
Suggested Reading
Aronin N, DiFiglia M. Huntingtin-lowering strategies in Huntington’s disease: antisense oligonucleotides, small RNAs, and gene editing. Mov Disord. 2014;29(11):1455-1461.
Skotte NH, Southwell AL, Østergaard ME, et al. Allele-specific suppression of mutant huntingtin using antisense oligonucleotides: providing a therapeutic option for all Huntington disease patients. PLoS One. 2014;9(9):e107434.
Wild EJ, Tabrizi SJ. Therapies targeting DNA and RNA in Huntington’s disease. Lancet Neurol. 2017;16(10):837-847.
How should electrolyte abnormalities be managed in patients with chronic kidney disease?
Case
A 55-year-old woman with diabetes, hypertension, and chronic kidney disease (CKD) stage 4 is admitted to the hospital for treatment of left lower-extremity cellulitis. Laboratory studies on admission show a creatinine level of 2.5 mg/dL (glomerular filtration rate [GFR] is 20 mL/min per 1.73 m2; baseline creatinine is between 2.2 and 2.6 mg/dL), potassium level of 3.0 mEq/L, magnesium level of 1.5 mEq/L, bicarbonate level of 18 mEq/L, phosphate level of 6.5 mg/dL, and calcium level of 7.5 mg/dL.
She is put on renally dosed vancomycin to treat her cellulitis. As the hospitalist, how should you manage her multiple electrolyte abnormalities?
Overview of the issue
CKD is also an important risk factor for acute kidney injury. Additionally, rates of readmission for CKD patients are higher than those without CKD. Given that CKD is a “silent disease” that many patients do not realize they have, it is very possible that the first documentation of CKD could happen during an acute hospitalization.
Among the various manifestations of CKD, electrolyte abnormalities are the most likely ones hospitalists will run into.
Overview of the data
Hypokalemia and Hypomagnesemia
Hypokalemia (potassium levels less than 3.5 mEq/L) is not as common as hyperkalemia (potassium levels greater than 5.0 mEq/L) in CKD, which is the result of impaired renal excretion of potassium. Hypokalemia can occur as a result of GI losses, urinary losses, or decreased intake and can be worsened by the use of certain drugs, such as non–K-sparing diuretics.
In the setting of diuretic use involving thiazides and loop diuretics, hypokalemia is dose and sodium-intake dependent. Potassium deficiency worsens the effects of detrimental sodium excess, which plays a role in hypertension and its associated complications. Potassium also has a protective vascular effect, which is a major reason why potassium should be kept normal in patients with CKD.
Acutely, hypokalemia can cause arrhythmias, ileus, and paralysis, which are all indications for immediate repletion. In these cases, hypokalemia must be repleted carefully in small increments (some suggest 20 mEq doses), and the patient must be monitored frequently to avoid hyperkalemia. If patients are persistently hypokalemic, several options can be considered based on the underlying cause. Dietary modifications with foods rich in potassium (containing 250mg/100g) can be suggested. Daily potassium chloride supplementation can be used in those on diuretic therapy who have hypokalemia and metabolic alkalosis (bicarbonate levels greater than 30 mEq/L). Alkalinizing salts, containing citrate or bicarbonate, can be used in hypokalemia without metabolic alkalosis. Initiation of angiotensin-converting-enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), beta-adrenergic blockers, and K-sparing diuretics can be used as well.
Potassium supplementation and K-sparing diuretics should be used with extreme caution in CKD 3 and 4 given the risk of overcorrection. If potassium supplements or drugs to raise serum potassium are initiated in house, potassium should be rechecked within a week. These treatments should be avoided in individuals with diabetes, who are at highest risk for hyperkalemia given hyporeninemic hypoaldosteronism (type IV renal tubular acidosis).
There is emerging evidence that hypomagnesemia can play a part in progression to end-stage renal disease. In the setting of cardiovascular disease, which often co-exists with CKD, the risk of hypomagnesemia precipitating arrhythmia necessitates repletion to a normal level. Any of the magnesium salts and antacids can be used for treatment. K-sparing diuretics are also magnesium sparing. An important side effect of magnesium repletion is diarrhea, which can potentiate electrolyte losses and reduce long-term adherence rates.
Metabolic acidosis
Acid-base balance is maintained by the kidney through urinary excretion of hydrogen ions both as titratable acids and ammonium. In CKD, renal excretion of the daily acid load is impaired, primarily from decreased ammonium excretion caused by there being too few functioning nephrons.
Metabolic acidosis in CKD is defined as a serum bicarbonate concentration of persistently less than 22 mEq/L. The overall prevalence of metabolic acidosis in cases of CKD that don’t require dialysis is about 15% and increases linearly with a decline in GFR. In the Chronic Renal Insufficiency Cohort study, 7%, 13%, and 37% of participants with CKD stages 2, 3, and 4 respectively had metabolic acidosis.
Metabolic acidosis has a variety of adverse outcomes, including bone demineralization, increased protein catabolism and muscle wasting, impaired cardiac function, impaired glucose homeostasis, and systemic inflammation. Additionally, multiple studies have shown an association between metabolic acidosis and progression of CKD and increased mortality.
The 2013 Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend maintaining the serum bicarbonate level within the reference range (23-29 mEq/L) with alkali therapy. Options include sodium bicarbonate or sodium citrate (which is rapidly metabolized to bicarbonate) in doses of 0.5-1.0 mEq/kg once per day. Sodium bicarbonate is inexpensive; however, it can lead to gastrointestinal upset as the bicarbonate is converted into CO2 in the stomach. This side effect is usually self-limited and improves with time. Typical starting doses are 650 mg twice a day if the serum bicarbonate level is 19-21 mEq/L or 1300 mg twice a day if the serum bicarbonate level is less than or equal to 18 mEq/L.
Sodium citrate can be used if gastrointestinal upset occurs, although caution should be used in those on aluminum binders or with liver disease. Alkali treatment should be started when bicarbonate levels are persistently low (for weeks or months) or if very low (less than or equal to 18 mEq/L) without an acute reversible cause. After patients have begun therapy, they should be monitored for the development of worsening hypertension or edema caused by sodium-mediated fluid retention, although this rarely occurs.
Hyperphosphatemia and Hypocalcemia
Hyperphosphatemia (phosphate levels greater than 4.6 mg/dL) develops early in CKD because of a reduced filtered-phosphate load. Hypocalcemia and hyperphosphatemia can lead to secondary hyperparathyroidism. Given that hyperphosphatemia has been associated with an increased mortality among patients with CKD, treatment is warranted, but the optimal phosphorus range is unknown. According to the KDIGO guidelines, the goal phosphorus level is less than 4.5 mg/dL in patients with CKD who are not on dialysis.
Treatment includes dietary restriction to 900 mg/day and phosphate binders. There is a high phosphate load in processed foods and colas because of food additives. It is therefore recommended to reduce consumption of these foods while encouraging consumption of meat and eggs, which offer additional nutritional value. Those who have failed dietary restrictions should be put on a phosphate binder, either calcium containing (calcium carbonate, calcium acetate) or non–calcium containing (Sevelamer, lanthanum). Non–calcium-containing binders are recommended for patients with hypercalcemia (levels greater than 9.5 mg/dL). There is some data that suggests that non–calcium-containing binders are superior to calcium-containing binders in terms of vascular disease outcomes, but non–calcium-containing binders are sometimes difficult to obtain because of cost and insurance coverage.
Hypocalcemia (calcium levels below 8.4 mg/dL) occurs in the setting of late stage untreated CKD because of decreased GI uptake of calcium from diet in the context of vitamin D deficiency (less than 30 ng/mL) in addition to hyperphosphatemia. Phosphate and vitamin D correction is preferred to calcium supplementation because hyperphosphatemia and vitamin D deficiency occur earlier in CKD. Phosphate reduction is described above.
Regarding vitamin D deficiency, it is recommended to start supplementation with either vitamin D2 or D3. Doses should be adjusted if GFR is less than 30 mL/min per 1.73 m2. It is important to monitor for hypercalcemia, which can also occur in CKD in this context, because it has also been associated with increased morbidity and mortality. If calcium levels are greater than 10.2 mg/dL, all vitamin D supplementation should be discontinued.
Back to the case
Our patient who was admitted for cellulitis has concomitant hypokalemia, hypomagnesemia, acidosis, and hyperphosphatemia with related hypocalcemia. She revealed that her diet was poor prior to her admission for her infection. She was given 20 mEq of potassium orally and placed on a potassium rich diet until potassium levels normalized. She was also given magnesium oxide orally on the first and second day of admission, with repeat levels that were normal. Her acidosis was treated with sodium bicarbonate – 1,300 mg orally twice daily. For her hyperphosphatemia and hypocalcemia, she was placed on phosphate restriction with nutritional counseling with plans to follow up as an outpatient to determine need for phosphate binders. In addition, vitamin D levels were checked, and she was started on repletion for vitamin D deficiency (27 ng/mL). Daily BMP, magnesium, and phosphorus were checked while in house until they were normal for 2 days, and follow-up lab work was requested with her nephrology appointment, which was scheduled for within 1 week.
Bottom line
Electrolyte abnormalities in CKD are numerous and have multiple adverse clinical outcomes. Early intervention and management, especially of metabolic acidosis and hyperphosphatemia, can have a significant effect, including prevention of progression of CKD and possibly reduced mortality.
Dr. Daya, Dr. Apgar, and Dr. Eniasivam are assistant clinical professors in the division of hospital medicine at the University of California, San Francisco.
References
1. Coresh J et al. Prevalence of chronic kidney disease in the United States. JAMA. 2007 Nov 7;298(17):2038-47.
2. Dhondup T et al. Electrolyte and acid-base disorders in chronic kidney disease and end-stage kidney failure. Blood Purif. 2017;43(1-3):179-188.
3. K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis. 2004 May;43(5 Suppl 1):S1-290.
4. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl (2011). 2013 Jan;3(1):1–150.
5. Sakaguchi Y et al. Hypomagnesemia in type 2 diabetic nephropathy: A novel predictor of end-stage renal disease. Diabetes Care. 2012 Jul;35(7):1591-7.
6. Palmer SC et al. Serum levels of phosphorus, parathyroid hormone, and calcium and risks of death and cardiovascular disease in individuals with chronic kidney disease: A systematic review and meta-analysis. JAMA. 2011 Mar 16;305(11):1119-27.
7. Patel L et al. Sevelamer versus calcium-based binders for treatment of hyperphosphatemia in CKD: A meta-analysis of randomized controlled trials. Clin J Am Soc Nephrol. 2016 Feb 5;11(2):232-44.
8. Raphael KL. Approach to the treatment of chronic metabolic acidosis in CKD. Am J Kidney Dis. 2016 Apr;67(4):696-702.
9. Raphael KL et al. Prevalence of and risk factors for reduced serum bicarbonate in chronic kidney disease. Nephrology (Carlton). 2014 Oct;19(10):648-54.
Additional reading
1. Chapter 3: Management of Progression and Complications of CKD. Kidney Int Suppl (2011). 2013 Jan:3(1):73-90.
2. Raphael KL. Approach to the treatment of chronic metabolic acidosis in CKD. Am J Kidney Dis. 2016 Apr;67(4):696-702.
Quiz
A 75-year-old male with hypertension and CKD Stage 4 is admitted to the hospital for a hip fracture following a fall. Laboratory studies on admission show a potassium level of 3.2 mEq/L, vitamin D level of 45 ng/mL, bicarbonate level of 17 mEq/L, phosphate level of 5.0 mg/dL, and calcium level of 10.3 mg/dL.
What electrolyte replacements should be initiated?
A. Dietary restriction of phosphate, sodium bicarbonate, potassium chloride, and vitamin D.
B. Non–calcium-containing phosphate binder, vitamin D, and potassium chloride.
C. Calcium-containing phosphate binder and sodium bicarbonate.
D. Non–calcium-containing phosphate binder, sodium bicarbonate, and potassium chloride.
Answer: D. Given the patient’s hypokalemia, potassium supplementation should be considered. Additionally, given his hyperphosphatemia and hypercalcemia, a non–calcium-containing phosphate binder like Sevelamer should be started. His metabolic acidosis should be corrected with sodium bicarbonate. There is no indication to supplement vitamin D based on his current lab values.
Key Points
- Identify and treat underlying causes of hypokalemia and hypomagnesemia.
- Do not hesitate to treat metabolic acidosis in CKD.
- Manage hyperphosphatemia and hypocalcemia by ordering appropriate lab studies and providing nutritional consultation with outpatient nephrology follow-up as indicated.
Case
A 55-year-old woman with diabetes, hypertension, and chronic kidney disease (CKD) stage 4 is admitted to the hospital for treatment of left lower-extremity cellulitis. Laboratory studies on admission show a creatinine level of 2.5 mg/dL (glomerular filtration rate [GFR] is 20 mL/min per 1.73 m2; baseline creatinine is between 2.2 and 2.6 mg/dL), potassium level of 3.0 mEq/L, magnesium level of 1.5 mEq/L, bicarbonate level of 18 mEq/L, phosphate level of 6.5 mg/dL, and calcium level of 7.5 mg/dL.
She is put on renally dosed vancomycin to treat her cellulitis. As the hospitalist, how should you manage her multiple electrolyte abnormalities?
Overview of the issue
CKD is also an important risk factor for acute kidney injury. Additionally, rates of readmission for CKD patients are higher than those without CKD. Given that CKD is a “silent disease” that many patients do not realize they have, it is very possible that the first documentation of CKD could happen during an acute hospitalization.
Among the various manifestations of CKD, electrolyte abnormalities are the most likely ones hospitalists will run into.
Overview of the data
Hypokalemia and Hypomagnesemia
Hypokalemia (potassium levels less than 3.5 mEq/L) is not as common as hyperkalemia (potassium levels greater than 5.0 mEq/L) in CKD, which is the result of impaired renal excretion of potassium. Hypokalemia can occur as a result of GI losses, urinary losses, or decreased intake and can be worsened by the use of certain drugs, such as non–K-sparing diuretics.
In the setting of diuretic use involving thiazides and loop diuretics, hypokalemia is dose and sodium-intake dependent. Potassium deficiency worsens the effects of detrimental sodium excess, which plays a role in hypertension and its associated complications. Potassium also has a protective vascular effect, which is a major reason why potassium should be kept normal in patients with CKD.
Acutely, hypokalemia can cause arrhythmias, ileus, and paralysis, which are all indications for immediate repletion. In these cases, hypokalemia must be repleted carefully in small increments (some suggest 20 mEq doses), and the patient must be monitored frequently to avoid hyperkalemia. If patients are persistently hypokalemic, several options can be considered based on the underlying cause. Dietary modifications with foods rich in potassium (containing 250mg/100g) can be suggested. Daily potassium chloride supplementation can be used in those on diuretic therapy who have hypokalemia and metabolic alkalosis (bicarbonate levels greater than 30 mEq/L). Alkalinizing salts, containing citrate or bicarbonate, can be used in hypokalemia without metabolic alkalosis. Initiation of angiotensin-converting-enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), beta-adrenergic blockers, and K-sparing diuretics can be used as well.
Potassium supplementation and K-sparing diuretics should be used with extreme caution in CKD 3 and 4 given the risk of overcorrection. If potassium supplements or drugs to raise serum potassium are initiated in house, potassium should be rechecked within a week. These treatments should be avoided in individuals with diabetes, who are at highest risk for hyperkalemia given hyporeninemic hypoaldosteronism (type IV renal tubular acidosis).
There is emerging evidence that hypomagnesemia can play a part in progression to end-stage renal disease. In the setting of cardiovascular disease, which often co-exists with CKD, the risk of hypomagnesemia precipitating arrhythmia necessitates repletion to a normal level. Any of the magnesium salts and antacids can be used for treatment. K-sparing diuretics are also magnesium sparing. An important side effect of magnesium repletion is diarrhea, which can potentiate electrolyte losses and reduce long-term adherence rates.
Metabolic acidosis
Acid-base balance is maintained by the kidney through urinary excretion of hydrogen ions both as titratable acids and ammonium. In CKD, renal excretion of the daily acid load is impaired, primarily from decreased ammonium excretion caused by there being too few functioning nephrons.
Metabolic acidosis in CKD is defined as a serum bicarbonate concentration of persistently less than 22 mEq/L. The overall prevalence of metabolic acidosis in cases of CKD that don’t require dialysis is about 15% and increases linearly with a decline in GFR. In the Chronic Renal Insufficiency Cohort study, 7%, 13%, and 37% of participants with CKD stages 2, 3, and 4 respectively had metabolic acidosis.
Metabolic acidosis has a variety of adverse outcomes, including bone demineralization, increased protein catabolism and muscle wasting, impaired cardiac function, impaired glucose homeostasis, and systemic inflammation. Additionally, multiple studies have shown an association between metabolic acidosis and progression of CKD and increased mortality.
The 2013 Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend maintaining the serum bicarbonate level within the reference range (23-29 mEq/L) with alkali therapy. Options include sodium bicarbonate or sodium citrate (which is rapidly metabolized to bicarbonate) in doses of 0.5-1.0 mEq/kg once per day. Sodium bicarbonate is inexpensive; however, it can lead to gastrointestinal upset as the bicarbonate is converted into CO2 in the stomach. This side effect is usually self-limited and improves with time. Typical starting doses are 650 mg twice a day if the serum bicarbonate level is 19-21 mEq/L or 1300 mg twice a day if the serum bicarbonate level is less than or equal to 18 mEq/L.
Sodium citrate can be used if gastrointestinal upset occurs, although caution should be used in those on aluminum binders or with liver disease. Alkali treatment should be started when bicarbonate levels are persistently low (for weeks or months) or if very low (less than or equal to 18 mEq/L) without an acute reversible cause. After patients have begun therapy, they should be monitored for the development of worsening hypertension or edema caused by sodium-mediated fluid retention, although this rarely occurs.
Hyperphosphatemia and Hypocalcemia
Hyperphosphatemia (phosphate levels greater than 4.6 mg/dL) develops early in CKD because of a reduced filtered-phosphate load. Hypocalcemia and hyperphosphatemia can lead to secondary hyperparathyroidism. Given that hyperphosphatemia has been associated with an increased mortality among patients with CKD, treatment is warranted, but the optimal phosphorus range is unknown. According to the KDIGO guidelines, the goal phosphorus level is less than 4.5 mg/dL in patients with CKD who are not on dialysis.
Treatment includes dietary restriction to 900 mg/day and phosphate binders. There is a high phosphate load in processed foods and colas because of food additives. It is therefore recommended to reduce consumption of these foods while encouraging consumption of meat and eggs, which offer additional nutritional value. Those who have failed dietary restrictions should be put on a phosphate binder, either calcium containing (calcium carbonate, calcium acetate) or non–calcium containing (Sevelamer, lanthanum). Non–calcium-containing binders are recommended for patients with hypercalcemia (levels greater than 9.5 mg/dL). There is some data that suggests that non–calcium-containing binders are superior to calcium-containing binders in terms of vascular disease outcomes, but non–calcium-containing binders are sometimes difficult to obtain because of cost and insurance coverage.
Hypocalcemia (calcium levels below 8.4 mg/dL) occurs in the setting of late stage untreated CKD because of decreased GI uptake of calcium from diet in the context of vitamin D deficiency (less than 30 ng/mL) in addition to hyperphosphatemia. Phosphate and vitamin D correction is preferred to calcium supplementation because hyperphosphatemia and vitamin D deficiency occur earlier in CKD. Phosphate reduction is described above.
Regarding vitamin D deficiency, it is recommended to start supplementation with either vitamin D2 or D3. Doses should be adjusted if GFR is less than 30 mL/min per 1.73 m2. It is important to monitor for hypercalcemia, which can also occur in CKD in this context, because it has also been associated with increased morbidity and mortality. If calcium levels are greater than 10.2 mg/dL, all vitamin D supplementation should be discontinued.
Back to the case
Our patient who was admitted for cellulitis has concomitant hypokalemia, hypomagnesemia, acidosis, and hyperphosphatemia with related hypocalcemia. She revealed that her diet was poor prior to her admission for her infection. She was given 20 mEq of potassium orally and placed on a potassium rich diet until potassium levels normalized. She was also given magnesium oxide orally on the first and second day of admission, with repeat levels that were normal. Her acidosis was treated with sodium bicarbonate – 1,300 mg orally twice daily. For her hyperphosphatemia and hypocalcemia, she was placed on phosphate restriction with nutritional counseling with plans to follow up as an outpatient to determine need for phosphate binders. In addition, vitamin D levels were checked, and she was started on repletion for vitamin D deficiency (27 ng/mL). Daily BMP, magnesium, and phosphorus were checked while in house until they were normal for 2 days, and follow-up lab work was requested with her nephrology appointment, which was scheduled for within 1 week.
Bottom line
Electrolyte abnormalities in CKD are numerous and have multiple adverse clinical outcomes. Early intervention and management, especially of metabolic acidosis and hyperphosphatemia, can have a significant effect, including prevention of progression of CKD and possibly reduced mortality.
Dr. Daya, Dr. Apgar, and Dr. Eniasivam are assistant clinical professors in the division of hospital medicine at the University of California, San Francisco.
References
1. Coresh J et al. Prevalence of chronic kidney disease in the United States. JAMA. 2007 Nov 7;298(17):2038-47.
2. Dhondup T et al. Electrolyte and acid-base disorders in chronic kidney disease and end-stage kidney failure. Blood Purif. 2017;43(1-3):179-188.
3. K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis. 2004 May;43(5 Suppl 1):S1-290.
4. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl (2011). 2013 Jan;3(1):1–150.
5. Sakaguchi Y et al. Hypomagnesemia in type 2 diabetic nephropathy: A novel predictor of end-stage renal disease. Diabetes Care. 2012 Jul;35(7):1591-7.
6. Palmer SC et al. Serum levels of phosphorus, parathyroid hormone, and calcium and risks of death and cardiovascular disease in individuals with chronic kidney disease: A systematic review and meta-analysis. JAMA. 2011 Mar 16;305(11):1119-27.
7. Patel L et al. Sevelamer versus calcium-based binders for treatment of hyperphosphatemia in CKD: A meta-analysis of randomized controlled trials. Clin J Am Soc Nephrol. 2016 Feb 5;11(2):232-44.
8. Raphael KL. Approach to the treatment of chronic metabolic acidosis in CKD. Am J Kidney Dis. 2016 Apr;67(4):696-702.
9. Raphael KL et al. Prevalence of and risk factors for reduced serum bicarbonate in chronic kidney disease. Nephrology (Carlton). 2014 Oct;19(10):648-54.
Additional reading
1. Chapter 3: Management of Progression and Complications of CKD. Kidney Int Suppl (2011). 2013 Jan:3(1):73-90.
2. Raphael KL. Approach to the treatment of chronic metabolic acidosis in CKD. Am J Kidney Dis. 2016 Apr;67(4):696-702.
Quiz
A 75-year-old male with hypertension and CKD Stage 4 is admitted to the hospital for a hip fracture following a fall. Laboratory studies on admission show a potassium level of 3.2 mEq/L, vitamin D level of 45 ng/mL, bicarbonate level of 17 mEq/L, phosphate level of 5.0 mg/dL, and calcium level of 10.3 mg/dL.
What electrolyte replacements should be initiated?
A. Dietary restriction of phosphate, sodium bicarbonate, potassium chloride, and vitamin D.
B. Non–calcium-containing phosphate binder, vitamin D, and potassium chloride.
C. Calcium-containing phosphate binder and sodium bicarbonate.
D. Non–calcium-containing phosphate binder, sodium bicarbonate, and potassium chloride.
Answer: D. Given the patient’s hypokalemia, potassium supplementation should be considered. Additionally, given his hyperphosphatemia and hypercalcemia, a non–calcium-containing phosphate binder like Sevelamer should be started. His metabolic acidosis should be corrected with sodium bicarbonate. There is no indication to supplement vitamin D based on his current lab values.
Key Points
- Identify and treat underlying causes of hypokalemia and hypomagnesemia.
- Do not hesitate to treat metabolic acidosis in CKD.
- Manage hyperphosphatemia and hypocalcemia by ordering appropriate lab studies and providing nutritional consultation with outpatient nephrology follow-up as indicated.
Case
A 55-year-old woman with diabetes, hypertension, and chronic kidney disease (CKD) stage 4 is admitted to the hospital for treatment of left lower-extremity cellulitis. Laboratory studies on admission show a creatinine level of 2.5 mg/dL (glomerular filtration rate [GFR] is 20 mL/min per 1.73 m2; baseline creatinine is between 2.2 and 2.6 mg/dL), potassium level of 3.0 mEq/L, magnesium level of 1.5 mEq/L, bicarbonate level of 18 mEq/L, phosphate level of 6.5 mg/dL, and calcium level of 7.5 mg/dL.
She is put on renally dosed vancomycin to treat her cellulitis. As the hospitalist, how should you manage her multiple electrolyte abnormalities?
Overview of the issue
CKD is also an important risk factor for acute kidney injury. Additionally, rates of readmission for CKD patients are higher than those without CKD. Given that CKD is a “silent disease” that many patients do not realize they have, it is very possible that the first documentation of CKD could happen during an acute hospitalization.
Among the various manifestations of CKD, electrolyte abnormalities are the most likely ones hospitalists will run into.
Overview of the data
Hypokalemia and Hypomagnesemia
Hypokalemia (potassium levels less than 3.5 mEq/L) is not as common as hyperkalemia (potassium levels greater than 5.0 mEq/L) in CKD, which is the result of impaired renal excretion of potassium. Hypokalemia can occur as a result of GI losses, urinary losses, or decreased intake and can be worsened by the use of certain drugs, such as non–K-sparing diuretics.
In the setting of diuretic use involving thiazides and loop diuretics, hypokalemia is dose and sodium-intake dependent. Potassium deficiency worsens the effects of detrimental sodium excess, which plays a role in hypertension and its associated complications. Potassium also has a protective vascular effect, which is a major reason why potassium should be kept normal in patients with CKD.
Acutely, hypokalemia can cause arrhythmias, ileus, and paralysis, which are all indications for immediate repletion. In these cases, hypokalemia must be repleted carefully in small increments (some suggest 20 mEq doses), and the patient must be monitored frequently to avoid hyperkalemia. If patients are persistently hypokalemic, several options can be considered based on the underlying cause. Dietary modifications with foods rich in potassium (containing 250mg/100g) can be suggested. Daily potassium chloride supplementation can be used in those on diuretic therapy who have hypokalemia and metabolic alkalosis (bicarbonate levels greater than 30 mEq/L). Alkalinizing salts, containing citrate or bicarbonate, can be used in hypokalemia without metabolic alkalosis. Initiation of angiotensin-converting-enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), beta-adrenergic blockers, and K-sparing diuretics can be used as well.
Potassium supplementation and K-sparing diuretics should be used with extreme caution in CKD 3 and 4 given the risk of overcorrection. If potassium supplements or drugs to raise serum potassium are initiated in house, potassium should be rechecked within a week. These treatments should be avoided in individuals with diabetes, who are at highest risk for hyperkalemia given hyporeninemic hypoaldosteronism (type IV renal tubular acidosis).
There is emerging evidence that hypomagnesemia can play a part in progression to end-stage renal disease. In the setting of cardiovascular disease, which often co-exists with CKD, the risk of hypomagnesemia precipitating arrhythmia necessitates repletion to a normal level. Any of the magnesium salts and antacids can be used for treatment. K-sparing diuretics are also magnesium sparing. An important side effect of magnesium repletion is diarrhea, which can potentiate electrolyte losses and reduce long-term adherence rates.
Metabolic acidosis
Acid-base balance is maintained by the kidney through urinary excretion of hydrogen ions both as titratable acids and ammonium. In CKD, renal excretion of the daily acid load is impaired, primarily from decreased ammonium excretion caused by there being too few functioning nephrons.
Metabolic acidosis in CKD is defined as a serum bicarbonate concentration of persistently less than 22 mEq/L. The overall prevalence of metabolic acidosis in cases of CKD that don’t require dialysis is about 15% and increases linearly with a decline in GFR. In the Chronic Renal Insufficiency Cohort study, 7%, 13%, and 37% of participants with CKD stages 2, 3, and 4 respectively had metabolic acidosis.
Metabolic acidosis has a variety of adverse outcomes, including bone demineralization, increased protein catabolism and muscle wasting, impaired cardiac function, impaired glucose homeostasis, and systemic inflammation. Additionally, multiple studies have shown an association between metabolic acidosis and progression of CKD and increased mortality.
The 2013 Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend maintaining the serum bicarbonate level within the reference range (23-29 mEq/L) with alkali therapy. Options include sodium bicarbonate or sodium citrate (which is rapidly metabolized to bicarbonate) in doses of 0.5-1.0 mEq/kg once per day. Sodium bicarbonate is inexpensive; however, it can lead to gastrointestinal upset as the bicarbonate is converted into CO2 in the stomach. This side effect is usually self-limited and improves with time. Typical starting doses are 650 mg twice a day if the serum bicarbonate level is 19-21 mEq/L or 1300 mg twice a day if the serum bicarbonate level is less than or equal to 18 mEq/L.
Sodium citrate can be used if gastrointestinal upset occurs, although caution should be used in those on aluminum binders or with liver disease. Alkali treatment should be started when bicarbonate levels are persistently low (for weeks or months) or if very low (less than or equal to 18 mEq/L) without an acute reversible cause. After patients have begun therapy, they should be monitored for the development of worsening hypertension or edema caused by sodium-mediated fluid retention, although this rarely occurs.
Hyperphosphatemia and Hypocalcemia
Hyperphosphatemia (phosphate levels greater than 4.6 mg/dL) develops early in CKD because of a reduced filtered-phosphate load. Hypocalcemia and hyperphosphatemia can lead to secondary hyperparathyroidism. Given that hyperphosphatemia has been associated with an increased mortality among patients with CKD, treatment is warranted, but the optimal phosphorus range is unknown. According to the KDIGO guidelines, the goal phosphorus level is less than 4.5 mg/dL in patients with CKD who are not on dialysis.
Treatment includes dietary restriction to 900 mg/day and phosphate binders. There is a high phosphate load in processed foods and colas because of food additives. It is therefore recommended to reduce consumption of these foods while encouraging consumption of meat and eggs, which offer additional nutritional value. Those who have failed dietary restrictions should be put on a phosphate binder, either calcium containing (calcium carbonate, calcium acetate) or non–calcium containing (Sevelamer, lanthanum). Non–calcium-containing binders are recommended for patients with hypercalcemia (levels greater than 9.5 mg/dL). There is some data that suggests that non–calcium-containing binders are superior to calcium-containing binders in terms of vascular disease outcomes, but non–calcium-containing binders are sometimes difficult to obtain because of cost and insurance coverage.
Hypocalcemia (calcium levels below 8.4 mg/dL) occurs in the setting of late stage untreated CKD because of decreased GI uptake of calcium from diet in the context of vitamin D deficiency (less than 30 ng/mL) in addition to hyperphosphatemia. Phosphate and vitamin D correction is preferred to calcium supplementation because hyperphosphatemia and vitamin D deficiency occur earlier in CKD. Phosphate reduction is described above.
Regarding vitamin D deficiency, it is recommended to start supplementation with either vitamin D2 or D3. Doses should be adjusted if GFR is less than 30 mL/min per 1.73 m2. It is important to monitor for hypercalcemia, which can also occur in CKD in this context, because it has also been associated with increased morbidity and mortality. If calcium levels are greater than 10.2 mg/dL, all vitamin D supplementation should be discontinued.
Back to the case
Our patient who was admitted for cellulitis has concomitant hypokalemia, hypomagnesemia, acidosis, and hyperphosphatemia with related hypocalcemia. She revealed that her diet was poor prior to her admission for her infection. She was given 20 mEq of potassium orally and placed on a potassium rich diet until potassium levels normalized. She was also given magnesium oxide orally on the first and second day of admission, with repeat levels that were normal. Her acidosis was treated with sodium bicarbonate – 1,300 mg orally twice daily. For her hyperphosphatemia and hypocalcemia, she was placed on phosphate restriction with nutritional counseling with plans to follow up as an outpatient to determine need for phosphate binders. In addition, vitamin D levels were checked, and she was started on repletion for vitamin D deficiency (27 ng/mL). Daily BMP, magnesium, and phosphorus were checked while in house until they were normal for 2 days, and follow-up lab work was requested with her nephrology appointment, which was scheduled for within 1 week.
Bottom line
Electrolyte abnormalities in CKD are numerous and have multiple adverse clinical outcomes. Early intervention and management, especially of metabolic acidosis and hyperphosphatemia, can have a significant effect, including prevention of progression of CKD and possibly reduced mortality.
Dr. Daya, Dr. Apgar, and Dr. Eniasivam are assistant clinical professors in the division of hospital medicine at the University of California, San Francisco.
References
1. Coresh J et al. Prevalence of chronic kidney disease in the United States. JAMA. 2007 Nov 7;298(17):2038-47.
2. Dhondup T et al. Electrolyte and acid-base disorders in chronic kidney disease and end-stage kidney failure. Blood Purif. 2017;43(1-3):179-188.
3. K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis. 2004 May;43(5 Suppl 1):S1-290.
4. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl (2011). 2013 Jan;3(1):1–150.
5. Sakaguchi Y et al. Hypomagnesemia in type 2 diabetic nephropathy: A novel predictor of end-stage renal disease. Diabetes Care. 2012 Jul;35(7):1591-7.
6. Palmer SC et al. Serum levels of phosphorus, parathyroid hormone, and calcium and risks of death and cardiovascular disease in individuals with chronic kidney disease: A systematic review and meta-analysis. JAMA. 2011 Mar 16;305(11):1119-27.
7. Patel L et al. Sevelamer versus calcium-based binders for treatment of hyperphosphatemia in CKD: A meta-analysis of randomized controlled trials. Clin J Am Soc Nephrol. 2016 Feb 5;11(2):232-44.
8. Raphael KL. Approach to the treatment of chronic metabolic acidosis in CKD. Am J Kidney Dis. 2016 Apr;67(4):696-702.
9. Raphael KL et al. Prevalence of and risk factors for reduced serum bicarbonate in chronic kidney disease. Nephrology (Carlton). 2014 Oct;19(10):648-54.
Additional reading
1. Chapter 3: Management of Progression and Complications of CKD. Kidney Int Suppl (2011). 2013 Jan:3(1):73-90.
2. Raphael KL. Approach to the treatment of chronic metabolic acidosis in CKD. Am J Kidney Dis. 2016 Apr;67(4):696-702.
Quiz
A 75-year-old male with hypertension and CKD Stage 4 is admitted to the hospital for a hip fracture following a fall. Laboratory studies on admission show a potassium level of 3.2 mEq/L, vitamin D level of 45 ng/mL, bicarbonate level of 17 mEq/L, phosphate level of 5.0 mg/dL, and calcium level of 10.3 mg/dL.
What electrolyte replacements should be initiated?
A. Dietary restriction of phosphate, sodium bicarbonate, potassium chloride, and vitamin D.
B. Non–calcium-containing phosphate binder, vitamin D, and potassium chloride.
C. Calcium-containing phosphate binder and sodium bicarbonate.
D. Non–calcium-containing phosphate binder, sodium bicarbonate, and potassium chloride.
Answer: D. Given the patient’s hypokalemia, potassium supplementation should be considered. Additionally, given his hyperphosphatemia and hypercalcemia, a non–calcium-containing phosphate binder like Sevelamer should be started. His metabolic acidosis should be corrected with sodium bicarbonate. There is no indication to supplement vitamin D based on his current lab values.
Key Points
- Identify and treat underlying causes of hypokalemia and hypomagnesemia.
- Do not hesitate to treat metabolic acidosis in CKD.
- Manage hyperphosphatemia and hypocalcemia by ordering appropriate lab studies and providing nutritional consultation with outpatient nephrology follow-up as indicated.
Nutrition Early in Life Has Long-Term Effects on Neurodevelopment
Nutrition during a child’s first 1,000 days—from conception to age 2—is pivotal for a child’s neurodevelopment and lifelong health, according to an American Academy of Pediatrics (AAP) policy statement.
“Healthy, normal neurodevelopment is a complex process involving cellular and structural changes in the brain that proceed in a specified sequence,” said Sara Jane Schwarzenberg, MD, and Michael K. Georgieff, MD, both of the University of Minnesota Masonic Children’s Hospital, Minneapolis, and the AAP Committee on Nutrition, in the statement. “Changes that are too rapid or too slow in one part of the brain may result in the failure of crucial pathway connections to other parts of the brain. Timing is crucial; once a particular developmental sequence fails, it may not be possible to retrieve all the lost function.”
The policy statement was published in the February issue of Pediatrics.
A Crucial Period
Research shows that the most active period of neural development is in the first 1,000 days. During this time, structures and processes develop that influence behavior and provide a basis for later-developing structures, including auditory and visual systems, myelination, and brain circuits involved in social development.
The importance of macronutrients for development was highlighted in a study of rural Guatemalan children between 1969 and 1989. Children in some villages received a high-calorie, high-protein supplement, and some children received a low-calorie supplement without protein. Both supplements contained vitamins and minerals. Children who received the high-calorie, high-protein supplements before age 2 had higher test scores, better reading and vocabulary skills, and faster information processing, compared with children who received the low-calorie supplements.
Many populations lack access to high-quality macronutrient sources, however. In the United States in 2015, 16.6% of households (6.4 million) were food insecure (ie, their access to adequate food was limited by a lack of money or other resources). In households with incomes below 185% of the poverty line, 36.8% were food insecure, according to the Department of Agriculture.
Food insecurity extends to micronutrients such as vitamins and minerals like zinc; iron; choline; folate; iodine; vitamins A, D, B6, and B12; and long-chain polyunsaturated fatty acids. A lack of any of these micronutrients in early childhood can lead to neurodevelopmental issues later in life, the authors said. An important source of micronutrients is human milk, provided by breastfeeding. Studies have shown that infants who are fed human milk have improved cognitive performance, compared with infants who consume formula.
Government-sponsored programs exist that provide nutritional support to women, infants, and young children. The Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) is one of the most important programs, helping 53% of children under age 1, the authors said. The Supplemental Nutrition Assistance Program (SNAP) provides economic aid to buy food; it kept approximately 4.9 million children out of poverty in 2012, the authors said. SNAP Nutrition Education is intended to help people make healthy food choices with limited money.
10 Recommendations
The AAP policy statement includes the following 10 recommendations:
- Be knowledgeable about breastfeeding, and help breastfeeding mothers. The AAP recommends exclusive breastfeeding for the first six months and continued breastfeeding with the addition of food for at least the first year.
- Advocate at the local, state, and federal levels to preserve and strengthen programs focused on maternal, fetal, and neonatal nutrition.
- Be familiar with food sources that supply nutrients necessary for brain development, and make appropriate dietary recommendations. Know which nutrients are at risk in the breastfed infant after six months, such as zinc, iron, and vitamin D.
- Nutritional advice should convey that eating healthy is a positive choice, not just an avoidance of unhealthy foods.
- Existing assistance programs should aim to improve micro- and macronutrient offerings. For example, food pantries and soup kitchens can create food packages and meals that target the needs of pregnant women, breastfeeding women, and children up to age 2.
- Encourage parents to use programs that provide early childhood nutrition (eg, WIC), and advocate for the removal of barriers to enrolling or staying enrolled in these programs.
- Oppose changes in eligibility or financing structures that would adversely affect programs providing early childhood nutrition.
- Anticipate neurodevelopmental issues in children with early nutrient deficiency.
- Work with obstetricians and family physicians to encourage improvements in maternal diet and identify clinical situations that may limit the availability of crucial micronutrients to the fetus.
- Advocate to reduce hunger at the local, national, and global levels. The statement lists organizations focused on hunger, such as Feeding America, 1,000 Days, and Share Our Strength.
—Ian Lacy
Suggested Reading
Schwarzenberg SJ, Georgieff MK; Committee on Nutrition. Advocacy for improving nutrition in the first 1000 days to support childhood development and adult health. Pediatrics. 2018;141(2). pii: e20173716.
Nutrition during a child’s first 1,000 days—from conception to age 2—is pivotal for a child’s neurodevelopment and lifelong health, according to an American Academy of Pediatrics (AAP) policy statement.
“Healthy, normal neurodevelopment is a complex process involving cellular and structural changes in the brain that proceed in a specified sequence,” said Sara Jane Schwarzenberg, MD, and Michael K. Georgieff, MD, both of the University of Minnesota Masonic Children’s Hospital, Minneapolis, and the AAP Committee on Nutrition, in the statement. “Changes that are too rapid or too slow in one part of the brain may result in the failure of crucial pathway connections to other parts of the brain. Timing is crucial; once a particular developmental sequence fails, it may not be possible to retrieve all the lost function.”
The policy statement was published in the February issue of Pediatrics.
A Crucial Period
Research shows that the most active period of neural development is in the first 1,000 days. During this time, structures and processes develop that influence behavior and provide a basis for later-developing structures, including auditory and visual systems, myelination, and brain circuits involved in social development.
The importance of macronutrients for development was highlighted in a study of rural Guatemalan children between 1969 and 1989. Children in some villages received a high-calorie, high-protein supplement, and some children received a low-calorie supplement without protein. Both supplements contained vitamins and minerals. Children who received the high-calorie, high-protein supplements before age 2 had higher test scores, better reading and vocabulary skills, and faster information processing, compared with children who received the low-calorie supplements.
Many populations lack access to high-quality macronutrient sources, however. In the United States in 2015, 16.6% of households (6.4 million) were food insecure (ie, their access to adequate food was limited by a lack of money or other resources). In households with incomes below 185% of the poverty line, 36.8% were food insecure, according to the Department of Agriculture.
Food insecurity extends to micronutrients such as vitamins and minerals like zinc; iron; choline; folate; iodine; vitamins A, D, B6, and B12; and long-chain polyunsaturated fatty acids. A lack of any of these micronutrients in early childhood can lead to neurodevelopmental issues later in life, the authors said. An important source of micronutrients is human milk, provided by breastfeeding. Studies have shown that infants who are fed human milk have improved cognitive performance, compared with infants who consume formula.
Government-sponsored programs exist that provide nutritional support to women, infants, and young children. The Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) is one of the most important programs, helping 53% of children under age 1, the authors said. The Supplemental Nutrition Assistance Program (SNAP) provides economic aid to buy food; it kept approximately 4.9 million children out of poverty in 2012, the authors said. SNAP Nutrition Education is intended to help people make healthy food choices with limited money.
10 Recommendations
The AAP policy statement includes the following 10 recommendations:
- Be knowledgeable about breastfeeding, and help breastfeeding mothers. The AAP recommends exclusive breastfeeding for the first six months and continued breastfeeding with the addition of food for at least the first year.
- Advocate at the local, state, and federal levels to preserve and strengthen programs focused on maternal, fetal, and neonatal nutrition.
- Be familiar with food sources that supply nutrients necessary for brain development, and make appropriate dietary recommendations. Know which nutrients are at risk in the breastfed infant after six months, such as zinc, iron, and vitamin D.
- Nutritional advice should convey that eating healthy is a positive choice, not just an avoidance of unhealthy foods.
- Existing assistance programs should aim to improve micro- and macronutrient offerings. For example, food pantries and soup kitchens can create food packages and meals that target the needs of pregnant women, breastfeeding women, and children up to age 2.
- Encourage parents to use programs that provide early childhood nutrition (eg, WIC), and advocate for the removal of barriers to enrolling or staying enrolled in these programs.
- Oppose changes in eligibility or financing structures that would adversely affect programs providing early childhood nutrition.
- Anticipate neurodevelopmental issues in children with early nutrient deficiency.
- Work with obstetricians and family physicians to encourage improvements in maternal diet and identify clinical situations that may limit the availability of crucial micronutrients to the fetus.
- Advocate to reduce hunger at the local, national, and global levels. The statement lists organizations focused on hunger, such as Feeding America, 1,000 Days, and Share Our Strength.
—Ian Lacy
Suggested Reading
Schwarzenberg SJ, Georgieff MK; Committee on Nutrition. Advocacy for improving nutrition in the first 1000 days to support childhood development and adult health. Pediatrics. 2018;141(2). pii: e20173716.
Nutrition during a child’s first 1,000 days—from conception to age 2—is pivotal for a child’s neurodevelopment and lifelong health, according to an American Academy of Pediatrics (AAP) policy statement.
“Healthy, normal neurodevelopment is a complex process involving cellular and structural changes in the brain that proceed in a specified sequence,” said Sara Jane Schwarzenberg, MD, and Michael K. Georgieff, MD, both of the University of Minnesota Masonic Children’s Hospital, Minneapolis, and the AAP Committee on Nutrition, in the statement. “Changes that are too rapid or too slow in one part of the brain may result in the failure of crucial pathway connections to other parts of the brain. Timing is crucial; once a particular developmental sequence fails, it may not be possible to retrieve all the lost function.”
The policy statement was published in the February issue of Pediatrics.
A Crucial Period
Research shows that the most active period of neural development is in the first 1,000 days. During this time, structures and processes develop that influence behavior and provide a basis for later-developing structures, including auditory and visual systems, myelination, and brain circuits involved in social development.
The importance of macronutrients for development was highlighted in a study of rural Guatemalan children between 1969 and 1989. Children in some villages received a high-calorie, high-protein supplement, and some children received a low-calorie supplement without protein. Both supplements contained vitamins and minerals. Children who received the high-calorie, high-protein supplements before age 2 had higher test scores, better reading and vocabulary skills, and faster information processing, compared with children who received the low-calorie supplements.
Many populations lack access to high-quality macronutrient sources, however. In the United States in 2015, 16.6% of households (6.4 million) were food insecure (ie, their access to adequate food was limited by a lack of money or other resources). In households with incomes below 185% of the poverty line, 36.8% were food insecure, according to the Department of Agriculture.
Food insecurity extends to micronutrients such as vitamins and minerals like zinc; iron; choline; folate; iodine; vitamins A, D, B6, and B12; and long-chain polyunsaturated fatty acids. A lack of any of these micronutrients in early childhood can lead to neurodevelopmental issues later in life, the authors said. An important source of micronutrients is human milk, provided by breastfeeding. Studies have shown that infants who are fed human milk have improved cognitive performance, compared with infants who consume formula.
Government-sponsored programs exist that provide nutritional support to women, infants, and young children. The Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) is one of the most important programs, helping 53% of children under age 1, the authors said. The Supplemental Nutrition Assistance Program (SNAP) provides economic aid to buy food; it kept approximately 4.9 million children out of poverty in 2012, the authors said. SNAP Nutrition Education is intended to help people make healthy food choices with limited money.
10 Recommendations
The AAP policy statement includes the following 10 recommendations:
- Be knowledgeable about breastfeeding, and help breastfeeding mothers. The AAP recommends exclusive breastfeeding for the first six months and continued breastfeeding with the addition of food for at least the first year.
- Advocate at the local, state, and federal levels to preserve and strengthen programs focused on maternal, fetal, and neonatal nutrition.
- Be familiar with food sources that supply nutrients necessary for brain development, and make appropriate dietary recommendations. Know which nutrients are at risk in the breastfed infant after six months, such as zinc, iron, and vitamin D.
- Nutritional advice should convey that eating healthy is a positive choice, not just an avoidance of unhealthy foods.
- Existing assistance programs should aim to improve micro- and macronutrient offerings. For example, food pantries and soup kitchens can create food packages and meals that target the needs of pregnant women, breastfeeding women, and children up to age 2.
- Encourage parents to use programs that provide early childhood nutrition (eg, WIC), and advocate for the removal of barriers to enrolling or staying enrolled in these programs.
- Oppose changes in eligibility or financing structures that would adversely affect programs providing early childhood nutrition.
- Anticipate neurodevelopmental issues in children with early nutrient deficiency.
- Work with obstetricians and family physicians to encourage improvements in maternal diet and identify clinical situations that may limit the availability of crucial micronutrients to the fetus.
- Advocate to reduce hunger at the local, national, and global levels. The statement lists organizations focused on hunger, such as Feeding America, 1,000 Days, and Share Our Strength.
—Ian Lacy
Suggested Reading
Schwarzenberg SJ, Georgieff MK; Committee on Nutrition. Advocacy for improving nutrition in the first 1000 days to support childhood development and adult health. Pediatrics. 2018;141(2). pii: e20173716.
VIDEO: Considering systemic disease in dermatology patients
SAN DIEGO – Be mindful of what lies below the skin.
That was the message of Joseph Merola, MD, during a session on “rheumatology for the dermatologist” at the annual meeting of the American Academy of Dermatology.
“The idea is really to start to try to get our dermatology colleagues thinking more systemically and outside of just the skin,” said Dr. Merola, a rheumatologist and dermatologist who is codirector of the center for skin and related musculoskeletal diseases at Brigham and Women’s Hospital, Boston.
“ in up to 30% of patients,” he noted.
He urged his colleagues to ask patients functional questions; for example, those pertaining to sicca symptoms; and how to parse out whether a patient’s joint pain is inflammatory or non-inflammatory.
In a video interview, Dr. Merola also discussed lab tests used to evaluate patients with lupus, the value of a simple urine test, and recent work on the development of the first international classification criteria set for discoid type skin lupus.
SAN DIEGO – Be mindful of what lies below the skin.
That was the message of Joseph Merola, MD, during a session on “rheumatology for the dermatologist” at the annual meeting of the American Academy of Dermatology.
“The idea is really to start to try to get our dermatology colleagues thinking more systemically and outside of just the skin,” said Dr. Merola, a rheumatologist and dermatologist who is codirector of the center for skin and related musculoskeletal diseases at Brigham and Women’s Hospital, Boston.
“ in up to 30% of patients,” he noted.
He urged his colleagues to ask patients functional questions; for example, those pertaining to sicca symptoms; and how to parse out whether a patient’s joint pain is inflammatory or non-inflammatory.
In a video interview, Dr. Merola also discussed lab tests used to evaluate patients with lupus, the value of a simple urine test, and recent work on the development of the first international classification criteria set for discoid type skin lupus.
SAN DIEGO – Be mindful of what lies below the skin.
That was the message of Joseph Merola, MD, during a session on “rheumatology for the dermatologist” at the annual meeting of the American Academy of Dermatology.
“The idea is really to start to try to get our dermatology colleagues thinking more systemically and outside of just the skin,” said Dr. Merola, a rheumatologist and dermatologist who is codirector of the center for skin and related musculoskeletal diseases at Brigham and Women’s Hospital, Boston.
“ in up to 30% of patients,” he noted.
He urged his colleagues to ask patients functional questions; for example, those pertaining to sicca symptoms; and how to parse out whether a patient’s joint pain is inflammatory or non-inflammatory.
In a video interview, Dr. Merola also discussed lab tests used to evaluate patients with lupus, the value of a simple urine test, and recent work on the development of the first international classification criteria set for discoid type skin lupus.
REPORTING FROM AAD 18
VIDEO: PPACMAN aims to advance the combined rheum-derm clinic approach in the community
SAN DIEGO – A new endeavor that aims to promote the concept of the combined clinic approach to caring for psoriatic patients is now underway.
PPACMAN (Psoriasis and Psoriatic Arthritis Clinics Multicenter Advancement Network) is made up of dermatologists and rheumatologists who play a key role in the management of psoriatic disease and are interested in combined clinics, with the mission “to nucleate psoriatic disease combined clinics and centers to advance a multilevel approach to psoriatic patients, increase disease awareness, and accelerate management,” according to Joseph Merola, MD, codirector of the center for skin and related musculoskeletal diseases at Brigham and Women’s Hospital, Boston.
There are now about 12 centers in North America with formal rheumatology-dermatology clinics for patients with psoriasis and psoriatic arthritis, including the one at Brigham and Women’s, where Dr. Merola and his colleagues have seen the “myriad benefits that come with having a combined clinic,” he said in a video interview at the annual meeting of the American Academy of Dermatology. The idea behind starting PPACMAN was to help form new clinics at academic centers but, also, “to start to catalyze local-regional partnerships in the community so we could get dermatologists and rheumatologists in the community to start interacting, communicating, [and] sharing patients,” he explained.
“The group is really very much focused on this mission of getting combined ... treatment models out there,” added Dr. Merola, president and chair of the board of PPACMAN, which is a 501c3 nonprofit organization.
In the interview, he discusses other benefits of the combined clinic model and other elements of the PPACMAN mission, including education and the potential for shared EMR templates.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN DIEGO – A new endeavor that aims to promote the concept of the combined clinic approach to caring for psoriatic patients is now underway.
PPACMAN (Psoriasis and Psoriatic Arthritis Clinics Multicenter Advancement Network) is made up of dermatologists and rheumatologists who play a key role in the management of psoriatic disease and are interested in combined clinics, with the mission “to nucleate psoriatic disease combined clinics and centers to advance a multilevel approach to psoriatic patients, increase disease awareness, and accelerate management,” according to Joseph Merola, MD, codirector of the center for skin and related musculoskeletal diseases at Brigham and Women’s Hospital, Boston.
There are now about 12 centers in North America with formal rheumatology-dermatology clinics for patients with psoriasis and psoriatic arthritis, including the one at Brigham and Women’s, where Dr. Merola and his colleagues have seen the “myriad benefits that come with having a combined clinic,” he said in a video interview at the annual meeting of the American Academy of Dermatology. The idea behind starting PPACMAN was to help form new clinics at academic centers but, also, “to start to catalyze local-regional partnerships in the community so we could get dermatologists and rheumatologists in the community to start interacting, communicating, [and] sharing patients,” he explained.
“The group is really very much focused on this mission of getting combined ... treatment models out there,” added Dr. Merola, president and chair of the board of PPACMAN, which is a 501c3 nonprofit organization.
In the interview, he discusses other benefits of the combined clinic model and other elements of the PPACMAN mission, including education and the potential for shared EMR templates.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN DIEGO – A new endeavor that aims to promote the concept of the combined clinic approach to caring for psoriatic patients is now underway.
PPACMAN (Psoriasis and Psoriatic Arthritis Clinics Multicenter Advancement Network) is made up of dermatologists and rheumatologists who play a key role in the management of psoriatic disease and are interested in combined clinics, with the mission “to nucleate psoriatic disease combined clinics and centers to advance a multilevel approach to psoriatic patients, increase disease awareness, and accelerate management,” according to Joseph Merola, MD, codirector of the center for skin and related musculoskeletal diseases at Brigham and Women’s Hospital, Boston.
There are now about 12 centers in North America with formal rheumatology-dermatology clinics for patients with psoriasis and psoriatic arthritis, including the one at Brigham and Women’s, where Dr. Merola and his colleagues have seen the “myriad benefits that come with having a combined clinic,” he said in a video interview at the annual meeting of the American Academy of Dermatology. The idea behind starting PPACMAN was to help form new clinics at academic centers but, also, “to start to catalyze local-regional partnerships in the community so we could get dermatologists and rheumatologists in the community to start interacting, communicating, [and] sharing patients,” he explained.
“The group is really very much focused on this mission of getting combined ... treatment models out there,” added Dr. Merola, president and chair of the board of PPACMAN, which is a 501c3 nonprofit organization.
In the interview, he discusses other benefits of the combined clinic model and other elements of the PPACMAN mission, including education and the potential for shared EMR templates.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
REPORTING FROM AAD 18
On-Label Stent Use May Be Safe in Intracranial Atherosclerotic Disease
LOS ANGELES—A postmarketing study of the Wingspan stent shows that the safety of the device in the treatment of intracranial atherosclerotic disease (ICAD) is good enough for the device to be a reasonable alternative to medical management if the device is used on label. The data were presented at the International Stroke Conference 2018.
The results may reassure interventionalists who were concerned by results from the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial, in which patients treated with the stent had a 30-day rate of stroke or death of 14.7%. The new study showed a frequency of periprocedural morbidity of 2.6%, so long as the device was used on label. Off-label use yielded a frequency of 23.9%.
“It does suggest that there may be a re-evaluation of stenting as a treatment for symptomatic ICAD, particularly in patients who have failed medical therapy, based on the safety profile we are seeing now,” said Michael Alexander, MD, Director of the Neurovascular Center and of Endovascular Surgery at Cedars-Sinai in Los Angeles, during a presentation of the Wingspan Stent System Post Market Surveillance (WEAVE) study.
Inappropriate Patient Selection?
Approximately 10% of strokes in the United States result from ICAD, and the rate ranges between 20% and 46% in China. Early trials of the Wingspan device had initial success, with complication rates of between 4.5% and 6.2%, but the SAMMPRIS trial, which directly compared stenting with aggressive medical management, showed superior outcomes with medical management. The 30-day rate of stroke or death of 14.7% was higher than that of medical therapy, which included aspirin (325 mg/day), clopidogrel (75 mg/day for 90 days after enrollment), and management of primary and secondary risk factors.
The SAMMPRIS trial may not have employed favorable patient selection. “ICAD is variable,” said Dr. Alexander. “Some patients present with hemodynamic compromise, where stenting is probably beneficial. Some present with embolic stroke, and some present with small-vessel perforator strokes that are unlikely to be responsive to stenting and better treated with medical therapy. All these patients were grouped together” in SAMMPRIS.
After the SAMMPRIS findings were published, the use of stenting declined at many US hospitals. But studies conducted before SAMMPRIS had shown much lower periprocedural morbidity, and those studies looked at on-label use of stenting. Stenting was used off label in SAMMPRIS.
The WEAVE study, which was an FDA-mandated postmarketing surveillance study of Stryker’s Wingspan stent, suggests that the off-label use of the system in the SAMMPRIS trial may explain the poor results. The SAMMPRIS protocol went beyond the approved indications for stenting by treating patients who presented with transient ischemic attacks only, patients who had failed medical therapy, and patients who had experienced a stroke in the previous seven days. In fact, about half of the patients were treated within seven days of the previous event, sometimes within 24 hours.
Previous studies had shown that risk factors for poor outcomes included stenting within 10 days of the last event, stenting a posterior circulation target lesion, stenting presentations other than stroke, and treatment at sites with a low patient volume for stenting. Patient selection is vital to success, according to Dr. Alexander. Patients with hemodynamic compromise are good candidates for stenting, while those with perforator stroke alone are better off with medical therapy. Embolic stroke patients are candidates for either approach.
WEAVE Was Halted Early
WEAVE looked at 152 consecutive patients treated on label at 24 institutions. The primary analysis group consisted of patients with a 70% to 99% stenotic intracranial atherosclerotic lesion who were refractory to medical treatment, between ages 22 and 80, and had a modified Rankin Scale (mRS) score of 3 or less at baseline. The treatment was performed at least seven days after the last stroke. Finally, patients had to have experienced two or more strokes. This last requirement presented a problem for recruitment, according to Dr. Alexander. “That was never a criterion for any of the [previous] trials, so it is not clear why FDA added [it]. That made it difficult to enroll for this trial—to have patients who had two or more strokes and still had a functional mRS score,” he said.
The study tested whether its protocol would have a periprocedural morbidity rate of 6.6%. Periprocedural morbidity was defined as a stroke or death within 72 hours.
An interim analysis at 100 patients showed that the periprocedural morbidity frequency was below 4%, which met the agency’s requirement and allowed the trial to be halted once the trial enrolled 150 on-label patients. The total number of on-label patients reached 152. The researchers analyzed the results from an additional 46 patients who were treated with stenting, despite not meeting the study’s inclusion criteria, and these patients were considered to have been treated off label. The final analysis showed that the on-label group had a rate of periprocedural morbidity of 2.6%, compared with 23.9% in the off-label group.
The most notable difference in the patient populations was that half of the off-label group received the stent within seven days of stroke. Several factors could explain the likelihood of worse outcomes when stenting is performed within seven days. “There is speculation that the plaques might be hot, and those patients might have a higher thrombotic risk with putting a foreign body in the vessel, or there is capillary instability, so reperfusing a vessel that has a 99% stenosis has a higher risk for reperfusion hemorrhage,” said Dr. Alexander.
Experience may also be a factor. Interventionalists participating in the WEAVE trial had inserted a stent using Wingspan an average of 37 times before the study began, compared with a mean of 10 times for physicians in the SAMMPRIS trial. Those who had performed more than 50 procedures had no periprocedural morbidity outcomes at all.
The study was funded by Stryker Neurovascular. Dr. Alexander has consulted for Stryker.
—Jim Kling
Suggested Reading
Chimowitz
LOS ANGELES—A postmarketing study of the Wingspan stent shows that the safety of the device in the treatment of intracranial atherosclerotic disease (ICAD) is good enough for the device to be a reasonable alternative to medical management if the device is used on label. The data were presented at the International Stroke Conference 2018.
The results may reassure interventionalists who were concerned by results from the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial, in which patients treated with the stent had a 30-day rate of stroke or death of 14.7%. The new study showed a frequency of periprocedural morbidity of 2.6%, so long as the device was used on label. Off-label use yielded a frequency of 23.9%.
“It does suggest that there may be a re-evaluation of stenting as a treatment for symptomatic ICAD, particularly in patients who have failed medical therapy, based on the safety profile we are seeing now,” said Michael Alexander, MD, Director of the Neurovascular Center and of Endovascular Surgery at Cedars-Sinai in Los Angeles, during a presentation of the Wingspan Stent System Post Market Surveillance (WEAVE) study.
Inappropriate Patient Selection?
Approximately 10% of strokes in the United States result from ICAD, and the rate ranges between 20% and 46% in China. Early trials of the Wingspan device had initial success, with complication rates of between 4.5% and 6.2%, but the SAMMPRIS trial, which directly compared stenting with aggressive medical management, showed superior outcomes with medical management. The 30-day rate of stroke or death of 14.7% was higher than that of medical therapy, which included aspirin (325 mg/day), clopidogrel (75 mg/day for 90 days after enrollment), and management of primary and secondary risk factors.
The SAMMPRIS trial may not have employed favorable patient selection. “ICAD is variable,” said Dr. Alexander. “Some patients present with hemodynamic compromise, where stenting is probably beneficial. Some present with embolic stroke, and some present with small-vessel perforator strokes that are unlikely to be responsive to stenting and better treated with medical therapy. All these patients were grouped together” in SAMMPRIS.
After the SAMMPRIS findings were published, the use of stenting declined at many US hospitals. But studies conducted before SAMMPRIS had shown much lower periprocedural morbidity, and those studies looked at on-label use of stenting. Stenting was used off label in SAMMPRIS.
The WEAVE study, which was an FDA-mandated postmarketing surveillance study of Stryker’s Wingspan stent, suggests that the off-label use of the system in the SAMMPRIS trial may explain the poor results. The SAMMPRIS protocol went beyond the approved indications for stenting by treating patients who presented with transient ischemic attacks only, patients who had failed medical therapy, and patients who had experienced a stroke in the previous seven days. In fact, about half of the patients were treated within seven days of the previous event, sometimes within 24 hours.
Previous studies had shown that risk factors for poor outcomes included stenting within 10 days of the last event, stenting a posterior circulation target lesion, stenting presentations other than stroke, and treatment at sites with a low patient volume for stenting. Patient selection is vital to success, according to Dr. Alexander. Patients with hemodynamic compromise are good candidates for stenting, while those with perforator stroke alone are better off with medical therapy. Embolic stroke patients are candidates for either approach.
WEAVE Was Halted Early
WEAVE looked at 152 consecutive patients treated on label at 24 institutions. The primary analysis group consisted of patients with a 70% to 99% stenotic intracranial atherosclerotic lesion who were refractory to medical treatment, between ages 22 and 80, and had a modified Rankin Scale (mRS) score of 3 or less at baseline. The treatment was performed at least seven days after the last stroke. Finally, patients had to have experienced two or more strokes. This last requirement presented a problem for recruitment, according to Dr. Alexander. “That was never a criterion for any of the [previous] trials, so it is not clear why FDA added [it]. That made it difficult to enroll for this trial—to have patients who had two or more strokes and still had a functional mRS score,” he said.
The study tested whether its protocol would have a periprocedural morbidity rate of 6.6%. Periprocedural morbidity was defined as a stroke or death within 72 hours.
An interim analysis at 100 patients showed that the periprocedural morbidity frequency was below 4%, which met the agency’s requirement and allowed the trial to be halted once the trial enrolled 150 on-label patients. The total number of on-label patients reached 152. The researchers analyzed the results from an additional 46 patients who were treated with stenting, despite not meeting the study’s inclusion criteria, and these patients were considered to have been treated off label. The final analysis showed that the on-label group had a rate of periprocedural morbidity of 2.6%, compared with 23.9% in the off-label group.
The most notable difference in the patient populations was that half of the off-label group received the stent within seven days of stroke. Several factors could explain the likelihood of worse outcomes when stenting is performed within seven days. “There is speculation that the plaques might be hot, and those patients might have a higher thrombotic risk with putting a foreign body in the vessel, or there is capillary instability, so reperfusing a vessel that has a 99% stenosis has a higher risk for reperfusion hemorrhage,” said Dr. Alexander.
Experience may also be a factor. Interventionalists participating in the WEAVE trial had inserted a stent using Wingspan an average of 37 times before the study began, compared with a mean of 10 times for physicians in the SAMMPRIS trial. Those who had performed more than 50 procedures had no periprocedural morbidity outcomes at all.
The study was funded by Stryker Neurovascular. Dr. Alexander has consulted for Stryker.
—Jim Kling
Suggested Reading
Chimowitz
LOS ANGELES—A postmarketing study of the Wingspan stent shows that the safety of the device in the treatment of intracranial atherosclerotic disease (ICAD) is good enough for the device to be a reasonable alternative to medical management if the device is used on label. The data were presented at the International Stroke Conference 2018.
The results may reassure interventionalists who were concerned by results from the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial, in which patients treated with the stent had a 30-day rate of stroke or death of 14.7%. The new study showed a frequency of periprocedural morbidity of 2.6%, so long as the device was used on label. Off-label use yielded a frequency of 23.9%.
“It does suggest that there may be a re-evaluation of stenting as a treatment for symptomatic ICAD, particularly in patients who have failed medical therapy, based on the safety profile we are seeing now,” said Michael Alexander, MD, Director of the Neurovascular Center and of Endovascular Surgery at Cedars-Sinai in Los Angeles, during a presentation of the Wingspan Stent System Post Market Surveillance (WEAVE) study.
Inappropriate Patient Selection?
Approximately 10% of strokes in the United States result from ICAD, and the rate ranges between 20% and 46% in China. Early trials of the Wingspan device had initial success, with complication rates of between 4.5% and 6.2%, but the SAMMPRIS trial, which directly compared stenting with aggressive medical management, showed superior outcomes with medical management. The 30-day rate of stroke or death of 14.7% was higher than that of medical therapy, which included aspirin (325 mg/day), clopidogrel (75 mg/day for 90 days after enrollment), and management of primary and secondary risk factors.
The SAMMPRIS trial may not have employed favorable patient selection. “ICAD is variable,” said Dr. Alexander. “Some patients present with hemodynamic compromise, where stenting is probably beneficial. Some present with embolic stroke, and some present with small-vessel perforator strokes that are unlikely to be responsive to stenting and better treated with medical therapy. All these patients were grouped together” in SAMMPRIS.
After the SAMMPRIS findings were published, the use of stenting declined at many US hospitals. But studies conducted before SAMMPRIS had shown much lower periprocedural morbidity, and those studies looked at on-label use of stenting. Stenting was used off label in SAMMPRIS.
The WEAVE study, which was an FDA-mandated postmarketing surveillance study of Stryker’s Wingspan stent, suggests that the off-label use of the system in the SAMMPRIS trial may explain the poor results. The SAMMPRIS protocol went beyond the approved indications for stenting by treating patients who presented with transient ischemic attacks only, patients who had failed medical therapy, and patients who had experienced a stroke in the previous seven days. In fact, about half of the patients were treated within seven days of the previous event, sometimes within 24 hours.
Previous studies had shown that risk factors for poor outcomes included stenting within 10 days of the last event, stenting a posterior circulation target lesion, stenting presentations other than stroke, and treatment at sites with a low patient volume for stenting. Patient selection is vital to success, according to Dr. Alexander. Patients with hemodynamic compromise are good candidates for stenting, while those with perforator stroke alone are better off with medical therapy. Embolic stroke patients are candidates for either approach.
WEAVE Was Halted Early
WEAVE looked at 152 consecutive patients treated on label at 24 institutions. The primary analysis group consisted of patients with a 70% to 99% stenotic intracranial atherosclerotic lesion who were refractory to medical treatment, between ages 22 and 80, and had a modified Rankin Scale (mRS) score of 3 or less at baseline. The treatment was performed at least seven days after the last stroke. Finally, patients had to have experienced two or more strokes. This last requirement presented a problem for recruitment, according to Dr. Alexander. “That was never a criterion for any of the [previous] trials, so it is not clear why FDA added [it]. That made it difficult to enroll for this trial—to have patients who had two or more strokes and still had a functional mRS score,” he said.
The study tested whether its protocol would have a periprocedural morbidity rate of 6.6%. Periprocedural morbidity was defined as a stroke or death within 72 hours.
An interim analysis at 100 patients showed that the periprocedural morbidity frequency was below 4%, which met the agency’s requirement and allowed the trial to be halted once the trial enrolled 150 on-label patients. The total number of on-label patients reached 152. The researchers analyzed the results from an additional 46 patients who were treated with stenting, despite not meeting the study’s inclusion criteria, and these patients were considered to have been treated off label. The final analysis showed that the on-label group had a rate of periprocedural morbidity of 2.6%, compared with 23.9% in the off-label group.
The most notable difference in the patient populations was that half of the off-label group received the stent within seven days of stroke. Several factors could explain the likelihood of worse outcomes when stenting is performed within seven days. “There is speculation that the plaques might be hot, and those patients might have a higher thrombotic risk with putting a foreign body in the vessel, or there is capillary instability, so reperfusing a vessel that has a 99% stenosis has a higher risk for reperfusion hemorrhage,” said Dr. Alexander.
Experience may also be a factor. Interventionalists participating in the WEAVE trial had inserted a stent using Wingspan an average of 37 times before the study began, compared with a mean of 10 times for physicians in the SAMMPRIS trial. Those who had performed more than 50 procedures had no periprocedural morbidity outcomes at all.
The study was funded by Stryker Neurovascular. Dr. Alexander has consulted for Stryker.
—Jim Kling
Suggested Reading
Chimowitz
Blood transfusions are dropping in U.S. hospitals
The number of red blood cell (RBC) and plasma transfusions conducted in U.S. hospitals has declined steadily since 2011, perhaps as a result of hospitals instituting new blood management programs after randomized trials showed the safety of restrictive transfusion strategies.
There has been no change in the frequency of platelet transfusions since 2011.
The researchers analyzed data from the National Inpatient Sample, using ICD-9-CM procedure codes to identify transfusion procedures. They examined the percentage of hospitalizations with one or more RBC transfusions, since these represent the majority of transfusions. Secondary outcomes included hospitalizations with one or more plasma or one or more platelet transfusions. The findings were published in a research letter in JAMA.
The study included data from the period of 1993-2014. The frequency of transfusions has trended upward since 1993, but a joinpoint analysis found an inflection point at 2011. The researchers then focused their analysis on the period from 2011 to 2014.
The researchers found reductions in RBC transfusions among all sexes, race/ethnicities, patient risk severities, payer types, and admission types. They found no statistically significant reductions in RBC transfusions in private investor–owned hospitals or in patients under the age of 18, though they noted that there is limited evidence to guide clinical practice in the pediatric population.
The decline in RBC transfusions was greater for elective admissions (aRR, 0.74, 95% CI, 0.67-0.80) than it was for nonelective admissions (aRR, 0.86; 95% CI, 0.81-0.91; P for interaction less than .001).
“The observed decreases in RBC and plasma transfusions from 2011 to 2014 may reflect evidence demonstrating the safety of restricting RBC transfusions, patient blood management programs, conservation initiatives (e.g., cell salvage, pharmacotherapy, improved surgical techniques), advocacy from medical organizations, and publication of transfusion guidelines,” the researchers wrote.
The study is limited by its retrospective design and may not be generalizable to outpatient settings.
The study was supported by grants from the National Institutes of Health and Weill Cornell Medical College. Two of the study authors reported personal fees from Terumo BCT, Haemonetics, and Octapharma. No other disclosures were reported.
SOURCE: Goel R et al. JAMA. 2018 Feb 27;319(8):825-7.
The number of red blood cell (RBC) and plasma transfusions conducted in U.S. hospitals has declined steadily since 2011, perhaps as a result of hospitals instituting new blood management programs after randomized trials showed the safety of restrictive transfusion strategies.
There has been no change in the frequency of platelet transfusions since 2011.
The researchers analyzed data from the National Inpatient Sample, using ICD-9-CM procedure codes to identify transfusion procedures. They examined the percentage of hospitalizations with one or more RBC transfusions, since these represent the majority of transfusions. Secondary outcomes included hospitalizations with one or more plasma or one or more platelet transfusions. The findings were published in a research letter in JAMA.
The study included data from the period of 1993-2014. The frequency of transfusions has trended upward since 1993, but a joinpoint analysis found an inflection point at 2011. The researchers then focused their analysis on the period from 2011 to 2014.
The researchers found reductions in RBC transfusions among all sexes, race/ethnicities, patient risk severities, payer types, and admission types. They found no statistically significant reductions in RBC transfusions in private investor–owned hospitals or in patients under the age of 18, though they noted that there is limited evidence to guide clinical practice in the pediatric population.
The decline in RBC transfusions was greater for elective admissions (aRR, 0.74, 95% CI, 0.67-0.80) than it was for nonelective admissions (aRR, 0.86; 95% CI, 0.81-0.91; P for interaction less than .001).
“The observed decreases in RBC and plasma transfusions from 2011 to 2014 may reflect evidence demonstrating the safety of restricting RBC transfusions, patient blood management programs, conservation initiatives (e.g., cell salvage, pharmacotherapy, improved surgical techniques), advocacy from medical organizations, and publication of transfusion guidelines,” the researchers wrote.
The study is limited by its retrospective design and may not be generalizable to outpatient settings.
The study was supported by grants from the National Institutes of Health and Weill Cornell Medical College. Two of the study authors reported personal fees from Terumo BCT, Haemonetics, and Octapharma. No other disclosures were reported.
SOURCE: Goel R et al. JAMA. 2018 Feb 27;319(8):825-7.
The number of red blood cell (RBC) and plasma transfusions conducted in U.S. hospitals has declined steadily since 2011, perhaps as a result of hospitals instituting new blood management programs after randomized trials showed the safety of restrictive transfusion strategies.
There has been no change in the frequency of platelet transfusions since 2011.
The researchers analyzed data from the National Inpatient Sample, using ICD-9-CM procedure codes to identify transfusion procedures. They examined the percentage of hospitalizations with one or more RBC transfusions, since these represent the majority of transfusions. Secondary outcomes included hospitalizations with one or more plasma or one or more platelet transfusions. The findings were published in a research letter in JAMA.
The study included data from the period of 1993-2014. The frequency of transfusions has trended upward since 1993, but a joinpoint analysis found an inflection point at 2011. The researchers then focused their analysis on the period from 2011 to 2014.
The researchers found reductions in RBC transfusions among all sexes, race/ethnicities, patient risk severities, payer types, and admission types. They found no statistically significant reductions in RBC transfusions in private investor–owned hospitals or in patients under the age of 18, though they noted that there is limited evidence to guide clinical practice in the pediatric population.
The decline in RBC transfusions was greater for elective admissions (aRR, 0.74, 95% CI, 0.67-0.80) than it was for nonelective admissions (aRR, 0.86; 95% CI, 0.81-0.91; P for interaction less than .001).
“The observed decreases in RBC and plasma transfusions from 2011 to 2014 may reflect evidence demonstrating the safety of restricting RBC transfusions, patient blood management programs, conservation initiatives (e.g., cell salvage, pharmacotherapy, improved surgical techniques), advocacy from medical organizations, and publication of transfusion guidelines,” the researchers wrote.
The study is limited by its retrospective design and may not be generalizable to outpatient settings.
The study was supported by grants from the National Institutes of Health and Weill Cornell Medical College. Two of the study authors reported personal fees from Terumo BCT, Haemonetics, and Octapharma. No other disclosures were reported.
SOURCE: Goel R et al. JAMA. 2018 Feb 27;319(8):825-7.
FROM JAMA
Key clinical point:
Major finding: The frequency of red blood cell transfusions among hospital inpatients dropped from 6.8% to 5.7% from 2011 to 2014.
Study details: A retrospective analysis of procedures codes at U.S. hospitals from 1993 to 2014.
Disclosures: The study was supported by grants from the National Institutes of Health and Weill Cornell Medical College. Two of the study authors reported personal fees from Terumo BCT, Haemonetics, and Octapharma. No other disclosures were reported.
Source: Goel R et al. JAMA. 2018 Feb 27;319(8):825-7.
Zonisamide May Improve Motor Symptoms in Patients With Dementia With Lewy Bodies
Zonisamide may improve parkinsonism in patients with dementia with Lewy bodies (DLB) without worsening cognitive function or psychiatric symptoms, according to a study published in the February 20 issue of Neurology.
“This study provides Class I evidence that zonisamide (adjunctive to levodopa) improves parkinsonism and is well tolerated in patients with DLB,” said Miho Murata, MD, PhD, of the National Center of Neurology and Psychiatry in Tokyo, and colleagues. “We found that the Unified Parkinson’s Disease Rating Scale (UPDRS) part 3 total score at week 12 was significantly improved in the zonisamide 50 mg/day group, compared with the placebo group.”
Four placebo-controlled, randomized trials have found that zonisamide—a drug used to treat seizures—improves motor symptoms in Parkinson’s disease with a low incidence of motor complications such as dyskinesia or psychiatric symptoms such as hallucinations. In another study that included three patients with DLB, zonisamide was associated with improved parkinsonism and reduced caregiver burden without worsening cognition or behavioral or psychological symptoms.
A Phase II, Placebo-Controlled, Double-Blind Study
Based on results from these studies, Dr. Murata and colleagues conducted a phase II, placebo-controlled, randomized double-blind study to examine the efficacy and safety of zonisamide as an adjunct to levodopa therapy for parkinsonism in patients with DLB.
Eligible participants were between ages 20 and 84 and had a UPDRS part 3 score of 10 or greater. The investigators excluded patients with Parkinson’s disease with dementia (ie, well-established Parkinson’s disease followed by onset of dementia), those who did not respond to levodopa therapy, and patients with epilepsy.
The primary end point was change from baseline in UPDRS part 3 score at week 12. Secondary end points included changes from baseline in total UPDRS score, each UPDRS part, and each UPDRS item at each evaluation.
The study included a four-week run-in period and a 12-week treatment period. During the run-in period, patients received placebo tablets once daily under single-blind conditions to eliminate any confounding effects of other antiparkinson drugs.
Participants were randomized 1:1:1 to placebo, zonisamide (25 mg), or zonisamide (50 mg) daily. Patients visited study sites every four weeks for five visits. Dosage and administration of antidementia drugs were unchanged from 12 weeks before the run-in period throughout the treatment period. Dosage and administration of levodopa/decarboxylase inhibitor therapy and other antiparkinson, antihypertensive, CNS, cardiovascular, or gastrointestinal drugs or herbal medicine were unchanged from two weeks before the run-in period throughout the treatment period.
Zonisamide Did Not Worsen Cognitive Function or Behavior
In all, 158 patients were randomized to receive zonisamide or placebo, and 137 patients completed treatment. Zonisamide (50 mg) was associated with significantly greater improvement in UPDRS part 3 scores at week 12, compared with placebo (between group difference, –4.1). In addition, zonisamide did not worsen cognitive function, behavior or psychological symptoms of dementia, or caregiver burden.
The incidence of adverse events was higher in the zonisamide (50 mg) group than in the zonisamide (25 mg) group and placebo group (65.3%, 43.1%, and 50.0%, respectively). The incidences of common drug-related adverse events (eg, decreased weight, decreased appetite, and rash) were higher among patients who received zonisamide, compared with patients who received placebo. The rates of serious adverse events were similar between the groups.
“There is an urgent need for new treatments for DLB,” said Linda A. Hershey, MD, PhD, Professor of Neurology at the University of Oklahoma Health Sciences Center in Oklahoma City, who wrote an accompanying editorial. “The successful execution of this trial is a major accomplishment, which provides evidence that future trials are warranted.”
—Erica Tricarico
Suggested Reading
Hershey LA, Irwin DJ. Zonisamide for DLB parkinsonism: An old drug used in a new context. Neurology. 2018;90(8):349-350.
Murata M, Odawara T, Hasegawa K, et al. Adjunct zonisamide to levodopa for DLB parkinsonism: A randomized double-blind phase 2 study. Neurology. 2018;90(8):e664-e672.
Zonisamide may improve parkinsonism in patients with dementia with Lewy bodies (DLB) without worsening cognitive function or psychiatric symptoms, according to a study published in the February 20 issue of Neurology.
“This study provides Class I evidence that zonisamide (adjunctive to levodopa) improves parkinsonism and is well tolerated in patients with DLB,” said Miho Murata, MD, PhD, of the National Center of Neurology and Psychiatry in Tokyo, and colleagues. “We found that the Unified Parkinson’s Disease Rating Scale (UPDRS) part 3 total score at week 12 was significantly improved in the zonisamide 50 mg/day group, compared with the placebo group.”
Four placebo-controlled, randomized trials have found that zonisamide—a drug used to treat seizures—improves motor symptoms in Parkinson’s disease with a low incidence of motor complications such as dyskinesia or psychiatric symptoms such as hallucinations. In another study that included three patients with DLB, zonisamide was associated with improved parkinsonism and reduced caregiver burden without worsening cognition or behavioral or psychological symptoms.
A Phase II, Placebo-Controlled, Double-Blind Study
Based on results from these studies, Dr. Murata and colleagues conducted a phase II, placebo-controlled, randomized double-blind study to examine the efficacy and safety of zonisamide as an adjunct to levodopa therapy for parkinsonism in patients with DLB.
Eligible participants were between ages 20 and 84 and had a UPDRS part 3 score of 10 or greater. The investigators excluded patients with Parkinson’s disease with dementia (ie, well-established Parkinson’s disease followed by onset of dementia), those who did not respond to levodopa therapy, and patients with epilepsy.
The primary end point was change from baseline in UPDRS part 3 score at week 12. Secondary end points included changes from baseline in total UPDRS score, each UPDRS part, and each UPDRS item at each evaluation.
The study included a four-week run-in period and a 12-week treatment period. During the run-in period, patients received placebo tablets once daily under single-blind conditions to eliminate any confounding effects of other antiparkinson drugs.
Participants were randomized 1:1:1 to placebo, zonisamide (25 mg), or zonisamide (50 mg) daily. Patients visited study sites every four weeks for five visits. Dosage and administration of antidementia drugs were unchanged from 12 weeks before the run-in period throughout the treatment period. Dosage and administration of levodopa/decarboxylase inhibitor therapy and other antiparkinson, antihypertensive, CNS, cardiovascular, or gastrointestinal drugs or herbal medicine were unchanged from two weeks before the run-in period throughout the treatment period.
Zonisamide Did Not Worsen Cognitive Function or Behavior
In all, 158 patients were randomized to receive zonisamide or placebo, and 137 patients completed treatment. Zonisamide (50 mg) was associated with significantly greater improvement in UPDRS part 3 scores at week 12, compared with placebo (between group difference, –4.1). In addition, zonisamide did not worsen cognitive function, behavior or psychological symptoms of dementia, or caregiver burden.
The incidence of adverse events was higher in the zonisamide (50 mg) group than in the zonisamide (25 mg) group and placebo group (65.3%, 43.1%, and 50.0%, respectively). The incidences of common drug-related adverse events (eg, decreased weight, decreased appetite, and rash) were higher among patients who received zonisamide, compared with patients who received placebo. The rates of serious adverse events were similar between the groups.
“There is an urgent need for new treatments for DLB,” said Linda A. Hershey, MD, PhD, Professor of Neurology at the University of Oklahoma Health Sciences Center in Oklahoma City, who wrote an accompanying editorial. “The successful execution of this trial is a major accomplishment, which provides evidence that future trials are warranted.”
—Erica Tricarico
Suggested Reading
Hershey LA, Irwin DJ. Zonisamide for DLB parkinsonism: An old drug used in a new context. Neurology. 2018;90(8):349-350.
Murata M, Odawara T, Hasegawa K, et al. Adjunct zonisamide to levodopa for DLB parkinsonism: A randomized double-blind phase 2 study. Neurology. 2018;90(8):e664-e672.
Zonisamide may improve parkinsonism in patients with dementia with Lewy bodies (DLB) without worsening cognitive function or psychiatric symptoms, according to a study published in the February 20 issue of Neurology.
“This study provides Class I evidence that zonisamide (adjunctive to levodopa) improves parkinsonism and is well tolerated in patients with DLB,” said Miho Murata, MD, PhD, of the National Center of Neurology and Psychiatry in Tokyo, and colleagues. “We found that the Unified Parkinson’s Disease Rating Scale (UPDRS) part 3 total score at week 12 was significantly improved in the zonisamide 50 mg/day group, compared with the placebo group.”
Four placebo-controlled, randomized trials have found that zonisamide—a drug used to treat seizures—improves motor symptoms in Parkinson’s disease with a low incidence of motor complications such as dyskinesia or psychiatric symptoms such as hallucinations. In another study that included three patients with DLB, zonisamide was associated with improved parkinsonism and reduced caregiver burden without worsening cognition or behavioral or psychological symptoms.
A Phase II, Placebo-Controlled, Double-Blind Study
Based on results from these studies, Dr. Murata and colleagues conducted a phase II, placebo-controlled, randomized double-blind study to examine the efficacy and safety of zonisamide as an adjunct to levodopa therapy for parkinsonism in patients with DLB.
Eligible participants were between ages 20 and 84 and had a UPDRS part 3 score of 10 or greater. The investigators excluded patients with Parkinson’s disease with dementia (ie, well-established Parkinson’s disease followed by onset of dementia), those who did not respond to levodopa therapy, and patients with epilepsy.
The primary end point was change from baseline in UPDRS part 3 score at week 12. Secondary end points included changes from baseline in total UPDRS score, each UPDRS part, and each UPDRS item at each evaluation.
The study included a four-week run-in period and a 12-week treatment period. During the run-in period, patients received placebo tablets once daily under single-blind conditions to eliminate any confounding effects of other antiparkinson drugs.
Participants were randomized 1:1:1 to placebo, zonisamide (25 mg), or zonisamide (50 mg) daily. Patients visited study sites every four weeks for five visits. Dosage and administration of antidementia drugs were unchanged from 12 weeks before the run-in period throughout the treatment period. Dosage and administration of levodopa/decarboxylase inhibitor therapy and other antiparkinson, antihypertensive, CNS, cardiovascular, or gastrointestinal drugs or herbal medicine were unchanged from two weeks before the run-in period throughout the treatment period.
Zonisamide Did Not Worsen Cognitive Function or Behavior
In all, 158 patients were randomized to receive zonisamide or placebo, and 137 patients completed treatment. Zonisamide (50 mg) was associated with significantly greater improvement in UPDRS part 3 scores at week 12, compared with placebo (between group difference, –4.1). In addition, zonisamide did not worsen cognitive function, behavior or psychological symptoms of dementia, or caregiver burden.
The incidence of adverse events was higher in the zonisamide (50 mg) group than in the zonisamide (25 mg) group and placebo group (65.3%, 43.1%, and 50.0%, respectively). The incidences of common drug-related adverse events (eg, decreased weight, decreased appetite, and rash) were higher among patients who received zonisamide, compared with patients who received placebo. The rates of serious adverse events were similar between the groups.
“There is an urgent need for new treatments for DLB,” said Linda A. Hershey, MD, PhD, Professor of Neurology at the University of Oklahoma Health Sciences Center in Oklahoma City, who wrote an accompanying editorial. “The successful execution of this trial is a major accomplishment, which provides evidence that future trials are warranted.”
—Erica Tricarico
Suggested Reading
Hershey LA, Irwin DJ. Zonisamide for DLB parkinsonism: An old drug used in a new context. Neurology. 2018;90(8):349-350.
Murata M, Odawara T, Hasegawa K, et al. Adjunct zonisamide to levodopa for DLB parkinsonism: A randomized double-blind phase 2 study. Neurology. 2018;90(8):e664-e672.