A tic is described by the DSM-5 as a sudden, rapid, recurrent, nonrhythmic movement or vocalization. Tics are a common occurrence in childhood and can range from mild to severe, transient to chronic, simple to complex. It is not uncommon for parents to ask pediatric care providers when and how to manage tics in children. Here, we present a case to illustrate just such an issue.

Case summary

Adam is an 8-year-old with a previous diagnosis of attention-deficit/hyperactivity disorder (ADHD) who is being seen for follow-up after being started on a stimulant 3 months ago because of declining performance in school and at home, despite adequate accommodations, parent education, and nonpharmacologic treatments. He has done well on a small dose of methylphenidate (0.5 mg/kg per day), but in the context of being asked about other symptoms, his mother, Mary, mentions that she has noticed that Adam is frequently clearing his throat. This began about 6 weeks ago after experiencing allergic rhinitis for almost a week. Since that time, Mary has noticed that he clears his throat as frequently as once every 5 minutes.

The behavior was reported to occur in the classroom, but not nearly with the frequency experienced at home. If asked to not clear his throat, Adam can suppress it. None of his classmates have said anything or appear to have noticed. His parents have never noticed any tics previously. There is a family history of ADHD in his father. There is no other family history of neurodevelopmental disorders, including no obsessive compulsive disorder (OCD), Tourette’s disorder, or other chronic tic disorders. There is nothing else of concern on physical or mental status examination. His mother has concerns that the stimulant medication may be inducing a tic and wonders about stopping it.

Case discussion

Adam has a mild simple vocal tic. The vast majority of tics that develop in childhood will not last the requisite 1 year required to make the diagnosis of a persistent (chronic) motor or vocal tic, nor will they occur with both vocal and motor tics over 1 year required to make the diagnosis of Tourette’s disorder. In the DSM-IV, tics lasting less than 1 year would have been given the diagnosis of transient tic disorder.

In the DSM-5, the diagnosis is now provisional tic disorder because there is no way to tell which tics will be transient and which will be persistent or chronic. Chronic tics occur with a prevalence of between 0.5% and 3%¹, with a male predominance, and are more common in children with ADHD and OCD. In addition, children with chronic tic disorders often have higher incidence of learning problems and, perhaps, autism spectrum disorders. Simple motor and vocal tics (those involving a single muscle group) are more common than complex tics, in which coordinated movements are made. Despite the portrayal in the popular media, it is particularly rare to have complex tics that include copropraxia (an obscene gesture), coprolalia (an obscene movement), echolalia (repeating another’s words), or echopraxia (repeating another’s actions).

Tics tend to have their onset in early school age, with the highest prevalence and severity between the ages of 9 and 12 years.² When present, tics tend to be somewhat suppressed when the child is in school or when the child is engaged in a task. Furthermore, most tics, even when chronic, do not lead to impairment. When impairment does occur, it is often the result of social problems from teasing by peers. Most tics wax and wane over time, but eventually resolve without intervention.

In the case of Adam, there is no clear reason to begin to treat immediately. If one wanted to follow his tics, there are several parent and clinic measures that are available. Taking a history of his case would include ensuring that there are no other predisposing causes and no other psychiatric comorbidities. Induction of tics by the initiation of a stimulant might be considered, although recent data suggest that stimulants are less likely to induce or worsen tics in the course of treatment for ADHD than previously thought.^3,4 If concerned, however, alternative ADHD treatment such as alpha-2 agonist treatment could be considered. Education could be provided to the parents regarding the likelihood of resolution. Should the tics worsen in severity and/or become chronic, there are several behavioral interventions, including habit reversal training and the Comprehensive Behavioral Intervention for Tics, which could be considered as first line.

Medications could be considered if the tics are moderate to severe and behavioral interventions are not sufficient to reduce impairment. The only Food and Drug Administration–approved agents are haloperidol and pimozide, although there is ample support for other agents, and practitioners are most likely to use alternatives, given the side-effect profiles of these typical antipsychotics. Co-occurring symptoms should be considered when thinking about medication. Alpha-2 agonists appear to be most effective in the context of ADHD, while second-generation antipsychotics appear to be more useful if OCD is comorbid. In general, though, in cases like Adam’s, taking a watchful-waiting approach will most often lead to symptom resolution.

References

1. Eur Child Adolesc Psychiatry. 2012 Jan;21(1):5-13.

2. J Am Acad Child Adolesc Psychiatry. 2013 Dec;52(12):1341-59.

3. J Am Acad Child Adolesc Psychiatry. 2015 Sep;54(9):728-36.

4. Cochrane Database Syst Rev. 2011 Apr 13;(4):CD007990.

Dr. Althoff is associate professor of psychiatry, psychology, and pediatrics at the University of Vermont, Burlington. He is director of the division of behavioral genetics and conducts research on the development of self-regulation in children. Email him at [email protected].

A tic is described by the DSM-5 as a sudden, rapid, recurrent, nonrhythmic movement or vocalization. Tics are a common occurrence in childhood and can range from mild to severe, transient to chronic, simple to complex. It is not uncommon for parents to ask pediatric care providers when and how to manage tics in children. Here, we present a case to illustrate just such an issue.

Case summary

Adam is an 8-year-old with a previous diagnosis of attention-deficit/hyperactivity disorder (ADHD) who is being seen for follow-up after being started on a stimulant 3 months ago because of declining performance in school and at home, despite adequate accommodations, parent education, and nonpharmacologic treatments. He has done well on a small dose of methylphenidate (0.5 mg/kg per day), but in the context of being asked about other symptoms, his mother, Mary, mentions that she has noticed that Adam is frequently clearing his throat. This began about 6 weeks ago after experiencing allergic rhinitis for almost a week. Since that time, Mary has noticed that he clears his throat as frequently as once every 5 minutes.

The behavior was reported to occur in the classroom, but not nearly with the frequency experienced at home. If asked to not clear his throat, Adam can suppress it. None of his classmates have said anything or appear to have noticed. His parents have never noticed any tics previously. There is a family history of ADHD in his father. There is no other family history of neurodevelopmental disorders, including no obsessive compulsive disorder (OCD), Tourette’s disorder, or other chronic tic disorders. There is nothing else of concern on physical or mental status examination. His mother has concerns that the stimulant medication may be inducing a tic and wonders about stopping it.

Case discussion

Adam has a mild simple vocal tic. The vast majority of tics that develop in childhood will not last the requisite 1 year required to make the diagnosis of a persistent (chronic) motor or vocal tic, nor will they occur with both vocal and motor tics over 1 year required to make the diagnosis of Tourette’s disorder. In the DSM-IV, tics lasting less than 1 year would have been given the diagnosis of transient tic disorder.

In the DSM-5, the diagnosis is now provisional tic disorder because there is no way to tell which tics will be transient and which will be persistent or chronic. Chronic tics occur with a prevalence of between 0.5% and 3%¹, with a male predominance, and are more common in children with ADHD and OCD. In addition, children with chronic tic disorders often have higher incidence of learning problems and, perhaps, autism spectrum disorders. Simple motor and vocal tics (those involving a single muscle group) are more common than complex tics, in which coordinated movements are made. Despite the portrayal in the popular media, it is particularly rare to have complex tics that include copropraxia (an obscene gesture), coprolalia (an obscene movement), echolalia (repeating another’s words), or echopraxia (repeating another’s actions).

Tics tend to have their onset in early school age, with the highest prevalence and severity between the ages of 9 and 12 years.² When present, tics tend to be somewhat suppressed when the child is in school or when the child is engaged in a task. Furthermore, most tics, even when chronic, do not lead to impairment. When impairment does occur, it is often the result of social problems from teasing by peers. Most tics wax and wane over time, but eventually resolve without intervention.

In the case of Adam, there is no clear reason to begin to treat immediately. If one wanted to follow his tics, there are several parent and clinic measures that are available. Taking a history of his case would include ensuring that there are no other predisposing causes and no other psychiatric comorbidities. Induction of tics by the initiation of a stimulant might be considered, although recent data suggest that stimulants are less likely to induce or worsen tics in the course of treatment for ADHD than previously thought.^3,4 If concerned, however, alternative ADHD treatment such as alpha-2 agonist treatment could be considered. Education could be provided to the parents regarding the likelihood of resolution. Should the tics worsen in severity and/or become chronic, there are several behavioral interventions, including habit reversal training and the Comprehensive Behavioral Intervention for Tics, which could be considered as first line.

Medications could be considered if the tics are moderate to severe and behavioral interventions are not sufficient to reduce impairment. The only Food and Drug Administration–approved agents are haloperidol and pimozide, although there is ample support for other agents, and practitioners are most likely to use alternatives, given the side-effect profiles of these typical antipsychotics. Co-occurring symptoms should be considered when thinking about medication. Alpha-2 agonists appear to be most effective in the context of ADHD, while second-generation antipsychotics appear to be more useful if OCD is comorbid. In general, though, in cases like Adam’s, taking a watchful-waiting approach will most often lead to symptom resolution.

References

1. Eur Child Adolesc Psychiatry. 2012 Jan;21(1):5-13.

2. J Am Acad Child Adolesc Psychiatry. 2013 Dec;52(12):1341-59.

3. J Am Acad Child Adolesc Psychiatry. 2015 Sep;54(9):728-36.

4. Cochrane Database Syst Rev. 2011 Apr 13;(4):CD007990.

Dr. Althoff is associate professor of psychiatry, psychology, and pediatrics at the University of Vermont, Burlington. He is director of the division of behavioral genetics and conducts research on the development of self-regulation in children. Email him at [email protected].

A tic is described by the DSM-5 as a sudden, rapid, recurrent, nonrhythmic movement or vocalization. Tics are a common occurrence in childhood and can range from mild to severe, transient to chronic, simple to complex. It is not uncommon for parents to ask pediatric care providers when and how to manage tics in children. Here, we present a case to illustrate just such an issue.

Case summary

Adam is an 8-year-old with a previous diagnosis of attention-deficit/hyperactivity disorder (ADHD) who is being seen for follow-up after being started on a stimulant 3 months ago because of declining performance in school and at home, despite adequate accommodations, parent education, and nonpharmacologic treatments. He has done well on a small dose of methylphenidate (0.5 mg/kg per day), but in the context of being asked about other symptoms, his mother, Mary, mentions that she has noticed that Adam is frequently clearing his throat. This began about 6 weeks ago after experiencing allergic rhinitis for almost a week. Since that time, Mary has noticed that he clears his throat as frequently as once every 5 minutes.

The behavior was reported to occur in the classroom, but not nearly with the frequency experienced at home. If asked to not clear his throat, Adam can suppress it. None of his classmates have said anything or appear to have noticed. His parents have never noticed any tics previously. There is a family history of ADHD in his father. There is no other family history of neurodevelopmental disorders, including no obsessive compulsive disorder (OCD), Tourette’s disorder, or other chronic tic disorders. There is nothing else of concern on physical or mental status examination. His mother has concerns that the stimulant medication may be inducing a tic and wonders about stopping it.

Case discussion

Adam has a mild simple vocal tic. The vast majority of tics that develop in childhood will not last the requisite 1 year required to make the diagnosis of a persistent (chronic) motor or vocal tic, nor will they occur with both vocal and motor tics over 1 year required to make the diagnosis of Tourette’s disorder. In the DSM-IV, tics lasting less than 1 year would have been given the diagnosis of transient tic disorder.

In the DSM-5, the diagnosis is now provisional tic disorder because there is no way to tell which tics will be transient and which will be persistent or chronic. Chronic tics occur with a prevalence of between 0.5% and 3%¹, with a male predominance, and are more common in children with ADHD and OCD. In addition, children with chronic tic disorders often have higher incidence of learning problems and, perhaps, autism spectrum disorders. Simple motor and vocal tics (those involving a single muscle group) are more common than complex tics, in which coordinated movements are made. Despite the portrayal in the popular media, it is particularly rare to have complex tics that include copropraxia (an obscene gesture), coprolalia (an obscene movement), echolalia (repeating another’s words), or echopraxia (repeating another’s actions).

Tics tend to have their onset in early school age, with the highest prevalence and severity between the ages of 9 and 12 years.² When present, tics tend to be somewhat suppressed when the child is in school or when the child is engaged in a task. Furthermore, most tics, even when chronic, do not lead to impairment. When impairment does occur, it is often the result of social problems from teasing by peers. Most tics wax and wane over time, but eventually resolve without intervention.

In the case of Adam, there is no clear reason to begin to treat immediately. If one wanted to follow his tics, there are several parent and clinic measures that are available. Taking a history of his case would include ensuring that there are no other predisposing causes and no other psychiatric comorbidities. Induction of tics by the initiation of a stimulant might be considered, although recent data suggest that stimulants are less likely to induce or worsen tics in the course of treatment for ADHD than previously thought.^3,4 If concerned, however, alternative ADHD treatment such as alpha-2 agonist treatment could be considered. Education could be provided to the parents regarding the likelihood of resolution. Should the tics worsen in severity and/or become chronic, there are several behavioral interventions, including habit reversal training and the Comprehensive Behavioral Intervention for Tics, which could be considered as first line.

Medications could be considered if the tics are moderate to severe and behavioral interventions are not sufficient to reduce impairment. The only Food and Drug Administration–approved agents are haloperidol and pimozide, although there is ample support for other agents, and practitioners are most likely to use alternatives, given the side-effect profiles of these typical antipsychotics. Co-occurring symptoms should be considered when thinking about medication. Alpha-2 agonists appear to be most effective in the context of ADHD, while second-generation antipsychotics appear to be more useful if OCD is comorbid. In general, though, in cases like Adam’s, taking a watchful-waiting approach will most often lead to symptom resolution.

References

1. Eur Child Adolesc Psychiatry. 2012 Jan;21(1):5-13.

2. J Am Acad Child Adolesc Psychiatry. 2013 Dec;52(12):1341-59.

3. J Am Acad Child Adolesc Psychiatry. 2015 Sep;54(9):728-36.

4. Cochrane Database Syst Rev. 2011 Apr 13;(4):CD007990.

Dr. Althoff is associate professor of psychiatry, psychology, and pediatrics at the University of Vermont, Burlington. He is director of the division of behavioral genetics and conducts research on the development of self-regulation in children. Email him at [email protected].

Antipsychotics should be used judiciously when patients with dementia develop agitation or psychosis, according to the American Psychiatric Association’s first practice guideline on this issue published May 1 in the American Journal of Psychiatry.

Most patients with dementia develop psychosis or agitation during their illness, and treatment, based on expert consensus, often has involved antipsychotics. Antipsychotics have been thought to minimize the risk of violence, reduce patient distress, improve the patient’s quality of life, and reduce the burden on caregivers. But recent clinical trial results suggest that the benefits in this patient population are small at best, while the harms – including increased mortality and accelerated cognitive decline – are significant, said Dr. Victor I. Reus, chair of the APA Practice Guideline Writing Group and his associates.

The group developed this guideline based on a systematic review of the evidence, including results of a survey of experts in the treatment of agitation or psychosis in people with dementia. Overall, the guideline’s 15 recommendations stress that these medications must be just one part of a comprehensive, patient-centered treatment plan that includes both drug and nondrug components, said Dr. Reus, also professor of psychiatry at the University of California, San Francisco, and his associates.

Among the new recommendations, the APA emphasizes that antipsychotics should be used only when agitation or psychosis are severe, dangerous, and/or cause the patient significant distress. The potential risks and benefits should be discussed with the patient (if feasible), family, and other caregivers.

If antipsychotic treatment is initiated, it should be started at low doses and titrated up to the minimum effective dose tolerated. Haloperidol should not be used as a first-line agent, and long-acting injectable antipsychotics should not be used unless indicated for a concomitant chronic psychotic disorder, Dr. Reus and his associates said (Am J Psychiatry. 2016;173:1-4 doi: 10.1176/appi.ajp.2015.173501).

If any side effects develop, the clinician should review all side effects, risks, and benefits, and discuss these with the patient, family, and caregivers, to determine whether tapering or discontinuing the drug is indicated.

Response to treatment should be assessed using a quantitative measure. If there is no clinically relevant response after a 4-week trial of an adequate dose of an antipsychotic medication, it should be tapered and withdrawn. If there is a positive response, eventual tapering of the drug should be discussed with the patient, family, and caregivers, including the potential risks of continued use of these agents.

Attempts to taper and withdraw the antipsychotic should commence within 4 months. Symptoms should be monitored at least monthly during drug tapering and for at least 4 months after treatment cessation to identify signs of recurrence of psychosis or agitation.

The full Guideline is available online at http://psychiatryonline.org.

Antipsychotics should be used judiciously when patients with dementia develop agitation or psychosis, according to the American Psychiatric Association’s first practice guideline on this issue published May 1 in the American Journal of Psychiatry.

Most patients with dementia develop psychosis or agitation during their illness, and treatment, based on expert consensus, often has involved antipsychotics. Antipsychotics have been thought to minimize the risk of violence, reduce patient distress, improve the patient’s quality of life, and reduce the burden on caregivers. But recent clinical trial results suggest that the benefits in this patient population are small at best, while the harms – including increased mortality and accelerated cognitive decline – are significant, said Dr. Victor I. Reus, chair of the APA Practice Guideline Writing Group and his associates.

The group developed this guideline based on a systematic review of the evidence, including results of a survey of experts in the treatment of agitation or psychosis in people with dementia. Overall, the guideline’s 15 recommendations stress that these medications must be just one part of a comprehensive, patient-centered treatment plan that includes both drug and nondrug components, said Dr. Reus, also professor of psychiatry at the University of California, San Francisco, and his associates.

Among the new recommendations, the APA emphasizes that antipsychotics should be used only when agitation or psychosis are severe, dangerous, and/or cause the patient significant distress. The potential risks and benefits should be discussed with the patient (if feasible), family, and other caregivers.

If antipsychotic treatment is initiated, it should be started at low doses and titrated up to the minimum effective dose tolerated. Haloperidol should not be used as a first-line agent, and long-acting injectable antipsychotics should not be used unless indicated for a concomitant chronic psychotic disorder, Dr. Reus and his associates said (Am J Psychiatry. 2016;173:1-4 doi: 10.1176/appi.ajp.2015.173501).

If any side effects develop, the clinician should review all side effects, risks, and benefits, and discuss these with the patient, family, and caregivers, to determine whether tapering or discontinuing the drug is indicated.

Response to treatment should be assessed using a quantitative measure. If there is no clinically relevant response after a 4-week trial of an adequate dose of an antipsychotic medication, it should be tapered and withdrawn. If there is a positive response, eventual tapering of the drug should be discussed with the patient, family, and caregivers, including the potential risks of continued use of these agents.

Attempts to taper and withdraw the antipsychotic should commence within 4 months. Symptoms should be monitored at least monthly during drug tapering and for at least 4 months after treatment cessation to identify signs of recurrence of psychosis or agitation.

The full Guideline is available online at http://psychiatryonline.org.

Antipsychotics should be used judiciously when patients with dementia develop agitation or psychosis, according to the American Psychiatric Association’s first practice guideline on this issue published May 1 in the American Journal of Psychiatry.

Most patients with dementia develop psychosis or agitation during their illness, and treatment, based on expert consensus, often has involved antipsychotics. Antipsychotics have been thought to minimize the risk of violence, reduce patient distress, improve the patient’s quality of life, and reduce the burden on caregivers. But recent clinical trial results suggest that the benefits in this patient population are small at best, while the harms – including increased mortality and accelerated cognitive decline – are significant, said Dr. Victor I. Reus, chair of the APA Practice Guideline Writing Group and his associates.

The group developed this guideline based on a systematic review of the evidence, including results of a survey of experts in the treatment of agitation or psychosis in people with dementia. Overall, the guideline’s 15 recommendations stress that these medications must be just one part of a comprehensive, patient-centered treatment plan that includes both drug and nondrug components, said Dr. Reus, also professor of psychiatry at the University of California, San Francisco, and his associates.

Among the new recommendations, the APA emphasizes that antipsychotics should be used only when agitation or psychosis are severe, dangerous, and/or cause the patient significant distress. The potential risks and benefits should be discussed with the patient (if feasible), family, and other caregivers.

If antipsychotic treatment is initiated, it should be started at low doses and titrated up to the minimum effective dose tolerated. Haloperidol should not be used as a first-line agent, and long-acting injectable antipsychotics should not be used unless indicated for a concomitant chronic psychotic disorder, Dr. Reus and his associates said (Am J Psychiatry. 2016;173:1-4 doi: 10.1176/appi.ajp.2015.173501).

If any side effects develop, the clinician should review all side effects, risks, and benefits, and discuss these with the patient, family, and caregivers, to determine whether tapering or discontinuing the drug is indicated.

Response to treatment should be assessed using a quantitative measure. If there is no clinically relevant response after a 4-week trial of an adequate dose of an antipsychotic medication, it should be tapered and withdrawn. If there is a positive response, eventual tapering of the drug should be discussed with the patient, family, and caregivers, including the potential risks of continued use of these agents.

Attempts to taper and withdraw the antipsychotic should commence within 4 months. Symptoms should be monitored at least monthly during drug tapering and for at least 4 months after treatment cessation to identify signs of recurrence of psychosis or agitation.

The full Guideline is available online at http://psychiatryonline.org.

Patients who have type 1 diabetes have an increased risk of developing epilepsy, according to a study published online ahead of print March 31 in Diabetologia. This study cohort included 2,568 patients with type 1 diabetes, each of whom was frequency-matched by sex, residence, and index year with 10 patients without type 1 diabetes. Cox proportional hazard regression analysis was conducted to estimate the effects of type 1 diabetes on epilepsy risk. After adjusting for potential confounders, the type 1 diabetes cohort was 2.84 times more likely to develop epilepsy than the control cohort. “Metabolic abnormalities of type 1 diabetes, such as hyperglycemia and hypoglycemia, may have a damaging effect on the central nervous system and be associated with significant long-term neurological sequelae,” said the authors.

Antipsychotics are associated with a significantly increased mortality risk in patients with Parkinson’s disease, after adjusting for measurable confounders, according to a study published online ahead of print March 21 in JAMA Neurology. This retrospective matched-cohort study used data from the fiscal years of 1999 to 2010. The rates of 180-day mortality were compared in 7,877 patients initiating antipsychotic therapy and in 7,877 patients who did not initiate antipsychotic therapy. Antipsychotic use was associated with more than twice the hazard ratio of death, compared with nonuse. The hazard ratio was significantly higher for patients who used typical versus atypical antipsychotics. Among the atypical antipsychotics used, hazard ratios relative to nonuse of antipsychotics were, in descending order, 2.79 for olanzapine, 2.46 for risperidone, and 2.16 for quetiapine fumarate.

White matter tracts related to regulation of sleep and wakefulness, and limbic cognitive and sensorimotor regions, are disrupted in the right brain in patients with primary insomnia, according to a study published online ahead of print April 5 in Radiology. Investigators used tract-based spatial statistics to compare changes in diffusion parameters of white matter tracts from 23 patients with primary insomnia and 30 healthy controls. They evaluated how accurately these changes could distinguish patients with insomnia from healthy controls. Patients with primary insomnia had lower fractional anisotropy values mainly in the right anterior limb of the internal capsule, the right posterior limb of the internal capsule, the right anterior corona radiata, the right superior corona radiata, the right superior longitudinal fasciculus, the body of the corpus callosum, and the right thalamus.

Among Chinese adults, a higher level of fruit consumption is associated with lower blood pressure and blood glucose levels and, largely independent of these and other factors, with significantly lower risks of major cardiovascular diseases, according to a study published April 7 in the New England Journal of Medicine. Between 2004 and 2008, researchers recruited 512,891 adults between ages 30 and 79 from 10 locations in China. In all, 5,173 deaths from cardiovascular disease, 2,551 incident major coronary events, 14,579 ischemic strokes, and 3,523 intracerebral hemorrhages were recorded among the 451,665 participants without a history of cardiovascular disease or antihypertensive treatments at baseline. The adjusted hazard ratios for daily consumption versus nonconsumption were 0.75 for ischemic stroke and 0.64 for hemorrhagic stroke.

A low level of leisure-time physical activity is independently associated with greater decline in cognitive performance over time, according to a study published online ahead of print March 23 in Neurology. Researchers assessed cognition in participants in the Northern Manhattan Study using a standard neuropsychologic examination. The neuropsychologic examination was repeated five years later and subcategorized using standardized z scores over validated domains. No or low levels of leisure-time physical activity were associated with worse executive function, semantic memory, and processing speed scores on the first neuropsychologic examination. The associations were slightly attenuated and not significant after adjusting for vascular risk factors. Cognitively unimpaired participants who reported no to low leisure-time physical activity versus moderate to high levels declined more over time in processing speed and episodic memory.

Participation in the “Sleep for Success” education program is associated with significant improvement in children’s sleep and academic performance, according to a study published in Sleep Medicine. Using a community-based participatory research approach, researchers composed a program of four modules that addressed the children, their family and community, the school staff, and decision-makers within the school setting. In all, 71 students participated in the evaluation of the program. The effectiveness of the program was evaluated using nonrandomized, controlled before-and-after study groups that were assessed at two time points. In the intervention group, true sleep was extended by 18.2 minutes per night, sleep efficiency improved by 2.3%, and sleep latency was shortened by 2.3 minutes. Report card grades also improved significantly in English and mathematics.

The combination of rosuvastatin, candesartan, and hydrochlorothiazide is associated with a significantly lower rate of cardiovascular events than dual placebo in people who do not have cardiovascular disease, according to a study published online ahead of print April 2 in the New England Journal of Medicine. Researchers randomly assigned 12,705 participants at intermediate risk who did not have cardiovascular disease to 10 mg/day of rosuvastatin or placebo, and to 16 mg/day of candesartan, plus 12.5 mg/day of hydrochlorothiazide or placebo. The decrease in the low-density lipoprotein cholesterol level was 33.7 mg/dL greater in the combined-therapy group than in the dual-placebo group, and the decrease in systolic blood pressure was 6.2 mm Hg greater with combined therapy than with dual placebo.

Right hemisphere white matter integrity is related to speech fluency measures in patients with chronic aphasia, according to a study published online ahead of print March 30 in Neurology. The study included 33 people with an average age of 58 who had a stroke on the left side of their brain. Fractional anisotropy values for the right middle temporal gyrus, precentral gyrus, and pars opercularis significantly predicted speech fluency, but fractional anisotropy values of the pars triangularis and superior parietal lobule did not. A multiple regression analysis showed that combining fractional anisotropy of the significant right hemisphere regions with the lesion load of the left arcuate fasciculus provided the best model for predicting speech fluency. Fractional anisotropy of corpus callosum fibers connecting left and right supplementary motor areas was also correlated with speech fluency.

Differences in white matter microstructure may partially account for the variance in functional outcomes among veterans with combat-related mild traumatic brain injury (mTBI), according to a study published online ahead of print March 29 in Radiology. From 2010 to 2013, an initial post deployment evaluation, including clinical assessment and brain MRI with diffusion tensor imaging, was performed in combat veterans who sustained mTBI while deployed. Veterans who did and did not return to work were also compared for differences in clinical variables by using t and χ² tests. After a mean follow-up of 1.4 years, 34 of 57 veterans had returned to work. Cumulative health care visits over time were inversely correlated with diffusion anisotropy of the splenium of the corpus callosum and adjacent parietal white matter.

Cognitive status and intelligibility may be associated with everyday communicative outcomes in Parkinson’s disease, according to a study published online ahead of print March 16 in the Journal of Parkinson’s Disease. Investigators searched five online databases in May 2015 and also conducted supplementary searches. In all, 4,816 records were identified through database searches, and 16 additional records were identified through supplementary searches. Forty-one articles were suitable for full-text screening, and 15 articles met the eligibility criteria. Ten studies assessed the role of cognitive status, and nine found that participants with greater cognitive impairment had greater everyday communication difficulties. Four studies assessed the role of intelligibility, and all found that participants with greater intelligibility impairment had greater everyday communication difficulties. Effects often were weak, however, and not consistent.

Common variants near FOXF2 are associated with increased stroke susceptibility, according to a study published online ahead of print April 7 in the Lancet Neurology. Researchers completed a genome-wide analysis of common genetic variants associated with incident stroke risk in 18 population-based cohorts consisting of 84,961 participants, of whom 4,348 had stroke. Investigators completed validation analyses for variants yielding a significant association with all stroke, ischemic stroke, cardioembolic ischemic stroke, or noncardioembolic ischemic stroke. Study authors replicated seven of eight known loci associated with risk for ischemic stroke and identified a novel locus at chromosome 6p25 associated with risk of all stroke. The rs12204590 stroke risk allele was also associated with increased white matter hyperintensity in adults without stroke. Young patients with segmental deletions of FOXF2 showed extensive white matter hyperintensity.

Young women with musculoskeletal pain complaints may have comorbid sleep problems that require treatment, according to a study published in the April issue of Pain. Researchers investigated the cross-sectional and longitudinal relationship between sleep problems and chronic pain, and musculoskeletal pain, headache, and abdominal pain severity in a general population of adults between ages 19 and 22. They studied whether relationships were moderated by sex and whether symptoms of anxiety and depression, fatigue, or physical inactivity mediated these effects. Follow-up data were collected in 1,753 participants. Sleep problems were associated with chronic pain, musculoskeletal pain, headache, and abdominal pain severity. They also predicted chronic pain and an increase in musculoskeletal pain severity at three years of follow-up. The effect was stronger in females than in males.

—Kimberly Williams

Patients who have type 1 diabetes have an increased risk of developing epilepsy, according to a study published online ahead of print March 31 in Diabetologia. This study cohort included 2,568 patients with type 1 diabetes, each of whom was frequency-matched by sex, residence, and index year with 10 patients without type 1 diabetes. Cox proportional hazard regression analysis was conducted to estimate the effects of type 1 diabetes on epilepsy risk. After adjusting for potential confounders, the type 1 diabetes cohort was 2.84 times more likely to develop epilepsy than the control cohort. “Metabolic abnormalities of type 1 diabetes, such as hyperglycemia and hypoglycemia, may have a damaging effect on the central nervous system and be associated with significant long-term neurological sequelae,” said the authors.

Antipsychotics are associated with a significantly increased mortality risk in patients with Parkinson’s disease, after adjusting for measurable confounders, according to a study published online ahead of print March 21 in JAMA Neurology. This retrospective matched-cohort study used data from the fiscal years of 1999 to 2010. The rates of 180-day mortality were compared in 7,877 patients initiating antipsychotic therapy and in 7,877 patients who did not initiate antipsychotic therapy. Antipsychotic use was associated with more than twice the hazard ratio of death, compared with nonuse. The hazard ratio was significantly higher for patients who used typical versus atypical antipsychotics. Among the atypical antipsychotics used, hazard ratios relative to nonuse of antipsychotics were, in descending order, 2.79 for olanzapine, 2.46 for risperidone, and 2.16 for quetiapine fumarate.

White matter tracts related to regulation of sleep and wakefulness, and limbic cognitive and sensorimotor regions, are disrupted in the right brain in patients with primary insomnia, according to a study published online ahead of print April 5 in Radiology. Investigators used tract-based spatial statistics to compare changes in diffusion parameters of white matter tracts from 23 patients with primary insomnia and 30 healthy controls. They evaluated how accurately these changes could distinguish patients with insomnia from healthy controls. Patients with primary insomnia had lower fractional anisotropy values mainly in the right anterior limb of the internal capsule, the right posterior limb of the internal capsule, the right anterior corona radiata, the right superior corona radiata, the right superior longitudinal fasciculus, the body of the corpus callosum, and the right thalamus.

Among Chinese adults, a higher level of fruit consumption is associated with lower blood pressure and blood glucose levels and, largely independent of these and other factors, with significantly lower risks of major cardiovascular diseases, according to a study published April 7 in the New England Journal of Medicine. Between 2004 and 2008, researchers recruited 512,891 adults between ages 30 and 79 from 10 locations in China. In all, 5,173 deaths from cardiovascular disease, 2,551 incident major coronary events, 14,579 ischemic strokes, and 3,523 intracerebral hemorrhages were recorded among the 451,665 participants without a history of cardiovascular disease or antihypertensive treatments at baseline. The adjusted hazard ratios for daily consumption versus nonconsumption were 0.75 for ischemic stroke and 0.64 for hemorrhagic stroke.

A low level of leisure-time physical activity is independently associated with greater decline in cognitive performance over time, according to a study published online ahead of print March 23 in Neurology. Researchers assessed cognition in participants in the Northern Manhattan Study using a standard neuropsychologic examination. The neuropsychologic examination was repeated five years later and subcategorized using standardized z scores over validated domains. No or low levels of leisure-time physical activity were associated with worse executive function, semantic memory, and processing speed scores on the first neuropsychologic examination. The associations were slightly attenuated and not significant after adjusting for vascular risk factors. Cognitively unimpaired participants who reported no to low leisure-time physical activity versus moderate to high levels declined more over time in processing speed and episodic memory.

Participation in the “Sleep for Success” education program is associated with significant improvement in children’s sleep and academic performance, according to a study published in Sleep Medicine. Using a community-based participatory research approach, researchers composed a program of four modules that addressed the children, their family and community, the school staff, and decision-makers within the school setting. In all, 71 students participated in the evaluation of the program. The effectiveness of the program was evaluated using nonrandomized, controlled before-and-after study groups that were assessed at two time points. In the intervention group, true sleep was extended by 18.2 minutes per night, sleep efficiency improved by 2.3%, and sleep latency was shortened by 2.3 minutes. Report card grades also improved significantly in English and mathematics.

The combination of rosuvastatin, candesartan, and hydrochlorothiazide is associated with a significantly lower rate of cardiovascular events than dual placebo in people who do not have cardiovascular disease, according to a study published online ahead of print April 2 in the New England Journal of Medicine. Researchers randomly assigned 12,705 participants at intermediate risk who did not have cardiovascular disease to 10 mg/day of rosuvastatin or placebo, and to 16 mg/day of candesartan, plus 12.5 mg/day of hydrochlorothiazide or placebo. The decrease in the low-density lipoprotein cholesterol level was 33.7 mg/dL greater in the combined-therapy group than in the dual-placebo group, and the decrease in systolic blood pressure was 6.2 mm Hg greater with combined therapy than with dual placebo.

Right hemisphere white matter integrity is related to speech fluency measures in patients with chronic aphasia, according to a study published online ahead of print March 30 in Neurology. The study included 33 people with an average age of 58 who had a stroke on the left side of their brain. Fractional anisotropy values for the right middle temporal gyrus, precentral gyrus, and pars opercularis significantly predicted speech fluency, but fractional anisotropy values of the pars triangularis and superior parietal lobule did not. A multiple regression analysis showed that combining fractional anisotropy of the significant right hemisphere regions with the lesion load of the left arcuate fasciculus provided the best model for predicting speech fluency. Fractional anisotropy of corpus callosum fibers connecting left and right supplementary motor areas was also correlated with speech fluency.

Differences in white matter microstructure may partially account for the variance in functional outcomes among veterans with combat-related mild traumatic brain injury (mTBI), according to a study published online ahead of print March 29 in Radiology. From 2010 to 2013, an initial post deployment evaluation, including clinical assessment and brain MRI with diffusion tensor imaging, was performed in combat veterans who sustained mTBI while deployed. Veterans who did and did not return to work were also compared for differences in clinical variables by using t and χ² tests. After a mean follow-up of 1.4 years, 34 of 57 veterans had returned to work. Cumulative health care visits over time were inversely correlated with diffusion anisotropy of the splenium of the corpus callosum and adjacent parietal white matter.

Cognitive status and intelligibility may be associated with everyday communicative outcomes in Parkinson’s disease, according to a study published online ahead of print March 16 in the Journal of Parkinson’s Disease. Investigators searched five online databases in May 2015 and also conducted supplementary searches. In all, 4,816 records were identified through database searches, and 16 additional records were identified through supplementary searches. Forty-one articles were suitable for full-text screening, and 15 articles met the eligibility criteria. Ten studies assessed the role of cognitive status, and nine found that participants with greater cognitive impairment had greater everyday communication difficulties. Four studies assessed the role of intelligibility, and all found that participants with greater intelligibility impairment had greater everyday communication difficulties. Effects often were weak, however, and not consistent.

Common variants near FOXF2 are associated with increased stroke susceptibility, according to a study published online ahead of print April 7 in the Lancet Neurology. Researchers completed a genome-wide analysis of common genetic variants associated with incident stroke risk in 18 population-based cohorts consisting of 84,961 participants, of whom 4,348 had stroke. Investigators completed validation analyses for variants yielding a significant association with all stroke, ischemic stroke, cardioembolic ischemic stroke, or noncardioembolic ischemic stroke. Study authors replicated seven of eight known loci associated with risk for ischemic stroke and identified a novel locus at chromosome 6p25 associated with risk of all stroke. The rs12204590 stroke risk allele was also associated with increased white matter hyperintensity in adults without stroke. Young patients with segmental deletions of FOXF2 showed extensive white matter hyperintensity.

Young women with musculoskeletal pain complaints may have comorbid sleep problems that require treatment, according to a study published in the April issue of Pain. Researchers investigated the cross-sectional and longitudinal relationship between sleep problems and chronic pain, and musculoskeletal pain, headache, and abdominal pain severity in a general population of adults between ages 19 and 22. They studied whether relationships were moderated by sex and whether symptoms of anxiety and depression, fatigue, or physical inactivity mediated these effects. Follow-up data were collected in 1,753 participants. Sleep problems were associated with chronic pain, musculoskeletal pain, headache, and abdominal pain severity. They also predicted chronic pain and an increase in musculoskeletal pain severity at three years of follow-up. The effect was stronger in females than in males.

—Kimberly Williams

Patients who have type 1 diabetes have an increased risk of developing epilepsy, according to a study published online ahead of print March 31 in Diabetologia. This study cohort included 2,568 patients with type 1 diabetes, each of whom was frequency-matched by sex, residence, and index year with 10 patients without type 1 diabetes. Cox proportional hazard regression analysis was conducted to estimate the effects of type 1 diabetes on epilepsy risk. After adjusting for potential confounders, the type 1 diabetes cohort was 2.84 times more likely to develop epilepsy than the control cohort. “Metabolic abnormalities of type 1 diabetes, such as hyperglycemia and hypoglycemia, may have a damaging effect on the central nervous system and be associated with significant long-term neurological sequelae,” said the authors.

Antipsychotics are associated with a significantly increased mortality risk in patients with Parkinson’s disease, after adjusting for measurable confounders, according to a study published online ahead of print March 21 in JAMA Neurology. This retrospective matched-cohort study used data from the fiscal years of 1999 to 2010. The rates of 180-day mortality were compared in 7,877 patients initiating antipsychotic therapy and in 7,877 patients who did not initiate antipsychotic therapy. Antipsychotic use was associated with more than twice the hazard ratio of death, compared with nonuse. The hazard ratio was significantly higher for patients who used typical versus atypical antipsychotics. Among the atypical antipsychotics used, hazard ratios relative to nonuse of antipsychotics were, in descending order, 2.79 for olanzapine, 2.46 for risperidone, and 2.16 for quetiapine fumarate.

White matter tracts related to regulation of sleep and wakefulness, and limbic cognitive and sensorimotor regions, are disrupted in the right brain in patients with primary insomnia, according to a study published online ahead of print April 5 in Radiology. Investigators used tract-based spatial statistics to compare changes in diffusion parameters of white matter tracts from 23 patients with primary insomnia and 30 healthy controls. They evaluated how accurately these changes could distinguish patients with insomnia from healthy controls. Patients with primary insomnia had lower fractional anisotropy values mainly in the right anterior limb of the internal capsule, the right posterior limb of the internal capsule, the right anterior corona radiata, the right superior corona radiata, the right superior longitudinal fasciculus, the body of the corpus callosum, and the right thalamus.

Among Chinese adults, a higher level of fruit consumption is associated with lower blood pressure and blood glucose levels and, largely independent of these and other factors, with significantly lower risks of major cardiovascular diseases, according to a study published April 7 in the New England Journal of Medicine. Between 2004 and 2008, researchers recruited 512,891 adults between ages 30 and 79 from 10 locations in China. In all, 5,173 deaths from cardiovascular disease, 2,551 incident major coronary events, 14,579 ischemic strokes, and 3,523 intracerebral hemorrhages were recorded among the 451,665 participants without a history of cardiovascular disease or antihypertensive treatments at baseline. The adjusted hazard ratios for daily consumption versus nonconsumption were 0.75 for ischemic stroke and 0.64 for hemorrhagic stroke.

A low level of leisure-time physical activity is independently associated with greater decline in cognitive performance over time, according to a study published online ahead of print March 23 in Neurology. Researchers assessed cognition in participants in the Northern Manhattan Study using a standard neuropsychologic examination. The neuropsychologic examination was repeated five years later and subcategorized using standardized z scores over validated domains. No or low levels of leisure-time physical activity were associated with worse executive function, semantic memory, and processing speed scores on the first neuropsychologic examination. The associations were slightly attenuated and not significant after adjusting for vascular risk factors. Cognitively unimpaired participants who reported no to low leisure-time physical activity versus moderate to high levels declined more over time in processing speed and episodic memory.

Participation in the “Sleep for Success” education program is associated with significant improvement in children’s sleep and academic performance, according to a study published in Sleep Medicine. Using a community-based participatory research approach, researchers composed a program of four modules that addressed the children, their family and community, the school staff, and decision-makers within the school setting. In all, 71 students participated in the evaluation of the program. The effectiveness of the program was evaluated using nonrandomized, controlled before-and-after study groups that were assessed at two time points. In the intervention group, true sleep was extended by 18.2 minutes per night, sleep efficiency improved by 2.3%, and sleep latency was shortened by 2.3 minutes. Report card grades also improved significantly in English and mathematics.

The combination of rosuvastatin, candesartan, and hydrochlorothiazide is associated with a significantly lower rate of cardiovascular events than dual placebo in people who do not have cardiovascular disease, according to a study published online ahead of print April 2 in the New England Journal of Medicine. Researchers randomly assigned 12,705 participants at intermediate risk who did not have cardiovascular disease to 10 mg/day of rosuvastatin or placebo, and to 16 mg/day of candesartan, plus 12.5 mg/day of hydrochlorothiazide or placebo. The decrease in the low-density lipoprotein cholesterol level was 33.7 mg/dL greater in the combined-therapy group than in the dual-placebo group, and the decrease in systolic blood pressure was 6.2 mm Hg greater with combined therapy than with dual placebo.

Right hemisphere white matter integrity is related to speech fluency measures in patients with chronic aphasia, according to a study published online ahead of print March 30 in Neurology. The study included 33 people with an average age of 58 who had a stroke on the left side of their brain. Fractional anisotropy values for the right middle temporal gyrus, precentral gyrus, and pars opercularis significantly predicted speech fluency, but fractional anisotropy values of the pars triangularis and superior parietal lobule did not. A multiple regression analysis showed that combining fractional anisotropy of the significant right hemisphere regions with the lesion load of the left arcuate fasciculus provided the best model for predicting speech fluency. Fractional anisotropy of corpus callosum fibers connecting left and right supplementary motor areas was also correlated with speech fluency.

Differences in white matter microstructure may partially account for the variance in functional outcomes among veterans with combat-related mild traumatic brain injury (mTBI), according to a study published online ahead of print March 29 in Radiology. From 2010 to 2013, an initial post deployment evaluation, including clinical assessment and brain MRI with diffusion tensor imaging, was performed in combat veterans who sustained mTBI while deployed. Veterans who did and did not return to work were also compared for differences in clinical variables by using t and χ² tests. After a mean follow-up of 1.4 years, 34 of 57 veterans had returned to work. Cumulative health care visits over time were inversely correlated with diffusion anisotropy of the splenium of the corpus callosum and adjacent parietal white matter.

Cognitive status and intelligibility may be associated with everyday communicative outcomes in Parkinson’s disease, according to a study published online ahead of print March 16 in the Journal of Parkinson’s Disease. Investigators searched five online databases in May 2015 and also conducted supplementary searches. In all, 4,816 records were identified through database searches, and 16 additional records were identified through supplementary searches. Forty-one articles were suitable for full-text screening, and 15 articles met the eligibility criteria. Ten studies assessed the role of cognitive status, and nine found that participants with greater cognitive impairment had greater everyday communication difficulties. Four studies assessed the role of intelligibility, and all found that participants with greater intelligibility impairment had greater everyday communication difficulties. Effects often were weak, however, and not consistent.

Common variants near FOXF2 are associated with increased stroke susceptibility, according to a study published online ahead of print April 7 in the Lancet Neurology. Researchers completed a genome-wide analysis of common genetic variants associated with incident stroke risk in 18 population-based cohorts consisting of 84,961 participants, of whom 4,348 had stroke. Investigators completed validation analyses for variants yielding a significant association with all stroke, ischemic stroke, cardioembolic ischemic stroke, or noncardioembolic ischemic stroke. Study authors replicated seven of eight known loci associated with risk for ischemic stroke and identified a novel locus at chromosome 6p25 associated with risk of all stroke. The rs12204590 stroke risk allele was also associated with increased white matter hyperintensity in adults without stroke. Young patients with segmental deletions of FOXF2 showed extensive white matter hyperintensity.

Young women with musculoskeletal pain complaints may have comorbid sleep problems that require treatment, according to a study published in the April issue of Pain. Researchers investigated the cross-sectional and longitudinal relationship between sleep problems and chronic pain, and musculoskeletal pain, headache, and abdominal pain severity in a general population of adults between ages 19 and 22. They studied whether relationships were moderated by sex and whether symptoms of anxiety and depression, fatigue, or physical inactivity mediated these effects. Follow-up data were collected in 1,753 participants. Sleep problems were associated with chronic pain, musculoskeletal pain, headache, and abdominal pain severity. They also predicted chronic pain and an increase in musculoskeletal pain severity at three years of follow-up. The effect was stronger in females than in males.

—Kimberly Williams

BALTIMORE – Performing a parathyroidectomy in kidney transplant patients before their transplant can reduce the risk of graft failure and provide other benefits, the findings of a retrospective study of 913 patients suggest.

Uremic hyperparathyroidism (UHPT) is common in patients with end-stage kidney disease, and elevated parathyroid hormone (PTH) levels have been linked with delayed graft function after kidney transplants, but current guidelines for PTH levels may not go far enough to reduce the risk of graft failure and other post–kidney transplant complications in people with elevated PTH before transplant, according to Dr. Glenda G. Callender of Yale University, New Haven, Conn., and her colleagues.

“Uremic hyperparathyroidism was associated with an increased risk of complications in the first year post kidney transplant,” Dr. Callender said at the annual meeting of the American Association of Endocrine Surgeons. “Pre–kidney transplant parathyroidectomy was associated with a decreased risk of post–kidney transplant graft failure. This implies that pre–kidney transplant reduction of PTH levels should be considered in patients with UPHT.”

The Yale researchers reviewed outcomes of 913 patients at their institution who had a kidney transplant from 2005 to 2014. They analyzed biochemical values before kidney transplant and at three intervals post transplant: at 1 month, 6 months, and 1 year. Among the outcomes they evaluated were calcium and PTH levels, estimated glomerular filtration rate, complications, delayed graft function, and graft failure. The overall graft survival rate was 97.8% 1 year after kidney transplantation.

Overall, 49.4% of patients (451) had a diagnosis with UHPT before kidney transplant; 6.2% of all patients (57) had parathyroidectomy before kidney transplant and another 2% (18) had parathyroidectomy at some point after their kidney transplant operations. Median baseline PTH levels were higher in the UHPT patients: 206 pg/mL vs. 159 pg/mL for the non-UHPT group, Dr. Callender reported.

The researchers captured complete data on 37 of the 57 patients who had pretransplant parathyroidectomy. Twenty-four (65% of the group) had subtotal parathyroidectomy in which 3.5 glands were removed, and 12 (32%) had fewer than 3.5 glands removed. One patient had total parathyroidectomy, she said.

Among the patients with UHPT, the median pre–kidney transplant PTH was similar between the pretransplant parathyroidectomy and the no-parathyroidectomy groups: 218 pg/mL and 180 pg/mL, respectively, Dr. Callender said.

Pre–kidney transplant diagnosis of UHPT had an odds ratio of 1.44 for complications in the first year after transplant surgery, but not necessarily a greater risk for graft function or graft failure, she said. However, those relative risks changed with the degree of PTH above normal. Patients with UHPT who had pretransplant parathyroidectomy had a lower risk of graft failure, with an odds ratio of 0.547.

Current Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend maintaining PTH levels in patients with UHPT before they have kidney transplant surgery at no more than nine times normal. To test the optimal PTH levels before kidney transplant, the researchers analyzed thresholds ranging from two to nine times the normal limit.

“A pre–kidney transplant [PTH] level greater than or equal to six times normal was associated with post-transplant graft failure but not with delayed graft function or complications in the first year post kidney transplant,” Dr. Callender said. “Although the thresholds at two and four times normal were statistically significant, there was a continued risk significant for graft failure above six times normal.”

This finding “suggests that perhaps the current KDIGO guideline of maintaining patient PTH at up to nine times normal is too liberal,” Dr. Callender said.

She acknowledged several limitations of the study: its retrospective nature, small sample size, and “many missing data points” because a wide variety of dialysis centers with varying documentation standards collected information.

“However,” Dr. Callender said, “we believe these findings support the design and implementation of a multi-institutional, prospective, randomized control trial to evaluate whether a change in management of patients with uremic hyperparathyroidism is warranted.”

Dr. Callender and her coauthors had no financial relationships to disclose.

BALTIMORE – Performing a parathyroidectomy in kidney transplant patients before their transplant can reduce the risk of graft failure and provide other benefits, the findings of a retrospective study of 913 patients suggest.

Uremic hyperparathyroidism (UHPT) is common in patients with end-stage kidney disease, and elevated parathyroid hormone (PTH) levels have been linked with delayed graft function after kidney transplants, but current guidelines for PTH levels may not go far enough to reduce the risk of graft failure and other post–kidney transplant complications in people with elevated PTH before transplant, according to Dr. Glenda G. Callender of Yale University, New Haven, Conn., and her colleagues.

“Uremic hyperparathyroidism was associated with an increased risk of complications in the first year post kidney transplant,” Dr. Callender said at the annual meeting of the American Association of Endocrine Surgeons. “Pre–kidney transplant parathyroidectomy was associated with a decreased risk of post–kidney transplant graft failure. This implies that pre–kidney transplant reduction of PTH levels should be considered in patients with UPHT.”

The Yale researchers reviewed outcomes of 913 patients at their institution who had a kidney transplant from 2005 to 2014. They analyzed biochemical values before kidney transplant and at three intervals post transplant: at 1 month, 6 months, and 1 year. Among the outcomes they evaluated were calcium and PTH levels, estimated glomerular filtration rate, complications, delayed graft function, and graft failure. The overall graft survival rate was 97.8% 1 year after kidney transplantation.

Overall, 49.4% of patients (451) had a diagnosis with UHPT before kidney transplant; 6.2% of all patients (57) had parathyroidectomy before kidney transplant and another 2% (18) had parathyroidectomy at some point after their kidney transplant operations. Median baseline PTH levels were higher in the UHPT patients: 206 pg/mL vs. 159 pg/mL for the non-UHPT group, Dr. Callender reported.

The researchers captured complete data on 37 of the 57 patients who had pretransplant parathyroidectomy. Twenty-four (65% of the group) had subtotal parathyroidectomy in which 3.5 glands were removed, and 12 (32%) had fewer than 3.5 glands removed. One patient had total parathyroidectomy, she said.

Among the patients with UHPT, the median pre–kidney transplant PTH was similar between the pretransplant parathyroidectomy and the no-parathyroidectomy groups: 218 pg/mL and 180 pg/mL, respectively, Dr. Callender said.

Pre–kidney transplant diagnosis of UHPT had an odds ratio of 1.44 for complications in the first year after transplant surgery, but not necessarily a greater risk for graft function or graft failure, she said. However, those relative risks changed with the degree of PTH above normal. Patients with UHPT who had pretransplant parathyroidectomy had a lower risk of graft failure, with an odds ratio of 0.547.

Current Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend maintaining PTH levels in patients with UHPT before they have kidney transplant surgery at no more than nine times normal. To test the optimal PTH levels before kidney transplant, the researchers analyzed thresholds ranging from two to nine times the normal limit.

“A pre–kidney transplant [PTH] level greater than or equal to six times normal was associated with post-transplant graft failure but not with delayed graft function or complications in the first year post kidney transplant,” Dr. Callender said. “Although the thresholds at two and four times normal were statistically significant, there was a continued risk significant for graft failure above six times normal.”

This finding “suggests that perhaps the current KDIGO guideline of maintaining patient PTH at up to nine times normal is too liberal,” Dr. Callender said.

She acknowledged several limitations of the study: its retrospective nature, small sample size, and “many missing data points” because a wide variety of dialysis centers with varying documentation standards collected information.

“However,” Dr. Callender said, “we believe these findings support the design and implementation of a multi-institutional, prospective, randomized control trial to evaluate whether a change in management of patients with uremic hyperparathyroidism is warranted.”

Dr. Callender and her coauthors had no financial relationships to disclose.

BALTIMORE – Performing a parathyroidectomy in kidney transplant patients before their transplant can reduce the risk of graft failure and provide other benefits, the findings of a retrospective study of 913 patients suggest.

Uremic hyperparathyroidism (UHPT) is common in patients with end-stage kidney disease, and elevated parathyroid hormone (PTH) levels have been linked with delayed graft function after kidney transplants, but current guidelines for PTH levels may not go far enough to reduce the risk of graft failure and other post–kidney transplant complications in people with elevated PTH before transplant, according to Dr. Glenda G. Callender of Yale University, New Haven, Conn., and her colleagues.

“Uremic hyperparathyroidism was associated with an increased risk of complications in the first year post kidney transplant,” Dr. Callender said at the annual meeting of the American Association of Endocrine Surgeons. “Pre–kidney transplant parathyroidectomy was associated with a decreased risk of post–kidney transplant graft failure. This implies that pre–kidney transplant reduction of PTH levels should be considered in patients with UPHT.”

The Yale researchers reviewed outcomes of 913 patients at their institution who had a kidney transplant from 2005 to 2014. They analyzed biochemical values before kidney transplant and at three intervals post transplant: at 1 month, 6 months, and 1 year. Among the outcomes they evaluated were calcium and PTH levels, estimated glomerular filtration rate, complications, delayed graft function, and graft failure. The overall graft survival rate was 97.8% 1 year after kidney transplantation.

Overall, 49.4% of patients (451) had a diagnosis with UHPT before kidney transplant; 6.2% of all patients (57) had parathyroidectomy before kidney transplant and another 2% (18) had parathyroidectomy at some point after their kidney transplant operations. Median baseline PTH levels were higher in the UHPT patients: 206 pg/mL vs. 159 pg/mL for the non-UHPT group, Dr. Callender reported.

The researchers captured complete data on 37 of the 57 patients who had pretransplant parathyroidectomy. Twenty-four (65% of the group) had subtotal parathyroidectomy in which 3.5 glands were removed, and 12 (32%) had fewer than 3.5 glands removed. One patient had total parathyroidectomy, she said.

Among the patients with UHPT, the median pre–kidney transplant PTH was similar between the pretransplant parathyroidectomy and the no-parathyroidectomy groups: 218 pg/mL and 180 pg/mL, respectively, Dr. Callender said.

Pre–kidney transplant diagnosis of UHPT had an odds ratio of 1.44 for complications in the first year after transplant surgery, but not necessarily a greater risk for graft function or graft failure, she said. However, those relative risks changed with the degree of PTH above normal. Patients with UHPT who had pretransplant parathyroidectomy had a lower risk of graft failure, with an odds ratio of 0.547.

Current Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend maintaining PTH levels in patients with UHPT before they have kidney transplant surgery at no more than nine times normal. To test the optimal PTH levels before kidney transplant, the researchers analyzed thresholds ranging from two to nine times the normal limit.

“A pre–kidney transplant [PTH] level greater than or equal to six times normal was associated with post-transplant graft failure but not with delayed graft function or complications in the first year post kidney transplant,” Dr. Callender said. “Although the thresholds at two and four times normal were statistically significant, there was a continued risk significant for graft failure above six times normal.”

This finding “suggests that perhaps the current KDIGO guideline of maintaining patient PTH at up to nine times normal is too liberal,” Dr. Callender said.

She acknowledged several limitations of the study: its retrospective nature, small sample size, and “many missing data points” because a wide variety of dialysis centers with varying documentation standards collected information.

“However,” Dr. Callender said, “we believe these findings support the design and implementation of a multi-institutional, prospective, randomized control trial to evaluate whether a change in management of patients with uremic hyperparathyroidism is warranted.”

Dr. Callender and her coauthors had no financial relationships to disclose.

BALTIMORE – Three months of daily, oral treatment with a relatively high but safe dosage of a vitamin D supplement to pregnant mothers during late gestation followed by continued oral supplementation to their neonates during the first 6 months of life led to a significant reduction in the prevalence of dust-mite skin reactivity in those children once they reached 18 months old in a randomized, controlled trial with 259 mothers and infants.

And in a preliminary assessment that tallied the number of children who required primary care office visits for asthma through age 18 months, children who had received the highest vitamin D supplementation also showed a statistically significant reduction of these visits, compared with the placebo control children, Dr. Cameron C. Grant reported at the annual meeting of the Pediatric Academic Societies.

This suggestion that the vitamin D intervention could cut asthma development is not completely certain because in 18-month-old children, diagnosis of asthma is “very insecure,” noted Dr. Grant, a pediatrician at the University of Auckland, New Zealand and at Starship Children’s Hospital, also in Auckland. In addition, a limitation of the observed effect on dust mite atopy on skin-test challenge was that this follow-up occurred in only 186 (72%) of the 259 infants who participated in the study.

The study’s premise was that vitamin D is an immune system modulator, and that New Zealand provides an excellent setting to test the hypothesis that normalized vitamin D levels can help prevent development of atopy and asthma because many of the country’s residents are vitamin D deficient due to their diet and sun avoidance to prevent skin cancers. Results from prior studies had shown that 57% of New Zealand neonates have inadequate levels of vitamin D at birth, defined as a serum level of 25-hydroxyvitamin D of less than 20 ng/ml (less than 50 nmol/L), Dr. Grant noted.

“I think this intervention will only work in populations that are vitamin D deficient,” Dr. Grant said in an interview. In his study, the average serum level of 25-hydroxyvitamin D among control neonates was 38 nmol/L (about 15 ng/mL). In contrast, neonates born to mothers who had received a daily, higher-dose vitamin D supplement during the third trimester had serum measures that were roughly twice that level.

The study enrolled 260 pregnant women from the Auckland area with a single pregnancy at 26-30 weeks’ gestation; average gestational age at baseline was 27 weeks. Dr. Grant and his associates randomized the mothers to receive 1,000 IU oral vitamin D daily, 2,000 oral vitamin D daily, or placebo. The women delivered 259 infants. Infants born to women on the lower dosage supplement then received 400 IU vitamin daily for 6 months, those born to mothers on the higher level supplement received 800 IU vitamin D daily for 6 months, and those born to mothers in the placebo group received placebo supplements daily for 6 months.

Both supplement regimens led to statistically significant increases in serum levels of 25-hydroxyvitamin D in maternal serum at 36 weeks’ gestation, in cord blood at delivery, in the neonates’ serum at ages 2 months and 4 months, and in infant serum in the higher dosage group at 6 months of age, compared with similar measures taken at all these time points in the placebo group.

In addition, the neonates in the higher dosage group had significantly higher serum levels at 2, 4, and 6 months, compared with the lower dosage group. When measured a final time at 18-month follow-up, a year after the end of vitamin D supplementation, average serum levels of 25-hydroxyvitamin D in an three subgroups of children were virtually identical and similar to maternal serum levels at baseline. Dr. Grant and his associates had previously reported these findings and also had documented the safety of both the low and high levels of vitamin D supplements for both mothers and their children (Pediatrics. 2014 Jan;133[1]:e143-53).

The new findings reported by Dr. Grant focused on clinical outcomes at 18 months. He and his colleagues ran skin-prick testing on 186 of the 259 (72%) children in the study (the remaining children weren’t available for this follow-up assessment). They tested three aeroallergens: cat, pollen, and house dust mite. They saw no significant differences in the prevalence of positive skin-prick reactions among the three study groups to cat and pollen, but prevalence levels of positive reactions to dust mite were 9% in the controls, 3% of children in the low-dosage group, and none in the high dosage group. The difference between the controls and high dosage groups was statistically significant; the difference between the controls and the low dosage group was not significant, Dr. Grant said. Additional testing of specific IgE responses to four different dust mite antigens showed statistically significant reductions in responses to each of the four antigens among the high dosage children, compared with the controls and with the low dosage children.

The researchers also tallied the number of acute, primary care office visits during the first 18 months of life among the children in each of the three subgroups for a variety of respiratory diagnoses. The three groups showed no significant differences in total number of office visits for most of these diagnoses, including colds, otitis media, croup, and bronchitis. However, about 12% of children in the control group had been seen in a primary care office for a diagnosis of asthma, compared with none of the children in the low dosage group and about 4% in the high-dosage group. The differences between the two intervention groups and the control group were statistically significant. Dr. Grant cautioned that this finding is very preliminary and that any conclusions about the impact of vitamin D supplements on asthma incidence must await studies with larger numbers of children who are followed to an older age.

Dr. Grant had no disclosures.

[email protected]

On Twitter @mitchelzoler

BALTIMORE – Three months of daily, oral treatment with a relatively high but safe dosage of a vitamin D supplement to pregnant mothers during late gestation followed by continued oral supplementation to their neonates during the first 6 months of life led to a significant reduction in the prevalence of dust-mite skin reactivity in those children once they reached 18 months old in a randomized, controlled trial with 259 mothers and infants.

And in a preliminary assessment that tallied the number of children who required primary care office visits for asthma through age 18 months, children who had received the highest vitamin D supplementation also showed a statistically significant reduction of these visits, compared with the placebo control children, Dr. Cameron C. Grant reported at the annual meeting of the Pediatric Academic Societies.

This suggestion that the vitamin D intervention could cut asthma development is not completely certain because in 18-month-old children, diagnosis of asthma is “very insecure,” noted Dr. Grant, a pediatrician at the University of Auckland, New Zealand and at Starship Children’s Hospital, also in Auckland. In addition, a limitation of the observed effect on dust mite atopy on skin-test challenge was that this follow-up occurred in only 186 (72%) of the 259 infants who participated in the study.

The study’s premise was that vitamin D is an immune system modulator, and that New Zealand provides an excellent setting to test the hypothesis that normalized vitamin D levels can help prevent development of atopy and asthma because many of the country’s residents are vitamin D deficient due to their diet and sun avoidance to prevent skin cancers. Results from prior studies had shown that 57% of New Zealand neonates have inadequate levels of vitamin D at birth, defined as a serum level of 25-hydroxyvitamin D of less than 20 ng/ml (less than 50 nmol/L), Dr. Grant noted.

“I think this intervention will only work in populations that are vitamin D deficient,” Dr. Grant said in an interview. In his study, the average serum level of 25-hydroxyvitamin D among control neonates was 38 nmol/L (about 15 ng/mL). In contrast, neonates born to mothers who had received a daily, higher-dose vitamin D supplement during the third trimester had serum measures that were roughly twice that level.

The study enrolled 260 pregnant women from the Auckland area with a single pregnancy at 26-30 weeks’ gestation; average gestational age at baseline was 27 weeks. Dr. Grant and his associates randomized the mothers to receive 1,000 IU oral vitamin D daily, 2,000 oral vitamin D daily, or placebo. The women delivered 259 infants. Infants born to women on the lower dosage supplement then received 400 IU vitamin daily for 6 months, those born to mothers on the higher level supplement received 800 IU vitamin D daily for 6 months, and those born to mothers in the placebo group received placebo supplements daily for 6 months.

Both supplement regimens led to statistically significant increases in serum levels of 25-hydroxyvitamin D in maternal serum at 36 weeks’ gestation, in cord blood at delivery, in the neonates’ serum at ages 2 months and 4 months, and in infant serum in the higher dosage group at 6 months of age, compared with similar measures taken at all these time points in the placebo group.

In addition, the neonates in the higher dosage group had significantly higher serum levels at 2, 4, and 6 months, compared with the lower dosage group. When measured a final time at 18-month follow-up, a year after the end of vitamin D supplementation, average serum levels of 25-hydroxyvitamin D in an three subgroups of children were virtually identical and similar to maternal serum levels at baseline. Dr. Grant and his associates had previously reported these findings and also had documented the safety of both the low and high levels of vitamin D supplements for both mothers and their children (Pediatrics. 2014 Jan;133[1]:e143-53).

The new findings reported by Dr. Grant focused on clinical outcomes at 18 months. He and his colleagues ran skin-prick testing on 186 of the 259 (72%) children in the study (the remaining children weren’t available for this follow-up assessment). They tested three aeroallergens: cat, pollen, and house dust mite. They saw no significant differences in the prevalence of positive skin-prick reactions among the three study groups to cat and pollen, but prevalence levels of positive reactions to dust mite were 9% in the controls, 3% of children in the low-dosage group, and none in the high dosage group. The difference between the controls and high dosage groups was statistically significant; the difference between the controls and the low dosage group was not significant, Dr. Grant said. Additional testing of specific IgE responses to four different dust mite antigens showed statistically significant reductions in responses to each of the four antigens among the high dosage children, compared with the controls and with the low dosage children.

The researchers also tallied the number of acute, primary care office visits during the first 18 months of life among the children in each of the three subgroups for a variety of respiratory diagnoses. The three groups showed no significant differences in total number of office visits for most of these diagnoses, including colds, otitis media, croup, and bronchitis. However, about 12% of children in the control group had been seen in a primary care office for a diagnosis of asthma, compared with none of the children in the low dosage group and about 4% in the high-dosage group. The differences between the two intervention groups and the control group were statistically significant. Dr. Grant cautioned that this finding is very preliminary and that any conclusions about the impact of vitamin D supplements on asthma incidence must await studies with larger numbers of children who are followed to an older age.

Dr. Grant had no disclosures.

[email protected]

On Twitter @mitchelzoler

BALTIMORE – Three months of daily, oral treatment with a relatively high but safe dosage of a vitamin D supplement to pregnant mothers during late gestation followed by continued oral supplementation to their neonates during the first 6 months of life led to a significant reduction in the prevalence of dust-mite skin reactivity in those children once they reached 18 months old in a randomized, controlled trial with 259 mothers and infants.

And in a preliminary assessment that tallied the number of children who required primary care office visits for asthma through age 18 months, children who had received the highest vitamin D supplementation also showed a statistically significant reduction of these visits, compared with the placebo control children, Dr. Cameron C. Grant reported at the annual meeting of the Pediatric Academic Societies.

This suggestion that the vitamin D intervention could cut asthma development is not completely certain because in 18-month-old children, diagnosis of asthma is “very insecure,” noted Dr. Grant, a pediatrician at the University of Auckland, New Zealand and at Starship Children’s Hospital, also in Auckland. In addition, a limitation of the observed effect on dust mite atopy on skin-test challenge was that this follow-up occurred in only 186 (72%) of the 259 infants who participated in the study.

The study’s premise was that vitamin D is an immune system modulator, and that New Zealand provides an excellent setting to test the hypothesis that normalized vitamin D levels can help prevent development of atopy and asthma because many of the country’s residents are vitamin D deficient due to their diet and sun avoidance to prevent skin cancers. Results from prior studies had shown that 57% of New Zealand neonates have inadequate levels of vitamin D at birth, defined as a serum level of 25-hydroxyvitamin D of less than 20 ng/ml (less than 50 nmol/L), Dr. Grant noted.

“I think this intervention will only work in populations that are vitamin D deficient,” Dr. Grant said in an interview. In his study, the average serum level of 25-hydroxyvitamin D among control neonates was 38 nmol/L (about 15 ng/mL). In contrast, neonates born to mothers who had received a daily, higher-dose vitamin D supplement during the third trimester had serum measures that were roughly twice that level.

The study enrolled 260 pregnant women from the Auckland area with a single pregnancy at 26-30 weeks’ gestation; average gestational age at baseline was 27 weeks. Dr. Grant and his associates randomized the mothers to receive 1,000 IU oral vitamin D daily, 2,000 oral vitamin D daily, or placebo. The women delivered 259 infants. Infants born to women on the lower dosage supplement then received 400 IU vitamin daily for 6 months, those born to mothers on the higher level supplement received 800 IU vitamin D daily for 6 months, and those born to mothers in the placebo group received placebo supplements daily for 6 months.

Both supplement regimens led to statistically significant increases in serum levels of 25-hydroxyvitamin D in maternal serum at 36 weeks’ gestation, in cord blood at delivery, in the neonates’ serum at ages 2 months and 4 months, and in infant serum in the higher dosage group at 6 months of age, compared with similar measures taken at all these time points in the placebo group.

In addition, the neonates in the higher dosage group had significantly higher serum levels at 2, 4, and 6 months, compared with the lower dosage group. When measured a final time at 18-month follow-up, a year after the end of vitamin D supplementation, average serum levels of 25-hydroxyvitamin D in an three subgroups of children were virtually identical and similar to maternal serum levels at baseline. Dr. Grant and his associates had previously reported these findings and also had documented the safety of both the low and high levels of vitamin D supplements for both mothers and their children (Pediatrics. 2014 Jan;133[1]:e143-53).

The new findings reported by Dr. Grant focused on clinical outcomes at 18 months. He and his colleagues ran skin-prick testing on 186 of the 259 (72%) children in the study (the remaining children weren’t available for this follow-up assessment). They tested three aeroallergens: cat, pollen, and house dust mite. They saw no significant differences in the prevalence of positive skin-prick reactions among the three study groups to cat and pollen, but prevalence levels of positive reactions to dust mite were 9% in the controls, 3% of children in the low-dosage group, and none in the high dosage group. The difference between the controls and high dosage groups was statistically significant; the difference between the controls and the low dosage group was not significant, Dr. Grant said. Additional testing of specific IgE responses to four different dust mite antigens showed statistically significant reductions in responses to each of the four antigens among the high dosage children, compared with the controls and with the low dosage children.

The researchers also tallied the number of acute, primary care office visits during the first 18 months of life among the children in each of the three subgroups for a variety of respiratory diagnoses. The three groups showed no significant differences in total number of office visits for most of these diagnoses, including colds, otitis media, croup, and bronchitis. However, about 12% of children in the control group had been seen in a primary care office for a diagnosis of asthma, compared with none of the children in the low dosage group and about 4% in the high-dosage group. The differences between the two intervention groups and the control group were statistically significant. Dr. Grant cautioned that this finding is very preliminary and that any conclusions about the impact of vitamin D supplements on asthma incidence must await studies with larger numbers of children who are followed to an older age.

Dr. Grant had no disclosures.

[email protected]

On Twitter @mitchelzoler

BALTIMORE – The vast majority of reported U.S. episodes of cough and cold medication serious adverse event episodes in young children occurred by an accidental, self-administration overdose, according to a review of all pediatric episodes collected by the designated national surveillance system during 2008-2014.

This pattern highlights the continued need for diligent education of families about the potential danger posed by these largely OTC products as well as a possible additional need for further improvement in protective packaging, Dr. G. Sam Wang said at the annual meeting of the Pediatric Academic Societies.

Mitchel L. Zoler/Frontline Medical News

Although the manufacturers of these products voluntarily changed their labeling in 2007 to say “do not use” in children younger than 4 years old, the continued vulnerability of very young children and the high rate of self-administration suggests that labeling restrictions alone are “unlikely to have a significant impact” on the problem, he said. “What could be better is storage and [packaging] engineering controls to prevent the accidental ingestions that seem to represent the majority of cases,” Dr. Wang said in an interview.

The good news was that the 4,250 reported U.S. cases during 2008-2014 in children younger than age 12 years and judged by an expert review panel to be at least potentially related to cold and cough medications represents a significant decline, compared with earlier periods, and is also “quite low” when compared with the millions of units in annual U.S. sales.

“The overall adverse event rate compared with the volume sold is in the single digits per million of products sold, and the rate has been declining,” said Dr. Wang, a pediatric toxicologist at the University of Colorado in Denver and a consultant to the Rocky Mountain Poison & Drug Center, also in Denver, the group that maintains and reviews this registry, begun in January 2008. “I think we’re making progress,” but diligent education by physicians and other health care providers about the dangers posed by these drugs must continue, he said.

The analysis also identified that two drugs were by far the top culprits in causing pediatric adverse reactions to cough and cold medications, diphenhydramine and dextromethorphan. Diphenhydramine played a role in 53% of the 4,224 nonfatal adverse reaction cases and 54% of the 26 fatal cases identified by the registry panel as at least potentially related to a cough and cold medication, while dextromethorphan was responsible for 41% of the nonfatal and 19% of the fatal cases. In a majority of cases, these drugs were in products with a single active ingredient, although products with combined ingredients also played a role for some cases. Most often these drugs were in OTC formulations and in pediatric formulations.

Dr. Wang called it unlikely that manufacturers would formulate cold and cough medications without diphenhydramine or dextromethorphan because these drugs have the antitussive and sedative properties that consumers seek from cough and cold medications. He also noted that the addition of bittering agents to formulations have not had a history of reducing accidental self-administrations by children, but added “a good taste doesn’t help.”

During 2008-2014 U.S. surveillance by the registry review panel identified a total of 5,342 unique case reports of serious adverse events in children less than 12 years old and believed related to any of eight drugs commonly found in cold and cough medications. The reports came from any of five sources: the National Poison Data System, the Food and Drug Administration’s adverse event reporting system, safety reports to manufacturers, and through surveillance of the medical literature, and the news media. The panel winnowed these down to 4,250 cases at least potentially related to these drugs.

Among the 26 fatal cases, 16 (62%) occurred in children less than 2 years old and an additional four (15%) were in children aged 2 years to less than 4 years. Nine of these cases (35%) involved parental administration, with only two cases (8%) involving self-administration. An additional nine cases (35%) had no reported source of administration, and the remaining six (23%) cases involved other sources of administration. Seven of the 26 fatalities involved confirmed overdoses, with the dose unknown for the remaining 19 cases, Dr. Wang reported.

Among the 4,224 nonfatal cases, 15% occurred in children less than 2 years, 46% in children ages 2 years to less than 4 years, 19% in children 4 years to less than 6 years and 20% in children 6 years to less than 12 years. These cases involved a confirmed overdose in 73% of cases, a therapeutic range dose in 7%, with the remainder involving a dose of unknown size. Self-administration occurred 75% of the time.

[email protected]

On Twitter @mitchelzoler

BALTIMORE – The vast majority of reported U.S. episodes of cough and cold medication serious adverse event episodes in young children occurred by an accidental, self-administration overdose, according to a review of all pediatric episodes collected by the designated national surveillance system during 2008-2014.

This pattern highlights the continued need for diligent education of families about the potential danger posed by these largely OTC products as well as a possible additional need for further improvement in protective packaging, Dr. G. Sam Wang said at the annual meeting of the Pediatric Academic Societies.

Mitchel L. Zoler/Frontline Medical News

Although the manufacturers of these products voluntarily changed their labeling in 2007 to say “do not use” in children younger than 4 years old, the continued vulnerability of very young children and the high rate of self-administration suggests that labeling restrictions alone are “unlikely to have a significant impact” on the problem, he said. “What could be better is storage and [packaging] engineering controls to prevent the accidental ingestions that seem to represent the majority of cases,” Dr. Wang said in an interview.

The good news was that the 4,250 reported U.S. cases during 2008-2014 in children younger than age 12 years and judged by an expert review panel to be at least potentially related to cold and cough medications represents a significant decline, compared with earlier periods, and is also “quite low” when compared with the millions of units in annual U.S. sales.

“The overall adverse event rate compared with the volume sold is in the single digits per million of products sold, and the rate has been declining,” said Dr. Wang, a pediatric toxicologist at the University of Colorado in Denver and a consultant to the Rocky Mountain Poison & Drug Center, also in Denver, the group that maintains and reviews this registry, begun in January 2008. “I think we’re making progress,” but diligent education by physicians and other health care providers about the dangers posed by these drugs must continue, he said.

The analysis also identified that two drugs were by far the top culprits in causing pediatric adverse reactions to cough and cold medications, diphenhydramine and dextromethorphan. Diphenhydramine played a role in 53% of the 4,224 nonfatal adverse reaction cases and 54% of the 26 fatal cases identified by the registry panel as at least potentially related to a cough and cold medication, while dextromethorphan was responsible for 41% of the nonfatal and 19% of the fatal cases. In a majority of cases, these drugs were in products with a single active ingredient, although products with combined ingredients also played a role for some cases. Most often these drugs were in OTC formulations and in pediatric formulations.

Dr. Wang called it unlikely that manufacturers would formulate cold and cough medications without diphenhydramine or dextromethorphan because these drugs have the antitussive and sedative properties that consumers seek from cough and cold medications. He also noted that the addition of bittering agents to formulations have not had a history of reducing accidental self-administrations by children, but added “a good taste doesn’t help.”

During 2008-2014 U.S. surveillance by the registry review panel identified a total of 5,342 unique case reports of serious adverse events in children less than 12 years old and believed related to any of eight drugs commonly found in cold and cough medications. The reports came from any of five sources: the National Poison Data System, the Food and Drug Administration’s adverse event reporting system, safety reports to manufacturers, and through surveillance of the medical literature, and the news media. The panel winnowed these down to 4,250 cases at least potentially related to these drugs.

Among the 26 fatal cases, 16 (62%) occurred in children less than 2 years old and an additional four (15%) were in children aged 2 years to less than 4 years. Nine of these cases (35%) involved parental administration, with only two cases (8%) involving self-administration. An additional nine cases (35%) had no reported source of administration, and the remaining six (23%) cases involved other sources of administration. Seven of the 26 fatalities involved confirmed overdoses, with the dose unknown for the remaining 19 cases, Dr. Wang reported.

Among the 4,224 nonfatal cases, 15% occurred in children less than 2 years, 46% in children ages 2 years to less than 4 years, 19% in children 4 years to less than 6 years and 20% in children 6 years to less than 12 years. These cases involved a confirmed overdose in 73% of cases, a therapeutic range dose in 7%, with the remainder involving a dose of unknown size. Self-administration occurred 75% of the time.

[email protected]

On Twitter @mitchelzoler

BALTIMORE – The vast majority of reported U.S. episodes of cough and cold medication serious adverse event episodes in young children occurred by an accidental, self-administration overdose, according to a review of all pediatric episodes collected by the designated national surveillance system during 2008-2014.

This pattern highlights the continued need for diligent education of families about the potential danger posed by these largely OTC products as well as a possible additional need for further improvement in protective packaging, Dr. G. Sam Wang said at the annual meeting of the Pediatric Academic Societies.

Mitchel L. Zoler/Frontline Medical News

Although the manufacturers of these products voluntarily changed their labeling in 2007 to say “do not use” in children younger than 4 years old, the continued vulnerability of very young children and the high rate of self-administration suggests that labeling restrictions alone are “unlikely to have a significant impact” on the problem, he said. “What could be better is storage and [packaging] engineering controls to prevent the accidental ingestions that seem to represent the majority of cases,” Dr. Wang said in an interview.

The good news was that the 4,250 reported U.S. cases during 2008-2014 in children younger than age 12 years and judged by an expert review panel to be at least potentially related to cold and cough medications represents a significant decline, compared with earlier periods, and is also “quite low” when compared with the millions of units in annual U.S. sales.

“The overall adverse event rate compared with the volume sold is in the single digits per million of products sold, and the rate has been declining,” said Dr. Wang, a pediatric toxicologist at the University of Colorado in Denver and a consultant to the Rocky Mountain Poison & Drug Center, also in Denver, the group that maintains and reviews this registry, begun in January 2008. “I think we’re making progress,” but diligent education by physicians and other health care providers about the dangers posed by these drugs must continue, he said.

The analysis also identified that two drugs were by far the top culprits in causing pediatric adverse reactions to cough and cold medications, diphenhydramine and dextromethorphan. Diphenhydramine played a role in 53% of the 4,224 nonfatal adverse reaction cases and 54% of the 26 fatal cases identified by the registry panel as at least potentially related to a cough and cold medication, while dextromethorphan was responsible for 41% of the nonfatal and 19% of the fatal cases. In a majority of cases, these drugs were in products with a single active ingredient, although products with combined ingredients also played a role for some cases. Most often these drugs were in OTC formulations and in pediatric formulations.

Dr. Wang called it unlikely that manufacturers would formulate cold and cough medications without diphenhydramine or dextromethorphan because these drugs have the antitussive and sedative properties that consumers seek from cough and cold medications. He also noted that the addition of bittering agents to formulations have not had a history of reducing accidental self-administrations by children, but added “a good taste doesn’t help.”

During 2008-2014 U.S. surveillance by the registry review panel identified a total of 5,342 unique case reports of serious adverse events in children less than 12 years old and believed related to any of eight drugs commonly found in cold and cough medications. The reports came from any of five sources: the National Poison Data System, the Food and Drug Administration’s adverse event reporting system, safety reports to manufacturers, and through surveillance of the medical literature, and the news media. The panel winnowed these down to 4,250 cases at least potentially related to these drugs.

Among the 26 fatal cases, 16 (62%) occurred in children less than 2 years old and an additional four (15%) were in children aged 2 years to less than 4 years. Nine of these cases (35%) involved parental administration, with only two cases (8%) involving self-administration. An additional nine cases (35%) had no reported source of administration, and the remaining six (23%) cases involved other sources of administration. Seven of the 26 fatalities involved confirmed overdoses, with the dose unknown for the remaining 19 cases, Dr. Wang reported.

Among the 4,224 nonfatal cases, 15% occurred in children less than 2 years, 46% in children ages 2 years to less than 4 years, 19% in children 4 years to less than 6 years and 20% in children 6 years to less than 12 years. These cases involved a confirmed overdose in 73% of cases, a therapeutic range dose in 7%, with the remainder involving a dose of unknown size. Self-administration occurred 75% of the time.

[email protected]

On Twitter @mitchelzoler

To the Editor:

A 71-year-old woman with hypertension and atrial fibrillation due to thyrotoxicosis was prescribed dabigatran for stroke prevention by her cardiologist. She also was taking pantoprazole, methimazole, and amiodarone at the time of presentation, all managed by her endocrinologist. She had no known drug allergies but reported a remote history of a palmar rash after eating shellfish. She otherwise had never had any problems with her skin and had no family history of psoriasis. She had a history of smoking 50 packs per year but had quit 6 months prior to presentation. After two 150-mg doses of dabigatran, she noticed numerous mildly tender and itchy eruptions on the palmar and plantar surfaces with no associated respiratory, oropharyngeal, or constitutional symptoms. She denied any recent shellfish ingestion. On dermatologic examination, numerous discreet pustules were present on the bilateral palmar and plantar surfaces with minimal erythema of the underlying skin (Figure).

A punch biopsy was taken from a newly forming lesion on the right palm. Histopathology revealed mild hyperkeratosis, spongiosis with lymphocyte exocytosis, intraepidermal vesiculation, and a sparse upper dermal and perivascular lymphohistiocytic infiltration. No neutrophils or microabscesses were seen. Staining with periodic acid–Schiff revealed no fungi, and S-100 staining revealed numerous Langerhans cells in the epidermis. Although the skin lesions clinically appeared pustular, the results were consistent with an eczematous drug reaction. Laboratory values, including a complete blood cell count, iron studies, chemistry panels, liver function, thyroid function, and coagulation studies, were remarkable only for mild anemia. The patient declined any topical or systemic skin treatment. Dabigatran was discontinued, and the lesions began to clear immediately thereafter. Dabigatran was not reintroduced. Enoxaparin subsequently was prescribed for anticoagulation. The diagnosis of a drug reaction due to dabigatran was made, which was supported with a score of 7 on the Naranjo scale (0=doubtful; 1–4=possible; 5–8=probable; ≥9=definite) for determining probability of drug-induced adverse reactions.¹ The differential diagnosis for the skin eruption included palmoplantar pustular psoriasis, dyshidrotic eczema, and allergic contact dermatitis, but the clinical history did not support these diagnoses.

Dabigatran is a direct thrombin inhibitor used to reduce the risk for stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Based on results of the RE-LY (Randomization Evaluation of Long-term Anticoagulation Therapy) trial published in 2009, dabigatran 150 mg twice daily significantly reduced the risk for stroke and systemic emboli in patients with atrial fibrillation compared to warfarin (annual risk, 1.11% vs 1.69%; relative risk, 0.66; 95% CI, 0.53-0.82; P<.001) with the advantage of not requiring frequent monitoring of the international normalized ratio.² The most common adverse effect of dabigatran in this trial was dyspepsia (11.3% vs 5.8%). Drug hypersensitivity, allergic edema, and anaphylaxis were reported in less than 0.1% of patients taking dabigatran.²

According to a PubMed search of articles indexed for MEDLINE using the search terms dabigatran cutaneous reaction and dabigatran rash, 4 case reports of cutaneous eruption due to dabigatran were identified. In one report, a 20-year-old man with atrial fibrillation developed an eruption similar to our patient on the thigh and forearm after 2 weeks of taking oral dabigatran 150 mg twice daily. It resolved without complication after topical corticosteroid use and discontinuation of dabigatran.³ In another report, a 78-year-old man presented to the emergency department after taking two 150-mg doses of dabigatran with a diffuse, full-body, pruritic rash that resolved with oral diphenhydramine and discontinuation of dabigatran.⁴ A third case described a 59-year-old man who was taking 150 mg dabigatran twice daily for 5 days before developing a rash.⁵ The fourth case involved a 74-year-old woman who developed leukocytoclastic vasculitis 1 week after taking dabigatran 150 mg twice daily.⁶

It is important to monitor for and report hypersensitivity reactions in patients taking dabigatran. Drug exanthems may cause discomfort or even herald more serious hypersensitivity reactions. Patients experiencing these reactions may discontinue therapy without notifying a physician and consequently place themselves at risk for embolism or stroke.

To the Editor:

A 71-year-old woman with hypertension and atrial fibrillation due to thyrotoxicosis was prescribed dabigatran for stroke prevention by her cardiologist. She also was taking pantoprazole, methimazole, and amiodarone at the time of presentation, all managed by her endocrinologist. She had no known drug allergies but reported a remote history of a palmar rash after eating shellfish. She otherwise had never had any problems with her skin and had no family history of psoriasis. She had a history of smoking 50 packs per year but had quit 6 months prior to presentation. After two 150-mg doses of dabigatran, she noticed numerous mildly tender and itchy eruptions on the palmar and plantar surfaces with no associated respiratory, oropharyngeal, or constitutional symptoms. She denied any recent shellfish ingestion. On dermatologic examination, numerous discreet pustules were present on the bilateral palmar and plantar surfaces with minimal erythema of the underlying skin (Figure).

A punch biopsy was taken from a newly forming lesion on the right palm. Histopathology revealed mild hyperkeratosis, spongiosis with lymphocyte exocytosis, intraepidermal vesiculation, and a sparse upper dermal and perivascular lymphohistiocytic infiltration. No neutrophils or microabscesses were seen. Staining with periodic acid–Schiff revealed no fungi, and S-100 staining revealed numerous Langerhans cells in the epidermis. Although the skin lesions clinically appeared pustular, the results were consistent with an eczematous drug reaction. Laboratory values, including a complete blood cell count, iron studies, chemistry panels, liver function, thyroid function, and coagulation studies, were remarkable only for mild anemia. The patient declined any topical or systemic skin treatment. Dabigatran was discontinued, and the lesions began to clear immediately thereafter. Dabigatran was not reintroduced. Enoxaparin subsequently was prescribed for anticoagulation. The diagnosis of a drug reaction due to dabigatran was made, which was supported with a score of 7 on the Naranjo scale (0=doubtful; 1–4=possible; 5–8=probable; ≥9=definite) for determining probability of drug-induced adverse reactions.¹ The differential diagnosis for the skin eruption included palmoplantar pustular psoriasis, dyshidrotic eczema, and allergic contact dermatitis, but the clinical history did not support these diagnoses.

Dabigatran is a direct thrombin inhibitor used to reduce the risk for stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Based on results of the RE-LY (Randomization Evaluation of Long-term Anticoagulation Therapy) trial published in 2009, dabigatran 150 mg twice daily significantly reduced the risk for stroke and systemic emboli in patients with atrial fibrillation compared to warfarin (annual risk, 1.11% vs 1.69%; relative risk, 0.66; 95% CI, 0.53-0.82; P<.001) with the advantage of not requiring frequent monitoring of the international normalized ratio.² The most common adverse effect of dabigatran in this trial was dyspepsia (11.3% vs 5.8%). Drug hypersensitivity, allergic edema, and anaphylaxis were reported in less than 0.1% of patients taking dabigatran.²

According to a PubMed search of articles indexed for MEDLINE using the search terms dabigatran cutaneous reaction and dabigatran rash, 4 case reports of cutaneous eruption due to dabigatran were identified. In one report, a 20-year-old man with atrial fibrillation developed an eruption similar to our patient on the thigh and forearm after 2 weeks of taking oral dabigatran 150 mg twice daily. It resolved without complication after topical corticosteroid use and discontinuation of dabigatran.³ In another report, a 78-year-old man presented to the emergency department after taking two 150-mg doses of dabigatran with a diffuse, full-body, pruritic rash that resolved with oral diphenhydramine and discontinuation of dabigatran.⁴ A third case described a 59-year-old man who was taking 150 mg dabigatran twice daily for 5 days before developing a rash.⁵ The fourth case involved a 74-year-old woman who developed leukocytoclastic vasculitis 1 week after taking dabigatran 150 mg twice daily.⁶

It is important to monitor for and report hypersensitivity reactions in patients taking dabigatran. Drug exanthems may cause discomfort or even herald more serious hypersensitivity reactions. Patients experiencing these reactions may discontinue therapy without notifying a physician and consequently place themselves at risk for embolism or stroke.

To the Editor:

A 71-year-old woman with hypertension and atrial fibrillation due to thyrotoxicosis was prescribed dabigatran for stroke prevention by her cardiologist. She also was taking pantoprazole, methimazole, and amiodarone at the time of presentation, all managed by her endocrinologist. She had no known drug allergies but reported a remote history of a palmar rash after eating shellfish. She otherwise had never had any problems with her skin and had no family history of psoriasis. She had a history of smoking 50 packs per year but had quit 6 months prior to presentation. After two 150-mg doses of dabigatran, she noticed numerous mildly tender and itchy eruptions on the palmar and plantar surfaces with no associated respiratory, oropharyngeal, or constitutional symptoms. She denied any recent shellfish ingestion. On dermatologic examination, numerous discreet pustules were present on the bilateral palmar and plantar surfaces with minimal erythema of the underlying skin (Figure).

A punch biopsy was taken from a newly forming lesion on the right palm. Histopathology revealed mild hyperkeratosis, spongiosis with lymphocyte exocytosis, intraepidermal vesiculation, and a sparse upper dermal and perivascular lymphohistiocytic infiltration. No neutrophils or microabscesses were seen. Staining with periodic acid–Schiff revealed no fungi, and S-100 staining revealed numerous Langerhans cells in the epidermis. Although the skin lesions clinically appeared pustular, the results were consistent with an eczematous drug reaction. Laboratory values, including a complete blood cell count, iron studies, chemistry panels, liver function, thyroid function, and coagulation studies, were remarkable only for mild anemia. The patient declined any topical or systemic skin treatment. Dabigatran was discontinued, and the lesions began to clear immediately thereafter. Dabigatran was not reintroduced. Enoxaparin subsequently was prescribed for anticoagulation. The diagnosis of a drug reaction due to dabigatran was made, which was supported with a score of 7 on the Naranjo scale (0=doubtful; 1–4=possible; 5–8=probable; ≥9=definite) for determining probability of drug-induced adverse reactions.¹ The differential diagnosis for the skin eruption included palmoplantar pustular psoriasis, dyshidrotic eczema, and allergic contact dermatitis, but the clinical history did not support these diagnoses.

Dabigatran is a direct thrombin inhibitor used to reduce the risk for stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Based on results of the RE-LY (Randomization Evaluation of Long-term Anticoagulation Therapy) trial published in 2009, dabigatran 150 mg twice daily significantly reduced the risk for stroke and systemic emboli in patients with atrial fibrillation compared to warfarin (annual risk, 1.11% vs 1.69%; relative risk, 0.66; 95% CI, 0.53-0.82; P<.001) with the advantage of not requiring frequent monitoring of the international normalized ratio.² The most common adverse effect of dabigatran in this trial was dyspepsia (11.3% vs 5.8%). Drug hypersensitivity, allergic edema, and anaphylaxis were reported in less than 0.1% of patients taking dabigatran.²

According to a PubMed search of articles indexed for MEDLINE using the search terms dabigatran cutaneous reaction and dabigatran rash, 4 case reports of cutaneous eruption due to dabigatran were identified. In one report, a 20-year-old man with atrial fibrillation developed an eruption similar to our patient on the thigh and forearm after 2 weeks of taking oral dabigatran 150 mg twice daily. It resolved without complication after topical corticosteroid use and discontinuation of dabigatran.³ In another report, a 78-year-old man presented to the emergency department after taking two 150-mg doses of dabigatran with a diffuse, full-body, pruritic rash that resolved with oral diphenhydramine and discontinuation of dabigatran.⁴ A third case described a 59-year-old man who was taking 150 mg dabigatran twice daily for 5 days before developing a rash.⁵ The fourth case involved a 74-year-old woman who developed leukocytoclastic vasculitis 1 week after taking dabigatran 150 mg twice daily.⁶

It is important to monitor for and report hypersensitivity reactions in patients taking dabigatran. Drug exanthems may cause discomfort or even herald more serious hypersensitivity reactions. Patients experiencing these reactions may discontinue therapy without notifying a physician and consequently place themselves at risk for embolism or stroke.

Special room rates at the VAM headquarters hotel, the Gaylord National Resort & Convention Center, are good through Thursday, May 11. Enjoy the stunning 19-story glass atrium, with views of the Potomac River, on-site restaurants, luxury spa and fitness center and more. It’s just steps from National Harbor’s entertainment and shopping district and only eight miles from Washington, D.C.

Register here.

Special room rates at the VAM headquarters hotel, the Gaylord National Resort & Convention Center, are good through Thursday, May 11. Enjoy the stunning 19-story glass atrium, with views of the Potomac River, on-site restaurants, luxury spa and fitness center and more. It’s just steps from National Harbor’s entertainment and shopping district and only eight miles from Washington, D.C.

Register here.

Special room rates at the VAM headquarters hotel, the Gaylord National Resort & Convention Center, are good through Thursday, May 11. Enjoy the stunning 19-story glass atrium, with views of the Potomac River, on-site restaurants, luxury spa and fitness center and more. It’s just steps from National Harbor’s entertainment and shopping district and only eight miles from Washington, D.C.

Register here.

Register today for hands-on training at the Vascular Annual Meeting’s hands-on-workshop (limit 15 participants each) on Wednesday, June 8. Twelve topics -- with tips, tricks, tools and more -- are offered during four 90-minute sessions.

The workshops are $100 each (preregistration is required) and are not included in the VAM registration fee. Simply add the desired workshops when registering. Already registered? Just return to the registration page and add the workshops separately.

Learn more here.

Register today for hands-on training at the Vascular Annual Meeting’s hands-on-workshop (limit 15 participants each) on Wednesday, June 8. Twelve topics -- with tips, tricks, tools and more -- are offered during four 90-minute sessions.

The workshops are $100 each (preregistration is required) and are not included in the VAM registration fee. Simply add the desired workshops when registering. Already registered? Just return to the registration page and add the workshops separately.

Learn more here.

Register today for hands-on training at the Vascular Annual Meeting’s hands-on-workshop (limit 15 participants each) on Wednesday, June 8. Twelve topics -- with tips, tricks, tools and more -- are offered during four 90-minute sessions.

The workshops are $100 each (preregistration is required) and are not included in the VAM registration fee. Simply add the desired workshops when registering. Already registered? Just return to the registration page and add the workshops separately.

Learn more here.

Up to four $5,000 scholarships to attend the 2017 Vascular Annual Meeting in San Diego are available to qualified young vascular surgeons living outside of North America.

In addition to the meeting, scholars also will visit clinical, teaching and research programs in the United States and Canada. Applications can be completed online.

The application deadline is June 17, 2016. For questions, email [email protected] or call 312-334-2300. More information is available here.

Up to four $5,000 scholarships to attend the 2017 Vascular Annual Meeting in San Diego are available to qualified young vascular surgeons living outside of North America.

In addition to the meeting, scholars also will visit clinical, teaching and research programs in the United States and Canada. Applications can be completed online.

The application deadline is June 17, 2016. For questions, email [email protected] or call 312-334-2300. More information is available here.

Up to four $5,000 scholarships to attend the 2017 Vascular Annual Meeting in San Diego are available to qualified young vascular surgeons living outside of North America.

In addition to the meeting, scholars also will visit clinical, teaching and research programs in the United States and Canada. Applications can be completed online.

The application deadline is June 17, 2016. For questions, email [email protected] or call 312-334-2300. More information is available here.