Neurodevelopmental Disorders

Schizophrenia is a complex disease caused by dysfunction in specific brain regions or circuits. In fact, schizophrenia is not a single disease but several hundred different diseases, according to Henry A. Nasrallah, MD, who spoke on the topic at a virtual meeting presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.

The underlying causes of schizophrenia can be either genetic or environmental, but all involve changes in brain development in the fetus or newborn. Psychosis can occur in a range of disorders, including epilepsy, Parkinson’s disease, cerebral tumors, and narcolepsy, to name just a few. Although it starts out as a neurodevelopmental disorder, schizophrenia becomes neurodegenerative after onset, with each new psychotic episode leading to further damage, said Dr. Nasrallah, professor of psychiatry, neurology, and neuroscience at the University of Cincinnati. Further damage leaves patients with greater and greater disability over time, said Dr. Nasrallah at the meeting presented by MedscapeLive. MedscapeLive and this news organization are owned by the same parent company.

The course of illness in some ways resembles the cascading disability associated with strokes. Schizophrenia relapses lead to subcortical atrophy, ventricular enlargement, and further loss of white matter. The accumulating damage is a result of microglia activation, which leads to neuroinflammation and oxidative stress. Mitochondria may also produce insufficient amounts of the antioxidant glutathione.

This pattern in schizophrenia makes it all the more important to ensure that patients stay on medication to prevent future episodes. “The main reason for relapse in schizophrenia is poor adherence to antipsychotic medications, due to anosognosia, memory impairment, avolition, and substance use. It is absolutely necessary to realize that, while oral antipsychotics are effective in the hospital due to enforced compliance by the nursing staff, patients should be switched to long-acting injectable antipsychotics (LAIs) upon discharge from the first episode, which astonishingly is rarely done by 99% of clinicians,” said Dr. Nasrallah in an interview.

That frequent failure leads to further neurodegeneration and increasing disability, which in turn can lead to high rates of homelessness, suicide, and as well as incarceration, because many state hospitals that used to provide medical care for relapsing individuals have been closed down. All of these consequences place great financial and emotional burdens on families and loved ones.
 

Reconceptualizing the illness

Dr. Nasrallah also advocated that schizophrenia should be classified as a neurologic disorder instead of a psychiatric disorder. He said that the neuropsychiatric mechanisms behind these related diseases support that classification, and neurologic disorders receive much more insurance coverage.

The neuroinflammatory mechanisms underlying schizophrenia suggest that therapies such as omega-3 fatty acids could provide benefit during the prodromal stages of illness. Antioxidants like N-acetyl cysteine could potentially be useful during psychotic episodes, since it boosts levels of glutathione to reduce damaging free radicals. Other approaches could prevent microglia activation, which appears to initiate neurodegeneration.

Another consequence of psychosis is programmed cell death, or apoptosis, in response to reduced levels of neurotropic agents. That could potentially be countered using agents to prevent apoptosis.

Dr. Nasrallah believes clinicians should not use first-generation antipsychotics such as haloperidol, because research has shown that those drugs, while effective, also destroy neurons. Second-generation antipsychotics (SGAs) are safer and avoid that neurotoxicity, and they also have a neuroprotective effect. The SGAs may owe their improved efficacy and safety to the fact that they don’t bind as strongly to dopamine receptors, and they are stronger 5-hydroxytryptamine_2A antagonists, according to Dr. Nasrallah. A meta-analysis of 18 studies showed that patients on SGAs maintained gray matter volume, and may even achieve increases in the hippocampus and the prefrontal cortex.

In the Q&A session after the presentation, Dr. Nasrallah was asked whether treatment should be kept up for the rest of the patient’s life, or whether medication should be tapered – and perhaps stopped. He likened treatment of schizophrenia to diabetes or high blood pressure.

“It’s an illness. A lot of medical disorders require lifetime treatment, and there is no difference between psychiatry and the rest of medicine,” he said. “You have to continue the medication at the dose that worked in the acute episode, hopefully the lowest possible dose.”

Dr. Nasrallah did concede that it can be challenging to get patients to accept permanent treatment, and he shared his own strategy to achieve that outcome. “I don’t tell the patient, ‘You’re going to take this the rest of your life.’ It depresses them. So I say, ‘Let’s keep this on board for a year, and I’ll see you regularly, and I’ll monitor you, and we’ll see how it goes, and then we will make another decision at the end of the year.’ ”

During that year, Dr. Nasrallah educates the patient and develops a rapport. “I will show them a lot of data and information about the illness and the hazards of stopping [treatment]. And by the end of the year, most of my patients say: ‘Yeah, I agree. Let’s continue the good thing and let’s not fix something that’s not broken.’ ”

Dr. Nasrallah has consulted for Acadia, Alkermes, Allergan, Boehringer-Ingelheim, Indivior, Intra-Cellular, Janssen, Neurocrine, Otsuka, Sunovion, and Teva. He has also served on a speaker’s bureau for most of those companies, in addition to that of Noven.

Schizophrenia is a complex disease caused by dysfunction in specific brain regions or circuits. In fact, schizophrenia is not a single disease but several hundred different diseases, according to Henry A. Nasrallah, MD, who spoke on the topic at a virtual meeting presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.

The underlying causes of schizophrenia can be either genetic or environmental, but all involve changes in brain development in the fetus or newborn. Psychosis can occur in a range of disorders, including epilepsy, Parkinson’s disease, cerebral tumors, and narcolepsy, to name just a few. Although it starts out as a neurodevelopmental disorder, schizophrenia becomes neurodegenerative after onset, with each new psychotic episode leading to further damage, said Dr. Nasrallah, professor of psychiatry, neurology, and neuroscience at the University of Cincinnati. Further damage leaves patients with greater and greater disability over time, said Dr. Nasrallah at the meeting presented by MedscapeLive. MedscapeLive and this news organization are owned by the same parent company.

The course of illness in some ways resembles the cascading disability associated with strokes. Schizophrenia relapses lead to subcortical atrophy, ventricular enlargement, and further loss of white matter. The accumulating damage is a result of microglia activation, which leads to neuroinflammation and oxidative stress. Mitochondria may also produce insufficient amounts of the antioxidant glutathione.

This pattern in schizophrenia makes it all the more important to ensure that patients stay on medication to prevent future episodes. “The main reason for relapse in schizophrenia is poor adherence to antipsychotic medications, due to anosognosia, memory impairment, avolition, and substance use. It is absolutely necessary to realize that, while oral antipsychotics are effective in the hospital due to enforced compliance by the nursing staff, patients should be switched to long-acting injectable antipsychotics (LAIs) upon discharge from the first episode, which astonishingly is rarely done by 99% of clinicians,” said Dr. Nasrallah in an interview.

That frequent failure leads to further neurodegeneration and increasing disability, which in turn can lead to high rates of homelessness, suicide, and as well as incarceration, because many state hospitals that used to provide medical care for relapsing individuals have been closed down. All of these consequences place great financial and emotional burdens on families and loved ones.
 

Reconceptualizing the illness

Dr. Nasrallah also advocated that schizophrenia should be classified as a neurologic disorder instead of a psychiatric disorder. He said that the neuropsychiatric mechanisms behind these related diseases support that classification, and neurologic disorders receive much more insurance coverage.

The neuroinflammatory mechanisms underlying schizophrenia suggest that therapies such as omega-3 fatty acids could provide benefit during the prodromal stages of illness. Antioxidants like N-acetyl cysteine could potentially be useful during psychotic episodes, since it boosts levels of glutathione to reduce damaging free radicals. Other approaches could prevent microglia activation, which appears to initiate neurodegeneration.

Another consequence of psychosis is programmed cell death, or apoptosis, in response to reduced levels of neurotropic agents. That could potentially be countered using agents to prevent apoptosis.

Dr. Nasrallah believes clinicians should not use first-generation antipsychotics such as haloperidol, because research has shown that those drugs, while effective, also destroy neurons. Second-generation antipsychotics (SGAs) are safer and avoid that neurotoxicity, and they also have a neuroprotective effect. The SGAs may owe their improved efficacy and safety to the fact that they don’t bind as strongly to dopamine receptors, and they are stronger 5-hydroxytryptamine_2A antagonists, according to Dr. Nasrallah. A meta-analysis of 18 studies showed that patients on SGAs maintained gray matter volume, and may even achieve increases in the hippocampus and the prefrontal cortex.

In the Q&A session after the presentation, Dr. Nasrallah was asked whether treatment should be kept up for the rest of the patient’s life, or whether medication should be tapered – and perhaps stopped. He likened treatment of schizophrenia to diabetes or high blood pressure.

“It’s an illness. A lot of medical disorders require lifetime treatment, and there is no difference between psychiatry and the rest of medicine,” he said. “You have to continue the medication at the dose that worked in the acute episode, hopefully the lowest possible dose.”

Dr. Nasrallah did concede that it can be challenging to get patients to accept permanent treatment, and he shared his own strategy to achieve that outcome. “I don’t tell the patient, ‘You’re going to take this the rest of your life.’ It depresses them. So I say, ‘Let’s keep this on board for a year, and I’ll see you regularly, and I’ll monitor you, and we’ll see how it goes, and then we will make another decision at the end of the year.’ ”

During that year, Dr. Nasrallah educates the patient and develops a rapport. “I will show them a lot of data and information about the illness and the hazards of stopping [treatment]. And by the end of the year, most of my patients say: ‘Yeah, I agree. Let’s continue the good thing and let’s not fix something that’s not broken.’ ”

Dr. Nasrallah has consulted for Acadia, Alkermes, Allergan, Boehringer-Ingelheim, Indivior, Intra-Cellular, Janssen, Neurocrine, Otsuka, Sunovion, and Teva. He has also served on a speaker’s bureau for most of those companies, in addition to that of Noven.

Schizophrenia is a complex disease caused by dysfunction in specific brain regions or circuits. In fact, schizophrenia is not a single disease but several hundred different diseases, according to Henry A. Nasrallah, MD, who spoke on the topic at a virtual meeting presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.

The underlying causes of schizophrenia can be either genetic or environmental, but all involve changes in brain development in the fetus or newborn. Psychosis can occur in a range of disorders, including epilepsy, Parkinson’s disease, cerebral tumors, and narcolepsy, to name just a few. Although it starts out as a neurodevelopmental disorder, schizophrenia becomes neurodegenerative after onset, with each new psychotic episode leading to further damage, said Dr. Nasrallah, professor of psychiatry, neurology, and neuroscience at the University of Cincinnati. Further damage leaves patients with greater and greater disability over time, said Dr. Nasrallah at the meeting presented by MedscapeLive. MedscapeLive and this news organization are owned by the same parent company.

The course of illness in some ways resembles the cascading disability associated with strokes. Schizophrenia relapses lead to subcortical atrophy, ventricular enlargement, and further loss of white matter. The accumulating damage is a result of microglia activation, which leads to neuroinflammation and oxidative stress. Mitochondria may also produce insufficient amounts of the antioxidant glutathione.

This pattern in schizophrenia makes it all the more important to ensure that patients stay on medication to prevent future episodes. “The main reason for relapse in schizophrenia is poor adherence to antipsychotic medications, due to anosognosia, memory impairment, avolition, and substance use. It is absolutely necessary to realize that, while oral antipsychotics are effective in the hospital due to enforced compliance by the nursing staff, patients should be switched to long-acting injectable antipsychotics (LAIs) upon discharge from the first episode, which astonishingly is rarely done by 99% of clinicians,” said Dr. Nasrallah in an interview.

That frequent failure leads to further neurodegeneration and increasing disability, which in turn can lead to high rates of homelessness, suicide, and as well as incarceration, because many state hospitals that used to provide medical care for relapsing individuals have been closed down. All of these consequences place great financial and emotional burdens on families and loved ones.
 

Reconceptualizing the illness

Dr. Nasrallah also advocated that schizophrenia should be classified as a neurologic disorder instead of a psychiatric disorder. He said that the neuropsychiatric mechanisms behind these related diseases support that classification, and neurologic disorders receive much more insurance coverage.

The neuroinflammatory mechanisms underlying schizophrenia suggest that therapies such as omega-3 fatty acids could provide benefit during the prodromal stages of illness. Antioxidants like N-acetyl cysteine could potentially be useful during psychotic episodes, since it boosts levels of glutathione to reduce damaging free radicals. Other approaches could prevent microglia activation, which appears to initiate neurodegeneration.

Another consequence of psychosis is programmed cell death, or apoptosis, in response to reduced levels of neurotropic agents. That could potentially be countered using agents to prevent apoptosis.

Dr. Nasrallah believes clinicians should not use first-generation antipsychotics such as haloperidol, because research has shown that those drugs, while effective, also destroy neurons. Second-generation antipsychotics (SGAs) are safer and avoid that neurotoxicity, and they also have a neuroprotective effect. The SGAs may owe their improved efficacy and safety to the fact that they don’t bind as strongly to dopamine receptors, and they are stronger 5-hydroxytryptamine_2A antagonists, according to Dr. Nasrallah. A meta-analysis of 18 studies showed that patients on SGAs maintained gray matter volume, and may even achieve increases in the hippocampus and the prefrontal cortex.

In the Q&A session after the presentation, Dr. Nasrallah was asked whether treatment should be kept up for the rest of the patient’s life, or whether medication should be tapered – and perhaps stopped. He likened treatment of schizophrenia to diabetes or high blood pressure.

“It’s an illness. A lot of medical disorders require lifetime treatment, and there is no difference between psychiatry and the rest of medicine,” he said. “You have to continue the medication at the dose that worked in the acute episode, hopefully the lowest possible dose.”

Dr. Nasrallah did concede that it can be challenging to get patients to accept permanent treatment, and he shared his own strategy to achieve that outcome. “I don’t tell the patient, ‘You’re going to take this the rest of your life.’ It depresses them. So I say, ‘Let’s keep this on board for a year, and I’ll see you regularly, and I’ll monitor you, and we’ll see how it goes, and then we will make another decision at the end of the year.’ ”

During that year, Dr. Nasrallah educates the patient and develops a rapport. “I will show them a lot of data and information about the illness and the hazards of stopping [treatment]. And by the end of the year, most of my patients say: ‘Yeah, I agree. Let’s continue the good thing and let’s not fix something that’s not broken.’ ”

Dr. Nasrallah has consulted for Acadia, Alkermes, Allergan, Boehringer-Ingelheim, Indivior, Intra-Cellular, Janssen, Neurocrine, Otsuka, Sunovion, and Teva. He has also served on a speaker’s bureau for most of those companies, in addition to that of Noven.

Oral delta-9-tetrahydracannabinol (delta-9-THC) and palmitoylethanolamide (PEA), in a proprietary combination known as THX-110, is promising for reducing tic symptoms in adults with Tourette syndrome (TS), new research suggests.

In a small phase 2 trial, investigators administered THX-110 to 16 adults with treatment-resistant TS for 12 weeks. Results showed a reduction of more than 20% in tic symptoms after the first week of treatment compared with baseline.

“We conducted an uncontrolled study in adults with severe TS and found that their tics improved over time while they took THX-110,” lead author Michael Bloch, MD, associate professor and co-director of the Tic and OCD Program at the Child Study Center, Yale University, New Haven, Conn., told this news organization.

Dr. Bloch added that the next step in this line of research will be to conduct a placebo-controlled trial of the compound in order to assess whether tic improvement observed over time in this study “was due to the effects of the medication and not related to the natural waxing-and-waning course of tic symptoms or treatment expectancy.”

The findings were published online August 2 in the Journal of Neuropsychiatry and Clinical Neurosciences. 
 

‘Entourage effect’

“Several lines of evidence from clinical observation and even randomized controlled trials” suggest that cannabis (cannabis sativa) and delta-9-THC may be effective in treatment of tic disorders, Dr. Bloch said.

“Cannabinoid receptors are present in the motor regions important for tics, and thus, there is a potential mechanism of action to lead to improvement of tics,” he added.

However, “the major limitations of both cannabis and dronabinol [a synthetic form of delta-9-THC] use are the adverse psychoactive effects they induce in higher doses,” he said.

Dr. Bloch noted that PEA is a lipid messenger “known to mimic several endocannabinoid-driven activities.”

For this reason, combining delta-9-THC with PEA is hypothesized to reduce the dose of delta-9-THC needed to improve tics and also potentially lessen its side effects.

This initial open-label trial examined safety and tolerability of THX-110, as well as its effect on tic symptoms in adults with TS. The researchers hoped to “use the entourage effect to deliver the therapeutic benefits of delta-9-THC in reducing tics with decrease psychoactive effects by combining with PEA.”

The “entourage effect” refers to “endocannabinoid regulation by which multiple endogenous cannabinoid chemical species display a cooperative effect in eliciting a cellular response,” they write.

The investigators conducted a 12-week uncontrolled trial of THX-110, used at its maximum daily dose of delta-9-THC (10 mg) and a constant 800-mg dose of PEA in 16 adults with TS (mean age, 35 years; mean TS illness duration, 26.6 years).

Participants had a mean baseline Yale Global Tic Severity Scale (YGTSS) score of 38.1 and a mean worst-ever total tic score of 45.4.

All participants were experiencing persistent tics, despite having tried an array of previous evidence-based treatments for TS, including antipsychotics, alpha-2 agonists, VMAT2 inhibitors, benzodiazepines, and topiramate (Topamax).
 

Significant improvement

Results showed significant improvement in tic symptoms with TXH-110 treatment over time (general linear model time factor: F = 3.06, df = 7.91, P = .006).

These improvements were statistically significant as early as within the first week of starting treatment. At first assessment point, mean YGTSS improvement was 3.5 (95% confidence interval, 0.1-6.9; P = .047). The improvement not only remained significant but continued to increase throughout the 12-week trial period.

At 12 weeks, the maximal improvement in tic symptoms was observed, with a mean YGTSS improvement at endpoint of 7.6 (95% CI, 2.5-12.8; P = .007).

Four patients experienced a greater than 35% improvement in tic symptoms during the trial, whereas 6 experienced a 25% or greater improvement. The mean improvement in tic symptoms over the course of the trial was 20.6%.

There was also a significant improvement between baseline and endpoint on other measures of tic symptoms – but not on premonitory urges.

The patients experienced “modest” but not significant improvement in comorbid symptoms, including attentional, anxiety, depressive, and obsessive-compulsive symptoms.
 

Adverse events

All participants experienced some mild side effects for “a couple hours” after taking the medication, particularly during the course of dose escalation and maintenance. However, these were not serious enough to warrant stopping the medication.

These effects typically included fatigue/drowsiness, feeling “high,” dry mouth, dizziness/lightheadedness, and difficulty concentrating.

Side effects of moderate or greater severity necessitating changes in medication dosing were “less common,” the investigators report. No participants experienced significant laboratory abnormalities.

One patient discontinued the trial early because he felt that the study medication was not helpful, and a second discontinued because of drowsiness and fatigue related to the study medication.

Twelve participants elected to continue treatment with THX-110 during an open extension phase and 7 of these completed the additional 24 weeks.

“THX-110 treatment led to an average improvement in tic symptoms of roughly 20%, or a 7-point decrease in the YGTSS total tic score. This improvement translates to a large effect size (d = 0.92) of improvement over time,” the investigators write.
 

More data needed

Commenting on the findings, Yolanda Holler-Managan, MD, assistant professor of pediatrics (neurology), Northwestern University, Chicago, cautioned that this was not a randomized, double-blind, parallel-group placebo-controlled study.

Instead, it was a clinical study to prove safety, tolerability, and dosing of the combination medication in adult patients with TS and “does not provide as much weight, since we do not have many studies on the efficacy of cannabinoids,” said Dr. Holler-Managan, who was not involved with the research.

She noted that the American Academy of Neurology’s 2019 practice guideline recommendations for treatment of tics in individuals with TS and tic disorders reported “limited evidence” that delta-9-THC is “possibly more likely than placebo to reduce tic severity in adults with TS, therefore we need more data.”

The current investigators agree. “Although these initial data are promising, future randomized double-blind placebo-controlled trials are necessary to demonstrate efficacy of TXH-110 treatment,” they write.

They add that the psychoactive properties of cannabis-derived compounds make it challenging to design a properly blinded trial.

“Incorporation of physiologic biomarkers and objective measures of symptoms (e.g., videotaped tic counts by blinded raters) may be particularly important when examining these medications with psychoactive properties that may be prone to reporting bias,” the authors write.

The study was supported by an investigator-initiated grant to Dr. Bloch from Therapix Biosciences. The state of Connecticut also provided resource support via the Abraham Ribicoff Research Facilities at the Connecticut Mental Health Center. Dr. Bloch serves on the scientific advisory boards of Therapix Biosciences, and he receives research support from Biohaven Pharmaceuticals, Janssen Pharmaceuticals, NARSAD, Neurocrine Biosciences, NIH, and the Patterson Foundation. The other investigators and Dr. Holler-Managan have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Oral delta-9-tetrahydracannabinol (delta-9-THC) and palmitoylethanolamide (PEA), in a proprietary combination known as THX-110, is promising for reducing tic symptoms in adults with Tourette syndrome (TS), new research suggests.

In a small phase 2 trial, investigators administered THX-110 to 16 adults with treatment-resistant TS for 12 weeks. Results showed a reduction of more than 20% in tic symptoms after the first week of treatment compared with baseline.

“We conducted an uncontrolled study in adults with severe TS and found that their tics improved over time while they took THX-110,” lead author Michael Bloch, MD, associate professor and co-director of the Tic and OCD Program at the Child Study Center, Yale University, New Haven, Conn., told this news organization.

Dr. Bloch added that the next step in this line of research will be to conduct a placebo-controlled trial of the compound in order to assess whether tic improvement observed over time in this study “was due to the effects of the medication and not related to the natural waxing-and-waning course of tic symptoms or treatment expectancy.”

The findings were published online August 2 in the Journal of Neuropsychiatry and Clinical Neurosciences. 
 

‘Entourage effect’

“Several lines of evidence from clinical observation and even randomized controlled trials” suggest that cannabis (cannabis sativa) and delta-9-THC may be effective in treatment of tic disorders, Dr. Bloch said.

“Cannabinoid receptors are present in the motor regions important for tics, and thus, there is a potential mechanism of action to lead to improvement of tics,” he added.

However, “the major limitations of both cannabis and dronabinol [a synthetic form of delta-9-THC] use are the adverse psychoactive effects they induce in higher doses,” he said.

Dr. Bloch noted that PEA is a lipid messenger “known to mimic several endocannabinoid-driven activities.”

For this reason, combining delta-9-THC with PEA is hypothesized to reduce the dose of delta-9-THC needed to improve tics and also potentially lessen its side effects.

This initial open-label trial examined safety and tolerability of THX-110, as well as its effect on tic symptoms in adults with TS. The researchers hoped to “use the entourage effect to deliver the therapeutic benefits of delta-9-THC in reducing tics with decrease psychoactive effects by combining with PEA.”

The “entourage effect” refers to “endocannabinoid regulation by which multiple endogenous cannabinoid chemical species display a cooperative effect in eliciting a cellular response,” they write.

The investigators conducted a 12-week uncontrolled trial of THX-110, used at its maximum daily dose of delta-9-THC (10 mg) and a constant 800-mg dose of PEA in 16 adults with TS (mean age, 35 years; mean TS illness duration, 26.6 years).

Participants had a mean baseline Yale Global Tic Severity Scale (YGTSS) score of 38.1 and a mean worst-ever total tic score of 45.4.

All participants were experiencing persistent tics, despite having tried an array of previous evidence-based treatments for TS, including antipsychotics, alpha-2 agonists, VMAT2 inhibitors, benzodiazepines, and topiramate (Topamax).
 

Significant improvement

Results showed significant improvement in tic symptoms with TXH-110 treatment over time (general linear model time factor: F = 3.06, df = 7.91, P = .006).

These improvements were statistically significant as early as within the first week of starting treatment. At first assessment point, mean YGTSS improvement was 3.5 (95% confidence interval, 0.1-6.9; P = .047). The improvement not only remained significant but continued to increase throughout the 12-week trial period.

At 12 weeks, the maximal improvement in tic symptoms was observed, with a mean YGTSS improvement at endpoint of 7.6 (95% CI, 2.5-12.8; P = .007).

Four patients experienced a greater than 35% improvement in tic symptoms during the trial, whereas 6 experienced a 25% or greater improvement. The mean improvement in tic symptoms over the course of the trial was 20.6%.

There was also a significant improvement between baseline and endpoint on other measures of tic symptoms – but not on premonitory urges.

The patients experienced “modest” but not significant improvement in comorbid symptoms, including attentional, anxiety, depressive, and obsessive-compulsive symptoms.
 

Adverse events

All participants experienced some mild side effects for “a couple hours” after taking the medication, particularly during the course of dose escalation and maintenance. However, these were not serious enough to warrant stopping the medication.

These effects typically included fatigue/drowsiness, feeling “high,” dry mouth, dizziness/lightheadedness, and difficulty concentrating.

Side effects of moderate or greater severity necessitating changes in medication dosing were “less common,” the investigators report. No participants experienced significant laboratory abnormalities.

One patient discontinued the trial early because he felt that the study medication was not helpful, and a second discontinued because of drowsiness and fatigue related to the study medication.

Twelve participants elected to continue treatment with THX-110 during an open extension phase and 7 of these completed the additional 24 weeks.

“THX-110 treatment led to an average improvement in tic symptoms of roughly 20%, or a 7-point decrease in the YGTSS total tic score. This improvement translates to a large effect size (d = 0.92) of improvement over time,” the investigators write.
 

More data needed

Commenting on the findings, Yolanda Holler-Managan, MD, assistant professor of pediatrics (neurology), Northwestern University, Chicago, cautioned that this was not a randomized, double-blind, parallel-group placebo-controlled study.

Instead, it was a clinical study to prove safety, tolerability, and dosing of the combination medication in adult patients with TS and “does not provide as much weight, since we do not have many studies on the efficacy of cannabinoids,” said Dr. Holler-Managan, who was not involved with the research.

She noted that the American Academy of Neurology’s 2019 practice guideline recommendations for treatment of tics in individuals with TS and tic disorders reported “limited evidence” that delta-9-THC is “possibly more likely than placebo to reduce tic severity in adults with TS, therefore we need more data.”

The current investigators agree. “Although these initial data are promising, future randomized double-blind placebo-controlled trials are necessary to demonstrate efficacy of TXH-110 treatment,” they write.

They add that the psychoactive properties of cannabis-derived compounds make it challenging to design a properly blinded trial.

“Incorporation of physiologic biomarkers and objective measures of symptoms (e.g., videotaped tic counts by blinded raters) may be particularly important when examining these medications with psychoactive properties that may be prone to reporting bias,” the authors write.

The study was supported by an investigator-initiated grant to Dr. Bloch from Therapix Biosciences. The state of Connecticut also provided resource support via the Abraham Ribicoff Research Facilities at the Connecticut Mental Health Center. Dr. Bloch serves on the scientific advisory boards of Therapix Biosciences, and he receives research support from Biohaven Pharmaceuticals, Janssen Pharmaceuticals, NARSAD, Neurocrine Biosciences, NIH, and the Patterson Foundation. The other investigators and Dr. Holler-Managan have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Oral delta-9-tetrahydracannabinol (delta-9-THC) and palmitoylethanolamide (PEA), in a proprietary combination known as THX-110, is promising for reducing tic symptoms in adults with Tourette syndrome (TS), new research suggests.

In a small phase 2 trial, investigators administered THX-110 to 16 adults with treatment-resistant TS for 12 weeks. Results showed a reduction of more than 20% in tic symptoms after the first week of treatment compared with baseline.

“We conducted an uncontrolled study in adults with severe TS and found that their tics improved over time while they took THX-110,” lead author Michael Bloch, MD, associate professor and co-director of the Tic and OCD Program at the Child Study Center, Yale University, New Haven, Conn., told this news organization.

Dr. Bloch added that the next step in this line of research will be to conduct a placebo-controlled trial of the compound in order to assess whether tic improvement observed over time in this study “was due to the effects of the medication and not related to the natural waxing-and-waning course of tic symptoms or treatment expectancy.”

The findings were published online August 2 in the Journal of Neuropsychiatry and Clinical Neurosciences. 
 

‘Entourage effect’

“Several lines of evidence from clinical observation and even randomized controlled trials” suggest that cannabis (cannabis sativa) and delta-9-THC may be effective in treatment of tic disorders, Dr. Bloch said.

“Cannabinoid receptors are present in the motor regions important for tics, and thus, there is a potential mechanism of action to lead to improvement of tics,” he added.

However, “the major limitations of both cannabis and dronabinol [a synthetic form of delta-9-THC] use are the adverse psychoactive effects they induce in higher doses,” he said.

Dr. Bloch noted that PEA is a lipid messenger “known to mimic several endocannabinoid-driven activities.”

For this reason, combining delta-9-THC with PEA is hypothesized to reduce the dose of delta-9-THC needed to improve tics and also potentially lessen its side effects.

This initial open-label trial examined safety and tolerability of THX-110, as well as its effect on tic symptoms in adults with TS. The researchers hoped to “use the entourage effect to deliver the therapeutic benefits of delta-9-THC in reducing tics with decrease psychoactive effects by combining with PEA.”

The “entourage effect” refers to “endocannabinoid regulation by which multiple endogenous cannabinoid chemical species display a cooperative effect in eliciting a cellular response,” they write.

The investigators conducted a 12-week uncontrolled trial of THX-110, used at its maximum daily dose of delta-9-THC (10 mg) and a constant 800-mg dose of PEA in 16 adults with TS (mean age, 35 years; mean TS illness duration, 26.6 years).

Participants had a mean baseline Yale Global Tic Severity Scale (YGTSS) score of 38.1 and a mean worst-ever total tic score of 45.4.

All participants were experiencing persistent tics, despite having tried an array of previous evidence-based treatments for TS, including antipsychotics, alpha-2 agonists, VMAT2 inhibitors, benzodiazepines, and topiramate (Topamax).
 

Significant improvement

Results showed significant improvement in tic symptoms with TXH-110 treatment over time (general linear model time factor: F = 3.06, df = 7.91, P = .006).

These improvements were statistically significant as early as within the first week of starting treatment. At first assessment point, mean YGTSS improvement was 3.5 (95% confidence interval, 0.1-6.9; P = .047). The improvement not only remained significant but continued to increase throughout the 12-week trial period.

At 12 weeks, the maximal improvement in tic symptoms was observed, with a mean YGTSS improvement at endpoint of 7.6 (95% CI, 2.5-12.8; P = .007).

Four patients experienced a greater than 35% improvement in tic symptoms during the trial, whereas 6 experienced a 25% or greater improvement. The mean improvement in tic symptoms over the course of the trial was 20.6%.

There was also a significant improvement between baseline and endpoint on other measures of tic symptoms – but not on premonitory urges.

The patients experienced “modest” but not significant improvement in comorbid symptoms, including attentional, anxiety, depressive, and obsessive-compulsive symptoms.
 

Adverse events

All participants experienced some mild side effects for “a couple hours” after taking the medication, particularly during the course of dose escalation and maintenance. However, these were not serious enough to warrant stopping the medication.

These effects typically included fatigue/drowsiness, feeling “high,” dry mouth, dizziness/lightheadedness, and difficulty concentrating.

Side effects of moderate or greater severity necessitating changes in medication dosing were “less common,” the investigators report. No participants experienced significant laboratory abnormalities.

One patient discontinued the trial early because he felt that the study medication was not helpful, and a second discontinued because of drowsiness and fatigue related to the study medication.

Twelve participants elected to continue treatment with THX-110 during an open extension phase and 7 of these completed the additional 24 weeks.

“THX-110 treatment led to an average improvement in tic symptoms of roughly 20%, or a 7-point decrease in the YGTSS total tic score. This improvement translates to a large effect size (d = 0.92) of improvement over time,” the investigators write.
 

More data needed

Commenting on the findings, Yolanda Holler-Managan, MD, assistant professor of pediatrics (neurology), Northwestern University, Chicago, cautioned that this was not a randomized, double-blind, parallel-group placebo-controlled study.

Instead, it was a clinical study to prove safety, tolerability, and dosing of the combination medication in adult patients with TS and “does not provide as much weight, since we do not have many studies on the efficacy of cannabinoids,” said Dr. Holler-Managan, who was not involved with the research.

She noted that the American Academy of Neurology’s 2019 practice guideline recommendations for treatment of tics in individuals with TS and tic disorders reported “limited evidence” that delta-9-THC is “possibly more likely than placebo to reduce tic severity in adults with TS, therefore we need more data.”

The current investigators agree. “Although these initial data are promising, future randomized double-blind placebo-controlled trials are necessary to demonstrate efficacy of TXH-110 treatment,” they write.

They add that the psychoactive properties of cannabis-derived compounds make it challenging to design a properly blinded trial.

“Incorporation of physiologic biomarkers and objective measures of symptoms (e.g., videotaped tic counts by blinded raters) may be particularly important when examining these medications with psychoactive properties that may be prone to reporting bias,” the authors write.

The study was supported by an investigator-initiated grant to Dr. Bloch from Therapix Biosciences. The state of Connecticut also provided resource support via the Abraham Ribicoff Research Facilities at the Connecticut Mental Health Center. Dr. Bloch serves on the scientific advisory boards of Therapix Biosciences, and he receives research support from Biohaven Pharmaceuticals, Janssen Pharmaceuticals, NARSAD, Neurocrine Biosciences, NIH, and the Patterson Foundation. The other investigators and Dr. Holler-Managan have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A stimulant used in patients with attention-deficit/hyperactivity disorder might prove useful for other comorbid symptoms, results of a randomized, crossover trial suggest.

In the trial, the investigators reported that lisdexamfetamine (Vyvanse) reduced self-reported symptoms of sluggish cognitive tempo (SCT) by 30%, in addition to lowering ADHD symptoms by more than 40%.

The drug also corrected deficits in executive brain function. Patients had fewer episodes of procrastination, were better able to prioritize, and showed improvements in keeping things in mind.

“These findings highlight the importance of assessing symptoms of sluggish cognitive tempo and executive brain function in patients when they are initially diagnosed with ADHD,” Lenard A. Adler, MD, the lead author, said in a press release. The results were published June 29, 2021, in the Journal of Clinical Psychiatry.

The trial is groundbreaking because it is the first treatment study for ADHD with SCT in adults, Dr. Adler, director of the adult ADHD program at New York University Langone Health, said in an interview. He said that Russell A. Barkley, PhD, a clinical professor of psychiatry at Virginia Commonwealth University, Richmond, defines SCT as having nine cardinal symptoms: prone to daydreaming, easy boredom, trouble staying awake, feeling foggy, spaciness, lethargy, underachieving, less energy, and not processing information quickly or accurately.

Dr. Barkley, who studied more than 1,200 individuals with SCT, discovered that nearly half also had ADHD, Dr. Adler said. Those with the comorbid symptoms also had more impairment.

Whether or not the symptom set of SCT is a distinct disorder or a cotraveling symptom set that goes along with ADHD has been an area of investigation, said Dr. Adler, also a professor in the departments of psychiatry and child and adolescent psychiatry at New York University. Other known comorbid symptoms include executive function deficits and trouble with emotional control.

Stimulants to date have only shown success in children, as far as improving SCT. The goal of this study was to determine the efficacy of lisdexamfetamine on the nature and severity of ADHD symptoms and SCT behavioral indicators in adults with ADHD and SCT.
 

Two cohorts, alternating regimens

The investigators enrolled 38 adults with DSM-5 ADHD and SCT. Patients were recruited from two academic centers, New York University and the Icahn School of Medicine at Mount Sinai. The randomized 10-week crossover trial included two double-blind treatment periods, each 4 weeks long, with an intervening 2-week, single-blind placebo washout period.

“In crossover design, patients act as their own control, because they receive both treatments,” Dr. Adler said. Recruiting a smaller number of subjects helps to achieve significance in results.

For the first 4 weeks, participants received daily doses of either lisdexamfetamine (30-70 mg/day; mean, 59.1 mg/day) or a placebo sugar pill (mean, 66.6 mg/day). Researchers used standardized tests for SCT signs and symptoms, ADHD, and other measures of brain function to track psychiatric health on a weekly basis. After a month, the two cohorts switched regimens – those taking the placebo started the daily doses of lisdexamfetamine, and the other half stopped the drug and started taking the placebo.

Primary outcomes included the ADHD Rating Scale and Barkley Adult ADHD Rating Scale-IV SCT subscale.

Compared with placebo, adults with ADHD and comorbid SCT showed significant improvement after taking lisdexamfetamine in ratings of SCT and total ADHD symptoms. This was also true of other comorbid symptoms, such as executive function deficits.

In the crossover design, patients who received the drug first hadn’t gone fully back to baseline by the time the investigators crossed them over into the placebo group. “So, we couldn’t combine the two treatment epochs,” Dr. Adler said. However, the effect of the drug versus placebo was comparable in both study arms.
 

SCT alone was not studied

The trial had some limitations, mainly that it was an initial study with a modest sample size, Dr. Adler said. It also did not examine SCT alone, “so we can’t really say whether the stimulant medicine would improve SCT in patients who don’t have ADHD. What’s notable is when you look at how much of the improvement in SCT was due to improvement in ADHD, it was just 25%.” This means the effects occurring on SCT symptoms were not solely caused by effects on ADHD.

“We can’t say definitively that patients without SCT would respond to a stimulant. That’s a subject for future study,” he said.

Dr. Adler would like to see treatment studies of adults with ADHD and SCT in a larger sample, potentially with other stimulants. In addition, future trials could examine the effects of stimulants on adults with SCT that do not have ADHD.

The results of this trial underscore the importance of evaluating adults with ADHD for comorbid symptoms, such as executive function and emotional control, he continued. “Impairing SCT symptoms may very well fall under that umbrella,” Dr. Adler said. “If you don’t identify them, you can’t track them in terms of treatment.”
 

SCT as a ‘flavor’ of ADHD

The outcome of this study demonstrates that lisdexamfetamine significantly improves both ADHD symptoms and SCT symptoms, said David W. Goodman MD, LFAPA, an assistant professor in the department of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore.

Dr. Goodman, who was not involved in the study, agreed that clinicians should be aware of SCT when assessing adults with ADHD and conceptualize SCT as a “flavor” of ADHD. “SCT is not widely recognized by clinicians outside of the research arena but will likely become an important characteristic of ADHD presentation,” he said in an interview.

“Future studies in adult ADHD should further clarify the prevalence of SCT in the ADHD population and address more specific effective treatment options,” he said.

James M. Swanson, PhD, who also was not involved with the study, agreed in an interview that it documents the clear short-term benefit of stimulants on symptoms of SCT. The study “may be very timely, since adults who were affected by COVID-19 often have residual sequelae manifested as ‘brain fog,’ which resemble SCT,” said Dr. Swanson, professor of pediatrics at the University of California, Irvine.

The study was funded by Takeda Pharmaceutical, manufacturer of lisdexamfetamine. Dr. Adler has received grant/research support and has served as a consultant from Shire/Takeda and other companies. Dr. Goodman is a scientific consultant to Takeda and other pharmaceutical companies in the ADHD arena. Dr. Swanson had no disclosures.

A stimulant used in patients with attention-deficit/hyperactivity disorder might prove useful for other comorbid symptoms, results of a randomized, crossover trial suggest.

In the trial, the investigators reported that lisdexamfetamine (Vyvanse) reduced self-reported symptoms of sluggish cognitive tempo (SCT) by 30%, in addition to lowering ADHD symptoms by more than 40%.

The drug also corrected deficits in executive brain function. Patients had fewer episodes of procrastination, were better able to prioritize, and showed improvements in keeping things in mind.

“These findings highlight the importance of assessing symptoms of sluggish cognitive tempo and executive brain function in patients when they are initially diagnosed with ADHD,” Lenard A. Adler, MD, the lead author, said in a press release. The results were published June 29, 2021, in the Journal of Clinical Psychiatry.

The trial is groundbreaking because it is the first treatment study for ADHD with SCT in adults, Dr. Adler, director of the adult ADHD program at New York University Langone Health, said in an interview. He said that Russell A. Barkley, PhD, a clinical professor of psychiatry at Virginia Commonwealth University, Richmond, defines SCT as having nine cardinal symptoms: prone to daydreaming, easy boredom, trouble staying awake, feeling foggy, spaciness, lethargy, underachieving, less energy, and not processing information quickly or accurately.

Dr. Barkley, who studied more than 1,200 individuals with SCT, discovered that nearly half also had ADHD, Dr. Adler said. Those with the comorbid symptoms also had more impairment.

Whether or not the symptom set of SCT is a distinct disorder or a cotraveling symptom set that goes along with ADHD has been an area of investigation, said Dr. Adler, also a professor in the departments of psychiatry and child and adolescent psychiatry at New York University. Other known comorbid symptoms include executive function deficits and trouble with emotional control.

Stimulants to date have only shown success in children, as far as improving SCT. The goal of this study was to determine the efficacy of lisdexamfetamine on the nature and severity of ADHD symptoms and SCT behavioral indicators in adults with ADHD and SCT.
 

Two cohorts, alternating regimens

The investigators enrolled 38 adults with DSM-5 ADHD and SCT. Patients were recruited from two academic centers, New York University and the Icahn School of Medicine at Mount Sinai. The randomized 10-week crossover trial included two double-blind treatment periods, each 4 weeks long, with an intervening 2-week, single-blind placebo washout period.

“In crossover design, patients act as their own control, because they receive both treatments,” Dr. Adler said. Recruiting a smaller number of subjects helps to achieve significance in results.

For the first 4 weeks, participants received daily doses of either lisdexamfetamine (30-70 mg/day; mean, 59.1 mg/day) or a placebo sugar pill (mean, 66.6 mg/day). Researchers used standardized tests for SCT signs and symptoms, ADHD, and other measures of brain function to track psychiatric health on a weekly basis. After a month, the two cohorts switched regimens – those taking the placebo started the daily doses of lisdexamfetamine, and the other half stopped the drug and started taking the placebo.

Primary outcomes included the ADHD Rating Scale and Barkley Adult ADHD Rating Scale-IV SCT subscale.

Compared with placebo, adults with ADHD and comorbid SCT showed significant improvement after taking lisdexamfetamine in ratings of SCT and total ADHD symptoms. This was also true of other comorbid symptoms, such as executive function deficits.

In the crossover design, patients who received the drug first hadn’t gone fully back to baseline by the time the investigators crossed them over into the placebo group. “So, we couldn’t combine the two treatment epochs,” Dr. Adler said. However, the effect of the drug versus placebo was comparable in both study arms.
 

SCT alone was not studied

The trial had some limitations, mainly that it was an initial study with a modest sample size, Dr. Adler said. It also did not examine SCT alone, “so we can’t really say whether the stimulant medicine would improve SCT in patients who don’t have ADHD. What’s notable is when you look at how much of the improvement in SCT was due to improvement in ADHD, it was just 25%.” This means the effects occurring on SCT symptoms were not solely caused by effects on ADHD.

“We can’t say definitively that patients without SCT would respond to a stimulant. That’s a subject for future study,” he said.

Dr. Adler would like to see treatment studies of adults with ADHD and SCT in a larger sample, potentially with other stimulants. In addition, future trials could examine the effects of stimulants on adults with SCT that do not have ADHD.

The results of this trial underscore the importance of evaluating adults with ADHD for comorbid symptoms, such as executive function and emotional control, he continued. “Impairing SCT symptoms may very well fall under that umbrella,” Dr. Adler said. “If you don’t identify them, you can’t track them in terms of treatment.”
 

SCT as a ‘flavor’ of ADHD

The outcome of this study demonstrates that lisdexamfetamine significantly improves both ADHD symptoms and SCT symptoms, said David W. Goodman MD, LFAPA, an assistant professor in the department of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore.

Dr. Goodman, who was not involved in the study, agreed that clinicians should be aware of SCT when assessing adults with ADHD and conceptualize SCT as a “flavor” of ADHD. “SCT is not widely recognized by clinicians outside of the research arena but will likely become an important characteristic of ADHD presentation,” he said in an interview.

“Future studies in adult ADHD should further clarify the prevalence of SCT in the ADHD population and address more specific effective treatment options,” he said.

James M. Swanson, PhD, who also was not involved with the study, agreed in an interview that it documents the clear short-term benefit of stimulants on symptoms of SCT. The study “may be very timely, since adults who were affected by COVID-19 often have residual sequelae manifested as ‘brain fog,’ which resemble SCT,” said Dr. Swanson, professor of pediatrics at the University of California, Irvine.

The study was funded by Takeda Pharmaceutical, manufacturer of lisdexamfetamine. Dr. Adler has received grant/research support and has served as a consultant from Shire/Takeda and other companies. Dr. Goodman is a scientific consultant to Takeda and other pharmaceutical companies in the ADHD arena. Dr. Swanson had no disclosures.

A stimulant used in patients with attention-deficit/hyperactivity disorder might prove useful for other comorbid symptoms, results of a randomized, crossover trial suggest.

In the trial, the investigators reported that lisdexamfetamine (Vyvanse) reduced self-reported symptoms of sluggish cognitive tempo (SCT) by 30%, in addition to lowering ADHD symptoms by more than 40%.

The drug also corrected deficits in executive brain function. Patients had fewer episodes of procrastination, were better able to prioritize, and showed improvements in keeping things in mind.

“These findings highlight the importance of assessing symptoms of sluggish cognitive tempo and executive brain function in patients when they are initially diagnosed with ADHD,” Lenard A. Adler, MD, the lead author, said in a press release. The results were published June 29, 2021, in the Journal of Clinical Psychiatry.

The trial is groundbreaking because it is the first treatment study for ADHD with SCT in adults, Dr. Adler, director of the adult ADHD program at New York University Langone Health, said in an interview. He said that Russell A. Barkley, PhD, a clinical professor of psychiatry at Virginia Commonwealth University, Richmond, defines SCT as having nine cardinal symptoms: prone to daydreaming, easy boredom, trouble staying awake, feeling foggy, spaciness, lethargy, underachieving, less energy, and not processing information quickly or accurately.

Dr. Barkley, who studied more than 1,200 individuals with SCT, discovered that nearly half also had ADHD, Dr. Adler said. Those with the comorbid symptoms also had more impairment.

Whether or not the symptom set of SCT is a distinct disorder or a cotraveling symptom set that goes along with ADHD has been an area of investigation, said Dr. Adler, also a professor in the departments of psychiatry and child and adolescent psychiatry at New York University. Other known comorbid symptoms include executive function deficits and trouble with emotional control.

Stimulants to date have only shown success in children, as far as improving SCT. The goal of this study was to determine the efficacy of lisdexamfetamine on the nature and severity of ADHD symptoms and SCT behavioral indicators in adults with ADHD and SCT.
 

Two cohorts, alternating regimens

The investigators enrolled 38 adults with DSM-5 ADHD and SCT. Patients were recruited from two academic centers, New York University and the Icahn School of Medicine at Mount Sinai. The randomized 10-week crossover trial included two double-blind treatment periods, each 4 weeks long, with an intervening 2-week, single-blind placebo washout period.

“In crossover design, patients act as their own control, because they receive both treatments,” Dr. Adler said. Recruiting a smaller number of subjects helps to achieve significance in results.

For the first 4 weeks, participants received daily doses of either lisdexamfetamine (30-70 mg/day; mean, 59.1 mg/day) or a placebo sugar pill (mean, 66.6 mg/day). Researchers used standardized tests for SCT signs and symptoms, ADHD, and other measures of brain function to track psychiatric health on a weekly basis. After a month, the two cohorts switched regimens – those taking the placebo started the daily doses of lisdexamfetamine, and the other half stopped the drug and started taking the placebo.

Primary outcomes included the ADHD Rating Scale and Barkley Adult ADHD Rating Scale-IV SCT subscale.

Compared with placebo, adults with ADHD and comorbid SCT showed significant improvement after taking lisdexamfetamine in ratings of SCT and total ADHD symptoms. This was also true of other comorbid symptoms, such as executive function deficits.

In the crossover design, patients who received the drug first hadn’t gone fully back to baseline by the time the investigators crossed them over into the placebo group. “So, we couldn’t combine the two treatment epochs,” Dr. Adler said. However, the effect of the drug versus placebo was comparable in both study arms.
 

SCT alone was not studied

The trial had some limitations, mainly that it was an initial study with a modest sample size, Dr. Adler said. It also did not examine SCT alone, “so we can’t really say whether the stimulant medicine would improve SCT in patients who don’t have ADHD. What’s notable is when you look at how much of the improvement in SCT was due to improvement in ADHD, it was just 25%.” This means the effects occurring on SCT symptoms were not solely caused by effects on ADHD.

“We can’t say definitively that patients without SCT would respond to a stimulant. That’s a subject for future study,” he said.

Dr. Adler would like to see treatment studies of adults with ADHD and SCT in a larger sample, potentially with other stimulants. In addition, future trials could examine the effects of stimulants on adults with SCT that do not have ADHD.

The results of this trial underscore the importance of evaluating adults with ADHD for comorbid symptoms, such as executive function and emotional control, he continued. “Impairing SCT symptoms may very well fall under that umbrella,” Dr. Adler said. “If you don’t identify them, you can’t track them in terms of treatment.”
 

SCT as a ‘flavor’ of ADHD

The outcome of this study demonstrates that lisdexamfetamine significantly improves both ADHD symptoms and SCT symptoms, said David W. Goodman MD, LFAPA, an assistant professor in the department of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore.

Dr. Goodman, who was not involved in the study, agreed that clinicians should be aware of SCT when assessing adults with ADHD and conceptualize SCT as a “flavor” of ADHD. “SCT is not widely recognized by clinicians outside of the research arena but will likely become an important characteristic of ADHD presentation,” he said in an interview.

“Future studies in adult ADHD should further clarify the prevalence of SCT in the ADHD population and address more specific effective treatment options,” he said.

James M. Swanson, PhD, who also was not involved with the study, agreed in an interview that it documents the clear short-term benefit of stimulants on symptoms of SCT. The study “may be very timely, since adults who were affected by COVID-19 often have residual sequelae manifested as ‘brain fog,’ which resemble SCT,” said Dr. Swanson, professor of pediatrics at the University of California, Irvine.

The study was funded by Takeda Pharmaceutical, manufacturer of lisdexamfetamine. Dr. Adler has received grant/research support and has served as a consultant from Shire/Takeda and other companies. Dr. Goodman is a scientific consultant to Takeda and other pharmaceutical companies in the ADHD arena. Dr. Swanson had no disclosures.

The Food and Drug Administration has approved marketing for a device that will help diagnose autism spectrum disorder (ASD) in children between the ages of 18 months and 5 years old who exhibit potential symptoms.

Cognoa ASD Diagnosis Aid is a machine learning–based software program that receives information from parents or caregivers, video analysts, and health care providers to assist physicians in evaluating whether a child is at risk of having autism.

Autism is a developmental disorder that can cause social, communication, and behavioral challenges, according to the Centers for Disease Control and Prevention. The disorder affects about 1 in 54 children. The disorder is difficult to diagnose because there isn’t a medical test to diagnose the it. Instead, physicians have to look at a child’s developmental history and behavior to make a diagnosis.

Many children are not diagnosed with ASD until later in childhood, which in some cases delays treatment and early intervention. ASD may be detected as early as 18 months, but the average age of diagnosis for ASD is 4.3 years, according to the FDA.

“[ASD] can delay a child’s physical, cognitive, and social development, including motor skill development, learning, communication, and interacting with others. The earlier ASD can be diagnosed, the more quickly intervention strategies and appropriate therapies can begin,” Jeff Shuren, MD, JD, director of the FDA’s Center for Devices and Radiological Health, said in a statement. “Today’s marketing authorization provides a new tool for helping diagnose children with ASD.”

The safety and efficacy of the Cognoa ASD Diagnosis Aid was assessed in a study of 425 patients between the ages of 18 months and 5 years old. For the study, researchers compared the diagnostic assessments made by the device to those made by a panel of clinical experts who used the current standard ASD diagnostic process. The device diagnosed 32% of the children with either a “Positive for ASD” or a “Negative for ASD” result. Researchers found that the device matched the panel’s conclusions for 81% of the patients who received a positive diagnosis. For those who received a negative diagnosis, the device matched the panel’s conclusions for 98% of the patients. In addition, the device made an accurate ASD determination in 98.4% of patients with the condition and in 78.9% of patients without the condition.

Cognoa ASD Diagnosis Aid has three main components. One component includes a mobile app for caregivers to answer questions about the child’s behavioral problems and to upload videos of the child. The next component is a video analysis portal for specialists to view and analyze uploaded videos of patients. Another component is a portal for health care providers that allows them to enter answers to preloaded questions about behavior problems, track the information provided by parents, and review a report of the results.

After the machine learning–based device processes the information provided by parents and health care providers, it reports either a positive or a negative diagnosis. If there is insufficient information to make either a positive or a negative diagnosis, the ASD Diagnostic AID will report that no result can be generated.

Some of the risks associated with this device include misdiagnosis and delayed diagnosis of ASD because of a false-positive or false-negative result, or when no result is generated. Researchers said a false-positive result occurred in 15 out of 303 study subjects without ASD and a false-negative result occurred in 1 out of 122 study subjects with ASD.

The FDA emphasized that the device is indicated to aid physicians in the process of diagnosing ASD in children. This means it shouldn’t be treated as a standalone diagnostic device, but as an adjunct to the diagnostic process.

The Food and Drug Administration has approved marketing for a device that will help diagnose autism spectrum disorder (ASD) in children between the ages of 18 months and 5 years old who exhibit potential symptoms.

Cognoa ASD Diagnosis Aid is a machine learning–based software program that receives information from parents or caregivers, video analysts, and health care providers to assist physicians in evaluating whether a child is at risk of having autism.

Autism is a developmental disorder that can cause social, communication, and behavioral challenges, according to the Centers for Disease Control and Prevention. The disorder affects about 1 in 54 children. The disorder is difficult to diagnose because there isn’t a medical test to diagnose the it. Instead, physicians have to look at a child’s developmental history and behavior to make a diagnosis.

Many children are not diagnosed with ASD until later in childhood, which in some cases delays treatment and early intervention. ASD may be detected as early as 18 months, but the average age of diagnosis for ASD is 4.3 years, according to the FDA.

“[ASD] can delay a child’s physical, cognitive, and social development, including motor skill development, learning, communication, and interacting with others. The earlier ASD can be diagnosed, the more quickly intervention strategies and appropriate therapies can begin,” Jeff Shuren, MD, JD, director of the FDA’s Center for Devices and Radiological Health, said in a statement. “Today’s marketing authorization provides a new tool for helping diagnose children with ASD.”

The safety and efficacy of the Cognoa ASD Diagnosis Aid was assessed in a study of 425 patients between the ages of 18 months and 5 years old. For the study, researchers compared the diagnostic assessments made by the device to those made by a panel of clinical experts who used the current standard ASD diagnostic process. The device diagnosed 32% of the children with either a “Positive for ASD” or a “Negative for ASD” result. Researchers found that the device matched the panel’s conclusions for 81% of the patients who received a positive diagnosis. For those who received a negative diagnosis, the device matched the panel’s conclusions for 98% of the patients. In addition, the device made an accurate ASD determination in 98.4% of patients with the condition and in 78.9% of patients without the condition.

Cognoa ASD Diagnosis Aid has three main components. One component includes a mobile app for caregivers to answer questions about the child’s behavioral problems and to upload videos of the child. The next component is a video analysis portal for specialists to view and analyze uploaded videos of patients. Another component is a portal for health care providers that allows them to enter answers to preloaded questions about behavior problems, track the information provided by parents, and review a report of the results.

After the machine learning–based device processes the information provided by parents and health care providers, it reports either a positive or a negative diagnosis. If there is insufficient information to make either a positive or a negative diagnosis, the ASD Diagnostic AID will report that no result can be generated.

Some of the risks associated with this device include misdiagnosis and delayed diagnosis of ASD because of a false-positive or false-negative result, or when no result is generated. Researchers said a false-positive result occurred in 15 out of 303 study subjects without ASD and a false-negative result occurred in 1 out of 122 study subjects with ASD.

The FDA emphasized that the device is indicated to aid physicians in the process of diagnosing ASD in children. This means it shouldn’t be treated as a standalone diagnostic device, but as an adjunct to the diagnostic process.

The Food and Drug Administration has approved marketing for a device that will help diagnose autism spectrum disorder (ASD) in children between the ages of 18 months and 5 years old who exhibit potential symptoms.

Cognoa ASD Diagnosis Aid is a machine learning–based software program that receives information from parents or caregivers, video analysts, and health care providers to assist physicians in evaluating whether a child is at risk of having autism.

Autism is a developmental disorder that can cause social, communication, and behavioral challenges, according to the Centers for Disease Control and Prevention. The disorder affects about 1 in 54 children. The disorder is difficult to diagnose because there isn’t a medical test to diagnose the it. Instead, physicians have to look at a child’s developmental history and behavior to make a diagnosis.

Many children are not diagnosed with ASD until later in childhood, which in some cases delays treatment and early intervention. ASD may be detected as early as 18 months, but the average age of diagnosis for ASD is 4.3 years, according to the FDA.

“[ASD] can delay a child’s physical, cognitive, and social development, including motor skill development, learning, communication, and interacting with others. The earlier ASD can be diagnosed, the more quickly intervention strategies and appropriate therapies can begin,” Jeff Shuren, MD, JD, director of the FDA’s Center for Devices and Radiological Health, said in a statement. “Today’s marketing authorization provides a new tool for helping diagnose children with ASD.”

The safety and efficacy of the Cognoa ASD Diagnosis Aid was assessed in a study of 425 patients between the ages of 18 months and 5 years old. For the study, researchers compared the diagnostic assessments made by the device to those made by a panel of clinical experts who used the current standard ASD diagnostic process. The device diagnosed 32% of the children with either a “Positive for ASD” or a “Negative for ASD” result. Researchers found that the device matched the panel’s conclusions for 81% of the patients who received a positive diagnosis. For those who received a negative diagnosis, the device matched the panel’s conclusions for 98% of the patients. In addition, the device made an accurate ASD determination in 98.4% of patients with the condition and in 78.9% of patients without the condition.

Cognoa ASD Diagnosis Aid has three main components. One component includes a mobile app for caregivers to answer questions about the child’s behavioral problems and to upload videos of the child. The next component is a video analysis portal for specialists to view and analyze uploaded videos of patients. Another component is a portal for health care providers that allows them to enter answers to preloaded questions about behavior problems, track the information provided by parents, and review a report of the results.

After the machine learning–based device processes the information provided by parents and health care providers, it reports either a positive or a negative diagnosis. If there is insufficient information to make either a positive or a negative diagnosis, the ASD Diagnostic AID will report that no result can be generated.

Some of the risks associated with this device include misdiagnosis and delayed diagnosis of ASD because of a false-positive or false-negative result, or when no result is generated. Researchers said a false-positive result occurred in 15 out of 303 study subjects without ASD and a false-negative result occurred in 1 out of 122 study subjects with ASD.

The FDA emphasized that the device is indicated to aid physicians in the process of diagnosing ASD in children. This means it shouldn’t be treated as a standalone diagnostic device, but as an adjunct to the diagnostic process.

Exposure to Group A streptococcus (GAS) does not appear to worsen symptoms of Tourette syndrome and other chronic tic disorders (CTDs) in children and adolescents, new research suggests.

Investigators studied over 700 children and teenagers with CTDs, one-third of whom also had attention deficit hyperactivity disorder and one-third who had obsessive-compulsive disorder (OCD).

The youngsters were followed for an average of 16 months and evaluated at 4-month intervals to see if they were infected with GAS. Tic severity was monitored through telephone interviews, in-person visits, and parental reports.

A little less than half the children experienced worsening of tics during the study period, but the researchers found no association between these exacerbations and GAS exposure.

There was also no link between GAS and worsening OCD. However, researchers did find an association between GAS exposure and an increase in hyperactivity and impulsivity in patients with ADHD.

“This study does not support GAS exposures as contributing factors for tic exacerbations in children with CTD,” the authors note.

“Specific work-up or active management of GAS infections is unlikely to help modifying the course of tics in CTD and is therefore not recommended,” they conclude.

The study was published online in Neurology.
 

‘Intense debate’

The association between GAS and CTD stems from the description of Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection (PANDAS) – a condition that is now incorporated in the pediatric acute neuropsychiatric syndromes (PANS), the authors note. Tics constitute an “accompanying feature” of this condition.

However, neither population-based nor longitudinal clinical studies “could definitely establish if tic exacerbations in CTD are associated with GAS infections,” they note.  

“The link between streptococcus and tics in children is still a matter of intense debate,” said study author Davide Martino, MD, PhD, director of the Movement Disorders Program at the University of Calgary (Alta.), in a press release.

“We wanted to look at that question, as well as a possible link between strep and behavioral symptoms like obsessive-compulsive disorder and attention deficit hyperactivity disorder,” he said.

The researchers followed 715 children with CTD (mean age 10.7 years, 76.8% male) who were drawn from 16 specialist clinics in nine countries. Almost all (90.8%) had a diagnosis of Tourette syndrome (TS); 31.7% had OCD, and 36.1% had ADHD.

Participants received a throat swab at baseline, and of these, 8.4% tested positive for GAS.

Participants were evaluated over a 16- to 18-month period, consisting of:

• Face-to-face interviews and collection of throat swabs and serum at 4-month intervals.
• Telephone interviews at 4-month intervals, which took place at 2 months between study visit.
• Weekly diaries: Parents were asked to indicate any worsening of tics and focus on detecting the earliest possible tic exacerbation.

Beyond the regularly scheduled visits, parents were instructed to report, by phone or email, any noticeable increase in tic severity and then attend an in-person visit.

Tic exacerbations were defined as an increase of greater than or equal to 6 points on the Yale Global Tic Severity Scale-Total Tic Severity Score (YGTSS-TTS), compared with the previous assessment.

OCD and ADHD symptoms were assessed according to the Yale-Brown Obsessive-Compulsive Scale and the parent-reported Swanson, Nolan, and Pelham-IV (SNAP-IV) questionnaire.

The researchers divided GAS exposures into four categories: new definite exposure; new possible exposure; ongoing definite exposure; and ongoing possible exposure.
 

Unlikely trigger

During the follow-up period, 43.1% (n = 308) of participants experienced tic exacerbations. Of these, 218 participants experienced one exacerbation, while 90 participants experienced two, three, or four exacerbations.

The researchers did not find a significant association between GAS exposure status and tic exacerbation.

Participants who did develop a GAS-associated exacerbation (n = 49) were younger at study exit (9.63 vs. 11.4 years, P < .0001) and were more likely to be male (46/49 vs. 210/259, Fisher’s = .035), compared with participants who developed a non-GAS-associated tic exacerbation (n = 259).

Additional analyses were adjusted for sex, age at onset, exposure to psychotropic medications, exposures to antibiotics, geographical regions, and number of visits in the time interval of interest. These analyses continued to yield no significant association between new or ongoing concurrent GAS exposure episodes and tic exacerbation events.

Of the children in the study, 103 had a positive throat swab, indicating a new definite GAS exposure, whereas 46 had a positive throat swab indicating an ongoing definite exposure (n = 149 visits). Of these visits, only 20 corresponded to tic exacerbations.

There was also no association between GAS exposure and OCD symptom severity. However, it was associated with longitudinal changes (between 17% and 21%, depending on GAS exposure definition) in the severity of hyperactivity-impulsivity symptoms in children with ADHD.

“It is known that immune activation may concur with tic severity in youth with CTDs and that psychosocial stress levels may predict short-term future tic severity in these patients,” the authors write.

“Our findings suggest that GAS is unlikely to be the main trigger for immune activation in these patients,” they add.
 

Brick or cornerstone?

Commenting on the study for this news organization, Margo Thienemann, MD, clinical professor of psychiatry, Stanford (Calif.) University, said that in the clinic population they treat, GAS, other pathogens, and other stresses can “each be associated with PANS symptom exacerbations.”

However, these “would not be likely to cause PANS symptoms exacerbations in the vast majority of individuals, only individuals with genetic backgrounds and immunologic dysfunctions creating susceptibility,” said Dr. Thienemann, who also directs the Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) Clinic at Stanford Children’s Health. She was not involved with the study.

In an accompanying editorial, Andrea Cavanna, MD, PhD, honorary reader in neuropsychiatry, Birmingham (England) Medical School and Keith Coffman, MD, director, Tourette Syndrome Center of Excellence, Children’s Mercy Hospital, Kansas City, Mo., suggest that perhaps the “interaction of psychosocial stress and GAS infections contributes more to tic exacerbation than psychosocial stress alone.”

“Time will tell whether this study stands as another brick – a cornerstone? – in the wall that separates streptococcus from tics,” they write.

The study was supported by the European Union’s Seventh Framework Program. Dr. Martino has received honoraria for lecturing from the Movement Disorders Society, Tourette Syndrome Association of America, and Dystonia Medical Research Foundation Canada; research funding support from Dystonia Medical Research Foundation Canada, the University of Calgary (Alta.), the Michael P. Smith Family, the Owerko Foundation, Ipsen Corporate, the Parkinson Association of Alberta, and the Canadian Institutes for Health Research; and royalties from Springer-Verlag. The other authors’ disclosures are listed in the original article. Dr. Cavanna, Dr. Coffman, and Dr. Thienemann have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Exposure to Group A streptococcus (GAS) does not appear to worsen symptoms of Tourette syndrome and other chronic tic disorders (CTDs) in children and adolescents, new research suggests.

Investigators studied over 700 children and teenagers with CTDs, one-third of whom also had attention deficit hyperactivity disorder and one-third who had obsessive-compulsive disorder (OCD).

The youngsters were followed for an average of 16 months and evaluated at 4-month intervals to see if they were infected with GAS. Tic severity was monitored through telephone interviews, in-person visits, and parental reports.

A little less than half the children experienced worsening of tics during the study period, but the researchers found no association between these exacerbations and GAS exposure.

There was also no link between GAS and worsening OCD. However, researchers did find an association between GAS exposure and an increase in hyperactivity and impulsivity in patients with ADHD.

“This study does not support GAS exposures as contributing factors for tic exacerbations in children with CTD,” the authors note.

“Specific work-up or active management of GAS infections is unlikely to help modifying the course of tics in CTD and is therefore not recommended,” they conclude.

The study was published online in Neurology.
 

‘Intense debate’

The association between GAS and CTD stems from the description of Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection (PANDAS) – a condition that is now incorporated in the pediatric acute neuropsychiatric syndromes (PANS), the authors note. Tics constitute an “accompanying feature” of this condition.

However, neither population-based nor longitudinal clinical studies “could definitely establish if tic exacerbations in CTD are associated with GAS infections,” they note.  

“The link between streptococcus and tics in children is still a matter of intense debate,” said study author Davide Martino, MD, PhD, director of the Movement Disorders Program at the University of Calgary (Alta.), in a press release.

“We wanted to look at that question, as well as a possible link between strep and behavioral symptoms like obsessive-compulsive disorder and attention deficit hyperactivity disorder,” he said.

The researchers followed 715 children with CTD (mean age 10.7 years, 76.8% male) who were drawn from 16 specialist clinics in nine countries. Almost all (90.8%) had a diagnosis of Tourette syndrome (TS); 31.7% had OCD, and 36.1% had ADHD.

Participants received a throat swab at baseline, and of these, 8.4% tested positive for GAS.

Participants were evaluated over a 16- to 18-month period, consisting of:

• Face-to-face interviews and collection of throat swabs and serum at 4-month intervals.
• Telephone interviews at 4-month intervals, which took place at 2 months between study visit.
• Weekly diaries: Parents were asked to indicate any worsening of tics and focus on detecting the earliest possible tic exacerbation.

Beyond the regularly scheduled visits, parents were instructed to report, by phone or email, any noticeable increase in tic severity and then attend an in-person visit.

Tic exacerbations were defined as an increase of greater than or equal to 6 points on the Yale Global Tic Severity Scale-Total Tic Severity Score (YGTSS-TTS), compared with the previous assessment.

OCD and ADHD symptoms were assessed according to the Yale-Brown Obsessive-Compulsive Scale and the parent-reported Swanson, Nolan, and Pelham-IV (SNAP-IV) questionnaire.

The researchers divided GAS exposures into four categories: new definite exposure; new possible exposure; ongoing definite exposure; and ongoing possible exposure.
 

Unlikely trigger

During the follow-up period, 43.1% (n = 308) of participants experienced tic exacerbations. Of these, 218 participants experienced one exacerbation, while 90 participants experienced two, three, or four exacerbations.

The researchers did not find a significant association between GAS exposure status and tic exacerbation.

Participants who did develop a GAS-associated exacerbation (n = 49) were younger at study exit (9.63 vs. 11.4 years, P < .0001) and were more likely to be male (46/49 vs. 210/259, Fisher’s = .035), compared with participants who developed a non-GAS-associated tic exacerbation (n = 259).

Additional analyses were adjusted for sex, age at onset, exposure to psychotropic medications, exposures to antibiotics, geographical regions, and number of visits in the time interval of interest. These analyses continued to yield no significant association between new or ongoing concurrent GAS exposure episodes and tic exacerbation events.

Of the children in the study, 103 had a positive throat swab, indicating a new definite GAS exposure, whereas 46 had a positive throat swab indicating an ongoing definite exposure (n = 149 visits). Of these visits, only 20 corresponded to tic exacerbations.

There was also no association between GAS exposure and OCD symptom severity. However, it was associated with longitudinal changes (between 17% and 21%, depending on GAS exposure definition) in the severity of hyperactivity-impulsivity symptoms in children with ADHD.

“It is known that immune activation may concur with tic severity in youth with CTDs and that psychosocial stress levels may predict short-term future tic severity in these patients,” the authors write.

“Our findings suggest that GAS is unlikely to be the main trigger for immune activation in these patients,” they add.
 

Brick or cornerstone?

Commenting on the study for this news organization, Margo Thienemann, MD, clinical professor of psychiatry, Stanford (Calif.) University, said that in the clinic population they treat, GAS, other pathogens, and other stresses can “each be associated with PANS symptom exacerbations.”

However, these “would not be likely to cause PANS symptoms exacerbations in the vast majority of individuals, only individuals with genetic backgrounds and immunologic dysfunctions creating susceptibility,” said Dr. Thienemann, who also directs the Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) Clinic at Stanford Children’s Health. She was not involved with the study.

In an accompanying editorial, Andrea Cavanna, MD, PhD, honorary reader in neuropsychiatry, Birmingham (England) Medical School and Keith Coffman, MD, director, Tourette Syndrome Center of Excellence, Children’s Mercy Hospital, Kansas City, Mo., suggest that perhaps the “interaction of psychosocial stress and GAS infections contributes more to tic exacerbation than psychosocial stress alone.”

“Time will tell whether this study stands as another brick – a cornerstone? – in the wall that separates streptococcus from tics,” they write.

The study was supported by the European Union’s Seventh Framework Program. Dr. Martino has received honoraria for lecturing from the Movement Disorders Society, Tourette Syndrome Association of America, and Dystonia Medical Research Foundation Canada; research funding support from Dystonia Medical Research Foundation Canada, the University of Calgary (Alta.), the Michael P. Smith Family, the Owerko Foundation, Ipsen Corporate, the Parkinson Association of Alberta, and the Canadian Institutes for Health Research; and royalties from Springer-Verlag. The other authors’ disclosures are listed in the original article. Dr. Cavanna, Dr. Coffman, and Dr. Thienemann have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Exposure to Group A streptococcus (GAS) does not appear to worsen symptoms of Tourette syndrome and other chronic tic disorders (CTDs) in children and adolescents, new research suggests.

Investigators studied over 700 children and teenagers with CTDs, one-third of whom also had attention deficit hyperactivity disorder and one-third who had obsessive-compulsive disorder (OCD).

The youngsters were followed for an average of 16 months and evaluated at 4-month intervals to see if they were infected with GAS. Tic severity was monitored through telephone interviews, in-person visits, and parental reports.

A little less than half the children experienced worsening of tics during the study period, but the researchers found no association between these exacerbations and GAS exposure.

There was also no link between GAS and worsening OCD. However, researchers did find an association between GAS exposure and an increase in hyperactivity and impulsivity in patients with ADHD.

“This study does not support GAS exposures as contributing factors for tic exacerbations in children with CTD,” the authors note.

“Specific work-up or active management of GAS infections is unlikely to help modifying the course of tics in CTD and is therefore not recommended,” they conclude.

The study was published online in Neurology.
 

‘Intense debate’

The association between GAS and CTD stems from the description of Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection (PANDAS) – a condition that is now incorporated in the pediatric acute neuropsychiatric syndromes (PANS), the authors note. Tics constitute an “accompanying feature” of this condition.

However, neither population-based nor longitudinal clinical studies “could definitely establish if tic exacerbations in CTD are associated with GAS infections,” they note.  

“The link between streptococcus and tics in children is still a matter of intense debate,” said study author Davide Martino, MD, PhD, director of the Movement Disorders Program at the University of Calgary (Alta.), in a press release.

“We wanted to look at that question, as well as a possible link between strep and behavioral symptoms like obsessive-compulsive disorder and attention deficit hyperactivity disorder,” he said.

The researchers followed 715 children with CTD (mean age 10.7 years, 76.8% male) who were drawn from 16 specialist clinics in nine countries. Almost all (90.8%) had a diagnosis of Tourette syndrome (TS); 31.7% had OCD, and 36.1% had ADHD.

Participants received a throat swab at baseline, and of these, 8.4% tested positive for GAS.

Participants were evaluated over a 16- to 18-month period, consisting of:

• Face-to-face interviews and collection of throat swabs and serum at 4-month intervals.
• Telephone interviews at 4-month intervals, which took place at 2 months between study visit.
• Weekly diaries: Parents were asked to indicate any worsening of tics and focus on detecting the earliest possible tic exacerbation.

Beyond the regularly scheduled visits, parents were instructed to report, by phone or email, any noticeable increase in tic severity and then attend an in-person visit.

Tic exacerbations were defined as an increase of greater than or equal to 6 points on the Yale Global Tic Severity Scale-Total Tic Severity Score (YGTSS-TTS), compared with the previous assessment.

OCD and ADHD symptoms were assessed according to the Yale-Brown Obsessive-Compulsive Scale and the parent-reported Swanson, Nolan, and Pelham-IV (SNAP-IV) questionnaire.

The researchers divided GAS exposures into four categories: new definite exposure; new possible exposure; ongoing definite exposure; and ongoing possible exposure.
 

Unlikely trigger

During the follow-up period, 43.1% (n = 308) of participants experienced tic exacerbations. Of these, 218 participants experienced one exacerbation, while 90 participants experienced two, three, or four exacerbations.

The researchers did not find a significant association between GAS exposure status and tic exacerbation.

Participants who did develop a GAS-associated exacerbation (n = 49) were younger at study exit (9.63 vs. 11.4 years, P < .0001) and were more likely to be male (46/49 vs. 210/259, Fisher’s = .035), compared with participants who developed a non-GAS-associated tic exacerbation (n = 259).

Additional analyses were adjusted for sex, age at onset, exposure to psychotropic medications, exposures to antibiotics, geographical regions, and number of visits in the time interval of interest. These analyses continued to yield no significant association between new or ongoing concurrent GAS exposure episodes and tic exacerbation events.

Of the children in the study, 103 had a positive throat swab, indicating a new definite GAS exposure, whereas 46 had a positive throat swab indicating an ongoing definite exposure (n = 149 visits). Of these visits, only 20 corresponded to tic exacerbations.

There was also no association between GAS exposure and OCD symptom severity. However, it was associated with longitudinal changes (between 17% and 21%, depending on GAS exposure definition) in the severity of hyperactivity-impulsivity symptoms in children with ADHD.

“It is known that immune activation may concur with tic severity in youth with CTDs and that psychosocial stress levels may predict short-term future tic severity in these patients,” the authors write.

“Our findings suggest that GAS is unlikely to be the main trigger for immune activation in these patients,” they add.
 

Brick or cornerstone?

Commenting on the study for this news organization, Margo Thienemann, MD, clinical professor of psychiatry, Stanford (Calif.) University, said that in the clinic population they treat, GAS, other pathogens, and other stresses can “each be associated with PANS symptom exacerbations.”

However, these “would not be likely to cause PANS symptoms exacerbations in the vast majority of individuals, only individuals with genetic backgrounds and immunologic dysfunctions creating susceptibility,” said Dr. Thienemann, who also directs the Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) Clinic at Stanford Children’s Health. She was not involved with the study.

In an accompanying editorial, Andrea Cavanna, MD, PhD, honorary reader in neuropsychiatry, Birmingham (England) Medical School and Keith Coffman, MD, director, Tourette Syndrome Center of Excellence, Children’s Mercy Hospital, Kansas City, Mo., suggest that perhaps the “interaction of psychosocial stress and GAS infections contributes more to tic exacerbation than psychosocial stress alone.”

“Time will tell whether this study stands as another brick – a cornerstone? – in the wall that separates streptococcus from tics,” they write.

The study was supported by the European Union’s Seventh Framework Program. Dr. Martino has received honoraria for lecturing from the Movement Disorders Society, Tourette Syndrome Association of America, and Dystonia Medical Research Foundation Canada; research funding support from Dystonia Medical Research Foundation Canada, the University of Calgary (Alta.), the Michael P. Smith Family, the Owerko Foundation, Ipsen Corporate, the Parkinson Association of Alberta, and the Canadian Institutes for Health Research; and royalties from Springer-Verlag. The other authors’ disclosures are listed in the original article. Dr. Cavanna, Dr. Coffman, and Dr. Thienemann have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A commonly used newborn hearing test shows promise in the early detection of autism spectrum disorder (ASD), new research shows.  

Results from one of the largest studies of its kind show the auditory brainstem response (ABR) test, which is carried out on most newborns, represents “a huge untapped potential” to detect autism, lead author Oren Miron, research associate, department of biomedical informatics, Harvard Medical School, Boston, and a PhD candidate at Ben Gurion University in Beersheba, Israel, said in an interview.

“The findings further reinforce our understanding that autism, in many cases, has a sensorial and auditory aspect to it,” said Mr. Miron, adding that an adverse response to sound is one of the earliest behavioral signs of autism.

The research was published online Oct. 31 in Autism Research.
 

Early intervention critical

Autism spectrum disorder (ASD), which involves problems in social communication and interaction, affects an estimated 1 in 59 children. Early identification and intervention are critical for improving outcomes and decreasing the economic burden associated with ASD.

The ABR test, which is used for Universal Newborn Hearing Screening (UNHS), uses surface electrodes to measure auditory nerve and brainstem responses to sound.

Previous studies identified abnormal ABR amplitude in children with ASD. However, it’s unclear whether healthy newborns who later develop autism also show ABR differences vs those who don’t develop the disorder.

Researchers used UNHS data, which allowed them to examine a larger, younger, and healthier sample compared with previous studies. The study included 321 newborns later diagnosed with ASD and 138,844 controls without a subsequent ASD diagnosis.

The mean ABR testing age was 1.76 days for newborns later diagnosed with ASD and 1.86 for those in the non-ASD group.

The ASD group was 77% male and the non-ASD group was 51% male. The rate of neonatal intensive care unit admission was 8% in the ASD group and 10% in the non-ASD group.

The hearing test involves placing an earpiece in the baby’s ear and delivering a click sound at 35 dB above normal hearing level (nHL) at a rate of 77 clicks per second in the right ear and 79 clicks per second in the left ear.
 

Brainstem abnormalities?

The clicks create electrical activity, which is recorded by a surface electrode and used to extract the ABR waveform. When a sound reaches the brain stem, it creates five consecutive waveforms – waves I, II, III, IV, and V.

Previous studies focused on wave V, which is easiest to detect. The current study used low intensity sound that resulted in a weaker signal.

To overcome this low intensity issue, researchers focused on the negative drop (latency) after the wave V (Vn), which is easier to detect, and on the ABR phase, or entire waveform. They illustrated the differences between the ASD and non-ASD groups in a series of graphs.

Results showed that the ABR phase in the right ear was significantly prolonged in the ASD vs non-ASD group (P < .001). ABR phase in the left ear was also significantly prolonged in the ASD group (P = .021)

Vn latency in the right ear was significantly prolonged in the ASD group compared with the non-ASD group (P = .048); however, this was not the case in the left ear.

The prolongation could mean that the V-negative wave might appear after 8 ms in normally developing children compared with 8.5 or 9 ms in children with autism, said Mr. Miron.

The new study is the first to show V-negative and phase abnormalities are associated with ASD, the authors note. The brainstem prolongation could be due to anatomical abnormalities in the brainstem in individuals with ASD, the researchers added.
 

Present before birth?

The presence of ABR biomarkers of ASD in the first weeks after birth suggests the disorder is likely present before birth in a large group of these individuals, the researchers note.

It’s possible the ABR test could be modified to use lower intensities not only to detect hearing impairment but autism risk, said Mr. Miron. “The test has been optimized to detect hearing impairment, and it does so brilliantly and helps thousands of children. We want to do the same kind of optimization for autism.”

This could lead to earlier behavioral diagnoses, which, in turn, could lead to earlier treatment and better outcomes for children with ASD, said Mr. Miron.

At this time, the level of prolongation to detect ASD is unclear. “I would think a lot of people would want to make it one standard deviation, but it depends on a lot of factors, including for example, whether a baby is preterm,” said Mr. Miron.

More research and better accuracy and specificity are needed before the newborn hearing test is clinically useful.

He noted that the hearing test is only one marker of autism and that it could potentially be combined with other behavioral signs and genetic markers to facilitate earlier diagnosis and treatment and improve outcomes for patients with ASD.

Future research by his group will investigate whether the degree of auditory prolongation relates to autism severity. They also plan to research ASD subgroups including children with comorbid epilepsy.
 

Terrific, clever research

Jeremy Veenstra-VanderWeele, MD, professor, child and adolescent psychiatry, Columbia University, New York, said in an interview that the study is “terrific” and a “clever use” of an existing dataset.

“They showed a difference between a large group of kids with autism and a large group of kids without.”

However, he added, more research is needed before the test can be used as an autism screening tool.

“In order for this to be a screening test that could be broadly applied you would need to identify a cutoff where you’d think a child was at risk for autism, and if you look at the graphs in the article, there are no clear cutoffs,” said Dr. Veenstra-VanderWeele.

To turn this into a useful test, “you would have to establish sensitivity and specificity, you would have to look not just at the comparison of kids with autism and kids without but apply it in a predictive way in a second population.”

The study authors and Dr. Veenstra-VanderWeele have reported no relevant financial relationships. Veenstra-VanderWeele is an associate editor at Autism Research, which published the article, but he did not handle or view it before being interviewed.

A version of this article originally appeared on Medscape.com.

A commonly used newborn hearing test shows promise in the early detection of autism spectrum disorder (ASD), new research shows.  

Results from one of the largest studies of its kind show the auditory brainstem response (ABR) test, which is carried out on most newborns, represents “a huge untapped potential” to detect autism, lead author Oren Miron, research associate, department of biomedical informatics, Harvard Medical School, Boston, and a PhD candidate at Ben Gurion University in Beersheba, Israel, said in an interview.

“The findings further reinforce our understanding that autism, in many cases, has a sensorial and auditory aspect to it,” said Mr. Miron, adding that an adverse response to sound is one of the earliest behavioral signs of autism.

The research was published online Oct. 31 in Autism Research.
 

Early intervention critical

Autism spectrum disorder (ASD), which involves problems in social communication and interaction, affects an estimated 1 in 59 children. Early identification and intervention are critical for improving outcomes and decreasing the economic burden associated with ASD.

The ABR test, which is used for Universal Newborn Hearing Screening (UNHS), uses surface electrodes to measure auditory nerve and brainstem responses to sound.

Previous studies identified abnormal ABR amplitude in children with ASD. However, it’s unclear whether healthy newborns who later develop autism also show ABR differences vs those who don’t develop the disorder.

Researchers used UNHS data, which allowed them to examine a larger, younger, and healthier sample compared with previous studies. The study included 321 newborns later diagnosed with ASD and 138,844 controls without a subsequent ASD diagnosis.

The mean ABR testing age was 1.76 days for newborns later diagnosed with ASD and 1.86 for those in the non-ASD group.

The ASD group was 77% male and the non-ASD group was 51% male. The rate of neonatal intensive care unit admission was 8% in the ASD group and 10% in the non-ASD group.

The hearing test involves placing an earpiece in the baby’s ear and delivering a click sound at 35 dB above normal hearing level (nHL) at a rate of 77 clicks per second in the right ear and 79 clicks per second in the left ear.
 

Brainstem abnormalities?

The clicks create electrical activity, which is recorded by a surface electrode and used to extract the ABR waveform. When a sound reaches the brain stem, it creates five consecutive waveforms – waves I, II, III, IV, and V.

Previous studies focused on wave V, which is easiest to detect. The current study used low intensity sound that resulted in a weaker signal.

To overcome this low intensity issue, researchers focused on the negative drop (latency) after the wave V (Vn), which is easier to detect, and on the ABR phase, or entire waveform. They illustrated the differences between the ASD and non-ASD groups in a series of graphs.

Results showed that the ABR phase in the right ear was significantly prolonged in the ASD vs non-ASD group (P < .001). ABR phase in the left ear was also significantly prolonged in the ASD group (P = .021)

Vn latency in the right ear was significantly prolonged in the ASD group compared with the non-ASD group (P = .048); however, this was not the case in the left ear.

The prolongation could mean that the V-negative wave might appear after 8 ms in normally developing children compared with 8.5 or 9 ms in children with autism, said Mr. Miron.

The new study is the first to show V-negative and phase abnormalities are associated with ASD, the authors note. The brainstem prolongation could be due to anatomical abnormalities in the brainstem in individuals with ASD, the researchers added.
 

Present before birth?

The presence of ABR biomarkers of ASD in the first weeks after birth suggests the disorder is likely present before birth in a large group of these individuals, the researchers note.

It’s possible the ABR test could be modified to use lower intensities not only to detect hearing impairment but autism risk, said Mr. Miron. “The test has been optimized to detect hearing impairment, and it does so brilliantly and helps thousands of children. We want to do the same kind of optimization for autism.”

This could lead to earlier behavioral diagnoses, which, in turn, could lead to earlier treatment and better outcomes for children with ASD, said Mr. Miron.

At this time, the level of prolongation to detect ASD is unclear. “I would think a lot of people would want to make it one standard deviation, but it depends on a lot of factors, including for example, whether a baby is preterm,” said Mr. Miron.

More research and better accuracy and specificity are needed before the newborn hearing test is clinically useful.

He noted that the hearing test is only one marker of autism and that it could potentially be combined with other behavioral signs and genetic markers to facilitate earlier diagnosis and treatment and improve outcomes for patients with ASD.

Future research by his group will investigate whether the degree of auditory prolongation relates to autism severity. They also plan to research ASD subgroups including children with comorbid epilepsy.
 

Terrific, clever research

Jeremy Veenstra-VanderWeele, MD, professor, child and adolescent psychiatry, Columbia University, New York, said in an interview that the study is “terrific” and a “clever use” of an existing dataset.

“They showed a difference between a large group of kids with autism and a large group of kids without.”

However, he added, more research is needed before the test can be used as an autism screening tool.

“In order for this to be a screening test that could be broadly applied you would need to identify a cutoff where you’d think a child was at risk for autism, and if you look at the graphs in the article, there are no clear cutoffs,” said Dr. Veenstra-VanderWeele.

To turn this into a useful test, “you would have to establish sensitivity and specificity, you would have to look not just at the comparison of kids with autism and kids without but apply it in a predictive way in a second population.”

The study authors and Dr. Veenstra-VanderWeele have reported no relevant financial relationships. Veenstra-VanderWeele is an associate editor at Autism Research, which published the article, but he did not handle or view it before being interviewed.

A version of this article originally appeared on Medscape.com.

A commonly used newborn hearing test shows promise in the early detection of autism spectrum disorder (ASD), new research shows.  

Results from one of the largest studies of its kind show the auditory brainstem response (ABR) test, which is carried out on most newborns, represents “a huge untapped potential” to detect autism, lead author Oren Miron, research associate, department of biomedical informatics, Harvard Medical School, Boston, and a PhD candidate at Ben Gurion University in Beersheba, Israel, said in an interview.

“The findings further reinforce our understanding that autism, in many cases, has a sensorial and auditory aspect to it,” said Mr. Miron, adding that an adverse response to sound is one of the earliest behavioral signs of autism.

The research was published online Oct. 31 in Autism Research.
 

Early intervention critical

Autism spectrum disorder (ASD), which involves problems in social communication and interaction, affects an estimated 1 in 59 children. Early identification and intervention are critical for improving outcomes and decreasing the economic burden associated with ASD.

The ABR test, which is used for Universal Newborn Hearing Screening (UNHS), uses surface electrodes to measure auditory nerve and brainstem responses to sound.

Previous studies identified abnormal ABR amplitude in children with ASD. However, it’s unclear whether healthy newborns who later develop autism also show ABR differences vs those who don’t develop the disorder.

Researchers used UNHS data, which allowed them to examine a larger, younger, and healthier sample compared with previous studies. The study included 321 newborns later diagnosed with ASD and 138,844 controls without a subsequent ASD diagnosis.

The mean ABR testing age was 1.76 days for newborns later diagnosed with ASD and 1.86 for those in the non-ASD group.

The ASD group was 77% male and the non-ASD group was 51% male. The rate of neonatal intensive care unit admission was 8% in the ASD group and 10% in the non-ASD group.

The hearing test involves placing an earpiece in the baby’s ear and delivering a click sound at 35 dB above normal hearing level (nHL) at a rate of 77 clicks per second in the right ear and 79 clicks per second in the left ear.
 

Brainstem abnormalities?

The clicks create electrical activity, which is recorded by a surface electrode and used to extract the ABR waveform. When a sound reaches the brain stem, it creates five consecutive waveforms – waves I, II, III, IV, and V.

Previous studies focused on wave V, which is easiest to detect. The current study used low intensity sound that resulted in a weaker signal.

To overcome this low intensity issue, researchers focused on the negative drop (latency) after the wave V (Vn), which is easier to detect, and on the ABR phase, or entire waveform. They illustrated the differences between the ASD and non-ASD groups in a series of graphs.

Results showed that the ABR phase in the right ear was significantly prolonged in the ASD vs non-ASD group (P < .001). ABR phase in the left ear was also significantly prolonged in the ASD group (P = .021)

Vn latency in the right ear was significantly prolonged in the ASD group compared with the non-ASD group (P = .048); however, this was not the case in the left ear.

The prolongation could mean that the V-negative wave might appear after 8 ms in normally developing children compared with 8.5 or 9 ms in children with autism, said Mr. Miron.

The new study is the first to show V-negative and phase abnormalities are associated with ASD, the authors note. The brainstem prolongation could be due to anatomical abnormalities in the brainstem in individuals with ASD, the researchers added.
 

Present before birth?

The presence of ABR biomarkers of ASD in the first weeks after birth suggests the disorder is likely present before birth in a large group of these individuals, the researchers note.

It’s possible the ABR test could be modified to use lower intensities not only to detect hearing impairment but autism risk, said Mr. Miron. “The test has been optimized to detect hearing impairment, and it does so brilliantly and helps thousands of children. We want to do the same kind of optimization for autism.”

This could lead to earlier behavioral diagnoses, which, in turn, could lead to earlier treatment and better outcomes for children with ASD, said Mr. Miron.

At this time, the level of prolongation to detect ASD is unclear. “I would think a lot of people would want to make it one standard deviation, but it depends on a lot of factors, including for example, whether a baby is preterm,” said Mr. Miron.

More research and better accuracy and specificity are needed before the newborn hearing test is clinically useful.

He noted that the hearing test is only one marker of autism and that it could potentially be combined with other behavioral signs and genetic markers to facilitate earlier diagnosis and treatment and improve outcomes for patients with ASD.

Future research by his group will investigate whether the degree of auditory prolongation relates to autism severity. They also plan to research ASD subgroups including children with comorbid epilepsy.
 

Terrific, clever research

Jeremy Veenstra-VanderWeele, MD, professor, child and adolescent psychiatry, Columbia University, New York, said in an interview that the study is “terrific” and a “clever use” of an existing dataset.

“They showed a difference between a large group of kids with autism and a large group of kids without.”

However, he added, more research is needed before the test can be used as an autism screening tool.

“In order for this to be a screening test that could be broadly applied you would need to identify a cutoff where you’d think a child was at risk for autism, and if you look at the graphs in the article, there are no clear cutoffs,” said Dr. Veenstra-VanderWeele.

To turn this into a useful test, “you would have to establish sensitivity and specificity, you would have to look not just at the comparison of kids with autism and kids without but apply it in a predictive way in a second population.”

The study authors and Dr. Veenstra-VanderWeele have reported no relevant financial relationships. Veenstra-VanderWeele is an associate editor at Autism Research, which published the article, but he did not handle or view it before being interviewed.

A version of this article originally appeared on Medscape.com.

A mutation of the ODC1 gene, which plays a key role in polyamine metabolism, has been implicated in a syndromic neurodevelopmental disorder first described in 2018 and linked to a number of dysmorphic features and brain abnormalities, but it may be treated with diet modifications and available therapies, according to the researcher whose group first identified the disorder.

Lance Rodan, MD, of Boston Children’s Hospital and Harvard Medical School, reported on research into ODC1 gain-of-function disorder –named for ornithine decarboxylase 1, the rate-limiting enzyme involved in polyamine synthesis – in the Linda De Meirleir Neurometabolic award lecture at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year. Dr. Rodan and colleagues first described ODC1 disorder in a multicenter case series.

Dr. Rodan noted that dysregulated polyamine levels are associated with cancer, and that ODC1 is expressed “ubiquitously” throughout the body.
 

Pathophysiology and phenotypes

In an interview, he described the metabolic process more fully. “GI flora can produce putrescine, which is the polyamine that accumulates in excess in the ODC1 gain-of-function disorder. It is yet to be elucidated if decreasing putrescine production by GI flora and/or reducing dietary sources of putrescine may play a role in the management of this disorder.” 

In the De Meirleir lecture, Dr. Rodan described four patients from his group’s published case series, all found to have heterozygous de novo variants in the ODC1 gene, along with a fifth patient reported by Caleb Bupp, MD, and colleagues at Michigan State University, East Lansing.

“There’s a recognizable phenotype to this disorder,” Dr. Rodan said. “These individuals have neurodevelopment abnormalities. They may have behavioral concerns. They have low-tone central hypertonia and macrocephaly.”

One of the most distinctive characteristics of ODC1 disorder is alopecia, he said, “which in almost everybody with this condition involves the eyebrows and eyelashes and in some individuals also involves the scalp hair.”

These patients also have what Dr. Rodan called “a common yet subtle facial gestalt.” That can include hypertelorism, spareness of the eyebrows and eyelashes, and a tubular- shaped nose with a short columella and a short philtrum.

They may also have abnormalities of the nails and cryptorchidism, and typically a prenatal history of polyhydramnios, he said.

MRI findings include prominent perivascular spaces, periventricular cysts, abnormal white matter and corpus callosum abnormalities, he said, adding that the fetal case MRI demonstrated subepidermal cysts, white matter cysts in the temporal pole, deficiency of the falx cerebri and abnormal white-matter signals.

Biochemical features of ODC1 disorder include increased N-acetylputrescine levels with normal spermine and spermidine levels, Dr. Rodan said. He also noted that Dr. Bupp’s group reported increased putrescine in fibroblasts and increased ODC1 protein levels in red blood cells.

Dr. Rodan also described possible molecular mechanisms in ODC1 disorder. One was the location of the ODC1 variants: all were reported closely located to truncating variants in the final exon of the ODC1 gene. This allows truncating proteins to survive, adding to the degradation that results in a net gain-of-function of ODC1 enzyme activity.

With regard to pathophysiology of ODC1 disorder, Dr. Rodan noted that research has implicated chronically elevated putrescine levels in the alopecia, a finding animal models support. “Since putrescine is a precursor for gamma-aminobutyric acid, it’s possible perturbed GABA levels may also be involved,” he said. Abnormal modulation N-methyl-D-aspirate receptors may also be involved, he said.

Another hypothesis purports that potential of elevated levels of toxic aldehydes/H₂O₂ similar to Snyder-Robinson syndrome, the better known polyamine-related neurometabolic disorder. “Along those lines, maybe there’s also a secondary mitochondrial or lysosomal dysfunction, but this is something that’s still being actively studied,” Dr. Rodan said.
 

Treatment

Because ODC1 disorder was only first described 2 years ago, research into treatment is nascent. “In terms of management, I think one of the more fundamental questions is whether this is more of a static developmental disorder or whether this actually represents a progressive degenerative disorder,” Dr. Rodan said.

One potential treatment that has been explored, he said, is difluoromethylornithine, a synthetic ODC1 inhibitor already Food and Drug Administration approved for African sleeping sickness and as a topical treatment for hirsutism. It is also the subject of ongoing clinical trials in colon cancer and neuroblastoma. Potential side effects include myelosuppression, seizures and hearing loss.

Dr. Rodan noted that a single-center study reported that difluoromethylornithine in a 3-year-old patient with ODC1 disorder reduced ODC protein activity and putrescine to control levels.

Other potential treatments include the natural ODC1 inhibitors agmatine and turmeric/curcumin, flagyl/rifaximin to decrease putrescine production in the gut, a low-dairy diet to lower putrescine levels, and antioxidants. “There could be a role for antioxidant stress similar to what is seen in Snyder-Robinson syndrome,” Dr. Rodan said.

Based on mouse studies, patients with ODC1 may be at risk of skin cancer, so regular skin checks along with sun protection should be part of management, he said. “This also raises the question of whether there should be surveillance for other types of cancer given the role of polyamine in various types of tumors.”

Dr. Rodan has no relevant financial relationships to disclose.

A mutation of the ODC1 gene, which plays a key role in polyamine metabolism, has been implicated in a syndromic neurodevelopmental disorder first described in 2018 and linked to a number of dysmorphic features and brain abnormalities, but it may be treated with diet modifications and available therapies, according to the researcher whose group first identified the disorder.

Lance Rodan, MD, of Boston Children’s Hospital and Harvard Medical School, reported on research into ODC1 gain-of-function disorder –named for ornithine decarboxylase 1, the rate-limiting enzyme involved in polyamine synthesis – in the Linda De Meirleir Neurometabolic award lecture at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year. Dr. Rodan and colleagues first described ODC1 disorder in a multicenter case series.

Dr. Rodan noted that dysregulated polyamine levels are associated with cancer, and that ODC1 is expressed “ubiquitously” throughout the body.
 

Pathophysiology and phenotypes

In an interview, he described the metabolic process more fully. “GI flora can produce putrescine, which is the polyamine that accumulates in excess in the ODC1 gain-of-function disorder. It is yet to be elucidated if decreasing putrescine production by GI flora and/or reducing dietary sources of putrescine may play a role in the management of this disorder.” 

In the De Meirleir lecture, Dr. Rodan described four patients from his group’s published case series, all found to have heterozygous de novo variants in the ODC1 gene, along with a fifth patient reported by Caleb Bupp, MD, and colleagues at Michigan State University, East Lansing.

“There’s a recognizable phenotype to this disorder,” Dr. Rodan said. “These individuals have neurodevelopment abnormalities. They may have behavioral concerns. They have low-tone central hypertonia and macrocephaly.”

One of the most distinctive characteristics of ODC1 disorder is alopecia, he said, “which in almost everybody with this condition involves the eyebrows and eyelashes and in some individuals also involves the scalp hair.”

These patients also have what Dr. Rodan called “a common yet subtle facial gestalt.” That can include hypertelorism, spareness of the eyebrows and eyelashes, and a tubular- shaped nose with a short columella and a short philtrum.

They may also have abnormalities of the nails and cryptorchidism, and typically a prenatal history of polyhydramnios, he said.

MRI findings include prominent perivascular spaces, periventricular cysts, abnormal white matter and corpus callosum abnormalities, he said, adding that the fetal case MRI demonstrated subepidermal cysts, white matter cysts in the temporal pole, deficiency of the falx cerebri and abnormal white-matter signals.

Biochemical features of ODC1 disorder include increased N-acetylputrescine levels with normal spermine and spermidine levels, Dr. Rodan said. He also noted that Dr. Bupp’s group reported increased putrescine in fibroblasts and increased ODC1 protein levels in red blood cells.

Dr. Rodan also described possible molecular mechanisms in ODC1 disorder. One was the location of the ODC1 variants: all were reported closely located to truncating variants in the final exon of the ODC1 gene. This allows truncating proteins to survive, adding to the degradation that results in a net gain-of-function of ODC1 enzyme activity.

With regard to pathophysiology of ODC1 disorder, Dr. Rodan noted that research has implicated chronically elevated putrescine levels in the alopecia, a finding animal models support. “Since putrescine is a precursor for gamma-aminobutyric acid, it’s possible perturbed GABA levels may also be involved,” he said. Abnormal modulation N-methyl-D-aspirate receptors may also be involved, he said.

Another hypothesis purports that potential of elevated levels of toxic aldehydes/H₂O₂ similar to Snyder-Robinson syndrome, the better known polyamine-related neurometabolic disorder. “Along those lines, maybe there’s also a secondary mitochondrial or lysosomal dysfunction, but this is something that’s still being actively studied,” Dr. Rodan said.
 

Treatment

Because ODC1 disorder was only first described 2 years ago, research into treatment is nascent. “In terms of management, I think one of the more fundamental questions is whether this is more of a static developmental disorder or whether this actually represents a progressive degenerative disorder,” Dr. Rodan said.

One potential treatment that has been explored, he said, is difluoromethylornithine, a synthetic ODC1 inhibitor already Food and Drug Administration approved for African sleeping sickness and as a topical treatment for hirsutism. It is also the subject of ongoing clinical trials in colon cancer and neuroblastoma. Potential side effects include myelosuppression, seizures and hearing loss.

Dr. Rodan noted that a single-center study reported that difluoromethylornithine in a 3-year-old patient with ODC1 disorder reduced ODC protein activity and putrescine to control levels.

Other potential treatments include the natural ODC1 inhibitors agmatine and turmeric/curcumin, flagyl/rifaximin to decrease putrescine production in the gut, a low-dairy diet to lower putrescine levels, and antioxidants. “There could be a role for antioxidant stress similar to what is seen in Snyder-Robinson syndrome,” Dr. Rodan said.

Based on mouse studies, patients with ODC1 may be at risk of skin cancer, so regular skin checks along with sun protection should be part of management, he said. “This also raises the question of whether there should be surveillance for other types of cancer given the role of polyamine in various types of tumors.”

Dr. Rodan has no relevant financial relationships to disclose.

A mutation of the ODC1 gene, which plays a key role in polyamine metabolism, has been implicated in a syndromic neurodevelopmental disorder first described in 2018 and linked to a number of dysmorphic features and brain abnormalities, but it may be treated with diet modifications and available therapies, according to the researcher whose group first identified the disorder.

Lance Rodan, MD, of Boston Children’s Hospital and Harvard Medical School, reported on research into ODC1 gain-of-function disorder –named for ornithine decarboxylase 1, the rate-limiting enzyme involved in polyamine synthesis – in the Linda De Meirleir Neurometabolic award lecture at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year. Dr. Rodan and colleagues first described ODC1 disorder in a multicenter case series.

Dr. Rodan noted that dysregulated polyamine levels are associated with cancer, and that ODC1 is expressed “ubiquitously” throughout the body.
 

Pathophysiology and phenotypes

In an interview, he described the metabolic process more fully. “GI flora can produce putrescine, which is the polyamine that accumulates in excess in the ODC1 gain-of-function disorder. It is yet to be elucidated if decreasing putrescine production by GI flora and/or reducing dietary sources of putrescine may play a role in the management of this disorder.” 

In the De Meirleir lecture, Dr. Rodan described four patients from his group’s published case series, all found to have heterozygous de novo variants in the ODC1 gene, along with a fifth patient reported by Caleb Bupp, MD, and colleagues at Michigan State University, East Lansing.

“There’s a recognizable phenotype to this disorder,” Dr. Rodan said. “These individuals have neurodevelopment abnormalities. They may have behavioral concerns. They have low-tone central hypertonia and macrocephaly.”

One of the most distinctive characteristics of ODC1 disorder is alopecia, he said, “which in almost everybody with this condition involves the eyebrows and eyelashes and in some individuals also involves the scalp hair.”

These patients also have what Dr. Rodan called “a common yet subtle facial gestalt.” That can include hypertelorism, spareness of the eyebrows and eyelashes, and a tubular- shaped nose with a short columella and a short philtrum.

They may also have abnormalities of the nails and cryptorchidism, and typically a prenatal history of polyhydramnios, he said.

MRI findings include prominent perivascular spaces, periventricular cysts, abnormal white matter and corpus callosum abnormalities, he said, adding that the fetal case MRI demonstrated subepidermal cysts, white matter cysts in the temporal pole, deficiency of the falx cerebri and abnormal white-matter signals.

Biochemical features of ODC1 disorder include increased N-acetylputrescine levels with normal spermine and spermidine levels, Dr. Rodan said. He also noted that Dr. Bupp’s group reported increased putrescine in fibroblasts and increased ODC1 protein levels in red blood cells.

Dr. Rodan also described possible molecular mechanisms in ODC1 disorder. One was the location of the ODC1 variants: all were reported closely located to truncating variants in the final exon of the ODC1 gene. This allows truncating proteins to survive, adding to the degradation that results in a net gain-of-function of ODC1 enzyme activity.

With regard to pathophysiology of ODC1 disorder, Dr. Rodan noted that research has implicated chronically elevated putrescine levels in the alopecia, a finding animal models support. “Since putrescine is a precursor for gamma-aminobutyric acid, it’s possible perturbed GABA levels may also be involved,” he said. Abnormal modulation N-methyl-D-aspirate receptors may also be involved, he said.

Another hypothesis purports that potential of elevated levels of toxic aldehydes/H₂O₂ similar to Snyder-Robinson syndrome, the better known polyamine-related neurometabolic disorder. “Along those lines, maybe there’s also a secondary mitochondrial or lysosomal dysfunction, but this is something that’s still being actively studied,” Dr. Rodan said.
 

Treatment

Because ODC1 disorder was only first described 2 years ago, research into treatment is nascent. “In terms of management, I think one of the more fundamental questions is whether this is more of a static developmental disorder or whether this actually represents a progressive degenerative disorder,” Dr. Rodan said.

One potential treatment that has been explored, he said, is difluoromethylornithine, a synthetic ODC1 inhibitor already Food and Drug Administration approved for African sleeping sickness and as a topical treatment for hirsutism. It is also the subject of ongoing clinical trials in colon cancer and neuroblastoma. Potential side effects include myelosuppression, seizures and hearing loss.

Dr. Rodan noted that a single-center study reported that difluoromethylornithine in a 3-year-old patient with ODC1 disorder reduced ODC protein activity and putrescine to control levels.

Other potential treatments include the natural ODC1 inhibitors agmatine and turmeric/curcumin, flagyl/rifaximin to decrease putrescine production in the gut, a low-dairy diet to lower putrescine levels, and antioxidants. “There could be a role for antioxidant stress similar to what is seen in Snyder-Robinson syndrome,” Dr. Rodan said.

Based on mouse studies, patients with ODC1 may be at risk of skin cancer, so regular skin checks along with sun protection should be part of management, he said. “This also raises the question of whether there should be surveillance for other types of cancer given the role of polyamine in various types of tumors.”

Dr. Rodan has no relevant financial relationships to disclose.

Nusinersen provides continued, long-term benefits to infants with spinal muscular atrophy (SMA) who begin treatment before symptom onset, according to an analysis presented at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year.

“Children are developing in a manner more consistent with normal development than that expected for children with two and three SMN2 gene copies,” said Russell Chin, MD, a neurologist at New York–Presbyterian Hospital. “These data demonstrate the durability of effect over a median of 3.8 years of follow-up, with children aged 2.8-4.8 years at the last visit.”

Many participants in the study achieved motor milestones within normal time limits, and no participant lost any major motor milestones. The investigators did not identify any new safety concerns during a maximum of 4.7 years of follow-up. They will follow participants until they reach approximately 8 years of age.
 

An ongoing open-label study

Dr. Chin presented interim results of the ongoing NURTURE study, which is examining the efficacy and safety of intrathecal nusinersen when administered to presymptomatic infants with SMA. The open-label, single-arm, phase 2 study is being conducted in various countries. Eligible participants were 6 weeks old or younger at first dose and had two or three copies of SMN2. The primary end point of NURTURE is time to death or respiratory intervention (i.e., invasive or noninvasive ventilation for 6 or more hours per day continuously for 7 or more days or tracheostomy). The natural history of SMA type 1 indicates that the median age at death or requirement for ventilation support is 13.5 months.

The investigators enrolled 25 infants: 15 with two copies of the gene and 10 with three copies. At the February 2020 interim analysis, participants had been in the study for 3.8 years and were aged 2.8-4.8 years at the last visit. No children had discontinued treatment or withdrawn from the study. All participants are alive, and four participants (all of whom have two copies of SMN2) required respiratory intervention. The latter children initiated respiratory support during an acute reversible illness. No subjects have required permanent ventilation, which the investigators define as ventilation for 16 or more hours per day for more than 21 days in the absence of an acute reversible event, or tracheostomy.
 

Treatment improved motor development

Approximately 84% of children achieved a maximum score on the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scale. The population’s mean CHOP INTEND score increased steadily from baseline and stabilized at approximately the maximum score of 64. The population’s mean change in CHOP INTEND score from baseline to last visit was 13.6 points. The mean score at last visit was 62.0 among patients with two copies of SMN2 and 63.4 among patients with three copies. In addition, the time to first achievement of maximum CHOP INTEND score was shorter in participants with three copies of SMN2, compared with those with two. Four participants with two copies of the gene have not yet achieved a maximum CHOP INTEND score.

Many of the children in the study achieved World Health Organization motor milestones within time frames consistent with normal development. About 84% of participants became able to sit without support within the normal time frame in healthy children. Approximately 60% of children achieved walking with assistance within the normal window, and 64% achieved walking alone within the normal window. Of 25 participants, 24 are walking with assistance, and 22 of 25 (88%) can walk alone. Dr. Chin and colleagues observed that lower levels of phosphorylated neurofilament heavy chain in plasma and cerebrospinal fluid on treatment at day 64 were significantly correlated with higher total score on the Hammersmith Infant Neurological Examination at day 302 and with earlier achievement of the WHO milestone walking alone.

Nusinersen and lumbar puncture were well tolerated. No children discontinued treatment or withdrew from the study because of an adverse event. The investigators did not consider any adverse events or serious adverse events to be related to the study drug. They also did not observe any clinically relevant trends related to nusinersen in hematology, blood chemistry, urinalysis, coagulation, vital signs, or ECGs.

Dr. Chin is an employee of and holds stock in Biogen, which manufactures nusinersen and is sponsoring the study.

[email protected]

SOURCE: Chin R et al. CNS-ICNA 2020, Abstract PL78.

Nusinersen provides continued, long-term benefits to infants with spinal muscular atrophy (SMA) who begin treatment before symptom onset, according to an analysis presented at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year.

“Children are developing in a manner more consistent with normal development than that expected for children with two and three SMN2 gene copies,” said Russell Chin, MD, a neurologist at New York–Presbyterian Hospital. “These data demonstrate the durability of effect over a median of 3.8 years of follow-up, with children aged 2.8-4.8 years at the last visit.”

Many participants in the study achieved motor milestones within normal time limits, and no participant lost any major motor milestones. The investigators did not identify any new safety concerns during a maximum of 4.7 years of follow-up. They will follow participants until they reach approximately 8 years of age.
 

An ongoing open-label study

Dr. Chin presented interim results of the ongoing NURTURE study, which is examining the efficacy and safety of intrathecal nusinersen when administered to presymptomatic infants with SMA. The open-label, single-arm, phase 2 study is being conducted in various countries. Eligible participants were 6 weeks old or younger at first dose and had two or three copies of SMN2. The primary end point of NURTURE is time to death or respiratory intervention (i.e., invasive or noninvasive ventilation for 6 or more hours per day continuously for 7 or more days or tracheostomy). The natural history of SMA type 1 indicates that the median age at death or requirement for ventilation support is 13.5 months.

The investigators enrolled 25 infants: 15 with two copies of the gene and 10 with three copies. At the February 2020 interim analysis, participants had been in the study for 3.8 years and were aged 2.8-4.8 years at the last visit. No children had discontinued treatment or withdrawn from the study. All participants are alive, and four participants (all of whom have two copies of SMN2) required respiratory intervention. The latter children initiated respiratory support during an acute reversible illness. No subjects have required permanent ventilation, which the investigators define as ventilation for 16 or more hours per day for more than 21 days in the absence of an acute reversible event, or tracheostomy.
 

Treatment improved motor development

Approximately 84% of children achieved a maximum score on the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scale. The population’s mean CHOP INTEND score increased steadily from baseline and stabilized at approximately the maximum score of 64. The population’s mean change in CHOP INTEND score from baseline to last visit was 13.6 points. The mean score at last visit was 62.0 among patients with two copies of SMN2 and 63.4 among patients with three copies. In addition, the time to first achievement of maximum CHOP INTEND score was shorter in participants with three copies of SMN2, compared with those with two. Four participants with two copies of the gene have not yet achieved a maximum CHOP INTEND score.

Many of the children in the study achieved World Health Organization motor milestones within time frames consistent with normal development. About 84% of participants became able to sit without support within the normal time frame in healthy children. Approximately 60% of children achieved walking with assistance within the normal window, and 64% achieved walking alone within the normal window. Of 25 participants, 24 are walking with assistance, and 22 of 25 (88%) can walk alone. Dr. Chin and colleagues observed that lower levels of phosphorylated neurofilament heavy chain in plasma and cerebrospinal fluid on treatment at day 64 were significantly correlated with higher total score on the Hammersmith Infant Neurological Examination at day 302 and with earlier achievement of the WHO milestone walking alone.

Nusinersen and lumbar puncture were well tolerated. No children discontinued treatment or withdrew from the study because of an adverse event. The investigators did not consider any adverse events or serious adverse events to be related to the study drug. They also did not observe any clinically relevant trends related to nusinersen in hematology, blood chemistry, urinalysis, coagulation, vital signs, or ECGs.

Dr. Chin is an employee of and holds stock in Biogen, which manufactures nusinersen and is sponsoring the study.

[email protected]

SOURCE: Chin R et al. CNS-ICNA 2020, Abstract PL78.

Nusinersen provides continued, long-term benefits to infants with spinal muscular atrophy (SMA) who begin treatment before symptom onset, according to an analysis presented at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year.

“Children are developing in a manner more consistent with normal development than that expected for children with two and three SMN2 gene copies,” said Russell Chin, MD, a neurologist at New York–Presbyterian Hospital. “These data demonstrate the durability of effect over a median of 3.8 years of follow-up, with children aged 2.8-4.8 years at the last visit.”

Many participants in the study achieved motor milestones within normal time limits, and no participant lost any major motor milestones. The investigators did not identify any new safety concerns during a maximum of 4.7 years of follow-up. They will follow participants until they reach approximately 8 years of age.
 

An ongoing open-label study

Dr. Chin presented interim results of the ongoing NURTURE study, which is examining the efficacy and safety of intrathecal nusinersen when administered to presymptomatic infants with SMA. The open-label, single-arm, phase 2 study is being conducted in various countries. Eligible participants were 6 weeks old or younger at first dose and had two or three copies of SMN2. The primary end point of NURTURE is time to death or respiratory intervention (i.e., invasive or noninvasive ventilation for 6 or more hours per day continuously for 7 or more days or tracheostomy). The natural history of SMA type 1 indicates that the median age at death or requirement for ventilation support is 13.5 months.

The investigators enrolled 25 infants: 15 with two copies of the gene and 10 with three copies. At the February 2020 interim analysis, participants had been in the study for 3.8 years and were aged 2.8-4.8 years at the last visit. No children had discontinued treatment or withdrawn from the study. All participants are alive, and four participants (all of whom have two copies of SMN2) required respiratory intervention. The latter children initiated respiratory support during an acute reversible illness. No subjects have required permanent ventilation, which the investigators define as ventilation for 16 or more hours per day for more than 21 days in the absence of an acute reversible event, or tracheostomy.
 

Treatment improved motor development

Approximately 84% of children achieved a maximum score on the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scale. The population’s mean CHOP INTEND score increased steadily from baseline and stabilized at approximately the maximum score of 64. The population’s mean change in CHOP INTEND score from baseline to last visit was 13.6 points. The mean score at last visit was 62.0 among patients with two copies of SMN2 and 63.4 among patients with three copies. In addition, the time to first achievement of maximum CHOP INTEND score was shorter in participants with three copies of SMN2, compared with those with two. Four participants with two copies of the gene have not yet achieved a maximum CHOP INTEND score.

Many of the children in the study achieved World Health Organization motor milestones within time frames consistent with normal development. About 84% of participants became able to sit without support within the normal time frame in healthy children. Approximately 60% of children achieved walking with assistance within the normal window, and 64% achieved walking alone within the normal window. Of 25 participants, 24 are walking with assistance, and 22 of 25 (88%) can walk alone. Dr. Chin and colleagues observed that lower levels of phosphorylated neurofilament heavy chain in plasma and cerebrospinal fluid on treatment at day 64 were significantly correlated with higher total score on the Hammersmith Infant Neurological Examination at day 302 and with earlier achievement of the WHO milestone walking alone.

Nusinersen and lumbar puncture were well tolerated. No children discontinued treatment or withdrew from the study because of an adverse event. The investigators did not consider any adverse events or serious adverse events to be related to the study drug. They also did not observe any clinically relevant trends related to nusinersen in hematology, blood chemistry, urinalysis, coagulation, vital signs, or ECGs.

Dr. Chin is an employee of and holds stock in Biogen, which manufactures nusinersen and is sponsoring the study.

[email protected]

SOURCE: Chin R et al. CNS-ICNA 2020, Abstract PL78.

The Food and Drug Administration has approved  viltolarsen (Viltepso, NS Pharma), the second drug therapy for Duchenne muscular dystrophy in patients with a confirmed mutation amenable to exon 53 skipping. The FDA approved golodirsen (Vyondys 53, Sarepta Therapeutics) for this indication last year.  

“The FDA is committed to fostering drug development for serious neurological disorders like Duchenne muscular dystrophy,” Billy Dunn, MD, director, Office of Neuroscience of the FDA’s Center for Drug Evaluation and Research, said in a statement.

The approval of viltolarsen provides “an important treatment option for Duchenne muscular dystrophy patients with this confirmed mutation,” Dr. Dunn said.

Viltolarsen is an antisense oligonucleotide that promotes production of functional dystrophin by masking exon 53 in the dystrophin gene. It was evaluated in two studies involving 32 male patients.

In one study of 16 patients, the increase in dystrophin production was established in eight patients receiving viltolarsen at the recommended dose. In this study, dystrophin levels increased, on average, from 0.6% of normal at baseline to 5.9% of normal at week 25.

The increase in dystrophin production is “reasonably likely to predict clinical benefit,” but a “clinical benefit of the drug has not been established,” the FDA said.

In making the decision, the FDA considered the potential risks associated with the drug, the life-threatening and debilitating nature of the disease, and the lack of available therapies.

Viltolarsen was approved under the FDA’s accelerated approval pathway, which provides for the approval of drugs that treat serious or life-threatening diseases and generally offer a meaningful advantage over existing treatments.

As part of the accelerated approval, the FDA requires the company to do a clinical trial to confirm the drug’s clinical benefit. If the trial fails to verify clinical benefit, the FDA may start proceedings to withdraw approval of the drug, the agency said.

The most common side effects with viltolarsen are upper respiratory tract infection, injection-site reaction, cough, and fever.

Kidney toxicity was not observed in the clinical studies, but the clinical experience with the drug is limited, and kidney toxicity, including potentially fatal glomerulonephritis, has been observed with some antisense oligonucleotides.

“Kidney function should be monitored in patients taking Viltepso,” the FDA advises.

A version of this article originally appeared on Medscape.com.

The Food and Drug Administration has approved  viltolarsen (Viltepso, NS Pharma), the second drug therapy for Duchenne muscular dystrophy in patients with a confirmed mutation amenable to exon 53 skipping. The FDA approved golodirsen (Vyondys 53, Sarepta Therapeutics) for this indication last year.  

“The FDA is committed to fostering drug development for serious neurological disorders like Duchenne muscular dystrophy,” Billy Dunn, MD, director, Office of Neuroscience of the FDA’s Center for Drug Evaluation and Research, said in a statement.

The approval of viltolarsen provides “an important treatment option for Duchenne muscular dystrophy patients with this confirmed mutation,” Dr. Dunn said.

Viltolarsen is an antisense oligonucleotide that promotes production of functional dystrophin by masking exon 53 in the dystrophin gene. It was evaluated in two studies involving 32 male patients.

In one study of 16 patients, the increase in dystrophin production was established in eight patients receiving viltolarsen at the recommended dose. In this study, dystrophin levels increased, on average, from 0.6% of normal at baseline to 5.9% of normal at week 25.

The increase in dystrophin production is “reasonably likely to predict clinical benefit,” but a “clinical benefit of the drug has not been established,” the FDA said.

In making the decision, the FDA considered the potential risks associated with the drug, the life-threatening and debilitating nature of the disease, and the lack of available therapies.

Viltolarsen was approved under the FDA’s accelerated approval pathway, which provides for the approval of drugs that treat serious or life-threatening diseases and generally offer a meaningful advantage over existing treatments.

As part of the accelerated approval, the FDA requires the company to do a clinical trial to confirm the drug’s clinical benefit. If the trial fails to verify clinical benefit, the FDA may start proceedings to withdraw approval of the drug, the agency said.

The most common side effects with viltolarsen are upper respiratory tract infection, injection-site reaction, cough, and fever.

Kidney toxicity was not observed in the clinical studies, but the clinical experience with the drug is limited, and kidney toxicity, including potentially fatal glomerulonephritis, has been observed with some antisense oligonucleotides.

“Kidney function should be monitored in patients taking Viltepso,” the FDA advises.

A version of this article originally appeared on Medscape.com.

The Food and Drug Administration has approved  viltolarsen (Viltepso, NS Pharma), the second drug therapy for Duchenne muscular dystrophy in patients with a confirmed mutation amenable to exon 53 skipping. The FDA approved golodirsen (Vyondys 53, Sarepta Therapeutics) for this indication last year.  

“The FDA is committed to fostering drug development for serious neurological disorders like Duchenne muscular dystrophy,” Billy Dunn, MD, director, Office of Neuroscience of the FDA’s Center for Drug Evaluation and Research, said in a statement.

The approval of viltolarsen provides “an important treatment option for Duchenne muscular dystrophy patients with this confirmed mutation,” Dr. Dunn said.

Viltolarsen is an antisense oligonucleotide that promotes production of functional dystrophin by masking exon 53 in the dystrophin gene. It was evaluated in two studies involving 32 male patients.

In one study of 16 patients, the increase in dystrophin production was established in eight patients receiving viltolarsen at the recommended dose. In this study, dystrophin levels increased, on average, from 0.6% of normal at baseline to 5.9% of normal at week 25.

The increase in dystrophin production is “reasonably likely to predict clinical benefit,” but a “clinical benefit of the drug has not been established,” the FDA said.

In making the decision, the FDA considered the potential risks associated with the drug, the life-threatening and debilitating nature of the disease, and the lack of available therapies.

Viltolarsen was approved under the FDA’s accelerated approval pathway, which provides for the approval of drugs that treat serious or life-threatening diseases and generally offer a meaningful advantage over existing treatments.

As part of the accelerated approval, the FDA requires the company to do a clinical trial to confirm the drug’s clinical benefit. If the trial fails to verify clinical benefit, the FDA may start proceedings to withdraw approval of the drug, the agency said.

The most common side effects with viltolarsen are upper respiratory tract infection, injection-site reaction, cough, and fever.

Kidney toxicity was not observed in the clinical studies, but the clinical experience with the drug is limited, and kidney toxicity, including potentially fatal glomerulonephritis, has been observed with some antisense oligonucleotides.

“Kidney function should be monitored in patients taking Viltepso,” the FDA advises.

A version of this article originally appeared on Medscape.com.

NEW ORLEANS – After Massachusetts passed antibullying legislation in 2009, Peter C. Raffalli, MD, saw an opportunity to improve care for the increasing numbers of children presenting to his neurology practice at Boston Children’s Hospital who were victims of bullying – especially those with developmental disabilities.

omgimages/thinkstockphotos.com

“I had been thinking of a clinic to help kids with these issues, aside from just helping them deal with the fallout: the depression, anxiety, et cetera, that comes with being bullied,” Dr. Raffalli recalled at the annual meeting of the American Academy of Pediatrics. “I wanted to do something to help present to families the evidence-based strategies regarding bullying prevention, detection, and intervention that might help to stop the bullying.”

This led him to launch the Bullying and Cyberbullying Prevention and Advocacy Collaborative (BACPAC) at Boston Children’s Hospital, which began in 2009 as an educational resource for families, medical colleagues, and schools. Dr. Raffalli also formed an alliance with the Massachusetts Aggression Reduction Center at Bridgewater State University (Ann Neurol. 2016;79[2]:167-8).

Two years later in 2011, BACPAC became a formal clinic at Boston Children’s that serves as a subspecialty consult service for victims of bullying and their families. The clinic team consists of a child neurologist, a social worker, and an education resource specialist who meet with the bullying victim and his/her family in initial consultation for 90 minutes. The goal is to develop an evidence-based plan for bullying prevention, detection, and intervention that is individualized to the patient’s developmental and social needs.

“We tell families that bullying is recognized medically and legally as a form of abuse,” said Dr. Raffalli. “The medical and psychological consequences are similar to other forms of abuse. In the clinic, I explain to families that bullying is never the victim’s fault, and they should not blame themselves for the bullying. You’d be surprised how often patients do think the bullying is their fault.”
 

The extent of the problem

Researchers estimate that 25%-30% of children will experience some form of bullying between kindergarten and grade 12, and about 8% will engage in bullying themselves. When BACPAC began in 2009, Dr. Raffalli conducted an informal search of peer-reviewed literature on bullying in children with special needs; it yielded just four articles. “Since then, there’s been an exponential explosion of literature on various aspects of bullying,” he said. Now there is ample evidence in the peer-reviewed literature to show the increased risk for bullying/cyberbullying in children/teens, not just with neurodevelopmental disorders, but also for kids with other medical disorders such as obesity, asthma, and allergies.

“We’ve had a good number of kids over the years with peanut allergy who were literally threatened physically with peanut butter at school,” he said. “It’s incredible how callous some kids can be. Kids with oppositional defiant disorder, impulse control disorder, and callous/unemotional traits from a psychological standpoint are hardest to reach when it comes to getting them to stop bullying. You’d be surprised how frequently bullies use the phrase [to their victims], ‘You should kill yourself.’ They don’t realize the damage they’re doing to people. Bullying can lead to severe psychological but also long-term medical problems, including suicidal ideation.”

Published studies show that the highest incidences of bullying occur in children with neurodevelopmental conditions such as ADHD, autistic spectrum disorders, Tourette syndrome, and other learning disabilities (Eur J Spec Needs Ed. 2010;25[1]:77-91). This population of children is overrepresented in bullying “because the services they receive at school make their disabilities more visible,” explained Dr. Raffalli, who is also an assistant professor of neurology at Harvard Medical School, Boston. “They stand out, and they have social information–processing deficits or distortions that exacerbate bullying involvement. They also have difficulty interpreting social cues or attributing hostile characteristics to their peer’s behavior.”
 

The consequences of bullying

The psychological and educational consequences of bullying among children in general include being more likely to develop depression, loneliness, low self-esteem, alcohol and drug abuse, sleeping difficulties, self-harm, and suicidal ideation and attempts. “We’re social creatures, and when we don’t have those social connections, we get very depressed.”

Bullying victims also are more likely to develop school avoidance and absence, decreased school performance, poor concentration, high anxiety, and social withdrawal – all of which limit their opportunities to learn. “The No. 1 thing you can do to help these kids is to believe their story – to explain to them that it’s not their fault, and to explain that you are there for them and that you support them,” he said. “When a kid gets the feeling that someone is willing to listen to them and believe them, it does an enormous good for their emotional state.”

Doug Brunk/MDedge News

Dr. Raffalli added that a toxic stress response can occur when a child experiences strong, frequent, and/or prolonged adversity – such as physical or emotional abuse, chronic neglect, caregiver substance abuse or mental illness, exposure to violence, and/or the accumulated burdens of family economic hardship – without adequate adult support. This kind of prolonged activation of the stress response systems can disrupt the development of brain architecture and other organ systems, and increase the risk for stress-related disease and cognitive impairment well into the adult years.

In the Harvard Review of Psychiatry, researchers set out to investigate what’s known about the long-term health effects of childhood bullying. They found that bullying can induce “aspects of the stress response, via epigenetic, inflammatory, and metabolic mediators [that] have the capacity to compromise mental and physical health, and to increase the risk of disease.” The researchers advised clinicians who care for children to assess the mental and physical health effects of bullying (Harv Rev Psychiatry. 2017;25[2]:89-95).

Additional vulnerabilities for bullying victims include parents and children whose primary language is not English, as well as parents with mental illness or substance abuse and families living in poverty. “We have to keep in mind how much additional stress they may be dealing with. This can make it harder for them to cope. Bullies also are shown to be at higher risk for psychological and legal trouble into adulthood, so we should be trying to help them too. We have to keep in mind that these are all developing kids.”
 

Cyberbullying

In Dr. Raffalli’s clinical experience, cyberbullying has become the bully’s weapon of choice. “I call it the stealth bomber of bullying,” he said. “Cyberbullying can start as early as the second or third grade. Most parents are not giving phones to second-graders. I’m worried that it’s going to get worse, though, with the excuse that ‘I feel safer if they have a cell phone so they can call me.’ I tell parents that they still make flip phones. You don’t have to get a smartphone for a second- or third-grader, or even for a sixth-grader.”

By the time kids reach fourth and fifth grade, he continued, they begin to form their opinion “about what they believe is cool and not cool, and they begin to get into cliques that have similar beliefs, and support each other, and may break off from old friends.” He added that, while adult predation “makes the news and is certainly something we should all be concerned about, the incidence of being harassed and bullied by someone in your own age group at school is actually much higher and still has serious outcomes, including the possibility of death.”

The Massachusetts antibullying law stipulates that all teachers and all school personnel have to participate in mandatory bullying training. Schools also are required to draft and follow a bullying investigative protocol.

“Apparently the schools have all done this, yet the number of times that schools use interventions that are not advisable, such as mediation, is incredible to me,” Dr. Raffalli said. “Bringing the bully and the victim together for a ‘cup of coffee and a handshake’ is not advisable. Mediation has been shown in a number of studies to be detrimental in bullying situations. Things can easily get worse.”

Often, family members who bring their child to the BACPAC “feel that their child’s school is not helping them,” he said. “We should try to figure out why those schools are having such a hard time and see if we can help them.”

Dr. Raffalli reported having no financial disclosures.

[email protected]

NEW ORLEANS – After Massachusetts passed antibullying legislation in 2009, Peter C. Raffalli, MD, saw an opportunity to improve care for the increasing numbers of children presenting to his neurology practice at Boston Children’s Hospital who were victims of bullying – especially those with developmental disabilities.

omgimages/thinkstockphotos.com

“I had been thinking of a clinic to help kids with these issues, aside from just helping them deal with the fallout: the depression, anxiety, et cetera, that comes with being bullied,” Dr. Raffalli recalled at the annual meeting of the American Academy of Pediatrics. “I wanted to do something to help present to families the evidence-based strategies regarding bullying prevention, detection, and intervention that might help to stop the bullying.”

This led him to launch the Bullying and Cyberbullying Prevention and Advocacy Collaborative (BACPAC) at Boston Children’s Hospital, which began in 2009 as an educational resource for families, medical colleagues, and schools. Dr. Raffalli also formed an alliance with the Massachusetts Aggression Reduction Center at Bridgewater State University (Ann Neurol. 2016;79[2]:167-8).

Two years later in 2011, BACPAC became a formal clinic at Boston Children’s that serves as a subspecialty consult service for victims of bullying and their families. The clinic team consists of a child neurologist, a social worker, and an education resource specialist who meet with the bullying victim and his/her family in initial consultation for 90 minutes. The goal is to develop an evidence-based plan for bullying prevention, detection, and intervention that is individualized to the patient’s developmental and social needs.

“We tell families that bullying is recognized medically and legally as a form of abuse,” said Dr. Raffalli. “The medical and psychological consequences are similar to other forms of abuse. In the clinic, I explain to families that bullying is never the victim’s fault, and they should not blame themselves for the bullying. You’d be surprised how often patients do think the bullying is their fault.”
 

The extent of the problem

Researchers estimate that 25%-30% of children will experience some form of bullying between kindergarten and grade 12, and about 8% will engage in bullying themselves. When BACPAC began in 2009, Dr. Raffalli conducted an informal search of peer-reviewed literature on bullying in children with special needs; it yielded just four articles. “Since then, there’s been an exponential explosion of literature on various aspects of bullying,” he said. Now there is ample evidence in the peer-reviewed literature to show the increased risk for bullying/cyberbullying in children/teens, not just with neurodevelopmental disorders, but also for kids with other medical disorders such as obesity, asthma, and allergies.

“We’ve had a good number of kids over the years with peanut allergy who were literally threatened physically with peanut butter at school,” he said. “It’s incredible how callous some kids can be. Kids with oppositional defiant disorder, impulse control disorder, and callous/unemotional traits from a psychological standpoint are hardest to reach when it comes to getting them to stop bullying. You’d be surprised how frequently bullies use the phrase [to their victims], ‘You should kill yourself.’ They don’t realize the damage they’re doing to people. Bullying can lead to severe psychological but also long-term medical problems, including suicidal ideation.”

Published studies show that the highest incidences of bullying occur in children with neurodevelopmental conditions such as ADHD, autistic spectrum disorders, Tourette syndrome, and other learning disabilities (Eur J Spec Needs Ed. 2010;25[1]:77-91). This population of children is overrepresented in bullying “because the services they receive at school make their disabilities more visible,” explained Dr. Raffalli, who is also an assistant professor of neurology at Harvard Medical School, Boston. “They stand out, and they have social information–processing deficits or distortions that exacerbate bullying involvement. They also have difficulty interpreting social cues or attributing hostile characteristics to their peer’s behavior.”
 

The consequences of bullying

The psychological and educational consequences of bullying among children in general include being more likely to develop depression, loneliness, low self-esteem, alcohol and drug abuse, sleeping difficulties, self-harm, and suicidal ideation and attempts. “We’re social creatures, and when we don’t have those social connections, we get very depressed.”

Bullying victims also are more likely to develop school avoidance and absence, decreased school performance, poor concentration, high anxiety, and social withdrawal – all of which limit their opportunities to learn. “The No. 1 thing you can do to help these kids is to believe their story – to explain to them that it’s not their fault, and to explain that you are there for them and that you support them,” he said. “When a kid gets the feeling that someone is willing to listen to them and believe them, it does an enormous good for their emotional state.”

Doug Brunk/MDedge News

Dr. Raffalli added that a toxic stress response can occur when a child experiences strong, frequent, and/or prolonged adversity – such as physical or emotional abuse, chronic neglect, caregiver substance abuse or mental illness, exposure to violence, and/or the accumulated burdens of family economic hardship – without adequate adult support. This kind of prolonged activation of the stress response systems can disrupt the development of brain architecture and other organ systems, and increase the risk for stress-related disease and cognitive impairment well into the adult years.

In the Harvard Review of Psychiatry, researchers set out to investigate what’s known about the long-term health effects of childhood bullying. They found that bullying can induce “aspects of the stress response, via epigenetic, inflammatory, and metabolic mediators [that] have the capacity to compromise mental and physical health, and to increase the risk of disease.” The researchers advised clinicians who care for children to assess the mental and physical health effects of bullying (Harv Rev Psychiatry. 2017;25[2]:89-95).

Additional vulnerabilities for bullying victims include parents and children whose primary language is not English, as well as parents with mental illness or substance abuse and families living in poverty. “We have to keep in mind how much additional stress they may be dealing with. This can make it harder for them to cope. Bullies also are shown to be at higher risk for psychological and legal trouble into adulthood, so we should be trying to help them too. We have to keep in mind that these are all developing kids.”
 

Cyberbullying

In Dr. Raffalli’s clinical experience, cyberbullying has become the bully’s weapon of choice. “I call it the stealth bomber of bullying,” he said. “Cyberbullying can start as early as the second or third grade. Most parents are not giving phones to second-graders. I’m worried that it’s going to get worse, though, with the excuse that ‘I feel safer if they have a cell phone so they can call me.’ I tell parents that they still make flip phones. You don’t have to get a smartphone for a second- or third-grader, or even for a sixth-grader.”

By the time kids reach fourth and fifth grade, he continued, they begin to form their opinion “about what they believe is cool and not cool, and they begin to get into cliques that have similar beliefs, and support each other, and may break off from old friends.” He added that, while adult predation “makes the news and is certainly something we should all be concerned about, the incidence of being harassed and bullied by someone in your own age group at school is actually much higher and still has serious outcomes, including the possibility of death.”

The Massachusetts antibullying law stipulates that all teachers and all school personnel have to participate in mandatory bullying training. Schools also are required to draft and follow a bullying investigative protocol.

“Apparently the schools have all done this, yet the number of times that schools use interventions that are not advisable, such as mediation, is incredible to me,” Dr. Raffalli said. “Bringing the bully and the victim together for a ‘cup of coffee and a handshake’ is not advisable. Mediation has been shown in a number of studies to be detrimental in bullying situations. Things can easily get worse.”

Often, family members who bring their child to the BACPAC “feel that their child’s school is not helping them,” he said. “We should try to figure out why those schools are having such a hard time and see if we can help them.”

Dr. Raffalli reported having no financial disclosures.

[email protected]

NEW ORLEANS – After Massachusetts passed antibullying legislation in 2009, Peter C. Raffalli, MD, saw an opportunity to improve care for the increasing numbers of children presenting to his neurology practice at Boston Children’s Hospital who were victims of bullying – especially those with developmental disabilities.

omgimages/thinkstockphotos.com

“I had been thinking of a clinic to help kids with these issues, aside from just helping them deal with the fallout: the depression, anxiety, et cetera, that comes with being bullied,” Dr. Raffalli recalled at the annual meeting of the American Academy of Pediatrics. “I wanted to do something to help present to families the evidence-based strategies regarding bullying prevention, detection, and intervention that might help to stop the bullying.”

This led him to launch the Bullying and Cyberbullying Prevention and Advocacy Collaborative (BACPAC) at Boston Children’s Hospital, which began in 2009 as an educational resource for families, medical colleagues, and schools. Dr. Raffalli also formed an alliance with the Massachusetts Aggression Reduction Center at Bridgewater State University (Ann Neurol. 2016;79[2]:167-8).

Two years later in 2011, BACPAC became a formal clinic at Boston Children’s that serves as a subspecialty consult service for victims of bullying and their families. The clinic team consists of a child neurologist, a social worker, and an education resource specialist who meet with the bullying victim and his/her family in initial consultation for 90 minutes. The goal is to develop an evidence-based plan for bullying prevention, detection, and intervention that is individualized to the patient’s developmental and social needs.

“We tell families that bullying is recognized medically and legally as a form of abuse,” said Dr. Raffalli. “The medical and psychological consequences are similar to other forms of abuse. In the clinic, I explain to families that bullying is never the victim’s fault, and they should not blame themselves for the bullying. You’d be surprised how often patients do think the bullying is their fault.”
 

The extent of the problem

Researchers estimate that 25%-30% of children will experience some form of bullying between kindergarten and grade 12, and about 8% will engage in bullying themselves. When BACPAC began in 2009, Dr. Raffalli conducted an informal search of peer-reviewed literature on bullying in children with special needs; it yielded just four articles. “Since then, there’s been an exponential explosion of literature on various aspects of bullying,” he said. Now there is ample evidence in the peer-reviewed literature to show the increased risk for bullying/cyberbullying in children/teens, not just with neurodevelopmental disorders, but also for kids with other medical disorders such as obesity, asthma, and allergies.

“We’ve had a good number of kids over the years with peanut allergy who were literally threatened physically with peanut butter at school,” he said. “It’s incredible how callous some kids can be. Kids with oppositional defiant disorder, impulse control disorder, and callous/unemotional traits from a psychological standpoint are hardest to reach when it comes to getting them to stop bullying. You’d be surprised how frequently bullies use the phrase [to their victims], ‘You should kill yourself.’ They don’t realize the damage they’re doing to people. Bullying can lead to severe psychological but also long-term medical problems, including suicidal ideation.”

Published studies show that the highest incidences of bullying occur in children with neurodevelopmental conditions such as ADHD, autistic spectrum disorders, Tourette syndrome, and other learning disabilities (Eur J Spec Needs Ed. 2010;25[1]:77-91). This population of children is overrepresented in bullying “because the services they receive at school make their disabilities more visible,” explained Dr. Raffalli, who is also an assistant professor of neurology at Harvard Medical School, Boston. “They stand out, and they have social information–processing deficits or distortions that exacerbate bullying involvement. They also have difficulty interpreting social cues or attributing hostile characteristics to their peer’s behavior.”
 

The consequences of bullying

The psychological and educational consequences of bullying among children in general include being more likely to develop depression, loneliness, low self-esteem, alcohol and drug abuse, sleeping difficulties, self-harm, and suicidal ideation and attempts. “We’re social creatures, and when we don’t have those social connections, we get very depressed.”

Bullying victims also are more likely to develop school avoidance and absence, decreased school performance, poor concentration, high anxiety, and social withdrawal – all of which limit their opportunities to learn. “The No. 1 thing you can do to help these kids is to believe their story – to explain to them that it’s not their fault, and to explain that you are there for them and that you support them,” he said. “When a kid gets the feeling that someone is willing to listen to them and believe them, it does an enormous good for their emotional state.”

Doug Brunk/MDedge News

Dr. Raffalli added that a toxic stress response can occur when a child experiences strong, frequent, and/or prolonged adversity – such as physical or emotional abuse, chronic neglect, caregiver substance abuse or mental illness, exposure to violence, and/or the accumulated burdens of family economic hardship – without adequate adult support. This kind of prolonged activation of the stress response systems can disrupt the development of brain architecture and other organ systems, and increase the risk for stress-related disease and cognitive impairment well into the adult years.

In the Harvard Review of Psychiatry, researchers set out to investigate what’s known about the long-term health effects of childhood bullying. They found that bullying can induce “aspects of the stress response, via epigenetic, inflammatory, and metabolic mediators [that] have the capacity to compromise mental and physical health, and to increase the risk of disease.” The researchers advised clinicians who care for children to assess the mental and physical health effects of bullying (Harv Rev Psychiatry. 2017;25[2]:89-95).

Additional vulnerabilities for bullying victims include parents and children whose primary language is not English, as well as parents with mental illness or substance abuse and families living in poverty. “We have to keep in mind how much additional stress they may be dealing with. This can make it harder for them to cope. Bullies also are shown to be at higher risk for psychological and legal trouble into adulthood, so we should be trying to help them too. We have to keep in mind that these are all developing kids.”
 

Cyberbullying

In Dr. Raffalli’s clinical experience, cyberbullying has become the bully’s weapon of choice. “I call it the stealth bomber of bullying,” he said. “Cyberbullying can start as early as the second or third grade. Most parents are not giving phones to second-graders. I’m worried that it’s going to get worse, though, with the excuse that ‘I feel safer if they have a cell phone so they can call me.’ I tell parents that they still make flip phones. You don’t have to get a smartphone for a second- or third-grader, or even for a sixth-grader.”

By the time kids reach fourth and fifth grade, he continued, they begin to form their opinion “about what they believe is cool and not cool, and they begin to get into cliques that have similar beliefs, and support each other, and may break off from old friends.” He added that, while adult predation “makes the news and is certainly something we should all be concerned about, the incidence of being harassed and bullied by someone in your own age group at school is actually much higher and still has serious outcomes, including the possibility of death.”

The Massachusetts antibullying law stipulates that all teachers and all school personnel have to participate in mandatory bullying training. Schools also are required to draft and follow a bullying investigative protocol.

“Apparently the schools have all done this, yet the number of times that schools use interventions that are not advisable, such as mediation, is incredible to me,” Dr. Raffalli said. “Bringing the bully and the victim together for a ‘cup of coffee and a handshake’ is not advisable. Mediation has been shown in a number of studies to be detrimental in bullying situations. Things can easily get worse.”

Often, family members who bring their child to the BACPAC “feel that their child’s school is not helping them,” he said. “We should try to figure out why those schools are having such a hard time and see if we can help them.”

Dr. Raffalli reported having no financial disclosures.

[email protected]