Literature Review

People with early, untreated Parkinson’s disease who have low vitamin B₁₂ levels appear to have greater worsening of mobility and cognitive decline over time, according to research published online ahead of print March 6 in Movement Disorders. The results suggest that correcting low levels may slow disease progression.

Previous research revealed that low serum vitamin B₁₂ levels are common in patients with moderately advanced Parkinson’s disease and are associated with neuropathy and cognitive impairment. Investigators led by Chadwick W. Christine, MD, a neurologist at the University of California, San Francisco, sought to understand what contributes to variation in the progression of Parkinson’s disease.

An Analysis of the DATATOP Study

Because little is known about B₁₂’s role in early disease, the investigators analyzed data from patients with early, untreated Parkinson’s disease who participated in the DATATOP study, a double-blind, randomized trial designed to test whether treatment with selegiline, the antioxidant alpha-tocopherol, or both slowed disease progression.

They measured serum methylmalonic acid, homocysteine, and holotranscobalamin in addition to B₁₂ because of the limited sensitivity of serum B₁₂ testing alone to detect B₁₂ deficiency. At baseline, 13% of 680 patients had borderline-low B₁₂ levels (ie, less than 184 pmol/L), and 5% had deficient B₁₂ levels (ie, less than 157 pmol/L). Homocysteine was moderately elevated (ie, greater than 15 mmol/L) in 7% of subjects, and 14% of patients with borderline-low B₁₂ also had elevated homocysteine.

Homocysteine Was Associated With Cognitive Outcomes

Low B₁₂ at baseline predicted greater worsening of mobility, in terms of a higher ambulatory capacity score. Investigators calculated this score by adding the falling, freezing when walking, walking, gait, and postural stability scores of the Unified Parkinson’s Disease Rating Scale (UPDRS). Participants in the low-B₁₂ tertile (ie, less than 234 pmol/L) developed greater morbidity, as assessed by greater annualized worsening of the ambulatory capacity score. Participants in the low-B₁₂ tertile had annualized change of 1.53, compared with 0.77 in the upper tertile. The worsening score mostly resulted from poorer gait and postural instability.

“We consider the magnitude of difference to be clinically relevant, particularly given that components of gait dysfunction that develop in Parkinson’s disease may not respond to dopaminergic treatments or [deep brain stimulation],” said Dr. Christine and colleagues.

Elevated homocysteine predicted greater cognitive decline. Baseline elevated homocysteine was associated with lower baseline Mini-Mental State Examination (MMSE) score, as well as greater annualized decline in MMSE (–1.96 vs 0.06).

Of the 456 subjects who continued in the study for nine to 24 months and had a second blood sample available, 226 had an increase of more than 20% in B₁₂ levels, 210 stayed within 20% of the original B₁₂ measurement, and 19 had a decrease greater than 20%.

Overall, mean annualized increase in B₁₂ was 52.6 pmol/L, mean annualized decrease of homocysteine was 0.83 mmol/L, and mean annualized increase of holotranscobalamin was 14.7 pmol/L.

“These findings are consistent with improved nutritional status during the course of the study, likely attributed to subjects starting the optional [multivitamin] after the baseline visit and/or subjects changing their diets,” said the investigators.

While the improvement in B₁₂ status did not lead to statistically significant improvements in UPDRS scores, there was a trend toward improvement, which provides “support for a disease-modifying effect of B₁₂,” they added.

The researchers speculated that a link between low B₁₂ levels and worse outcomes could be attributed to an independent comorbid effect on the CNS and peripheral nervous system or a direct effect on Parkinson’s disease pathogenesis. Alternatively, low B₁₂ may be a marker of an unknown associated factor.

“Given that low B₁₂ status is associated with neurologic and other medical morbidities and is readily treated, great care would be needed to design an ethically acceptable randomized, prospective study to evaluate the effect of B₁₂ supplementation on Parkinson’s disease progression, given that serum measurements collected as part of a prospective study in unsupplemented patients would likely reveal some subjects with B₁₂ deficiency,” said Dr. Christine and colleagues.

Study Raises Questions

“The course of Parkinson’s disease can be quite variable, and it is difficult for clinicians to predict what will happen to an individual person with Parkinson’s disease, but identifying prognostic factors ought to help practitioners answer their patients’ questions and potentially improve the understanding of mechanisms underlying the disease pathogenesis,” said Francisco Cardoso, MD, PhD, Professor of Neurology at the Federal University of Minas Gerais in Belo Horizonte, Brazil, in an accompanying editorial.

If vitamin B₁₂ is related to the progression of Parkinson’s disease, then replacing it may slow patients’ decline. But the findings raise questions that need to be addressed, said Dr. Cardoso.

“First, what constitutes a low vitamin B₁₂ level is not a simple issue. If the evaluation is limited to measurement of vitamin B₁₂ concentration, the diagnosis of genuine deficiency is unreliable. Most experts agree that combined measurement of vitamin B₁₂ with determination of homocysteine levels is necessary, and while Christine et al measured both levels, their statistical analysis and subsequent conclusions are exclusively based on the levels of the vitamin.

“Moreover, 34 patients in the study were classified as having ‘borderline-low’ vitamin B₁₂ levels, and 14 had both borderline-low B₁₂ level and high homocysteine concentration. This brings into question whether the researchers identified Parkinson’s disease patients who actually had low B₁₂ levels.

“The design of the DATATOP trial could also introduce some bias into the findings. At the time of publication, the study was criticized for disregarding the symptomatic effect of selegiline and for a lack of objective definition of criteria for the trial’s primary end point—introduction of levodopa.

“This could have led to the termination of individuals at different stages of the disease, introducing a potential bias in the sample of patients who remained in the study for enough time to undergo subsequent determination of B₁₂ levels.”

Furthermore, the findings of Christine et al contrast with those of previous research. The underlying mechanism of vitamin B₁₂ in Parkinson’s disease is unclear. “Nevertheless, the results of the study by Dr. Christine and his colleagues are intriguing, and further investigations to address this hypothesis are warranted,” Dr. Cardoso concluded.

—Nicola Garrett

Suggested Reading

Cardoso F. Vitamin B₁₂ and Parkinson’s disease: What is the relationship? Mov Disord. 2018 Mar 6 [Epub ahead of print].

Christine CW, Auinger P, Joslin A, et al. Vitamin B₁₂ and homocysteine levels predict different outcomes in early Parkinson’s disease. Mov Disord. 2018 Mar 6 [Epub ahead of print].

People with early, untreated Parkinson’s disease who have low vitamin B₁₂ levels appear to have greater worsening of mobility and cognitive decline over time, according to research published online ahead of print March 6 in Movement Disorders. The results suggest that correcting low levels may slow disease progression.

Previous research revealed that low serum vitamin B₁₂ levels are common in patients with moderately advanced Parkinson’s disease and are associated with neuropathy and cognitive impairment. Investigators led by Chadwick W. Christine, MD, a neurologist at the University of California, San Francisco, sought to understand what contributes to variation in the progression of Parkinson’s disease.

An Analysis of the DATATOP Study

Because little is known about B₁₂’s role in early disease, the investigators analyzed data from patients with early, untreated Parkinson’s disease who participated in the DATATOP study, a double-blind, randomized trial designed to test whether treatment with selegiline, the antioxidant alpha-tocopherol, or both slowed disease progression.

They measured serum methylmalonic acid, homocysteine, and holotranscobalamin in addition to B₁₂ because of the limited sensitivity of serum B₁₂ testing alone to detect B₁₂ deficiency. At baseline, 13% of 680 patients had borderline-low B₁₂ levels (ie, less than 184 pmol/L), and 5% had deficient B₁₂ levels (ie, less than 157 pmol/L). Homocysteine was moderately elevated (ie, greater than 15 mmol/L) in 7% of subjects, and 14% of patients with borderline-low B₁₂ also had elevated homocysteine.

Homocysteine Was Associated With Cognitive Outcomes

Low B₁₂ at baseline predicted greater worsening of mobility, in terms of a higher ambulatory capacity score. Investigators calculated this score by adding the falling, freezing when walking, walking, gait, and postural stability scores of the Unified Parkinson’s Disease Rating Scale (UPDRS). Participants in the low-B₁₂ tertile (ie, less than 234 pmol/L) developed greater morbidity, as assessed by greater annualized worsening of the ambulatory capacity score. Participants in the low-B₁₂ tertile had annualized change of 1.53, compared with 0.77 in the upper tertile. The worsening score mostly resulted from poorer gait and postural instability.

“We consider the magnitude of difference to be clinically relevant, particularly given that components of gait dysfunction that develop in Parkinson’s disease may not respond to dopaminergic treatments or [deep brain stimulation],” said Dr. Christine and colleagues.

Elevated homocysteine predicted greater cognitive decline. Baseline elevated homocysteine was associated with lower baseline Mini-Mental State Examination (MMSE) score, as well as greater annualized decline in MMSE (–1.96 vs 0.06).

Of the 456 subjects who continued in the study for nine to 24 months and had a second blood sample available, 226 had an increase of more than 20% in B₁₂ levels, 210 stayed within 20% of the original B₁₂ measurement, and 19 had a decrease greater than 20%.

Overall, mean annualized increase in B₁₂ was 52.6 pmol/L, mean annualized decrease of homocysteine was 0.83 mmol/L, and mean annualized increase of holotranscobalamin was 14.7 pmol/L.

“These findings are consistent with improved nutritional status during the course of the study, likely attributed to subjects starting the optional [multivitamin] after the baseline visit and/or subjects changing their diets,” said the investigators.

While the improvement in B₁₂ status did not lead to statistically significant improvements in UPDRS scores, there was a trend toward improvement, which provides “support for a disease-modifying effect of B₁₂,” they added.

The researchers speculated that a link between low B₁₂ levels and worse outcomes could be attributed to an independent comorbid effect on the CNS and peripheral nervous system or a direct effect on Parkinson’s disease pathogenesis. Alternatively, low B₁₂ may be a marker of an unknown associated factor.

“Given that low B₁₂ status is associated with neurologic and other medical morbidities and is readily treated, great care would be needed to design an ethically acceptable randomized, prospective study to evaluate the effect of B₁₂ supplementation on Parkinson’s disease progression, given that serum measurements collected as part of a prospective study in unsupplemented patients would likely reveal some subjects with B₁₂ deficiency,” said Dr. Christine and colleagues.

Study Raises Questions

“The course of Parkinson’s disease can be quite variable, and it is difficult for clinicians to predict what will happen to an individual person with Parkinson’s disease, but identifying prognostic factors ought to help practitioners answer their patients’ questions and potentially improve the understanding of mechanisms underlying the disease pathogenesis,” said Francisco Cardoso, MD, PhD, Professor of Neurology at the Federal University of Minas Gerais in Belo Horizonte, Brazil, in an accompanying editorial.

If vitamin B₁₂ is related to the progression of Parkinson’s disease, then replacing it may slow patients’ decline. But the findings raise questions that need to be addressed, said Dr. Cardoso.

“First, what constitutes a low vitamin B₁₂ level is not a simple issue. If the evaluation is limited to measurement of vitamin B₁₂ concentration, the diagnosis of genuine deficiency is unreliable. Most experts agree that combined measurement of vitamin B₁₂ with determination of homocysteine levels is necessary, and while Christine et al measured both levels, their statistical analysis and subsequent conclusions are exclusively based on the levels of the vitamin.

“Moreover, 34 patients in the study were classified as having ‘borderline-low’ vitamin B₁₂ levels, and 14 had both borderline-low B₁₂ level and high homocysteine concentration. This brings into question whether the researchers identified Parkinson’s disease patients who actually had low B₁₂ levels.

“The design of the DATATOP trial could also introduce some bias into the findings. At the time of publication, the study was criticized for disregarding the symptomatic effect of selegiline and for a lack of objective definition of criteria for the trial’s primary end point—introduction of levodopa.

“This could have led to the termination of individuals at different stages of the disease, introducing a potential bias in the sample of patients who remained in the study for enough time to undergo subsequent determination of B₁₂ levels.”

Furthermore, the findings of Christine et al contrast with those of previous research. The underlying mechanism of vitamin B₁₂ in Parkinson’s disease is unclear. “Nevertheless, the results of the study by Dr. Christine and his colleagues are intriguing, and further investigations to address this hypothesis are warranted,” Dr. Cardoso concluded.

—Nicola Garrett

Suggested Reading

Cardoso F. Vitamin B₁₂ and Parkinson’s disease: What is the relationship? Mov Disord. 2018 Mar 6 [Epub ahead of print].

Christine CW, Auinger P, Joslin A, et al. Vitamin B₁₂ and homocysteine levels predict different outcomes in early Parkinson’s disease. Mov Disord. 2018 Mar 6 [Epub ahead of print].

People with early, untreated Parkinson’s disease who have low vitamin B₁₂ levels appear to have greater worsening of mobility and cognitive decline over time, according to research published online ahead of print March 6 in Movement Disorders. The results suggest that correcting low levels may slow disease progression.

Previous research revealed that low serum vitamin B₁₂ levels are common in patients with moderately advanced Parkinson’s disease and are associated with neuropathy and cognitive impairment. Investigators led by Chadwick W. Christine, MD, a neurologist at the University of California, San Francisco, sought to understand what contributes to variation in the progression of Parkinson’s disease.

An Analysis of the DATATOP Study

Because little is known about B₁₂’s role in early disease, the investigators analyzed data from patients with early, untreated Parkinson’s disease who participated in the DATATOP study, a double-blind, randomized trial designed to test whether treatment with selegiline, the antioxidant alpha-tocopherol, or both slowed disease progression.

They measured serum methylmalonic acid, homocysteine, and holotranscobalamin in addition to B₁₂ because of the limited sensitivity of serum B₁₂ testing alone to detect B₁₂ deficiency. At baseline, 13% of 680 patients had borderline-low B₁₂ levels (ie, less than 184 pmol/L), and 5% had deficient B₁₂ levels (ie, less than 157 pmol/L). Homocysteine was moderately elevated (ie, greater than 15 mmol/L) in 7% of subjects, and 14% of patients with borderline-low B₁₂ also had elevated homocysteine.

Homocysteine Was Associated With Cognitive Outcomes

Low B₁₂ at baseline predicted greater worsening of mobility, in terms of a higher ambulatory capacity score. Investigators calculated this score by adding the falling, freezing when walking, walking, gait, and postural stability scores of the Unified Parkinson’s Disease Rating Scale (UPDRS). Participants in the low-B₁₂ tertile (ie, less than 234 pmol/L) developed greater morbidity, as assessed by greater annualized worsening of the ambulatory capacity score. Participants in the low-B₁₂ tertile had annualized change of 1.53, compared with 0.77 in the upper tertile. The worsening score mostly resulted from poorer gait and postural instability.

“We consider the magnitude of difference to be clinically relevant, particularly given that components of gait dysfunction that develop in Parkinson’s disease may not respond to dopaminergic treatments or [deep brain stimulation],” said Dr. Christine and colleagues.

Elevated homocysteine predicted greater cognitive decline. Baseline elevated homocysteine was associated with lower baseline Mini-Mental State Examination (MMSE) score, as well as greater annualized decline in MMSE (–1.96 vs 0.06).

Of the 456 subjects who continued in the study for nine to 24 months and had a second blood sample available, 226 had an increase of more than 20% in B₁₂ levels, 210 stayed within 20% of the original B₁₂ measurement, and 19 had a decrease greater than 20%.

Overall, mean annualized increase in B₁₂ was 52.6 pmol/L, mean annualized decrease of homocysteine was 0.83 mmol/L, and mean annualized increase of holotranscobalamin was 14.7 pmol/L.

“These findings are consistent with improved nutritional status during the course of the study, likely attributed to subjects starting the optional [multivitamin] after the baseline visit and/or subjects changing their diets,” said the investigators.

While the improvement in B₁₂ status did not lead to statistically significant improvements in UPDRS scores, there was a trend toward improvement, which provides “support for a disease-modifying effect of B₁₂,” they added.

The researchers speculated that a link between low B₁₂ levels and worse outcomes could be attributed to an independent comorbid effect on the CNS and peripheral nervous system or a direct effect on Parkinson’s disease pathogenesis. Alternatively, low B₁₂ may be a marker of an unknown associated factor.

“Given that low B₁₂ status is associated with neurologic and other medical morbidities and is readily treated, great care would be needed to design an ethically acceptable randomized, prospective study to evaluate the effect of B₁₂ supplementation on Parkinson’s disease progression, given that serum measurements collected as part of a prospective study in unsupplemented patients would likely reveal some subjects with B₁₂ deficiency,” said Dr. Christine and colleagues.

Study Raises Questions

“The course of Parkinson’s disease can be quite variable, and it is difficult for clinicians to predict what will happen to an individual person with Parkinson’s disease, but identifying prognostic factors ought to help practitioners answer their patients’ questions and potentially improve the understanding of mechanisms underlying the disease pathogenesis,” said Francisco Cardoso, MD, PhD, Professor of Neurology at the Federal University of Minas Gerais in Belo Horizonte, Brazil, in an accompanying editorial.

If vitamin B₁₂ is related to the progression of Parkinson’s disease, then replacing it may slow patients’ decline. But the findings raise questions that need to be addressed, said Dr. Cardoso.

“First, what constitutes a low vitamin B₁₂ level is not a simple issue. If the evaluation is limited to measurement of vitamin B₁₂ concentration, the diagnosis of genuine deficiency is unreliable. Most experts agree that combined measurement of vitamin B₁₂ with determination of homocysteine levels is necessary, and while Christine et al measured both levels, their statistical analysis and subsequent conclusions are exclusively based on the levels of the vitamin.

“Moreover, 34 patients in the study were classified as having ‘borderline-low’ vitamin B₁₂ levels, and 14 had both borderline-low B₁₂ level and high homocysteine concentration. This brings into question whether the researchers identified Parkinson’s disease patients who actually had low B₁₂ levels.

“The design of the DATATOP trial could also introduce some bias into the findings. At the time of publication, the study was criticized for disregarding the symptomatic effect of selegiline and for a lack of objective definition of criteria for the trial’s primary end point—introduction of levodopa.

“This could have led to the termination of individuals at different stages of the disease, introducing a potential bias in the sample of patients who remained in the study for enough time to undergo subsequent determination of B₁₂ levels.”

Furthermore, the findings of Christine et al contrast with those of previous research. The underlying mechanism of vitamin B₁₂ in Parkinson’s disease is unclear. “Nevertheless, the results of the study by Dr. Christine and his colleagues are intriguing, and further investigations to address this hypothesis are warranted,” Dr. Cardoso concluded.

—Nicola Garrett

Suggested Reading

Cardoso F. Vitamin B₁₂ and Parkinson’s disease: What is the relationship? Mov Disord. 2018 Mar 6 [Epub ahead of print].

Christine CW, Auinger P, Joslin A, et al. Vitamin B₁₂ and homocysteine levels predict different outcomes in early Parkinson’s disease. Mov Disord. 2018 Mar 6 [Epub ahead of print].

When compared with the general population, young women with stroke have more pregnancy loss throughout their lives, according to research published in the April issue of Stroke. After stroke, nulliparous women more frequently experience serious pregnancy complications, compared with the general population. “We found that one out of three women experiences a serious pregnancy complication after stroke,” said Mayte E. van Alebeek, MD, of the Department of Neurology at the Donders Institute for Brain, Cognition, and Behavior, Center for Neuroscience in Nijmegen, the Netherlands, and colleagues.

“Our cohort shows high rates of miscarriages, multiple miscarriages, and extremely high rates of fetal death,” said Dr. van Alebeek. “Our study provides insight about the frequency of pregnancy complications in women who experience a stroke at young age.”

A Prospective Stroke Study

Although 16 to 59 per 100,000 women of childbearing age have stroke every year, there is limited research about the risks of future pregnancy complications after stroke. Dr. van Alebeek and colleagues hypothesized that women with stroke have an increased risk of future pregnancy complications. To test this hypothesis, they conducted a prospective study to investigate the prevalence of pregnancy complications and pregnancy loss in young women before, during, and after ischemic stroke or transient ischemic attack (TIA).

The study was a part of the Dutch Follow-Up of TIA and Stroke Patients and Unelucidated Risk Factor Evaluation (FUTURE) study. Eligible participants were women with first-ever TIA or ischemic stroke who reported that they had been pregnant at least once. Exclusion criteria were cerebral venous sinus thrombosis and retinal infarction. The investigators defined TIA as rapidly evolving focal neurologic deficit without positive phenomena such as twitches, jerks, or myoclonus, with vascular cause only, and persisting for fewer than 24 hours. They defined stroke as focal neurologic deficit persisting for more than 24 hours.

The primary outcome was the occurrence of pregnancy complications (ie, gestational hypertension; preeclampsia; hemolysis, elevated liver enzymes, low platelet count [HELLP] syndrome; preterm delivery; gestational diabetes mellitus; and miscarriage). The secondary outcome was the risk of any vascular event after stroke, stratified by the occurrence of pregnancy complications. Researchers identified the occurrence of recurrent vascular events during a telephone assessment.

Miscarriages Occurred in 35.2% of Women With Stroke

Two hundred thirteen participants completed follow-up assessment on vascular events and pregnancy complications. The mean age at event was 39.6, with a mean follow-up of 12.7 years. The number of pregnancies was unknown for three women. Of the remaining 210 women, 569 pregnancies resulted in 425 live births. All pregnancy complications were equally reported in the nulliparious (patients who experienced stroke/TIA before their first pregnancy of a live-born child), primi/multiparous (patients who have had one more pregnancies), and the gravidas (during pregnancy or postpartum, defined as within six weeks after delivery) groups.

Miscarriage occurred in 35.2% of women with stroke vs 13.5% of the Dutch population. Fetal death occurred in 6.1% of women with stroke vs 0.9% of the Dutch population.

Compared with the Dutch population, nulliparous women after stroke had a high prevalence of hypertensive disorders in pregnancy (12.2% vs 33.3%), HELLP syndrome (0.5% vs 9.5%), and early preterm delivery less than 32 weeks (1.4% vs 9.0%).

In primiparous and multiparous women after stroke, 29 events occurred. None of these events occurred during subsequent pregnancies. A history of hypertensive disorder in pregnancy did not modify this risk.

This is the first study to address the risk of pregnancy complications in a large group of women after their stroke, said the researchers.

These findings “may imply that women with a history of stroke should be put under intensive control of a gynecologist during pregnancy to prevent serious and possibly life-threatening pregnancy complications,” Dr. van Alebeek and his team concluded.

—Erica Tricarico

Suggested Reading

van Alebeek ME, de Vrijer M, Arntz RM, et al. Increased risk of pregnancy complications after stroke: the FUTURE study (Follow-Up of Transient Ischemic Attack and Stroke Patients and Unelucidated Risk Factor Evaluation). Stroke. 2018;49(4):877-883.

When compared with the general population, young women with stroke have more pregnancy loss throughout their lives, according to research published in the April issue of Stroke. After stroke, nulliparous women more frequently experience serious pregnancy complications, compared with the general population. “We found that one out of three women experiences a serious pregnancy complication after stroke,” said Mayte E. van Alebeek, MD, of the Department of Neurology at the Donders Institute for Brain, Cognition, and Behavior, Center for Neuroscience in Nijmegen, the Netherlands, and colleagues.

“Our cohort shows high rates of miscarriages, multiple miscarriages, and extremely high rates of fetal death,” said Dr. van Alebeek. “Our study provides insight about the frequency of pregnancy complications in women who experience a stroke at young age.”

A Prospective Stroke Study

Although 16 to 59 per 100,000 women of childbearing age have stroke every year, there is limited research about the risks of future pregnancy complications after stroke. Dr. van Alebeek and colleagues hypothesized that women with stroke have an increased risk of future pregnancy complications. To test this hypothesis, they conducted a prospective study to investigate the prevalence of pregnancy complications and pregnancy loss in young women before, during, and after ischemic stroke or transient ischemic attack (TIA).

The study was a part of the Dutch Follow-Up of TIA and Stroke Patients and Unelucidated Risk Factor Evaluation (FUTURE) study. Eligible participants were women with first-ever TIA or ischemic stroke who reported that they had been pregnant at least once. Exclusion criteria were cerebral venous sinus thrombosis and retinal infarction. The investigators defined TIA as rapidly evolving focal neurologic deficit without positive phenomena such as twitches, jerks, or myoclonus, with vascular cause only, and persisting for fewer than 24 hours. They defined stroke as focal neurologic deficit persisting for more than 24 hours.

The primary outcome was the occurrence of pregnancy complications (ie, gestational hypertension; preeclampsia; hemolysis, elevated liver enzymes, low platelet count [HELLP] syndrome; preterm delivery; gestational diabetes mellitus; and miscarriage). The secondary outcome was the risk of any vascular event after stroke, stratified by the occurrence of pregnancy complications. Researchers identified the occurrence of recurrent vascular events during a telephone assessment.

Miscarriages Occurred in 35.2% of Women With Stroke

Two hundred thirteen participants completed follow-up assessment on vascular events and pregnancy complications. The mean age at event was 39.6, with a mean follow-up of 12.7 years. The number of pregnancies was unknown for three women. Of the remaining 210 women, 569 pregnancies resulted in 425 live births. All pregnancy complications were equally reported in the nulliparious (patients who experienced stroke/TIA before their first pregnancy of a live-born child), primi/multiparous (patients who have had one more pregnancies), and the gravidas (during pregnancy or postpartum, defined as within six weeks after delivery) groups.

Miscarriage occurred in 35.2% of women with stroke vs 13.5% of the Dutch population. Fetal death occurred in 6.1% of women with stroke vs 0.9% of the Dutch population.

Compared with the Dutch population, nulliparous women after stroke had a high prevalence of hypertensive disorders in pregnancy (12.2% vs 33.3%), HELLP syndrome (0.5% vs 9.5%), and early preterm delivery less than 32 weeks (1.4% vs 9.0%).

In primiparous and multiparous women after stroke, 29 events occurred. None of these events occurred during subsequent pregnancies. A history of hypertensive disorder in pregnancy did not modify this risk.

This is the first study to address the risk of pregnancy complications in a large group of women after their stroke, said the researchers.

These findings “may imply that women with a history of stroke should be put under intensive control of a gynecologist during pregnancy to prevent serious and possibly life-threatening pregnancy complications,” Dr. van Alebeek and his team concluded.

—Erica Tricarico

Suggested Reading

van Alebeek ME, de Vrijer M, Arntz RM, et al. Increased risk of pregnancy complications after stroke: the FUTURE study (Follow-Up of Transient Ischemic Attack and Stroke Patients and Unelucidated Risk Factor Evaluation). Stroke. 2018;49(4):877-883.

When compared with the general population, young women with stroke have more pregnancy loss throughout their lives, according to research published in the April issue of Stroke. After stroke, nulliparous women more frequently experience serious pregnancy complications, compared with the general population. “We found that one out of three women experiences a serious pregnancy complication after stroke,” said Mayte E. van Alebeek, MD, of the Department of Neurology at the Donders Institute for Brain, Cognition, and Behavior, Center for Neuroscience in Nijmegen, the Netherlands, and colleagues.

“Our cohort shows high rates of miscarriages, multiple miscarriages, and extremely high rates of fetal death,” said Dr. van Alebeek. “Our study provides insight about the frequency of pregnancy complications in women who experience a stroke at young age.”

A Prospective Stroke Study

Although 16 to 59 per 100,000 women of childbearing age have stroke every year, there is limited research about the risks of future pregnancy complications after stroke. Dr. van Alebeek and colleagues hypothesized that women with stroke have an increased risk of future pregnancy complications. To test this hypothesis, they conducted a prospective study to investigate the prevalence of pregnancy complications and pregnancy loss in young women before, during, and after ischemic stroke or transient ischemic attack (TIA).

The study was a part of the Dutch Follow-Up of TIA and Stroke Patients and Unelucidated Risk Factor Evaluation (FUTURE) study. Eligible participants were women with first-ever TIA or ischemic stroke who reported that they had been pregnant at least once. Exclusion criteria were cerebral venous sinus thrombosis and retinal infarction. The investigators defined TIA as rapidly evolving focal neurologic deficit without positive phenomena such as twitches, jerks, or myoclonus, with vascular cause only, and persisting for fewer than 24 hours. They defined stroke as focal neurologic deficit persisting for more than 24 hours.

The primary outcome was the occurrence of pregnancy complications (ie, gestational hypertension; preeclampsia; hemolysis, elevated liver enzymes, low platelet count [HELLP] syndrome; preterm delivery; gestational diabetes mellitus; and miscarriage). The secondary outcome was the risk of any vascular event after stroke, stratified by the occurrence of pregnancy complications. Researchers identified the occurrence of recurrent vascular events during a telephone assessment.

Miscarriages Occurred in 35.2% of Women With Stroke

Two hundred thirteen participants completed follow-up assessment on vascular events and pregnancy complications. The mean age at event was 39.6, with a mean follow-up of 12.7 years. The number of pregnancies was unknown for three women. Of the remaining 210 women, 569 pregnancies resulted in 425 live births. All pregnancy complications were equally reported in the nulliparious (patients who experienced stroke/TIA before their first pregnancy of a live-born child), primi/multiparous (patients who have had one more pregnancies), and the gravidas (during pregnancy or postpartum, defined as within six weeks after delivery) groups.

Miscarriage occurred in 35.2% of women with stroke vs 13.5% of the Dutch population. Fetal death occurred in 6.1% of women with stroke vs 0.9% of the Dutch population.

Compared with the Dutch population, nulliparous women after stroke had a high prevalence of hypertensive disorders in pregnancy (12.2% vs 33.3%), HELLP syndrome (0.5% vs 9.5%), and early preterm delivery less than 32 weeks (1.4% vs 9.0%).

In primiparous and multiparous women after stroke, 29 events occurred. None of these events occurred during subsequent pregnancies. A history of hypertensive disorder in pregnancy did not modify this risk.

This is the first study to address the risk of pregnancy complications in a large group of women after their stroke, said the researchers.

These findings “may imply that women with a history of stroke should be put under intensive control of a gynecologist during pregnancy to prevent serious and possibly life-threatening pregnancy complications,” Dr. van Alebeek and his team concluded.

—Erica Tricarico

Suggested Reading

van Alebeek ME, de Vrijer M, Arntz RM, et al. Increased risk of pregnancy complications after stroke: the FUTURE study (Follow-Up of Transient Ischemic Attack and Stroke Patients and Unelucidated Risk Factor Evaluation). Stroke. 2018;49(4):877-883.

Among patients with secondary progressive multiple sclerosis (MS), siponimod appears to decrease the risk of disability progression, according to data published online ahead of print March 22 in Lancet. The drug’s safety profile is similar to those of other sphingosine-1-phosphate receptor modulators, and siponimod “might be a useful treatment for patients with secondary progressive MS,” according to the authors.

To date, no molecule has slowed disability progression consistently in clinical trials of patients with secondary progressive MS. Preclinical data indicate that siponimod might prevent synaptic neurodegeneration and promote remyelination. The drug reduced the number of active brain lesions and the annualized relapse rate in a phase II study.

Patients Received 2 mg/day of Oral Siponimod

Ludwig Kappos, MD, Professor of Neurology at the University of Basel in Switzerland, and colleagues conducted a double-blind, phase III trial to assess siponimod’s efficacy and safety in patients with secondary progressive MS. They enrolled 1,651 patients at 292 hospitals and MS centers in 31 countries. Eligible participants were between ages 18 and 60, had an Expanded Disability Status Scale (EDSS) score of 3.0 to 6.5, a history of relapsing-remitting MS, EDSS progression in the previous two years, and no evidence of relapse in the three months before randomization.

The investigators randomized patients 2:1 to once-daily oral siponimod (2 mg) or matching placebo. A trained assessor performed a full neurologic examination every three months. Participants underwent MRI scans at baseline, 12 months, 24 months, 36 months, and the end of the controlled treatment phase. Patients with six-month confirmed disability progression during the double-blind phase were given the opportunity to continue double-blind treatment, switch to open-label siponimod, or stop study treatment and remain untreated or receive another therapy.

The study’s primary end point was time to three-month confirmed disability progression, which was defined as a one-point increase in EDSS for patients with a baseline score of 3.0 to 5.0, or a 0.5-point increase for patients with a baseline score of 5.5 to 6.5. The key secondary end points were time to three-month confirmed worsening of at least 20% from baseline on the Timed 25-Foot Walk (T25FW) and change from baseline in T2 lesion volume.

Treatment Did Not Affect the T25FW

Dr. Kappos and colleagues randomized 1,105 patients to siponimod and 546 patients to placebo. Baseline characteristics were similar between the two study arms. Mean age was 48, and about 60% of patients were women. Participants’ median time in the study was 21 months, and median exposure to study drug was 18 months. Approximately 82% of the siponimod group and 78% of controls completed the study.

The rate of three-month confirmed disability progression was 26% in the siponimod group and 32% in the placebo group. Siponimod thus reduced the risk of this outcome by 21%. The researchers did not observe a significant difference between groups in time to three-month confirmed worsening of at least 20% on the T25FW. The mean increase in T2 lesion volume from baseline was 183.9 mm3 in the siponimod group and 879.2 mm3 among controls.

Siponimod reduced the risk of six-month confirmed disability progression by 26%, compared with placebo. It also was associated with a lower annualized relapse rate and a longer time to confirmed first relapse, compared with placebo.

The rate of adverse events was 89% in the siponimod group and 82% among controls. The rate of serious adverse events was 18% in the siponimod group and 15% among controls. The most frequent adverse events were headache, nasopharyngitis, urinary tract infection, and falls. Serious adverse events included increased liver transaminase concentrations, basal cell carcinoma, concussion, depression, urinary tract infection, suicide attempt, gait disturbance, MS relapse, and paraparesis. The rate of discontinuation because of adverse events was 8% for siponimod and 5% for placebo.

Subgroup analyses suggested that the treatment effect of siponimod decreased with increasing age, disability, baseline disease duration, and diminishing signs of disease activity. One interpretation of this finding “is that siponimod exerts its effect on both aspects of the pathogenesis of secondary progressive disease, albeit not equally,” according to the authors.

The study was funded by Novartis Pharma, which helped design and conduct the study; collect, manage, analyze, and interpret the data; and write the study report.

Drug Might Affect Inflammatory Activity

“The reduction in the proportion of participants reaching the primary end point of only 6% and the absence of a significant difference for the key secondary clinical outcome are disappointing results and do not suggest that siponimod is an effective treatment for secondary progressive MS,” said Luanne M. Metz, MD, Professor of Medicine, and Wei-Qiao Liu, MD, a doctoral student, both at the University of Calgary, Alberta, in an accompanying editorial.

Although siponimod had a “small benefit” on the primary end point, it did not reduce the time to three-month confirmed worsening of the T25FW, said the authors. “Worsening of the T25FW by 20%, as required in this trial, is a reliable measure of change and suggests clinical significance.”

The significant differences between the siponimod group and controls on the other secondary outcomes “might all reflect an effect on the inflammatory disease activity that characterizes relapsing-remitting MS, and this trial does not, in our opinion, provide convincing evidence that we have found a treatment that exerts its clinical effect through other mechanisms,” said Drs. Metz and Liu.

“Confidence in the treatment benefit of siponimod in progressive MS will … require confirmation in a second trial,” they continued. “Trials of other novel treatments that target noninflammatory mechanisms are still needed.”

—Erik Greb

Suggested Reading

Kappos L, Bar-Or A, Cree BAC, et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet. 2018 Mar 22 [Epub ahead of print].

Metz LM, Liu WQ. Effective treatment of progressive MS remains elusive. Lancet. 2018 Mar 22 [Epub ahead of print].

Among patients with secondary progressive multiple sclerosis (MS), siponimod appears to decrease the risk of disability progression, according to data published online ahead of print March 22 in Lancet. The drug’s safety profile is similar to those of other sphingosine-1-phosphate receptor modulators, and siponimod “might be a useful treatment for patients with secondary progressive MS,” according to the authors.

To date, no molecule has slowed disability progression consistently in clinical trials of patients with secondary progressive MS. Preclinical data indicate that siponimod might prevent synaptic neurodegeneration and promote remyelination. The drug reduced the number of active brain lesions and the annualized relapse rate in a phase II study.

Patients Received 2 mg/day of Oral Siponimod

Ludwig Kappos, MD, Professor of Neurology at the University of Basel in Switzerland, and colleagues conducted a double-blind, phase III trial to assess siponimod’s efficacy and safety in patients with secondary progressive MS. They enrolled 1,651 patients at 292 hospitals and MS centers in 31 countries. Eligible participants were between ages 18 and 60, had an Expanded Disability Status Scale (EDSS) score of 3.0 to 6.5, a history of relapsing-remitting MS, EDSS progression in the previous two years, and no evidence of relapse in the three months before randomization.

The investigators randomized patients 2:1 to once-daily oral siponimod (2 mg) or matching placebo. A trained assessor performed a full neurologic examination every three months. Participants underwent MRI scans at baseline, 12 months, 24 months, 36 months, and the end of the controlled treatment phase. Patients with six-month confirmed disability progression during the double-blind phase were given the opportunity to continue double-blind treatment, switch to open-label siponimod, or stop study treatment and remain untreated or receive another therapy.

The study’s primary end point was time to three-month confirmed disability progression, which was defined as a one-point increase in EDSS for patients with a baseline score of 3.0 to 5.0, or a 0.5-point increase for patients with a baseline score of 5.5 to 6.5. The key secondary end points were time to three-month confirmed worsening of at least 20% from baseline on the Timed 25-Foot Walk (T25FW) and change from baseline in T2 lesion volume.

Treatment Did Not Affect the T25FW

Dr. Kappos and colleagues randomized 1,105 patients to siponimod and 546 patients to placebo. Baseline characteristics were similar between the two study arms. Mean age was 48, and about 60% of patients were women. Participants’ median time in the study was 21 months, and median exposure to study drug was 18 months. Approximately 82% of the siponimod group and 78% of controls completed the study.

The rate of three-month confirmed disability progression was 26% in the siponimod group and 32% in the placebo group. Siponimod thus reduced the risk of this outcome by 21%. The researchers did not observe a significant difference between groups in time to three-month confirmed worsening of at least 20% on the T25FW. The mean increase in T2 lesion volume from baseline was 183.9 mm3 in the siponimod group and 879.2 mm3 among controls.

Siponimod reduced the risk of six-month confirmed disability progression by 26%, compared with placebo. It also was associated with a lower annualized relapse rate and a longer time to confirmed first relapse, compared with placebo.

The rate of adverse events was 89% in the siponimod group and 82% among controls. The rate of serious adverse events was 18% in the siponimod group and 15% among controls. The most frequent adverse events were headache, nasopharyngitis, urinary tract infection, and falls. Serious adverse events included increased liver transaminase concentrations, basal cell carcinoma, concussion, depression, urinary tract infection, suicide attempt, gait disturbance, MS relapse, and paraparesis. The rate of discontinuation because of adverse events was 8% for siponimod and 5% for placebo.

Subgroup analyses suggested that the treatment effect of siponimod decreased with increasing age, disability, baseline disease duration, and diminishing signs of disease activity. One interpretation of this finding “is that siponimod exerts its effect on both aspects of the pathogenesis of secondary progressive disease, albeit not equally,” according to the authors.

The study was funded by Novartis Pharma, which helped design and conduct the study; collect, manage, analyze, and interpret the data; and write the study report.

Drug Might Affect Inflammatory Activity

“The reduction in the proportion of participants reaching the primary end point of only 6% and the absence of a significant difference for the key secondary clinical outcome are disappointing results and do not suggest that siponimod is an effective treatment for secondary progressive MS,” said Luanne M. Metz, MD, Professor of Medicine, and Wei-Qiao Liu, MD, a doctoral student, both at the University of Calgary, Alberta, in an accompanying editorial.

Although siponimod had a “small benefit” on the primary end point, it did not reduce the time to three-month confirmed worsening of the T25FW, said the authors. “Worsening of the T25FW by 20%, as required in this trial, is a reliable measure of change and suggests clinical significance.”

The significant differences between the siponimod group and controls on the other secondary outcomes “might all reflect an effect on the inflammatory disease activity that characterizes relapsing-remitting MS, and this trial does not, in our opinion, provide convincing evidence that we have found a treatment that exerts its clinical effect through other mechanisms,” said Drs. Metz and Liu.

“Confidence in the treatment benefit of siponimod in progressive MS will … require confirmation in a second trial,” they continued. “Trials of other novel treatments that target noninflammatory mechanisms are still needed.”

—Erik Greb

Suggested Reading

Kappos L, Bar-Or A, Cree BAC, et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet. 2018 Mar 22 [Epub ahead of print].

Metz LM, Liu WQ. Effective treatment of progressive MS remains elusive. Lancet. 2018 Mar 22 [Epub ahead of print].

Among patients with secondary progressive multiple sclerosis (MS), siponimod appears to decrease the risk of disability progression, according to data published online ahead of print March 22 in Lancet. The drug’s safety profile is similar to those of other sphingosine-1-phosphate receptor modulators, and siponimod “might be a useful treatment for patients with secondary progressive MS,” according to the authors.

To date, no molecule has slowed disability progression consistently in clinical trials of patients with secondary progressive MS. Preclinical data indicate that siponimod might prevent synaptic neurodegeneration and promote remyelination. The drug reduced the number of active brain lesions and the annualized relapse rate in a phase II study.

Patients Received 2 mg/day of Oral Siponimod

Ludwig Kappos, MD, Professor of Neurology at the University of Basel in Switzerland, and colleagues conducted a double-blind, phase III trial to assess siponimod’s efficacy and safety in patients with secondary progressive MS. They enrolled 1,651 patients at 292 hospitals and MS centers in 31 countries. Eligible participants were between ages 18 and 60, had an Expanded Disability Status Scale (EDSS) score of 3.0 to 6.5, a history of relapsing-remitting MS, EDSS progression in the previous two years, and no evidence of relapse in the three months before randomization.

The investigators randomized patients 2:1 to once-daily oral siponimod (2 mg) or matching placebo. A trained assessor performed a full neurologic examination every three months. Participants underwent MRI scans at baseline, 12 months, 24 months, 36 months, and the end of the controlled treatment phase. Patients with six-month confirmed disability progression during the double-blind phase were given the opportunity to continue double-blind treatment, switch to open-label siponimod, or stop study treatment and remain untreated or receive another therapy.

The study’s primary end point was time to three-month confirmed disability progression, which was defined as a one-point increase in EDSS for patients with a baseline score of 3.0 to 5.0, or a 0.5-point increase for patients with a baseline score of 5.5 to 6.5. The key secondary end points were time to three-month confirmed worsening of at least 20% from baseline on the Timed 25-Foot Walk (T25FW) and change from baseline in T2 lesion volume.

Treatment Did Not Affect the T25FW

Dr. Kappos and colleagues randomized 1,105 patients to siponimod and 546 patients to placebo. Baseline characteristics were similar between the two study arms. Mean age was 48, and about 60% of patients were women. Participants’ median time in the study was 21 months, and median exposure to study drug was 18 months. Approximately 82% of the siponimod group and 78% of controls completed the study.

The rate of three-month confirmed disability progression was 26% in the siponimod group and 32% in the placebo group. Siponimod thus reduced the risk of this outcome by 21%. The researchers did not observe a significant difference between groups in time to three-month confirmed worsening of at least 20% on the T25FW. The mean increase in T2 lesion volume from baseline was 183.9 mm3 in the siponimod group and 879.2 mm3 among controls.

Siponimod reduced the risk of six-month confirmed disability progression by 26%, compared with placebo. It also was associated with a lower annualized relapse rate and a longer time to confirmed first relapse, compared with placebo.

The rate of adverse events was 89% in the siponimod group and 82% among controls. The rate of serious adverse events was 18% in the siponimod group and 15% among controls. The most frequent adverse events were headache, nasopharyngitis, urinary tract infection, and falls. Serious adverse events included increased liver transaminase concentrations, basal cell carcinoma, concussion, depression, urinary tract infection, suicide attempt, gait disturbance, MS relapse, and paraparesis. The rate of discontinuation because of adverse events was 8% for siponimod and 5% for placebo.

Subgroup analyses suggested that the treatment effect of siponimod decreased with increasing age, disability, baseline disease duration, and diminishing signs of disease activity. One interpretation of this finding “is that siponimod exerts its effect on both aspects of the pathogenesis of secondary progressive disease, albeit not equally,” according to the authors.

The study was funded by Novartis Pharma, which helped design and conduct the study; collect, manage, analyze, and interpret the data; and write the study report.

Drug Might Affect Inflammatory Activity

“The reduction in the proportion of participants reaching the primary end point of only 6% and the absence of a significant difference for the key secondary clinical outcome are disappointing results and do not suggest that siponimod is an effective treatment for secondary progressive MS,” said Luanne M. Metz, MD, Professor of Medicine, and Wei-Qiao Liu, MD, a doctoral student, both at the University of Calgary, Alberta, in an accompanying editorial.

Although siponimod had a “small benefit” on the primary end point, it did not reduce the time to three-month confirmed worsening of the T25FW, said the authors. “Worsening of the T25FW by 20%, as required in this trial, is a reliable measure of change and suggests clinical significance.”

The significant differences between the siponimod group and controls on the other secondary outcomes “might all reflect an effect on the inflammatory disease activity that characterizes relapsing-remitting MS, and this trial does not, in our opinion, provide convincing evidence that we have found a treatment that exerts its clinical effect through other mechanisms,” said Drs. Metz and Liu.

“Confidence in the treatment benefit of siponimod in progressive MS will … require confirmation in a second trial,” they continued. “Trials of other novel treatments that target noninflammatory mechanisms are still needed.”

—Erik Greb

Suggested Reading

Kappos L, Bar-Or A, Cree BAC, et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet. 2018 Mar 22 [Epub ahead of print].

Metz LM, Liu WQ. Effective treatment of progressive MS remains elusive. Lancet. 2018 Mar 22 [Epub ahead of print].

Severe headache and migraine remain significant public health problems, and their prevalence has been stable for years, according to a review published online ahead of print March 12 in Headache. Results confirm that “migraine disproportionately affects women and several other historically disadvantaged segments of the population,” according to the authors. “These inequities could be exacerbated if new high-cost treatments are inaccessible to those who need them most.”

Rebecca Burch, MD, Instructor in Neurology at Harvard Medical School in Boston, and colleagues reviewed population-based US government surveys to obtain updated estimates of the prevalence of migraine and severe headache in adults. The authors examined the most recent data from the National Health Interview Survey, the National Hospital Ambulatory Medical Care Survey, and the National Ambulatory Medical Care Survey.

—Erik Greb

Suggested Reading

Burch R, Rizzoli P, Loder E. The prevalence and impact of migraine and severe headache in the United States: figures and trends from government health studies. Headache. 2018 Mar 12 [Epub ahead of print].

Severe headache and migraine remain significant public health problems, and their prevalence has been stable for years, according to a review published online ahead of print March 12 in Headache. Results confirm that “migraine disproportionately affects women and several other historically disadvantaged segments of the population,” according to the authors. “These inequities could be exacerbated if new high-cost treatments are inaccessible to those who need them most.”

Rebecca Burch, MD, Instructor in Neurology at Harvard Medical School in Boston, and colleagues reviewed population-based US government surveys to obtain updated estimates of the prevalence of migraine and severe headache in adults. The authors examined the most recent data from the National Health Interview Survey, the National Hospital Ambulatory Medical Care Survey, and the National Ambulatory Medical Care Survey.

—Erik Greb

Suggested Reading

Burch R, Rizzoli P, Loder E. The prevalence and impact of migraine and severe headache in the United States: figures and trends from government health studies. Headache. 2018 Mar 12 [Epub ahead of print].

Severe headache and migraine remain significant public health problems, and their prevalence has been stable for years, according to a review published online ahead of print March 12 in Headache. Results confirm that “migraine disproportionately affects women and several other historically disadvantaged segments of the population,” according to the authors. “These inequities could be exacerbated if new high-cost treatments are inaccessible to those who need them most.”

Rebecca Burch, MD, Instructor in Neurology at Harvard Medical School in Boston, and colleagues reviewed population-based US government surveys to obtain updated estimates of the prevalence of migraine and severe headache in adults. The authors examined the most recent data from the National Health Interview Survey, the National Hospital Ambulatory Medical Care Survey, and the National Ambulatory Medical Care Survey.

—Erik Greb

Suggested Reading

Burch R, Rizzoli P, Loder E. The prevalence and impact of migraine and severe headache in the United States: figures and trends from government health studies. Headache. 2018 Mar 12 [Epub ahead of print].

Patients with persistent posttraumatic headache have less cortical thickness in bilateral frontal regions and right hemisphere parietal regions of the brain, compared with healthy controls, according to research published in the January issue of Headache. Among patients with persistent posttraumatic headache, more frequent headaches are associated with less cortical thickness in the left and right superior frontal regions, the researchers said.

“These results indicate that, although general linear model vertex-by-vertex comparisons indicate that large areas over the frontal cortex are overall thinner in patients with persistent posttraumatic headache, it is specifically the frequency of headaches that associates with cortical thinning in the superior frontal regions,” said Catherine D. Chong, PhD, a researcher at the Mayo Clinic in Phoenix.

Patients With Persistent Posttraumatic Headache vs Healthy Controls

Posttraumatic headaches are common after concussion. When these headaches persist for longer than three months, they are classified as persistent posttraumatic headaches. Studies have shown functional changes and anatomical changes such as volume loss and cortical thinning following concussion, but there are insufficient data about the association between brain morphologic changes and headache symptoms in patients with persistent posttraumatic headache, the researchers said.

To investigate differences in cortical thickness between patients with persistent posttraumatic headaches and healthy controls and to assess whether cortical morphology relates to headache burden, Dr. Chong and colleagues studied 33 patients with persistent posttraumatic headache and 33 healthy controls. Healthy controls had never had headaches or had infrequent tension-type headache. Exclusion criteria for all subjects included pregnancy, contraindications to MRI, moderate or severe head trauma, and previous history of migraine. Patients with persistent posttraumatic headache who were taking abortive or preventive headache medications were not excluded.

Patients with persistent posttraumatic headache were diagnosed according to ICHD-3 beta criteria. Participants underwent brain MRI on a 3-T scanner. Researchers calculated vertex-by-vertex whole brain estimates of cortical thickness. They used a general linear model design to determine differences in cortical thickness between patients with persistent posttraumatic headache and healthy controls.

Anxiety and Depression Scores Differed Between Groups

Researchers enrolled 68 patients into the study. They excluded data for two because of abnormal findings. The median age of participants with persistent posttraumatic headache was 36, and the median age of healthy controls was 33. About 39% of subjects with persistent posttraumatic headaches were female, and about 58% of healthy controls were female. Six participants reported one traumatic brain injury (TBI) in their lifetime, 15 reported two TBIs, three reported five TBIs, and six participants reported six or more TBIs. Concussions that led to persistent posttraumatic headache were due to explosion or blast injuries, sports-related accidents, falls, and motor vehicle accidents. In addition, there were significant between-group differences in levels of anxiety and depression.

“Patients with persistent posttraumatic headache had comorbid symptoms of mild depression and anxiety. Although there was not an association between mood alteration and headache frequency in patients with persistent posttraumatic headache, it is impossible to completely disentangle the effect that mood dysfunctions may have had on altering cortical thickness patterns in patients with persistent posttraumatic headache,” said the researchers.

Thinner Cortex in Patients With Persistent Posttraumatic Headache

Overall, patients with persistent posttraumatic headache had less cortical thickness in the left and right frontal (superior frontal, caudal middle frontal, and precentral) regions and right parietal (precuneus supramarginal, inferior, and superior parietal) regions. In addition, there were no regions in which patients with persistent posttraumatic headache had more cortical thickness, relative to healthy controls.

A correlation analysis of regions with less cortical thickness in patients with persistent posttraumatic headache found a negative correlation between left and right superior frontal thickness and headache frequency. No association was observed between regional cortical thickness and years lived with persistent posttraumatic headache.

“Further investigation is required to determine if the findings of our study are specific for persistent posttraumatic headache or if they are generalizable to other chronic pain conditions and other symptoms that occur following concussion,” said Dr. Chong and colleagues.

“Future studies using larger patient cohorts will be needed to better detect how repetitive concussions, concussion mechanism (sports-related vs motor vehicle accident vs blast injuries vs falls), and medical history alter brain pathophysiological processes, as well as affect headache patterns in patients with persistent posttraumatic headache.”

—Erica Tricarico

Suggested Reading

Chong CD, Berisha V, Chiang CC, et al. Less cortical thickness in patients with persistent posttraumatic headache compared with healthy controls: an MRI study. Headache. 2018;58(1):53-61.

Patients with persistent posttraumatic headache have less cortical thickness in bilateral frontal regions and right hemisphere parietal regions of the brain, compared with healthy controls, according to research published in the January issue of Headache. Among patients with persistent posttraumatic headache, more frequent headaches are associated with less cortical thickness in the left and right superior frontal regions, the researchers said.

“These results indicate that, although general linear model vertex-by-vertex comparisons indicate that large areas over the frontal cortex are overall thinner in patients with persistent posttraumatic headache, it is specifically the frequency of headaches that associates with cortical thinning in the superior frontal regions,” said Catherine D. Chong, PhD, a researcher at the Mayo Clinic in Phoenix.

Patients With Persistent Posttraumatic Headache vs Healthy Controls

Posttraumatic headaches are common after concussion. When these headaches persist for longer than three months, they are classified as persistent posttraumatic headaches. Studies have shown functional changes and anatomical changes such as volume loss and cortical thinning following concussion, but there are insufficient data about the association between brain morphologic changes and headache symptoms in patients with persistent posttraumatic headache, the researchers said.

To investigate differences in cortical thickness between patients with persistent posttraumatic headaches and healthy controls and to assess whether cortical morphology relates to headache burden, Dr. Chong and colleagues studied 33 patients with persistent posttraumatic headache and 33 healthy controls. Healthy controls had never had headaches or had infrequent tension-type headache. Exclusion criteria for all subjects included pregnancy, contraindications to MRI, moderate or severe head trauma, and previous history of migraine. Patients with persistent posttraumatic headache who were taking abortive or preventive headache medications were not excluded.

Patients with persistent posttraumatic headache were diagnosed according to ICHD-3 beta criteria. Participants underwent brain MRI on a 3-T scanner. Researchers calculated vertex-by-vertex whole brain estimates of cortical thickness. They used a general linear model design to determine differences in cortical thickness between patients with persistent posttraumatic headache and healthy controls.

Anxiety and Depression Scores Differed Between Groups

Researchers enrolled 68 patients into the study. They excluded data for two because of abnormal findings. The median age of participants with persistent posttraumatic headache was 36, and the median age of healthy controls was 33. About 39% of subjects with persistent posttraumatic headaches were female, and about 58% of healthy controls were female. Six participants reported one traumatic brain injury (TBI) in their lifetime, 15 reported two TBIs, three reported five TBIs, and six participants reported six or more TBIs. Concussions that led to persistent posttraumatic headache were due to explosion or blast injuries, sports-related accidents, falls, and motor vehicle accidents. In addition, there were significant between-group differences in levels of anxiety and depression.

“Patients with persistent posttraumatic headache had comorbid symptoms of mild depression and anxiety. Although there was not an association between mood alteration and headache frequency in patients with persistent posttraumatic headache, it is impossible to completely disentangle the effect that mood dysfunctions may have had on altering cortical thickness patterns in patients with persistent posttraumatic headache,” said the researchers.

Thinner Cortex in Patients With Persistent Posttraumatic Headache

Overall, patients with persistent posttraumatic headache had less cortical thickness in the left and right frontal (superior frontal, caudal middle frontal, and precentral) regions and right parietal (precuneus supramarginal, inferior, and superior parietal) regions. In addition, there were no regions in which patients with persistent posttraumatic headache had more cortical thickness, relative to healthy controls.

A correlation analysis of regions with less cortical thickness in patients with persistent posttraumatic headache found a negative correlation between left and right superior frontal thickness and headache frequency. No association was observed between regional cortical thickness and years lived with persistent posttraumatic headache.

“Further investigation is required to determine if the findings of our study are specific for persistent posttraumatic headache or if they are generalizable to other chronic pain conditions and other symptoms that occur following concussion,” said Dr. Chong and colleagues.

“Future studies using larger patient cohorts will be needed to better detect how repetitive concussions, concussion mechanism (sports-related vs motor vehicle accident vs blast injuries vs falls), and medical history alter brain pathophysiological processes, as well as affect headache patterns in patients with persistent posttraumatic headache.”

—Erica Tricarico

Suggested Reading

Chong CD, Berisha V, Chiang CC, et al. Less cortical thickness in patients with persistent posttraumatic headache compared with healthy controls: an MRI study. Headache. 2018;58(1):53-61.

Patients with persistent posttraumatic headache have less cortical thickness in bilateral frontal regions and right hemisphere parietal regions of the brain, compared with healthy controls, according to research published in the January issue of Headache. Among patients with persistent posttraumatic headache, more frequent headaches are associated with less cortical thickness in the left and right superior frontal regions, the researchers said.

“These results indicate that, although general linear model vertex-by-vertex comparisons indicate that large areas over the frontal cortex are overall thinner in patients with persistent posttraumatic headache, it is specifically the frequency of headaches that associates with cortical thinning in the superior frontal regions,” said Catherine D. Chong, PhD, a researcher at the Mayo Clinic in Phoenix.

Patients With Persistent Posttraumatic Headache vs Healthy Controls

Posttraumatic headaches are common after concussion. When these headaches persist for longer than three months, they are classified as persistent posttraumatic headaches. Studies have shown functional changes and anatomical changes such as volume loss and cortical thinning following concussion, but there are insufficient data about the association between brain morphologic changes and headache symptoms in patients with persistent posttraumatic headache, the researchers said.

To investigate differences in cortical thickness between patients with persistent posttraumatic headaches and healthy controls and to assess whether cortical morphology relates to headache burden, Dr. Chong and colleagues studied 33 patients with persistent posttraumatic headache and 33 healthy controls. Healthy controls had never had headaches or had infrequent tension-type headache. Exclusion criteria for all subjects included pregnancy, contraindications to MRI, moderate or severe head trauma, and previous history of migraine. Patients with persistent posttraumatic headache who were taking abortive or preventive headache medications were not excluded.

Patients with persistent posttraumatic headache were diagnosed according to ICHD-3 beta criteria. Participants underwent brain MRI on a 3-T scanner. Researchers calculated vertex-by-vertex whole brain estimates of cortical thickness. They used a general linear model design to determine differences in cortical thickness between patients with persistent posttraumatic headache and healthy controls.

Anxiety and Depression Scores Differed Between Groups

Researchers enrolled 68 patients into the study. They excluded data for two because of abnormal findings. The median age of participants with persistent posttraumatic headache was 36, and the median age of healthy controls was 33. About 39% of subjects with persistent posttraumatic headaches were female, and about 58% of healthy controls were female. Six participants reported one traumatic brain injury (TBI) in their lifetime, 15 reported two TBIs, three reported five TBIs, and six participants reported six or more TBIs. Concussions that led to persistent posttraumatic headache were due to explosion or blast injuries, sports-related accidents, falls, and motor vehicle accidents. In addition, there were significant between-group differences in levels of anxiety and depression.

“Patients with persistent posttraumatic headache had comorbid symptoms of mild depression and anxiety. Although there was not an association between mood alteration and headache frequency in patients with persistent posttraumatic headache, it is impossible to completely disentangle the effect that mood dysfunctions may have had on altering cortical thickness patterns in patients with persistent posttraumatic headache,” said the researchers.

Thinner Cortex in Patients With Persistent Posttraumatic Headache

Overall, patients with persistent posttraumatic headache had less cortical thickness in the left and right frontal (superior frontal, caudal middle frontal, and precentral) regions and right parietal (precuneus supramarginal, inferior, and superior parietal) regions. In addition, there were no regions in which patients with persistent posttraumatic headache had more cortical thickness, relative to healthy controls.

A correlation analysis of regions with less cortical thickness in patients with persistent posttraumatic headache found a negative correlation between left and right superior frontal thickness and headache frequency. No association was observed between regional cortical thickness and years lived with persistent posttraumatic headache.

“Further investigation is required to determine if the findings of our study are specific for persistent posttraumatic headache or if they are generalizable to other chronic pain conditions and other symptoms that occur following concussion,” said Dr. Chong and colleagues.

“Future studies using larger patient cohorts will be needed to better detect how repetitive concussions, concussion mechanism (sports-related vs motor vehicle accident vs blast injuries vs falls), and medical history alter brain pathophysiological processes, as well as affect headache patterns in patients with persistent posttraumatic headache.”

—Erica Tricarico

Suggested Reading

Chong CD, Berisha V, Chiang CC, et al. Less cortical thickness in patients with persistent posttraumatic headache compared with healthy controls: an MRI study. Headache. 2018;58(1):53-61.

REM sleep behavior disorder (RBD), excessive daytime sleepiness (EDS), and a high burden of autonomic symptoms are associated with increased risk of future psychotic symptoms in patients with Parkinson’s disease, according to research published online ahead of print April 4 in Neurology. These symptoms also correlate with low density of the cholinergic nucleus 4 (Ch4) of the basal forebrain.

Data From the Parkinson’s Progression Markers Initiative

Parkinson’s disease psychosis indicates advanced disease and is associated with dementia and increased mortality. Research indicates that degeneration of the nucleus basalis of Meynert is characteristic of Parkinson’s disease and Parkinson’s disease dementia, but this brain region is difficult to measure with MRI because of its size. It is possible, however, to measure Ch4, which incorporates the nucleus basalis of Meynert.

Matthew J. Barrett, MD, Assistant Professor of Neurology at the University of Virginia in Charlottesville, and colleagues studied a cohort of patients with de novo Parkinson’s disease to identify baseline clinical risk factors for future psychotic symptoms and to assess the relationship between baseline Ch4 density and future psychotic symptoms. All participants were untreated at baseline and had enrolled in the Parkinson’s Progression Markers Initiative (PPMI), a prospective, longitudinal, observational study.

Ch4 Density Could Predict Psychotic Symptoms

The investigators included 423 participants in their analysis. The population’s mean age at enrollment was approximately 61.5, and about 35% of the population was female. Mean disease duration was 0.57 years. The population’s median number of clinical visits was 11, and the median last visit occurred at 54 months after baseline.

In all, 138 participants (32.6%) reported psychotic symptoms at least once, and 84 (19.9%) reported them more than once. Dr. Barrett and colleagues identified 17 patients who, having once reported psychotic symptoms, reported these symptoms at each subsequent visit. Among patients who reported psychotic symptoms, approximately 79% reported them at only one visit.

The investigators categorized patients into three groups according to the number of psychotic events. The groups included participants with no psychotic events, those with one psychotic event, and those with two or more psychotic events.

After performing multivariate logistic regression and adjusting the results for age and sex, Dr. Barrett and colleagues found that greater autonomic symptoms (odds ratio [OR], 1.07 for a one-unit change in SCOPA-AUT), the presence of RBD (OR, 1.9), and EDS (OR, 2.5) at baseline were associated with increased risk of reporting psychotic symptoms on two or more occasions, compared to no or one psychotic event.

A logistic regression model adjusted for age and sex indicated that greater autonomic symptoms (OR, 1.08 for a one-unit change in SCOPA-AUT) and EDS (OR, 1.8) at baseline were associated with increased risk of psychotic symptoms on one or more occasions. A Cox regression model adjusted for EDS (hazard ratio [HR], 1.5) indicated that greater autonomic symptoms (HR, 1.03 for a one-unit change in SCOPA-AUT) and presence of RBD (HR, 1.47) were associated with increased risk of having a first psychotic event.

At the last assessment, patients with Parkinson’s disease and two or more psychotic events were more likely to have the postural instability and gait difficulty motor phenotype and lower scores on the Montreal Cognitive Assessment, Letter Number Sequencing test, and Symbol Digit Modalities Test.

The investigators had data about cholinergic nuclei densities at baseline for 228 participants with Parkinson’s disease and 101 controls. Ch4 density in Parkinson’s disease was associated with lower risk of reporting psychotic symptoms on two or more occasions (OR, 0.96 for an increase in density of one unit). Mean Ch4 densities were 1.7% greater for the control group, compared with the Parkinson’s disease group. Participants with Parkinson’s disease and two or more psychotic events had lower baseline Ch4 density, compared with healthy controls, but participants with Parkinson’s disease with no or one psychotic event did not.

In linear regression models adjusted for age and sex, autonomic symptoms were associated with baseline Ch4 density, but EDS and RBD were not. Having comorbid EDS and RBD was associated with lower Ch4 density.

Results Do Not Establish Causation

“Prior studies reported that EDS was associated with hallucinations in Parkinson’s disease, but we are not aware of other studies that found EDS to be a predictor of future psychotic symptoms,” said Dr. Barrett and colleagues.

“In univariate comparisons, participants with Parkinson’s disease with three or more psychotic events had worse visuospatial function, compared with those with two psychotic events. Considering the greater impairment in visuospatial and visuoperceptive function reported in Parkinson’s disease with visual hallucinations, this association should be evaluated in the future in the PPMI Parkinson’s disease cohort as additional follow-up visits occur.”

The current study’s finding of an association between autonomic dysfunction, RBD, and EDS and baseline Ch4 density in Parkinson’s disease is consistent with a recent analysis that found that the same symptoms were associated with a diffuse malignant subtype of Parkinson’s disease, said the authors. “Our finding that these three nonmotor symptoms are linked to future psychotic symptoms validates the prognostic value of these symptoms in predicting worse outcomes early in disease.”

Evidence does not support a causal relationship between lower Ch4 density and autonomic dysfunction, RBD, and EDS. These four characteristics may be associated with widespread subcortical pathology. “The relationship between this triad of clinical symptoms and lower Ch4 density supports the potential utility of this neuroimaging biomarker to identify a diffuse malignant subtype of Parkinson’s disease and to predict more rapid disease progression,” said Dr. Barrett and colleagues.

—Erik Greb

Suggested Reading

Barrett MJ, Blair JC, Sperling SA, et al. Baseline symptoms and basal forebrain volume predict future psychosis in early Parkinson disease. Neurology. 2018 Apr 4 [Epub ahead of print].

Bohnen NI, Teipel SJ. Cholinergic forebrain density loss in Parkinson disease: More than just cognitive changes. Neurology. 2018 Apr 4 [Epub ahead of print].

REM sleep behavior disorder (RBD), excessive daytime sleepiness (EDS), and a high burden of autonomic symptoms are associated with increased risk of future psychotic symptoms in patients with Parkinson’s disease, according to research published online ahead of print April 4 in Neurology. These symptoms also correlate with low density of the cholinergic nucleus 4 (Ch4) of the basal forebrain.

Data From the Parkinson’s Progression Markers Initiative

Parkinson’s disease psychosis indicates advanced disease and is associated with dementia and increased mortality. Research indicates that degeneration of the nucleus basalis of Meynert is characteristic of Parkinson’s disease and Parkinson’s disease dementia, but this brain region is difficult to measure with MRI because of its size. It is possible, however, to measure Ch4, which incorporates the nucleus basalis of Meynert.

Matthew J. Barrett, MD, Assistant Professor of Neurology at the University of Virginia in Charlottesville, and colleagues studied a cohort of patients with de novo Parkinson’s disease to identify baseline clinical risk factors for future psychotic symptoms and to assess the relationship between baseline Ch4 density and future psychotic symptoms. All participants were untreated at baseline and had enrolled in the Parkinson’s Progression Markers Initiative (PPMI), a prospective, longitudinal, observational study.

Ch4 Density Could Predict Psychotic Symptoms

The investigators included 423 participants in their analysis. The population’s mean age at enrollment was approximately 61.5, and about 35% of the population was female. Mean disease duration was 0.57 years. The population’s median number of clinical visits was 11, and the median last visit occurred at 54 months after baseline.

In all, 138 participants (32.6%) reported psychotic symptoms at least once, and 84 (19.9%) reported them more than once. Dr. Barrett and colleagues identified 17 patients who, having once reported psychotic symptoms, reported these symptoms at each subsequent visit. Among patients who reported psychotic symptoms, approximately 79% reported them at only one visit.

The investigators categorized patients into three groups according to the number of psychotic events. The groups included participants with no psychotic events, those with one psychotic event, and those with two or more psychotic events.

After performing multivariate logistic regression and adjusting the results for age and sex, Dr. Barrett and colleagues found that greater autonomic symptoms (odds ratio [OR], 1.07 for a one-unit change in SCOPA-AUT), the presence of RBD (OR, 1.9), and EDS (OR, 2.5) at baseline were associated with increased risk of reporting psychotic symptoms on two or more occasions, compared to no or one psychotic event.

A logistic regression model adjusted for age and sex indicated that greater autonomic symptoms (OR, 1.08 for a one-unit change in SCOPA-AUT) and EDS (OR, 1.8) at baseline were associated with increased risk of psychotic symptoms on one or more occasions. A Cox regression model adjusted for EDS (hazard ratio [HR], 1.5) indicated that greater autonomic symptoms (HR, 1.03 for a one-unit change in SCOPA-AUT) and presence of RBD (HR, 1.47) were associated with increased risk of having a first psychotic event.

At the last assessment, patients with Parkinson’s disease and two or more psychotic events were more likely to have the postural instability and gait difficulty motor phenotype and lower scores on the Montreal Cognitive Assessment, Letter Number Sequencing test, and Symbol Digit Modalities Test.

The investigators had data about cholinergic nuclei densities at baseline for 228 participants with Parkinson’s disease and 101 controls. Ch4 density in Parkinson’s disease was associated with lower risk of reporting psychotic symptoms on two or more occasions (OR, 0.96 for an increase in density of one unit). Mean Ch4 densities were 1.7% greater for the control group, compared with the Parkinson’s disease group. Participants with Parkinson’s disease and two or more psychotic events had lower baseline Ch4 density, compared with healthy controls, but participants with Parkinson’s disease with no or one psychotic event did not.

In linear regression models adjusted for age and sex, autonomic symptoms were associated with baseline Ch4 density, but EDS and RBD were not. Having comorbid EDS and RBD was associated with lower Ch4 density.

Results Do Not Establish Causation

“Prior studies reported that EDS was associated with hallucinations in Parkinson’s disease, but we are not aware of other studies that found EDS to be a predictor of future psychotic symptoms,” said Dr. Barrett and colleagues.

“In univariate comparisons, participants with Parkinson’s disease with three or more psychotic events had worse visuospatial function, compared with those with two psychotic events. Considering the greater impairment in visuospatial and visuoperceptive function reported in Parkinson’s disease with visual hallucinations, this association should be evaluated in the future in the PPMI Parkinson’s disease cohort as additional follow-up visits occur.”

The current study’s finding of an association between autonomic dysfunction, RBD, and EDS and baseline Ch4 density in Parkinson’s disease is consistent with a recent analysis that found that the same symptoms were associated with a diffuse malignant subtype of Parkinson’s disease, said the authors. “Our finding that these three nonmotor symptoms are linked to future psychotic symptoms validates the prognostic value of these symptoms in predicting worse outcomes early in disease.”

Evidence does not support a causal relationship between lower Ch4 density and autonomic dysfunction, RBD, and EDS. These four characteristics may be associated with widespread subcortical pathology. “The relationship between this triad of clinical symptoms and lower Ch4 density supports the potential utility of this neuroimaging biomarker to identify a diffuse malignant subtype of Parkinson’s disease and to predict more rapid disease progression,” said Dr. Barrett and colleagues.

—Erik Greb

Suggested Reading

Barrett MJ, Blair JC, Sperling SA, et al. Baseline symptoms and basal forebrain volume predict future psychosis in early Parkinson disease. Neurology. 2018 Apr 4 [Epub ahead of print].

Bohnen NI, Teipel SJ. Cholinergic forebrain density loss in Parkinson disease: More than just cognitive changes. Neurology. 2018 Apr 4 [Epub ahead of print].

REM sleep behavior disorder (RBD), excessive daytime sleepiness (EDS), and a high burden of autonomic symptoms are associated with increased risk of future psychotic symptoms in patients with Parkinson’s disease, according to research published online ahead of print April 4 in Neurology. These symptoms also correlate with low density of the cholinergic nucleus 4 (Ch4) of the basal forebrain.

Data From the Parkinson’s Progression Markers Initiative

Parkinson’s disease psychosis indicates advanced disease and is associated with dementia and increased mortality. Research indicates that degeneration of the nucleus basalis of Meynert is characteristic of Parkinson’s disease and Parkinson’s disease dementia, but this brain region is difficult to measure with MRI because of its size. It is possible, however, to measure Ch4, which incorporates the nucleus basalis of Meynert.

Matthew J. Barrett, MD, Assistant Professor of Neurology at the University of Virginia in Charlottesville, and colleagues studied a cohort of patients with de novo Parkinson’s disease to identify baseline clinical risk factors for future psychotic symptoms and to assess the relationship between baseline Ch4 density and future psychotic symptoms. All participants were untreated at baseline and had enrolled in the Parkinson’s Progression Markers Initiative (PPMI), a prospective, longitudinal, observational study.

Ch4 Density Could Predict Psychotic Symptoms

The investigators included 423 participants in their analysis. The population’s mean age at enrollment was approximately 61.5, and about 35% of the population was female. Mean disease duration was 0.57 years. The population’s median number of clinical visits was 11, and the median last visit occurred at 54 months after baseline.

In all, 138 participants (32.6%) reported psychotic symptoms at least once, and 84 (19.9%) reported them more than once. Dr. Barrett and colleagues identified 17 patients who, having once reported psychotic symptoms, reported these symptoms at each subsequent visit. Among patients who reported psychotic symptoms, approximately 79% reported them at only one visit.

The investigators categorized patients into three groups according to the number of psychotic events. The groups included participants with no psychotic events, those with one psychotic event, and those with two or more psychotic events.

After performing multivariate logistic regression and adjusting the results for age and sex, Dr. Barrett and colleagues found that greater autonomic symptoms (odds ratio [OR], 1.07 for a one-unit change in SCOPA-AUT), the presence of RBD (OR, 1.9), and EDS (OR, 2.5) at baseline were associated with increased risk of reporting psychotic symptoms on two or more occasions, compared to no or one psychotic event.

A logistic regression model adjusted for age and sex indicated that greater autonomic symptoms (OR, 1.08 for a one-unit change in SCOPA-AUT) and EDS (OR, 1.8) at baseline were associated with increased risk of psychotic symptoms on one or more occasions. A Cox regression model adjusted for EDS (hazard ratio [HR], 1.5) indicated that greater autonomic symptoms (HR, 1.03 for a one-unit change in SCOPA-AUT) and presence of RBD (HR, 1.47) were associated with increased risk of having a first psychotic event.

At the last assessment, patients with Parkinson’s disease and two or more psychotic events were more likely to have the postural instability and gait difficulty motor phenotype and lower scores on the Montreal Cognitive Assessment, Letter Number Sequencing test, and Symbol Digit Modalities Test.

The investigators had data about cholinergic nuclei densities at baseline for 228 participants with Parkinson’s disease and 101 controls. Ch4 density in Parkinson’s disease was associated with lower risk of reporting psychotic symptoms on two or more occasions (OR, 0.96 for an increase in density of one unit). Mean Ch4 densities were 1.7% greater for the control group, compared with the Parkinson’s disease group. Participants with Parkinson’s disease and two or more psychotic events had lower baseline Ch4 density, compared with healthy controls, but participants with Parkinson’s disease with no or one psychotic event did not.

In linear regression models adjusted for age and sex, autonomic symptoms were associated with baseline Ch4 density, but EDS and RBD were not. Having comorbid EDS and RBD was associated with lower Ch4 density.

Results Do Not Establish Causation

“Prior studies reported that EDS was associated with hallucinations in Parkinson’s disease, but we are not aware of other studies that found EDS to be a predictor of future psychotic symptoms,” said Dr. Barrett and colleagues.

“In univariate comparisons, participants with Parkinson’s disease with three or more psychotic events had worse visuospatial function, compared with those with two psychotic events. Considering the greater impairment in visuospatial and visuoperceptive function reported in Parkinson’s disease with visual hallucinations, this association should be evaluated in the future in the PPMI Parkinson’s disease cohort as additional follow-up visits occur.”

The current study’s finding of an association between autonomic dysfunction, RBD, and EDS and baseline Ch4 density in Parkinson’s disease is consistent with a recent analysis that found that the same symptoms were associated with a diffuse malignant subtype of Parkinson’s disease, said the authors. “Our finding that these three nonmotor symptoms are linked to future psychotic symptoms validates the prognostic value of these symptoms in predicting worse outcomes early in disease.”

Evidence does not support a causal relationship between lower Ch4 density and autonomic dysfunction, RBD, and EDS. These four characteristics may be associated with widespread subcortical pathology. “The relationship between this triad of clinical symptoms and lower Ch4 density supports the potential utility of this neuroimaging biomarker to identify a diffuse malignant subtype of Parkinson’s disease and to predict more rapid disease progression,” said Dr. Barrett and colleagues.

—Erik Greb

Suggested Reading

Barrett MJ, Blair JC, Sperling SA, et al. Baseline symptoms and basal forebrain volume predict future psychosis in early Parkinson disease. Neurology. 2018 Apr 4 [Epub ahead of print].

Bohnen NI, Teipel SJ. Cholinergic forebrain density loss in Parkinson disease: More than just cognitive changes. Neurology. 2018 Apr 4 [Epub ahead of print].

Preemptive HLA-A*31:01 genetic screening may significantly decrease the incidence of carbamazepine-induced cutaneous adverse reactions in Japanese patients, according to a report published online ahead of print April 2 in JAMA Neurology. According to the researchers, their finding suggests that such screening may be warranted in routine clinical practice.

Carbamazepine, which is widely used to treat seizures, neuropathic pain, and other disorders, is a common cause of cutaneous adverse drug reactions worldwide. The allele HLA-A*31:01 has been associated with carbamazepine-induced cutaneous drug reactions in Japanese and European populations. The clinical utility of HLA-A*31:01 screening, however, has not been evaluated.

Genetic Screening Informed Treatment

To assess the use of HLA-A*31:01 genetic screening to identify individuals at risk of carbamazepine-induced cutaneous drug reactions, researchers from the Genotype-Based Carbamazepine Therapy Study Group conducted a cohort study in 36 hospitals in Japan from January 2012 to November 2014. The investigators enrolled 1,202 patients who were eligible to receive carbamazepine during the study period. Preemptive HLA-A*31:01 screening was performed for 1,187 study participants. Patients who did not start treatment with carbamazepine or alternative drugs were excluded. Participants were interviewed once weekly for eight weeks to monitor the development of cutaneous adverse drug reactions.

Neuropsychiatrists were asked to prescribe carbamazepine for patients who tested negative for HLA-A*31:01 and alternative drugs for those who tested positive for the allele. The study’s main outcome was the incidence of carbamazepine-induced cutaneous adverse drug reactions.

Of the 1,130 patients who were prescribed carbamazepine or alternative drugs, the mean age was 37.4; 614 (54.3%) were men, and 198 (17.5%) were positive for HLA-A*31:01. Dermatologists identified 23 patients (2.0%) who had carbamazepine-induced cutaneous adverse drug reactions, of whom four patients required hospitalization. Drug-induced hypersensitivity syndrome was observed for three patients, maculopapular eruption for nine patients, erythema multiforme for five patients, and an undetermined type of cutaneous adverse drug reaction for six patients. No patient developed Stevens-Johnson syndrome or toxic epidermal necrolysis.

Comparison with a historical control indicated that the preemptive use of HLA-A*31:01 screening was associated with a 40% reduction in the incidence of carbamazepine-induced cutaneous adverse drug reactions.

Two Alleles

The researchers noted that the clinical utility of the HLA-B*15:02 genetic test for reducing carbamazepine-induced cutaneous drug reactions has already been established by preemptive screening. However, the frequency of the HLA-B*15:02 allele is low in Korean, Japanese, African, and European populations.

In contrast, the frequency of the HLA-A*31:01 allele is 7% to 9% in Japanese, 5% in Korean, 2% in Chinese, 2% to 3% in European, and 1% in African populations. Moreover, HLA-A*31:01 has been associated with a full spectrum of carbamazepine-induced cutaneous adverse drug reactions. Therefore, “HLA-A*31:01 genetic screening prior to prescribing carbamazepine would be useful for preventing many types of carbamazepine-induced cutaneous adverse drug reactions in a range of patient populations,” the researchers concluded.

A First Step in Precision Neurology?

The present study “provides initial data that preemptive strategies may allow for a more consistent approach to safely administer this commonly used medication,” said Yijing He, MD, PhD; Lucia Seminario-Vidal, MD, PhD; and Howard L. McLeod, PharmD, in an accompanying editorial. A substantial decrease in the incidence and severity of carbamazepine-associated cutaneous adverse drug reactions was documented. While the study did not have the statistical power to definitively demonstrate complete avoidance of the high-morbidity and -mortality forms of severe cutaneous adverse drug reactions (ie, Stevens-Johnson syndrome and toxic epidermal necrolysis), it had statistical power to detect an important reduction in mild or moderately severe forms of cutaneous adverse drug reactions.

“However, 23 patients experienced a carbamazepine-associated cutaneous adverse drug reaction,” and four patients required hospitalization, the editorialists noted. “Therefore, the use of HLA-A*31:01 testing will not eliminate the risk of carbamazepine-associated events, nor will it decrease the need for neurologists to provide skin-focused monitoring as part of their management of cases involving carbamazepine-treated patients.”

This research, the editorialists said, indicates that there is still more to discover. “To date, a small number of heroes has relentlessly pursued mechanistic and preventive research on drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis. However, the field needs to build on these efforts with a more systematic approach that will aid more rapid progress and provide more consistent influence across the globe.” Much still needs to be learned about the basic mechanisms, clinical confounders, biomarkers, and epidemiologic aspects of the various drug reactions that become Stevens-Johnson syndrome and toxic epidermal necrolysis. Attributing this clinical, immunologic, and therapeutic problem to various idiosyncratic reactions does not serve patients well, said the editorialists.

A key first step, the editorialists said, is to “apply existing preemptive strategies, including genomic analysis. Whether this is initially implemented broadly or in regions with higher probability of the risk alleles is less important than learning how to change a culture that tolerates adverse drug events and inventing informatics tools to make proactive approaches less of a burden. Although we will not get it completely right the first time, we need to start the iterative process to eradicate severe cutaneous adverse drug reactions.”

—Glenn S. Williams

Suggested Reading

Mushiroda T, Takahashi Y, Onuma T, et al. Association of HLA-A*31:01 screening with the incidence of carbamazepine-induced cutaneous adverse reactions in a Japanese population. JAMA Neurol. 2018 Apr 2 [Epub ahead of print].

He Y, Seminario-Vidal S, McLeod HL. Avoidance of severe cutaneous adverse drug events as a first step in precision neurology. JAMA Neurol. Apr 2 [Epub ahead of print].

Preemptive HLA-A*31:01 genetic screening may significantly decrease the incidence of carbamazepine-induced cutaneous adverse reactions in Japanese patients, according to a report published online ahead of print April 2 in JAMA Neurology. According to the researchers, their finding suggests that such screening may be warranted in routine clinical practice.

Carbamazepine, which is widely used to treat seizures, neuropathic pain, and other disorders, is a common cause of cutaneous adverse drug reactions worldwide. The allele HLA-A*31:01 has been associated with carbamazepine-induced cutaneous drug reactions in Japanese and European populations. The clinical utility of HLA-A*31:01 screening, however, has not been evaluated.

Genetic Screening Informed Treatment

To assess the use of HLA-A*31:01 genetic screening to identify individuals at risk of carbamazepine-induced cutaneous drug reactions, researchers from the Genotype-Based Carbamazepine Therapy Study Group conducted a cohort study in 36 hospitals in Japan from January 2012 to November 2014. The investigators enrolled 1,202 patients who were eligible to receive carbamazepine during the study period. Preemptive HLA-A*31:01 screening was performed for 1,187 study participants. Patients who did not start treatment with carbamazepine or alternative drugs were excluded. Participants were interviewed once weekly for eight weeks to monitor the development of cutaneous adverse drug reactions.

Neuropsychiatrists were asked to prescribe carbamazepine for patients who tested negative for HLA-A*31:01 and alternative drugs for those who tested positive for the allele. The study’s main outcome was the incidence of carbamazepine-induced cutaneous adverse drug reactions.

Of the 1,130 patients who were prescribed carbamazepine or alternative drugs, the mean age was 37.4; 614 (54.3%) were men, and 198 (17.5%) were positive for HLA-A*31:01. Dermatologists identified 23 patients (2.0%) who had carbamazepine-induced cutaneous adverse drug reactions, of whom four patients required hospitalization. Drug-induced hypersensitivity syndrome was observed for three patients, maculopapular eruption for nine patients, erythema multiforme for five patients, and an undetermined type of cutaneous adverse drug reaction for six patients. No patient developed Stevens-Johnson syndrome or toxic epidermal necrolysis.

Comparison with a historical control indicated that the preemptive use of HLA-A*31:01 screening was associated with a 40% reduction in the incidence of carbamazepine-induced cutaneous adverse drug reactions.

Two Alleles

The researchers noted that the clinical utility of the HLA-B*15:02 genetic test for reducing carbamazepine-induced cutaneous drug reactions has already been established by preemptive screening. However, the frequency of the HLA-B*15:02 allele is low in Korean, Japanese, African, and European populations.

In contrast, the frequency of the HLA-A*31:01 allele is 7% to 9% in Japanese, 5% in Korean, 2% in Chinese, 2% to 3% in European, and 1% in African populations. Moreover, HLA-A*31:01 has been associated with a full spectrum of carbamazepine-induced cutaneous adverse drug reactions. Therefore, “HLA-A*31:01 genetic screening prior to prescribing carbamazepine would be useful for preventing many types of carbamazepine-induced cutaneous adverse drug reactions in a range of patient populations,” the researchers concluded.

A First Step in Precision Neurology?

The present study “provides initial data that preemptive strategies may allow for a more consistent approach to safely administer this commonly used medication,” said Yijing He, MD, PhD; Lucia Seminario-Vidal, MD, PhD; and Howard L. McLeod, PharmD, in an accompanying editorial. A substantial decrease in the incidence and severity of carbamazepine-associated cutaneous adverse drug reactions was documented. While the study did not have the statistical power to definitively demonstrate complete avoidance of the high-morbidity and -mortality forms of severe cutaneous adverse drug reactions (ie, Stevens-Johnson syndrome and toxic epidermal necrolysis), it had statistical power to detect an important reduction in mild or moderately severe forms of cutaneous adverse drug reactions.

“However, 23 patients experienced a carbamazepine-associated cutaneous adverse drug reaction,” and four patients required hospitalization, the editorialists noted. “Therefore, the use of HLA-A*31:01 testing will not eliminate the risk of carbamazepine-associated events, nor will it decrease the need for neurologists to provide skin-focused monitoring as part of their management of cases involving carbamazepine-treated patients.”

This research, the editorialists said, indicates that there is still more to discover. “To date, a small number of heroes has relentlessly pursued mechanistic and preventive research on drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis. However, the field needs to build on these efforts with a more systematic approach that will aid more rapid progress and provide more consistent influence across the globe.” Much still needs to be learned about the basic mechanisms, clinical confounders, biomarkers, and epidemiologic aspects of the various drug reactions that become Stevens-Johnson syndrome and toxic epidermal necrolysis. Attributing this clinical, immunologic, and therapeutic problem to various idiosyncratic reactions does not serve patients well, said the editorialists.

A key first step, the editorialists said, is to “apply existing preemptive strategies, including genomic analysis. Whether this is initially implemented broadly or in regions with higher probability of the risk alleles is less important than learning how to change a culture that tolerates adverse drug events and inventing informatics tools to make proactive approaches less of a burden. Although we will not get it completely right the first time, we need to start the iterative process to eradicate severe cutaneous adverse drug reactions.”

—Glenn S. Williams

Suggested Reading

Mushiroda T, Takahashi Y, Onuma T, et al. Association of HLA-A*31:01 screening with the incidence of carbamazepine-induced cutaneous adverse reactions in a Japanese population. JAMA Neurol. 2018 Apr 2 [Epub ahead of print].

He Y, Seminario-Vidal S, McLeod HL. Avoidance of severe cutaneous adverse drug events as a first step in precision neurology. JAMA Neurol. Apr 2 [Epub ahead of print].

Preemptive HLA-A*31:01 genetic screening may significantly decrease the incidence of carbamazepine-induced cutaneous adverse reactions in Japanese patients, according to a report published online ahead of print April 2 in JAMA Neurology. According to the researchers, their finding suggests that such screening may be warranted in routine clinical practice.

Carbamazepine, which is widely used to treat seizures, neuropathic pain, and other disorders, is a common cause of cutaneous adverse drug reactions worldwide. The allele HLA-A*31:01 has been associated with carbamazepine-induced cutaneous drug reactions in Japanese and European populations. The clinical utility of HLA-A*31:01 screening, however, has not been evaluated.

Genetic Screening Informed Treatment

To assess the use of HLA-A*31:01 genetic screening to identify individuals at risk of carbamazepine-induced cutaneous drug reactions, researchers from the Genotype-Based Carbamazepine Therapy Study Group conducted a cohort study in 36 hospitals in Japan from January 2012 to November 2014. The investigators enrolled 1,202 patients who were eligible to receive carbamazepine during the study period. Preemptive HLA-A*31:01 screening was performed for 1,187 study participants. Patients who did not start treatment with carbamazepine or alternative drugs were excluded. Participants were interviewed once weekly for eight weeks to monitor the development of cutaneous adverse drug reactions.

Neuropsychiatrists were asked to prescribe carbamazepine for patients who tested negative for HLA-A*31:01 and alternative drugs for those who tested positive for the allele. The study’s main outcome was the incidence of carbamazepine-induced cutaneous adverse drug reactions.

Of the 1,130 patients who were prescribed carbamazepine or alternative drugs, the mean age was 37.4; 614 (54.3%) were men, and 198 (17.5%) were positive for HLA-A*31:01. Dermatologists identified 23 patients (2.0%) who had carbamazepine-induced cutaneous adverse drug reactions, of whom four patients required hospitalization. Drug-induced hypersensitivity syndrome was observed for three patients, maculopapular eruption for nine patients, erythema multiforme for five patients, and an undetermined type of cutaneous adverse drug reaction for six patients. No patient developed Stevens-Johnson syndrome or toxic epidermal necrolysis.

Comparison with a historical control indicated that the preemptive use of HLA-A*31:01 screening was associated with a 40% reduction in the incidence of carbamazepine-induced cutaneous adverse drug reactions.

Two Alleles

The researchers noted that the clinical utility of the HLA-B*15:02 genetic test for reducing carbamazepine-induced cutaneous drug reactions has already been established by preemptive screening. However, the frequency of the HLA-B*15:02 allele is low in Korean, Japanese, African, and European populations.

In contrast, the frequency of the HLA-A*31:01 allele is 7% to 9% in Japanese, 5% in Korean, 2% in Chinese, 2% to 3% in European, and 1% in African populations. Moreover, HLA-A*31:01 has been associated with a full spectrum of carbamazepine-induced cutaneous adverse drug reactions. Therefore, “HLA-A*31:01 genetic screening prior to prescribing carbamazepine would be useful for preventing many types of carbamazepine-induced cutaneous adverse drug reactions in a range of patient populations,” the researchers concluded.

A First Step in Precision Neurology?

The present study “provides initial data that preemptive strategies may allow for a more consistent approach to safely administer this commonly used medication,” said Yijing He, MD, PhD; Lucia Seminario-Vidal, MD, PhD; and Howard L. McLeod, PharmD, in an accompanying editorial. A substantial decrease in the incidence and severity of carbamazepine-associated cutaneous adverse drug reactions was documented. While the study did not have the statistical power to definitively demonstrate complete avoidance of the high-morbidity and -mortality forms of severe cutaneous adverse drug reactions (ie, Stevens-Johnson syndrome and toxic epidermal necrolysis), it had statistical power to detect an important reduction in mild or moderately severe forms of cutaneous adverse drug reactions.

“However, 23 patients experienced a carbamazepine-associated cutaneous adverse drug reaction,” and four patients required hospitalization, the editorialists noted. “Therefore, the use of HLA-A*31:01 testing will not eliminate the risk of carbamazepine-associated events, nor will it decrease the need for neurologists to provide skin-focused monitoring as part of their management of cases involving carbamazepine-treated patients.”

This research, the editorialists said, indicates that there is still more to discover. “To date, a small number of heroes has relentlessly pursued mechanistic and preventive research on drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis. However, the field needs to build on these efforts with a more systematic approach that will aid more rapid progress and provide more consistent influence across the globe.” Much still needs to be learned about the basic mechanisms, clinical confounders, biomarkers, and epidemiologic aspects of the various drug reactions that become Stevens-Johnson syndrome and toxic epidermal necrolysis. Attributing this clinical, immunologic, and therapeutic problem to various idiosyncratic reactions does not serve patients well, said the editorialists.

A key first step, the editorialists said, is to “apply existing preemptive strategies, including genomic analysis. Whether this is initially implemented broadly or in regions with higher probability of the risk alleles is less important than learning how to change a culture that tolerates adverse drug events and inventing informatics tools to make proactive approaches less of a burden. Although we will not get it completely right the first time, we need to start the iterative process to eradicate severe cutaneous adverse drug reactions.”

—Glenn S. Williams

Suggested Reading

Mushiroda T, Takahashi Y, Onuma T, et al. Association of HLA-A*31:01 screening with the incidence of carbamazepine-induced cutaneous adverse reactions in a Japanese population. JAMA Neurol. 2018 Apr 2 [Epub ahead of print].

He Y, Seminario-Vidal S, McLeod HL. Avoidance of severe cutaneous adverse drug events as a first step in precision neurology. JAMA Neurol. Apr 2 [Epub ahead of print].

Among military veterans with chronic posttraumatic stress disorder (PTSD) and frequent nightmares, prazosin does not alleviate distressing dreams or improve sleep quality, according to trial results published in the February 8 issue of the New England Journal of Medicine.

Prior single-center trials found that prazosin, an alpha 1-adrenoreceptor antagonist, may alleviate nightmares associated with PTSD and improve overall clinical status. The present study’s eligibility criteria may have led to selection bias that contributed to its negative results, the researchers said.

The PACT Trial

To investigate the efficacy of prazosin in patients with chronic combat-related PTSD and frequent nightmares, Murray A. Raskind, MD, and colleagues conducted the Prazosin and Combat Trauma PTSD (PACT) trial. Dr. Raskind is the Director of the Veterans Affairs (VA) Northwest Network Mental Illness Research, Education, and Clinical Center and Professor and Vice Chair of Psychiatry and Behavioral Sciences at the University of Washington School of Medicine in Seattle.

The 26-week, double-blind, randomized, controlled trial included 304 veterans from 12 VA medical centers. Participants met DSM-IV criteria for PTSD; had a total score of at least 50 on the 17-item Clinician-Administered PTSD Scale (CAPS); had been exposed to one or more traumatic, life-threatening events in a war zone before the onset of recurrent nightmares; could recall combat-related nightmares; had a frequency score of at least 2 and a cumulative score of at least 5 on CAPS item B2 (ie, “recurrent distressing dreams”); and, for at least four weeks before randomization, were receiving a stable dose of nonexcluded medications or supportive psychotherapy. Exclusion criteria included unstable medical illness, a systolic blood pressure of less than 110 mm Hg in the supine position, active suicidal or homicidal ideation with plan or intent, and psychosocial instability.

Of 413 people screened, 304 underwent randomization (about 98% male; average age, 52); 152 patients were assigned to each treatment group. The two groups’ patient characteristics did not differ significantly at baseline. Researchers administered prazosin or placebo in escalating divided doses over five weeks to a daily maximum of 20 mg in men and 12 mg in women.

Primary Outcome Measures

The three primary outcome measures were change in score from baseline to 10 weeks on the CAPS item B2, change in score from baseline to 10 weeks on the Pittsburgh Sleep Quality Index, and the Clinical Global Impression of Change score at 10 weeks. None of the primary outcome measures significantly differed between the groups at 10 weeks. The groups’ outcome measures at 26 weeks and other secondary outcomes also were not significantly different.

The number of serious adverse events did not differ significantly by group. Of the adverse events, dizziness, lightheadedness, and urinary incontinence were significantly more common in the prazosin group, compared with the placebo group, whereas new or worsening suicidal ideation was significantly less common among participants who received prazosin, compared with patients who received placebo (8% vs 15%, respectively).

The investigators enrolled patients who were mainly in clinically stable condition, which may have led the trial to include patients whose distressing dreams were unlikely to respond to prazosin, Dr. Raskind and colleagues said.

Future Directions

“The failure of this new, large, multisite trial to replicate the previous studies is surprising and disappointing,” said Kerry J. Ressler, MD, PhD, Chief of the Division of Depression and Anxiety Disorders at McLean Hospital in Belmont, Massachusetts, and Professor of Psychiatry at Harvard Medical School in Boston, in an accompanying editorial. “PTSD remains a psychiatric malady that in some respects seems understandable and treatable on the basis of known neurobiologic pathways. Yet it is a complex syndrome with innumerable subtypes and variations…. There is a need to define clinical subtypes of PTSD on the basis of biologic markers.”

Studies of prazosin for the treatment of other conditions are under way. Investigators have initiated trials to examine whether prazosin reduces the frequency of chronic postconcussive headaches, compared with placebo.

—Jake Remaly

Suggested Reading

Raskind MA, Peskind ER, Chow B, et al. Trial of prazosin for post-traumatic stress disorder in military veterans. N Engl J Med. 2018;378(6):507-517.

Raskind MA, Peterson K, Williams T, et al. A trial of prazosin for combat trauma PTSD with nightmares in active-duty soldiers returned from Iraq and Afghanistan. Am J Psychiatry. 2013;170(9):1003-1010.

Ressler KJ. Alpha-adrenergic receptors in PTSD - Failure or time for precision medicine? N Engl J Med. 2018; 378(6):575-576.

Among military veterans with chronic posttraumatic stress disorder (PTSD) and frequent nightmares, prazosin does not alleviate distressing dreams or improve sleep quality, according to trial results published in the February 8 issue of the New England Journal of Medicine.

Prior single-center trials found that prazosin, an alpha 1-adrenoreceptor antagonist, may alleviate nightmares associated with PTSD and improve overall clinical status. The present study’s eligibility criteria may have led to selection bias that contributed to its negative results, the researchers said.

The PACT Trial

To investigate the efficacy of prazosin in patients with chronic combat-related PTSD and frequent nightmares, Murray A. Raskind, MD, and colleagues conducted the Prazosin and Combat Trauma PTSD (PACT) trial. Dr. Raskind is the Director of the Veterans Affairs (VA) Northwest Network Mental Illness Research, Education, and Clinical Center and Professor and Vice Chair of Psychiatry and Behavioral Sciences at the University of Washington School of Medicine in Seattle.

The 26-week, double-blind, randomized, controlled trial included 304 veterans from 12 VA medical centers. Participants met DSM-IV criteria for PTSD; had a total score of at least 50 on the 17-item Clinician-Administered PTSD Scale (CAPS); had been exposed to one or more traumatic, life-threatening events in a war zone before the onset of recurrent nightmares; could recall combat-related nightmares; had a frequency score of at least 2 and a cumulative score of at least 5 on CAPS item B2 (ie, “recurrent distressing dreams”); and, for at least four weeks before randomization, were receiving a stable dose of nonexcluded medications or supportive psychotherapy. Exclusion criteria included unstable medical illness, a systolic blood pressure of less than 110 mm Hg in the supine position, active suicidal or homicidal ideation with plan or intent, and psychosocial instability.

Of 413 people screened, 304 underwent randomization (about 98% male; average age, 52); 152 patients were assigned to each treatment group. The two groups’ patient characteristics did not differ significantly at baseline. Researchers administered prazosin or placebo in escalating divided doses over five weeks to a daily maximum of 20 mg in men and 12 mg in women.

Primary Outcome Measures

The three primary outcome measures were change in score from baseline to 10 weeks on the CAPS item B2, change in score from baseline to 10 weeks on the Pittsburgh Sleep Quality Index, and the Clinical Global Impression of Change score at 10 weeks. None of the primary outcome measures significantly differed between the groups at 10 weeks. The groups’ outcome measures at 26 weeks and other secondary outcomes also were not significantly different.

The number of serious adverse events did not differ significantly by group. Of the adverse events, dizziness, lightheadedness, and urinary incontinence were significantly more common in the prazosin group, compared with the placebo group, whereas new or worsening suicidal ideation was significantly less common among participants who received prazosin, compared with patients who received placebo (8% vs 15%, respectively).

The investigators enrolled patients who were mainly in clinically stable condition, which may have led the trial to include patients whose distressing dreams were unlikely to respond to prazosin, Dr. Raskind and colleagues said.

Future Directions

“The failure of this new, large, multisite trial to replicate the previous studies is surprising and disappointing,” said Kerry J. Ressler, MD, PhD, Chief of the Division of Depression and Anxiety Disorders at McLean Hospital in Belmont, Massachusetts, and Professor of Psychiatry at Harvard Medical School in Boston, in an accompanying editorial. “PTSD remains a psychiatric malady that in some respects seems understandable and treatable on the basis of known neurobiologic pathways. Yet it is a complex syndrome with innumerable subtypes and variations…. There is a need to define clinical subtypes of PTSD on the basis of biologic markers.”

Studies of prazosin for the treatment of other conditions are under way. Investigators have initiated trials to examine whether prazosin reduces the frequency of chronic postconcussive headaches, compared with placebo.

—Jake Remaly

Suggested Reading

Raskind MA, Peskind ER, Chow B, et al. Trial of prazosin for post-traumatic stress disorder in military veterans. N Engl J Med. 2018;378(6):507-517.

Raskind MA, Peterson K, Williams T, et al. A trial of prazosin for combat trauma PTSD with nightmares in active-duty soldiers returned from Iraq and Afghanistan. Am J Psychiatry. 2013;170(9):1003-1010.

Ressler KJ. Alpha-adrenergic receptors in PTSD - Failure or time for precision medicine? N Engl J Med. 2018; 378(6):575-576.

Among military veterans with chronic posttraumatic stress disorder (PTSD) and frequent nightmares, prazosin does not alleviate distressing dreams or improve sleep quality, according to trial results published in the February 8 issue of the New England Journal of Medicine.

Prior single-center trials found that prazosin, an alpha 1-adrenoreceptor antagonist, may alleviate nightmares associated with PTSD and improve overall clinical status. The present study’s eligibility criteria may have led to selection bias that contributed to its negative results, the researchers said.

The PACT Trial

To investigate the efficacy of prazosin in patients with chronic combat-related PTSD and frequent nightmares, Murray A. Raskind, MD, and colleagues conducted the Prazosin and Combat Trauma PTSD (PACT) trial. Dr. Raskind is the Director of the Veterans Affairs (VA) Northwest Network Mental Illness Research, Education, and Clinical Center and Professor and Vice Chair of Psychiatry and Behavioral Sciences at the University of Washington School of Medicine in Seattle.

The 26-week, double-blind, randomized, controlled trial included 304 veterans from 12 VA medical centers. Participants met DSM-IV criteria for PTSD; had a total score of at least 50 on the 17-item Clinician-Administered PTSD Scale (CAPS); had been exposed to one or more traumatic, life-threatening events in a war zone before the onset of recurrent nightmares; could recall combat-related nightmares; had a frequency score of at least 2 and a cumulative score of at least 5 on CAPS item B2 (ie, “recurrent distressing dreams”); and, for at least four weeks before randomization, were receiving a stable dose of nonexcluded medications or supportive psychotherapy. Exclusion criteria included unstable medical illness, a systolic blood pressure of less than 110 mm Hg in the supine position, active suicidal or homicidal ideation with plan or intent, and psychosocial instability.

Of 413 people screened, 304 underwent randomization (about 98% male; average age, 52); 152 patients were assigned to each treatment group. The two groups’ patient characteristics did not differ significantly at baseline. Researchers administered prazosin or placebo in escalating divided doses over five weeks to a daily maximum of 20 mg in men and 12 mg in women.

Primary Outcome Measures

The three primary outcome measures were change in score from baseline to 10 weeks on the CAPS item B2, change in score from baseline to 10 weeks on the Pittsburgh Sleep Quality Index, and the Clinical Global Impression of Change score at 10 weeks. None of the primary outcome measures significantly differed between the groups at 10 weeks. The groups’ outcome measures at 26 weeks and other secondary outcomes also were not significantly different.

The number of serious adverse events did not differ significantly by group. Of the adverse events, dizziness, lightheadedness, and urinary incontinence were significantly more common in the prazosin group, compared with the placebo group, whereas new or worsening suicidal ideation was significantly less common among participants who received prazosin, compared with patients who received placebo (8% vs 15%, respectively).

The investigators enrolled patients who were mainly in clinically stable condition, which may have led the trial to include patients whose distressing dreams were unlikely to respond to prazosin, Dr. Raskind and colleagues said.

Future Directions

“The failure of this new, large, multisite trial to replicate the previous studies is surprising and disappointing,” said Kerry J. Ressler, MD, PhD, Chief of the Division of Depression and Anxiety Disorders at McLean Hospital in Belmont, Massachusetts, and Professor of Psychiatry at Harvard Medical School in Boston, in an accompanying editorial. “PTSD remains a psychiatric malady that in some respects seems understandable and treatable on the basis of known neurobiologic pathways. Yet it is a complex syndrome with innumerable subtypes and variations…. There is a need to define clinical subtypes of PTSD on the basis of biologic markers.”

Studies of prazosin for the treatment of other conditions are under way. Investigators have initiated trials to examine whether prazosin reduces the frequency of chronic postconcussive headaches, compared with placebo.

—Jake Remaly

Suggested Reading

Raskind MA, Peskind ER, Chow B, et al. Trial of prazosin for post-traumatic stress disorder in military veterans. N Engl J Med. 2018;378(6):507-517.

Raskind MA, Peterson K, Williams T, et al. A trial of prazosin for combat trauma PTSD with nightmares in active-duty soldiers returned from Iraq and Afghanistan. Am J Psychiatry. 2013;170(9):1003-1010.

Ressler KJ. Alpha-adrenergic receptors in PTSD - Failure or time for precision medicine? N Engl J Med. 2018; 378(6):575-576.

A reasonable number of patients with treatment-resistant epilepsy may experience a decrease in the frequency of seizures when treated with pharmaceutical-grade cannabidiol, according to systematic review published online ahead of print March 6 in Journal of Neurology, Neurosurgery and Psychiatry.

The review focused on 36 studies of cannabinoids as adjunctive treatment for treatment-resistant epilepsy. It included six randomized controlled trials that involved 555 patients and 30 observational studies that involved 2,865 patients.

Two randomized controlled trials of cannabidiol (CBD)—one with 120 patients with Dravet syndrome and another with 171 patients with Lennox-Gastaut syndrome—found that cannabidiol (CBD) treatment was 74% more likely than placebo to reduce seizure frequency by more than 50%. In the observational studies of CBD, nearly half (48.5%) of the 970 patients across a range of epilepsy subtypes achieved a 50% or greater reduction in seizures.

Emily Stockings, PhD, a National Health and Medical Research Council Early Career Research Fellow at the National Drug and Alcohol Research Centre at the University of New South Wales in Sydney, and colleagues estimated that eight patients would need to receive CBD treatment for one patient to have a 50% reduction in seizures.

—Bianca Nogrady

Suggested Reading

Stockings E, Zagic D, Campbell G, et al. Evidence of cannabis and cannabinoids for epilepsy: a systematic review of controlled and observational evidence. J Neurol Neurosurg Psychiatry. 2018 Mar 6 [Epub ahead of print].

A reasonable number of patients with treatment-resistant epilepsy may experience a decrease in the frequency of seizures when treated with pharmaceutical-grade cannabidiol, according to systematic review published online ahead of print March 6 in Journal of Neurology, Neurosurgery and Psychiatry.

The review focused on 36 studies of cannabinoids as adjunctive treatment for treatment-resistant epilepsy. It included six randomized controlled trials that involved 555 patients and 30 observational studies that involved 2,865 patients.

Two randomized controlled trials of cannabidiol (CBD)—one with 120 patients with Dravet syndrome and another with 171 patients with Lennox-Gastaut syndrome—found that cannabidiol (CBD) treatment was 74% more likely than placebo to reduce seizure frequency by more than 50%. In the observational studies of CBD, nearly half (48.5%) of the 970 patients across a range of epilepsy subtypes achieved a 50% or greater reduction in seizures.

Emily Stockings, PhD, a National Health and Medical Research Council Early Career Research Fellow at the National Drug and Alcohol Research Centre at the University of New South Wales in Sydney, and colleagues estimated that eight patients would need to receive CBD treatment for one patient to have a 50% reduction in seizures.

—Bianca Nogrady

Suggested Reading

Stockings E, Zagic D, Campbell G, et al. Evidence of cannabis and cannabinoids for epilepsy: a systematic review of controlled and observational evidence. J Neurol Neurosurg Psychiatry. 2018 Mar 6 [Epub ahead of print].

A reasonable number of patients with treatment-resistant epilepsy may experience a decrease in the frequency of seizures when treated with pharmaceutical-grade cannabidiol, according to systematic review published online ahead of print March 6 in Journal of Neurology, Neurosurgery and Psychiatry.

The review focused on 36 studies of cannabinoids as adjunctive treatment for treatment-resistant epilepsy. It included six randomized controlled trials that involved 555 patients and 30 observational studies that involved 2,865 patients.

Two randomized controlled trials of cannabidiol (CBD)—one with 120 patients with Dravet syndrome and another with 171 patients with Lennox-Gastaut syndrome—found that cannabidiol (CBD) treatment was 74% more likely than placebo to reduce seizure frequency by more than 50%. In the observational studies of CBD, nearly half (48.5%) of the 970 patients across a range of epilepsy subtypes achieved a 50% or greater reduction in seizures.

Emily Stockings, PhD, a National Health and Medical Research Council Early Career Research Fellow at the National Drug and Alcohol Research Centre at the University of New South Wales in Sydney, and colleagues estimated that eight patients would need to receive CBD treatment for one patient to have a 50% reduction in seizures.

—Bianca Nogrady

Suggested Reading

Stockings E, Zagic D, Campbell G, et al. Evidence of cannabis and cannabinoids for epilepsy: a systematic review of controlled and observational evidence. J Neurol Neurosurg Psychiatry. 2018 Mar 6 [Epub ahead of print].

Adults with a patent foramen ovale (PFO) who undergo noncardiac surgery appear to have a significantly increased risk of perioperative ischemic stroke within 30 days after the procedure, according to research published February 6 in JAMA. Further research is needed to determine whether interventions would decrease this risk, the authors noted.

“An important finding from this study was that the PFO-attributable risk of perioperative stroke was highest among patients with an otherwise low probability of perioperative ischemic stroke, based on coexisting cardiovascular risk factors and intraoperative characteristics,” said Matthias Eikermann, MD, PhD, Professor of Anesthesia at Beth Israel Deaconess Medical Center in Boston, and colleagues.

—Erica Tricarico

Suggested Reading

Ng PY, Ng AK, Subramaniam B, et al. Association of preoperatively diagnosed patent foramen ovale with perioperative ischemic stroke. JAMA. 2018;319(5):452-462.

Adults with a patent foramen ovale (PFO) who undergo noncardiac surgery appear to have a significantly increased risk of perioperative ischemic stroke within 30 days after the procedure, according to research published February 6 in JAMA. Further research is needed to determine whether interventions would decrease this risk, the authors noted.

“An important finding from this study was that the PFO-attributable risk of perioperative stroke was highest among patients with an otherwise low probability of perioperative ischemic stroke, based on coexisting cardiovascular risk factors and intraoperative characteristics,” said Matthias Eikermann, MD, PhD, Professor of Anesthesia at Beth Israel Deaconess Medical Center in Boston, and colleagues.

—Erica Tricarico

Suggested Reading

Ng PY, Ng AK, Subramaniam B, et al. Association of preoperatively diagnosed patent foramen ovale with perioperative ischemic stroke. JAMA. 2018;319(5):452-462.

Adults with a patent foramen ovale (PFO) who undergo noncardiac surgery appear to have a significantly increased risk of perioperative ischemic stroke within 30 days after the procedure, according to research published February 6 in JAMA. Further research is needed to determine whether interventions would decrease this risk, the authors noted.

“An important finding from this study was that the PFO-attributable risk of perioperative stroke was highest among patients with an otherwise low probability of perioperative ischemic stroke, based on coexisting cardiovascular risk factors and intraoperative characteristics,” said Matthias Eikermann, MD, PhD, Professor of Anesthesia at Beth Israel Deaconess Medical Center in Boston, and colleagues.

—Erica Tricarico

Suggested Reading

Ng PY, Ng AK, Subramaniam B, et al. Association of preoperatively diagnosed patent foramen ovale with perioperative ischemic stroke. JAMA. 2018;319(5):452-462.