Literature Review

Headache in idiopathic intracranial hypertension (IIH) appears to be clinically independent of raised intracranial pressure and may require a different treatment approach than lowering intracranial pressure, according to a study published online ahead of print July 28 in Headache.

“Our findings provide the first class I evidence that CSF pressure and headaches are clinically independent features of IIH,” said Deborah I. Friedman, MD, Professor of Neurology, Neurotherapeutics, and Ophthalmology at the University of Texas Southwestern Medical School in Dallas.

The researchers examined data from 165 patients with untreated IIH and mild vision loss. The participants had been randomized to weight loss plus acetazolamide or placebo as a part of the IIH Treatment Trial.

In the 139 patients with headaches at baseline, the researchers saw no significant correlation between lumbar puncture opening pressure, which was measured at baseline and six months, and Headache Impact Test-6 (HIT-6) scores, or with the presence or absence of headache.

The researchers found no significant difference in headache outcomes between the acetazolamide and placebo groups at six months. Headaches in both groups improved overall during the course of the study, however.

At baseline, participants with headache reported taking various symptomatic headache treatments, including acetaminophen, ibuprofen, naproxen, and combination medications. Some also reported taking hydrocodone, tramadol, or combination formulations containing codeine.

Approximately 37% of the participants overused symptomatic pain medication. Fifteen of these patients met the criteria for overuse of opioids or combination medications. The mean HIT-6 scores were significantly higher in those who were overusing medications, compared with those who were not.

The most common headache phenotype was migraine (52%), followed by tension-type headache (22%), probable migraine (16%), and probable tension-type headache (4%), with 7% unclassified. Patients with headache also experienced associated symptoms such as photophobia, phonophobia, nausea, vomiting, visual loss or obscurations, diplopia, and dizziness.

—Bianca Nogrady

Suggested Reading

Friedman DI, Quiros PA, Subramanian PS, et al. Headache in idiopathic intracranial hypertension: Findings from the Idiopathic Intracranial Hypertension Treatment Trial. Headache. 2017 July 28 [Epub ahead of print].

Yri HM, Rönnbäck C, Wegener M, et al. The course of headache in idiopathic intracranial hypertension: a 12-month prospective follow-up study. Eur J Neurol. 2014;21(12):1458-1464.

Headache in idiopathic intracranial hypertension (IIH) appears to be clinically independent of raised intracranial pressure and may require a different treatment approach than lowering intracranial pressure, according to a study published online ahead of print July 28 in Headache.

“Our findings provide the first class I evidence that CSF pressure and headaches are clinically independent features of IIH,” said Deborah I. Friedman, MD, Professor of Neurology, Neurotherapeutics, and Ophthalmology at the University of Texas Southwestern Medical School in Dallas.

The researchers examined data from 165 patients with untreated IIH and mild vision loss. The participants had been randomized to weight loss plus acetazolamide or placebo as a part of the IIH Treatment Trial.

In the 139 patients with headaches at baseline, the researchers saw no significant correlation between lumbar puncture opening pressure, which was measured at baseline and six months, and Headache Impact Test-6 (HIT-6) scores, or with the presence or absence of headache.

The researchers found no significant difference in headache outcomes between the acetazolamide and placebo groups at six months. Headaches in both groups improved overall during the course of the study, however.

At baseline, participants with headache reported taking various symptomatic headache treatments, including acetaminophen, ibuprofen, naproxen, and combination medications. Some also reported taking hydrocodone, tramadol, or combination formulations containing codeine.

Approximately 37% of the participants overused symptomatic pain medication. Fifteen of these patients met the criteria for overuse of opioids or combination medications. The mean HIT-6 scores were significantly higher in those who were overusing medications, compared with those who were not.

The most common headache phenotype was migraine (52%), followed by tension-type headache (22%), probable migraine (16%), and probable tension-type headache (4%), with 7% unclassified. Patients with headache also experienced associated symptoms such as photophobia, phonophobia, nausea, vomiting, visual loss or obscurations, diplopia, and dizziness.

—Bianca Nogrady

Suggested Reading

Friedman DI, Quiros PA, Subramanian PS, et al. Headache in idiopathic intracranial hypertension: Findings from the Idiopathic Intracranial Hypertension Treatment Trial. Headache. 2017 July 28 [Epub ahead of print].

Yri HM, Rönnbäck C, Wegener M, et al. The course of headache in idiopathic intracranial hypertension: a 12-month prospective follow-up study. Eur J Neurol. 2014;21(12):1458-1464.

Headache in idiopathic intracranial hypertension (IIH) appears to be clinically independent of raised intracranial pressure and may require a different treatment approach than lowering intracranial pressure, according to a study published online ahead of print July 28 in Headache.

“Our findings provide the first class I evidence that CSF pressure and headaches are clinically independent features of IIH,” said Deborah I. Friedman, MD, Professor of Neurology, Neurotherapeutics, and Ophthalmology at the University of Texas Southwestern Medical School in Dallas.

The researchers examined data from 165 patients with untreated IIH and mild vision loss. The participants had been randomized to weight loss plus acetazolamide or placebo as a part of the IIH Treatment Trial.

In the 139 patients with headaches at baseline, the researchers saw no significant correlation between lumbar puncture opening pressure, which was measured at baseline and six months, and Headache Impact Test-6 (HIT-6) scores, or with the presence or absence of headache.

The researchers found no significant difference in headache outcomes between the acetazolamide and placebo groups at six months. Headaches in both groups improved overall during the course of the study, however.

At baseline, participants with headache reported taking various symptomatic headache treatments, including acetaminophen, ibuprofen, naproxen, and combination medications. Some also reported taking hydrocodone, tramadol, or combination formulations containing codeine.

Approximately 37% of the participants overused symptomatic pain medication. Fifteen of these patients met the criteria for overuse of opioids or combination medications. The mean HIT-6 scores were significantly higher in those who were overusing medications, compared with those who were not.

The most common headache phenotype was migraine (52%), followed by tension-type headache (22%), probable migraine (16%), and probable tension-type headache (4%), with 7% unclassified. Patients with headache also experienced associated symptoms such as photophobia, phonophobia, nausea, vomiting, visual loss or obscurations, diplopia, and dizziness.

—Bianca Nogrady

Suggested Reading

Friedman DI, Quiros PA, Subramanian PS, et al. Headache in idiopathic intracranial hypertension: Findings from the Idiopathic Intracranial Hypertension Treatment Trial. Headache. 2017 July 28 [Epub ahead of print].

Yri HM, Rönnbäck C, Wegener M, et al. The course of headache in idiopathic intracranial hypertension: a 12-month prospective follow-up study. Eur J Neurol. 2014;21(12):1458-1464.

In a case series of 202 former football players whose brains were donated for research, 87% of the participants had neuropathologic evidence of chronic traumatic encephalopathy (CTE), according to a study published in the July 25 issue of JAMA. Among 111 players who played in the National Football League (NFL), 99% had CTE. A progressive clinical course was common in players with mild and severe CTE pathology. The results suggest that CTE may be related to prior participation in football, the researchers said.

The report by Jesse Mez, MD, MS, Assistant Professor of Neurology at Boston University, and colleagues describes the largest CTE case series to date. A limitation of the study, however, is that brain donation programs are associated with ascertainment bias. Awareness of a possible link between repetitive head trauma and CTE may have motivated players with signs of brain injury and their families to participate in the study. “Therefore, caution must be used in interpreting the high frequency of CTE in this sample, and estimates of prevalence cannot be concluded or implied from this sample,” Dr. Mez and colleagues said.

Findings From a Brain Bank

CTE is a progressive neurodegenerative disease associated with repetitive head trauma. To study the neuropathology and clinical presentation of brain donors with exposure to repetitive head trauma, investigators in 2008 established the Veterans Affairs–Boston University–Concussion Legacy Foundation Brain Bank.

The present study assessed donors who participated in American football at any level of play. Outcomes included neuropathologic diagnoses of neurodegenerative diseases, including CTE; CTE neuropathologic severity; and informant-reported athletic history and clinical presentation.

Investigators conducted retrospective telephone clinical assessments with informants to determine participants’ clinical presentations, including timelines of behavior, mood, and cognitive symptoms. Neither the researchers nor the informants knew the participants’ neuropathology during the interview. Online questionnaires ascertained participants’ athletic and military histories. Pathologists were blinded to exposure data and clinical information.

Level of Play

Among the 202 former football players (median age at death, 66), CTE was neuropathologically diagnosed in 177 players. Participants with CTE had played football for a mean of 15.1 years.

Investigators diagnosed CTE in three of 14 players (21%) whose highest level of play was at the high school level, 48 of 53 players (91%) who played at the college level, nine of 14 players (64%) who played at the semiprofessional level, seven of eight players (88%) who played in the Canadian Football League, and 110 of 111 players (99%) who played in the NFL. Pathologists did not diagnose CTE in two participants whose highest level of play was before high school.

The three players with CTE whose highest level of play was in high school had mild CTE pathology (ie, stage I or II), whereas the majority of former college, semiprofessional, and professional players had severe pathology (ie, stage III or IV).

Among the 111 CTE cases with standardized informant reports on clinical symptoms, a progressive clinical course was reported in 85% of participants with mild CTE pathology and in 100% of participants with severe CTE pathology.

Among the 27 players with mild CTE pathology, 96% had behavioral or mood symptoms or both, 85% had cognitive symptoms, and 33% had signs of dementia. Among the 84 players with severe CTE pathology, 89% had behavioral or mood symptoms or both, 95% had cognitive symptoms, and 85% had signs of dementia.

“Nearly all of the former NFL players in this study had CTE pathology, and this pathology was frequently severe,” Dr. Mez and colleagues said. “These findings suggest that CTE may be related to prior participation in football and that a high level of play may be related to substantial disease burden.”

Future studies should assess how factors such as age at first exposure to football, duration of play, player position, cumulative hits, and linear and rotational acceleration of hits may influence outcomes, the researchers said.

Opportunities for Symptomatic Treatment

The rate of symptomatic CTE may be lower in an unselected population of former football players, said Gil D. Rabinovici, MD, Professor of Neurology at the University of California, San Francisco, in an accompanying editorial.

“The prevalence of cognitive and behavioral symptoms in the autopsy cohort was 88% and 95%, respectively,” he said. “In contrast, questionnaire-based ascertainment of neuropsychiatric symptoms among retired NFL players found that the prevalence of memory symptoms and depression was 5% to 20%. Acknowledging that questionnaires are an insensitive method for detecting neurodegenerative disease, the large discrepancy suggests that the rates of symptomatic CTE may be lower in an unselected cohort of former players.”

In addition, this study and prior studies suggest that there may be opportunities to improve care of patients with CTE. “Potentially treatable contributing factors are found in many patients, including high rates of substance abuse, affective disorders, headaches, and sleep disturbances,” Dr. Rabinovici said. “Thus, at-risk patients may benefit from a multidisciplinary medical team to optimize symptomatic treatment and maximize patient function and quality of life.”

—Jake Remaly

 

 

Suggested Reading

Mez J, Daneshvar DH, Kiernan PT, et al. Clinicopathological evaluation of chronic traumatic encephalopathy in players of American football. JAMA. 2017;318(4):360-370.

Rabinovici GD. Advances and gaps in understanding chronic traumatic encephalopathy: From pugilists to American football players. JAMA. 2017;318(4):338-340.

In a case series of 202 former football players whose brains were donated for research, 87% of the participants had neuropathologic evidence of chronic traumatic encephalopathy (CTE), according to a study published in the July 25 issue of JAMA. Among 111 players who played in the National Football League (NFL), 99% had CTE. A progressive clinical course was common in players with mild and severe CTE pathology. The results suggest that CTE may be related to prior participation in football, the researchers said.

The report by Jesse Mez, MD, MS, Assistant Professor of Neurology at Boston University, and colleagues describes the largest CTE case series to date. A limitation of the study, however, is that brain donation programs are associated with ascertainment bias. Awareness of a possible link between repetitive head trauma and CTE may have motivated players with signs of brain injury and their families to participate in the study. “Therefore, caution must be used in interpreting the high frequency of CTE in this sample, and estimates of prevalence cannot be concluded or implied from this sample,” Dr. Mez and colleagues said.

Findings From a Brain Bank

CTE is a progressive neurodegenerative disease associated with repetitive head trauma. To study the neuropathology and clinical presentation of brain donors with exposure to repetitive head trauma, investigators in 2008 established the Veterans Affairs–Boston University–Concussion Legacy Foundation Brain Bank.

The present study assessed donors who participated in American football at any level of play. Outcomes included neuropathologic diagnoses of neurodegenerative diseases, including CTE; CTE neuropathologic severity; and informant-reported athletic history and clinical presentation.

Investigators conducted retrospective telephone clinical assessments with informants to determine participants’ clinical presentations, including timelines of behavior, mood, and cognitive symptoms. Neither the researchers nor the informants knew the participants’ neuropathology during the interview. Online questionnaires ascertained participants’ athletic and military histories. Pathologists were blinded to exposure data and clinical information.

Level of Play

Among the 202 former football players (median age at death, 66), CTE was neuropathologically diagnosed in 177 players. Participants with CTE had played football for a mean of 15.1 years.

Investigators diagnosed CTE in three of 14 players (21%) whose highest level of play was at the high school level, 48 of 53 players (91%) who played at the college level, nine of 14 players (64%) who played at the semiprofessional level, seven of eight players (88%) who played in the Canadian Football League, and 110 of 111 players (99%) who played in the NFL. Pathologists did not diagnose CTE in two participants whose highest level of play was before high school.

The three players with CTE whose highest level of play was in high school had mild CTE pathology (ie, stage I or II), whereas the majority of former college, semiprofessional, and professional players had severe pathology (ie, stage III or IV).

Among the 111 CTE cases with standardized informant reports on clinical symptoms, a progressive clinical course was reported in 85% of participants with mild CTE pathology and in 100% of participants with severe CTE pathology.

Among the 27 players with mild CTE pathology, 96% had behavioral or mood symptoms or both, 85% had cognitive symptoms, and 33% had signs of dementia. Among the 84 players with severe CTE pathology, 89% had behavioral or mood symptoms or both, 95% had cognitive symptoms, and 85% had signs of dementia.

“Nearly all of the former NFL players in this study had CTE pathology, and this pathology was frequently severe,” Dr. Mez and colleagues said. “These findings suggest that CTE may be related to prior participation in football and that a high level of play may be related to substantial disease burden.”

Future studies should assess how factors such as age at first exposure to football, duration of play, player position, cumulative hits, and linear and rotational acceleration of hits may influence outcomes, the researchers said.

Opportunities for Symptomatic Treatment

The rate of symptomatic CTE may be lower in an unselected population of former football players, said Gil D. Rabinovici, MD, Professor of Neurology at the University of California, San Francisco, in an accompanying editorial.

“The prevalence of cognitive and behavioral symptoms in the autopsy cohort was 88% and 95%, respectively,” he said. “In contrast, questionnaire-based ascertainment of neuropsychiatric symptoms among retired NFL players found that the prevalence of memory symptoms and depression was 5% to 20%. Acknowledging that questionnaires are an insensitive method for detecting neurodegenerative disease, the large discrepancy suggests that the rates of symptomatic CTE may be lower in an unselected cohort of former players.”

In addition, this study and prior studies suggest that there may be opportunities to improve care of patients with CTE. “Potentially treatable contributing factors are found in many patients, including high rates of substance abuse, affective disorders, headaches, and sleep disturbances,” Dr. Rabinovici said. “Thus, at-risk patients may benefit from a multidisciplinary medical team to optimize symptomatic treatment and maximize patient function and quality of life.”

—Jake Remaly

 

 

Suggested Reading

Mez J, Daneshvar DH, Kiernan PT, et al. Clinicopathological evaluation of chronic traumatic encephalopathy in players of American football. JAMA. 2017;318(4):360-370.

Rabinovici GD. Advances and gaps in understanding chronic traumatic encephalopathy: From pugilists to American football players. JAMA. 2017;318(4):338-340.

In a case series of 202 former football players whose brains were donated for research, 87% of the participants had neuropathologic evidence of chronic traumatic encephalopathy (CTE), according to a study published in the July 25 issue of JAMA. Among 111 players who played in the National Football League (NFL), 99% had CTE. A progressive clinical course was common in players with mild and severe CTE pathology. The results suggest that CTE may be related to prior participation in football, the researchers said.

The report by Jesse Mez, MD, MS, Assistant Professor of Neurology at Boston University, and colleagues describes the largest CTE case series to date. A limitation of the study, however, is that brain donation programs are associated with ascertainment bias. Awareness of a possible link between repetitive head trauma and CTE may have motivated players with signs of brain injury and their families to participate in the study. “Therefore, caution must be used in interpreting the high frequency of CTE in this sample, and estimates of prevalence cannot be concluded or implied from this sample,” Dr. Mez and colleagues said.

Findings From a Brain Bank

CTE is a progressive neurodegenerative disease associated with repetitive head trauma. To study the neuropathology and clinical presentation of brain donors with exposure to repetitive head trauma, investigators in 2008 established the Veterans Affairs–Boston University–Concussion Legacy Foundation Brain Bank.

The present study assessed donors who participated in American football at any level of play. Outcomes included neuropathologic diagnoses of neurodegenerative diseases, including CTE; CTE neuropathologic severity; and informant-reported athletic history and clinical presentation.

Investigators conducted retrospective telephone clinical assessments with informants to determine participants’ clinical presentations, including timelines of behavior, mood, and cognitive symptoms. Neither the researchers nor the informants knew the participants’ neuropathology during the interview. Online questionnaires ascertained participants’ athletic and military histories. Pathologists were blinded to exposure data and clinical information.

Level of Play

Among the 202 former football players (median age at death, 66), CTE was neuropathologically diagnosed in 177 players. Participants with CTE had played football for a mean of 15.1 years.

Investigators diagnosed CTE in three of 14 players (21%) whose highest level of play was at the high school level, 48 of 53 players (91%) who played at the college level, nine of 14 players (64%) who played at the semiprofessional level, seven of eight players (88%) who played in the Canadian Football League, and 110 of 111 players (99%) who played in the NFL. Pathologists did not diagnose CTE in two participants whose highest level of play was before high school.

The three players with CTE whose highest level of play was in high school had mild CTE pathology (ie, stage I or II), whereas the majority of former college, semiprofessional, and professional players had severe pathology (ie, stage III or IV).

Among the 111 CTE cases with standardized informant reports on clinical symptoms, a progressive clinical course was reported in 85% of participants with mild CTE pathology and in 100% of participants with severe CTE pathology.

Among the 27 players with mild CTE pathology, 96% had behavioral or mood symptoms or both, 85% had cognitive symptoms, and 33% had signs of dementia. Among the 84 players with severe CTE pathology, 89% had behavioral or mood symptoms or both, 95% had cognitive symptoms, and 85% had signs of dementia.

“Nearly all of the former NFL players in this study had CTE pathology, and this pathology was frequently severe,” Dr. Mez and colleagues said. “These findings suggest that CTE may be related to prior participation in football and that a high level of play may be related to substantial disease burden.”

Future studies should assess how factors such as age at first exposure to football, duration of play, player position, cumulative hits, and linear and rotational acceleration of hits may influence outcomes, the researchers said.

Opportunities for Symptomatic Treatment

The rate of symptomatic CTE may be lower in an unselected population of former football players, said Gil D. Rabinovici, MD, Professor of Neurology at the University of California, San Francisco, in an accompanying editorial.

“The prevalence of cognitive and behavioral symptoms in the autopsy cohort was 88% and 95%, respectively,” he said. “In contrast, questionnaire-based ascertainment of neuropsychiatric symptoms among retired NFL players found that the prevalence of memory symptoms and depression was 5% to 20%. Acknowledging that questionnaires are an insensitive method for detecting neurodegenerative disease, the large discrepancy suggests that the rates of symptomatic CTE may be lower in an unselected cohort of former players.”

In addition, this study and prior studies suggest that there may be opportunities to improve care of patients with CTE. “Potentially treatable contributing factors are found in many patients, including high rates of substance abuse, affective disorders, headaches, and sleep disturbances,” Dr. Rabinovici said. “Thus, at-risk patients may benefit from a multidisciplinary medical team to optimize symptomatic treatment and maximize patient function and quality of life.”

—Jake Remaly

 

 

Suggested Reading

Mez J, Daneshvar DH, Kiernan PT, et al. Clinicopathological evaluation of chronic traumatic encephalopathy in players of American football. JAMA. 2017;318(4):360-370.

Rabinovici GD. Advances and gaps in understanding chronic traumatic encephalopathy: From pugilists to American football players. JAMA. 2017;318(4):338-340.

The pharmaceutical formulation of cannabidiol (CBD) is associated with significant changes in serum levels of clobazam, rufinamide, topiramate, zonisamide, and eslicarbazepine, according to research published online ahead of print August 6 in Epilepsia. Furthermore, patients taking CBD and valproate may have abnormal liver function test results.

“A perception exists that since CBD is plant-based, it is natural and safe; and while this may be mostly true, our study shows that CBD, just like other antiepileptic drugs [AEDs], has interactions with other seizure drugs that patients and providers need to be aware of,” said Tyler Gaston, MD, Assistant Professor of Neurology at the University of Alabama at Birmingham.

Patients in a Compassionate-Use Study

Few data about CBD’s interactions with AEDs are available. To gain more information, Dr. Gaston and colleagues examined 42 children and 39 adults in the University of Alabama’s open-label compassionate-use study of CBD as an add-on therapy for treatment-resistant epilepsy. At baseline, the investigators obtained participants’ serum AED levels. Participants initiated treatment with 5 mg/kg/day of CBD along with their other AEDs. Every two weeks, participants underwent a physical examination and laboratory testing. The investigators obtained serum AED levels and increased the dose of CBD by 5 mg/kg/day to a maximum of 50 mg/kg/day. AED doses were adjusted if a clinical symptom or laboratory result was related to a potential interaction.

Dr. Gaston and colleagues used a mixed linear model to determine whether the plasma levels of each AED changed significantly with increasing CBD dose.

Many Serum Levels Remained in Therapeutic Range

The mean age of pediatric participants was 10, and 20 of the children were female. The mean age of adults was 29, and 20 of the adult participants were female. The mean number of concomitant AEDs at enrollment for all participants was three.

The investigators noted increases in serum levels of topiramate, rufinamide, and N-desmethylclobazam (ie, the active metabolite of clobazam) and a decrease in serum levels of clobazam with increasing CBD dose. They also observed increases in serum levels of zonisamide and eslicarbazepine with increasing CBD dose in adults. All mean level changes were within the accepted therapeutic range, except for those in clobazam and N-desmethylclobazam. Sedation was more frequent with higher N-desmethylclobazam levels in adults. Levels of aspartate aminotransferase and alanine aminotransferase were significantly higher in participants taking concomitant valproate.

One of the study’s limitations was that the sample sizes of patients taking each AED were small, which may have masked potential interactions with CBD, according to the researchers. In addition, the naturalistic study design resulted in significant noise in the data for which the researchers could not completely account in their analyses. Nevertheless, “this study emphasizes the importance of monitoring serum AED levels and liver function tests during treatment with CBD,” said Dr. Gaston.

—Erik Greb

Suggested Reading

Gaston TE, Bebin EM, Cutter GR, et al. Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia. 2017 Aug 6 [Epub ahead of print].

The pharmaceutical formulation of cannabidiol (CBD) is associated with significant changes in serum levels of clobazam, rufinamide, topiramate, zonisamide, and eslicarbazepine, according to research published online ahead of print August 6 in Epilepsia. Furthermore, patients taking CBD and valproate may have abnormal liver function test results.

“A perception exists that since CBD is plant-based, it is natural and safe; and while this may be mostly true, our study shows that CBD, just like other antiepileptic drugs [AEDs], has interactions with other seizure drugs that patients and providers need to be aware of,” said Tyler Gaston, MD, Assistant Professor of Neurology at the University of Alabama at Birmingham.

Patients in a Compassionate-Use Study

Few data about CBD’s interactions with AEDs are available. To gain more information, Dr. Gaston and colleagues examined 42 children and 39 adults in the University of Alabama’s open-label compassionate-use study of CBD as an add-on therapy for treatment-resistant epilepsy. At baseline, the investigators obtained participants’ serum AED levels. Participants initiated treatment with 5 mg/kg/day of CBD along with their other AEDs. Every two weeks, participants underwent a physical examination and laboratory testing. The investigators obtained serum AED levels and increased the dose of CBD by 5 mg/kg/day to a maximum of 50 mg/kg/day. AED doses were adjusted if a clinical symptom or laboratory result was related to a potential interaction.

Dr. Gaston and colleagues used a mixed linear model to determine whether the plasma levels of each AED changed significantly with increasing CBD dose.

Many Serum Levels Remained in Therapeutic Range

The mean age of pediatric participants was 10, and 20 of the children were female. The mean age of adults was 29, and 20 of the adult participants were female. The mean number of concomitant AEDs at enrollment for all participants was three.

The investigators noted increases in serum levels of topiramate, rufinamide, and N-desmethylclobazam (ie, the active metabolite of clobazam) and a decrease in serum levels of clobazam with increasing CBD dose. They also observed increases in serum levels of zonisamide and eslicarbazepine with increasing CBD dose in adults. All mean level changes were within the accepted therapeutic range, except for those in clobazam and N-desmethylclobazam. Sedation was more frequent with higher N-desmethylclobazam levels in adults. Levels of aspartate aminotransferase and alanine aminotransferase were significantly higher in participants taking concomitant valproate.

One of the study’s limitations was that the sample sizes of patients taking each AED were small, which may have masked potential interactions with CBD, according to the researchers. In addition, the naturalistic study design resulted in significant noise in the data for which the researchers could not completely account in their analyses. Nevertheless, “this study emphasizes the importance of monitoring serum AED levels and liver function tests during treatment with CBD,” said Dr. Gaston.

—Erik Greb

Suggested Reading

Gaston TE, Bebin EM, Cutter GR, et al. Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia. 2017 Aug 6 [Epub ahead of print].

The pharmaceutical formulation of cannabidiol (CBD) is associated with significant changes in serum levels of clobazam, rufinamide, topiramate, zonisamide, and eslicarbazepine, according to research published online ahead of print August 6 in Epilepsia. Furthermore, patients taking CBD and valproate may have abnormal liver function test results.

“A perception exists that since CBD is plant-based, it is natural and safe; and while this may be mostly true, our study shows that CBD, just like other antiepileptic drugs [AEDs], has interactions with other seizure drugs that patients and providers need to be aware of,” said Tyler Gaston, MD, Assistant Professor of Neurology at the University of Alabama at Birmingham.

Patients in a Compassionate-Use Study

Few data about CBD’s interactions with AEDs are available. To gain more information, Dr. Gaston and colleagues examined 42 children and 39 adults in the University of Alabama’s open-label compassionate-use study of CBD as an add-on therapy for treatment-resistant epilepsy. At baseline, the investigators obtained participants’ serum AED levels. Participants initiated treatment with 5 mg/kg/day of CBD along with their other AEDs. Every two weeks, participants underwent a physical examination and laboratory testing. The investigators obtained serum AED levels and increased the dose of CBD by 5 mg/kg/day to a maximum of 50 mg/kg/day. AED doses were adjusted if a clinical symptom or laboratory result was related to a potential interaction.

Dr. Gaston and colleagues used a mixed linear model to determine whether the plasma levels of each AED changed significantly with increasing CBD dose.

Many Serum Levels Remained in Therapeutic Range

The mean age of pediatric participants was 10, and 20 of the children were female. The mean age of adults was 29, and 20 of the adult participants were female. The mean number of concomitant AEDs at enrollment for all participants was three.

The investigators noted increases in serum levels of topiramate, rufinamide, and N-desmethylclobazam (ie, the active metabolite of clobazam) and a decrease in serum levels of clobazam with increasing CBD dose. They also observed increases in serum levels of zonisamide and eslicarbazepine with increasing CBD dose in adults. All mean level changes were within the accepted therapeutic range, except for those in clobazam and N-desmethylclobazam. Sedation was more frequent with higher N-desmethylclobazam levels in adults. Levels of aspartate aminotransferase and alanine aminotransferase were significantly higher in participants taking concomitant valproate.

One of the study’s limitations was that the sample sizes of patients taking each AED were small, which may have masked potential interactions with CBD, according to the researchers. In addition, the naturalistic study design resulted in significant noise in the data for which the researchers could not completely account in their analyses. Nevertheless, “this study emphasizes the importance of monitoring serum AED levels and liver function tests during treatment with CBD,” said Dr. Gaston.

—Erik Greb

Suggested Reading

Gaston TE, Bebin EM, Cutter GR, et al. Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia. 2017 Aug 6 [Epub ahead of print].

An evidence-based model allows neurologists to predict individual patient outcomes following the withdrawal of antiepileptic drugs (AEDs), according to research published in the July issue of Epilepsia. The model indicates a patient’s risk of relapse and chance of long-term seizure freedom. The model therefore might help physicians and patients make individualized choices about treatment, said the authors.

Patients with epilepsy who have achieved seizure freedom may want to discontinue their AEDs to avoid their associated side effects. Discontinuation raises the risk of seizure recurrence, however. Previous prognostic meta-analyses have been unable to calculate individual outcome predictors’ effect sizes because of the heterogeneous methods and reporting in the literature.

Analyzing Individual Participant Data

To overcome this limitation, Herm J. Lamberink, MD, a doctoral student at University Medical Center Utrecht in the Netherlands, and colleagues conducted a meta-analysis using individual participant data from previous studies. They reviewed PubMed and Embase for articles that reported on patients with epilepsy who were seizure-free and had started withdrawal of AEDs. Eligible articles contained information regarding seizure recurrences during and after withdrawal. The investigators selected 25 candidate predictors based on a systematic review of the predictors of seizure recurrence after AED withdrawal.

Dr. Lamberink and colleagues identified 45 studies that included 7,082 patients in all. The meta-analysis included 10 studies with 1,769 patients. The populations included selected and nonselected children and adults. Median follow-up time was 5.3 years. In all, 812 patients (46%) had seizure relapse, which was a higher rate than the average reported in the literature. Approximately 9% of participants for whom data were available had seizures in their last year of follow-up, which suggests that they had not regained lasting seizure control.

Model Had Stable Performance

Epilepsy duration before remission, seizure-free interval before AED withdrawal, age at onset of epilepsy, history of febrile seizures, number of seizures before remission, absence of a self-limiting epilepsy syndrome, developmental delay, and epileptiform abnormality on EEG before withdrawal were independent predictors of seizure recurrence. Epilepsy duration before remission, seizure-free interval before AED withdrawal, number of AEDs before withdrawal, female sex, family history of epilepsy, number of seizures before remission, focal seizures, and epileptiform abnormality on EEG before withdrawal were independent predictors of seizures in the last year of follow-up.

The adjusted concordance statistics for the model were 0.65 for predicting seizure recurrence and 0.71 for predicting long-term seizure freedom. Internal–external cross validation indicated that the model had good and stable performance in all cohorts.

One limitation of the study is that the population included only participants who attempted to withdraw AEDs. In addition, too few cases of epileptic encephalopathy and juvenile myoclonic epilepsy were included in the population to determine whether these disorders predict outcomes after AED withdrawal.

—Erik Greb

Suggested Reading

Lamberink HJ, Otte WM, Geerts AT, et al. Individualised prediction model of seizure recurrence and long-term outcomes after withdrawal of antiepileptic drugs in seizure-free patients: a systematic review and individual participant data meta-analysis. Lancet Neurol. 2017;16(7):523-531.

An evidence-based model allows neurologists to predict individual patient outcomes following the withdrawal of antiepileptic drugs (AEDs), according to research published in the July issue of Epilepsia. The model indicates a patient’s risk of relapse and chance of long-term seizure freedom. The model therefore might help physicians and patients make individualized choices about treatment, said the authors.

Patients with epilepsy who have achieved seizure freedom may want to discontinue their AEDs to avoid their associated side effects. Discontinuation raises the risk of seizure recurrence, however. Previous prognostic meta-analyses have been unable to calculate individual outcome predictors’ effect sizes because of the heterogeneous methods and reporting in the literature.

Analyzing Individual Participant Data

To overcome this limitation, Herm J. Lamberink, MD, a doctoral student at University Medical Center Utrecht in the Netherlands, and colleagues conducted a meta-analysis using individual participant data from previous studies. They reviewed PubMed and Embase for articles that reported on patients with epilepsy who were seizure-free and had started withdrawal of AEDs. Eligible articles contained information regarding seizure recurrences during and after withdrawal. The investigators selected 25 candidate predictors based on a systematic review of the predictors of seizure recurrence after AED withdrawal.

Dr. Lamberink and colleagues identified 45 studies that included 7,082 patients in all. The meta-analysis included 10 studies with 1,769 patients. The populations included selected and nonselected children and adults. Median follow-up time was 5.3 years. In all, 812 patients (46%) had seizure relapse, which was a higher rate than the average reported in the literature. Approximately 9% of participants for whom data were available had seizures in their last year of follow-up, which suggests that they had not regained lasting seizure control.

Model Had Stable Performance

Epilepsy duration before remission, seizure-free interval before AED withdrawal, age at onset of epilepsy, history of febrile seizures, number of seizures before remission, absence of a self-limiting epilepsy syndrome, developmental delay, and epileptiform abnormality on EEG before withdrawal were independent predictors of seizure recurrence. Epilepsy duration before remission, seizure-free interval before AED withdrawal, number of AEDs before withdrawal, female sex, family history of epilepsy, number of seizures before remission, focal seizures, and epileptiform abnormality on EEG before withdrawal were independent predictors of seizures in the last year of follow-up.

The adjusted concordance statistics for the model were 0.65 for predicting seizure recurrence and 0.71 for predicting long-term seizure freedom. Internal–external cross validation indicated that the model had good and stable performance in all cohorts.

One limitation of the study is that the population included only participants who attempted to withdraw AEDs. In addition, too few cases of epileptic encephalopathy and juvenile myoclonic epilepsy were included in the population to determine whether these disorders predict outcomes after AED withdrawal.

—Erik Greb

Suggested Reading

Lamberink HJ, Otte WM, Geerts AT, et al. Individualised prediction model of seizure recurrence and long-term outcomes after withdrawal of antiepileptic drugs in seizure-free patients: a systematic review and individual participant data meta-analysis. Lancet Neurol. 2017;16(7):523-531.

An evidence-based model allows neurologists to predict individual patient outcomes following the withdrawal of antiepileptic drugs (AEDs), according to research published in the July issue of Epilepsia. The model indicates a patient’s risk of relapse and chance of long-term seizure freedom. The model therefore might help physicians and patients make individualized choices about treatment, said the authors.

Patients with epilepsy who have achieved seizure freedom may want to discontinue their AEDs to avoid their associated side effects. Discontinuation raises the risk of seizure recurrence, however. Previous prognostic meta-analyses have been unable to calculate individual outcome predictors’ effect sizes because of the heterogeneous methods and reporting in the literature.

Analyzing Individual Participant Data

To overcome this limitation, Herm J. Lamberink, MD, a doctoral student at University Medical Center Utrecht in the Netherlands, and colleagues conducted a meta-analysis using individual participant data from previous studies. They reviewed PubMed and Embase for articles that reported on patients with epilepsy who were seizure-free and had started withdrawal of AEDs. Eligible articles contained information regarding seizure recurrences during and after withdrawal. The investigators selected 25 candidate predictors based on a systematic review of the predictors of seizure recurrence after AED withdrawal.

Dr. Lamberink and colleagues identified 45 studies that included 7,082 patients in all. The meta-analysis included 10 studies with 1,769 patients. The populations included selected and nonselected children and adults. Median follow-up time was 5.3 years. In all, 812 patients (46%) had seizure relapse, which was a higher rate than the average reported in the literature. Approximately 9% of participants for whom data were available had seizures in their last year of follow-up, which suggests that they had not regained lasting seizure control.

Model Had Stable Performance

Epilepsy duration before remission, seizure-free interval before AED withdrawal, age at onset of epilepsy, history of febrile seizures, number of seizures before remission, absence of a self-limiting epilepsy syndrome, developmental delay, and epileptiform abnormality on EEG before withdrawal were independent predictors of seizure recurrence. Epilepsy duration before remission, seizure-free interval before AED withdrawal, number of AEDs before withdrawal, female sex, family history of epilepsy, number of seizures before remission, focal seizures, and epileptiform abnormality on EEG before withdrawal were independent predictors of seizures in the last year of follow-up.

The adjusted concordance statistics for the model were 0.65 for predicting seizure recurrence and 0.71 for predicting long-term seizure freedom. Internal–external cross validation indicated that the model had good and stable performance in all cohorts.

One limitation of the study is that the population included only participants who attempted to withdraw AEDs. In addition, too few cases of epileptic encephalopathy and juvenile myoclonic epilepsy were included in the population to determine whether these disorders predict outcomes after AED withdrawal.

—Erik Greb

Suggested Reading

Lamberink HJ, Otte WM, Geerts AT, et al. Individualised prediction model of seizure recurrence and long-term outcomes after withdrawal of antiepileptic drugs in seizure-free patients: a systematic review and individual participant data meta-analysis. Lancet Neurol. 2017;16(7):523-531.

Severity of depression may be associated with epilepsy risk and outcomes, according to a study published in the May issue of JAMA Neurology. “Treated depression is associated with worse epilepsy outcomes, suggesting that this [factor] may be a surrogate for more severe depression and that severity of depression is associated with severity of epilepsy,” said Colin B. Josephson, MD, Assistant Professor of Neurology at the University of Calgary in Alberta, and colleagues.

“If one assumes that depression treatment is a surrogate marker for depression severity, then there … appears to be a biological gradient,” the investigators said. “This assertion is corroborated by the incremental hazard of epilepsy among those receiving counseling alone (lowest hazard), antidepressants alone (intermediate hazard), and a combination of counseling and antidepressants (highest hazard).”

Prior research has found that the incidence and prevalence of depression are significantly elevated before and after an epilepsy diagnosis. Studies have not assessed, however, the risk of epilepsy after an incident diagnosis of depression or whether depression severity affects the level of risk or seizure outcomes, the authors said.

Two Data Sources

Dr. Josephson and colleagues examined two independent sources of data to explore the relationship between depression and epilepsy further. First, they conducted an observational study using The Health Improvement Network (THIN) database, a population-based primary care cohort. The THIN database contains prospective data that are broadly representative of the general population of the United Kingdom. All patients included in the study were free of prevalent depression and epilepsy and between the ages of 18 and 90. Separately, they analyzed prospective data from the Calgary Comprehensive Epilepsy Programme, a registry of adult outpatient encounters.

Of the more than 10.5 million eligible patients in the THIN database, 229,164 (2.2%) developed depression and 97,177 (0.9%) developed epilepsy. The median age was 44 among patients with depression and 56 among patients with epilepsy. Sixty-three percent of the patients with depression and 56% of the patients with epilepsy were women.

Incident epilepsy was associated with an increased hazard of developing depression (hazard ratio [HR], 2.04), and incident depression was associated with an increased hazard of developing epilepsy (HR, 2.55). “The association with incident epilepsy was even stronger for those with treated depression (HR, 3.42), compared with a combination of those who did not develop depression and those who developed depression not requiring therapy.”

In a sensitivity analysis controlling for age, sex, socioeconomic status, and Charlson Comorbidity Index, “there was an incremental hazard according to depression treatment type, with lowest risk for those receiving counselling alone (HR, 1.84), an intermediate risk for those receiving antidepressants alone (HR, 3.43), and the highest risk for those receiving both (HR, 9.85).”

Likelihood of Seizure Freedom

To assess the effect of depression on seizure outcomes, the researchers analyzed data from 2,573 patients in the Calgary Comprehensive Epilepsy Programme cohort. Data were derived from patients’ first-visit evaluation forms. A total of 504 (20%) of the patients had achieved one-year seizure freedom during the year prior to their first clinic visit. Patients with past or current depression had higher odds of failing to achieve seizure freedom during the previous year, compared with patients without depression (odds ratio, 1.41). When considering only patients with current or past depression (n = 738), current depression treatment (ie, antidepressants, counseling, or both) was associated with significantly higher odds of failing to achieve one-year seizure freedom (odds ratio, 1.75) after controlling for age at onset of epilepsy, sex, lesional epilepsy detected by MRI, history of generalized tonic-clonic seizures, and current antiepileptic drug use.

Overall, the results “indicate a shared relationship between depression and epilepsy, with each appearing to act as a risk factor for the other, and, therefore, should have a direct effect on counseling and management,” Dr. Josephson and colleagues said.

Limitations

The researchers noted that they were unable to control for etiology, epilepsy subtype, or conditions that could cause epilepsy and depression, and they did not have information about the duration, dose, or frequency of depression treatments. Although depression severity may not necessarily determine treatment type, primary care guidelines recommend counseling as first-line treatment for mild depression and combination therapy for severe depression, the researchers said.

Other possible interpretations of the results, such as the idea that antidepressant treatment augments the risk of epilepsy or that patients are more severely depressed because they have not achieved one-year seizure freedom, are less likely. “Counseling interacted with antidepressant exposure and resulted in a threefold increase in the hazard of epilepsy over that of medications alone,” which suggests that “treatment is acting as a proxy for depression severity and is thus consistent with the existence of a biological dose-response relationship,” the researchers said. In addition, “a recent review has indicated that virtually all antidepressants are safe for patients with epilepsy, thereby debunking the notion that these medications increase the risk of seizures.”

—Jake Remaly

 

 

Suggested Reading

Josephson CB, Lowerison M, Vallerand I, et al. Association of depression and treated depression with epilepsy and seizure outcomes: A multicohort analysis. JAMA Neurol. 2017;74(5):533-539.

Kanner AM. Most antidepressant drugs are safe for patients with epilepsy at therapeutic doses: A review of the evidence. Epilepsy Behav. 2016;61:282-286.

Severity of depression may be associated with epilepsy risk and outcomes, according to a study published in the May issue of JAMA Neurology. “Treated depression is associated with worse epilepsy outcomes, suggesting that this [factor] may be a surrogate for more severe depression and that severity of depression is associated with severity of epilepsy,” said Colin B. Josephson, MD, Assistant Professor of Neurology at the University of Calgary in Alberta, and colleagues.

“If one assumes that depression treatment is a surrogate marker for depression severity, then there … appears to be a biological gradient,” the investigators said. “This assertion is corroborated by the incremental hazard of epilepsy among those receiving counseling alone (lowest hazard), antidepressants alone (intermediate hazard), and a combination of counseling and antidepressants (highest hazard).”

Prior research has found that the incidence and prevalence of depression are significantly elevated before and after an epilepsy diagnosis. Studies have not assessed, however, the risk of epilepsy after an incident diagnosis of depression or whether depression severity affects the level of risk or seizure outcomes, the authors said.

Two Data Sources

Dr. Josephson and colleagues examined two independent sources of data to explore the relationship between depression and epilepsy further. First, they conducted an observational study using The Health Improvement Network (THIN) database, a population-based primary care cohort. The THIN database contains prospective data that are broadly representative of the general population of the United Kingdom. All patients included in the study were free of prevalent depression and epilepsy and between the ages of 18 and 90. Separately, they analyzed prospective data from the Calgary Comprehensive Epilepsy Programme, a registry of adult outpatient encounters.

Of the more than 10.5 million eligible patients in the THIN database, 229,164 (2.2%) developed depression and 97,177 (0.9%) developed epilepsy. The median age was 44 among patients with depression and 56 among patients with epilepsy. Sixty-three percent of the patients with depression and 56% of the patients with epilepsy were women.

Incident epilepsy was associated with an increased hazard of developing depression (hazard ratio [HR], 2.04), and incident depression was associated with an increased hazard of developing epilepsy (HR, 2.55). “The association with incident epilepsy was even stronger for those with treated depression (HR, 3.42), compared with a combination of those who did not develop depression and those who developed depression not requiring therapy.”

In a sensitivity analysis controlling for age, sex, socioeconomic status, and Charlson Comorbidity Index, “there was an incremental hazard according to depression treatment type, with lowest risk for those receiving counselling alone (HR, 1.84), an intermediate risk for those receiving antidepressants alone (HR, 3.43), and the highest risk for those receiving both (HR, 9.85).”

Likelihood of Seizure Freedom

To assess the effect of depression on seizure outcomes, the researchers analyzed data from 2,573 patients in the Calgary Comprehensive Epilepsy Programme cohort. Data were derived from patients’ first-visit evaluation forms. A total of 504 (20%) of the patients had achieved one-year seizure freedom during the year prior to their first clinic visit. Patients with past or current depression had higher odds of failing to achieve seizure freedom during the previous year, compared with patients without depression (odds ratio, 1.41). When considering only patients with current or past depression (n = 738), current depression treatment (ie, antidepressants, counseling, or both) was associated with significantly higher odds of failing to achieve one-year seizure freedom (odds ratio, 1.75) after controlling for age at onset of epilepsy, sex, lesional epilepsy detected by MRI, history of generalized tonic-clonic seizures, and current antiepileptic drug use.

Overall, the results “indicate a shared relationship between depression and epilepsy, with each appearing to act as a risk factor for the other, and, therefore, should have a direct effect on counseling and management,” Dr. Josephson and colleagues said.

Limitations

The researchers noted that they were unable to control for etiology, epilepsy subtype, or conditions that could cause epilepsy and depression, and they did not have information about the duration, dose, or frequency of depression treatments. Although depression severity may not necessarily determine treatment type, primary care guidelines recommend counseling as first-line treatment for mild depression and combination therapy for severe depression, the researchers said.

Other possible interpretations of the results, such as the idea that antidepressant treatment augments the risk of epilepsy or that patients are more severely depressed because they have not achieved one-year seizure freedom, are less likely. “Counseling interacted with antidepressant exposure and resulted in a threefold increase in the hazard of epilepsy over that of medications alone,” which suggests that “treatment is acting as a proxy for depression severity and is thus consistent with the existence of a biological dose-response relationship,” the researchers said. In addition, “a recent review has indicated that virtually all antidepressants are safe for patients with epilepsy, thereby debunking the notion that these medications increase the risk of seizures.”

—Jake Remaly

 

 

Suggested Reading

Josephson CB, Lowerison M, Vallerand I, et al. Association of depression and treated depression with epilepsy and seizure outcomes: A multicohort analysis. JAMA Neurol. 2017;74(5):533-539.

Kanner AM. Most antidepressant drugs are safe for patients with epilepsy at therapeutic doses: A review of the evidence. Epilepsy Behav. 2016;61:282-286.

Severity of depression may be associated with epilepsy risk and outcomes, according to a study published in the May issue of JAMA Neurology. “Treated depression is associated with worse epilepsy outcomes, suggesting that this [factor] may be a surrogate for more severe depression and that severity of depression is associated with severity of epilepsy,” said Colin B. Josephson, MD, Assistant Professor of Neurology at the University of Calgary in Alberta, and colleagues.

“If one assumes that depression treatment is a surrogate marker for depression severity, then there … appears to be a biological gradient,” the investigators said. “This assertion is corroborated by the incremental hazard of epilepsy among those receiving counseling alone (lowest hazard), antidepressants alone (intermediate hazard), and a combination of counseling and antidepressants (highest hazard).”

Prior research has found that the incidence and prevalence of depression are significantly elevated before and after an epilepsy diagnosis. Studies have not assessed, however, the risk of epilepsy after an incident diagnosis of depression or whether depression severity affects the level of risk or seizure outcomes, the authors said.

Two Data Sources

Dr. Josephson and colleagues examined two independent sources of data to explore the relationship between depression and epilepsy further. First, they conducted an observational study using The Health Improvement Network (THIN) database, a population-based primary care cohort. The THIN database contains prospective data that are broadly representative of the general population of the United Kingdom. All patients included in the study were free of prevalent depression and epilepsy and between the ages of 18 and 90. Separately, they analyzed prospective data from the Calgary Comprehensive Epilepsy Programme, a registry of adult outpatient encounters.

Of the more than 10.5 million eligible patients in the THIN database, 229,164 (2.2%) developed depression and 97,177 (0.9%) developed epilepsy. The median age was 44 among patients with depression and 56 among patients with epilepsy. Sixty-three percent of the patients with depression and 56% of the patients with epilepsy were women.

Incident epilepsy was associated with an increased hazard of developing depression (hazard ratio [HR], 2.04), and incident depression was associated with an increased hazard of developing epilepsy (HR, 2.55). “The association with incident epilepsy was even stronger for those with treated depression (HR, 3.42), compared with a combination of those who did not develop depression and those who developed depression not requiring therapy.”

In a sensitivity analysis controlling for age, sex, socioeconomic status, and Charlson Comorbidity Index, “there was an incremental hazard according to depression treatment type, with lowest risk for those receiving counselling alone (HR, 1.84), an intermediate risk for those receiving antidepressants alone (HR, 3.43), and the highest risk for those receiving both (HR, 9.85).”

Likelihood of Seizure Freedom

To assess the effect of depression on seizure outcomes, the researchers analyzed data from 2,573 patients in the Calgary Comprehensive Epilepsy Programme cohort. Data were derived from patients’ first-visit evaluation forms. A total of 504 (20%) of the patients had achieved one-year seizure freedom during the year prior to their first clinic visit. Patients with past or current depression had higher odds of failing to achieve seizure freedom during the previous year, compared with patients without depression (odds ratio, 1.41). When considering only patients with current or past depression (n = 738), current depression treatment (ie, antidepressants, counseling, or both) was associated with significantly higher odds of failing to achieve one-year seizure freedom (odds ratio, 1.75) after controlling for age at onset of epilepsy, sex, lesional epilepsy detected by MRI, history of generalized tonic-clonic seizures, and current antiepileptic drug use.

Overall, the results “indicate a shared relationship between depression and epilepsy, with each appearing to act as a risk factor for the other, and, therefore, should have a direct effect on counseling and management,” Dr. Josephson and colleagues said.

Limitations

The researchers noted that they were unable to control for etiology, epilepsy subtype, or conditions that could cause epilepsy and depression, and they did not have information about the duration, dose, or frequency of depression treatments. Although depression severity may not necessarily determine treatment type, primary care guidelines recommend counseling as first-line treatment for mild depression and combination therapy for severe depression, the researchers said.

Other possible interpretations of the results, such as the idea that antidepressant treatment augments the risk of epilepsy or that patients are more severely depressed because they have not achieved one-year seizure freedom, are less likely. “Counseling interacted with antidepressant exposure and resulted in a threefold increase in the hazard of epilepsy over that of medications alone,” which suggests that “treatment is acting as a proxy for depression severity and is thus consistent with the existence of a biological dose-response relationship,” the researchers said. In addition, “a recent review has indicated that virtually all antidepressants are safe for patients with epilepsy, thereby debunking the notion that these medications increase the risk of seizures.”

—Jake Remaly

 

 

Suggested Reading

Josephson CB, Lowerison M, Vallerand I, et al. Association of depression and treated depression with epilepsy and seizure outcomes: A multicohort analysis. JAMA Neurol. 2017;74(5):533-539.

Kanner AM. Most antidepressant drugs are safe for patients with epilepsy at therapeutic doses: A review of the evidence. Epilepsy Behav. 2016;61:282-286.

Light therapy may reduce excessive daytime sleepiness and improve sleep quality in patients with Parkinson’s disease, according to trial results published in the April issue of JAMA Neurology. The treatment modality is well tolerated, widely available, and “relatively easy to prescribe and incorporate into a clinical practice,” said Aleksandar Videnovic, MD, a neurologist at Massachusetts General Hospital in Boston, and colleagues.

Impaired sleep and alertness are common nonmotor manifestations of Parkinson’s disease with limited treatment options. Patients’ sleep disturbances have been attributed to Parkinson’s disease symptoms, adverse medication effects, and neurodegeneration of central sleep regulatory areas. Altered circadian rhythms also may play a role. Supplemental exposure to bright light improves sleep quality and daytime vigilance in healthy older people and patients with dementia, but the treatment modality has not been studied systematically in patients with Parkinson’s disease, the researchers said.

One-Hour Treatment Intervals

To determine the safety and efficacy of light therapy on excessive daytime sleepiness associated with Parkinson’s disease, Dr. Videnovic and colleagues conducted a randomized, placebo-controlled trial.

They enrolled 31 patients with Parkinson’s disease and excessive daytime sleepiness (ie, an Epworth Sleepiness Scale score of 12 or greater). Patients were receiving stable dopaminergic therapy and did not have cognitive impairment or a primary sleep disorder. Investigators randomized participants 1:1 to receive bright light therapy (10,000 lux) or a control condition of dim-red light therapy (less than 300 lux). After a two-week baseline phase, participants received light therapy in one-hour intervals twice daily—in the morning (between 9 am and 11 am) and in the afternoon (between 5 pm and 7 pm)—for 14 days. The primary outcome measure was change in Epworth Sleepiness Scale score from baseline. During the study, each patient wore an actigraphy monitor and completed a daily sleep log and various other assessments.

During treatment, a light box was placed 86.4 cm away from the patient. Participants were instructed to sit quietly and not nap. They could listen to music or audiobooks.

The 31 patients (18 females) had an average age of about 63 (range, 32 to 77) and an average disease duration of about six years. Among patients who received bright light therapy, mean Epworth Sleepiness Scale score significantly improved from 15.81 at baseline to 11.19 post intervention. The improvement was significantly greater than that for patients in the control group, who had a mean Epworth Sleepiness Scale score of 15.47 at baseline and 13.67 post intervention.

Improvements in sleep quality, latency, and fragmentation were significantly greater in the bright light therapy group than in the control group. In both treatment arms, light therapy was associated with increased daily physical activity, as assessed by actigraphy, and reduced disease severity, as assessed by the Unified Parkinson’s Disease Rating Scale. Light therapy was not associated with significant changes in depression, anxiety, or quality of life.

In the active treatment group, one patient reported headache, and another patient reported sleepiness. One participant in the control group reported itchy eyes. The adverse events resolved spontaneously, and adherence to the study protocol was excellent, the researchers said.

Although improvement in the control arm may have been due to the placebo effect, it is also possible that “anchoring the light therapy to a strict twice-daily regimen provided means for structuring daily activities, which itself may be an interesting possible mechanism underlying the beneficial effects of … light therapy,” Dr. Videnovic and colleagues said. Future studies should address the optimal treatment parameters for light therapy in Parkinson’s disease, they added.

Whether light therapy produces direct alerting effects, influences the circadian system, or works through another mechanism is not clear. A limitation of the study was that light levels were not measured throughout the day, so patients in the control group could have received more light from other sources overall, compared with patients in the active treatment group, the investigators noted.

Chronobiologic Interventions

The study shows that chronobiologic interventions “can be used therapeutically in patients with Parkinson’s disease” and “introduce a new concept into the much-studied phenomenon of disturbed sleep and wakefulness in Parkinson’s disease,” said Birgit Högl, MD, of the Department of Neurology at the Medical University of Innsbruck in Austria, in an accompanying editorial. Although the study of chronobiology is complex, certain aspects of chronobiology can be “integrated into routine medical practice and improve outcomes for patients,” Dr. Högl said.

—Jake Remaly

Suggested Reading

Högl B. Circadian rhythms and chronotherapeutics-Underappreciated approach to improving sleep and wakefulness in Parkinson disease. JAMA Neurol. 2017;74(4):387-388.

Videnovic A, Klerman EB, Wang W, et al. Timed light therapy for sleep and daytime sleepiness associated with Parkinson disease: A randomized clinical trial. JAMA Neurol. 2017;74(4):411-418.

Light therapy may reduce excessive daytime sleepiness and improve sleep quality in patients with Parkinson’s disease, according to trial results published in the April issue of JAMA Neurology. The treatment modality is well tolerated, widely available, and “relatively easy to prescribe and incorporate into a clinical practice,” said Aleksandar Videnovic, MD, a neurologist at Massachusetts General Hospital in Boston, and colleagues.

Impaired sleep and alertness are common nonmotor manifestations of Parkinson’s disease with limited treatment options. Patients’ sleep disturbances have been attributed to Parkinson’s disease symptoms, adverse medication effects, and neurodegeneration of central sleep regulatory areas. Altered circadian rhythms also may play a role. Supplemental exposure to bright light improves sleep quality and daytime vigilance in healthy older people and patients with dementia, but the treatment modality has not been studied systematically in patients with Parkinson’s disease, the researchers said.

One-Hour Treatment Intervals

To determine the safety and efficacy of light therapy on excessive daytime sleepiness associated with Parkinson’s disease, Dr. Videnovic and colleagues conducted a randomized, placebo-controlled trial.

They enrolled 31 patients with Parkinson’s disease and excessive daytime sleepiness (ie, an Epworth Sleepiness Scale score of 12 or greater). Patients were receiving stable dopaminergic therapy and did not have cognitive impairment or a primary sleep disorder. Investigators randomized participants 1:1 to receive bright light therapy (10,000 lux) or a control condition of dim-red light therapy (less than 300 lux). After a two-week baseline phase, participants received light therapy in one-hour intervals twice daily—in the morning (between 9 am and 11 am) and in the afternoon (between 5 pm and 7 pm)—for 14 days. The primary outcome measure was change in Epworth Sleepiness Scale score from baseline. During the study, each patient wore an actigraphy monitor and completed a daily sleep log and various other assessments.

During treatment, a light box was placed 86.4 cm away from the patient. Participants were instructed to sit quietly and not nap. They could listen to music or audiobooks.

The 31 patients (18 females) had an average age of about 63 (range, 32 to 77) and an average disease duration of about six years. Among patients who received bright light therapy, mean Epworth Sleepiness Scale score significantly improved from 15.81 at baseline to 11.19 post intervention. The improvement was significantly greater than that for patients in the control group, who had a mean Epworth Sleepiness Scale score of 15.47 at baseline and 13.67 post intervention.

Improvements in sleep quality, latency, and fragmentation were significantly greater in the bright light therapy group than in the control group. In both treatment arms, light therapy was associated with increased daily physical activity, as assessed by actigraphy, and reduced disease severity, as assessed by the Unified Parkinson’s Disease Rating Scale. Light therapy was not associated with significant changes in depression, anxiety, or quality of life.

In the active treatment group, one patient reported headache, and another patient reported sleepiness. One participant in the control group reported itchy eyes. The adverse events resolved spontaneously, and adherence to the study protocol was excellent, the researchers said.

Although improvement in the control arm may have been due to the placebo effect, it is also possible that “anchoring the light therapy to a strict twice-daily regimen provided means for structuring daily activities, which itself may be an interesting possible mechanism underlying the beneficial effects of … light therapy,” Dr. Videnovic and colleagues said. Future studies should address the optimal treatment parameters for light therapy in Parkinson’s disease, they added.

Whether light therapy produces direct alerting effects, influences the circadian system, or works through another mechanism is not clear. A limitation of the study was that light levels were not measured throughout the day, so patients in the control group could have received more light from other sources overall, compared with patients in the active treatment group, the investigators noted.

Chronobiologic Interventions

The study shows that chronobiologic interventions “can be used therapeutically in patients with Parkinson’s disease” and “introduce a new concept into the much-studied phenomenon of disturbed sleep and wakefulness in Parkinson’s disease,” said Birgit Högl, MD, of the Department of Neurology at the Medical University of Innsbruck in Austria, in an accompanying editorial. Although the study of chronobiology is complex, certain aspects of chronobiology can be “integrated into routine medical practice and improve outcomes for patients,” Dr. Högl said.

—Jake Remaly

Suggested Reading

Högl B. Circadian rhythms and chronotherapeutics-Underappreciated approach to improving sleep and wakefulness in Parkinson disease. JAMA Neurol. 2017;74(4):387-388.

Videnovic A, Klerman EB, Wang W, et al. Timed light therapy for sleep and daytime sleepiness associated with Parkinson disease: A randomized clinical trial. JAMA Neurol. 2017;74(4):411-418.

Light therapy may reduce excessive daytime sleepiness and improve sleep quality in patients with Parkinson’s disease, according to trial results published in the April issue of JAMA Neurology. The treatment modality is well tolerated, widely available, and “relatively easy to prescribe and incorporate into a clinical practice,” said Aleksandar Videnovic, MD, a neurologist at Massachusetts General Hospital in Boston, and colleagues.

Impaired sleep and alertness are common nonmotor manifestations of Parkinson’s disease with limited treatment options. Patients’ sleep disturbances have been attributed to Parkinson’s disease symptoms, adverse medication effects, and neurodegeneration of central sleep regulatory areas. Altered circadian rhythms also may play a role. Supplemental exposure to bright light improves sleep quality and daytime vigilance in healthy older people and patients with dementia, but the treatment modality has not been studied systematically in patients with Parkinson’s disease, the researchers said.

One-Hour Treatment Intervals

To determine the safety and efficacy of light therapy on excessive daytime sleepiness associated with Parkinson’s disease, Dr. Videnovic and colleagues conducted a randomized, placebo-controlled trial.

They enrolled 31 patients with Parkinson’s disease and excessive daytime sleepiness (ie, an Epworth Sleepiness Scale score of 12 or greater). Patients were receiving stable dopaminergic therapy and did not have cognitive impairment or a primary sleep disorder. Investigators randomized participants 1:1 to receive bright light therapy (10,000 lux) or a control condition of dim-red light therapy (less than 300 lux). After a two-week baseline phase, participants received light therapy in one-hour intervals twice daily—in the morning (between 9 am and 11 am) and in the afternoon (between 5 pm and 7 pm)—for 14 days. The primary outcome measure was change in Epworth Sleepiness Scale score from baseline. During the study, each patient wore an actigraphy monitor and completed a daily sleep log and various other assessments.

During treatment, a light box was placed 86.4 cm away from the patient. Participants were instructed to sit quietly and not nap. They could listen to music or audiobooks.

The 31 patients (18 females) had an average age of about 63 (range, 32 to 77) and an average disease duration of about six years. Among patients who received bright light therapy, mean Epworth Sleepiness Scale score significantly improved from 15.81 at baseline to 11.19 post intervention. The improvement was significantly greater than that for patients in the control group, who had a mean Epworth Sleepiness Scale score of 15.47 at baseline and 13.67 post intervention.

Improvements in sleep quality, latency, and fragmentation were significantly greater in the bright light therapy group than in the control group. In both treatment arms, light therapy was associated with increased daily physical activity, as assessed by actigraphy, and reduced disease severity, as assessed by the Unified Parkinson’s Disease Rating Scale. Light therapy was not associated with significant changes in depression, anxiety, or quality of life.

In the active treatment group, one patient reported headache, and another patient reported sleepiness. One participant in the control group reported itchy eyes. The adverse events resolved spontaneously, and adherence to the study protocol was excellent, the researchers said.

Although improvement in the control arm may have been due to the placebo effect, it is also possible that “anchoring the light therapy to a strict twice-daily regimen provided means for structuring daily activities, which itself may be an interesting possible mechanism underlying the beneficial effects of … light therapy,” Dr. Videnovic and colleagues said. Future studies should address the optimal treatment parameters for light therapy in Parkinson’s disease, they added.

Whether light therapy produces direct alerting effects, influences the circadian system, or works through another mechanism is not clear. A limitation of the study was that light levels were not measured throughout the day, so patients in the control group could have received more light from other sources overall, compared with patients in the active treatment group, the investigators noted.

Chronobiologic Interventions

The study shows that chronobiologic interventions “can be used therapeutically in patients with Parkinson’s disease” and “introduce a new concept into the much-studied phenomenon of disturbed sleep and wakefulness in Parkinson’s disease,” said Birgit Högl, MD, of the Department of Neurology at the Medical University of Innsbruck in Austria, in an accompanying editorial. Although the study of chronobiology is complex, certain aspects of chronobiology can be “integrated into routine medical practice and improve outcomes for patients,” Dr. Högl said.

—Jake Remaly

Suggested Reading

Högl B. Circadian rhythms and chronotherapeutics-Underappreciated approach to improving sleep and wakefulness in Parkinson disease. JAMA Neurol. 2017;74(4):387-388.

Videnovic A, Klerman EB, Wang W, et al. Timed light therapy for sleep and daytime sleepiness associated with Parkinson disease: A randomized clinical trial. JAMA Neurol. 2017;74(4):411-418.

A new tool called the tremor stability index (TSI) can aid the differential diagnosis of essential tremor and Parkinson’s disease, according to research published online ahead of print April 27 in Brain. The TSI has a diagnostic accuracy of approximately 90% for these syndromes, and neurologists can derive it from brief, inexpensive, and noninvasive tremor recordings.

Misdiagnosis of tremor syndromes is common and affects clinical care and research. The current gold standard for diagnosis is clinical evaluation by a specialist in movement disorders. In 2015, Brittain et al found that the frequency of tremor remains stable over a narrow range of frequencies in essential tremor, but remains stable over a broader range in Parkinson’s disease.

Lazzaro di Biase, PhD, a postdoctoral researcher at Università Campus Bio-Medico in Rome, and colleagues analyzed the overall tremor stability characteristics of essential tremor and Parkinson’s disease to develop the TSI, an interquartile range of the change in tremor frequency. The investigators performed kinematic measurements on a test cohort of 16 patients with tremor-dominant Parkinson’s disease and 20 patients with essential tremor. Data were collected after overnight withdrawal of medications. A validation cohort included new and original data taken from published studies and encompassed 42 rest tremor recordings of patients with Parkinson’s disease and eight postural tremor recordings of patients with essential tremor.

In the test cohort, Dr. di Biase and colleagues found no difference in mean instantaneous frequency between patient groups, but saw a difference in TSI between groups. For every unit increase in TSI, the odds of a patient having a diagnosis of essential tremor increased by a factor of 14.8. The optimal TSI threshold in the test cohort was 1.05; TSI values greater than 1.05 indicated a diagnosis of essential tremor, and TSI values of 1.05 or less indicated a diagnosis of Parkinson’s disease. Follow-up recordings made one year and seven months later confirmed the stability of the TSI over time for patients with Parkinson’s disease.

The investigators found a difference in mean instantaneous frequency between groups in the validation cohort, as well as a significant difference in TSI between essential tremor and Parkinson’s disease. For every unit increase in TSI, the odds of a patient having a diagnosis of essential tremor increased by a factor of 5.7. When the researchers applied the threshold of 1.05, they found that the TSI had excellent discriminatory ability. In addition, bootstrap analysis revealed that the TSI outperformed the mean harmonic power of postural tremor harmonics 72% of the time.

The TSI was robust when applied to various patient groups with differing demographics and clinical characteristics. The devices used to record tremor did not affect the TSI’s reliability, nor did postural context. According to the researchers, the TSI can be rapidly estimated from 10-second recordings of tremor.

“The TSI provides a promising diagnostic aid in clinical practice and could be a useful tool to avoid selection errors in clinical trials,” said Dr. di Biase. “It will be important to see if this index can also distinguish dystonic tremor, which may masquerade as Parkinson’s disease or essential tremor,” he added.

—Erik Greb

Suggested Reading

di Biase L, Brittain JS, Shah SA, et al. Tremor stability index: a new tool for differential diagnosis in tremor syndromes. Brain. 2017 Apr 27 [Epub ahead of print].

A new tool called the tremor stability index (TSI) can aid the differential diagnosis of essential tremor and Parkinson’s disease, according to research published online ahead of print April 27 in Brain. The TSI has a diagnostic accuracy of approximately 90% for these syndromes, and neurologists can derive it from brief, inexpensive, and noninvasive tremor recordings.

Misdiagnosis of tremor syndromes is common and affects clinical care and research. The current gold standard for diagnosis is clinical evaluation by a specialist in movement disorders. In 2015, Brittain et al found that the frequency of tremor remains stable over a narrow range of frequencies in essential tremor, but remains stable over a broader range in Parkinson’s disease.

Lazzaro di Biase, PhD, a postdoctoral researcher at Università Campus Bio-Medico in Rome, and colleagues analyzed the overall tremor stability characteristics of essential tremor and Parkinson’s disease to develop the TSI, an interquartile range of the change in tremor frequency. The investigators performed kinematic measurements on a test cohort of 16 patients with tremor-dominant Parkinson’s disease and 20 patients with essential tremor. Data were collected after overnight withdrawal of medications. A validation cohort included new and original data taken from published studies and encompassed 42 rest tremor recordings of patients with Parkinson’s disease and eight postural tremor recordings of patients with essential tremor.

In the test cohort, Dr. di Biase and colleagues found no difference in mean instantaneous frequency between patient groups, but saw a difference in TSI between groups. For every unit increase in TSI, the odds of a patient having a diagnosis of essential tremor increased by a factor of 14.8. The optimal TSI threshold in the test cohort was 1.05; TSI values greater than 1.05 indicated a diagnosis of essential tremor, and TSI values of 1.05 or less indicated a diagnosis of Parkinson’s disease. Follow-up recordings made one year and seven months later confirmed the stability of the TSI over time for patients with Parkinson’s disease.

The investigators found a difference in mean instantaneous frequency between groups in the validation cohort, as well as a significant difference in TSI between essential tremor and Parkinson’s disease. For every unit increase in TSI, the odds of a patient having a diagnosis of essential tremor increased by a factor of 5.7. When the researchers applied the threshold of 1.05, they found that the TSI had excellent discriminatory ability. In addition, bootstrap analysis revealed that the TSI outperformed the mean harmonic power of postural tremor harmonics 72% of the time.

The TSI was robust when applied to various patient groups with differing demographics and clinical characteristics. The devices used to record tremor did not affect the TSI’s reliability, nor did postural context. According to the researchers, the TSI can be rapidly estimated from 10-second recordings of tremor.

“The TSI provides a promising diagnostic aid in clinical practice and could be a useful tool to avoid selection errors in clinical trials,” said Dr. di Biase. “It will be important to see if this index can also distinguish dystonic tremor, which may masquerade as Parkinson’s disease or essential tremor,” he added.

—Erik Greb

Suggested Reading

di Biase L, Brittain JS, Shah SA, et al. Tremor stability index: a new tool for differential diagnosis in tremor syndromes. Brain. 2017 Apr 27 [Epub ahead of print].

A new tool called the tremor stability index (TSI) can aid the differential diagnosis of essential tremor and Parkinson’s disease, according to research published online ahead of print April 27 in Brain. The TSI has a diagnostic accuracy of approximately 90% for these syndromes, and neurologists can derive it from brief, inexpensive, and noninvasive tremor recordings.

Misdiagnosis of tremor syndromes is common and affects clinical care and research. The current gold standard for diagnosis is clinical evaluation by a specialist in movement disorders. In 2015, Brittain et al found that the frequency of tremor remains stable over a narrow range of frequencies in essential tremor, but remains stable over a broader range in Parkinson’s disease.

Lazzaro di Biase, PhD, a postdoctoral researcher at Università Campus Bio-Medico in Rome, and colleagues analyzed the overall tremor stability characteristics of essential tremor and Parkinson’s disease to develop the TSI, an interquartile range of the change in tremor frequency. The investigators performed kinematic measurements on a test cohort of 16 patients with tremor-dominant Parkinson’s disease and 20 patients with essential tremor. Data were collected after overnight withdrawal of medications. A validation cohort included new and original data taken from published studies and encompassed 42 rest tremor recordings of patients with Parkinson’s disease and eight postural tremor recordings of patients with essential tremor.

In the test cohort, Dr. di Biase and colleagues found no difference in mean instantaneous frequency between patient groups, but saw a difference in TSI between groups. For every unit increase in TSI, the odds of a patient having a diagnosis of essential tremor increased by a factor of 14.8. The optimal TSI threshold in the test cohort was 1.05; TSI values greater than 1.05 indicated a diagnosis of essential tremor, and TSI values of 1.05 or less indicated a diagnosis of Parkinson’s disease. Follow-up recordings made one year and seven months later confirmed the stability of the TSI over time for patients with Parkinson’s disease.

The investigators found a difference in mean instantaneous frequency between groups in the validation cohort, as well as a significant difference in TSI between essential tremor and Parkinson’s disease. For every unit increase in TSI, the odds of a patient having a diagnosis of essential tremor increased by a factor of 5.7. When the researchers applied the threshold of 1.05, they found that the TSI had excellent discriminatory ability. In addition, bootstrap analysis revealed that the TSI outperformed the mean harmonic power of postural tremor harmonics 72% of the time.

The TSI was robust when applied to various patient groups with differing demographics and clinical characteristics. The devices used to record tremor did not affect the TSI’s reliability, nor did postural context. According to the researchers, the TSI can be rapidly estimated from 10-second recordings of tremor.

“The TSI provides a promising diagnostic aid in clinical practice and could be a useful tool to avoid selection errors in clinical trials,” said Dr. di Biase. “It will be important to see if this index can also distinguish dystonic tremor, which may masquerade as Parkinson’s disease or essential tremor,” he added.

—Erik Greb

Suggested Reading

di Biase L, Brittain JS, Shah SA, et al. Tremor stability index: a new tool for differential diagnosis in tremor syndromes. Brain. 2017 Apr 27 [Epub ahead of print].

All forms of cirrhosis are associated with an increased risk of stroke, especially hemorrhagic stroke, according to a large, nationally representative cohort study published online ahead of print June 5 in JAMA Neurology.

Cirrhosis is commonly associated with “extrahepatic hemorrhagic and thrombotic processes, such as gastrointestinal bleeding and venous thromboembolism. [But] the cerebrovascular complications of cirrhosis are comparatively less well understood,” said Neal S. Parikh, MD, Resident Physician Neurologist at New York-Presbyterian Hospital in New York City, and colleagues. Previous studies of the association between cirrhosis and stroke have been small and have yielded conflicting results.

To examine the association between cirrhosis and stroke, Dr. Parikh and colleagues conducted a retrospective study that involved 1,618,059 Medicare beneficiaries hospitalized during a six-year period. In all, 15,586 patients (1%) had cirrhosis at baseline, and 77,268 patients developed stroke during a mean of 4.3 years of follow-up. In addition, the overall incidence of stroke was 2.17% per year among patients with cirrhosis, compared with 1.11% per year among patients without cirrhosis. After the data were adjusted to account for stroke risk factors, relevant comorbidities, and demographic traits, the annual incidence of any type of stroke was significantly higher with cirrhosis than without cirrhosis (hazard ratio [HR], 1.4). The association was stronger for intracranial hemorrhage (HR, 1.9) and subarachnoid hemorrhage (HR, 2.4) than for ischemic stroke (HR, 1.3).

The results of several secondary and sensitivity analyses were consistent with those of the primary analysis, regardless of whether the cirrhosis was alcohol-related or the stroke was fatal. The association was strongest among patients who had decompensated cirrhosis and was not evident at all among patients who had mild liver disease, said Dr. Parikh and colleagues.

Although this study was not designed to explore the reasons for an association between cirrhosis and stroke, the investigators noted several possible explanations. First, “cirrhosis is accompanied by a mixed coagulopathy, with potential implications for hemorrhagic and thrombotic processes.” It has been linked to many bleeding complications, including, most recently, cerebral microhemorrhages detectable on brain MRI. In addition, the underlying causes of cirrhosis, including alcohol abuse, hepatitis infection, and metabolic disease, may also contribute to stroke risk.

Alternatively, clinicians caring for patients with cirrhosis “may limit the aggressiveness of stroke prevention”—for example, by limiting antithrombotic medications or statins—because they are mindful of the patient’s increased risk of bleeding and hepatic toxicity, the authors said.

—Mary Ann Moon

Suggested Reading

Parikh NS, Navi BB, Schneider Y, et al. Association between cirrhosis and stroke in a nationally representative cohort. JAMA Neurol. 2017 Jun 5 [Epub ahead of print].

All forms of cirrhosis are associated with an increased risk of stroke, especially hemorrhagic stroke, according to a large, nationally representative cohort study published online ahead of print June 5 in JAMA Neurology.

Cirrhosis is commonly associated with “extrahepatic hemorrhagic and thrombotic processes, such as gastrointestinal bleeding and venous thromboembolism. [But] the cerebrovascular complications of cirrhosis are comparatively less well understood,” said Neal S. Parikh, MD, Resident Physician Neurologist at New York-Presbyterian Hospital in New York City, and colleagues. Previous studies of the association between cirrhosis and stroke have been small and have yielded conflicting results.

To examine the association between cirrhosis and stroke, Dr. Parikh and colleagues conducted a retrospective study that involved 1,618,059 Medicare beneficiaries hospitalized during a six-year period. In all, 15,586 patients (1%) had cirrhosis at baseline, and 77,268 patients developed stroke during a mean of 4.3 years of follow-up. In addition, the overall incidence of stroke was 2.17% per year among patients with cirrhosis, compared with 1.11% per year among patients without cirrhosis. After the data were adjusted to account for stroke risk factors, relevant comorbidities, and demographic traits, the annual incidence of any type of stroke was significantly higher with cirrhosis than without cirrhosis (hazard ratio [HR], 1.4). The association was stronger for intracranial hemorrhage (HR, 1.9) and subarachnoid hemorrhage (HR, 2.4) than for ischemic stroke (HR, 1.3).

The results of several secondary and sensitivity analyses were consistent with those of the primary analysis, regardless of whether the cirrhosis was alcohol-related or the stroke was fatal. The association was strongest among patients who had decompensated cirrhosis and was not evident at all among patients who had mild liver disease, said Dr. Parikh and colleagues.

Although this study was not designed to explore the reasons for an association between cirrhosis and stroke, the investigators noted several possible explanations. First, “cirrhosis is accompanied by a mixed coagulopathy, with potential implications for hemorrhagic and thrombotic processes.” It has been linked to many bleeding complications, including, most recently, cerebral microhemorrhages detectable on brain MRI. In addition, the underlying causes of cirrhosis, including alcohol abuse, hepatitis infection, and metabolic disease, may also contribute to stroke risk.

Alternatively, clinicians caring for patients with cirrhosis “may limit the aggressiveness of stroke prevention”—for example, by limiting antithrombotic medications or statins—because they are mindful of the patient’s increased risk of bleeding and hepatic toxicity, the authors said.

—Mary Ann Moon

Suggested Reading

Parikh NS, Navi BB, Schneider Y, et al. Association between cirrhosis and stroke in a nationally representative cohort. JAMA Neurol. 2017 Jun 5 [Epub ahead of print].

All forms of cirrhosis are associated with an increased risk of stroke, especially hemorrhagic stroke, according to a large, nationally representative cohort study published online ahead of print June 5 in JAMA Neurology.

Cirrhosis is commonly associated with “extrahepatic hemorrhagic and thrombotic processes, such as gastrointestinal bleeding and venous thromboembolism. [But] the cerebrovascular complications of cirrhosis are comparatively less well understood,” said Neal S. Parikh, MD, Resident Physician Neurologist at New York-Presbyterian Hospital in New York City, and colleagues. Previous studies of the association between cirrhosis and stroke have been small and have yielded conflicting results.

To examine the association between cirrhosis and stroke, Dr. Parikh and colleagues conducted a retrospective study that involved 1,618,059 Medicare beneficiaries hospitalized during a six-year period. In all, 15,586 patients (1%) had cirrhosis at baseline, and 77,268 patients developed stroke during a mean of 4.3 years of follow-up. In addition, the overall incidence of stroke was 2.17% per year among patients with cirrhosis, compared with 1.11% per year among patients without cirrhosis. After the data were adjusted to account for stroke risk factors, relevant comorbidities, and demographic traits, the annual incidence of any type of stroke was significantly higher with cirrhosis than without cirrhosis (hazard ratio [HR], 1.4). The association was stronger for intracranial hemorrhage (HR, 1.9) and subarachnoid hemorrhage (HR, 2.4) than for ischemic stroke (HR, 1.3).

The results of several secondary and sensitivity analyses were consistent with those of the primary analysis, regardless of whether the cirrhosis was alcohol-related or the stroke was fatal. The association was strongest among patients who had decompensated cirrhosis and was not evident at all among patients who had mild liver disease, said Dr. Parikh and colleagues.

Although this study was not designed to explore the reasons for an association between cirrhosis and stroke, the investigators noted several possible explanations. First, “cirrhosis is accompanied by a mixed coagulopathy, with potential implications for hemorrhagic and thrombotic processes.” It has been linked to many bleeding complications, including, most recently, cerebral microhemorrhages detectable on brain MRI. In addition, the underlying causes of cirrhosis, including alcohol abuse, hepatitis infection, and metabolic disease, may also contribute to stroke risk.

Alternatively, clinicians caring for patients with cirrhosis “may limit the aggressiveness of stroke prevention”—for example, by limiting antithrombotic medications or statins—because they are mindful of the patient’s increased risk of bleeding and hepatic toxicity, the authors said.

—Mary Ann Moon

Suggested Reading

Parikh NS, Navi BB, Schneider Y, et al. Association between cirrhosis and stroke in a nationally representative cohort. JAMA Neurol. 2017 Jun 5 [Epub ahead of print].

Eye tracking is a noninvasive technique that may help to assess two key physiologic signs of concussion, intracranial pressure (ICP) and ocular motility dysfunction, according to a study published online ahead of print June 2 in the Journal of Neurosurgery. This technique does not require a trained examiner, pupil dilation, imaging studies, or an invasive procedure such as lumbar or ventricular puncture, the authors noted.

“With these data, we are presenting a new application for eye-tracking technology, as well as a new mechanism for assessment of elevated ICP that is noninvasive, automatable, and could potentially be performed and analyzed remotely,” said Uzma Samadani, MD, PhD, Associate Professor of Neurosurgery at the University of Minnesota in Minneapolis, and colleagues.

The boundaries of normal and elevated intracranial pressure vary between patients, said the authors. People with elevated intracranial pressure can develop abnormalities in global cerebral functioning. Elevated ICP can also affect the function of cranial nerves, which may contribute to ocular dysmotility. Dr. Samadani and colleagues assessed the impact of elevated ICP on eye-tracking sessions performed while patients watched a short film clip.

Eligible participants ranged in age from 18 to 70, were admitted to the Bellevue Hospital neurosurgical intensive care unit in New York City with vision correctable to within 20/500 bilaterally, and had denied a history of ocular dysmotility. In addition, these patients were conscious and able to communicate and to provide an ophthalmologic, medical, and neurologic history, as well as medications, drugs, and alcohol consumed within 24 hours prior to eye tracking.

Awake patients who required placement of an ICP monitor for clinical purposes underwent eye tracking while watching a 220-second continuously playing video. The investigators recorded pupil position at 500 Hz and calculated metrics associated with each eye individually and both eyes together. In addition, the researchers performed linear regression with generalized estimating equations to test the association of eye-tracking metrics with changes in ICP.

The investigators performed eye tracking at ICP levels ranging from –3 mm Hg to 30 mm Hg in 23 patients (12 women, mean age 46.8) on 55 occasions. Eye-tracking measures correlating with cranial nerve function decreased linearly with increasing ICP.

Researchers also found that measures for cranial nerve VI were the most prominently affected. The area under the curve for eye-tracking metrics to discriminate between an ICP <12 mm Hg and one of ≥12 mm Hg was 0.798. To discriminate between an ICP <15 mm Hg and one of ≥15 mm Hg, the area under the curve was 0.833. Finally, to discriminate between an ICP <20 mm Hg and ≥20 mm Hg, the area under the curve was 0.889.

Overall, increasingly elevated ICP was associated with increasingly abnormal eye tracking detected while patients were watching the short film. The “technology has clinical applications for assessment of shunt malfunction, pseudotumor cerebri, concussion, and prevention of second-impact syndrome,” said Dr. Samadani and colleagues.

The major limitation of this study was the lack of continuous data in patients with higher ICP recordings, the authors said. Few patients with elevated ICP could open their eyes long enough to undergo eye tracking.

—Erica Tricarico

Suggested Reading

Kolecki R, Dammavalam V, Zahid A, et al. Elevated intracranial pressure and reversible eye-tracking changes detected while viewing a film clip. J Neurosurg. 2017 Jun 2 [Epub ahead of print].

Eye tracking is a noninvasive technique that may help to assess two key physiologic signs of concussion, intracranial pressure (ICP) and ocular motility dysfunction, according to a study published online ahead of print June 2 in the Journal of Neurosurgery. This technique does not require a trained examiner, pupil dilation, imaging studies, or an invasive procedure such as lumbar or ventricular puncture, the authors noted.

“With these data, we are presenting a new application for eye-tracking technology, as well as a new mechanism for assessment of elevated ICP that is noninvasive, automatable, and could potentially be performed and analyzed remotely,” said Uzma Samadani, MD, PhD, Associate Professor of Neurosurgery at the University of Minnesota in Minneapolis, and colleagues.

The boundaries of normal and elevated intracranial pressure vary between patients, said the authors. People with elevated intracranial pressure can develop abnormalities in global cerebral functioning. Elevated ICP can also affect the function of cranial nerves, which may contribute to ocular dysmotility. Dr. Samadani and colleagues assessed the impact of elevated ICP on eye-tracking sessions performed while patients watched a short film clip.

Eligible participants ranged in age from 18 to 70, were admitted to the Bellevue Hospital neurosurgical intensive care unit in New York City with vision correctable to within 20/500 bilaterally, and had denied a history of ocular dysmotility. In addition, these patients were conscious and able to communicate and to provide an ophthalmologic, medical, and neurologic history, as well as medications, drugs, and alcohol consumed within 24 hours prior to eye tracking.

Awake patients who required placement of an ICP monitor for clinical purposes underwent eye tracking while watching a 220-second continuously playing video. The investigators recorded pupil position at 500 Hz and calculated metrics associated with each eye individually and both eyes together. In addition, the researchers performed linear regression with generalized estimating equations to test the association of eye-tracking metrics with changes in ICP.

The investigators performed eye tracking at ICP levels ranging from –3 mm Hg to 30 mm Hg in 23 patients (12 women, mean age 46.8) on 55 occasions. Eye-tracking measures correlating with cranial nerve function decreased linearly with increasing ICP.

Researchers also found that measures for cranial nerve VI were the most prominently affected. The area under the curve for eye-tracking metrics to discriminate between an ICP <12 mm Hg and one of ≥12 mm Hg was 0.798. To discriminate between an ICP <15 mm Hg and one of ≥15 mm Hg, the area under the curve was 0.833. Finally, to discriminate between an ICP <20 mm Hg and ≥20 mm Hg, the area under the curve was 0.889.

Overall, increasingly elevated ICP was associated with increasingly abnormal eye tracking detected while patients were watching the short film. The “technology has clinical applications for assessment of shunt malfunction, pseudotumor cerebri, concussion, and prevention of second-impact syndrome,” said Dr. Samadani and colleagues.

The major limitation of this study was the lack of continuous data in patients with higher ICP recordings, the authors said. Few patients with elevated ICP could open their eyes long enough to undergo eye tracking.

—Erica Tricarico

Suggested Reading

Kolecki R, Dammavalam V, Zahid A, et al. Elevated intracranial pressure and reversible eye-tracking changes detected while viewing a film clip. J Neurosurg. 2017 Jun 2 [Epub ahead of print].

Eye tracking is a noninvasive technique that may help to assess two key physiologic signs of concussion, intracranial pressure (ICP) and ocular motility dysfunction, according to a study published online ahead of print June 2 in the Journal of Neurosurgery. This technique does not require a trained examiner, pupil dilation, imaging studies, or an invasive procedure such as lumbar or ventricular puncture, the authors noted.

“With these data, we are presenting a new application for eye-tracking technology, as well as a new mechanism for assessment of elevated ICP that is noninvasive, automatable, and could potentially be performed and analyzed remotely,” said Uzma Samadani, MD, PhD, Associate Professor of Neurosurgery at the University of Minnesota in Minneapolis, and colleagues.

The boundaries of normal and elevated intracranial pressure vary between patients, said the authors. People with elevated intracranial pressure can develop abnormalities in global cerebral functioning. Elevated ICP can also affect the function of cranial nerves, which may contribute to ocular dysmotility. Dr. Samadani and colleagues assessed the impact of elevated ICP on eye-tracking sessions performed while patients watched a short film clip.

Eligible participants ranged in age from 18 to 70, were admitted to the Bellevue Hospital neurosurgical intensive care unit in New York City with vision correctable to within 20/500 bilaterally, and had denied a history of ocular dysmotility. In addition, these patients were conscious and able to communicate and to provide an ophthalmologic, medical, and neurologic history, as well as medications, drugs, and alcohol consumed within 24 hours prior to eye tracking.

Awake patients who required placement of an ICP monitor for clinical purposes underwent eye tracking while watching a 220-second continuously playing video. The investigators recorded pupil position at 500 Hz and calculated metrics associated with each eye individually and both eyes together. In addition, the researchers performed linear regression with generalized estimating equations to test the association of eye-tracking metrics with changes in ICP.

The investigators performed eye tracking at ICP levels ranging from –3 mm Hg to 30 mm Hg in 23 patients (12 women, mean age 46.8) on 55 occasions. Eye-tracking measures correlating with cranial nerve function decreased linearly with increasing ICP.

Researchers also found that measures for cranial nerve VI were the most prominently affected. The area under the curve for eye-tracking metrics to discriminate between an ICP <12 mm Hg and one of ≥12 mm Hg was 0.798. To discriminate between an ICP <15 mm Hg and one of ≥15 mm Hg, the area under the curve was 0.833. Finally, to discriminate between an ICP <20 mm Hg and ≥20 mm Hg, the area under the curve was 0.889.

Overall, increasingly elevated ICP was associated with increasingly abnormal eye tracking detected while patients were watching the short film. The “technology has clinical applications for assessment of shunt malfunction, pseudotumor cerebri, concussion, and prevention of second-impact syndrome,” said Dr. Samadani and colleagues.

The major limitation of this study was the lack of continuous data in patients with higher ICP recordings, the authors said. Few patients with elevated ICP could open their eyes long enough to undergo eye tracking.

—Erica Tricarico

Suggested Reading

Kolecki R, Dammavalam V, Zahid A, et al. Elevated intracranial pressure and reversible eye-tracking changes detected while viewing a film clip. J Neurosurg. 2017 Jun 2 [Epub ahead of print].

The international Dementia With Lewy Bodies Consortium has updated its guideline for diagnosing and treating this disease. “The updated clinical criteria and associated biomarkers hopefully will lead to earlier and more accurate diagnosis, and that is key to helping patients confront this challenging illness and maximize their quality of life,” said Bradley Boeve, MD, Professor of Neurology at Mayo Clinic in Rochester, Minnesota, and a coauthor. The guideline was published online ahead of print June 7 in Neurology.

The new guideline is a refinement of the consortium’s previous guideline, which was published in December 2005. To develop the new document, the consortium solicited and reviewed reports from four multidisciplinary expert working groups. The consortium also held a meeting in which patients and caregivers participated.

The revised consensus criteria distinguish between the clinical features and diagnostic biomarkers of the disease. The core clinical features are fluctuation in cognition, attention, and arousal; visual hallucinations (eg, of people, children, or animals); parkinsonism; and REM sleep behavior disorder, according to the authors. The criteria now list hypersomnia and hyposmia as supportive clinical features.

Direct biomarker evidence of Lewy body pathology is not available, said the authors. Indicative indirect biomarkers include reduced dopamine transporter uptake in basal ganglia demonstrated by single-photon emission computerized tomography or PET imaging, reduced uptake on metaiodobenzylguanidine (MIBG) myocardial scintigraphy, and polysomnographic confirmation of REM sleep without atonia.

A neurologist can diagnose probable dementia with Lewy bodies if two or more of its core clinical features are present, with or without the presence of indicative biomarkers. This diagnosis also is warranted if only one core clinical feature is present, but one or more indicative biomarkers are present.

The document incorporates new information about previously reported aspects of dementia with Lewy bodies and gives greater diagnostic weight to REM sleep behavior disorder and 123iodine-MIBG myocardial scintigraphy. The authors describe the diagnostic role of other neuroimaging, electrophysiologic, and laboratory investigations. They recommend minor modifications to pathologic methods and criteria to take account of Alzheimer’s disease neuropathologic change, to add previously omitted Lewy-related pathology categories, and to include assessments for substantia nigra neuronal loss.

Because the literature contains few randomized controlled trials, the guideline’s recommendations about clinical management are based on expert opinion. Cholinesterase inhibitors can improve cognition, global function, activities of living, and neuropsychiatric symptoms, according to the authors. Nonpharmacologic management strategies should be developed and tested, they added.

“There remains a pressing need to understand the underlying neurobiology and pathophysiology of dementia with Lewy bodies, to develop and deliver clinical trials with both symptomatic and disease-modifying agents, and to help patients and carers worldwide to inform themselves about the disease, its prognosis, best available treatments, ongoing research, and how to get adequate support,” the authors concluded.

—Erik Greb

Suggested Reading

McKeith IG, Boeve BF, Dickson DW, et al. Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium. Neurology. 2017 Jun 7 [Epub ahead of print].

The international Dementia With Lewy Bodies Consortium has updated its guideline for diagnosing and treating this disease. “The updated clinical criteria and associated biomarkers hopefully will lead to earlier and more accurate diagnosis, and that is key to helping patients confront this challenging illness and maximize their quality of life,” said Bradley Boeve, MD, Professor of Neurology at Mayo Clinic in Rochester, Minnesota, and a coauthor. The guideline was published online ahead of print June 7 in Neurology.

The new guideline is a refinement of the consortium’s previous guideline, which was published in December 2005. To develop the new document, the consortium solicited and reviewed reports from four multidisciplinary expert working groups. The consortium also held a meeting in which patients and caregivers participated.

The revised consensus criteria distinguish between the clinical features and diagnostic biomarkers of the disease. The core clinical features are fluctuation in cognition, attention, and arousal; visual hallucinations (eg, of people, children, or animals); parkinsonism; and REM sleep behavior disorder, according to the authors. The criteria now list hypersomnia and hyposmia as supportive clinical features.

Direct biomarker evidence of Lewy body pathology is not available, said the authors. Indicative indirect biomarkers include reduced dopamine transporter uptake in basal ganglia demonstrated by single-photon emission computerized tomography or PET imaging, reduced uptake on metaiodobenzylguanidine (MIBG) myocardial scintigraphy, and polysomnographic confirmation of REM sleep without atonia.

A neurologist can diagnose probable dementia with Lewy bodies if two or more of its core clinical features are present, with or without the presence of indicative biomarkers. This diagnosis also is warranted if only one core clinical feature is present, but one or more indicative biomarkers are present.

The document incorporates new information about previously reported aspects of dementia with Lewy bodies and gives greater diagnostic weight to REM sleep behavior disorder and 123iodine-MIBG myocardial scintigraphy. The authors describe the diagnostic role of other neuroimaging, electrophysiologic, and laboratory investigations. They recommend minor modifications to pathologic methods and criteria to take account of Alzheimer’s disease neuropathologic change, to add previously omitted Lewy-related pathology categories, and to include assessments for substantia nigra neuronal loss.

Because the literature contains few randomized controlled trials, the guideline’s recommendations about clinical management are based on expert opinion. Cholinesterase inhibitors can improve cognition, global function, activities of living, and neuropsychiatric symptoms, according to the authors. Nonpharmacologic management strategies should be developed and tested, they added.

“There remains a pressing need to understand the underlying neurobiology and pathophysiology of dementia with Lewy bodies, to develop and deliver clinical trials with both symptomatic and disease-modifying agents, and to help patients and carers worldwide to inform themselves about the disease, its prognosis, best available treatments, ongoing research, and how to get adequate support,” the authors concluded.

—Erik Greb

Suggested Reading

McKeith IG, Boeve BF, Dickson DW, et al. Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium. Neurology. 2017 Jun 7 [Epub ahead of print].

The international Dementia With Lewy Bodies Consortium has updated its guideline for diagnosing and treating this disease. “The updated clinical criteria and associated biomarkers hopefully will lead to earlier and more accurate diagnosis, and that is key to helping patients confront this challenging illness and maximize their quality of life,” said Bradley Boeve, MD, Professor of Neurology at Mayo Clinic in Rochester, Minnesota, and a coauthor. The guideline was published online ahead of print June 7 in Neurology.

The new guideline is a refinement of the consortium’s previous guideline, which was published in December 2005. To develop the new document, the consortium solicited and reviewed reports from four multidisciplinary expert working groups. The consortium also held a meeting in which patients and caregivers participated.

The revised consensus criteria distinguish between the clinical features and diagnostic biomarkers of the disease. The core clinical features are fluctuation in cognition, attention, and arousal; visual hallucinations (eg, of people, children, or animals); parkinsonism; and REM sleep behavior disorder, according to the authors. The criteria now list hypersomnia and hyposmia as supportive clinical features.

Direct biomarker evidence of Lewy body pathology is not available, said the authors. Indicative indirect biomarkers include reduced dopamine transporter uptake in basal ganglia demonstrated by single-photon emission computerized tomography or PET imaging, reduced uptake on metaiodobenzylguanidine (MIBG) myocardial scintigraphy, and polysomnographic confirmation of REM sleep without atonia.

A neurologist can diagnose probable dementia with Lewy bodies if two or more of its core clinical features are present, with or without the presence of indicative biomarkers. This diagnosis also is warranted if only one core clinical feature is present, but one or more indicative biomarkers are present.

The document incorporates new information about previously reported aspects of dementia with Lewy bodies and gives greater diagnostic weight to REM sleep behavior disorder and 123iodine-MIBG myocardial scintigraphy. The authors describe the diagnostic role of other neuroimaging, electrophysiologic, and laboratory investigations. They recommend minor modifications to pathologic methods and criteria to take account of Alzheimer’s disease neuropathologic change, to add previously omitted Lewy-related pathology categories, and to include assessments for substantia nigra neuronal loss.

Because the literature contains few randomized controlled trials, the guideline’s recommendations about clinical management are based on expert opinion. Cholinesterase inhibitors can improve cognition, global function, activities of living, and neuropsychiatric symptoms, according to the authors. Nonpharmacologic management strategies should be developed and tested, they added.

“There remains a pressing need to understand the underlying neurobiology and pathophysiology of dementia with Lewy bodies, to develop and deliver clinical trials with both symptomatic and disease-modifying agents, and to help patients and carers worldwide to inform themselves about the disease, its prognosis, best available treatments, ongoing research, and how to get adequate support,” the authors concluded.

—Erik Greb

Suggested Reading

McKeith IG, Boeve BF, Dickson DW, et al. Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium. Neurology. 2017 Jun 7 [Epub ahead of print].