Neurology

Antiepileptic drugs were found to be linked with almost ninefold increased odds for two adverse skin reactions, Steven‐Johnson syndrome and toxic epidermal necrolysis, compared with non-AED medication classes in an analysis of adverse-event data from the Food and Drug Administration Adverse Event Reporting System.

Researchers at the University of Rhode Island College of Pharmacy in Kingston, who performed the retrospective study, also found that six drugs within the antiepileptic drug (AED) class had a reporting odds ratio estimate of more than 20, compared with other non-AEDs.

“Although several antiepileptic drugs have been associated with Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), the class effect and impact of other AEDs are not well described,” Eric P. Borrelli, PharmD, and his colleagues reported in Epilepsia.

The investigators examined rates of SJS and TEN for several AEDs using adverse event data from the Food and Drug Administration Adverse Event Reporting System between July 2014 and December 2017. The study investigators examined 198 adverse reaction reports related to AEDs, which was greater than any other drug class.

Overall, AEDs as a group had a reporting odds ratio risk estimate of 8.7 (95% confidence interval, 7.5-10.2), compared with non-AEDs. Similarly, the proportional reporting ratio was found to be 8.7 (95% CI, 7.5-10.2) in the AED group.

Within the class, the medications with the highest risk were zonisamide, rufinamide, and clorazepate, which had about 70-, 60-, and 56-fold higher odds for SJS and TEN, compared with all other medications. Other high-risk AEDs in the group included lamotrigine (reporting odds ratio, 53.0), carbamazepine (reporting OR, 24.5), and phenytoin (reporting OR, 26.3).

“Greater than 90% of SJS [and] TEN reactions associated with AEDs occur within the first 2 months of treatment initiation, although some AEDs have been associated with such reactions during long‐term use,” the researchers wrote.

The authors acknowledged that measures of prevalence and incidence could not be determined from these data since the number of patients taking AEDs is unknown.

“Increased awareness of this risk among both prescribers and patients, particularly variations in risk among different AEDs, along with education on early recognition of SJS [and] TEN signs [and] symptoms, may help mitigate the number and severity of these adverse events,” the researchers concluded.

The study was partially funded by the Department of Veterans Affairs. One coauthor reported receiving research funding from Pfizer, Merck (Cubist), and The Medicines Company.

SOURCE: Borrelli EP et al. Epilepsia. 2018 Nov 5. doi: 10.1111/epi.14591.

Antiepileptic drugs were found to be linked with almost ninefold increased odds for two adverse skin reactions, Steven‐Johnson syndrome and toxic epidermal necrolysis, compared with non-AED medication classes in an analysis of adverse-event data from the Food and Drug Administration Adverse Event Reporting System.

Researchers at the University of Rhode Island College of Pharmacy in Kingston, who performed the retrospective study, also found that six drugs within the antiepileptic drug (AED) class had a reporting odds ratio estimate of more than 20, compared with other non-AEDs.

“Although several antiepileptic drugs have been associated with Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), the class effect and impact of other AEDs are not well described,” Eric P. Borrelli, PharmD, and his colleagues reported in Epilepsia.

The investigators examined rates of SJS and TEN for several AEDs using adverse event data from the Food and Drug Administration Adverse Event Reporting System between July 2014 and December 2017. The study investigators examined 198 adverse reaction reports related to AEDs, which was greater than any other drug class.

Overall, AEDs as a group had a reporting odds ratio risk estimate of 8.7 (95% confidence interval, 7.5-10.2), compared with non-AEDs. Similarly, the proportional reporting ratio was found to be 8.7 (95% CI, 7.5-10.2) in the AED group.

Within the class, the medications with the highest risk were zonisamide, rufinamide, and clorazepate, which had about 70-, 60-, and 56-fold higher odds for SJS and TEN, compared with all other medications. Other high-risk AEDs in the group included lamotrigine (reporting odds ratio, 53.0), carbamazepine (reporting OR, 24.5), and phenytoin (reporting OR, 26.3).

“Greater than 90% of SJS [and] TEN reactions associated with AEDs occur within the first 2 months of treatment initiation, although some AEDs have been associated with such reactions during long‐term use,” the researchers wrote.

The authors acknowledged that measures of prevalence and incidence could not be determined from these data since the number of patients taking AEDs is unknown.

“Increased awareness of this risk among both prescribers and patients, particularly variations in risk among different AEDs, along with education on early recognition of SJS [and] TEN signs [and] symptoms, may help mitigate the number and severity of these adverse events,” the researchers concluded.

The study was partially funded by the Department of Veterans Affairs. One coauthor reported receiving research funding from Pfizer, Merck (Cubist), and The Medicines Company.

SOURCE: Borrelli EP et al. Epilepsia. 2018 Nov 5. doi: 10.1111/epi.14591.

Antiepileptic drugs were found to be linked with almost ninefold increased odds for two adverse skin reactions, Steven‐Johnson syndrome and toxic epidermal necrolysis, compared with non-AED medication classes in an analysis of adverse-event data from the Food and Drug Administration Adverse Event Reporting System.

Researchers at the University of Rhode Island College of Pharmacy in Kingston, who performed the retrospective study, also found that six drugs within the antiepileptic drug (AED) class had a reporting odds ratio estimate of more than 20, compared with other non-AEDs.

“Although several antiepileptic drugs have been associated with Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), the class effect and impact of other AEDs are not well described,” Eric P. Borrelli, PharmD, and his colleagues reported in Epilepsia.

The investigators examined rates of SJS and TEN for several AEDs using adverse event data from the Food and Drug Administration Adverse Event Reporting System between July 2014 and December 2017. The study investigators examined 198 adverse reaction reports related to AEDs, which was greater than any other drug class.

Overall, AEDs as a group had a reporting odds ratio risk estimate of 8.7 (95% confidence interval, 7.5-10.2), compared with non-AEDs. Similarly, the proportional reporting ratio was found to be 8.7 (95% CI, 7.5-10.2) in the AED group.

Within the class, the medications with the highest risk were zonisamide, rufinamide, and clorazepate, which had about 70-, 60-, and 56-fold higher odds for SJS and TEN, compared with all other medications. Other high-risk AEDs in the group included lamotrigine (reporting odds ratio, 53.0), carbamazepine (reporting OR, 24.5), and phenytoin (reporting OR, 26.3).

“Greater than 90% of SJS [and] TEN reactions associated with AEDs occur within the first 2 months of treatment initiation, although some AEDs have been associated with such reactions during long‐term use,” the researchers wrote.

The authors acknowledged that measures of prevalence and incidence could not be determined from these data since the number of patients taking AEDs is unknown.

“Increased awareness of this risk among both prescribers and patients, particularly variations in risk among different AEDs, along with education on early recognition of SJS [and] TEN signs [and] symptoms, may help mitigate the number and severity of these adverse events,” the researchers concluded.

The study was partially funded by the Department of Veterans Affairs. One coauthor reported receiving research funding from Pfizer, Merck (Cubist), and The Medicines Company.

SOURCE: Borrelli EP et al. Epilepsia. 2018 Nov 5. doi: 10.1111/epi.14591.

BERLIN – In children with an incident acquired demyelinating episode, the presence of antibodies against myelin oligodendrocyte glycoprotein (MOG) weighs against an eventual diagnosis of multiple sclerosis, especially if the child is younger than 11 years.

“Anti-MOG antibodies are present in about 30% of children with acquired demyelinating syndromes,” Giulia Fadda, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. “About 80% experience a monophasic disease course.”

The antibodies are found in almost all children who have a relapsing non-MS demyelinating disease, said Dr. Fadda, who is a postdoctoral research fellow at the University of Pennsylvania, Philadelphia. But when the antibodies are present in children with an MS diagnosis, they identify a very specific subset with atypical clinical and imaging features.

The large prospective Canadian Pediatric Demyelinating Disease Study provided the sample for the study she presented at ECTRIMS. Children are recruited into the study soon after a first demyelinating event, and they are followed clinically, serologically, and with regular brain MRI.


The cohort in Dr. Fadda’s study comprised 275 children who were a mean of about 11 years old at symptom onset. The mean clinical follow-up was 6.7 years; the mean serologic follow-up, 4 years, and the mean imaging follow-up, 3.5 years. The study examined 1,368 serum samples and 1,459 MRI scans.

Overall, 32% of the children were positive for anti-MOG antibodies. Positivity was not associated with sex, but children with antibodies were significantly younger than those without (7 vs. 12 years). In fact, 77% of anti-MOG–positive children were younger than 11 years; just 15% of older children were positive for the antibodies.

Anti-MOG positivity was also associated with certain clinical phenotypes. Among positive children, 40% presented with optic neuritis, 37% with acute disseminated encephalomyelitis, and 14% with transverse myelitis; the rest had other phenotypes. Optic neuritis was significantly less common among antibody-negative patients (22%), as was encephalomyelitis (17%). Transverse myelitis was significantly more common (31%).

The analysis of MRI scans was stratified according to age younger than 11 years and 11 years and older. “The first thing we noticed among the younger MOG-positive children is that they had a high number of lesions, which were more commonly ill-defined, diffuse, and bilateral,” Dr. Fadda said. “Almost all the brain areas were affected, with a slight preponderance of thalamic and juxtacortical lesions. Among the MOG-negative children, lesions were more often perpendicular to the major axis of the corpus callosum.”

Among the older MOG antibody–positive children, the diffuse pattern was rarer, and the lesions were frequently cerebellar. “But by far, the features that best differentiated positivity from negativity were black holes and enhancing lesions, which we saw in a high proportion of children without the antibodies” at 73% and 49%, respectively.

Over a mean imaging follow-up period of 4 years, lesions were more likely to resolve completely in antibody-positive children than in those without antibodies (50% vs. 21%). Serologically, children who were MOG-antibody negative at baseline were likely to stay that way, with 99% remaining seronegative. Positive children, on the other hand, were significantly more likely to change serologic status, with 56% turning negative and 8% serologically fluctuating over the follow-up period; only 36% remained persistently seropositive. Persistent positive status was significantly associated with younger age (7 vs. 9 years) and an optic neuritis presentation (62% vs. 27%).

Most children (81%) who were antibody positive at baseline experienced no relapses. Among the 16 children who did experience a clinical relapse, the mean time to a second event was about 1 year. Nine of these children stayed persistently positive, while five seroconverted and two had fluctuating status.

Of the 60 antibody-positive children who had a monophasic course, 23 were persistently positive, 34 seroconverted, and 3 had fluctuating serology.

Eventually, 54 children received an MS diagnosis. Of these, 83% were antibody negative at baseline. Ten children received a diagnosis of a relapsing non-MS demyelinating disorder; of these, 91% were antibody positive at baseline.

Dr. Fadda disclosed relationships with Atara Biotherapeutic and Sanofi-Genzyme.

[email protected]

SOURCE: Waters P et al. Mult Scler. 2018;24(S2):29-30, Abstract 65.

BERLIN – In children with an incident acquired demyelinating episode, the presence of antibodies against myelin oligodendrocyte glycoprotein (MOG) weighs against an eventual diagnosis of multiple sclerosis, especially if the child is younger than 11 years.

“Anti-MOG antibodies are present in about 30% of children with acquired demyelinating syndromes,” Giulia Fadda, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. “About 80% experience a monophasic disease course.”

The antibodies are found in almost all children who have a relapsing non-MS demyelinating disease, said Dr. Fadda, who is a postdoctoral research fellow at the University of Pennsylvania, Philadelphia. But when the antibodies are present in children with an MS diagnosis, they identify a very specific subset with atypical clinical and imaging features.

The large prospective Canadian Pediatric Demyelinating Disease Study provided the sample for the study she presented at ECTRIMS. Children are recruited into the study soon after a first demyelinating event, and they are followed clinically, serologically, and with regular brain MRI.


The cohort in Dr. Fadda’s study comprised 275 children who were a mean of about 11 years old at symptom onset. The mean clinical follow-up was 6.7 years; the mean serologic follow-up, 4 years, and the mean imaging follow-up, 3.5 years. The study examined 1,368 serum samples and 1,459 MRI scans.

Overall, 32% of the children were positive for anti-MOG antibodies. Positivity was not associated with sex, but children with antibodies were significantly younger than those without (7 vs. 12 years). In fact, 77% of anti-MOG–positive children were younger than 11 years; just 15% of older children were positive for the antibodies.

Anti-MOG positivity was also associated with certain clinical phenotypes. Among positive children, 40% presented with optic neuritis, 37% with acute disseminated encephalomyelitis, and 14% with transverse myelitis; the rest had other phenotypes. Optic neuritis was significantly less common among antibody-negative patients (22%), as was encephalomyelitis (17%). Transverse myelitis was significantly more common (31%).

The analysis of MRI scans was stratified according to age younger than 11 years and 11 years and older. “The first thing we noticed among the younger MOG-positive children is that they had a high number of lesions, which were more commonly ill-defined, diffuse, and bilateral,” Dr. Fadda said. “Almost all the brain areas were affected, with a slight preponderance of thalamic and juxtacortical lesions. Among the MOG-negative children, lesions were more often perpendicular to the major axis of the corpus callosum.”

Among the older MOG antibody–positive children, the diffuse pattern was rarer, and the lesions were frequently cerebellar. “But by far, the features that best differentiated positivity from negativity were black holes and enhancing lesions, which we saw in a high proportion of children without the antibodies” at 73% and 49%, respectively.

Over a mean imaging follow-up period of 4 years, lesions were more likely to resolve completely in antibody-positive children than in those without antibodies (50% vs. 21%). Serologically, children who were MOG-antibody negative at baseline were likely to stay that way, with 99% remaining seronegative. Positive children, on the other hand, were significantly more likely to change serologic status, with 56% turning negative and 8% serologically fluctuating over the follow-up period; only 36% remained persistently seropositive. Persistent positive status was significantly associated with younger age (7 vs. 9 years) and an optic neuritis presentation (62% vs. 27%).

Most children (81%) who were antibody positive at baseline experienced no relapses. Among the 16 children who did experience a clinical relapse, the mean time to a second event was about 1 year. Nine of these children stayed persistently positive, while five seroconverted and two had fluctuating status.

Of the 60 antibody-positive children who had a monophasic course, 23 were persistently positive, 34 seroconverted, and 3 had fluctuating serology.

Eventually, 54 children received an MS diagnosis. Of these, 83% were antibody negative at baseline. Ten children received a diagnosis of a relapsing non-MS demyelinating disorder; of these, 91% were antibody positive at baseline.

Dr. Fadda disclosed relationships with Atara Biotherapeutic and Sanofi-Genzyme.

[email protected]

SOURCE: Waters P et al. Mult Scler. 2018;24(S2):29-30, Abstract 65.

BERLIN – In children with an incident acquired demyelinating episode, the presence of antibodies against myelin oligodendrocyte glycoprotein (MOG) weighs against an eventual diagnosis of multiple sclerosis, especially if the child is younger than 11 years.

“Anti-MOG antibodies are present in about 30% of children with acquired demyelinating syndromes,” Giulia Fadda, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. “About 80% experience a monophasic disease course.”

The antibodies are found in almost all children who have a relapsing non-MS demyelinating disease, said Dr. Fadda, who is a postdoctoral research fellow at the University of Pennsylvania, Philadelphia. But when the antibodies are present in children with an MS diagnosis, they identify a very specific subset with atypical clinical and imaging features.

The large prospective Canadian Pediatric Demyelinating Disease Study provided the sample for the study she presented at ECTRIMS. Children are recruited into the study soon after a first demyelinating event, and they are followed clinically, serologically, and with regular brain MRI.


The cohort in Dr. Fadda’s study comprised 275 children who were a mean of about 11 years old at symptom onset. The mean clinical follow-up was 6.7 years; the mean serologic follow-up, 4 years, and the mean imaging follow-up, 3.5 years. The study examined 1,368 serum samples and 1,459 MRI scans.

Overall, 32% of the children were positive for anti-MOG antibodies. Positivity was not associated with sex, but children with antibodies were significantly younger than those without (7 vs. 12 years). In fact, 77% of anti-MOG–positive children were younger than 11 years; just 15% of older children were positive for the antibodies.

Anti-MOG positivity was also associated with certain clinical phenotypes. Among positive children, 40% presented with optic neuritis, 37% with acute disseminated encephalomyelitis, and 14% with transverse myelitis; the rest had other phenotypes. Optic neuritis was significantly less common among antibody-negative patients (22%), as was encephalomyelitis (17%). Transverse myelitis was significantly more common (31%).

The analysis of MRI scans was stratified according to age younger than 11 years and 11 years and older. “The first thing we noticed among the younger MOG-positive children is that they had a high number of lesions, which were more commonly ill-defined, diffuse, and bilateral,” Dr. Fadda said. “Almost all the brain areas were affected, with a slight preponderance of thalamic and juxtacortical lesions. Among the MOG-negative children, lesions were more often perpendicular to the major axis of the corpus callosum.”

Among the older MOG antibody–positive children, the diffuse pattern was rarer, and the lesions were frequently cerebellar. “But by far, the features that best differentiated positivity from negativity were black holes and enhancing lesions, which we saw in a high proportion of children without the antibodies” at 73% and 49%, respectively.

Over a mean imaging follow-up period of 4 years, lesions were more likely to resolve completely in antibody-positive children than in those without antibodies (50% vs. 21%). Serologically, children who were MOG-antibody negative at baseline were likely to stay that way, with 99% remaining seronegative. Positive children, on the other hand, were significantly more likely to change serologic status, with 56% turning negative and 8% serologically fluctuating over the follow-up period; only 36% remained persistently seropositive. Persistent positive status was significantly associated with younger age (7 vs. 9 years) and an optic neuritis presentation (62% vs. 27%).

Most children (81%) who were antibody positive at baseline experienced no relapses. Among the 16 children who did experience a clinical relapse, the mean time to a second event was about 1 year. Nine of these children stayed persistently positive, while five seroconverted and two had fluctuating status.

Of the 60 antibody-positive children who had a monophasic course, 23 were persistently positive, 34 seroconverted, and 3 had fluctuating serology.

Eventually, 54 children received an MS diagnosis. Of these, 83% were antibody negative at baseline. Ten children received a diagnosis of a relapsing non-MS demyelinating disorder; of these, 91% were antibody positive at baseline.

Dr. Fadda disclosed relationships with Atara Biotherapeutic and Sanofi-Genzyme.

[email protected]

SOURCE: Waters P et al. Mult Scler. 2018;24(S2):29-30, Abstract 65.

BERLIN – Demyelinating diseases appear to disrupt white matter development in children, slowing the trajectory of brain growth to almost unmeasurable levels, based on results from a single-center comparison study of 213 individuals.

While children with multiple sclerosis (MS) showed the most severe slowing, even a single demyelinating event slowed white matter growth, Robert A. Brown, PhD, said at the annual congress of the European Committees for Treatment and Research in Multiple Sclerosis.

Dr. Brown of the Montreal Neurological Institute at McGill University, Montreal, employed a signal mass correction of consecutive brain MRIs enhanced with magnetization transfer. Magnetization transfer ratio (MTR) quantifies myelin more effectively than does other imaging enhancement modalities, Dr. Brown said.

“It labels the macromolecules of myelin and correlates almost perfectly with Luxol fast blue stain on histology,” he said. And by measuring myelin instead of whole-brain volume, MTR sidesteps the confounders of inflammation and edema. “When tissue swells, the water dilutes the myelin. MRI is really sensitive to density, so dilution with water lowers that signal.”

But MTR isn’t failsafe either, he said, especially in teens. “A cautionary note: In healthy adolescents, white matter MTR can actually decrease, not increase, not because they are losing myelin but because the axons in brain tissue are growing so fast that they outstrip the production of new myelin. So, we can get another dilution effect here, except that instead of water, axons are diluting the myelin. We have to take that into account when using MTR.”

A volume-corrected MTR calculates both mass and volume to give what Dr. Brown termed signal mass. “We have demonstrated previously that signal mass is about twice as powerful as volume change alone for measuring the differences [in brain volume] between adults with MS and healthy controls.”

The study he presented at ECTRIMS used this technique to examine the trajectory of white matter change in a cohort of children from the Canadian Pediatric Demyelinating Disease Study who were all scanned at the same site in the same center. He compared brain volume at baseline and 1 year in 102 children with a monophasic demyelinating disease, 87 with MS, and 24 healthy, age-matched controls.

The children with MS were a median of about 17 years old at baseline, while those with a monophasic event and healthy controls were a median of about 12 years old. Median follow-up was 1 year in the healthy controls, 2 years in the MS cohort, and 4 years in the monophasic group. The investigators adjusted their comparisons for sex, since both bioavailable testosterone and androgen-receptor activity correlate with decreased MTR in young men. This doesn’t mean, though, that testosterone decreases myelination. Rather, it’s postulated that testosterone increases axonal caliber, which would decrease the number of neurons in each imaging voxel and, thus, the MTR signal (J Neurosci. 2008 Sep 17;28[38]:9519-24).

In the volume-only assessment, white matter in healthy controls increased at a rate of about 0.5% per year. White matter growth was about 0.2% per year in children with monophasic demyelination, which was significantly lower than in healthy controls.

“The MS children had no white matter growth that we could measure,” with an annual change of about 0.01%, Dr. Brown said. “It looks like a failure of normal development and was significantly lower than what we saw in the children with a demyelination event.”

MTR showed the expected age-associated decreases, which were highest among those with MS: –0.8% per year in healthy controls, –0.6% per year in those with a monophasic event, and –0.9% per year in those with MS.

The signal mass change showed the whole picture, Dr. Brown said. Signal mass declined 0.3% per year in healthy controls, 0.5% per year in the monophasic group, and 0.9% per year in the MS group – a significantly worse trajectory than either the control subjects or those with a monophasic event.

“Signal mass puts it all together and gives us the total picture of tissue loss, with quite severe loss in children with MS. It seems as though both monophasic insult and pediatric-onset MS disrupt brain development.”

Dr. Brown has been a consultant for NeuroRx Research and Biogen.

[email protected]

SOURCE: Brown RA et al. Mult Scler. 2018;24(S2):27-8, Abstract 63.

BERLIN – Demyelinating diseases appear to disrupt white matter development in children, slowing the trajectory of brain growth to almost unmeasurable levels, based on results from a single-center comparison study of 213 individuals.

While children with multiple sclerosis (MS) showed the most severe slowing, even a single demyelinating event slowed white matter growth, Robert A. Brown, PhD, said at the annual congress of the European Committees for Treatment and Research in Multiple Sclerosis.

Dr. Brown of the Montreal Neurological Institute at McGill University, Montreal, employed a signal mass correction of consecutive brain MRIs enhanced with magnetization transfer. Magnetization transfer ratio (MTR) quantifies myelin more effectively than does other imaging enhancement modalities, Dr. Brown said.

“It labels the macromolecules of myelin and correlates almost perfectly with Luxol fast blue stain on histology,” he said. And by measuring myelin instead of whole-brain volume, MTR sidesteps the confounders of inflammation and edema. “When tissue swells, the water dilutes the myelin. MRI is really sensitive to density, so dilution with water lowers that signal.”

But MTR isn’t failsafe either, he said, especially in teens. “A cautionary note: In healthy adolescents, white matter MTR can actually decrease, not increase, not because they are losing myelin but because the axons in brain tissue are growing so fast that they outstrip the production of new myelin. So, we can get another dilution effect here, except that instead of water, axons are diluting the myelin. We have to take that into account when using MTR.”

A volume-corrected MTR calculates both mass and volume to give what Dr. Brown termed signal mass. “We have demonstrated previously that signal mass is about twice as powerful as volume change alone for measuring the differences [in brain volume] between adults with MS and healthy controls.”

The study he presented at ECTRIMS used this technique to examine the trajectory of white matter change in a cohort of children from the Canadian Pediatric Demyelinating Disease Study who were all scanned at the same site in the same center. He compared brain volume at baseline and 1 year in 102 children with a monophasic demyelinating disease, 87 with MS, and 24 healthy, age-matched controls.

The children with MS were a median of about 17 years old at baseline, while those with a monophasic event and healthy controls were a median of about 12 years old. Median follow-up was 1 year in the healthy controls, 2 years in the MS cohort, and 4 years in the monophasic group. The investigators adjusted their comparisons for sex, since both bioavailable testosterone and androgen-receptor activity correlate with decreased MTR in young men. This doesn’t mean, though, that testosterone decreases myelination. Rather, it’s postulated that testosterone increases axonal caliber, which would decrease the number of neurons in each imaging voxel and, thus, the MTR signal (J Neurosci. 2008 Sep 17;28[38]:9519-24).

In the volume-only assessment, white matter in healthy controls increased at a rate of about 0.5% per year. White matter growth was about 0.2% per year in children with monophasic demyelination, which was significantly lower than in healthy controls.

“The MS children had no white matter growth that we could measure,” with an annual change of about 0.01%, Dr. Brown said. “It looks like a failure of normal development and was significantly lower than what we saw in the children with a demyelination event.”

MTR showed the expected age-associated decreases, which were highest among those with MS: –0.8% per year in healthy controls, –0.6% per year in those with a monophasic event, and –0.9% per year in those with MS.

The signal mass change showed the whole picture, Dr. Brown said. Signal mass declined 0.3% per year in healthy controls, 0.5% per year in the monophasic group, and 0.9% per year in the MS group – a significantly worse trajectory than either the control subjects or those with a monophasic event.

“Signal mass puts it all together and gives us the total picture of tissue loss, with quite severe loss in children with MS. It seems as though both monophasic insult and pediatric-onset MS disrupt brain development.”

Dr. Brown has been a consultant for NeuroRx Research and Biogen.

[email protected]

SOURCE: Brown RA et al. Mult Scler. 2018;24(S2):27-8, Abstract 63.

BERLIN – Demyelinating diseases appear to disrupt white matter development in children, slowing the trajectory of brain growth to almost unmeasurable levels, based on results from a single-center comparison study of 213 individuals.

While children with multiple sclerosis (MS) showed the most severe slowing, even a single demyelinating event slowed white matter growth, Robert A. Brown, PhD, said at the annual congress of the European Committees for Treatment and Research in Multiple Sclerosis.

Dr. Brown of the Montreal Neurological Institute at McGill University, Montreal, employed a signal mass correction of consecutive brain MRIs enhanced with magnetization transfer. Magnetization transfer ratio (MTR) quantifies myelin more effectively than does other imaging enhancement modalities, Dr. Brown said.

“It labels the macromolecules of myelin and correlates almost perfectly with Luxol fast blue stain on histology,” he said. And by measuring myelin instead of whole-brain volume, MTR sidesteps the confounders of inflammation and edema. “When tissue swells, the water dilutes the myelin. MRI is really sensitive to density, so dilution with water lowers that signal.”

But MTR isn’t failsafe either, he said, especially in teens. “A cautionary note: In healthy adolescents, white matter MTR can actually decrease, not increase, not because they are losing myelin but because the axons in brain tissue are growing so fast that they outstrip the production of new myelin. So, we can get another dilution effect here, except that instead of water, axons are diluting the myelin. We have to take that into account when using MTR.”

A volume-corrected MTR calculates both mass and volume to give what Dr. Brown termed signal mass. “We have demonstrated previously that signal mass is about twice as powerful as volume change alone for measuring the differences [in brain volume] between adults with MS and healthy controls.”

The study he presented at ECTRIMS used this technique to examine the trajectory of white matter change in a cohort of children from the Canadian Pediatric Demyelinating Disease Study who were all scanned at the same site in the same center. He compared brain volume at baseline and 1 year in 102 children with a monophasic demyelinating disease, 87 with MS, and 24 healthy, age-matched controls.

The children with MS were a median of about 17 years old at baseline, while those with a monophasic event and healthy controls were a median of about 12 years old. Median follow-up was 1 year in the healthy controls, 2 years in the MS cohort, and 4 years in the monophasic group. The investigators adjusted their comparisons for sex, since both bioavailable testosterone and androgen-receptor activity correlate with decreased MTR in young men. This doesn’t mean, though, that testosterone decreases myelination. Rather, it’s postulated that testosterone increases axonal caliber, which would decrease the number of neurons in each imaging voxel and, thus, the MTR signal (J Neurosci. 2008 Sep 17;28[38]:9519-24).

In the volume-only assessment, white matter in healthy controls increased at a rate of about 0.5% per year. White matter growth was about 0.2% per year in children with monophasic demyelination, which was significantly lower than in healthy controls.

“The MS children had no white matter growth that we could measure,” with an annual change of about 0.01%, Dr. Brown said. “It looks like a failure of normal development and was significantly lower than what we saw in the children with a demyelination event.”

MTR showed the expected age-associated decreases, which were highest among those with MS: –0.8% per year in healthy controls, –0.6% per year in those with a monophasic event, and –0.9% per year in those with MS.

The signal mass change showed the whole picture, Dr. Brown said. Signal mass declined 0.3% per year in healthy controls, 0.5% per year in the monophasic group, and 0.9% per year in the MS group – a significantly worse trajectory than either the control subjects or those with a monophasic event.

“Signal mass puts it all together and gives us the total picture of tissue loss, with quite severe loss in children with MS. It seems as though both monophasic insult and pediatric-onset MS disrupt brain development.”

Dr. Brown has been a consultant for NeuroRx Research and Biogen.

[email protected]

SOURCE: Brown RA et al. Mult Scler. 2018;24(S2):27-8, Abstract 63.

MONTREAL – Stimulation of the sphenopalatine ganglion (SPG) using a small, implanted electrode for 5 days in patients who had just had an acute ischemic stroke led to statistically significant and clinically meaningful improvements in the subset of patients with confirmed cortical involvement in a pivotal, sham-controlled trial.

Mitchel L. Zoler/MDedge News

SPG stimulation started within 24 hours of an acute ischemic stroke “reduced poststroke disability over the entire outcome range and increased the proportion of patients who were alive and independent 3 months after their stroke” in the subgroup with a confirmed cortical infarction (CCI), Jeffrey L. Saver, MD, said at the World Stroke Congress. Five days of SPG stimulation, done once daily starting within 24 hours of stroke onset, “enhances ipsilateral collateral blood flow” and may also stabilize the blood brain barrier, explained Dr. Saver, professor of neurology and director of the stroke center at the University of California, Los Angeles. The study included a prespecified primary endpoint analysis that focused exclusively on the CCI subgroup, 52% of the total enrolled population.

If the reported data result in Food and Drug Administration marketing approval for the system, Dr. Saver said that he anticipated “substantial uptake” of the strategy, which he tested in patients who had not undergone thrombectomy or thrombolysis treatment. In current U.S. practice, there is “a large group of patients with a missed opportunity for recanalization” who would be candidates for treatment with SPG stimulation, a treatment that appeared to provide benefits beyond current standard care, he said in an interview.

Ongoing studies are also testing whether SPG stimulation can benefit acute ischemic stroke patients who have already undergone treatment with thrombectomy or thrombolysis, he added. The same SPG stimulation device is additionally undergoing U.S. testing as a treatment for headache and has regulatory approval in the European Union for treating headache and migraine.

The ImpACT-24B (Implant for Augmentation of Cerebral Blood Flow Trial, Effectiveness and Safety in a 24-Hour Window) trial involved 1,000 patients at 73 centers in 18 countries, including the United States. The investigators enrolled acute ischemic stroke patients 8-24 hours after stroke onset who had a National Institutes of Health Stroke Scale (NIHSS) score of 7-18.

Each patient received an implant of a short, thin metal electrode placed through the soft palate at the rear roof of the mouth, near the SPG. Neurologists primarily performed the implants in a procedure that had a “skin to skin” time of less than 5 minutes. Patients received either electrical stimulation or a sham stimulation through the electrode immediately after placement and then daily for the next 4 days. The investigators titrated the strength of the treatment stimulation in each patient to maximize its strength while maintaining patient comfort. Subsequent analysis of the results showed that the stronger the tolerated stimulation, the bigger the treatment effect in a clear dose-response pattern, Dr. Saver reported.

The study’s primary endpoint was improvement in the modified Rankin scale (mRS) score at 90 days after the index stroke when measured against historical expectations. By this measure, the overall study cohort showed a small, statistically insignificant improvement in actively treated patients, compared with sham-treated patients. However, in the prespecified, coprimary endpoint cohort of patients with a CCI, active treatment resulted in 50% of patients having a better-than-expected 90-day outcome, compared with 40% of controls, a 48% relative improvement in this measure that met the prespecified definition of statistical significance. The results also showed about a 50% relative improvement in each of three secondary outcomes in the CCI cohort: the percentage of patients with a mRS score of 0-2 after 90 days, the percentage with a mRS score of 0-3 after 90 days, and average stroke-related quality of life at 90 days.

Dr. Saver also reported results of a meta-analysis that combined the results he reported from 520 patients with CCI with results from 87 CCI patients enrolled in the preceding pilot study of this treatment strategy, ImpACT-1. The pilot findings were completely consistent and when combined with the current results strengthened the statistical significance of the primary and secondary endpoints.

“There is a compelling story” of efficacy based on the study results, the dose-response relationship, and the meta-analysis results, Dr. Saver said. “I think it’s a very strong case.”

He also reported “no safety concerns” raised in the new study, with no serious adverse effects seen in or experienced by the patients on active treatment.

“The data are compelling” for safety and efficacy, for this novel approach for treating acute ischemic stroke, commented Pooja Khatri, MD, professor of neurology and director of the acute stroke program at the University of Cincinnati.

The study was sponsored by BrainsGate, the company developing the tested device. Dr. Saver has been a consultant to BrainsGate. Dr. Khatri has been a consultant to Biogen, Greenwich, Lumosa, and PTC Therapeutics.

[email protected]

SOURCE: Saver J et al. Int J. Stroke. 2018 Oct;13(2S):28, Abstract 104.

MONTREAL – Stimulation of the sphenopalatine ganglion (SPG) using a small, implanted electrode for 5 days in patients who had just had an acute ischemic stroke led to statistically significant and clinically meaningful improvements in the subset of patients with confirmed cortical involvement in a pivotal, sham-controlled trial.

Mitchel L. Zoler/MDedge News

SPG stimulation started within 24 hours of an acute ischemic stroke “reduced poststroke disability over the entire outcome range and increased the proportion of patients who were alive and independent 3 months after their stroke” in the subgroup with a confirmed cortical infarction (CCI), Jeffrey L. Saver, MD, said at the World Stroke Congress. Five days of SPG stimulation, done once daily starting within 24 hours of stroke onset, “enhances ipsilateral collateral blood flow” and may also stabilize the blood brain barrier, explained Dr. Saver, professor of neurology and director of the stroke center at the University of California, Los Angeles. The study included a prespecified primary endpoint analysis that focused exclusively on the CCI subgroup, 52% of the total enrolled population.

If the reported data result in Food and Drug Administration marketing approval for the system, Dr. Saver said that he anticipated “substantial uptake” of the strategy, which he tested in patients who had not undergone thrombectomy or thrombolysis treatment. In current U.S. practice, there is “a large group of patients with a missed opportunity for recanalization” who would be candidates for treatment with SPG stimulation, a treatment that appeared to provide benefits beyond current standard care, he said in an interview.

Ongoing studies are also testing whether SPG stimulation can benefit acute ischemic stroke patients who have already undergone treatment with thrombectomy or thrombolysis, he added. The same SPG stimulation device is additionally undergoing U.S. testing as a treatment for headache and has regulatory approval in the European Union for treating headache and migraine.

The ImpACT-24B (Implant for Augmentation of Cerebral Blood Flow Trial, Effectiveness and Safety in a 24-Hour Window) trial involved 1,000 patients at 73 centers in 18 countries, including the United States. The investigators enrolled acute ischemic stroke patients 8-24 hours after stroke onset who had a National Institutes of Health Stroke Scale (NIHSS) score of 7-18.

Each patient received an implant of a short, thin metal electrode placed through the soft palate at the rear roof of the mouth, near the SPG. Neurologists primarily performed the implants in a procedure that had a “skin to skin” time of less than 5 minutes. Patients received either electrical stimulation or a sham stimulation through the electrode immediately after placement and then daily for the next 4 days. The investigators titrated the strength of the treatment stimulation in each patient to maximize its strength while maintaining patient comfort. Subsequent analysis of the results showed that the stronger the tolerated stimulation, the bigger the treatment effect in a clear dose-response pattern, Dr. Saver reported.

The study’s primary endpoint was improvement in the modified Rankin scale (mRS) score at 90 days after the index stroke when measured against historical expectations. By this measure, the overall study cohort showed a small, statistically insignificant improvement in actively treated patients, compared with sham-treated patients. However, in the prespecified, coprimary endpoint cohort of patients with a CCI, active treatment resulted in 50% of patients having a better-than-expected 90-day outcome, compared with 40% of controls, a 48% relative improvement in this measure that met the prespecified definition of statistical significance. The results also showed about a 50% relative improvement in each of three secondary outcomes in the CCI cohort: the percentage of patients with a mRS score of 0-2 after 90 days, the percentage with a mRS score of 0-3 after 90 days, and average stroke-related quality of life at 90 days.

Dr. Saver also reported results of a meta-analysis that combined the results he reported from 520 patients with CCI with results from 87 CCI patients enrolled in the preceding pilot study of this treatment strategy, ImpACT-1. The pilot findings were completely consistent and when combined with the current results strengthened the statistical significance of the primary and secondary endpoints.

“There is a compelling story” of efficacy based on the study results, the dose-response relationship, and the meta-analysis results, Dr. Saver said. “I think it’s a very strong case.”

He also reported “no safety concerns” raised in the new study, with no serious adverse effects seen in or experienced by the patients on active treatment.

“The data are compelling” for safety and efficacy, for this novel approach for treating acute ischemic stroke, commented Pooja Khatri, MD, professor of neurology and director of the acute stroke program at the University of Cincinnati.

The study was sponsored by BrainsGate, the company developing the tested device. Dr. Saver has been a consultant to BrainsGate. Dr. Khatri has been a consultant to Biogen, Greenwich, Lumosa, and PTC Therapeutics.

[email protected]

SOURCE: Saver J et al. Int J. Stroke. 2018 Oct;13(2S):28, Abstract 104.

MONTREAL – Stimulation of the sphenopalatine ganglion (SPG) using a small, implanted electrode for 5 days in patients who had just had an acute ischemic stroke led to statistically significant and clinically meaningful improvements in the subset of patients with confirmed cortical involvement in a pivotal, sham-controlled trial.

Mitchel L. Zoler/MDedge News

SPG stimulation started within 24 hours of an acute ischemic stroke “reduced poststroke disability over the entire outcome range and increased the proportion of patients who were alive and independent 3 months after their stroke” in the subgroup with a confirmed cortical infarction (CCI), Jeffrey L. Saver, MD, said at the World Stroke Congress. Five days of SPG stimulation, done once daily starting within 24 hours of stroke onset, “enhances ipsilateral collateral blood flow” and may also stabilize the blood brain barrier, explained Dr. Saver, professor of neurology and director of the stroke center at the University of California, Los Angeles. The study included a prespecified primary endpoint analysis that focused exclusively on the CCI subgroup, 52% of the total enrolled population.

If the reported data result in Food and Drug Administration marketing approval for the system, Dr. Saver said that he anticipated “substantial uptake” of the strategy, which he tested in patients who had not undergone thrombectomy or thrombolysis treatment. In current U.S. practice, there is “a large group of patients with a missed opportunity for recanalization” who would be candidates for treatment with SPG stimulation, a treatment that appeared to provide benefits beyond current standard care, he said in an interview.

Ongoing studies are also testing whether SPG stimulation can benefit acute ischemic stroke patients who have already undergone treatment with thrombectomy or thrombolysis, he added. The same SPG stimulation device is additionally undergoing U.S. testing as a treatment for headache and has regulatory approval in the European Union for treating headache and migraine.

The ImpACT-24B (Implant for Augmentation of Cerebral Blood Flow Trial, Effectiveness and Safety in a 24-Hour Window) trial involved 1,000 patients at 73 centers in 18 countries, including the United States. The investigators enrolled acute ischemic stroke patients 8-24 hours after stroke onset who had a National Institutes of Health Stroke Scale (NIHSS) score of 7-18.

Each patient received an implant of a short, thin metal electrode placed through the soft palate at the rear roof of the mouth, near the SPG. Neurologists primarily performed the implants in a procedure that had a “skin to skin” time of less than 5 minutes. Patients received either electrical stimulation or a sham stimulation through the electrode immediately after placement and then daily for the next 4 days. The investigators titrated the strength of the treatment stimulation in each patient to maximize its strength while maintaining patient comfort. Subsequent analysis of the results showed that the stronger the tolerated stimulation, the bigger the treatment effect in a clear dose-response pattern, Dr. Saver reported.

The study’s primary endpoint was improvement in the modified Rankin scale (mRS) score at 90 days after the index stroke when measured against historical expectations. By this measure, the overall study cohort showed a small, statistically insignificant improvement in actively treated patients, compared with sham-treated patients. However, in the prespecified, coprimary endpoint cohort of patients with a CCI, active treatment resulted in 50% of patients having a better-than-expected 90-day outcome, compared with 40% of controls, a 48% relative improvement in this measure that met the prespecified definition of statistical significance. The results also showed about a 50% relative improvement in each of three secondary outcomes in the CCI cohort: the percentage of patients with a mRS score of 0-2 after 90 days, the percentage with a mRS score of 0-3 after 90 days, and average stroke-related quality of life at 90 days.

Dr. Saver also reported results of a meta-analysis that combined the results he reported from 520 patients with CCI with results from 87 CCI patients enrolled in the preceding pilot study of this treatment strategy, ImpACT-1. The pilot findings were completely consistent and when combined with the current results strengthened the statistical significance of the primary and secondary endpoints.

“There is a compelling story” of efficacy based on the study results, the dose-response relationship, and the meta-analysis results, Dr. Saver said. “I think it’s a very strong case.”

He also reported “no safety concerns” raised in the new study, with no serious adverse effects seen in or experienced by the patients on active treatment.

“The data are compelling” for safety and efficacy, for this novel approach for treating acute ischemic stroke, commented Pooja Khatri, MD, professor of neurology and director of the acute stroke program at the University of Cincinnati.

The study was sponsored by BrainsGate, the company developing the tested device. Dr. Saver has been a consultant to BrainsGate. Dr. Khatri has been a consultant to Biogen, Greenwich, Lumosa, and PTC Therapeutics.

[email protected]

SOURCE: Saver J et al. Int J. Stroke. 2018 Oct;13(2S):28, Abstract 104.

The presence of visual aura during migraine is associated with an increased risk of atrial fibrillation, a study in Neurology has found.

Researchers reported an analysis of data from the longitudinal, community-based Atherosclerosis Risk in Communities (ARIC) Study, which included 11,939 individuals with no history of atrial fibrillation or stroke. Of these, 426 experienced migraines with visual aura, 1,090 experienced migraines without aura, 1,018 experienced nonmigraine headache, and 9,405 experienced no headache.

After adjustment for age and sex, individuals who had migraine with visual aura showed a significant 46% increase in the risk of incident atrial fibrillation when compared with those who experienced migraine without aura and a 39% increased risk when compared with individuals who did not experience headache (P = .004). After adjustment for risk factors such as hypertension, smoking, coronary artery disease, and congestive heart failure, the hazard ratio of incident atrial fibrillation was 1.30 for migraineurs with aura, compared with people without headache. In addition, the hazard ratio of incident atrial fibrillation was 1.39 for migraineurs with aura, compared with migraineurs without aura.

In contrast, individuals who experienced migraines without aura did not show a significantly increased risk of atrial fibrillation.

“This finding has important clinical implications and may help us better understand the atrial fibrillation mediation of the migraine-stroke link,” wrote Souvik Sen, MD, MPH, a professor in the department of neurology at the University of South Carolina, Columbia, and his coauthors. “A randomized clinical trial may help ascertain whether patients with migraine with visual aura may benefit from atrial fibrillation detection and subsequent anticoagulation or antiplatelet therapy as a primary stroke prevention strategy.”

The study also showed a significant interaction with age and sex. While men who experienced migraine with aura had an 89% higher risk of atrial fibrillation, women with aura showed no increase in risk, compared with individuals who experienced no headache. Similarly, only individuals aged 60 years or older who experienced migraine with aura showed an increased risk of atrial fibrillation, while those younger than 60 years did not.

The authors noted that previous case reports have recorded the incidence of atrial fibrillation during a migraine attack. Autonomic dysfunction influences the pathophysiology of atrial fibrillation and migraine.

“Cardiac arrhythmia recordings have been shown to be present in ECGs of patients while experiencing migraine headaches as compared with migraine-free phases,” they wrote. “This hypothesis is further supported by atrial fibrillation ablation procedures that have shown tendencies to reduce migraine symptoms and frequencies.”

In regard to the role that migraine aura played in this, they speculated as to whether migraine aura could be the result of cardioembolic stroke that might have occurred because of the atrial fibrillation.

Overall, 167 patients had incident cardioembolic strokes, and researchers suggested strokes in 87% of these cases could be attributed to the atrial fibrillation that came before the stroke.

The stroke incidence rate also was around twice as high in individuals who experienced migraine with aura, compared with those who experienced migraine without aura (4.1 per 1,000 person-years vs. 2.07 per 1,000 person-years).

The study authors acknowledged that patent foramen ovale, which was not assessed in ARIC, is a possible confounder. Previous studies have showed that patent foramen ovale is more common in younger individuals with migraine and particularly in patients who experience migraine with aura.

However, they also noted that trials of patent foramen ovale closures as a treatment for migraine have not shown success in reducing migraine frequency and, therefore, argued against patent foramen ovale as being a major confounder.

The study was supported by the National Heart, Lung, and Blood Institute and the American Heart Association. One author declared grants from the National Institutes of health, one declared research support from Tian Medical, and one author is an associate editor for Neurology. No other conflicts of interest were declared.

SOURCE: Sen S et al. Neurology. 2018;91:1-9.

This article was updated 12/12/18.

The presence of visual aura during migraine is associated with an increased risk of atrial fibrillation, a study in Neurology has found.

Researchers reported an analysis of data from the longitudinal, community-based Atherosclerosis Risk in Communities (ARIC) Study, which included 11,939 individuals with no history of atrial fibrillation or stroke. Of these, 426 experienced migraines with visual aura, 1,090 experienced migraines without aura, 1,018 experienced nonmigraine headache, and 9,405 experienced no headache.

After adjustment for age and sex, individuals who had migraine with visual aura showed a significant 46% increase in the risk of incident atrial fibrillation when compared with those who experienced migraine without aura and a 39% increased risk when compared with individuals who did not experience headache (P = .004). After adjustment for risk factors such as hypertension, smoking, coronary artery disease, and congestive heart failure, the hazard ratio of incident atrial fibrillation was 1.30 for migraineurs with aura, compared with people without headache. In addition, the hazard ratio of incident atrial fibrillation was 1.39 for migraineurs with aura, compared with migraineurs without aura.

In contrast, individuals who experienced migraines without aura did not show a significantly increased risk of atrial fibrillation.

“This finding has important clinical implications and may help us better understand the atrial fibrillation mediation of the migraine-stroke link,” wrote Souvik Sen, MD, MPH, a professor in the department of neurology at the University of South Carolina, Columbia, and his coauthors. “A randomized clinical trial may help ascertain whether patients with migraine with visual aura may benefit from atrial fibrillation detection and subsequent anticoagulation or antiplatelet therapy as a primary stroke prevention strategy.”

The study also showed a significant interaction with age and sex. While men who experienced migraine with aura had an 89% higher risk of atrial fibrillation, women with aura showed no increase in risk, compared with individuals who experienced no headache. Similarly, only individuals aged 60 years or older who experienced migraine with aura showed an increased risk of atrial fibrillation, while those younger than 60 years did not.

The authors noted that previous case reports have recorded the incidence of atrial fibrillation during a migraine attack. Autonomic dysfunction influences the pathophysiology of atrial fibrillation and migraine.

“Cardiac arrhythmia recordings have been shown to be present in ECGs of patients while experiencing migraine headaches as compared with migraine-free phases,” they wrote. “This hypothesis is further supported by atrial fibrillation ablation procedures that have shown tendencies to reduce migraine symptoms and frequencies.”

In regard to the role that migraine aura played in this, they speculated as to whether migraine aura could be the result of cardioembolic stroke that might have occurred because of the atrial fibrillation.

Overall, 167 patients had incident cardioembolic strokes, and researchers suggested strokes in 87% of these cases could be attributed to the atrial fibrillation that came before the stroke.

The stroke incidence rate also was around twice as high in individuals who experienced migraine with aura, compared with those who experienced migraine without aura (4.1 per 1,000 person-years vs. 2.07 per 1,000 person-years).

The study authors acknowledged that patent foramen ovale, which was not assessed in ARIC, is a possible confounder. Previous studies have showed that patent foramen ovale is more common in younger individuals with migraine and particularly in patients who experience migraine with aura.

However, they also noted that trials of patent foramen ovale closures as a treatment for migraine have not shown success in reducing migraine frequency and, therefore, argued against patent foramen ovale as being a major confounder.

The study was supported by the National Heart, Lung, and Blood Institute and the American Heart Association. One author declared grants from the National Institutes of health, one declared research support from Tian Medical, and one author is an associate editor for Neurology. No other conflicts of interest were declared.

SOURCE: Sen S et al. Neurology. 2018;91:1-9.

This article was updated 12/12/18.

The presence of visual aura during migraine is associated with an increased risk of atrial fibrillation, a study in Neurology has found.

Researchers reported an analysis of data from the longitudinal, community-based Atherosclerosis Risk in Communities (ARIC) Study, which included 11,939 individuals with no history of atrial fibrillation or stroke. Of these, 426 experienced migraines with visual aura, 1,090 experienced migraines without aura, 1,018 experienced nonmigraine headache, and 9,405 experienced no headache.

After adjustment for age and sex, individuals who had migraine with visual aura showed a significant 46% increase in the risk of incident atrial fibrillation when compared with those who experienced migraine without aura and a 39% increased risk when compared with individuals who did not experience headache (P = .004). After adjustment for risk factors such as hypertension, smoking, coronary artery disease, and congestive heart failure, the hazard ratio of incident atrial fibrillation was 1.30 for migraineurs with aura, compared with people without headache. In addition, the hazard ratio of incident atrial fibrillation was 1.39 for migraineurs with aura, compared with migraineurs without aura.

In contrast, individuals who experienced migraines without aura did not show a significantly increased risk of atrial fibrillation.

“This finding has important clinical implications and may help us better understand the atrial fibrillation mediation of the migraine-stroke link,” wrote Souvik Sen, MD, MPH, a professor in the department of neurology at the University of South Carolina, Columbia, and his coauthors. “A randomized clinical trial may help ascertain whether patients with migraine with visual aura may benefit from atrial fibrillation detection and subsequent anticoagulation or antiplatelet therapy as a primary stroke prevention strategy.”

The study also showed a significant interaction with age and sex. While men who experienced migraine with aura had an 89% higher risk of atrial fibrillation, women with aura showed no increase in risk, compared with individuals who experienced no headache. Similarly, only individuals aged 60 years or older who experienced migraine with aura showed an increased risk of atrial fibrillation, while those younger than 60 years did not.

The authors noted that previous case reports have recorded the incidence of atrial fibrillation during a migraine attack. Autonomic dysfunction influences the pathophysiology of atrial fibrillation and migraine.

“Cardiac arrhythmia recordings have been shown to be present in ECGs of patients while experiencing migraine headaches as compared with migraine-free phases,” they wrote. “This hypothesis is further supported by atrial fibrillation ablation procedures that have shown tendencies to reduce migraine symptoms and frequencies.”

In regard to the role that migraine aura played in this, they speculated as to whether migraine aura could be the result of cardioembolic stroke that might have occurred because of the atrial fibrillation.

Overall, 167 patients had incident cardioembolic strokes, and researchers suggested strokes in 87% of these cases could be attributed to the atrial fibrillation that came before the stroke.

The stroke incidence rate also was around twice as high in individuals who experienced migraine with aura, compared with those who experienced migraine without aura (4.1 per 1,000 person-years vs. 2.07 per 1,000 person-years).

The study authors acknowledged that patent foramen ovale, which was not assessed in ARIC, is a possible confounder. Previous studies have showed that patent foramen ovale is more common in younger individuals with migraine and particularly in patients who experience migraine with aura.

However, they also noted that trials of patent foramen ovale closures as a treatment for migraine have not shown success in reducing migraine frequency and, therefore, argued against patent foramen ovale as being a major confounder.

The study was supported by the National Heart, Lung, and Blood Institute and the American Heart Association. One author declared grants from the National Institutes of health, one declared research support from Tian Medical, and one author is an associate editor for Neurology. No other conflicts of interest were declared.

SOURCE: Sen S et al. Neurology. 2018;91:1-9.

This article was updated 12/12/18.

Use of anti–calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) may benefit children with more than 8 headache days each month, a high Pediatric Migraine Disability Assessment (PedMIDAS) score, and failure of other treatments; however, researchers cautioned that long-term safety outcomes for the treatment are not yet known, according to a recent set of recommendations published in the journal Headache.

Christina L. Szperka, MD, MSCE, of the division of neurology at the Children’s Hospital of Philadelphia and members of the Pediatric and Adolescent Headache special interest group of the American Headache Society discussed the topic of anti-CGRP mAbs at the 2018 Annual Scientific Meeting of the American Headache Society. They noted clinical outcomes for anti-CGRP mAbs in pediatric patients will likely not be available for several years and created a set of recommendations based on expert opinion of anti-CGRP mAb use in children and adolescents.

Their recommendations support using anti-CGRP mAbs for children with migraine if patients meet the following criteria: headache frequency exceeding 8 headache days per month; a PedMIDAS score of 30 or greater; failure of two or more therapies, such as pharmacologic, nonpharmacologic, or nutraceutical ones; and in patients who are past puberty.

The special interest group recommended against use of anti-CGRP mAbs in children and adolescents with recent meningitis, recent peripheral nerve injury, neurosurgery, or a central nervous system injury caused by a potentially compromised blood-brain barrier. Children and adolescents with immunodeficiency, receiving immunosuppressive medications, with structural heart defects, with pulmonary hypertension, with coronary artery disease, with cardiomyopathy, or at risk for stroke should also avoid use of anti-CGRP mAbs. Anti-CGRP mAbs are also potentially teratogenic and should not be used by adolescents or women who are pregnant, breastfeeding, or have a pregnancy wish.

Pediatric patients with significant osteoporosis or bone disease should be monitored when prescribed anti-CGRP mAbs, and the recommendations specified monitoring height and linear growth or waiting until after puberty to prescribe anti-CGRP mAbs. Although there is currently no evidence that use of anti-CGRP mAb requires pituitary hormone monitoring, the recommendations noted that weight and body mass index should also be observed.

“Pediatric and adolescent trials of anti-CGRP mAbs should be designed to maximize the chances of determining efficacy in these age groups and should focus on those who have not been successful with current multidisciplinary care,” Dr. Szperka and her colleagues wrote in the recommendations. “In the interim, the use of anti-CGRP mAbs for the treatment of headache disorders in children and adolescents may be considered in appropriate cases but should be done with close follow-up and attention to patient characteristics such as age, pubertal state, and medical comorbidities.”

Dr. Szperka receives grant support from Pfizer and Amgen and research funding from NIH. Other authors have reported grants, consulting fees, speaking fees, royalties, advisory board memberships, speaker’s bureau memberships and travel funds from Alder, Allergan, American Academy of Neurology, Amgen, Aralez, Avanir, Autonomic Technologies Inc., Biohaven, Cambridge University Press, Curelator, Depomed, Dr. Reddy’s Laboratories, Electrocore, eNeura, Genentech, Healint, Impax, JAMA Neurology, Journal Watch, Lilly, Massachusetts Medical Society, MedDay, MedicoLegal, Merck, NIH, Novartis, Oxford University Press, Quest Diagnostics, Scion, Supernus, Teva, Trigemina Inc., Upsher-Smith, UpToDate, Wolters Kluwer and Zosano.

SOURCE: Szperka CL et al. Headache. 2018. doi: 10.1111/head.13414.

Use of anti–calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) may benefit children with more than 8 headache days each month, a high Pediatric Migraine Disability Assessment (PedMIDAS) score, and failure of other treatments; however, researchers cautioned that long-term safety outcomes for the treatment are not yet known, according to a recent set of recommendations published in the journal Headache.

Christina L. Szperka, MD, MSCE, of the division of neurology at the Children’s Hospital of Philadelphia and members of the Pediatric and Adolescent Headache special interest group of the American Headache Society discussed the topic of anti-CGRP mAbs at the 2018 Annual Scientific Meeting of the American Headache Society. They noted clinical outcomes for anti-CGRP mAbs in pediatric patients will likely not be available for several years and created a set of recommendations based on expert opinion of anti-CGRP mAb use in children and adolescents.

Their recommendations support using anti-CGRP mAbs for children with migraine if patients meet the following criteria: headache frequency exceeding 8 headache days per month; a PedMIDAS score of 30 or greater; failure of two or more therapies, such as pharmacologic, nonpharmacologic, or nutraceutical ones; and in patients who are past puberty.

The special interest group recommended against use of anti-CGRP mAbs in children and adolescents with recent meningitis, recent peripheral nerve injury, neurosurgery, or a central nervous system injury caused by a potentially compromised blood-brain barrier. Children and adolescents with immunodeficiency, receiving immunosuppressive medications, with structural heart defects, with pulmonary hypertension, with coronary artery disease, with cardiomyopathy, or at risk for stroke should also avoid use of anti-CGRP mAbs. Anti-CGRP mAbs are also potentially teratogenic and should not be used by adolescents or women who are pregnant, breastfeeding, or have a pregnancy wish.

Pediatric patients with significant osteoporosis or bone disease should be monitored when prescribed anti-CGRP mAbs, and the recommendations specified monitoring height and linear growth or waiting until after puberty to prescribe anti-CGRP mAbs. Although there is currently no evidence that use of anti-CGRP mAb requires pituitary hormone monitoring, the recommendations noted that weight and body mass index should also be observed.

“Pediatric and adolescent trials of anti-CGRP mAbs should be designed to maximize the chances of determining efficacy in these age groups and should focus on those who have not been successful with current multidisciplinary care,” Dr. Szperka and her colleagues wrote in the recommendations. “In the interim, the use of anti-CGRP mAbs for the treatment of headache disorders in children and adolescents may be considered in appropriate cases but should be done with close follow-up and attention to patient characteristics such as age, pubertal state, and medical comorbidities.”

Dr. Szperka receives grant support from Pfizer and Amgen and research funding from NIH. Other authors have reported grants, consulting fees, speaking fees, royalties, advisory board memberships, speaker’s bureau memberships and travel funds from Alder, Allergan, American Academy of Neurology, Amgen, Aralez, Avanir, Autonomic Technologies Inc., Biohaven, Cambridge University Press, Curelator, Depomed, Dr. Reddy’s Laboratories, Electrocore, eNeura, Genentech, Healint, Impax, JAMA Neurology, Journal Watch, Lilly, Massachusetts Medical Society, MedDay, MedicoLegal, Merck, NIH, Novartis, Oxford University Press, Quest Diagnostics, Scion, Supernus, Teva, Trigemina Inc., Upsher-Smith, UpToDate, Wolters Kluwer and Zosano.

SOURCE: Szperka CL et al. Headache. 2018. doi: 10.1111/head.13414.

Use of anti–calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) may benefit children with more than 8 headache days each month, a high Pediatric Migraine Disability Assessment (PedMIDAS) score, and failure of other treatments; however, researchers cautioned that long-term safety outcomes for the treatment are not yet known, according to a recent set of recommendations published in the journal Headache.

Christina L. Szperka, MD, MSCE, of the division of neurology at the Children’s Hospital of Philadelphia and members of the Pediatric and Adolescent Headache special interest group of the American Headache Society discussed the topic of anti-CGRP mAbs at the 2018 Annual Scientific Meeting of the American Headache Society. They noted clinical outcomes for anti-CGRP mAbs in pediatric patients will likely not be available for several years and created a set of recommendations based on expert opinion of anti-CGRP mAb use in children and adolescents.

Their recommendations support using anti-CGRP mAbs for children with migraine if patients meet the following criteria: headache frequency exceeding 8 headache days per month; a PedMIDAS score of 30 or greater; failure of two or more therapies, such as pharmacologic, nonpharmacologic, or nutraceutical ones; and in patients who are past puberty.

The special interest group recommended against use of anti-CGRP mAbs in children and adolescents with recent meningitis, recent peripheral nerve injury, neurosurgery, or a central nervous system injury caused by a potentially compromised blood-brain barrier. Children and adolescents with immunodeficiency, receiving immunosuppressive medications, with structural heart defects, with pulmonary hypertension, with coronary artery disease, with cardiomyopathy, or at risk for stroke should also avoid use of anti-CGRP mAbs. Anti-CGRP mAbs are also potentially teratogenic and should not be used by adolescents or women who are pregnant, breastfeeding, or have a pregnancy wish.

Pediatric patients with significant osteoporosis or bone disease should be monitored when prescribed anti-CGRP mAbs, and the recommendations specified monitoring height and linear growth or waiting until after puberty to prescribe anti-CGRP mAbs. Although there is currently no evidence that use of anti-CGRP mAb requires pituitary hormone monitoring, the recommendations noted that weight and body mass index should also be observed.

“Pediatric and adolescent trials of anti-CGRP mAbs should be designed to maximize the chances of determining efficacy in these age groups and should focus on those who have not been successful with current multidisciplinary care,” Dr. Szperka and her colleagues wrote in the recommendations. “In the interim, the use of anti-CGRP mAbs for the treatment of headache disorders in children and adolescents may be considered in appropriate cases but should be done with close follow-up and attention to patient characteristics such as age, pubertal state, and medical comorbidities.”

Dr. Szperka receives grant support from Pfizer and Amgen and research funding from NIH. Other authors have reported grants, consulting fees, speaking fees, royalties, advisory board memberships, speaker’s bureau memberships and travel funds from Alder, Allergan, American Academy of Neurology, Amgen, Aralez, Avanir, Autonomic Technologies Inc., Biohaven, Cambridge University Press, Curelator, Depomed, Dr. Reddy’s Laboratories, Electrocore, eNeura, Genentech, Healint, Impax, JAMA Neurology, Journal Watch, Lilly, Massachusetts Medical Society, MedDay, MedicoLegal, Merck, NIH, Novartis, Oxford University Press, Quest Diagnostics, Scion, Supernus, Teva, Trigemina Inc., Upsher-Smith, UpToDate, Wolters Kluwer and Zosano.

SOURCE: Szperka CL et al. Headache. 2018. doi: 10.1111/head.13414.

Children and adolescents who suffer sports-related concussion should engage in light activities for their minds and bodies, while being monitored and evaluated, according to a new clinical report from the American Academy of Pediatrics.

The update to the 2010 guidelines was needed to reflect the latest research “and it was necessary to provide this new information to guide pediatricians in evaluating and treating concussions they may see in their practice,” Mark Halstead, MD, of Washington University, St. Louis, said in an interview.

The biggest changes to the guidelines involve management of concussion, noted Dr. Halstead, who was a coauthor of the AAP clinical report. “The previous recommendation called for cognitive and physical rest, which unfortunately was interpreted as complete removal from all physical activity and limiting many other things including electronic use.

“Because of research that has been conducted since the original report, it has been shown that starting some light physical activity to increase heart rate, provided it does not worsen symptoms, can be beneficial in recovery. Also, the recommendation for complete removal of electronics and computer use has unfortunately created some issues with kids getting socially isolated,” he added.

James Boulette/iStockphoto

“For better or for worse, kids are connected through their electronic devices. Removing them, with no evidence that it worsens the concussion, essentially punishes kids for their injury. We also are trying to discourage prolonged removal of kids from school,” Dr. Halstead emphasized.

The new recommendations emphasize the unique nature of sports-related concussion (SRC) from one individual to another, and the need for individualized management.

Symptoms of SRC fall into five categories, according to the guidelines: somatic, vestibular, oculomotor, cognitive, and emotional/sleep. Pediatric health care providers should rule out more severe head injuries and recognize that concussion symptoms are nonspecific and may reflect preexisting conditions, such as migraine or headache disorders, learning disorders, ADHD, mental health conditions, or sleep disorders.

Use of assessments such as the Sport Concussion Management Tool (SCAT5 for 13 years and older or Child SCAT5 for 5-12 years) can help guide clinicians, but should not be used in isolation to diagnose a concussion, the guideline authors wrote.

Strategies for injury prevention are included in the guidelines as well, such as the use of appropriate headgear. As for management, computerized neurocognitive testing can play a role in decisions regarding return to play, but should not be used in isolation.

“The biggest thing we are lacking is an objective diagnostic test to determine the presence of a concussion or its resolution,” coauthor Kody A. Moffatt, MD, of Creighton University, Omaha, Nebraska, said in an interview.

“Mandatory baseline and postinjury computerized neurocognitive testing is not recommended,” he added.

Clinicians can best manage SRC with prompt recognition and diagnosis using the available tools, followed by relative rest and return to school, then noncontact physical activities, and eventually a return to sport if appropriate.

“Most concussions in children and adolescents will resolve within 4 weeks as long as there is not additional injury to the brain during that time,” Dr. Moffat said.

More research is needed in particular about concussions in elementary and middle school children, Dr. Halstead added.

In the meantime, the take-home message to pediatricians for managing SRC is one of common sense. “Extremes of removing all stimulus from a child is not likely to get them better sooner and research suggests may take them longer to get better,” Dr. Halstead noted. “That doesn’t mean they don’t have to reduce anything, as it is important to reduce physical activity and modify school workload while recovering but we should be avoiding the blanket recommendation to ‘stay home and do nothing until you are better’ approach to concussion management.”

Dr. Halstead and Dr. Moffatt reported no relevant financial conflicts to disclose; the same was true for the other report coauthors. There was no external funding for the report.

SOURCE: Halstead M et al. Pediatrics. 2018 Nov 12. doi: 10.1542/peds.2018-3074.

Children and adolescents who suffer sports-related concussion should engage in light activities for their minds and bodies, while being monitored and evaluated, according to a new clinical report from the American Academy of Pediatrics.

The update to the 2010 guidelines was needed to reflect the latest research “and it was necessary to provide this new information to guide pediatricians in evaluating and treating concussions they may see in their practice,” Mark Halstead, MD, of Washington University, St. Louis, said in an interview.

The biggest changes to the guidelines involve management of concussion, noted Dr. Halstead, who was a coauthor of the AAP clinical report. “The previous recommendation called for cognitive and physical rest, which unfortunately was interpreted as complete removal from all physical activity and limiting many other things including electronic use.

“Because of research that has been conducted since the original report, it has been shown that starting some light physical activity to increase heart rate, provided it does not worsen symptoms, can be beneficial in recovery. Also, the recommendation for complete removal of electronics and computer use has unfortunately created some issues with kids getting socially isolated,” he added.

James Boulette/iStockphoto

“For better or for worse, kids are connected through their electronic devices. Removing them, with no evidence that it worsens the concussion, essentially punishes kids for their injury. We also are trying to discourage prolonged removal of kids from school,” Dr. Halstead emphasized.

The new recommendations emphasize the unique nature of sports-related concussion (SRC) from one individual to another, and the need for individualized management.

Symptoms of SRC fall into five categories, according to the guidelines: somatic, vestibular, oculomotor, cognitive, and emotional/sleep. Pediatric health care providers should rule out more severe head injuries and recognize that concussion symptoms are nonspecific and may reflect preexisting conditions, such as migraine or headache disorders, learning disorders, ADHD, mental health conditions, or sleep disorders.

Use of assessments such as the Sport Concussion Management Tool (SCAT5 for 13 years and older or Child SCAT5 for 5-12 years) can help guide clinicians, but should not be used in isolation to diagnose a concussion, the guideline authors wrote.

Strategies for injury prevention are included in the guidelines as well, such as the use of appropriate headgear. As for management, computerized neurocognitive testing can play a role in decisions regarding return to play, but should not be used in isolation.

“The biggest thing we are lacking is an objective diagnostic test to determine the presence of a concussion or its resolution,” coauthor Kody A. Moffatt, MD, of Creighton University, Omaha, Nebraska, said in an interview.

“Mandatory baseline and postinjury computerized neurocognitive testing is not recommended,” he added.

Clinicians can best manage SRC with prompt recognition and diagnosis using the available tools, followed by relative rest and return to school, then noncontact physical activities, and eventually a return to sport if appropriate.

“Most concussions in children and adolescents will resolve within 4 weeks as long as there is not additional injury to the brain during that time,” Dr. Moffat said.

More research is needed in particular about concussions in elementary and middle school children, Dr. Halstead added.

In the meantime, the take-home message to pediatricians for managing SRC is one of common sense. “Extremes of removing all stimulus from a child is not likely to get them better sooner and research suggests may take them longer to get better,” Dr. Halstead noted. “That doesn’t mean they don’t have to reduce anything, as it is important to reduce physical activity and modify school workload while recovering but we should be avoiding the blanket recommendation to ‘stay home and do nothing until you are better’ approach to concussion management.”

Dr. Halstead and Dr. Moffatt reported no relevant financial conflicts to disclose; the same was true for the other report coauthors. There was no external funding for the report.

SOURCE: Halstead M et al. Pediatrics. 2018 Nov 12. doi: 10.1542/peds.2018-3074.

Children and adolescents who suffer sports-related concussion should engage in light activities for their minds and bodies, while being monitored and evaluated, according to a new clinical report from the American Academy of Pediatrics.

The update to the 2010 guidelines was needed to reflect the latest research “and it was necessary to provide this new information to guide pediatricians in evaluating and treating concussions they may see in their practice,” Mark Halstead, MD, of Washington University, St. Louis, said in an interview.

The biggest changes to the guidelines involve management of concussion, noted Dr. Halstead, who was a coauthor of the AAP clinical report. “The previous recommendation called for cognitive and physical rest, which unfortunately was interpreted as complete removal from all physical activity and limiting many other things including electronic use.

“Because of research that has been conducted since the original report, it has been shown that starting some light physical activity to increase heart rate, provided it does not worsen symptoms, can be beneficial in recovery. Also, the recommendation for complete removal of electronics and computer use has unfortunately created some issues with kids getting socially isolated,” he added.

James Boulette/iStockphoto

“For better or for worse, kids are connected through their electronic devices. Removing them, with no evidence that it worsens the concussion, essentially punishes kids for their injury. We also are trying to discourage prolonged removal of kids from school,” Dr. Halstead emphasized.

The new recommendations emphasize the unique nature of sports-related concussion (SRC) from one individual to another, and the need for individualized management.

Symptoms of SRC fall into five categories, according to the guidelines: somatic, vestibular, oculomotor, cognitive, and emotional/sleep. Pediatric health care providers should rule out more severe head injuries and recognize that concussion symptoms are nonspecific and may reflect preexisting conditions, such as migraine or headache disorders, learning disorders, ADHD, mental health conditions, or sleep disorders.

Use of assessments such as the Sport Concussion Management Tool (SCAT5 for 13 years and older or Child SCAT5 for 5-12 years) can help guide clinicians, but should not be used in isolation to diagnose a concussion, the guideline authors wrote.

Strategies for injury prevention are included in the guidelines as well, such as the use of appropriate headgear. As for management, computerized neurocognitive testing can play a role in decisions regarding return to play, but should not be used in isolation.

“The biggest thing we are lacking is an objective diagnostic test to determine the presence of a concussion or its resolution,” coauthor Kody A. Moffatt, MD, of Creighton University, Omaha, Nebraska, said in an interview.

“Mandatory baseline and postinjury computerized neurocognitive testing is not recommended,” he added.

Clinicians can best manage SRC with prompt recognition and diagnosis using the available tools, followed by relative rest and return to school, then noncontact physical activities, and eventually a return to sport if appropriate.

“Most concussions in children and adolescents will resolve within 4 weeks as long as there is not additional injury to the brain during that time,” Dr. Moffat said.

More research is needed in particular about concussions in elementary and middle school children, Dr. Halstead added.

In the meantime, the take-home message to pediatricians for managing SRC is one of common sense. “Extremes of removing all stimulus from a child is not likely to get them better sooner and research suggests may take them longer to get better,” Dr. Halstead noted. “That doesn’t mean they don’t have to reduce anything, as it is important to reduce physical activity and modify school workload while recovering but we should be avoiding the blanket recommendation to ‘stay home and do nothing until you are better’ approach to concussion management.”

Dr. Halstead and Dr. Moffatt reported no relevant financial conflicts to disclose; the same was true for the other report coauthors. There was no external funding for the report.

SOURCE: Halstead M et al. Pediatrics. 2018 Nov 12. doi: 10.1542/peds.2018-3074.

Acute flaccid myelitis (AFM) has stricken 90 patients in the United States this year and another 252 cases are being investigated, according to new data from the Centers for Disease Control and Prevention.

Sasiistock/iStock/Getty Images Plus

The number of confirmed cases is triple that seen in 2017.

Nearly all of the patients (90%) were children aged 2-8 years, and 99% experienced a fever and /or respiratory illness 7-10 days before the onset of symptoms. But although the prodrome and seasonality of AFM suggest an infective process, only 54% of the patients tested positive for the virus, Nancy Messonnier, MD, said during a briefing held by CDC officials. The most common findings were the enteroviruses EV-A71 (29%) and EV-D68 (37%); other viruses were recovered in the remaining pathogen-positive cases.

It’s not at all clear that these were causative agents, said Dr. Messonnier, director of the National Center for Immunization and Respiratory Diseases.

“At this time of year lots of children have a fever and respiratory infections,” she said. AFM may be caused by one of the identified viruses, a still-undetected pathogen, or a pathogen hiding in untested tissue. “Or, it could be an infection that’s kicking off an immune process,” attacking gray matter in the spinal cord.

The reported increase in cases must be viewed cautiously, Dr. Messonnier said. Physicians are becoming more aware of AFM, so the spike could represent an increase in reporting as well as actual incidence.

It’s not clear why the disease manifests almost exclusively in children, Dr. Messonnier said. Nor do health officials have much of a grasp on AFM’s long-term sequelae.

“We know that patients can recover fully, but at least half don’t, and some of those have serious sequelae. Unfortunately, we have not been following every patient, so this is a gap in our knowledge.”

A newly created national task force will examine AFM’s long-term effects, Dr. Messonnier said. The task force will also look at mortality; health departments across the country will examine mortality records to identify any past deaths preceded by AFM-like symptoms.

“One of the reasons we have convened this task force is to think about this hypothesis [of an autoimmune syndrome]. We have not backed off on the idea of an infectious organism causing it, but we are thinking more broadly,” Dr. Messonnier said.

Some anti-immunization groups are blaming vaccines for the disease, noting that several childhood vaccines list encephalomyelitis and transverse myelitis as possible adverse events.

“We are investigating every one of the cases in this and prior years and have a list of hypotheses based on the epidemiology,” Dr. Messonnier said. “I would say toxins are low on that list. Many of the children may have been vaccinated [before developing AFM] and that is something we will look at, but for now we recommend that all children should be vaccinated” according to the recommended schedule.

Additional details were published on 80 of the cases. Patients’ mean age was 4 years; 59% were male. Symptoms suggesting a viral illness occurred in 99%; these included fever (81%), cough, rhinorrhea, and congestion (78%), and vomiting and diarrhea (38%).

AFM symptoms varied; 47% had only upper limb involvement, 9% only lower limb, 15% two or three upper, and 29% all four limbs. All the patients with confirmed AFM were hospitalized, and 59% treated in intensive care units. There were no deaths (MMWR. 2018;ePub:13 November. DOI: http://dx.doi.org/10.15585/mmwr.mm6745e1).

AFM remains extremely rare, Dr. Messonnier said. But physicians should be alert for any signs of sudden limb weakness in children and report those immediately. The workup should include questions about recent fever with or without respiratory or gastrointestinal symptoms. Prompt collection of viral testing samples (cerebrospinal fluid, serum, respiratory, and stool specimens) is critical.

Additional information for health care professionals is available on the CDC AFM web page.

[email protected]

Acute flaccid myelitis (AFM) has stricken 90 patients in the United States this year and another 252 cases are being investigated, according to new data from the Centers for Disease Control and Prevention.

Sasiistock/iStock/Getty Images Plus

The number of confirmed cases is triple that seen in 2017.

Nearly all of the patients (90%) were children aged 2-8 years, and 99% experienced a fever and /or respiratory illness 7-10 days before the onset of symptoms. But although the prodrome and seasonality of AFM suggest an infective process, only 54% of the patients tested positive for the virus, Nancy Messonnier, MD, said during a briefing held by CDC officials. The most common findings were the enteroviruses EV-A71 (29%) and EV-D68 (37%); other viruses were recovered in the remaining pathogen-positive cases.

It’s not at all clear that these were causative agents, said Dr. Messonnier, director of the National Center for Immunization and Respiratory Diseases.

“At this time of year lots of children have a fever and respiratory infections,” she said. AFM may be caused by one of the identified viruses, a still-undetected pathogen, or a pathogen hiding in untested tissue. “Or, it could be an infection that’s kicking off an immune process,” attacking gray matter in the spinal cord.

The reported increase in cases must be viewed cautiously, Dr. Messonnier said. Physicians are becoming more aware of AFM, so the spike could represent an increase in reporting as well as actual incidence.

It’s not clear why the disease manifests almost exclusively in children, Dr. Messonnier said. Nor do health officials have much of a grasp on AFM’s long-term sequelae.

“We know that patients can recover fully, but at least half don’t, and some of those have serious sequelae. Unfortunately, we have not been following every patient, so this is a gap in our knowledge.”

A newly created national task force will examine AFM’s long-term effects, Dr. Messonnier said. The task force will also look at mortality; health departments across the country will examine mortality records to identify any past deaths preceded by AFM-like symptoms.

“One of the reasons we have convened this task force is to think about this hypothesis [of an autoimmune syndrome]. We have not backed off on the idea of an infectious organism causing it, but we are thinking more broadly,” Dr. Messonnier said.

Some anti-immunization groups are blaming vaccines for the disease, noting that several childhood vaccines list encephalomyelitis and transverse myelitis as possible adverse events.

“We are investigating every one of the cases in this and prior years and have a list of hypotheses based on the epidemiology,” Dr. Messonnier said. “I would say toxins are low on that list. Many of the children may have been vaccinated [before developing AFM] and that is something we will look at, but for now we recommend that all children should be vaccinated” according to the recommended schedule.

Additional details were published on 80 of the cases. Patients’ mean age was 4 years; 59% were male. Symptoms suggesting a viral illness occurred in 99%; these included fever (81%), cough, rhinorrhea, and congestion (78%), and vomiting and diarrhea (38%).

AFM symptoms varied; 47% had only upper limb involvement, 9% only lower limb, 15% two or three upper, and 29% all four limbs. All the patients with confirmed AFM were hospitalized, and 59% treated in intensive care units. There were no deaths (MMWR. 2018;ePub:13 November. DOI: http://dx.doi.org/10.15585/mmwr.mm6745e1).

AFM remains extremely rare, Dr. Messonnier said. But physicians should be alert for any signs of sudden limb weakness in children and report those immediately. The workup should include questions about recent fever with or without respiratory or gastrointestinal symptoms. Prompt collection of viral testing samples (cerebrospinal fluid, serum, respiratory, and stool specimens) is critical.

Additional information for health care professionals is available on the CDC AFM web page.

[email protected]

Acute flaccid myelitis (AFM) has stricken 90 patients in the United States this year and another 252 cases are being investigated, according to new data from the Centers for Disease Control and Prevention.

Sasiistock/iStock/Getty Images Plus

The number of confirmed cases is triple that seen in 2017.

Nearly all of the patients (90%) were children aged 2-8 years, and 99% experienced a fever and /or respiratory illness 7-10 days before the onset of symptoms. But although the prodrome and seasonality of AFM suggest an infective process, only 54% of the patients tested positive for the virus, Nancy Messonnier, MD, said during a briefing held by CDC officials. The most common findings were the enteroviruses EV-A71 (29%) and EV-D68 (37%); other viruses were recovered in the remaining pathogen-positive cases.

It’s not at all clear that these were causative agents, said Dr. Messonnier, director of the National Center for Immunization and Respiratory Diseases.

“At this time of year lots of children have a fever and respiratory infections,” she said. AFM may be caused by one of the identified viruses, a still-undetected pathogen, or a pathogen hiding in untested tissue. “Or, it could be an infection that’s kicking off an immune process,” attacking gray matter in the spinal cord.

The reported increase in cases must be viewed cautiously, Dr. Messonnier said. Physicians are becoming more aware of AFM, so the spike could represent an increase in reporting as well as actual incidence.

It’s not clear why the disease manifests almost exclusively in children, Dr. Messonnier said. Nor do health officials have much of a grasp on AFM’s long-term sequelae.

“We know that patients can recover fully, but at least half don’t, and some of those have serious sequelae. Unfortunately, we have not been following every patient, so this is a gap in our knowledge.”

A newly created national task force will examine AFM’s long-term effects, Dr. Messonnier said. The task force will also look at mortality; health departments across the country will examine mortality records to identify any past deaths preceded by AFM-like symptoms.

“One of the reasons we have convened this task force is to think about this hypothesis [of an autoimmune syndrome]. We have not backed off on the idea of an infectious organism causing it, but we are thinking more broadly,” Dr. Messonnier said.

Some anti-immunization groups are blaming vaccines for the disease, noting that several childhood vaccines list encephalomyelitis and transverse myelitis as possible adverse events.

“We are investigating every one of the cases in this and prior years and have a list of hypotheses based on the epidemiology,” Dr. Messonnier said. “I would say toxins are low on that list. Many of the children may have been vaccinated [before developing AFM] and that is something we will look at, but for now we recommend that all children should be vaccinated” according to the recommended schedule.

Additional details were published on 80 of the cases. Patients’ mean age was 4 years; 59% were male. Symptoms suggesting a viral illness occurred in 99%; these included fever (81%), cough, rhinorrhea, and congestion (78%), and vomiting and diarrhea (38%).

AFM symptoms varied; 47% had only upper limb involvement, 9% only lower limb, 15% two or three upper, and 29% all four limbs. All the patients with confirmed AFM were hospitalized, and 59% treated in intensive care units. There were no deaths (MMWR. 2018;ePub:13 November. DOI: http://dx.doi.org/10.15585/mmwr.mm6745e1).

AFM remains extremely rare, Dr. Messonnier said. But physicians should be alert for any signs of sudden limb weakness in children and report those immediately. The workup should include questions about recent fever with or without respiratory or gastrointestinal symptoms. Prompt collection of viral testing samples (cerebrospinal fluid, serum, respiratory, and stool specimens) is critical.

Additional information for health care professionals is available on the CDC AFM web page.

[email protected]

Clinical question: Can an opiate-prescribing standard that favors oral and subcutaneous over intravenous administration reduce exposure to intravenous opiates for hospitalized adults?

Background: IV opiates, while effective for analgesia, may have a higher addictive potential because of the rapid and intermittent rises of peak concentrations. Subcutaneous and/or oral administration is a proven method of opioid delivery with similar bioavailability and efficacy of intravenous administration with more favorable pharmacokinetics.

Study design: Intervention-based quality improvement project.

Dr. Chowdury is an assistant professor in the division of hospital medicine, University of Colorado, Denver.

Clinical question: Can an opiate-prescribing standard that favors oral and subcutaneous over intravenous administration reduce exposure to intravenous opiates for hospitalized adults?

Background: IV opiates, while effective for analgesia, may have a higher addictive potential because of the rapid and intermittent rises of peak concentrations. Subcutaneous and/or oral administration is a proven method of opioid delivery with similar bioavailability and efficacy of intravenous administration with more favorable pharmacokinetics.

Study design: Intervention-based quality improvement project.

Dr. Chowdury is an assistant professor in the division of hospital medicine, University of Colorado, Denver.

Clinical question: Can an opiate-prescribing standard that favors oral and subcutaneous over intravenous administration reduce exposure to intravenous opiates for hospitalized adults?

Background: IV opiates, while effective for analgesia, may have a higher addictive potential because of the rapid and intermittent rises of peak concentrations. Subcutaneous and/or oral administration is a proven method of opioid delivery with similar bioavailability and efficacy of intravenous administration with more favorable pharmacokinetics.

Study design: Intervention-based quality improvement project.

Dr. Chowdury is an assistant professor in the division of hospital medicine, University of Colorado, Denver.

Risk of suicide was doubled in persons who experienced a concussion or mild traumatic brain injury (TBI) earlier in life, according to results of a meta-analysis of 17 studies representing nearly 7 million patients.

However, the absolute risk of suicide remained quite low, according to Michael Fralick, MD, of the University of Toronto, and co-investigators.

“Nearly all patients diagnosed with concussion and/or mild TBI did not die by suicide,” Dr. Fralick and colleagues said in their report on the study, which appears in JAMA Neurology.

Nevertheless, the meta-analysis illustrates evidence for an increased risk of suicide, suicide attempts, and suicidal ideation for persons with a history of these injuries, they said in the report.

The meta-analysis included 10 cohort studies, 5 cross-sectional studies, and 2 case-control studies looking at the risk of suicide, suicide attempts, or suicidal ideation after a concussion or mild TBI. Those studies included a roughly 714,000 individuals with a concussion and/or TBI diagnosis, and 6,236,000 without a diagnosis.

For people diagnosed with at least one concussion and/or mild TBI, the risk of suicide was 2-fold higher (relative risk, 2.03; 95% CI, 1.47-2.80; P less than 0.001), according to the report.

The risk was “slightly stronger,” investigators said, when the analysis was limited to studies adjusting for factors associated with those brain injuries and with suicide (RR, 2.10; 95% CI, 1.40-3.13; P less than 0.01).

Four of the 5 cohort studies reported absolute risk of suicide, according to Dr. Fralick and coauthors. In one study with a median follow-up of 3.6 years, 0.50% of individuals with a concussion and/or TBI subsequently died of suicide, while similarly, 0.59% died in a study with 4.0 years of follow-up, 0.28% in a study with 9.3 years follow-up, and 0.49% in one with a 12.3 year median follow-up.

Most of the studies in the meta-analysis reported an increased risk of suicide attempt after concussion and/or mild TBI, according to Dr. Fralick and his collaborators, while the eight studies looking at suicidal ideation all reported heightened risk after those brain injuries.

The researchers acknowledged some limitations of their analysis. Recall bias could have led to an overestimation of the association between concussion and suicide risk, since suicide attempts may affect reporting of concussion history, they said.

Furthermore, most of the studies were retrospective, and did not include an active comparator group, such as individuals with non-neurologic injuries, they added.

“Until large prospective studies with sufficiently large durations of follow-up are available, we have to rely on the currently available data,” they said in the report.

Dr. Fralick and co-authors reported no conflict of interest disclosures related to the study.

SOURCE: Fralick M, et al. JAMA Neurol. 2018 Nov 12.

Risk of suicide was doubled in persons who experienced a concussion or mild traumatic brain injury (TBI) earlier in life, according to results of a meta-analysis of 17 studies representing nearly 7 million patients.

However, the absolute risk of suicide remained quite low, according to Michael Fralick, MD, of the University of Toronto, and co-investigators.

“Nearly all patients diagnosed with concussion and/or mild TBI did not die by suicide,” Dr. Fralick and colleagues said in their report on the study, which appears in JAMA Neurology.

Nevertheless, the meta-analysis illustrates evidence for an increased risk of suicide, suicide attempts, and suicidal ideation for persons with a history of these injuries, they said in the report.

The meta-analysis included 10 cohort studies, 5 cross-sectional studies, and 2 case-control studies looking at the risk of suicide, suicide attempts, or suicidal ideation after a concussion or mild TBI. Those studies included a roughly 714,000 individuals with a concussion and/or TBI diagnosis, and 6,236,000 without a diagnosis.

For people diagnosed with at least one concussion and/or mild TBI, the risk of suicide was 2-fold higher (relative risk, 2.03; 95% CI, 1.47-2.80; P less than 0.001), according to the report.

The risk was “slightly stronger,” investigators said, when the analysis was limited to studies adjusting for factors associated with those brain injuries and with suicide (RR, 2.10; 95% CI, 1.40-3.13; P less than 0.01).

Four of the 5 cohort studies reported absolute risk of suicide, according to Dr. Fralick and coauthors. In one study with a median follow-up of 3.6 years, 0.50% of individuals with a concussion and/or TBI subsequently died of suicide, while similarly, 0.59% died in a study with 4.0 years of follow-up, 0.28% in a study with 9.3 years follow-up, and 0.49% in one with a 12.3 year median follow-up.

Most of the studies in the meta-analysis reported an increased risk of suicide attempt after concussion and/or mild TBI, according to Dr. Fralick and his collaborators, while the eight studies looking at suicidal ideation all reported heightened risk after those brain injuries.

The researchers acknowledged some limitations of their analysis. Recall bias could have led to an overestimation of the association between concussion and suicide risk, since suicide attempts may affect reporting of concussion history, they said.

Furthermore, most of the studies were retrospective, and did not include an active comparator group, such as individuals with non-neurologic injuries, they added.

“Until large prospective studies with sufficiently large durations of follow-up are available, we have to rely on the currently available data,” they said in the report.

Dr. Fralick and co-authors reported no conflict of interest disclosures related to the study.

SOURCE: Fralick M, et al. JAMA Neurol. 2018 Nov 12.

Risk of suicide was doubled in persons who experienced a concussion or mild traumatic brain injury (TBI) earlier in life, according to results of a meta-analysis of 17 studies representing nearly 7 million patients.

However, the absolute risk of suicide remained quite low, according to Michael Fralick, MD, of the University of Toronto, and co-investigators.

“Nearly all patients diagnosed with concussion and/or mild TBI did not die by suicide,” Dr. Fralick and colleagues said in their report on the study, which appears in JAMA Neurology.

Nevertheless, the meta-analysis illustrates evidence for an increased risk of suicide, suicide attempts, and suicidal ideation for persons with a history of these injuries, they said in the report.

The meta-analysis included 10 cohort studies, 5 cross-sectional studies, and 2 case-control studies looking at the risk of suicide, suicide attempts, or suicidal ideation after a concussion or mild TBI. Those studies included a roughly 714,000 individuals with a concussion and/or TBI diagnosis, and 6,236,000 without a diagnosis.

For people diagnosed with at least one concussion and/or mild TBI, the risk of suicide was 2-fold higher (relative risk, 2.03; 95% CI, 1.47-2.80; P less than 0.001), according to the report.

The risk was “slightly stronger,” investigators said, when the analysis was limited to studies adjusting for factors associated with those brain injuries and with suicide (RR, 2.10; 95% CI, 1.40-3.13; P less than 0.01).

Four of the 5 cohort studies reported absolute risk of suicide, according to Dr. Fralick and coauthors. In one study with a median follow-up of 3.6 years, 0.50% of individuals with a concussion and/or TBI subsequently died of suicide, while similarly, 0.59% died in a study with 4.0 years of follow-up, 0.28% in a study with 9.3 years follow-up, and 0.49% in one with a 12.3 year median follow-up.

Most of the studies in the meta-analysis reported an increased risk of suicide attempt after concussion and/or mild TBI, according to Dr. Fralick and his collaborators, while the eight studies looking at suicidal ideation all reported heightened risk after those brain injuries.

The researchers acknowledged some limitations of their analysis. Recall bias could have led to an overestimation of the association between concussion and suicide risk, since suicide attempts may affect reporting of concussion history, they said.

Furthermore, most of the studies were retrospective, and did not include an active comparator group, such as individuals with non-neurologic injuries, they added.

“Until large prospective studies with sufficiently large durations of follow-up are available, we have to rely on the currently available data,” they said in the report.

Dr. Fralick and co-authors reported no conflict of interest disclosures related to the study.

SOURCE: Fralick M, et al. JAMA Neurol. 2018 Nov 12.