Epilepsy & Seizures

An epilepsy drug sold in Europe as Ospolot and also known as sulthiame showed promise in reducing sleep disordered breathing and other symptoms of obstructive sleep apnea (OSA), based on data from nearly 300 individuals presented in a late-breaking study at the annual congress of the European Respiratory Society.

“Current therapies are mechanical and based on the notion of an airway splint,” presenting author Jan Hedner, MD, professor of respiratory medicine at Sahlgrenska University Hospital and the University of Gothenburg, both in Sweden, said in an interview. “In other words, applying an airflow at elevated pressure [continuous positive airway pressure] or advancing the jaw with a dental device. Adherence to this type of therapy is limited. In the case of continuous positive airway pressure [CPAP], it is < 50% after 3-4 years of therapy.” Therefore, there is a need for a better-tolerated therapy, such as a drug, and possibly a combination of mechanical and pharmaceutical therapies.

The use of medication has emerged as a viable option for OSA, with a high rate of compliance and acceptable safety profile, Dr. Hedner said in his presentation.

“Modified carbonic anhydrase activity may be a pathophysiological mechanism in OSA,” said Dr. Hedner. Sulthiame, a carbonic anhydrase inhibitor, showed safety and effectiveness for improving OSA in a previous phase 2b trial.

In the current study, the researchers sought to determine the most effective dose of sulthiame for patients with OSA. They randomized 298 adults with OSA who could not accept or tolerate oral splints or CPAP to 100 mg, 200 mg, or 300 mg of sulthiame daily (74, 74, and 75 patients, respectively) or placebo (75 patients).

The mean age of the patients was 56 years, 26.2% were women, and the average apnea-hypopnea index (AHI3a) at baseline was 29 n/h. Patients were treated at centers in Spain, France, Belgium, Germany, and the Czech Republic. Baseline demographics and clinical characteristics were similar among the treatment groups.

The primary endpoint was the change in AHI3a from baseline to 15 weeks, and significant changes occurred in patients who received the 100-mg, 200-mg, and 300-mg doses, with decreases of 17.8%, 34.8%, and 39.9%, respectively.

Peak efficacy occurred in the range of 200-300 mg and was similar for patients with moderate or severe OSA, Dr. Hedner said in his presentation.

Notably, in a post hoc analysis, apnea improved by 47.1% at a 300-mg dose when the AHI4 measure (apnea/hypopnea with ≥ 4% O₂ desaturation) was used in a placebo-adjusted dose-dependent reduction, the researchers wrote. The changes in AHI4 from baseline in this analysis also were significant for 200 mg and 100 mg doses (36.8% and 26.2%, respectively).

Patients underwent polysomnography at baseline and at weeks 4 and 12.

Mean overnight oxygen saturation also improved significantly from baseline with doses of 200 mg and 300 mg, compared with placebo (P < .0001 for both).

In addition, scores on the Epworth Sleepiness Scale (ESS) improved from baseline to week 15 in all dosage groups, and the subgroup of patients with ESS scores of ≥ 11 at baseline showed even greater improvement in ESS, Dr. Hedner said in his presentation.

Total arousal index and sleep quality also improved from baseline compared with placebo, and no clinically relevant reduction in REM sleep was noted, Dr. Hedner added.

Treatment-emergent adverse events were in line with the known safety profile of sulthiame and included paresthesia, headache, fatigue, and nausea; these were mainly moderate and dose-dependent, with no evidence of cardiovascular safety issues, he said.

Although the study results were not surprising given previous research, the investigators were pleased with the potency of the therapy. “We are also happy about potential added values such as a blood pressure lowering effect, which is beneficial in this group of patients; however, we need to further study these mechanisms in detail,” Dr. Hedner noted.

The study findings were limited by the relatively small scale, and larger studies on long-term efficacy and tolerability are also needed, he said.

“The current study was a dose-finding study, and we now have useful information on most suitable dose,” he said.

However, the results support sulthiame as an effective, well-tolerated, and promising novel candidate for drug therapy in patients with OSA, worthy of phase 3 studies, Dr. Hedner said.
 

Oral Option Could Be Game-Changer, But Not Yet

The gold standard of treatment for OSA is a CPAP machine, but the effectiveness is limited by patient tolerance, Q. Afifa Shamim-Uzzaman, MD, an associate professor and a sleep medicine specialist at the University of Michigan, Ann Arbor, said in an interview.

“Presently, there are no effective pharmacological treatments for OSA — having a pill that treats OSA would be a total game changer and huge advance for the treatment of OSA and the field of sleep medicine,” said Dr. Shamim-Uzzaman, who was not involved in the study. “More patients may be able to obtain treatment for OSA and thereby reduce the potential complications of untreated OSA.

“Carbonic anhydrase inhibitors such as acetazolamide and sulthiame have been studied with limited success for the treatment of other forms of sleep disordered breathing such as central sleep apnea [CSA] but have shown less efficacy for OSA and are presently not recommended in the treatment of OSA by the American Academy of Sleep Medicine,” Dr. Shamim-Uzzaman said.

Recently, emerging evidence about different phenotypes of OSA suggests that nonanatomic features (such as high loop gain) may play a role in patients with OSA, not only in those with CSA, she said. Whether carbonic anhydrase inhibitors could play a greater role in treating sleep apnea in patients with predominantly nonanatomic pathophysiologic traits remains to be seen.

The sulthiame data are promising, but more research is needed, Dr. Shamim-Uzzaman said. Although patients in the highest dose group showed a reduction in AHI of nearly 40%, they still would have moderate OSA, and the OSA did not appear to decrease to a normal range in any of the treatment groups.

“More research is needed to identify which types of patients would be responders to this form of therapy, to understand if these effects are maintained long term (beyond 15 weeks), to evaluate patient-centered outcomes, especially in different sleep apnea subgroups (such as phenotypes with high loop gain vs those without), and to assess interactions with other therapies,” she said.

The study was supported by manufacturer Desitin. Dr. Hedner disclosed serving as a consultant to AstraZeneca, Bayer, CereusScience, Jazz Pharmaceuticals, MSD, Weinmann, Desitin, SomnoMed, and Itamar Medical; serving on the speakers’ bureau for Almirall, AstraZeneca, Jazz Pharmaceuticals, ResMed, Philips Respironics, and Weinmann; and receiving grants or research support from Bayer, ResMed, Philips Respironics, and SomnoMed. He also disclosed shared ownership of intellectual property related to sleep apnea therapy. Dr. Shamim-Uzzaman had no financial conflicts to disclose.

A version of this article appeared on Medscape.com.

An epilepsy drug sold in Europe as Ospolot and also known as sulthiame showed promise in reducing sleep disordered breathing and other symptoms of obstructive sleep apnea (OSA), based on data from nearly 300 individuals presented in a late-breaking study at the annual congress of the European Respiratory Society.

“Current therapies are mechanical and based on the notion of an airway splint,” presenting author Jan Hedner, MD, professor of respiratory medicine at Sahlgrenska University Hospital and the University of Gothenburg, both in Sweden, said in an interview. “In other words, applying an airflow at elevated pressure [continuous positive airway pressure] or advancing the jaw with a dental device. Adherence to this type of therapy is limited. In the case of continuous positive airway pressure [CPAP], it is < 50% after 3-4 years of therapy.” Therefore, there is a need for a better-tolerated therapy, such as a drug, and possibly a combination of mechanical and pharmaceutical therapies.

The use of medication has emerged as a viable option for OSA, with a high rate of compliance and acceptable safety profile, Dr. Hedner said in his presentation.

“Modified carbonic anhydrase activity may be a pathophysiological mechanism in OSA,” said Dr. Hedner. Sulthiame, a carbonic anhydrase inhibitor, showed safety and effectiveness for improving OSA in a previous phase 2b trial.

In the current study, the researchers sought to determine the most effective dose of sulthiame for patients with OSA. They randomized 298 adults with OSA who could not accept or tolerate oral splints or CPAP to 100 mg, 200 mg, or 300 mg of sulthiame daily (74, 74, and 75 patients, respectively) or placebo (75 patients).

The mean age of the patients was 56 years, 26.2% were women, and the average apnea-hypopnea index (AHI3a) at baseline was 29 n/h. Patients were treated at centers in Spain, France, Belgium, Germany, and the Czech Republic. Baseline demographics and clinical characteristics were similar among the treatment groups.

The primary endpoint was the change in AHI3a from baseline to 15 weeks, and significant changes occurred in patients who received the 100-mg, 200-mg, and 300-mg doses, with decreases of 17.8%, 34.8%, and 39.9%, respectively.

Peak efficacy occurred in the range of 200-300 mg and was similar for patients with moderate or severe OSA, Dr. Hedner said in his presentation.

Notably, in a post hoc analysis, apnea improved by 47.1% at a 300-mg dose when the AHI4 measure (apnea/hypopnea with ≥ 4% O₂ desaturation) was used in a placebo-adjusted dose-dependent reduction, the researchers wrote. The changes in AHI4 from baseline in this analysis also were significant for 200 mg and 100 mg doses (36.8% and 26.2%, respectively).

Patients underwent polysomnography at baseline and at weeks 4 and 12.

Mean overnight oxygen saturation also improved significantly from baseline with doses of 200 mg and 300 mg, compared with placebo (P < .0001 for both).

In addition, scores on the Epworth Sleepiness Scale (ESS) improved from baseline to week 15 in all dosage groups, and the subgroup of patients with ESS scores of ≥ 11 at baseline showed even greater improvement in ESS, Dr. Hedner said in his presentation.

Total arousal index and sleep quality also improved from baseline compared with placebo, and no clinically relevant reduction in REM sleep was noted, Dr. Hedner added.

Treatment-emergent adverse events were in line with the known safety profile of sulthiame and included paresthesia, headache, fatigue, and nausea; these were mainly moderate and dose-dependent, with no evidence of cardiovascular safety issues, he said.

Although the study results were not surprising given previous research, the investigators were pleased with the potency of the therapy. “We are also happy about potential added values such as a blood pressure lowering effect, which is beneficial in this group of patients; however, we need to further study these mechanisms in detail,” Dr. Hedner noted.

The study findings were limited by the relatively small scale, and larger studies on long-term efficacy and tolerability are also needed, he said.

“The current study was a dose-finding study, and we now have useful information on most suitable dose,” he said.

However, the results support sulthiame as an effective, well-tolerated, and promising novel candidate for drug therapy in patients with OSA, worthy of phase 3 studies, Dr. Hedner said.
 

Oral Option Could Be Game-Changer, But Not Yet

The gold standard of treatment for OSA is a CPAP machine, but the effectiveness is limited by patient tolerance, Q. Afifa Shamim-Uzzaman, MD, an associate professor and a sleep medicine specialist at the University of Michigan, Ann Arbor, said in an interview.

“Presently, there are no effective pharmacological treatments for OSA — having a pill that treats OSA would be a total game changer and huge advance for the treatment of OSA and the field of sleep medicine,” said Dr. Shamim-Uzzaman, who was not involved in the study. “More patients may be able to obtain treatment for OSA and thereby reduce the potential complications of untreated OSA.

“Carbonic anhydrase inhibitors such as acetazolamide and sulthiame have been studied with limited success for the treatment of other forms of sleep disordered breathing such as central sleep apnea [CSA] but have shown less efficacy for OSA and are presently not recommended in the treatment of OSA by the American Academy of Sleep Medicine,” Dr. Shamim-Uzzaman said.

Recently, emerging evidence about different phenotypes of OSA suggests that nonanatomic features (such as high loop gain) may play a role in patients with OSA, not only in those with CSA, she said. Whether carbonic anhydrase inhibitors could play a greater role in treating sleep apnea in patients with predominantly nonanatomic pathophysiologic traits remains to be seen.

The sulthiame data are promising, but more research is needed, Dr. Shamim-Uzzaman said. Although patients in the highest dose group showed a reduction in AHI of nearly 40%, they still would have moderate OSA, and the OSA did not appear to decrease to a normal range in any of the treatment groups.

“More research is needed to identify which types of patients would be responders to this form of therapy, to understand if these effects are maintained long term (beyond 15 weeks), to evaluate patient-centered outcomes, especially in different sleep apnea subgroups (such as phenotypes with high loop gain vs those without), and to assess interactions with other therapies,” she said.

The study was supported by manufacturer Desitin. Dr. Hedner disclosed serving as a consultant to AstraZeneca, Bayer, CereusScience, Jazz Pharmaceuticals, MSD, Weinmann, Desitin, SomnoMed, and Itamar Medical; serving on the speakers’ bureau for Almirall, AstraZeneca, Jazz Pharmaceuticals, ResMed, Philips Respironics, and Weinmann; and receiving grants or research support from Bayer, ResMed, Philips Respironics, and SomnoMed. He also disclosed shared ownership of intellectual property related to sleep apnea therapy. Dr. Shamim-Uzzaman had no financial conflicts to disclose.

A version of this article appeared on Medscape.com.

An epilepsy drug sold in Europe as Ospolot and also known as sulthiame showed promise in reducing sleep disordered breathing and other symptoms of obstructive sleep apnea (OSA), based on data from nearly 300 individuals presented in a late-breaking study at the annual congress of the European Respiratory Society.

“Current therapies are mechanical and based on the notion of an airway splint,” presenting author Jan Hedner, MD, professor of respiratory medicine at Sahlgrenska University Hospital and the University of Gothenburg, both in Sweden, said in an interview. “In other words, applying an airflow at elevated pressure [continuous positive airway pressure] or advancing the jaw with a dental device. Adherence to this type of therapy is limited. In the case of continuous positive airway pressure [CPAP], it is < 50% after 3-4 years of therapy.” Therefore, there is a need for a better-tolerated therapy, such as a drug, and possibly a combination of mechanical and pharmaceutical therapies.

The use of medication has emerged as a viable option for OSA, with a high rate of compliance and acceptable safety profile, Dr. Hedner said in his presentation.

“Modified carbonic anhydrase activity may be a pathophysiological mechanism in OSA,” said Dr. Hedner. Sulthiame, a carbonic anhydrase inhibitor, showed safety and effectiveness for improving OSA in a previous phase 2b trial.

In the current study, the researchers sought to determine the most effective dose of sulthiame for patients with OSA. They randomized 298 adults with OSA who could not accept or tolerate oral splints or CPAP to 100 mg, 200 mg, or 300 mg of sulthiame daily (74, 74, and 75 patients, respectively) or placebo (75 patients).

The mean age of the patients was 56 years, 26.2% were women, and the average apnea-hypopnea index (AHI3a) at baseline was 29 n/h. Patients were treated at centers in Spain, France, Belgium, Germany, and the Czech Republic. Baseline demographics and clinical characteristics were similar among the treatment groups.

The primary endpoint was the change in AHI3a from baseline to 15 weeks, and significant changes occurred in patients who received the 100-mg, 200-mg, and 300-mg doses, with decreases of 17.8%, 34.8%, and 39.9%, respectively.

Peak efficacy occurred in the range of 200-300 mg and was similar for patients with moderate or severe OSA, Dr. Hedner said in his presentation.

Notably, in a post hoc analysis, apnea improved by 47.1% at a 300-mg dose when the AHI4 measure (apnea/hypopnea with ≥ 4% O₂ desaturation) was used in a placebo-adjusted dose-dependent reduction, the researchers wrote. The changes in AHI4 from baseline in this analysis also were significant for 200 mg and 100 mg doses (36.8% and 26.2%, respectively).

Patients underwent polysomnography at baseline and at weeks 4 and 12.

Mean overnight oxygen saturation also improved significantly from baseline with doses of 200 mg and 300 mg, compared with placebo (P < .0001 for both).

In addition, scores on the Epworth Sleepiness Scale (ESS) improved from baseline to week 15 in all dosage groups, and the subgroup of patients with ESS scores of ≥ 11 at baseline showed even greater improvement in ESS, Dr. Hedner said in his presentation.

Total arousal index and sleep quality also improved from baseline compared with placebo, and no clinically relevant reduction in REM sleep was noted, Dr. Hedner added.

Treatment-emergent adverse events were in line with the known safety profile of sulthiame and included paresthesia, headache, fatigue, and nausea; these were mainly moderate and dose-dependent, with no evidence of cardiovascular safety issues, he said.

Although the study results were not surprising given previous research, the investigators were pleased with the potency of the therapy. “We are also happy about potential added values such as a blood pressure lowering effect, which is beneficial in this group of patients; however, we need to further study these mechanisms in detail,” Dr. Hedner noted.

The study findings were limited by the relatively small scale, and larger studies on long-term efficacy and tolerability are also needed, he said.

“The current study was a dose-finding study, and we now have useful information on most suitable dose,” he said.

However, the results support sulthiame as an effective, well-tolerated, and promising novel candidate for drug therapy in patients with OSA, worthy of phase 3 studies, Dr. Hedner said.
 

Oral Option Could Be Game-Changer, But Not Yet

The gold standard of treatment for OSA is a CPAP machine, but the effectiveness is limited by patient tolerance, Q. Afifa Shamim-Uzzaman, MD, an associate professor and a sleep medicine specialist at the University of Michigan, Ann Arbor, said in an interview.

“Presently, there are no effective pharmacological treatments for OSA — having a pill that treats OSA would be a total game changer and huge advance for the treatment of OSA and the field of sleep medicine,” said Dr. Shamim-Uzzaman, who was not involved in the study. “More patients may be able to obtain treatment for OSA and thereby reduce the potential complications of untreated OSA.

“Carbonic anhydrase inhibitors such as acetazolamide and sulthiame have been studied with limited success for the treatment of other forms of sleep disordered breathing such as central sleep apnea [CSA] but have shown less efficacy for OSA and are presently not recommended in the treatment of OSA by the American Academy of Sleep Medicine,” Dr. Shamim-Uzzaman said.

Recently, emerging evidence about different phenotypes of OSA suggests that nonanatomic features (such as high loop gain) may play a role in patients with OSA, not only in those with CSA, she said. Whether carbonic anhydrase inhibitors could play a greater role in treating sleep apnea in patients with predominantly nonanatomic pathophysiologic traits remains to be seen.

The sulthiame data are promising, but more research is needed, Dr. Shamim-Uzzaman said. Although patients in the highest dose group showed a reduction in AHI of nearly 40%, they still would have moderate OSA, and the OSA did not appear to decrease to a normal range in any of the treatment groups.

“More research is needed to identify which types of patients would be responders to this form of therapy, to understand if these effects are maintained long term (beyond 15 weeks), to evaluate patient-centered outcomes, especially in different sleep apnea subgroups (such as phenotypes with high loop gain vs those without), and to assess interactions with other therapies,” she said.

The study was supported by manufacturer Desitin. Dr. Hedner disclosed serving as a consultant to AstraZeneca, Bayer, CereusScience, Jazz Pharmaceuticals, MSD, Weinmann, Desitin, SomnoMed, and Itamar Medical; serving on the speakers’ bureau for Almirall, AstraZeneca, Jazz Pharmaceuticals, ResMed, Philips Respironics, and Weinmann; and receiving grants or research support from Bayer, ResMed, Philips Respironics, and SomnoMed. He also disclosed shared ownership of intellectual property related to sleep apnea therapy. Dr. Shamim-Uzzaman had no financial conflicts to disclose.

A version of this article appeared on Medscape.com.

TOPLINE:

First-generation antihistamines are linked to a 22% higher risk for seizures in children, new research shows. The risk appears to be most pronounced in children aged 6-24 months.

METHODOLOGY:

• Researchers in Korea used a self-controlled case-crossover design to assess the risk for seizures associated with prescriptions of first-generation antihistamines.
• They analyzed data from 11,729 children who had a seizure event (an emergency department visit with a diagnosis of epilepsy, status epilepticus, or convulsion) and had previously received a prescription for a first-generation antihistamine, including chlorpheniramine maleate, mequitazine, oxatomide, piprinhydrinate, or hydroxyzine hydrochloride.
• Prescriptions during the 15 days before a seizure were considered to have been received during a hazard period, whereas earlier prescriptions were considered to have been received during a control period.
• The researchers excluded patients with febrile seizures.

TAKEAWAY:

• In an adjusted analysis, a prescription for an antihistamine during the hazard period was associated with a 22% higher risk for seizures in children (adjusted odds ratio, 1.22; 95% CI, 1.13-1.31).
• The seizure risk was significant in children aged 6-24 months, with an adjusted odds ratio of 1.49 (95% CI, 1.31-1.70).
• For older children, the risk was not statistically significant.

IN PRACTICE:

“The study underscores a substantial increase in seizure risk associated with antihistamine prescription among children aged 6-24 months,” the authors of the study wrote. “We are not aware of any other studies that have pointed out the increased risk of seizures with first-generation antihistamines in this particular age group. ... The benefits and risks of antihistamine use should always be carefully considered, especially when prescribing H1 antihistamines to vulnerable infants.”

The findings raise a host of questions for clinicians, including how a “relatively small risk” should translate into practice, and whether the risk may be attenuated with newer antihistamines, wrote Frank Max Charles Besag, MB, ChB, with East London NHS Foundation Trust in England, in an editorial accompanying the study. “It would be reasonable to inform families that at least one study has suggested a relatively small increase in the risk of seizures with first-generation antihistamines, adding that there are still too few data to draw any firm conclusions and also providing families with the information on what to do if the child were to have a seizure.” 
 

SOURCE:

Seonkyeong Rhie, MD, and Man Yong Han, MD, both with the Department of Pediatrics at CHA University School of Medicine, in Seongnam, South Korea, were the corresponding authors on the study. The research was published online in JAMA Network Open.

LIMITATIONS:

The researchers did not have details about seizure symptoms, did not include children seen in outpatient clinics, and were unable to verify the actual intake of the prescribed antihistamines. Although second-generation antihistamines may be less likely to cross the blood-brain barrier, one newer medication, desloratadine, has been associated with seizures.

DISCLOSURES:

The study was supported by grants from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, the Ministry of Health and Welfare, Republic of Korea.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

First-generation antihistamines are linked to a 22% higher risk for seizures in children, new research shows. The risk appears to be most pronounced in children aged 6-24 months.

METHODOLOGY:

• Researchers in Korea used a self-controlled case-crossover design to assess the risk for seizures associated with prescriptions of first-generation antihistamines.
• They analyzed data from 11,729 children who had a seizure event (an emergency department visit with a diagnosis of epilepsy, status epilepticus, or convulsion) and had previously received a prescription for a first-generation antihistamine, including chlorpheniramine maleate, mequitazine, oxatomide, piprinhydrinate, or hydroxyzine hydrochloride.
• Prescriptions during the 15 days before a seizure were considered to have been received during a hazard period, whereas earlier prescriptions were considered to have been received during a control period.
• The researchers excluded patients with febrile seizures.

TAKEAWAY:

• In an adjusted analysis, a prescription for an antihistamine during the hazard period was associated with a 22% higher risk for seizures in children (adjusted odds ratio, 1.22; 95% CI, 1.13-1.31).
• The seizure risk was significant in children aged 6-24 months, with an adjusted odds ratio of 1.49 (95% CI, 1.31-1.70).
• For older children, the risk was not statistically significant.

IN PRACTICE:

“The study underscores a substantial increase in seizure risk associated with antihistamine prescription among children aged 6-24 months,” the authors of the study wrote. “We are not aware of any other studies that have pointed out the increased risk of seizures with first-generation antihistamines in this particular age group. ... The benefits and risks of antihistamine use should always be carefully considered, especially when prescribing H1 antihistamines to vulnerable infants.”

The findings raise a host of questions for clinicians, including how a “relatively small risk” should translate into practice, and whether the risk may be attenuated with newer antihistamines, wrote Frank Max Charles Besag, MB, ChB, with East London NHS Foundation Trust in England, in an editorial accompanying the study. “It would be reasonable to inform families that at least one study has suggested a relatively small increase in the risk of seizures with first-generation antihistamines, adding that there are still too few data to draw any firm conclusions and also providing families with the information on what to do if the child were to have a seizure.” 
 

SOURCE:

Seonkyeong Rhie, MD, and Man Yong Han, MD, both with the Department of Pediatrics at CHA University School of Medicine, in Seongnam, South Korea, were the corresponding authors on the study. The research was published online in JAMA Network Open.

LIMITATIONS:

The researchers did not have details about seizure symptoms, did not include children seen in outpatient clinics, and were unable to verify the actual intake of the prescribed antihistamines. Although second-generation antihistamines may be less likely to cross the blood-brain barrier, one newer medication, desloratadine, has been associated with seizures.

DISCLOSURES:

The study was supported by grants from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, the Ministry of Health and Welfare, Republic of Korea.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

First-generation antihistamines are linked to a 22% higher risk for seizures in children, new research shows. The risk appears to be most pronounced in children aged 6-24 months.

METHODOLOGY:

• Researchers in Korea used a self-controlled case-crossover design to assess the risk for seizures associated with prescriptions of first-generation antihistamines.
• They analyzed data from 11,729 children who had a seizure event (an emergency department visit with a diagnosis of epilepsy, status epilepticus, or convulsion) and had previously received a prescription for a first-generation antihistamine, including chlorpheniramine maleate, mequitazine, oxatomide, piprinhydrinate, or hydroxyzine hydrochloride.
• Prescriptions during the 15 days before a seizure were considered to have been received during a hazard period, whereas earlier prescriptions were considered to have been received during a control period.
• The researchers excluded patients with febrile seizures.

TAKEAWAY:

• In an adjusted analysis, a prescription for an antihistamine during the hazard period was associated with a 22% higher risk for seizures in children (adjusted odds ratio, 1.22; 95% CI, 1.13-1.31).
• The seizure risk was significant in children aged 6-24 months, with an adjusted odds ratio of 1.49 (95% CI, 1.31-1.70).
• For older children, the risk was not statistically significant.

IN PRACTICE:

“The study underscores a substantial increase in seizure risk associated with antihistamine prescription among children aged 6-24 months,” the authors of the study wrote. “We are not aware of any other studies that have pointed out the increased risk of seizures with first-generation antihistamines in this particular age group. ... The benefits and risks of antihistamine use should always be carefully considered, especially when prescribing H1 antihistamines to vulnerable infants.”

The findings raise a host of questions for clinicians, including how a “relatively small risk” should translate into practice, and whether the risk may be attenuated with newer antihistamines, wrote Frank Max Charles Besag, MB, ChB, with East London NHS Foundation Trust in England, in an editorial accompanying the study. “It would be reasonable to inform families that at least one study has suggested a relatively small increase in the risk of seizures with first-generation antihistamines, adding that there are still too few data to draw any firm conclusions and also providing families with the information on what to do if the child were to have a seizure.” 
 

SOURCE:

Seonkyeong Rhie, MD, and Man Yong Han, MD, both with the Department of Pediatrics at CHA University School of Medicine, in Seongnam, South Korea, were the corresponding authors on the study. The research was published online in JAMA Network Open.

LIMITATIONS:

The researchers did not have details about seizure symptoms, did not include children seen in outpatient clinics, and were unable to verify the actual intake of the prescribed antihistamines. Although second-generation antihistamines may be less likely to cross the blood-brain barrier, one newer medication, desloratadine, has been associated with seizures.

DISCLOSURES:

The study was supported by grants from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, the Ministry of Health and Welfare, Republic of Korea.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

Artificial intelligence (AI) can accurately interpret routine clinical EEGs across a diverse population of patients, equipment types, and recording settings, according to investigators.

These findings suggest that SCORE-AI, the model tested, can reliably interpret common EEGs in real-world practice, supporting its recent FDA approval, reported lead author Daniel Mansilla, MD, a neurologist at Montreal Neurological Institute and Hospital, and colleagues.

“Overinterpretation of clinical EEG is the most common cause of misdiagnosing epilepsy,” the investigators wrote in Epilepsia. “AI tools may be a solution for this challenge, both as an additional resource for confirmation and classification of epilepsy, and as an aid for the interpretation of EEG in critical care medicine.”

To date, however, AI tools have struggled with the variability encountered in real-world neurology practice.“When tested on external data from different centers and diverse patient populations, and using equipment distinct from the initial study, medical AI models frequently exhibit modest performance, and only a few AI tools have successfully transitioned into medical practice,” the investigators wrote.
 

SCORE-AI Matches Expert Interpretation of Routine EEGs

The present study put SCORE-AI to the test with EEGs from 104 patients between 16 and 91 years. These individuals hailed from “geographically distinct” regions, while recording equipment and conditions also varied widely, according to Dr. Mansilla and colleagues.

To set an external gold-standard for comparison, EEGs were first interpreted by three human expert raters, who were blinded to all case information except the EEGs themselves. The dataset comprised 50% normal and 50% abnormal EEGs. Four major classes of EEG abnormalities were included: focal epileptiform, generalized epileptiform, focal nonepileptiform, and diffuse nonepileptiform.

Comparing SCORE-AI interpretations with the experts’ interpretations revealed no significant difference in any metric or category. The AI tool had an overall accuracy of 92%, compared with 94% for the human experts. Of note, SCORE-AI maintained this level of performance regardless of vigilance state or normal variants.

“SCORE-AI has obtained FDA approval for routine clinical EEGs and is presently being integrated into broadly available EEG software (Natus NeuroWorks),” the investigators wrote.
 

Further Validation May Be Needed

Wesley T. Kerr, MD, PhD, functional (nonepileptic) seizures clinic lead epileptologist at the University of Pittsburgh Medical Center, and handling associate editor for this study in Epilepsia, said the present findings are important because they show that SCORE-AI can perform in scenarios beyond the one in which it was developed.

Still, it may be premature for broad commercial rollout.

University of Pittsburgh

NYU Langone

AI-Assisted EEG Interpretation Is Here to Stay

When asked about the long-term future of AI-assisted EEG interpretation, Dr. Friedman predicted that it will be “critical” for helping improve the accuracy of epilepsy diagnoses, particularly because most EEGs worldwide are interpreted by non-experts, leading to the known issue with epilepsy misdiagnosis.

“However,” he added, “it is important to note that epilepsy is a clinical diagnosis ... [EEG] is only one piece of evidence in neurologic decision making. History and accurate eyewitness description of the events of concern are extremely critical to the diagnosis and cannot be replaced by AI yet.”

Dr. Kerr offered a similar view, highlighting the potential for SCORE-AI to raise the game of non-epileptologists.

“My anticipation is that neurologists who don’t use SCORE-AI will be replaced by neurologists who use SCORE-AI well,” he said. “Neurologists who use it well will be able to read more EEGs in less time without sacrificing quality. This will allow the neurologist to spend more time talking with the patient about the interpretation of the tests and how that impacts clinical care.”

Then again, that time spent talking with the patient may also one day be delegated to a machine.

“It is certainly imaginable that AI chatbots using large language models to interact with patients and family could be developed to extract consistent epilepsy histories for diagnostic support,” Dr. Wesley said.

This work was supported by a project grant from the Canadian Institutes of Health Research and Duke Neurology start-up funding. The investigators and interviewees reported no relevant conflicts of interest.

Artificial intelligence (AI) can accurately interpret routine clinical EEGs across a diverse population of patients, equipment types, and recording settings, according to investigators.

These findings suggest that SCORE-AI, the model tested, can reliably interpret common EEGs in real-world practice, supporting its recent FDA approval, reported lead author Daniel Mansilla, MD, a neurologist at Montreal Neurological Institute and Hospital, and colleagues.

“Overinterpretation of clinical EEG is the most common cause of misdiagnosing epilepsy,” the investigators wrote in Epilepsia. “AI tools may be a solution for this challenge, both as an additional resource for confirmation and classification of epilepsy, and as an aid for the interpretation of EEG in critical care medicine.”

To date, however, AI tools have struggled with the variability encountered in real-world neurology practice.“When tested on external data from different centers and diverse patient populations, and using equipment distinct from the initial study, medical AI models frequently exhibit modest performance, and only a few AI tools have successfully transitioned into medical practice,” the investigators wrote.
 

SCORE-AI Matches Expert Interpretation of Routine EEGs

The present study put SCORE-AI to the test with EEGs from 104 patients between 16 and 91 years. These individuals hailed from “geographically distinct” regions, while recording equipment and conditions also varied widely, according to Dr. Mansilla and colleagues.

To set an external gold-standard for comparison, EEGs were first interpreted by three human expert raters, who were blinded to all case information except the EEGs themselves. The dataset comprised 50% normal and 50% abnormal EEGs. Four major classes of EEG abnormalities were included: focal epileptiform, generalized epileptiform, focal nonepileptiform, and diffuse nonepileptiform.

Comparing SCORE-AI interpretations with the experts’ interpretations revealed no significant difference in any metric or category. The AI tool had an overall accuracy of 92%, compared with 94% for the human experts. Of note, SCORE-AI maintained this level of performance regardless of vigilance state or normal variants.

“SCORE-AI has obtained FDA approval for routine clinical EEGs and is presently being integrated into broadly available EEG software (Natus NeuroWorks),” the investigators wrote.
 

Further Validation May Be Needed

Wesley T. Kerr, MD, PhD, functional (nonepileptic) seizures clinic lead epileptologist at the University of Pittsburgh Medical Center, and handling associate editor for this study in Epilepsia, said the present findings are important because they show that SCORE-AI can perform in scenarios beyond the one in which it was developed.

Still, it may be premature for broad commercial rollout.

University of Pittsburgh

NYU Langone

AI-Assisted EEG Interpretation Is Here to Stay

When asked about the long-term future of AI-assisted EEG interpretation, Dr. Friedman predicted that it will be “critical” for helping improve the accuracy of epilepsy diagnoses, particularly because most EEGs worldwide are interpreted by non-experts, leading to the known issue with epilepsy misdiagnosis.

“However,” he added, “it is important to note that epilepsy is a clinical diagnosis ... [EEG] is only one piece of evidence in neurologic decision making. History and accurate eyewitness description of the events of concern are extremely critical to the diagnosis and cannot be replaced by AI yet.”

Dr. Kerr offered a similar view, highlighting the potential for SCORE-AI to raise the game of non-epileptologists.

“My anticipation is that neurologists who don’t use SCORE-AI will be replaced by neurologists who use SCORE-AI well,” he said. “Neurologists who use it well will be able to read more EEGs in less time without sacrificing quality. This will allow the neurologist to spend more time talking with the patient about the interpretation of the tests and how that impacts clinical care.”

Then again, that time spent talking with the patient may also one day be delegated to a machine.

“It is certainly imaginable that AI chatbots using large language models to interact with patients and family could be developed to extract consistent epilepsy histories for diagnostic support,” Dr. Wesley said.

This work was supported by a project grant from the Canadian Institutes of Health Research and Duke Neurology start-up funding. The investigators and interviewees reported no relevant conflicts of interest.

Artificial intelligence (AI) can accurately interpret routine clinical EEGs across a diverse population of patients, equipment types, and recording settings, according to investigators.

These findings suggest that SCORE-AI, the model tested, can reliably interpret common EEGs in real-world practice, supporting its recent FDA approval, reported lead author Daniel Mansilla, MD, a neurologist at Montreal Neurological Institute and Hospital, and colleagues.

“Overinterpretation of clinical EEG is the most common cause of misdiagnosing epilepsy,” the investigators wrote in Epilepsia. “AI tools may be a solution for this challenge, both as an additional resource for confirmation and classification of epilepsy, and as an aid for the interpretation of EEG in critical care medicine.”

To date, however, AI tools have struggled with the variability encountered in real-world neurology practice.“When tested on external data from different centers and diverse patient populations, and using equipment distinct from the initial study, medical AI models frequently exhibit modest performance, and only a few AI tools have successfully transitioned into medical practice,” the investigators wrote.
 

SCORE-AI Matches Expert Interpretation of Routine EEGs

The present study put SCORE-AI to the test with EEGs from 104 patients between 16 and 91 years. These individuals hailed from “geographically distinct” regions, while recording equipment and conditions also varied widely, according to Dr. Mansilla and colleagues.

To set an external gold-standard for comparison, EEGs were first interpreted by three human expert raters, who were blinded to all case information except the EEGs themselves. The dataset comprised 50% normal and 50% abnormal EEGs. Four major classes of EEG abnormalities were included: focal epileptiform, generalized epileptiform, focal nonepileptiform, and diffuse nonepileptiform.

Comparing SCORE-AI interpretations with the experts’ interpretations revealed no significant difference in any metric or category. The AI tool had an overall accuracy of 92%, compared with 94% for the human experts. Of note, SCORE-AI maintained this level of performance regardless of vigilance state or normal variants.

“SCORE-AI has obtained FDA approval for routine clinical EEGs and is presently being integrated into broadly available EEG software (Natus NeuroWorks),” the investigators wrote.
 

Further Validation May Be Needed

Wesley T. Kerr, MD, PhD, functional (nonepileptic) seizures clinic lead epileptologist at the University of Pittsburgh Medical Center, and handling associate editor for this study in Epilepsia, said the present findings are important because they show that SCORE-AI can perform in scenarios beyond the one in which it was developed.

Still, it may be premature for broad commercial rollout.

University of Pittsburgh

NYU Langone

AI-Assisted EEG Interpretation Is Here to Stay

When asked about the long-term future of AI-assisted EEG interpretation, Dr. Friedman predicted that it will be “critical” for helping improve the accuracy of epilepsy diagnoses, particularly because most EEGs worldwide are interpreted by non-experts, leading to the known issue with epilepsy misdiagnosis.

“However,” he added, “it is important to note that epilepsy is a clinical diagnosis ... [EEG] is only one piece of evidence in neurologic decision making. History and accurate eyewitness description of the events of concern are extremely critical to the diagnosis and cannot be replaced by AI yet.”

Dr. Kerr offered a similar view, highlighting the potential for SCORE-AI to raise the game of non-epileptologists.

“My anticipation is that neurologists who don’t use SCORE-AI will be replaced by neurologists who use SCORE-AI well,” he said. “Neurologists who use it well will be able to read more EEGs in less time without sacrificing quality. This will allow the neurologist to spend more time talking with the patient about the interpretation of the tests and how that impacts clinical care.”

Then again, that time spent talking with the patient may also one day be delegated to a machine.

“It is certainly imaginable that AI chatbots using large language models to interact with patients and family could be developed to extract consistent epilepsy histories for diagnostic support,” Dr. Wesley said.

This work was supported by a project grant from the Canadian Institutes of Health Research and Duke Neurology start-up funding. The investigators and interviewees reported no relevant conflicts of interest.

Avoiding severe skin reactions to antiseizure medications (ASMs) requires assessing patient risk factors and prescribing lower-risk drugs wherever possible, according to authors of a recent review. And if putting higher-risk patients on drugs most associated with human leukocyte antigen (HLA)–related reaction risk before test results are available, authors advised starting at low doses and titrating slowly.

“When someone is having a seizure drug prescribed,” said senior author Ram Mani, MD, MSCE, chief of epilepsy at Rutgers Robert Wood Johnson Medical School in New Brunswick, New Jersey, “it’s often a tense clinical situation because the patient has either had the first few seizures of their life, or they’ve had a worsening in their seizures.”

courtesy Rutgers Robert Wood Johnson Medical School

To help physicians optimize choices, Dr. Mani and colleagues reviewed literature regarding 31 ASMs. Their study was published in Current Treatment Options in Neurology.

Overall, said Dr. Mani, incidence of benign skin reactions such as morbilliform exanthematous eruptions, which account for 95% of cutaneous adverse drug reactions (CADRs), ranges from a few percent up to 15%. “It’s a somewhat common occurrence. Fortunately, the reactions that can lead to morbidity and mortality are fairly rare.”
 

Severe Cutaneous Adverse Reactions

Among the five ASMs approved by the Food and Drug Administration since 2018, cenobamate has sparked the greatest concern. In early clinical development for epilepsy, a fast titration schedule (starting at 50 mg/day and increasing by 50 mg every 2 weeks to at least 200 mg/day) resulted in three cases of drug reaction with eosinophilia and systemic symptoms (DRESS, also called drug-induced hypersensitivity reaction/DIHS), including one fatal case. Based on a phase 3 trial, the drug’s manufacturer now recommends starting at 12.5 mg and titrating more slowly.

DRESS/DIHS appears within 2-6 weeks of drug exposure. Along with malaise, fever, and conjunctivitis, symptoms can include skin eruptions ranging from morbilliform to hemorrhagic and bullous. “Facial edema and early facial rash are classic findings,” the authors added. DRESS also can involve painful lymphadenopathy and potentially life-threatening damage to the liver, heart, and other organs.

Stevens-Johnson syndrome (SJS), which is characterized by detached skin measuring less than 10% of the entire body surface area, typically happens within the first month of drug exposure. Flu-like symptoms can appear 1-3 days before erythematous to dusky macules, commonly on the chest, as well as cutaneous and mucosal erosions. Along with the skin and conjunctiva, SJS can affect the eyes, lungs, liver, bone marrow, and gastrointestinal tract.

When patients present with possible DRESS or SJS, the authors recommended inpatient multidisciplinary care. Having ready access to blood tests can help assess severity and prognosis, Dr. Mani explained. Inpatient evaluation and treatment also may allow faster access to other specialists as needed, and monitoring of potential seizure exacerbation in patients with uncontrolled seizures for whom the drug provided benefit but required abrupt discontinuation.

Often, he added, all hope is not lost for future use of the medication after a minor skin reaction. A case series and literature review of mild lamotrigine-associated CADRs showed that most patients could reintroduce and titrate lamotrigine by waiting at least 4 weeks, beginning at 5 mg/day, and gradually increasing to 25 mg/day.
 

Identifying Those at Risk

With millions of patients being newly prescribed ASMs annually, accurately screening out all people at risk of severe cutaneous adverse reactions based on available genetic information is impossible. The complexity of evolving recommendations for HLA testing makes them hard to remember, Dr. Mani said. “Development and better use of clinical decision support systems can help.”

Accordingly, he starts with a thorough history and physical examination, inquiring about prior skin reactions or hypersensitivity, which are risk factors for future reactions to drugs such as carbamazepine, phenytoin, phenobarbital, oxcarbazepine, lamotrigine, rufinamide, and zonisamide. “Most of the medicines that the HLA tests are being done for are not the initial medicines I typically prescribe for a patient with newly diagnosed epilepsy,” said Dr. Mani. For ASM-naive patients with moderate or high risk of skin hypersensitivity reactions, he usually starts with lacosamide, levetiracetam, or brivaracetam. Additional low-risk drugs he considers in more complex cases include valproate, topiramate, and clobazam.

Only if a patient’s initial ASM causes problems will Dr. Mani consider higher-risk options and order HLA tests for patients belonging to indicated groups — such as testing for HLA-B*15:02 in Asian patients being considered for carbamazepine. About once weekly, he must put a patient on a potentially higher-risk drug before test results are available. If after a thorough risk-benefit discussion, he and the patient agree that the higher-risk drug is warranted, Dr. Mani starts at a lower-than-labeled dose, with a slower titration schedule that typically extends the ramp-up period by 1 week.

Fortunately, Dr. Mani said that, in 20 years of practice, he has seen more misdiagnoses — involving rashes from poison ivy, viral infections, or allergies — than actual ASM-induced reactions. “That’s why the patient, family, and practitioner need to be open-minded about what could be causing the rash.”

Dr. Mani reported no relevant conflicts. The study authors reported no funding sources.

Avoiding severe skin reactions to antiseizure medications (ASMs) requires assessing patient risk factors and prescribing lower-risk drugs wherever possible, according to authors of a recent review. And if putting higher-risk patients on drugs most associated with human leukocyte antigen (HLA)–related reaction risk before test results are available, authors advised starting at low doses and titrating slowly.

“When someone is having a seizure drug prescribed,” said senior author Ram Mani, MD, MSCE, chief of epilepsy at Rutgers Robert Wood Johnson Medical School in New Brunswick, New Jersey, “it’s often a tense clinical situation because the patient has either had the first few seizures of their life, or they’ve had a worsening in their seizures.”

courtesy Rutgers Robert Wood Johnson Medical School

To help physicians optimize choices, Dr. Mani and colleagues reviewed literature regarding 31 ASMs. Their study was published in Current Treatment Options in Neurology.

Overall, said Dr. Mani, incidence of benign skin reactions such as morbilliform exanthematous eruptions, which account for 95% of cutaneous adverse drug reactions (CADRs), ranges from a few percent up to 15%. “It’s a somewhat common occurrence. Fortunately, the reactions that can lead to morbidity and mortality are fairly rare.”
 

Severe Cutaneous Adverse Reactions

Among the five ASMs approved by the Food and Drug Administration since 2018, cenobamate has sparked the greatest concern. In early clinical development for epilepsy, a fast titration schedule (starting at 50 mg/day and increasing by 50 mg every 2 weeks to at least 200 mg/day) resulted in three cases of drug reaction with eosinophilia and systemic symptoms (DRESS, also called drug-induced hypersensitivity reaction/DIHS), including one fatal case. Based on a phase 3 trial, the drug’s manufacturer now recommends starting at 12.5 mg and titrating more slowly.

DRESS/DIHS appears within 2-6 weeks of drug exposure. Along with malaise, fever, and conjunctivitis, symptoms can include skin eruptions ranging from morbilliform to hemorrhagic and bullous. “Facial edema and early facial rash are classic findings,” the authors added. DRESS also can involve painful lymphadenopathy and potentially life-threatening damage to the liver, heart, and other organs.

Stevens-Johnson syndrome (SJS), which is characterized by detached skin measuring less than 10% of the entire body surface area, typically happens within the first month of drug exposure. Flu-like symptoms can appear 1-3 days before erythematous to dusky macules, commonly on the chest, as well as cutaneous and mucosal erosions. Along with the skin and conjunctiva, SJS can affect the eyes, lungs, liver, bone marrow, and gastrointestinal tract.

When patients present with possible DRESS or SJS, the authors recommended inpatient multidisciplinary care. Having ready access to blood tests can help assess severity and prognosis, Dr. Mani explained. Inpatient evaluation and treatment also may allow faster access to other specialists as needed, and monitoring of potential seizure exacerbation in patients with uncontrolled seizures for whom the drug provided benefit but required abrupt discontinuation.

Often, he added, all hope is not lost for future use of the medication after a minor skin reaction. A case series and literature review of mild lamotrigine-associated CADRs showed that most patients could reintroduce and titrate lamotrigine by waiting at least 4 weeks, beginning at 5 mg/day, and gradually increasing to 25 mg/day.
 

Identifying Those at Risk

With millions of patients being newly prescribed ASMs annually, accurately screening out all people at risk of severe cutaneous adverse reactions based on available genetic information is impossible. The complexity of evolving recommendations for HLA testing makes them hard to remember, Dr. Mani said. “Development and better use of clinical decision support systems can help.”

Accordingly, he starts with a thorough history and physical examination, inquiring about prior skin reactions or hypersensitivity, which are risk factors for future reactions to drugs such as carbamazepine, phenytoin, phenobarbital, oxcarbazepine, lamotrigine, rufinamide, and zonisamide. “Most of the medicines that the HLA tests are being done for are not the initial medicines I typically prescribe for a patient with newly diagnosed epilepsy,” said Dr. Mani. For ASM-naive patients with moderate or high risk of skin hypersensitivity reactions, he usually starts with lacosamide, levetiracetam, or brivaracetam. Additional low-risk drugs he considers in more complex cases include valproate, topiramate, and clobazam.

Only if a patient’s initial ASM causes problems will Dr. Mani consider higher-risk options and order HLA tests for patients belonging to indicated groups — such as testing for HLA-B*15:02 in Asian patients being considered for carbamazepine. About once weekly, he must put a patient on a potentially higher-risk drug before test results are available. If after a thorough risk-benefit discussion, he and the patient agree that the higher-risk drug is warranted, Dr. Mani starts at a lower-than-labeled dose, with a slower titration schedule that typically extends the ramp-up period by 1 week.

Fortunately, Dr. Mani said that, in 20 years of practice, he has seen more misdiagnoses — involving rashes from poison ivy, viral infections, or allergies — than actual ASM-induced reactions. “That’s why the patient, family, and practitioner need to be open-minded about what could be causing the rash.”

Dr. Mani reported no relevant conflicts. The study authors reported no funding sources.

Avoiding severe skin reactions to antiseizure medications (ASMs) requires assessing patient risk factors and prescribing lower-risk drugs wherever possible, according to authors of a recent review. And if putting higher-risk patients on drugs most associated with human leukocyte antigen (HLA)–related reaction risk before test results are available, authors advised starting at low doses and titrating slowly.

“When someone is having a seizure drug prescribed,” said senior author Ram Mani, MD, MSCE, chief of epilepsy at Rutgers Robert Wood Johnson Medical School in New Brunswick, New Jersey, “it’s often a tense clinical situation because the patient has either had the first few seizures of their life, or they’ve had a worsening in their seizures.”

courtesy Rutgers Robert Wood Johnson Medical School

To help physicians optimize choices, Dr. Mani and colleagues reviewed literature regarding 31 ASMs. Their study was published in Current Treatment Options in Neurology.

Overall, said Dr. Mani, incidence of benign skin reactions such as morbilliform exanthematous eruptions, which account for 95% of cutaneous adverse drug reactions (CADRs), ranges from a few percent up to 15%. “It’s a somewhat common occurrence. Fortunately, the reactions that can lead to morbidity and mortality are fairly rare.”
 

Severe Cutaneous Adverse Reactions

Among the five ASMs approved by the Food and Drug Administration since 2018, cenobamate has sparked the greatest concern. In early clinical development for epilepsy, a fast titration schedule (starting at 50 mg/day and increasing by 50 mg every 2 weeks to at least 200 mg/day) resulted in three cases of drug reaction with eosinophilia and systemic symptoms (DRESS, also called drug-induced hypersensitivity reaction/DIHS), including one fatal case. Based on a phase 3 trial, the drug’s manufacturer now recommends starting at 12.5 mg and titrating more slowly.

DRESS/DIHS appears within 2-6 weeks of drug exposure. Along with malaise, fever, and conjunctivitis, symptoms can include skin eruptions ranging from morbilliform to hemorrhagic and bullous. “Facial edema and early facial rash are classic findings,” the authors added. DRESS also can involve painful lymphadenopathy and potentially life-threatening damage to the liver, heart, and other organs.

Stevens-Johnson syndrome (SJS), which is characterized by detached skin measuring less than 10% of the entire body surface area, typically happens within the first month of drug exposure. Flu-like symptoms can appear 1-3 days before erythematous to dusky macules, commonly on the chest, as well as cutaneous and mucosal erosions. Along with the skin and conjunctiva, SJS can affect the eyes, lungs, liver, bone marrow, and gastrointestinal tract.

When patients present with possible DRESS or SJS, the authors recommended inpatient multidisciplinary care. Having ready access to blood tests can help assess severity and prognosis, Dr. Mani explained. Inpatient evaluation and treatment also may allow faster access to other specialists as needed, and monitoring of potential seizure exacerbation in patients with uncontrolled seizures for whom the drug provided benefit but required abrupt discontinuation.

Often, he added, all hope is not lost for future use of the medication after a minor skin reaction. A case series and literature review of mild lamotrigine-associated CADRs showed that most patients could reintroduce and titrate lamotrigine by waiting at least 4 weeks, beginning at 5 mg/day, and gradually increasing to 25 mg/day.
 

Identifying Those at Risk

With millions of patients being newly prescribed ASMs annually, accurately screening out all people at risk of severe cutaneous adverse reactions based on available genetic information is impossible. The complexity of evolving recommendations for HLA testing makes them hard to remember, Dr. Mani said. “Development and better use of clinical decision support systems can help.”

Accordingly, he starts with a thorough history and physical examination, inquiring about prior skin reactions or hypersensitivity, which are risk factors for future reactions to drugs such as carbamazepine, phenytoin, phenobarbital, oxcarbazepine, lamotrigine, rufinamide, and zonisamide. “Most of the medicines that the HLA tests are being done for are not the initial medicines I typically prescribe for a patient with newly diagnosed epilepsy,” said Dr. Mani. For ASM-naive patients with moderate or high risk of skin hypersensitivity reactions, he usually starts with lacosamide, levetiracetam, or brivaracetam. Additional low-risk drugs he considers in more complex cases include valproate, topiramate, and clobazam.

Only if a patient’s initial ASM causes problems will Dr. Mani consider higher-risk options and order HLA tests for patients belonging to indicated groups — such as testing for HLA-B*15:02 in Asian patients being considered for carbamazepine. About once weekly, he must put a patient on a potentially higher-risk drug before test results are available. If after a thorough risk-benefit discussion, he and the patient agree that the higher-risk drug is warranted, Dr. Mani starts at a lower-than-labeled dose, with a slower titration schedule that typically extends the ramp-up period by 1 week.

Fortunately, Dr. Mani said that, in 20 years of practice, he has seen more misdiagnoses — involving rashes from poison ivy, viral infections, or allergies — than actual ASM-induced reactions. “That’s why the patient, family, and practitioner need to be open-minded about what could be causing the rash.”

Dr. Mani reported no relevant conflicts. The study authors reported no funding sources.

Veterans diagnosed with epilepsy have a significantly higher mortality rate if they experience a traumatic brain injury either before or within 6 months of an epilepsy diagnosis, according to recent research published in Epilepsia.

In a retrospective cohort study, Ali Roghani, PhD, of the division of epidemiology at the University of Utah School of Medicine in Salt Lake City, and colleagues evaluated 938,890 veterans between 2000 and 2019 in the Defense Health Agency and the Veterans Health Administration who served in the US military after the September 11 attacks. Overall, 27,436 veterans met criteria for a diagnosis of epilepsy, 264,890 had received a diagnosis for a traumatic brain injury (TBI), and the remaining patients had neither epilepsy nor TBI.

Among the veterans with no epilepsy, 248,714 veterans had a TBI diagnosis, while in the group of patients with epilepsy, 10,358 veterans experienced a TBI before their epilepsy diagnosis, 1598 were diagnosed with a TBI within 6 months of epilepsy, and 4310 veterans had a TBI 6 months after an epilepsy diagnosis. The researchers assessed all-cause mortality in each group, calculating cumulative mortality rates compared with the group of veterans who had no TBI and no epilepsy diagnosis.

Dr. Roghani and colleagues found a significantly higher mortality rate among veterans who developed epilepsy compared with a control group with neither epilepsy nor TBI (6.26% vs. 1.12%; P < .01), with a majority of veterans in the group who died being White (67.4%) men (89.9%). Compared with veterans who were deceased, nondeceased veterans were significantly more likely to have a history of being deployed (70.7% vs. 64.8%; P < .001), were less likely to be in the army (52.2% vs. 55.0%; P < .001), and were more likely to reach the rank of officer or warrant officer (8.1% vs. 7.6%; P = .014).

There were also significant differences in clinical characteristics between nondeceased and deceased veterans, including a higher rate of substance abuse disorder, smoking history, cardiovascular disease, stroke, transient ischemic attack, cancer, liver disease, kidney disease, or other injury as well as overdose, suicidal ideation, and homelessness. “Most clinical conditions were significantly different between deceased and nondeceased in part due to the large cohort size,” the researchers said.

After performing Cox regression analyses, the researchers found a higher mortality risk in veterans with epilepsy and/or TBIs among those who developed a TBI within 6 months of an epilepsy diagnosis (hazard ratio [HR], 5.02; 95% CI, 4.21-5.99), had a TBI prior to epilepsy (HR, 4.25; 95% CI, 3.89-4.58), had epilepsy alone (HR, 4.00; 95% CI, 3.67-4.36), had a TBI more than 6 months after an epilepsy diagnosis (HR, 2.49; 95% CI, 2.17-2.85), and those who had epilepsy alone (HR, 1.30; 95% CI, 1.25-1.36) compared with veterans who had neither epilepsy nor a TBI.

“The temporal relationship with TBI that occurred within 6 months after epilepsy diagnosis may suggest an increased vulnerability to accidents, severe injuries, or TBI resulting from seizures, potentially elevating mortality risk,” Dr. Roghani and colleagues wrote.

The researchers said the results “raise concerns” about the subgroup of patients who are diagnosed with epilepsy close to experiencing a TBI.

“Our results provide information regarding the temporal relationship between epilepsy and TBI regarding mortality in a cohort of post-9/11 veterans, which highlights the need for enhanced primary prevention, such as more access to health care among people with epilepsy and TBI,” they said. “Given the rising incidence of TBI in both the military and civilian populations, these findings suggest close monitoring might be crucial to develop effective prevention strategies for long-term complications, particularly [post-traumatic epilepsy].”
 

Reevaluating the Treatment of Epilepsy

Juliann Paolicchi, MD, a neurologist and member of the epilepsy team at Northwell Health in New York, who was not involved with the study, said in an interview that TBIs have been studied more closely since the beginning of conflicts in the Middle East, particularly in Iran and Afghanistan, where “newer artillery causes more diffuse traumatic injury to the brain and the body than the effects of more typical weaponry.”

Northwell Health

Veterans diagnosed with epilepsy have a significantly higher mortality rate if they experience a traumatic brain injury either before or within 6 months of an epilepsy diagnosis, according to recent research published in Epilepsia.

In a retrospective cohort study, Ali Roghani, PhD, of the division of epidemiology at the University of Utah School of Medicine in Salt Lake City, and colleagues evaluated 938,890 veterans between 2000 and 2019 in the Defense Health Agency and the Veterans Health Administration who served in the US military after the September 11 attacks. Overall, 27,436 veterans met criteria for a diagnosis of epilepsy, 264,890 had received a diagnosis for a traumatic brain injury (TBI), and the remaining patients had neither epilepsy nor TBI.

Among the veterans with no epilepsy, 248,714 veterans had a TBI diagnosis, while in the group of patients with epilepsy, 10,358 veterans experienced a TBI before their epilepsy diagnosis, 1598 were diagnosed with a TBI within 6 months of epilepsy, and 4310 veterans had a TBI 6 months after an epilepsy diagnosis. The researchers assessed all-cause mortality in each group, calculating cumulative mortality rates compared with the group of veterans who had no TBI and no epilepsy diagnosis.

Dr. Roghani and colleagues found a significantly higher mortality rate among veterans who developed epilepsy compared with a control group with neither epilepsy nor TBI (6.26% vs. 1.12%; P < .01), with a majority of veterans in the group who died being White (67.4%) men (89.9%). Compared with veterans who were deceased, nondeceased veterans were significantly more likely to have a history of being deployed (70.7% vs. 64.8%; P < .001), were less likely to be in the army (52.2% vs. 55.0%; P < .001), and were more likely to reach the rank of officer or warrant officer (8.1% vs. 7.6%; P = .014).

There were also significant differences in clinical characteristics between nondeceased and deceased veterans, including a higher rate of substance abuse disorder, smoking history, cardiovascular disease, stroke, transient ischemic attack, cancer, liver disease, kidney disease, or other injury as well as overdose, suicidal ideation, and homelessness. “Most clinical conditions were significantly different between deceased and nondeceased in part due to the large cohort size,” the researchers said.

After performing Cox regression analyses, the researchers found a higher mortality risk in veterans with epilepsy and/or TBIs among those who developed a TBI within 6 months of an epilepsy diagnosis (hazard ratio [HR], 5.02; 95% CI, 4.21-5.99), had a TBI prior to epilepsy (HR, 4.25; 95% CI, 3.89-4.58), had epilepsy alone (HR, 4.00; 95% CI, 3.67-4.36), had a TBI more than 6 months after an epilepsy diagnosis (HR, 2.49; 95% CI, 2.17-2.85), and those who had epilepsy alone (HR, 1.30; 95% CI, 1.25-1.36) compared with veterans who had neither epilepsy nor a TBI.

“The temporal relationship with TBI that occurred within 6 months after epilepsy diagnosis may suggest an increased vulnerability to accidents, severe injuries, or TBI resulting from seizures, potentially elevating mortality risk,” Dr. Roghani and colleagues wrote.

The researchers said the results “raise concerns” about the subgroup of patients who are diagnosed with epilepsy close to experiencing a TBI.

“Our results provide information regarding the temporal relationship between epilepsy and TBI regarding mortality in a cohort of post-9/11 veterans, which highlights the need for enhanced primary prevention, such as more access to health care among people with epilepsy and TBI,” they said. “Given the rising incidence of TBI in both the military and civilian populations, these findings suggest close monitoring might be crucial to develop effective prevention strategies for long-term complications, particularly [post-traumatic epilepsy].”
 

Reevaluating the Treatment of Epilepsy

Juliann Paolicchi, MD, a neurologist and member of the epilepsy team at Northwell Health in New York, who was not involved with the study, said in an interview that TBIs have been studied more closely since the beginning of conflicts in the Middle East, particularly in Iran and Afghanistan, where “newer artillery causes more diffuse traumatic injury to the brain and the body than the effects of more typical weaponry.”

Northwell Health

Veterans diagnosed with epilepsy have a significantly higher mortality rate if they experience a traumatic brain injury either before or within 6 months of an epilepsy diagnosis, according to recent research published in Epilepsia.

In a retrospective cohort study, Ali Roghani, PhD, of the division of epidemiology at the University of Utah School of Medicine in Salt Lake City, and colleagues evaluated 938,890 veterans between 2000 and 2019 in the Defense Health Agency and the Veterans Health Administration who served in the US military after the September 11 attacks. Overall, 27,436 veterans met criteria for a diagnosis of epilepsy, 264,890 had received a diagnosis for a traumatic brain injury (TBI), and the remaining patients had neither epilepsy nor TBI.

Among the veterans with no epilepsy, 248,714 veterans had a TBI diagnosis, while in the group of patients with epilepsy, 10,358 veterans experienced a TBI before their epilepsy diagnosis, 1598 were diagnosed with a TBI within 6 months of epilepsy, and 4310 veterans had a TBI 6 months after an epilepsy diagnosis. The researchers assessed all-cause mortality in each group, calculating cumulative mortality rates compared with the group of veterans who had no TBI and no epilepsy diagnosis.

Dr. Roghani and colleagues found a significantly higher mortality rate among veterans who developed epilepsy compared with a control group with neither epilepsy nor TBI (6.26% vs. 1.12%; P < .01), with a majority of veterans in the group who died being White (67.4%) men (89.9%). Compared with veterans who were deceased, nondeceased veterans were significantly more likely to have a history of being deployed (70.7% vs. 64.8%; P < .001), were less likely to be in the army (52.2% vs. 55.0%; P < .001), and were more likely to reach the rank of officer or warrant officer (8.1% vs. 7.6%; P = .014).

There were also significant differences in clinical characteristics between nondeceased and deceased veterans, including a higher rate of substance abuse disorder, smoking history, cardiovascular disease, stroke, transient ischemic attack, cancer, liver disease, kidney disease, or other injury as well as overdose, suicidal ideation, and homelessness. “Most clinical conditions were significantly different between deceased and nondeceased in part due to the large cohort size,” the researchers said.

After performing Cox regression analyses, the researchers found a higher mortality risk in veterans with epilepsy and/or TBIs among those who developed a TBI within 6 months of an epilepsy diagnosis (hazard ratio [HR], 5.02; 95% CI, 4.21-5.99), had a TBI prior to epilepsy (HR, 4.25; 95% CI, 3.89-4.58), had epilepsy alone (HR, 4.00; 95% CI, 3.67-4.36), had a TBI more than 6 months after an epilepsy diagnosis (HR, 2.49; 95% CI, 2.17-2.85), and those who had epilepsy alone (HR, 1.30; 95% CI, 1.25-1.36) compared with veterans who had neither epilepsy nor a TBI.

“The temporal relationship with TBI that occurred within 6 months after epilepsy diagnosis may suggest an increased vulnerability to accidents, severe injuries, or TBI resulting from seizures, potentially elevating mortality risk,” Dr. Roghani and colleagues wrote.

The researchers said the results “raise concerns” about the subgroup of patients who are diagnosed with epilepsy close to experiencing a TBI.

“Our results provide information regarding the temporal relationship between epilepsy and TBI regarding mortality in a cohort of post-9/11 veterans, which highlights the need for enhanced primary prevention, such as more access to health care among people with epilepsy and TBI,” they said. “Given the rising incidence of TBI in both the military and civilian populations, these findings suggest close monitoring might be crucial to develop effective prevention strategies for long-term complications, particularly [post-traumatic epilepsy].”
 

Reevaluating the Treatment of Epilepsy

Juliann Paolicchi, MD, a neurologist and member of the epilepsy team at Northwell Health in New York, who was not involved with the study, said in an interview that TBIs have been studied more closely since the beginning of conflicts in the Middle East, particularly in Iran and Afghanistan, where “newer artillery causes more diffuse traumatic injury to the brain and the body than the effects of more typical weaponry.”

Northwell Health

HELSINKI, FINLAND — When it comes to caring for women with epilepsy who become pregnant, there is a great deal of room for improvement, experts say. 

“Too many women with epilepsy receive information about epilepsy and pregnancy only after pregnancy. We can do better,” Torbjörn Tomson, MD, PhD, senior professor of neurology and epileptology, Karolinska Institutet, Stockholm, Sweden, told delegates attending the Congress of the European Academy of Neurology 2024.

The goal in epilepsy is to maintain seizure control while minimizing exposure to potentially teratogenic medications, Dr. Tomson said. He added that pregnancy planning in women with epilepsy is important but also conceded that most pregnancies in this patient population are unplanned. 

Overall, it’s important to tell patients that “there is a high likelihood of an uneventful pregnancy and a healthy offspring,” he said. 

In recent years, new data have emerged on the risks to the fetus with exposure to different antiseizure medications (ASMs), said Dr. Tomson. This has led regulators, such as the US Food and Drug Administration and the European Medicines Agency, to issue restrictions on the use of some ASMs, particularly valproate and topiramate, in females of childbearing age. 

Session chair Marte Bjørk, MD, PhD, of the Department of Neurology of Haukeland University Hospital, Bergen, Norway, questioned whether the latest recommendations from regulatory authorities have “sacrificed seizure control at the expense of teratogenic safety.”

To an extent, this is true, said Dr. Tomson, “as the regulations prioritize fetal health over women’s health.” However, “we have not seen poorer seizure control with newer medications” in recent datasets. 

It’s about good planning, said Dr. Bjork, who is responsible for the clinical guidelines for treatment of epilepsy in pregnancy in Norway. 
 

Start With Folic Acid

One simple measure is to ensure that all women with epilepsy of childbearing age are prescribed low-dose folic acid, Dr. Tomson said — even those who report that they are not considering pregnancy. 

When it comes to folic acid, recently published guidelines on ASM use during pregnancy are relatively straightforward, he said.

The data do not show that folic acid reduces the risk for major congenital malformations, but they do show that it improves neurocognitive outcomes in children of mothers who received folic acid supplements prior to and throughout pregnancy.

Dr. Tomson said the new American Academy of Neurology (AAN) guidelines recommend a dosage of 0.4 mg/d, which balances the demonstrated benefits of supplementation and potential negative consequences of high doses of folic acid. 

“Consider 0.4 mg of folic acid for all women on ASMs that are of childbearing potential, whether they become pregnant or not,” he said. However, well-designed, preferably randomized, studies are needed to better define the optimal folic acid dosing for pregnancy in women with epilepsy. 
 

Choosing the Right ASM 

The choice of the most appropriate ASM in pregnancy is based on the potential for an individual drug to cause major congenital malformations and, in more recent years, the likelihood that a woman with epilepsy is using any other medications associated with neurodevelopmental disorders in offspring. 

Balanced against this must be the effect of pregnancy on seizure control, and the maternal and fetal risks associated with seizures during pregnancy.

“There are ways to optimize seizure control and to reduce teratogenic risks,” said Dr. Tomson, adding that the new AAN guidelines provide updated evidence-based conclusions on this topic.

The good news is that “there has been almost a 40% decline in the rate of major congenital malformations associated with ASM use in pregnancy, in parallel with a shift from use of ASMs such as carbamazepine and valproate to lamotrigine and levetiracetam.” The latter two medications are associated with a much lower risk for such birth defects, he added. 

This is based on the average rate of major congenital malformations in the EURAP registry that tracks the comparative risk for major fetal malformations after ASM use during pregnancy in over 40 countries. The latest reporting from the registry shows that this risk has decreased from 6.1% in 1998-2004 to 3.7% in 2015-2022.

Taking valproate during pregnancy is associated with a significantly increased risk for neurodevelopmental outcomes, including autism spectrum disorder. However, the jury is still out on whether topiramate escalates the risk for neurodevelopmental disorders, because findings across studies have been inconsistent.

Overall, the AAN guidance, and similar advice from European regulatory authorities, is that valproate is associated with high risk for major congenital malformations and neurodevelopmental disorders. Topiramate has also been shown to increase the risk for major congenital malformations. Consequently, these two anticonvulsants are generally contraindicated in pregnancy, Dr. Tomson noted.

On the other hand, levetiracetam, lamotrigine, and oxcarbazepine seem to be the safest ASMs with respect to congenital malformation risk, and lamotrigine has the best documented safety profile when it comes to the risk for neurodevelopmental disorders.

Although there are newer ASMs on the market, including brivaracetam, cannabidiol, cenobamate, eslicarbazepine acetate, fenfluramine, lacosamide, perampanel, and zonisamide, at this juncture data on the risk potential of these agents are insufficient.

“For some of these newer meds, we don’t even have a single exposure in our large databases, even if you combine them all. We need to collect more data, and that will take time,” Dr. Tomson said. 
 

Dose Optimization 

Dose optimization of ASMs is also important — and for this to be accurate, it’s important to document an individual’s optimal ASM serum levels before pregnancy that can be used as a baseline target during pregnancy. However, Dr. Tomson noted, this information is not always available.

He pointed out that, with many ASMs, there can be a significant decline in serum concentration levels during pregnancy, which can increase seizure risk.

To address the uncertainty surrounding this issue, Dr. Tomson recommended that physicians consider future pregnancy when prescribing ASMs to women of childbearing age. He also advised discussing contraception with these patients, even if they indicate they are not currently planning to conceive.

The data clearly show the importance of planning a pregnancy so that the most appropriate and safest medications are prescribed, he said.

Dr. Tomson reported receiving research support, on behalf of EURAP, from Accord, Angelini, Bial, EcuPharma, Eisai, GlaxoSmithKline, Glenmark, GW Pharma, Hazz, Sanofi, Teva, USB, Zentiva, and SF Group. He has received speakers’ honoraria from Angelini, Eisai, and UCB. Dr. Bjørk reports receiving speakers’ honoraria from Pfizer, Eisai, AbbVie, Best Practice, Lilly, Novartis, and Teva. She has received unrestricted educational grants from The Research Council of Norway, the Research Council of the Nordic Countries (NordForsk), and the Norwegian Epilepsy Association. She has received consulting honoraria from Novartis and is on the advisory board of Eisai, Lundbeck, Angelini Pharma, and Jazz Pharmaceuticals. Dr. Bjørk also received institutional grants from marked authorization holders of valproate.

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

HELSINKI, FINLAND — When it comes to caring for women with epilepsy who become pregnant, there is a great deal of room for improvement, experts say. 

“Too many women with epilepsy receive information about epilepsy and pregnancy only after pregnancy. We can do better,” Torbjörn Tomson, MD, PhD, senior professor of neurology and epileptology, Karolinska Institutet, Stockholm, Sweden, told delegates attending the Congress of the European Academy of Neurology 2024.

The goal in epilepsy is to maintain seizure control while minimizing exposure to potentially teratogenic medications, Dr. Tomson said. He added that pregnancy planning in women with epilepsy is important but also conceded that most pregnancies in this patient population are unplanned. 

Overall, it’s important to tell patients that “there is a high likelihood of an uneventful pregnancy and a healthy offspring,” he said. 

In recent years, new data have emerged on the risks to the fetus with exposure to different antiseizure medications (ASMs), said Dr. Tomson. This has led regulators, such as the US Food and Drug Administration and the European Medicines Agency, to issue restrictions on the use of some ASMs, particularly valproate and topiramate, in females of childbearing age. 

Session chair Marte Bjørk, MD, PhD, of the Department of Neurology of Haukeland University Hospital, Bergen, Norway, questioned whether the latest recommendations from regulatory authorities have “sacrificed seizure control at the expense of teratogenic safety.”

To an extent, this is true, said Dr. Tomson, “as the regulations prioritize fetal health over women’s health.” However, “we have not seen poorer seizure control with newer medications” in recent datasets. 

It’s about good planning, said Dr. Bjork, who is responsible for the clinical guidelines for treatment of epilepsy in pregnancy in Norway. 
 

Start With Folic Acid

One simple measure is to ensure that all women with epilepsy of childbearing age are prescribed low-dose folic acid, Dr. Tomson said — even those who report that they are not considering pregnancy. 

When it comes to folic acid, recently published guidelines on ASM use during pregnancy are relatively straightforward, he said.

The data do not show that folic acid reduces the risk for major congenital malformations, but they do show that it improves neurocognitive outcomes in children of mothers who received folic acid supplements prior to and throughout pregnancy.

Dr. Tomson said the new American Academy of Neurology (AAN) guidelines recommend a dosage of 0.4 mg/d, which balances the demonstrated benefits of supplementation and potential negative consequences of high doses of folic acid. 

“Consider 0.4 mg of folic acid for all women on ASMs that are of childbearing potential, whether they become pregnant or not,” he said. However, well-designed, preferably randomized, studies are needed to better define the optimal folic acid dosing for pregnancy in women with epilepsy. 
 

Choosing the Right ASM 

The choice of the most appropriate ASM in pregnancy is based on the potential for an individual drug to cause major congenital malformations and, in more recent years, the likelihood that a woman with epilepsy is using any other medications associated with neurodevelopmental disorders in offspring. 

Balanced against this must be the effect of pregnancy on seizure control, and the maternal and fetal risks associated with seizures during pregnancy.

“There are ways to optimize seizure control and to reduce teratogenic risks,” said Dr. Tomson, adding that the new AAN guidelines provide updated evidence-based conclusions on this topic.

The good news is that “there has been almost a 40% decline in the rate of major congenital malformations associated with ASM use in pregnancy, in parallel with a shift from use of ASMs such as carbamazepine and valproate to lamotrigine and levetiracetam.” The latter two medications are associated with a much lower risk for such birth defects, he added. 

This is based on the average rate of major congenital malformations in the EURAP registry that tracks the comparative risk for major fetal malformations after ASM use during pregnancy in over 40 countries. The latest reporting from the registry shows that this risk has decreased from 6.1% in 1998-2004 to 3.7% in 2015-2022.

Taking valproate during pregnancy is associated with a significantly increased risk for neurodevelopmental outcomes, including autism spectrum disorder. However, the jury is still out on whether topiramate escalates the risk for neurodevelopmental disorders, because findings across studies have been inconsistent.

Overall, the AAN guidance, and similar advice from European regulatory authorities, is that valproate is associated with high risk for major congenital malformations and neurodevelopmental disorders. Topiramate has also been shown to increase the risk for major congenital malformations. Consequently, these two anticonvulsants are generally contraindicated in pregnancy, Dr. Tomson noted.

On the other hand, levetiracetam, lamotrigine, and oxcarbazepine seem to be the safest ASMs with respect to congenital malformation risk, and lamotrigine has the best documented safety profile when it comes to the risk for neurodevelopmental disorders.

Although there are newer ASMs on the market, including brivaracetam, cannabidiol, cenobamate, eslicarbazepine acetate, fenfluramine, lacosamide, perampanel, and zonisamide, at this juncture data on the risk potential of these agents are insufficient.

“For some of these newer meds, we don’t even have a single exposure in our large databases, even if you combine them all. We need to collect more data, and that will take time,” Dr. Tomson said. 
 

Dose Optimization 

Dose optimization of ASMs is also important — and for this to be accurate, it’s important to document an individual’s optimal ASM serum levels before pregnancy that can be used as a baseline target during pregnancy. However, Dr. Tomson noted, this information is not always available.

He pointed out that, with many ASMs, there can be a significant decline in serum concentration levels during pregnancy, which can increase seizure risk.

To address the uncertainty surrounding this issue, Dr. Tomson recommended that physicians consider future pregnancy when prescribing ASMs to women of childbearing age. He also advised discussing contraception with these patients, even if they indicate they are not currently planning to conceive.

The data clearly show the importance of planning a pregnancy so that the most appropriate and safest medications are prescribed, he said.

Dr. Tomson reported receiving research support, on behalf of EURAP, from Accord, Angelini, Bial, EcuPharma, Eisai, GlaxoSmithKline, Glenmark, GW Pharma, Hazz, Sanofi, Teva, USB, Zentiva, and SF Group. He has received speakers’ honoraria from Angelini, Eisai, and UCB. Dr. Bjørk reports receiving speakers’ honoraria from Pfizer, Eisai, AbbVie, Best Practice, Lilly, Novartis, and Teva. She has received unrestricted educational grants from The Research Council of Norway, the Research Council of the Nordic Countries (NordForsk), and the Norwegian Epilepsy Association. She has received consulting honoraria from Novartis and is on the advisory board of Eisai, Lundbeck, Angelini Pharma, and Jazz Pharmaceuticals. Dr. Bjørk also received institutional grants from marked authorization holders of valproate.

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

HELSINKI, FINLAND — When it comes to caring for women with epilepsy who become pregnant, there is a great deal of room for improvement, experts say. 

“Too many women with epilepsy receive information about epilepsy and pregnancy only after pregnancy. We can do better,” Torbjörn Tomson, MD, PhD, senior professor of neurology and epileptology, Karolinska Institutet, Stockholm, Sweden, told delegates attending the Congress of the European Academy of Neurology 2024.

The goal in epilepsy is to maintain seizure control while minimizing exposure to potentially teratogenic medications, Dr. Tomson said. He added that pregnancy planning in women with epilepsy is important but also conceded that most pregnancies in this patient population are unplanned. 

Overall, it’s important to tell patients that “there is a high likelihood of an uneventful pregnancy and a healthy offspring,” he said. 

In recent years, new data have emerged on the risks to the fetus with exposure to different antiseizure medications (ASMs), said Dr. Tomson. This has led regulators, such as the US Food and Drug Administration and the European Medicines Agency, to issue restrictions on the use of some ASMs, particularly valproate and topiramate, in females of childbearing age. 

Session chair Marte Bjørk, MD, PhD, of the Department of Neurology of Haukeland University Hospital, Bergen, Norway, questioned whether the latest recommendations from regulatory authorities have “sacrificed seizure control at the expense of teratogenic safety.”

To an extent, this is true, said Dr. Tomson, “as the regulations prioritize fetal health over women’s health.” However, “we have not seen poorer seizure control with newer medications” in recent datasets. 

It’s about good planning, said Dr. Bjork, who is responsible for the clinical guidelines for treatment of epilepsy in pregnancy in Norway. 
 

Start With Folic Acid

One simple measure is to ensure that all women with epilepsy of childbearing age are prescribed low-dose folic acid, Dr. Tomson said — even those who report that they are not considering pregnancy. 

When it comes to folic acid, recently published guidelines on ASM use during pregnancy are relatively straightforward, he said.

The data do not show that folic acid reduces the risk for major congenital malformations, but they do show that it improves neurocognitive outcomes in children of mothers who received folic acid supplements prior to and throughout pregnancy.

Dr. Tomson said the new American Academy of Neurology (AAN) guidelines recommend a dosage of 0.4 mg/d, which balances the demonstrated benefits of supplementation and potential negative consequences of high doses of folic acid. 

“Consider 0.4 mg of folic acid for all women on ASMs that are of childbearing potential, whether they become pregnant or not,” he said. However, well-designed, preferably randomized, studies are needed to better define the optimal folic acid dosing for pregnancy in women with epilepsy. 
 

Choosing the Right ASM 

The choice of the most appropriate ASM in pregnancy is based on the potential for an individual drug to cause major congenital malformations and, in more recent years, the likelihood that a woman with epilepsy is using any other medications associated with neurodevelopmental disorders in offspring. 

Balanced against this must be the effect of pregnancy on seizure control, and the maternal and fetal risks associated with seizures during pregnancy.

“There are ways to optimize seizure control and to reduce teratogenic risks,” said Dr. Tomson, adding that the new AAN guidelines provide updated evidence-based conclusions on this topic.

The good news is that “there has been almost a 40% decline in the rate of major congenital malformations associated with ASM use in pregnancy, in parallel with a shift from use of ASMs such as carbamazepine and valproate to lamotrigine and levetiracetam.” The latter two medications are associated with a much lower risk for such birth defects, he added. 

This is based on the average rate of major congenital malformations in the EURAP registry that tracks the comparative risk for major fetal malformations after ASM use during pregnancy in over 40 countries. The latest reporting from the registry shows that this risk has decreased from 6.1% in 1998-2004 to 3.7% in 2015-2022.

Taking valproate during pregnancy is associated with a significantly increased risk for neurodevelopmental outcomes, including autism spectrum disorder. However, the jury is still out on whether topiramate escalates the risk for neurodevelopmental disorders, because findings across studies have been inconsistent.

Overall, the AAN guidance, and similar advice from European regulatory authorities, is that valproate is associated with high risk for major congenital malformations and neurodevelopmental disorders. Topiramate has also been shown to increase the risk for major congenital malformations. Consequently, these two anticonvulsants are generally contraindicated in pregnancy, Dr. Tomson noted.

On the other hand, levetiracetam, lamotrigine, and oxcarbazepine seem to be the safest ASMs with respect to congenital malformation risk, and lamotrigine has the best documented safety profile when it comes to the risk for neurodevelopmental disorders.

Although there are newer ASMs on the market, including brivaracetam, cannabidiol, cenobamate, eslicarbazepine acetate, fenfluramine, lacosamide, perampanel, and zonisamide, at this juncture data on the risk potential of these agents are insufficient.

“For some of these newer meds, we don’t even have a single exposure in our large databases, even if you combine them all. We need to collect more data, and that will take time,” Dr. Tomson said. 
 

Dose Optimization 

Dose optimization of ASMs is also important — and for this to be accurate, it’s important to document an individual’s optimal ASM serum levels before pregnancy that can be used as a baseline target during pregnancy. However, Dr. Tomson noted, this information is not always available.

He pointed out that, with many ASMs, there can be a significant decline in serum concentration levels during pregnancy, which can increase seizure risk.

To address the uncertainty surrounding this issue, Dr. Tomson recommended that physicians consider future pregnancy when prescribing ASMs to women of childbearing age. He also advised discussing contraception with these patients, even if they indicate they are not currently planning to conceive.

The data clearly show the importance of planning a pregnancy so that the most appropriate and safest medications are prescribed, he said.

Dr. Tomson reported receiving research support, on behalf of EURAP, from Accord, Angelini, Bial, EcuPharma, Eisai, GlaxoSmithKline, Glenmark, GW Pharma, Hazz, Sanofi, Teva, USB, Zentiva, and SF Group. He has received speakers’ honoraria from Angelini, Eisai, and UCB. Dr. Bjørk reports receiving speakers’ honoraria from Pfizer, Eisai, AbbVie, Best Practice, Lilly, Novartis, and Teva. She has received unrestricted educational grants from The Research Council of Norway, the Research Council of the Nordic Countries (NordForsk), and the Norwegian Epilepsy Association. She has received consulting honoraria from Novartis and is on the advisory board of Eisai, Lundbeck, Angelini Pharma, and Jazz Pharmaceuticals. Dr. Bjørk also received institutional grants from marked authorization holders of valproate.

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

Do drugs work better if taken by the clock?

A new analysis published in The Lancet journal’s eClinicalMedicine suggests: Yes, they do — if you consider the patient’s individual body clock. The study is the first to find that timing blood pressure drugs to a person’s personal “chronotype” — that is, whether they are a night owl or an early bird — may reduce the risk for a heart attack.

The findings represent a significant advance in the field of circadian medicine or “chronotherapy” — timing drug administration to circadian rhythms. A growing stack of research suggests this approach could reduce side effects and improve the effectiveness of a wide range of therapies, including vaccines, cancer treatments, and drugs for depression, glaucoma, pain, seizures, and other conditions. Still, despite decades of research, time of day is rarely considered in writing prescriptions.

“We are really just at the beginning of an exciting new way of looking at patient care,” said Kenneth A. Dyar, PhD, whose lab at Helmholtz Zentrum München’s Institute for Diabetes and Cancer focuses on metabolic physiology. Dr. Dyar is co-lead author of the new blood pressure analysis.

“Chronotherapy is a rapidly growing field,” he said, “and I suspect we are soon going to see more and more studies focused on ‘personalized chronotherapy,’ not only in hypertension but also potentially in other clinical areas.”
 

The ‘Missing Piece’ in Chronotherapy Research

Blood pressure drugs have long been chronotherapy’s battleground. After all, blood pressure follows a circadian rhythm, peaking in the morning and dropping at night.

That healthy overnight dip can disappear in people with diabetes, kidney disease, and obstructive sleep apnea. Some physicians have suggested a bed-time dose to restore that dip. But studies have had mixed results, so “take at bedtime” has become a less common recommendation in recent years.

But the debate continued. After a large 2019 Spanish study found that bedtime doses had benefits so big that the results drew questions, an even larger, 2022 randomized, controlled trial from the University of Dundee in Dundee, Scotland — called the TIME study — aimed to settle the question.

Researchers assigned over 21,000 people to take morning or night hypertension drugs for several years and found no difference in cardiovascular outcomes.

“We did this study thinking nocturnal blood pressure tablets might be better,” said Thomas MacDonald, MD, professor emeritus of clinical pharmacology and pharmacoepidemiology at the University of Dundee and principal investigator for the TIME study and the recent chronotype analysis. “But there was no difference for heart attacks, strokes, or vascular death.”

So, the researchers then looked at participants’ chronotypes, sorting outcomes based on whether the participants were late-to-bed, late-to-rise “night owls” or early-to-bed, early-to-rise “morning larks.”

Their analysis of these 5358 TIME participants found the following results: Risk for hospitalization for a heart attack was at least 34% lower for “owls” who took their drugs at bedtime. By contrast, owls’ heart attack risk was at least 62% higher with morning doses. For “larks,” the opposite was true. Morning doses were associated with an 11% lower heart attack risk and night doses with an 11% higher risk, according to supplemental data.

The personalized approach could explain why some previous chronotherapy studies have failed to show a benefit. Those studies did not individualize drug timing as this one did. But personalization could be key to circadian medicine’s success.

“Our ‘internal personal time’ appears to be an important variable to consider when dosing antihypertensives,” said co-lead author Filippo Pigazzani, MD, PhD, clinical senior lecturer and honorary consultant cardiologist at the University of Dundee School of Medicine. “Chronotherapy research has been going on for decades. We knew there was something important with time of day. But researchers haven’t considered the internal time of individual people. I think that is the missing piece.”

The analysis has several important limitations, the researchers said. A total of 95% of participants were White. And it was an observational study, not a true randomized comparison. “We started it late in the original TIME study,” Dr. MacDonald said. “You could argue we were reporting on those who survived long enough to get into the analysis.” More research is needed, they concluded.
 

Looking Beyond Blood Pressure

What about the rest of the body? “Almost all the cells of our body contain ‘circadian clocks’ that are synchronized by daily environmental cues, including light-dark, activity-rest, and feeding-fasting cycles,” said Dr. Dyar.

An estimated 50% of prescription drugs hit targets in the body that have circadian patterns. So, experts suspect that syncing a drug with a person’s body clock might increase effectiveness of many drugs.

A handful of US Food and Drug Administration–approved drugs already have time-of-day recommendations on the label for effectiveness or to limit side effects, including bedtime or evening for the insomnia drug Ambien, the HIV antiviral Atripla, and cholesterol-lowering Zocor. Others are intended to be taken with or after your last meal of the day, such as the long-acting insulin Levemir and the cardiovascular drug Xarelto. A morning recommendation comes with the proton pump inhibitor Nexium and the attention-deficit/hyperactivity disorder drug Ritalin.

Interest is expanding. About one third of the papers published about chronotherapy in the past 25 years have come out in the past 5 years. The May 2024 meeting of the Society for Research on Biological Rhythms featured a day-long session aimed at bringing clinicians up to speed. An organization called the International Association of Circadian Health Clinics is trying to bring circadian medicine findings to clinicians and their patients and to support research.

Moreover, while recent research suggests minding the clock could have benefits for a wide range of treatments, ignoring it could cause problems.

In a Massachusetts Institute of Technology study published in April in Science Advances, researchers looked at engineered livers made from human donor cells and found more than 300 genes that operate on a circadian schedule, many with roles in drug metabolism. They also found that circadian patterns affected the toxicity of acetaminophen and atorvastatin. Identifying the time of day to take these drugs could maximize effectiveness and minimize adverse effects, the researchers said.
 

Timing and the Immune System

Circadian rhythms are also seen in immune processes. In a 2023 study in The Journal of Clinical Investigation of vaccine data from 1.5 million people in Israel, researchers found that children and older adults who got their second dose of the Pfizer mRNA COVID vaccine earlier in the day were about 36% less likely to be hospitalized with SARS-CoV-2 infection than those who got an evening shot.

“The sweet spot in our data was somewhere around late morning to late afternoon,” said lead researcher Jeffrey Haspel, MD, PhD, associate professor of medicine in the division of pulmonary and critical care medicine at Washington University School of Medicine in St. Louis.

In a multicenter, 2024 analysis of 13 studies of immunotherapy for advanced cancers in 1663 people, researchers found treatment earlier in the day was associated with longer survival time and longer survival without cancer progression.

“Patients with selected metastatic cancers seemed to largely benefit from early [time of day] infusions, which is consistent with circadian mechanisms in immune-cell functions and trafficking,” the researchers noted. But “retrospective randomized trials are needed to establish recommendations for optimal circadian timing.”

Other research suggests or is investigating possible chronotherapy benefits for depression, glaucoma, respiratory diseases, stroke treatment, epilepsy, and sedatives used in surgery. So why aren’t healthcare providers adding time of day to more prescriptions? “What’s missing is more reliable data,” Dr. Dyar said.
 

Should You Use Chronotherapy Now?

Experts emphasize that more research is needed before doctors use chronotherapy and before medical organizations include it in treatment recommendations. But for some patients, circadian dosing may be worth a try:

Night owls whose blood pressure isn’t well controlled. Dr. Dyar and Dr. Pigazzani said night-time blood pressure drugs may be helpful for people with a “late chronotype.” Of course, patients shouldn’t change their medication schedule on their own, they said. And doctors may want to consider other concerns, like more overnight bathroom visits with evening diuretics.

In their study, the researchers determined participants’ chronotype with a few questions from the Munich Chronotype Questionnaire about what time they fell asleep and woke up on workdays and days off and whether they considered themselves “morning types” or “evening types.” (The questions can be found in supplementary data for the study.)

If a physician thinks matching the timing of a dose with chronotype would help, they can consider it, Dr. Pigazzani said. “However, I must add that this was an observational study, so I would advise healthcare practitioners to wait for our data to be confirmed in new RCTs of personalized chronotherapy of hypertension.”

Children and older adults getting vaccines. Timing COVID shots and possibly other vaccines from late morning to mid-afternoon could have a small benefit for individuals and a bigger public-health benefit, Dr. Haspel said. But the most important thing is getting vaccinated. “If you can only get one in the evening, it’s still worthwhile. Timing may add oomph at a public-health level for more vulnerable groups.”
 

A version of this article appeared on Medscape.com.

Do drugs work better if taken by the clock?

A new analysis published in The Lancet journal’s eClinicalMedicine suggests: Yes, they do — if you consider the patient’s individual body clock. The study is the first to find that timing blood pressure drugs to a person’s personal “chronotype” — that is, whether they are a night owl or an early bird — may reduce the risk for a heart attack.

The findings represent a significant advance in the field of circadian medicine or “chronotherapy” — timing drug administration to circadian rhythms. A growing stack of research suggests this approach could reduce side effects and improve the effectiveness of a wide range of therapies, including vaccines, cancer treatments, and drugs for depression, glaucoma, pain, seizures, and other conditions. Still, despite decades of research, time of day is rarely considered in writing prescriptions.

“We are really just at the beginning of an exciting new way of looking at patient care,” said Kenneth A. Dyar, PhD, whose lab at Helmholtz Zentrum München’s Institute for Diabetes and Cancer focuses on metabolic physiology. Dr. Dyar is co-lead author of the new blood pressure analysis.

“Chronotherapy is a rapidly growing field,” he said, “and I suspect we are soon going to see more and more studies focused on ‘personalized chronotherapy,’ not only in hypertension but also potentially in other clinical areas.”
 

The ‘Missing Piece’ in Chronotherapy Research

Blood pressure drugs have long been chronotherapy’s battleground. After all, blood pressure follows a circadian rhythm, peaking in the morning and dropping at night.

That healthy overnight dip can disappear in people with diabetes, kidney disease, and obstructive sleep apnea. Some physicians have suggested a bed-time dose to restore that dip. But studies have had mixed results, so “take at bedtime” has become a less common recommendation in recent years.

But the debate continued. After a large 2019 Spanish study found that bedtime doses had benefits so big that the results drew questions, an even larger, 2022 randomized, controlled trial from the University of Dundee in Dundee, Scotland — called the TIME study — aimed to settle the question.

Researchers assigned over 21,000 people to take morning or night hypertension drugs for several years and found no difference in cardiovascular outcomes.

“We did this study thinking nocturnal blood pressure tablets might be better,” said Thomas MacDonald, MD, professor emeritus of clinical pharmacology and pharmacoepidemiology at the University of Dundee and principal investigator for the TIME study and the recent chronotype analysis. “But there was no difference for heart attacks, strokes, or vascular death.”

So, the researchers then looked at participants’ chronotypes, sorting outcomes based on whether the participants were late-to-bed, late-to-rise “night owls” or early-to-bed, early-to-rise “morning larks.”

Their analysis of these 5358 TIME participants found the following results: Risk for hospitalization for a heart attack was at least 34% lower for “owls” who took their drugs at bedtime. By contrast, owls’ heart attack risk was at least 62% higher with morning doses. For “larks,” the opposite was true. Morning doses were associated with an 11% lower heart attack risk and night doses with an 11% higher risk, according to supplemental data.

The personalized approach could explain why some previous chronotherapy studies have failed to show a benefit. Those studies did not individualize drug timing as this one did. But personalization could be key to circadian medicine’s success.

“Our ‘internal personal time’ appears to be an important variable to consider when dosing antihypertensives,” said co-lead author Filippo Pigazzani, MD, PhD, clinical senior lecturer and honorary consultant cardiologist at the University of Dundee School of Medicine. “Chronotherapy research has been going on for decades. We knew there was something important with time of day. But researchers haven’t considered the internal time of individual people. I think that is the missing piece.”

The analysis has several important limitations, the researchers said. A total of 95% of participants were White. And it was an observational study, not a true randomized comparison. “We started it late in the original TIME study,” Dr. MacDonald said. “You could argue we were reporting on those who survived long enough to get into the analysis.” More research is needed, they concluded.
 

Looking Beyond Blood Pressure

What about the rest of the body? “Almost all the cells of our body contain ‘circadian clocks’ that are synchronized by daily environmental cues, including light-dark, activity-rest, and feeding-fasting cycles,” said Dr. Dyar.

An estimated 50% of prescription drugs hit targets in the body that have circadian patterns. So, experts suspect that syncing a drug with a person’s body clock might increase effectiveness of many drugs.

A handful of US Food and Drug Administration–approved drugs already have time-of-day recommendations on the label for effectiveness or to limit side effects, including bedtime or evening for the insomnia drug Ambien, the HIV antiviral Atripla, and cholesterol-lowering Zocor. Others are intended to be taken with or after your last meal of the day, such as the long-acting insulin Levemir and the cardiovascular drug Xarelto. A morning recommendation comes with the proton pump inhibitor Nexium and the attention-deficit/hyperactivity disorder drug Ritalin.

Interest is expanding. About one third of the papers published about chronotherapy in the past 25 years have come out in the past 5 years. The May 2024 meeting of the Society for Research on Biological Rhythms featured a day-long session aimed at bringing clinicians up to speed. An organization called the International Association of Circadian Health Clinics is trying to bring circadian medicine findings to clinicians and their patients and to support research.

Moreover, while recent research suggests minding the clock could have benefits for a wide range of treatments, ignoring it could cause problems.

In a Massachusetts Institute of Technology study published in April in Science Advances, researchers looked at engineered livers made from human donor cells and found more than 300 genes that operate on a circadian schedule, many with roles in drug metabolism. They also found that circadian patterns affected the toxicity of acetaminophen and atorvastatin. Identifying the time of day to take these drugs could maximize effectiveness and minimize adverse effects, the researchers said.
 

Timing and the Immune System

Circadian rhythms are also seen in immune processes. In a 2023 study in The Journal of Clinical Investigation of vaccine data from 1.5 million people in Israel, researchers found that children and older adults who got their second dose of the Pfizer mRNA COVID vaccine earlier in the day were about 36% less likely to be hospitalized with SARS-CoV-2 infection than those who got an evening shot.

“The sweet spot in our data was somewhere around late morning to late afternoon,” said lead researcher Jeffrey Haspel, MD, PhD, associate professor of medicine in the division of pulmonary and critical care medicine at Washington University School of Medicine in St. Louis.

In a multicenter, 2024 analysis of 13 studies of immunotherapy for advanced cancers in 1663 people, researchers found treatment earlier in the day was associated with longer survival time and longer survival without cancer progression.

“Patients with selected metastatic cancers seemed to largely benefit from early [time of day] infusions, which is consistent with circadian mechanisms in immune-cell functions and trafficking,” the researchers noted. But “retrospective randomized trials are needed to establish recommendations for optimal circadian timing.”

Other research suggests or is investigating possible chronotherapy benefits for depression, glaucoma, respiratory diseases, stroke treatment, epilepsy, and sedatives used in surgery. So why aren’t healthcare providers adding time of day to more prescriptions? “What’s missing is more reliable data,” Dr. Dyar said.
 

Should You Use Chronotherapy Now?

Experts emphasize that more research is needed before doctors use chronotherapy and before medical organizations include it in treatment recommendations. But for some patients, circadian dosing may be worth a try:

Night owls whose blood pressure isn’t well controlled. Dr. Dyar and Dr. Pigazzani said night-time blood pressure drugs may be helpful for people with a “late chronotype.” Of course, patients shouldn’t change their medication schedule on their own, they said. And doctors may want to consider other concerns, like more overnight bathroom visits with evening diuretics.

In their study, the researchers determined participants’ chronotype with a few questions from the Munich Chronotype Questionnaire about what time they fell asleep and woke up on workdays and days off and whether they considered themselves “morning types” or “evening types.” (The questions can be found in supplementary data for the study.)

If a physician thinks matching the timing of a dose with chronotype would help, they can consider it, Dr. Pigazzani said. “However, I must add that this was an observational study, so I would advise healthcare practitioners to wait for our data to be confirmed in new RCTs of personalized chronotherapy of hypertension.”

Children and older adults getting vaccines. Timing COVID shots and possibly other vaccines from late morning to mid-afternoon could have a small benefit for individuals and a bigger public-health benefit, Dr. Haspel said. But the most important thing is getting vaccinated. “If you can only get one in the evening, it’s still worthwhile. Timing may add oomph at a public-health level for more vulnerable groups.”
 

A version of this article appeared on Medscape.com.

Do drugs work better if taken by the clock?

A new analysis published in The Lancet journal’s eClinicalMedicine suggests: Yes, they do — if you consider the patient’s individual body clock. The study is the first to find that timing blood pressure drugs to a person’s personal “chronotype” — that is, whether they are a night owl or an early bird — may reduce the risk for a heart attack.

The findings represent a significant advance in the field of circadian medicine or “chronotherapy” — timing drug administration to circadian rhythms. A growing stack of research suggests this approach could reduce side effects and improve the effectiveness of a wide range of therapies, including vaccines, cancer treatments, and drugs for depression, glaucoma, pain, seizures, and other conditions. Still, despite decades of research, time of day is rarely considered in writing prescriptions.

“We are really just at the beginning of an exciting new way of looking at patient care,” said Kenneth A. Dyar, PhD, whose lab at Helmholtz Zentrum München’s Institute for Diabetes and Cancer focuses on metabolic physiology. Dr. Dyar is co-lead author of the new blood pressure analysis.

“Chronotherapy is a rapidly growing field,” he said, “and I suspect we are soon going to see more and more studies focused on ‘personalized chronotherapy,’ not only in hypertension but also potentially in other clinical areas.”
 

The ‘Missing Piece’ in Chronotherapy Research

Blood pressure drugs have long been chronotherapy’s battleground. After all, blood pressure follows a circadian rhythm, peaking in the morning and dropping at night.

That healthy overnight dip can disappear in people with diabetes, kidney disease, and obstructive sleep apnea. Some physicians have suggested a bed-time dose to restore that dip. But studies have had mixed results, so “take at bedtime” has become a less common recommendation in recent years.

But the debate continued. After a large 2019 Spanish study found that bedtime doses had benefits so big that the results drew questions, an even larger, 2022 randomized, controlled trial from the University of Dundee in Dundee, Scotland — called the TIME study — aimed to settle the question.

Researchers assigned over 21,000 people to take morning or night hypertension drugs for several years and found no difference in cardiovascular outcomes.

“We did this study thinking nocturnal blood pressure tablets might be better,” said Thomas MacDonald, MD, professor emeritus of clinical pharmacology and pharmacoepidemiology at the University of Dundee and principal investigator for the TIME study and the recent chronotype analysis. “But there was no difference for heart attacks, strokes, or vascular death.”

So, the researchers then looked at participants’ chronotypes, sorting outcomes based on whether the participants were late-to-bed, late-to-rise “night owls” or early-to-bed, early-to-rise “morning larks.”

Their analysis of these 5358 TIME participants found the following results: Risk for hospitalization for a heart attack was at least 34% lower for “owls” who took their drugs at bedtime. By contrast, owls’ heart attack risk was at least 62% higher with morning doses. For “larks,” the opposite was true. Morning doses were associated with an 11% lower heart attack risk and night doses with an 11% higher risk, according to supplemental data.

The personalized approach could explain why some previous chronotherapy studies have failed to show a benefit. Those studies did not individualize drug timing as this one did. But personalization could be key to circadian medicine’s success.

“Our ‘internal personal time’ appears to be an important variable to consider when dosing antihypertensives,” said co-lead author Filippo Pigazzani, MD, PhD, clinical senior lecturer and honorary consultant cardiologist at the University of Dundee School of Medicine. “Chronotherapy research has been going on for decades. We knew there was something important with time of day. But researchers haven’t considered the internal time of individual people. I think that is the missing piece.”

The analysis has several important limitations, the researchers said. A total of 95% of participants were White. And it was an observational study, not a true randomized comparison. “We started it late in the original TIME study,” Dr. MacDonald said. “You could argue we were reporting on those who survived long enough to get into the analysis.” More research is needed, they concluded.
 

Looking Beyond Blood Pressure

What about the rest of the body? “Almost all the cells of our body contain ‘circadian clocks’ that are synchronized by daily environmental cues, including light-dark, activity-rest, and feeding-fasting cycles,” said Dr. Dyar.

An estimated 50% of prescription drugs hit targets in the body that have circadian patterns. So, experts suspect that syncing a drug with a person’s body clock might increase effectiveness of many drugs.

A handful of US Food and Drug Administration–approved drugs already have time-of-day recommendations on the label for effectiveness or to limit side effects, including bedtime or evening for the insomnia drug Ambien, the HIV antiviral Atripla, and cholesterol-lowering Zocor. Others are intended to be taken with or after your last meal of the day, such as the long-acting insulin Levemir and the cardiovascular drug Xarelto. A morning recommendation comes with the proton pump inhibitor Nexium and the attention-deficit/hyperactivity disorder drug Ritalin.

Interest is expanding. About one third of the papers published about chronotherapy in the past 25 years have come out in the past 5 years. The May 2024 meeting of the Society for Research on Biological Rhythms featured a day-long session aimed at bringing clinicians up to speed. An organization called the International Association of Circadian Health Clinics is trying to bring circadian medicine findings to clinicians and their patients and to support research.

Moreover, while recent research suggests minding the clock could have benefits for a wide range of treatments, ignoring it could cause problems.

In a Massachusetts Institute of Technology study published in April in Science Advances, researchers looked at engineered livers made from human donor cells and found more than 300 genes that operate on a circadian schedule, many with roles in drug metabolism. They also found that circadian patterns affected the toxicity of acetaminophen and atorvastatin. Identifying the time of day to take these drugs could maximize effectiveness and minimize adverse effects, the researchers said.
 

Timing and the Immune System

Circadian rhythms are also seen in immune processes. In a 2023 study in The Journal of Clinical Investigation of vaccine data from 1.5 million people in Israel, researchers found that children and older adults who got their second dose of the Pfizer mRNA COVID vaccine earlier in the day were about 36% less likely to be hospitalized with SARS-CoV-2 infection than those who got an evening shot.

“The sweet spot in our data was somewhere around late morning to late afternoon,” said lead researcher Jeffrey Haspel, MD, PhD, associate professor of medicine in the division of pulmonary and critical care medicine at Washington University School of Medicine in St. Louis.

In a multicenter, 2024 analysis of 13 studies of immunotherapy for advanced cancers in 1663 people, researchers found treatment earlier in the day was associated with longer survival time and longer survival without cancer progression.

“Patients with selected metastatic cancers seemed to largely benefit from early [time of day] infusions, which is consistent with circadian mechanisms in immune-cell functions and trafficking,” the researchers noted. But “retrospective randomized trials are needed to establish recommendations for optimal circadian timing.”

Other research suggests or is investigating possible chronotherapy benefits for depression, glaucoma, respiratory diseases, stroke treatment, epilepsy, and sedatives used in surgery. So why aren’t healthcare providers adding time of day to more prescriptions? “What’s missing is more reliable data,” Dr. Dyar said.
 

Should You Use Chronotherapy Now?

Experts emphasize that more research is needed before doctors use chronotherapy and before medical organizations include it in treatment recommendations. But for some patients, circadian dosing may be worth a try:

Night owls whose blood pressure isn’t well controlled. Dr. Dyar and Dr. Pigazzani said night-time blood pressure drugs may be helpful for people with a “late chronotype.” Of course, patients shouldn’t change their medication schedule on their own, they said. And doctors may want to consider other concerns, like more overnight bathroom visits with evening diuretics.

In their study, the researchers determined participants’ chronotype with a few questions from the Munich Chronotype Questionnaire about what time they fell asleep and woke up on workdays and days off and whether they considered themselves “morning types” or “evening types.” (The questions can be found in supplementary data for the study.)

If a physician thinks matching the timing of a dose with chronotype would help, they can consider it, Dr. Pigazzani said. “However, I must add that this was an observational study, so I would advise healthcare practitioners to wait for our data to be confirmed in new RCTs of personalized chronotherapy of hypertension.”

Children and older adults getting vaccines. Timing COVID shots and possibly other vaccines from late morning to mid-afternoon could have a small benefit for individuals and a bigger public-health benefit, Dr. Haspel said. But the most important thing is getting vaccinated. “If you can only get one in the evening, it’s still worthwhile. Timing may add oomph at a public-health level for more vulnerable groups.”
 

A version of this article appeared on Medscape.com.

Neuropsychiatric symptoms, including nightmares and hallucinatory “daymares,” may be a more important aspect of systemic lupus erythematosus (SLE) than formerly recognized, according to a qualitative mixed methods study published in The Lancet Discovery Science’s eClinicalMedicine. The findings suggested these neuropsychiatric symptoms can sometimes present as prodromal and other times act as an early warning system for a forthcoming flare.

“For clinicians, the key point is to be aware that neurological and psychiatric symptoms are much more common in patients with lupus and other autoimmune systemic rheumatic diseases than previously thought,” lead author Melanie Sloan, PhD, of the Department of Public Health and Primary Care at the University of Cambridge in England, told this news organization.

“If clinicians — and some do already — could all ask about and document these symptoms for each patient, the usual progression of symptoms in a flare can then be monitored, and patients could be supported and treated at an earlier stage,” Dr. Sloan said. “Another key point is to consider systemic autoimmune diseases at an early stage if a patient presents with multiple seemingly unconnected symptoms, which often include both physical and mental health symptoms.”

Alfred Kim, MD, PhD, associate professor of medicine in rheumatology at Washington University School of Medicine in St. Louis, Missouri, noted the difficulty of determining what neuropsychiatric symptoms may be linked to lupus vs those occurring independently or as part of a different condition.

Dr. Kim

Study Details

In planning for the study, the researchers first searched the existing literature for studies involving neuropsychiatric symptoms in patients with systemic autoimmune rheumatic diseases (SARDs). “The literature indicated frequent underreporting and misattributions of neuropsychiatric symptoms in SLE and other SARD patients, and clinician-patient discordance in neuropsychiatric symptom attribution,” the authors reported.

During 2022-2023, the researchers conducted two surveys, one with 676 adult patients with SLE and one with 400 clinicians, recruited through social media, online patient support groups, and professional networks. All patients self-reported an SLE diagnosis that the researchers did not independently confirm. The patients were predominantly White (80%) and female (94%), ranging in age from 18 to over 70, with most falling between ages 40 and 69. Most patients lived in the United Kingdom (76%) or Europe (15%).

The clinicians included 51% rheumatologists, 24% psychiatrists, 13% neurologists, 5% rheumatology nurses, 3% primary care physicians, and 7% other clinicians. Nearly half of the clinicians (45%) were from the United Kingdom, with others from the United States or Canada (16%), Europe (17%), Asia (9%), Latin America (8%), Australia or New Zealand (3%), or elsewhere (3%).

The patient surveys asked whether they had experienced any of the 29 neuropsychiatric symptoms. For the symptoms that patients had experienced at least three times in their lives, the survey asked when they first experienced the symptom in relation to their SLE onset or other SLE symptoms: Over a year before, within a year of (on either side), 1-4 years after, or more than 5 years after onset/other symptoms. “Other quantitative data included timings of disrupted dreaming sleep in relation to hallucinations for those patients reporting experiencing these,” the authors wrote.

The researchers also conducted video conference interviews with 50 clinicians, including 20 rheumatologists, and 69 interviews with patients who had a systemic autoimmune rheumatic disease, including 27 patients with SLE. Other conditions among those interviewed included inflammatory arthritis, vasculitis, Sjögren disease, systemic sclerosis, myositis, undifferentiated and mixed connective tissue diseases, and polymyalgia rheumatica. During interviews, the term “daymare” was used to discuss possible hallucinations.
 

Linking Neuropsychiatric Symptoms and Disease

Four themes emerged from the analysis of the surveys and interviews. First, despite many rheumatologists stating that it was an “established theory” that most neuropsychiatric symptoms related to SLE would initially present around the time of diagnosis or disease onset, the findings from patients and interviews with psychiatrists did not align with this theory. The first presentation of each neuropsychiatric symptom only occurred around the onset of other SLE symptoms, about one fifth to one third of the time. In fact, more than half of the patients with SLE who had experienced hallucinations or delusions/paranoia said they occurred more than a year after they first experienced their other SLE symptoms.

Patient experiences differed in terms of whether they believed their neuropsychiatric symptoms were directly related to their SLE or other rheumatic disease. Some did attribute the symptoms, such as hypomania, to their rheumatic illness, while others, such as a patient with major depression, did not see the two as linked.

A second theme focused on pattern recognition of neuropsychiatric symptoms and the onset of a disease flare. “For example, several patients described how they felt that some types of depressive symptoms were directly attributable to active inflammation due to its time of onset and differences in type and intensity compared to their more ‘reactive’ low mood that could be more attributable to a consequence of psychological distress,” the authors wrote. Another common report from patients was experiencing a sudden, intense fatigue that coincided with a flare and differed from other types of fatigue.

Some patients could recognize that a flare was coming because of familiar neuropsychiatric symptoms that acted like an “early warning system.” Often, however, these symptoms “were absent from current diagnostic guidelines and only rarely identified by clinician interviewees as related to SLE/NPSLE,” the authors found. “These neuropsychiatric prodromal symptoms were reported as sometimes preceding the more widely recognized SLE and other SARD symptoms such as joint pain, rashes, and other organ involvement.” These symptoms included sudden changes in mood (usually a lowering but sometimes mania), increased nightmares, a “feeling of unreality,” or increased sensory symptoms.

Other patients, on the other hand, had not considered a link between neuropsychiatric symptoms and their rheumatic disease until the interview, and many of the clinicians, aside from psychiatrists and nurses, said they had little time in clinic to gather information about symptom progression.
 

Nightmares and Daymares

A third theme centered on disrupted dreaming sleep, nightmares, and “daymares” as a prodromal symptom in particular. Some patients had already drawn a connection between an oncoming flare of their disease and these dreaming-related symptoms, while others had not considered a link until the interviews.

“Several SLE patients recounted flares consistently involving the segueing of increasingly vivid and distressing nightmares into distorted reality and daytime hallucinations,” the authors reported. Flare-related nightmares in particular “often involved being attacked, trapped, crushed, or falling.” Patients tended to be more forthcoming about hallucinatory experiences when the term “daymare” was used to describe them, and they often related to the idea of feeling “in-between asleep and awake.”

Only one of the rheumatologists interviewed had considered nightmares as potentially related to SLE flares, and several appeared skeptical about a link but planned to ask their patients about it. Most of the specialists interviewed, meanwhile, said they often discussed sleep disruption with patients.

“There was agreement that recognizing and eliciting these early flare symptoms may improve care and even reduce clinic times by averting flares at any earlier stage, although some rheumatologists were clear that limited appointment times meant that these symptoms would not be prioritized for discussion,” the authors wrote.

Though Dr. Kim acknowledged the possibility of nightmares as prodromal, he noted other ways in which nightmares may be indirectly linked to lupus. “Trauma is a major risk factor for lupus,” Dr. Kim said, with multiple studies showing childhood traumatic experiences and even posttraumatic stress disorder to be risk factors for lupus. “Whether nightmares represent a traumatic event or prior traumatic events is not clear to me, but one could hypothesize that this may be a manifestation of trauma,” Dr. Kim said.

In addition, nightmares represent a sleep disorder that can substantially reduce sleep quality, Dr. Kim said, and poor sleep is also associated with lupus. “One has to wonder whether disruptive dreaming sleep is one of several specific manifestations of poor sleep quality, which then increases the risk of lupus in those patients,” Dr. Kim said.
 

Misattribution of Neuropsychiatric Symptoms

The final theme to emerge from the findings was patients had been misdiagnosed with psychiatric or psychosomatic conditions shortly before getting their rheumatic disease diagnosis. One patient, for example, reported being diagnosed with borderline personality disorder just 6 months before the lupus diagnosis at age 19 and noticed that the symptoms of one “got under control” when the symptoms of the other did.

“Early misattributions of SARD symptoms to primary psychiatric or psychosomatic conditions were frequently reported to have delayed SARD diagnosis and led to future misattributions,” the authors reported. “Whilst some of these misdiagnoses likely reflect the widespread lack of knowledge and limited definitive tests for SLE, it is plausible that some early SLE neurological and/or psychiatric symptoms may represent a neuropsychiatric prodrome for SLE itself.”

Dr. Kim agreed that misattribution of symptoms to other diagnoses is common with lupus and a common reason for delays in diagnosis, even with symptoms that are not neuropsychiatric. The findings in this study broaden “the type of symptoms we need to put on our radar pre-diagnosis,” Dr. Kim said. “We just also have to be aware that these prodromal symptoms are not diagnostic for lupus, though.”

Dr. Sloan cited earlier work in recommending an “ABC” approach to improving clinician-patient relationships: “Availability is being accessible when patients need them, Belief is demonstrating belief and validating patient self-reports of symptoms, and Continuity is when the same clinician sees the same patient each clinic visit to build up a trusting relationship.” She noted the importance of asking about and normalizing the existence of these symptoms with rheumatic diseases.

The research was funded by The Lupus Trust. Three authors reported consultancy, speaker, or advisory fees from Alumis, Amgen, AstraZeneca, Eli Lilly, GlaxoSmithKline, Janssen, MGP, Novartis, Pfizer, Sanofi, UCB, Vifor, and/or Werfen Group. The other authors, including Dr. Sloan, had no industry-related disclosures. Dr. Kim reported research support from AstraZeneca, GlaxoSmithKline, and Novartis; speaking fees from Exagen Diagnostics and GlaxoSmithKline; and consulting fees from AbbVie, Amgen, ANI Pharmaceuticals, AstraZeneca, Atara Bio, Aurinia Pharmaceuticals, Cargo Therapeutics, Exagen Diagnostics, Hinge Bio, GlaxoSmithKline, Kypha, Miltenyi Biotec, Synthekine, and Tectonic Therapeutic.
 

A version of this article appeared on Medscape.com.

Neuropsychiatric symptoms, including nightmares and hallucinatory “daymares,” may be a more important aspect of systemic lupus erythematosus (SLE) than formerly recognized, according to a qualitative mixed methods study published in The Lancet Discovery Science’s eClinicalMedicine. The findings suggested these neuropsychiatric symptoms can sometimes present as prodromal and other times act as an early warning system for a forthcoming flare.

“For clinicians, the key point is to be aware that neurological and psychiatric symptoms are much more common in patients with lupus and other autoimmune systemic rheumatic diseases than previously thought,” lead author Melanie Sloan, PhD, of the Department of Public Health and Primary Care at the University of Cambridge in England, told this news organization.

“If clinicians — and some do already — could all ask about and document these symptoms for each patient, the usual progression of symptoms in a flare can then be monitored, and patients could be supported and treated at an earlier stage,” Dr. Sloan said. “Another key point is to consider systemic autoimmune diseases at an early stage if a patient presents with multiple seemingly unconnected symptoms, which often include both physical and mental health symptoms.”

Alfred Kim, MD, PhD, associate professor of medicine in rheumatology at Washington University School of Medicine in St. Louis, Missouri, noted the difficulty of determining what neuropsychiatric symptoms may be linked to lupus vs those occurring independently or as part of a different condition.

Dr. Kim

Study Details

In planning for the study, the researchers first searched the existing literature for studies involving neuropsychiatric symptoms in patients with systemic autoimmune rheumatic diseases (SARDs). “The literature indicated frequent underreporting and misattributions of neuropsychiatric symptoms in SLE and other SARD patients, and clinician-patient discordance in neuropsychiatric symptom attribution,” the authors reported.

During 2022-2023, the researchers conducted two surveys, one with 676 adult patients with SLE and one with 400 clinicians, recruited through social media, online patient support groups, and professional networks. All patients self-reported an SLE diagnosis that the researchers did not independently confirm. The patients were predominantly White (80%) and female (94%), ranging in age from 18 to over 70, with most falling between ages 40 and 69. Most patients lived in the United Kingdom (76%) or Europe (15%).

The clinicians included 51% rheumatologists, 24% psychiatrists, 13% neurologists, 5% rheumatology nurses, 3% primary care physicians, and 7% other clinicians. Nearly half of the clinicians (45%) were from the United Kingdom, with others from the United States or Canada (16%), Europe (17%), Asia (9%), Latin America (8%), Australia or New Zealand (3%), or elsewhere (3%).

The patient surveys asked whether they had experienced any of the 29 neuropsychiatric symptoms. For the symptoms that patients had experienced at least three times in their lives, the survey asked when they first experienced the symptom in relation to their SLE onset or other SLE symptoms: Over a year before, within a year of (on either side), 1-4 years after, or more than 5 years after onset/other symptoms. “Other quantitative data included timings of disrupted dreaming sleep in relation to hallucinations for those patients reporting experiencing these,” the authors wrote.

The researchers also conducted video conference interviews with 50 clinicians, including 20 rheumatologists, and 69 interviews with patients who had a systemic autoimmune rheumatic disease, including 27 patients with SLE. Other conditions among those interviewed included inflammatory arthritis, vasculitis, Sjögren disease, systemic sclerosis, myositis, undifferentiated and mixed connective tissue diseases, and polymyalgia rheumatica. During interviews, the term “daymare” was used to discuss possible hallucinations.
 

Linking Neuropsychiatric Symptoms and Disease

Four themes emerged from the analysis of the surveys and interviews. First, despite many rheumatologists stating that it was an “established theory” that most neuropsychiatric symptoms related to SLE would initially present around the time of diagnosis or disease onset, the findings from patients and interviews with psychiatrists did not align with this theory. The first presentation of each neuropsychiatric symptom only occurred around the onset of other SLE symptoms, about one fifth to one third of the time. In fact, more than half of the patients with SLE who had experienced hallucinations or delusions/paranoia said they occurred more than a year after they first experienced their other SLE symptoms.

Patient experiences differed in terms of whether they believed their neuropsychiatric symptoms were directly related to their SLE or other rheumatic disease. Some did attribute the symptoms, such as hypomania, to their rheumatic illness, while others, such as a patient with major depression, did not see the two as linked.

A second theme focused on pattern recognition of neuropsychiatric symptoms and the onset of a disease flare. “For example, several patients described how they felt that some types of depressive symptoms were directly attributable to active inflammation due to its time of onset and differences in type and intensity compared to their more ‘reactive’ low mood that could be more attributable to a consequence of psychological distress,” the authors wrote. Another common report from patients was experiencing a sudden, intense fatigue that coincided with a flare and differed from other types of fatigue.

Some patients could recognize that a flare was coming because of familiar neuropsychiatric symptoms that acted like an “early warning system.” Often, however, these symptoms “were absent from current diagnostic guidelines and only rarely identified by clinician interviewees as related to SLE/NPSLE,” the authors found. “These neuropsychiatric prodromal symptoms were reported as sometimes preceding the more widely recognized SLE and other SARD symptoms such as joint pain, rashes, and other organ involvement.” These symptoms included sudden changes in mood (usually a lowering but sometimes mania), increased nightmares, a “feeling of unreality,” or increased sensory symptoms.

Other patients, on the other hand, had not considered a link between neuropsychiatric symptoms and their rheumatic disease until the interview, and many of the clinicians, aside from psychiatrists and nurses, said they had little time in clinic to gather information about symptom progression.
 

Nightmares and Daymares

A third theme centered on disrupted dreaming sleep, nightmares, and “daymares” as a prodromal symptom in particular. Some patients had already drawn a connection between an oncoming flare of their disease and these dreaming-related symptoms, while others had not considered a link until the interviews.

“Several SLE patients recounted flares consistently involving the segueing of increasingly vivid and distressing nightmares into distorted reality and daytime hallucinations,” the authors reported. Flare-related nightmares in particular “often involved being attacked, trapped, crushed, or falling.” Patients tended to be more forthcoming about hallucinatory experiences when the term “daymare” was used to describe them, and they often related to the idea of feeling “in-between asleep and awake.”

Only one of the rheumatologists interviewed had considered nightmares as potentially related to SLE flares, and several appeared skeptical about a link but planned to ask their patients about it. Most of the specialists interviewed, meanwhile, said they often discussed sleep disruption with patients.

“There was agreement that recognizing and eliciting these early flare symptoms may improve care and even reduce clinic times by averting flares at any earlier stage, although some rheumatologists were clear that limited appointment times meant that these symptoms would not be prioritized for discussion,” the authors wrote.

Though Dr. Kim acknowledged the possibility of nightmares as prodromal, he noted other ways in which nightmares may be indirectly linked to lupus. “Trauma is a major risk factor for lupus,” Dr. Kim said, with multiple studies showing childhood traumatic experiences and even posttraumatic stress disorder to be risk factors for lupus. “Whether nightmares represent a traumatic event or prior traumatic events is not clear to me, but one could hypothesize that this may be a manifestation of trauma,” Dr. Kim said.

In addition, nightmares represent a sleep disorder that can substantially reduce sleep quality, Dr. Kim said, and poor sleep is also associated with lupus. “One has to wonder whether disruptive dreaming sleep is one of several specific manifestations of poor sleep quality, which then increases the risk of lupus in those patients,” Dr. Kim said.
 

Misattribution of Neuropsychiatric Symptoms

The final theme to emerge from the findings was patients had been misdiagnosed with psychiatric or psychosomatic conditions shortly before getting their rheumatic disease diagnosis. One patient, for example, reported being diagnosed with borderline personality disorder just 6 months before the lupus diagnosis at age 19 and noticed that the symptoms of one “got under control” when the symptoms of the other did.

“Early misattributions of SARD symptoms to primary psychiatric or psychosomatic conditions were frequently reported to have delayed SARD diagnosis and led to future misattributions,” the authors reported. “Whilst some of these misdiagnoses likely reflect the widespread lack of knowledge and limited definitive tests for SLE, it is plausible that some early SLE neurological and/or psychiatric symptoms may represent a neuropsychiatric prodrome for SLE itself.”

Dr. Kim agreed that misattribution of symptoms to other diagnoses is common with lupus and a common reason for delays in diagnosis, even with symptoms that are not neuropsychiatric. The findings in this study broaden “the type of symptoms we need to put on our radar pre-diagnosis,” Dr. Kim said. “We just also have to be aware that these prodromal symptoms are not diagnostic for lupus, though.”

Dr. Sloan cited earlier work in recommending an “ABC” approach to improving clinician-patient relationships: “Availability is being accessible when patients need them, Belief is demonstrating belief and validating patient self-reports of symptoms, and Continuity is when the same clinician sees the same patient each clinic visit to build up a trusting relationship.” She noted the importance of asking about and normalizing the existence of these symptoms with rheumatic diseases.

The research was funded by The Lupus Trust. Three authors reported consultancy, speaker, or advisory fees from Alumis, Amgen, AstraZeneca, Eli Lilly, GlaxoSmithKline, Janssen, MGP, Novartis, Pfizer, Sanofi, UCB, Vifor, and/or Werfen Group. The other authors, including Dr. Sloan, had no industry-related disclosures. Dr. Kim reported research support from AstraZeneca, GlaxoSmithKline, and Novartis; speaking fees from Exagen Diagnostics and GlaxoSmithKline; and consulting fees from AbbVie, Amgen, ANI Pharmaceuticals, AstraZeneca, Atara Bio, Aurinia Pharmaceuticals, Cargo Therapeutics, Exagen Diagnostics, Hinge Bio, GlaxoSmithKline, Kypha, Miltenyi Biotec, Synthekine, and Tectonic Therapeutic.
 

A version of this article appeared on Medscape.com.

Neuropsychiatric symptoms, including nightmares and hallucinatory “daymares,” may be a more important aspect of systemic lupus erythematosus (SLE) than formerly recognized, according to a qualitative mixed methods study published in The Lancet Discovery Science’s eClinicalMedicine. The findings suggested these neuropsychiatric symptoms can sometimes present as prodromal and other times act as an early warning system for a forthcoming flare.

“For clinicians, the key point is to be aware that neurological and psychiatric symptoms are much more common in patients with lupus and other autoimmune systemic rheumatic diseases than previously thought,” lead author Melanie Sloan, PhD, of the Department of Public Health and Primary Care at the University of Cambridge in England, told this news organization.

“If clinicians — and some do already — could all ask about and document these symptoms for each patient, the usual progression of symptoms in a flare can then be monitored, and patients could be supported and treated at an earlier stage,” Dr. Sloan said. “Another key point is to consider systemic autoimmune diseases at an early stage if a patient presents with multiple seemingly unconnected symptoms, which often include both physical and mental health symptoms.”

Alfred Kim, MD, PhD, associate professor of medicine in rheumatology at Washington University School of Medicine in St. Louis, Missouri, noted the difficulty of determining what neuropsychiatric symptoms may be linked to lupus vs those occurring independently or as part of a different condition.

Dr. Kim

Study Details

In planning for the study, the researchers first searched the existing literature for studies involving neuropsychiatric symptoms in patients with systemic autoimmune rheumatic diseases (SARDs). “The literature indicated frequent underreporting and misattributions of neuropsychiatric symptoms in SLE and other SARD patients, and clinician-patient discordance in neuropsychiatric symptom attribution,” the authors reported.

During 2022-2023, the researchers conducted two surveys, one with 676 adult patients with SLE and one with 400 clinicians, recruited through social media, online patient support groups, and professional networks. All patients self-reported an SLE diagnosis that the researchers did not independently confirm. The patients were predominantly White (80%) and female (94%), ranging in age from 18 to over 70, with most falling between ages 40 and 69. Most patients lived in the United Kingdom (76%) or Europe (15%).

The clinicians included 51% rheumatologists, 24% psychiatrists, 13% neurologists, 5% rheumatology nurses, 3% primary care physicians, and 7% other clinicians. Nearly half of the clinicians (45%) were from the United Kingdom, with others from the United States or Canada (16%), Europe (17%), Asia (9%), Latin America (8%), Australia or New Zealand (3%), or elsewhere (3%).

The patient surveys asked whether they had experienced any of the 29 neuropsychiatric symptoms. For the symptoms that patients had experienced at least three times in their lives, the survey asked when they first experienced the symptom in relation to their SLE onset or other SLE symptoms: Over a year before, within a year of (on either side), 1-4 years after, or more than 5 years after onset/other symptoms. “Other quantitative data included timings of disrupted dreaming sleep in relation to hallucinations for those patients reporting experiencing these,” the authors wrote.

The researchers also conducted video conference interviews with 50 clinicians, including 20 rheumatologists, and 69 interviews with patients who had a systemic autoimmune rheumatic disease, including 27 patients with SLE. Other conditions among those interviewed included inflammatory arthritis, vasculitis, Sjögren disease, systemic sclerosis, myositis, undifferentiated and mixed connective tissue diseases, and polymyalgia rheumatica. During interviews, the term “daymare” was used to discuss possible hallucinations.
 

Linking Neuropsychiatric Symptoms and Disease

Four themes emerged from the analysis of the surveys and interviews. First, despite many rheumatologists stating that it was an “established theory” that most neuropsychiatric symptoms related to SLE would initially present around the time of diagnosis or disease onset, the findings from patients and interviews with psychiatrists did not align with this theory. The first presentation of each neuropsychiatric symptom only occurred around the onset of other SLE symptoms, about one fifth to one third of the time. In fact, more than half of the patients with SLE who had experienced hallucinations or delusions/paranoia said they occurred more than a year after they first experienced their other SLE symptoms.

Patient experiences differed in terms of whether they believed their neuropsychiatric symptoms were directly related to their SLE or other rheumatic disease. Some did attribute the symptoms, such as hypomania, to their rheumatic illness, while others, such as a patient with major depression, did not see the two as linked.

A second theme focused on pattern recognition of neuropsychiatric symptoms and the onset of a disease flare. “For example, several patients described how they felt that some types of depressive symptoms were directly attributable to active inflammation due to its time of onset and differences in type and intensity compared to their more ‘reactive’ low mood that could be more attributable to a consequence of psychological distress,” the authors wrote. Another common report from patients was experiencing a sudden, intense fatigue that coincided with a flare and differed from other types of fatigue.

Some patients could recognize that a flare was coming because of familiar neuropsychiatric symptoms that acted like an “early warning system.” Often, however, these symptoms “were absent from current diagnostic guidelines and only rarely identified by clinician interviewees as related to SLE/NPSLE,” the authors found. “These neuropsychiatric prodromal symptoms were reported as sometimes preceding the more widely recognized SLE and other SARD symptoms such as joint pain, rashes, and other organ involvement.” These symptoms included sudden changes in mood (usually a lowering but sometimes mania), increased nightmares, a “feeling of unreality,” or increased sensory symptoms.

Other patients, on the other hand, had not considered a link between neuropsychiatric symptoms and their rheumatic disease until the interview, and many of the clinicians, aside from psychiatrists and nurses, said they had little time in clinic to gather information about symptom progression.
 

Nightmares and Daymares

A third theme centered on disrupted dreaming sleep, nightmares, and “daymares” as a prodromal symptom in particular. Some patients had already drawn a connection between an oncoming flare of their disease and these dreaming-related symptoms, while others had not considered a link until the interviews.

“Several SLE patients recounted flares consistently involving the segueing of increasingly vivid and distressing nightmares into distorted reality and daytime hallucinations,” the authors reported. Flare-related nightmares in particular “often involved being attacked, trapped, crushed, or falling.” Patients tended to be more forthcoming about hallucinatory experiences when the term “daymare” was used to describe them, and they often related to the idea of feeling “in-between asleep and awake.”

Only one of the rheumatologists interviewed had considered nightmares as potentially related to SLE flares, and several appeared skeptical about a link but planned to ask their patients about it. Most of the specialists interviewed, meanwhile, said they often discussed sleep disruption with patients.

“There was agreement that recognizing and eliciting these early flare symptoms may improve care and even reduce clinic times by averting flares at any earlier stage, although some rheumatologists were clear that limited appointment times meant that these symptoms would not be prioritized for discussion,” the authors wrote.

Though Dr. Kim acknowledged the possibility of nightmares as prodromal, he noted other ways in which nightmares may be indirectly linked to lupus. “Trauma is a major risk factor for lupus,” Dr. Kim said, with multiple studies showing childhood traumatic experiences and even posttraumatic stress disorder to be risk factors for lupus. “Whether nightmares represent a traumatic event or prior traumatic events is not clear to me, but one could hypothesize that this may be a manifestation of trauma,” Dr. Kim said.

In addition, nightmares represent a sleep disorder that can substantially reduce sleep quality, Dr. Kim said, and poor sleep is also associated with lupus. “One has to wonder whether disruptive dreaming sleep is one of several specific manifestations of poor sleep quality, which then increases the risk of lupus in those patients,” Dr. Kim said.
 

Misattribution of Neuropsychiatric Symptoms

The final theme to emerge from the findings was patients had been misdiagnosed with psychiatric or psychosomatic conditions shortly before getting their rheumatic disease diagnosis. One patient, for example, reported being diagnosed with borderline personality disorder just 6 months before the lupus diagnosis at age 19 and noticed that the symptoms of one “got under control” when the symptoms of the other did.

“Early misattributions of SARD symptoms to primary psychiatric or psychosomatic conditions were frequently reported to have delayed SARD diagnosis and led to future misattributions,” the authors reported. “Whilst some of these misdiagnoses likely reflect the widespread lack of knowledge and limited definitive tests for SLE, it is plausible that some early SLE neurological and/or psychiatric symptoms may represent a neuropsychiatric prodrome for SLE itself.”

Dr. Kim agreed that misattribution of symptoms to other diagnoses is common with lupus and a common reason for delays in diagnosis, even with symptoms that are not neuropsychiatric. The findings in this study broaden “the type of symptoms we need to put on our radar pre-diagnosis,” Dr. Kim said. “We just also have to be aware that these prodromal symptoms are not diagnostic for lupus, though.”

Dr. Sloan cited earlier work in recommending an “ABC” approach to improving clinician-patient relationships: “Availability is being accessible when patients need them, Belief is demonstrating belief and validating patient self-reports of symptoms, and Continuity is when the same clinician sees the same patient each clinic visit to build up a trusting relationship.” She noted the importance of asking about and normalizing the existence of these symptoms with rheumatic diseases.

The research was funded by The Lupus Trust. Three authors reported consultancy, speaker, or advisory fees from Alumis, Amgen, AstraZeneca, Eli Lilly, GlaxoSmithKline, Janssen, MGP, Novartis, Pfizer, Sanofi, UCB, Vifor, and/or Werfen Group. The other authors, including Dr. Sloan, had no industry-related disclosures. Dr. Kim reported research support from AstraZeneca, GlaxoSmithKline, and Novartis; speaking fees from Exagen Diagnostics and GlaxoSmithKline; and consulting fees from AbbVie, Amgen, ANI Pharmaceuticals, AstraZeneca, Atara Bio, Aurinia Pharmaceuticals, Cargo Therapeutics, Exagen Diagnostics, Hinge Bio, GlaxoSmithKline, Kypha, Miltenyi Biotec, Synthekine, and Tectonic Therapeutic.
 

A version of this article appeared on Medscape.com.

The most reliable predictors of remission in newly diagnosed epilepsy include patient history, seizure characteristics, and onset age, according to authors of a recent review. Clinical prediction models can help neurologists identify which patients could benefit from more aggressive early treatment, authors added, although concerns over bias and model applicability leave room for improvement.

Triggering Aggressive Treatments

“These models are helpful because if you can predict that someone is going to do well with one or two medications, that’s great,” said Aatif M. Husain, MD. “But if you know early on that someone likely will not do well, will need many medications, and still not have their seizures under control, you’re much more likely to be more aggressive with their management, such as closely refer them to a specialist epilepsy center and evaluate them for surgical treatment options. This could minimize the amount of time their seizures are inadequately controlled.” Dr. Husain is an epileptologist, neurologist, and sleep medicine specialist at Duke University Health System in Durham, North Carolina. Dr. Husain was not involved with the study, which was published in Epilepsia.

“But the other important finding is that these models so far have not been that great,” he added.

Prognosis Predictors

Investigators Corey Ratcliffe of the University of Liverpool in England and colleagues systematically searched MEDLINE and Embase for relevant publications, ultimately analyzing 48 models across 32 studies. The strongest predictors of seizure remission were history and seizure types or characteristics, the authors wrote, followed by onset age.

Regarding seizure history, a March 2018 JAMA Neurology study and a December 2013 BMC Neurology study linked factors such as history of seizures in the year pre-diagnosis, family history of epilepsy, and history of febrile seizures and of migraines with lower chances of seizure remission. Seizure types with increased chances of poor outcomes in the review included status epilepticus and seizures with complex or mixed etiologies. Additional seizure types associated with poor control include tonic-clonic seizures, frequent focal seizures, and seizures stemming from certain genetic predispositions, said Dr. Husain.

Although the roles of many of the foregoing factors are easily explained, he added, other variables’ impact is less clear. Younger onset often signals more refractory seizures, for example, while data regarding older onset are mixed. “Sometimes older individuals will have mild epilepsy due to a stroke, tumor, or something that can be relatively easily treated,” said Dr. Husain. Conversely, epilepsy can become more complicated if such patients take several medications and/or have coexisting medical problems that seizures or antiseizure medications exacerbate. “So sometimes it’s not so obvious.”
 

Incorporating Imaging, AI

Dr. Husain found it surprising that very few of the selected models incorporated EEG and MRI findings. “Subsequent research should look at those, since they are important diagnostic tests.” Moreover, he recommended including more sophisticated quantitative and connectivity analyses of EEG and MRI data. These analyses might provide additional prognostic information beyond a simple visual analysis of these tests, Dr. Husain explained, although their potential here remains unproven.

As for factors not represented in the review, he said, future studies will help clarify AI’s role in predicting newly diagnosed epilepsy outcomes. A study published in Epilepsia showed that among 248 potential pediatric surgical candidates, those whose providers received alerts based on machine learning analysis of prior visit notes were more likely to be referred for presurgical evaluation (9.8% versus 3.1%). Future clinical models will use AI to examine not only established elements of neurologic history, said Dr. Husain, but also other types of history such as socioeconomic characteristics, geographic location, and other such data.

Additionally, study authors recommended a standardized approach to prediction modeling, using Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) guidelines. Using consistent definitions, outcomes, and reporting requirements will facilitate communication among researchers, reduce bias, and support systematic between-study comparisons, Mr. Ratcliffe and colleagues wrote.
 

Reaching General Neurologists

Epilepsy specialists are generally aware of reliable outcome predictors, Dr. Husain said, though they do not use models per se. “But the vast majority of patients with epilepsy are seen by general neurologists.” And the lack of awareness among these physicians and primary care practitioners drives a need for education to facilitate appropriate referrals to subspecialty centers, he said.

The stakes for timely referrals can be high. Although using appropriate outcome models improves patients’ quality of life sooner, said Dr. Husain, allowing seizures to go untreated or undertreated results in neuroplastic changes that hinder long-term seizure control.

The fact that all 32 included studies reflected a high risk of bias, and 9 studies raised high applicability concerns, raises questions regarding the models’ validity, he added. Mr. Ratcliffe and colleagues attributed both types of concerns to the fact that 20% of included studies used baseline treatment response data as outcome predictors.

Nevertheless, Dr. Husain cautioned against dismissing prediction models in newly diagnosed epilepsy. “Practicing neurologists need to realize that the perfect model has yet to be developed. But the current tools can be used to help manage patients with epilepsy and predict who will do well and not as well,” he said.

Dr. Husain is a member of the American Epilepsy Society. He has been a consultant and researcher for Marinus Pharmaceuticals, PranaQ, and UCB, and a consultant for Eisai, Jazz Pharmaceuticals, Merck, and uniQure. Study authors reported no funding sources or relevant conflicts of interest.

The most reliable predictors of remission in newly diagnosed epilepsy include patient history, seizure characteristics, and onset age, according to authors of a recent review. Clinical prediction models can help neurologists identify which patients could benefit from more aggressive early treatment, authors added, although concerns over bias and model applicability leave room for improvement.

Triggering Aggressive Treatments

“These models are helpful because if you can predict that someone is going to do well with one or two medications, that’s great,” said Aatif M. Husain, MD. “But if you know early on that someone likely will not do well, will need many medications, and still not have their seizures under control, you’re much more likely to be more aggressive with their management, such as closely refer them to a specialist epilepsy center and evaluate them for surgical treatment options. This could minimize the amount of time their seizures are inadequately controlled.” Dr. Husain is an epileptologist, neurologist, and sleep medicine specialist at Duke University Health System in Durham, North Carolina. Dr. Husain was not involved with the study, which was published in Epilepsia.

“But the other important finding is that these models so far have not been that great,” he added.

Prognosis Predictors

Investigators Corey Ratcliffe of the University of Liverpool in England and colleagues systematically searched MEDLINE and Embase for relevant publications, ultimately analyzing 48 models across 32 studies. The strongest predictors of seizure remission were history and seizure types or characteristics, the authors wrote, followed by onset age.

Regarding seizure history, a March 2018 JAMA Neurology study and a December 2013 BMC Neurology study linked factors such as history of seizures in the year pre-diagnosis, family history of epilepsy, and history of febrile seizures and of migraines with lower chances of seizure remission. Seizure types with increased chances of poor outcomes in the review included status epilepticus and seizures with complex or mixed etiologies. Additional seizure types associated with poor control include tonic-clonic seizures, frequent focal seizures, and seizures stemming from certain genetic predispositions, said Dr. Husain.

Although the roles of many of the foregoing factors are easily explained, he added, other variables’ impact is less clear. Younger onset often signals more refractory seizures, for example, while data regarding older onset are mixed. “Sometimes older individuals will have mild epilepsy due to a stroke, tumor, or something that can be relatively easily treated,” said Dr. Husain. Conversely, epilepsy can become more complicated if such patients take several medications and/or have coexisting medical problems that seizures or antiseizure medications exacerbate. “So sometimes it’s not so obvious.”
 

Incorporating Imaging, AI

Dr. Husain found it surprising that very few of the selected models incorporated EEG and MRI findings. “Subsequent research should look at those, since they are important diagnostic tests.” Moreover, he recommended including more sophisticated quantitative and connectivity analyses of EEG and MRI data. These analyses might provide additional prognostic information beyond a simple visual analysis of these tests, Dr. Husain explained, although their potential here remains unproven.

As for factors not represented in the review, he said, future studies will help clarify AI’s role in predicting newly diagnosed epilepsy outcomes. A study published in Epilepsia showed that among 248 potential pediatric surgical candidates, those whose providers received alerts based on machine learning analysis of prior visit notes were more likely to be referred for presurgical evaluation (9.8% versus 3.1%). Future clinical models will use AI to examine not only established elements of neurologic history, said Dr. Husain, but also other types of history such as socioeconomic characteristics, geographic location, and other such data.

Additionally, study authors recommended a standardized approach to prediction modeling, using Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) guidelines. Using consistent definitions, outcomes, and reporting requirements will facilitate communication among researchers, reduce bias, and support systematic between-study comparisons, Mr. Ratcliffe and colleagues wrote.
 

Reaching General Neurologists

Epilepsy specialists are generally aware of reliable outcome predictors, Dr. Husain said, though they do not use models per se. “But the vast majority of patients with epilepsy are seen by general neurologists.” And the lack of awareness among these physicians and primary care practitioners drives a need for education to facilitate appropriate referrals to subspecialty centers, he said.

The stakes for timely referrals can be high. Although using appropriate outcome models improves patients’ quality of life sooner, said Dr. Husain, allowing seizures to go untreated or undertreated results in neuroplastic changes that hinder long-term seizure control.

The fact that all 32 included studies reflected a high risk of bias, and 9 studies raised high applicability concerns, raises questions regarding the models’ validity, he added. Mr. Ratcliffe and colleagues attributed both types of concerns to the fact that 20% of included studies used baseline treatment response data as outcome predictors.

Nevertheless, Dr. Husain cautioned against dismissing prediction models in newly diagnosed epilepsy. “Practicing neurologists need to realize that the perfect model has yet to be developed. But the current tools can be used to help manage patients with epilepsy and predict who will do well and not as well,” he said.

Dr. Husain is a member of the American Epilepsy Society. He has been a consultant and researcher for Marinus Pharmaceuticals, PranaQ, and UCB, and a consultant for Eisai, Jazz Pharmaceuticals, Merck, and uniQure. Study authors reported no funding sources or relevant conflicts of interest.

The most reliable predictors of remission in newly diagnosed epilepsy include patient history, seizure characteristics, and onset age, according to authors of a recent review. Clinical prediction models can help neurologists identify which patients could benefit from more aggressive early treatment, authors added, although concerns over bias and model applicability leave room for improvement.

Triggering Aggressive Treatments

“These models are helpful because if you can predict that someone is going to do well with one or two medications, that’s great,” said Aatif M. Husain, MD. “But if you know early on that someone likely will not do well, will need many medications, and still not have their seizures under control, you’re much more likely to be more aggressive with their management, such as closely refer them to a specialist epilepsy center and evaluate them for surgical treatment options. This could minimize the amount of time their seizures are inadequately controlled.” Dr. Husain is an epileptologist, neurologist, and sleep medicine specialist at Duke University Health System in Durham, North Carolina. Dr. Husain was not involved with the study, which was published in Epilepsia.

“But the other important finding is that these models so far have not been that great,” he added.

Prognosis Predictors

Investigators Corey Ratcliffe of the University of Liverpool in England and colleagues systematically searched MEDLINE and Embase for relevant publications, ultimately analyzing 48 models across 32 studies. The strongest predictors of seizure remission were history and seizure types or characteristics, the authors wrote, followed by onset age.

Regarding seizure history, a March 2018 JAMA Neurology study and a December 2013 BMC Neurology study linked factors such as history of seizures in the year pre-diagnosis, family history of epilepsy, and history of febrile seizures and of migraines with lower chances of seizure remission. Seizure types with increased chances of poor outcomes in the review included status epilepticus and seizures with complex or mixed etiologies. Additional seizure types associated with poor control include tonic-clonic seizures, frequent focal seizures, and seizures stemming from certain genetic predispositions, said Dr. Husain.

Although the roles of many of the foregoing factors are easily explained, he added, other variables’ impact is less clear. Younger onset often signals more refractory seizures, for example, while data regarding older onset are mixed. “Sometimes older individuals will have mild epilepsy due to a stroke, tumor, or something that can be relatively easily treated,” said Dr. Husain. Conversely, epilepsy can become more complicated if such patients take several medications and/or have coexisting medical problems that seizures or antiseizure medications exacerbate. “So sometimes it’s not so obvious.”
 

Incorporating Imaging, AI

Dr. Husain found it surprising that very few of the selected models incorporated EEG and MRI findings. “Subsequent research should look at those, since they are important diagnostic tests.” Moreover, he recommended including more sophisticated quantitative and connectivity analyses of EEG and MRI data. These analyses might provide additional prognostic information beyond a simple visual analysis of these tests, Dr. Husain explained, although their potential here remains unproven.

As for factors not represented in the review, he said, future studies will help clarify AI’s role in predicting newly diagnosed epilepsy outcomes. A study published in Epilepsia showed that among 248 potential pediatric surgical candidates, those whose providers received alerts based on machine learning analysis of prior visit notes were more likely to be referred for presurgical evaluation (9.8% versus 3.1%). Future clinical models will use AI to examine not only established elements of neurologic history, said Dr. Husain, but also other types of history such as socioeconomic characteristics, geographic location, and other such data.

Additionally, study authors recommended a standardized approach to prediction modeling, using Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) guidelines. Using consistent definitions, outcomes, and reporting requirements will facilitate communication among researchers, reduce bias, and support systematic between-study comparisons, Mr. Ratcliffe and colleagues wrote.
 

Reaching General Neurologists

Epilepsy specialists are generally aware of reliable outcome predictors, Dr. Husain said, though they do not use models per se. “But the vast majority of patients with epilepsy are seen by general neurologists.” And the lack of awareness among these physicians and primary care practitioners drives a need for education to facilitate appropriate referrals to subspecialty centers, he said.

The stakes for timely referrals can be high. Although using appropriate outcome models improves patients’ quality of life sooner, said Dr. Husain, allowing seizures to go untreated or undertreated results in neuroplastic changes that hinder long-term seizure control.

The fact that all 32 included studies reflected a high risk of bias, and 9 studies raised high applicability concerns, raises questions regarding the models’ validity, he added. Mr. Ratcliffe and colleagues attributed both types of concerns to the fact that 20% of included studies used baseline treatment response data as outcome predictors.

Nevertheless, Dr. Husain cautioned against dismissing prediction models in newly diagnosed epilepsy. “Practicing neurologists need to realize that the perfect model has yet to be developed. But the current tools can be used to help manage patients with epilepsy and predict who will do well and not as well,” he said.

Dr. Husain is a member of the American Epilepsy Society. He has been a consultant and researcher for Marinus Pharmaceuticals, PranaQ, and UCB, and a consultant for Eisai, Jazz Pharmaceuticals, Merck, and uniQure. Study authors reported no funding sources or relevant conflicts of interest.

New expert guidance to help clinicians manage the treatment of patients with epilepsy during pregnancy has been released.

Issued by the American Academy of Neurology, the American Epilepsy Society, and the Society for Maternal-Fetal Medicine, the new practice guideline covers the use of antiseizure medications (ASMs) and folic acid supplementation before conception and during pregnancy.

“Most children born to people with epilepsy are healthy, but there is a small risk of pregnancy-related problems, partly due to seizures and partly due to the effects of antiseizure medications,” the guidelines’ lead author Alison M. Pack, MD, MPH, professor of neurology and chief of the Epilepsy and Sleep Division, Columbia University, New York City, said in a news release.

“This guideline provides recommendations regarding the effects of antiseizure medications and folic acid supplementation on malformations at birth and the development of children during pregnancy, so that doctors and people with epilepsy can determine which treatments may be best for them,” she added. 

The guideline was published online in Neurology.
 

Why Now? 

The new guideline updates the 2009 guidance on epilepsy management during pregnancy. Since then, Dr. Pack told this news organization, there has been a wealth of new data on differential effects of different ASMs — notably, lamotrigine and levetiracetam — the most commonly prescribed medications in this population.

“In this guideline, we were able to assess differential effects of different ASMs on outcomes of interest, including major congenital malformations [MCMs], perinatal outcomes, and neurodevelopmental outcomes. In addition, we looked at the effect of folic acid supplementation on each of these outcomes,” she said.

The overarching goals of care for patients are to “optimize health outcomes both for individuals and their future offspring,” the authors wrote. Shared decision-making, they add, leads to better decision-making by providing a better understanding of the available treatment options and their potential risks, resulting in enhanced decision-making that aligns with personal values.

Clinicians should recommend ASMs that optimize seizure control and fetal outcomes, in the event of a pregnancy, at the earliest possible preconception time, the guideline authors note.

“Overall, treating clinicians need to balance treating the person with epilepsy to control convulsive seizures (generalized tonic-clonic seizures and focal-to-bilateral tonic-clonic seizures) to minimize potential risks to the birth parent and the possible risks of certain ASMs on the fetus if pregnancy occurs,” they wrote.

If a patient is already pregnant, the experts recommend that clinicians “exercise caution” in removing or replacing an ASM that controls convulsive seizures, even if it’s “not an optimal choice” for the fetus. 

In addition, they advise that ASM levels should be monitored throughout the pregnancy, guided by individual ASM pharmacokinetics and an individual patient’s clinical presentation. ASM dose, they note, should be adjusted during pregnancy in response to decreasing serum ASM levels or worsening seizure control.

The authors point out that there are limited data on “pregnancy-related outcomes with respect to acetazolamide, eslicarbazepine, ethosuximide, lacosamide, nitrazepam, perampanel, piracetam, pregabalin, rufinamide, stiripentol, tiagabine, and vigabatrin.”

Patients should be informed that the birth prevalence of any major congenital malformation in the general population ranges between 2.4% and 2.9%.
 

If Feasible, Avoid Valproic Acid 

“One of the most important take-home messages is that valproic acid has the highest unadjusted birth prevalence of all major congenital malformations — 9.7% — and the highest unadjusted birth prevalence of neural tube defects at 1.4%,” Dr. Pack said. As a result, the guideline authors advise against using valproic acid, if clinically feasible.

Valproic acid also has the highest prevalence of negative neurodevelopmental outcomes, including a reduction in global IQ and an increased prevalence of autism spectrum disorder (ASD). Patients should be counseled accordingly and advised of the increased risk for ASD and decreased IQ resulting from valproic acid.

Clinicians should consider using lamotrigine, levetiracetam, or oxcarbazepine when appropriate. Serum concentrations of most ASMs have a “defined therapeutic window” for effective seizure control and that concentration may decrease during pregnancy, particularly with lamotrigine and levetiracetam, the authors note.

Phenobarbital, topiramate, and valproic acid should because of the increased risk for cardiac malformations, oral clefts, and urogenital and renal malformations.

Fetal screening for major congenital malformations is recommended to enable early detection and timely intervention in patients treated with any ASM during pregnancy Patients receiving phenobarbital during pregnancy should also undergo fetal cardiac screenings.

Valproic acid and topiramate are also associated with children who are small for their gestational age. To enable early identification of fetal growth restriction, patients taking valproic acid or topiramate should be monitored. In addition, children exposed to these medications in utero should be monitored during childhood to ensure they are meeting age-appropriate developmental milestones. 

Folic acid taken during pregnancy can reduce the prevalence of negative neurodevelopment outcomes, but not major congenital malformations, Dr. Pack noted. 

“Due to limited available data, we were unable to define an optimal dose of folic acid supplementation beyond at least 0.4 mg/d,” Dr. Pack said. “Future studies, preferably randomized clinical trials, are needed to better define the optimal dose.”

She emphasized that epilepsy is one of the most common neurologic disorders, and 1 in 5 of those affected are people of childbearing potential. Understanding the effects of ASMs on pregnancy outcomes is critical for physicians who manage these patients.
 

Uncertainty Remains 

Commenting for this news organization, Kimford Meador, MD, a professor in the Department of Neurology and Neurological Sciences at Stanford University School of Medicine , Stanford Neuroscience Health Center, Palo Alto, California, noted that the new guidelines reflect the gains in knowledge since 2009 and that the recommendations are “reasonable, based on available data.”

However, “one very important point is how much remains unknown,” said Dr. Meador, who was not involved in writing the current guideline. “Many ASMs have no data, and several have estimates based on small samples or a single observational study.” Thus, “the risks for the majority of ASMs are uncertain.”

Given that randomized trials “are not possible in this population, and that all observational studies are subject to residual confounding, a reliable signal across multiple studies in humans is required to be certain of findings,” he stated.

This practice guideline was developed with financial support from the American Academy of Neurology. Dr. Pack serves on the editorial board for the journal Epilepsy Currents, receives royalties from UpToDate, receives funding from the National Institutes of Health for serving as coinvestigator and site principal investigator for the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study, and receives funding from Bayer for serving as a co-investigator on a study on women with epilepsy initiating a progestin intrauterine device. One of Dr. Pack’s immediate family members has received personal compensation for serving as an employee of REGENEXBIO. The other authors’ disclosures are listed on the original paper. Dr. Meador has received research support from the National Institutes of Health, Veterans Administration, Eisai, Inc, and Suno Medtronic Navigation, Inc, and the Epilepsy Study Consortium pays Dr. Meador’s university for his research on the Human Epilepsy Project and consultant time related to Eisai, UCB Pharma, and Xenon.

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

New expert guidance to help clinicians manage the treatment of patients with epilepsy during pregnancy has been released.

Issued by the American Academy of Neurology, the American Epilepsy Society, and the Society for Maternal-Fetal Medicine, the new practice guideline covers the use of antiseizure medications (ASMs) and folic acid supplementation before conception and during pregnancy.

“Most children born to people with epilepsy are healthy, but there is a small risk of pregnancy-related problems, partly due to seizures and partly due to the effects of antiseizure medications,” the guidelines’ lead author Alison M. Pack, MD, MPH, professor of neurology and chief of the Epilepsy and Sleep Division, Columbia University, New York City, said in a news release.

“This guideline provides recommendations regarding the effects of antiseizure medications and folic acid supplementation on malformations at birth and the development of children during pregnancy, so that doctors and people with epilepsy can determine which treatments may be best for them,” she added. 

The guideline was published online in Neurology.
 

Why Now? 

The new guideline updates the 2009 guidance on epilepsy management during pregnancy. Since then, Dr. Pack told this news organization, there has been a wealth of new data on differential effects of different ASMs — notably, lamotrigine and levetiracetam — the most commonly prescribed medications in this population.

“In this guideline, we were able to assess differential effects of different ASMs on outcomes of interest, including major congenital malformations [MCMs], perinatal outcomes, and neurodevelopmental outcomes. In addition, we looked at the effect of folic acid supplementation on each of these outcomes,” she said.

The overarching goals of care for patients are to “optimize health outcomes both for individuals and their future offspring,” the authors wrote. Shared decision-making, they add, leads to better decision-making by providing a better understanding of the available treatment options and their potential risks, resulting in enhanced decision-making that aligns with personal values.

Clinicians should recommend ASMs that optimize seizure control and fetal outcomes, in the event of a pregnancy, at the earliest possible preconception time, the guideline authors note.

“Overall, treating clinicians need to balance treating the person with epilepsy to control convulsive seizures (generalized tonic-clonic seizures and focal-to-bilateral tonic-clonic seizures) to minimize potential risks to the birth parent and the possible risks of certain ASMs on the fetus if pregnancy occurs,” they wrote.

If a patient is already pregnant, the experts recommend that clinicians “exercise caution” in removing or replacing an ASM that controls convulsive seizures, even if it’s “not an optimal choice” for the fetus. 

In addition, they advise that ASM levels should be monitored throughout the pregnancy, guided by individual ASM pharmacokinetics and an individual patient’s clinical presentation. ASM dose, they note, should be adjusted during pregnancy in response to decreasing serum ASM levels or worsening seizure control.

The authors point out that there are limited data on “pregnancy-related outcomes with respect to acetazolamide, eslicarbazepine, ethosuximide, lacosamide, nitrazepam, perampanel, piracetam, pregabalin, rufinamide, stiripentol, tiagabine, and vigabatrin.”

Patients should be informed that the birth prevalence of any major congenital malformation in the general population ranges between 2.4% and 2.9%.
 

If Feasible, Avoid Valproic Acid 

“One of the most important take-home messages is that valproic acid has the highest unadjusted birth prevalence of all major congenital malformations — 9.7% — and the highest unadjusted birth prevalence of neural tube defects at 1.4%,” Dr. Pack said. As a result, the guideline authors advise against using valproic acid, if clinically feasible.

Valproic acid also has the highest prevalence of negative neurodevelopmental outcomes, including a reduction in global IQ and an increased prevalence of autism spectrum disorder (ASD). Patients should be counseled accordingly and advised of the increased risk for ASD and decreased IQ resulting from valproic acid.

Clinicians should consider using lamotrigine, levetiracetam, or oxcarbazepine when appropriate. Serum concentrations of most ASMs have a “defined therapeutic window” for effective seizure control and that concentration may decrease during pregnancy, particularly with lamotrigine and levetiracetam, the authors note.

Phenobarbital, topiramate, and valproic acid should because of the increased risk for cardiac malformations, oral clefts, and urogenital and renal malformations.

Fetal screening for major congenital malformations is recommended to enable early detection and timely intervention in patients treated with any ASM during pregnancy Patients receiving phenobarbital during pregnancy should also undergo fetal cardiac screenings.

Valproic acid and topiramate are also associated with children who are small for their gestational age. To enable early identification of fetal growth restriction, patients taking valproic acid or topiramate should be monitored. In addition, children exposed to these medications in utero should be monitored during childhood to ensure they are meeting age-appropriate developmental milestones. 

Folic acid taken during pregnancy can reduce the prevalence of negative neurodevelopment outcomes, but not major congenital malformations, Dr. Pack noted. 

“Due to limited available data, we were unable to define an optimal dose of folic acid supplementation beyond at least 0.4 mg/d,” Dr. Pack said. “Future studies, preferably randomized clinical trials, are needed to better define the optimal dose.”

She emphasized that epilepsy is one of the most common neurologic disorders, and 1 in 5 of those affected are people of childbearing potential. Understanding the effects of ASMs on pregnancy outcomes is critical for physicians who manage these patients.
 

Uncertainty Remains 

Commenting for this news organization, Kimford Meador, MD, a professor in the Department of Neurology and Neurological Sciences at Stanford University School of Medicine , Stanford Neuroscience Health Center, Palo Alto, California, noted that the new guidelines reflect the gains in knowledge since 2009 and that the recommendations are “reasonable, based on available data.”

However, “one very important point is how much remains unknown,” said Dr. Meador, who was not involved in writing the current guideline. “Many ASMs have no data, and several have estimates based on small samples or a single observational study.” Thus, “the risks for the majority of ASMs are uncertain.”

Given that randomized trials “are not possible in this population, and that all observational studies are subject to residual confounding, a reliable signal across multiple studies in humans is required to be certain of findings,” he stated.

This practice guideline was developed with financial support from the American Academy of Neurology. Dr. Pack serves on the editorial board for the journal Epilepsy Currents, receives royalties from UpToDate, receives funding from the National Institutes of Health for serving as coinvestigator and site principal investigator for the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study, and receives funding from Bayer for serving as a co-investigator on a study on women with epilepsy initiating a progestin intrauterine device. One of Dr. Pack’s immediate family members has received personal compensation for serving as an employee of REGENEXBIO. The other authors’ disclosures are listed on the original paper. Dr. Meador has received research support from the National Institutes of Health, Veterans Administration, Eisai, Inc, and Suno Medtronic Navigation, Inc, and the Epilepsy Study Consortium pays Dr. Meador’s university for his research on the Human Epilepsy Project and consultant time related to Eisai, UCB Pharma, and Xenon.

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

New expert guidance to help clinicians manage the treatment of patients with epilepsy during pregnancy has been released.

Issued by the American Academy of Neurology, the American Epilepsy Society, and the Society for Maternal-Fetal Medicine, the new practice guideline covers the use of antiseizure medications (ASMs) and folic acid supplementation before conception and during pregnancy.

“Most children born to people with epilepsy are healthy, but there is a small risk of pregnancy-related problems, partly due to seizures and partly due to the effects of antiseizure medications,” the guidelines’ lead author Alison M. Pack, MD, MPH, professor of neurology and chief of the Epilepsy and Sleep Division, Columbia University, New York City, said in a news release.

“This guideline provides recommendations regarding the effects of antiseizure medications and folic acid supplementation on malformations at birth and the development of children during pregnancy, so that doctors and people with epilepsy can determine which treatments may be best for them,” she added. 

The guideline was published online in Neurology.
 

Why Now? 

The new guideline updates the 2009 guidance on epilepsy management during pregnancy. Since then, Dr. Pack told this news organization, there has been a wealth of new data on differential effects of different ASMs — notably, lamotrigine and levetiracetam — the most commonly prescribed medications in this population.

“In this guideline, we were able to assess differential effects of different ASMs on outcomes of interest, including major congenital malformations [MCMs], perinatal outcomes, and neurodevelopmental outcomes. In addition, we looked at the effect of folic acid supplementation on each of these outcomes,” she said.

The overarching goals of care for patients are to “optimize health outcomes both for individuals and their future offspring,” the authors wrote. Shared decision-making, they add, leads to better decision-making by providing a better understanding of the available treatment options and their potential risks, resulting in enhanced decision-making that aligns with personal values.

Clinicians should recommend ASMs that optimize seizure control and fetal outcomes, in the event of a pregnancy, at the earliest possible preconception time, the guideline authors note.

“Overall, treating clinicians need to balance treating the person with epilepsy to control convulsive seizures (generalized tonic-clonic seizures and focal-to-bilateral tonic-clonic seizures) to minimize potential risks to the birth parent and the possible risks of certain ASMs on the fetus if pregnancy occurs,” they wrote.

If a patient is already pregnant, the experts recommend that clinicians “exercise caution” in removing or replacing an ASM that controls convulsive seizures, even if it’s “not an optimal choice” for the fetus. 

In addition, they advise that ASM levels should be monitored throughout the pregnancy, guided by individual ASM pharmacokinetics and an individual patient’s clinical presentation. ASM dose, they note, should be adjusted during pregnancy in response to decreasing serum ASM levels or worsening seizure control.

The authors point out that there are limited data on “pregnancy-related outcomes with respect to acetazolamide, eslicarbazepine, ethosuximide, lacosamide, nitrazepam, perampanel, piracetam, pregabalin, rufinamide, stiripentol, tiagabine, and vigabatrin.”

Patients should be informed that the birth prevalence of any major congenital malformation in the general population ranges between 2.4% and 2.9%.
 

If Feasible, Avoid Valproic Acid 

“One of the most important take-home messages is that valproic acid has the highest unadjusted birth prevalence of all major congenital malformations — 9.7% — and the highest unadjusted birth prevalence of neural tube defects at 1.4%,” Dr. Pack said. As a result, the guideline authors advise against using valproic acid, if clinically feasible.

Valproic acid also has the highest prevalence of negative neurodevelopmental outcomes, including a reduction in global IQ and an increased prevalence of autism spectrum disorder (ASD). Patients should be counseled accordingly and advised of the increased risk for ASD and decreased IQ resulting from valproic acid.

Clinicians should consider using lamotrigine, levetiracetam, or oxcarbazepine when appropriate. Serum concentrations of most ASMs have a “defined therapeutic window” for effective seizure control and that concentration may decrease during pregnancy, particularly with lamotrigine and levetiracetam, the authors note.

Phenobarbital, topiramate, and valproic acid should because of the increased risk for cardiac malformations, oral clefts, and urogenital and renal malformations.

Fetal screening for major congenital malformations is recommended to enable early detection and timely intervention in patients treated with any ASM during pregnancy Patients receiving phenobarbital during pregnancy should also undergo fetal cardiac screenings.

Valproic acid and topiramate are also associated with children who are small for their gestational age. To enable early identification of fetal growth restriction, patients taking valproic acid or topiramate should be monitored. In addition, children exposed to these medications in utero should be monitored during childhood to ensure they are meeting age-appropriate developmental milestones. 

Folic acid taken during pregnancy can reduce the prevalence of negative neurodevelopment outcomes, but not major congenital malformations, Dr. Pack noted. 

“Due to limited available data, we were unable to define an optimal dose of folic acid supplementation beyond at least 0.4 mg/d,” Dr. Pack said. “Future studies, preferably randomized clinical trials, are needed to better define the optimal dose.”

She emphasized that epilepsy is one of the most common neurologic disorders, and 1 in 5 of those affected are people of childbearing potential. Understanding the effects of ASMs on pregnancy outcomes is critical for physicians who manage these patients.
 

Uncertainty Remains 

Commenting for this news organization, Kimford Meador, MD, a professor in the Department of Neurology and Neurological Sciences at Stanford University School of Medicine , Stanford Neuroscience Health Center, Palo Alto, California, noted that the new guidelines reflect the gains in knowledge since 2009 and that the recommendations are “reasonable, based on available data.”

However, “one very important point is how much remains unknown,” said Dr. Meador, who was not involved in writing the current guideline. “Many ASMs have no data, and several have estimates based on small samples or a single observational study.” Thus, “the risks for the majority of ASMs are uncertain.”

Given that randomized trials “are not possible in this population, and that all observational studies are subject to residual confounding, a reliable signal across multiple studies in humans is required to be certain of findings,” he stated.

This practice guideline was developed with financial support from the American Academy of Neurology. Dr. Pack serves on the editorial board for the journal Epilepsy Currents, receives royalties from UpToDate, receives funding from the National Institutes of Health for serving as coinvestigator and site principal investigator for the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study, and receives funding from Bayer for serving as a co-investigator on a study on women with epilepsy initiating a progestin intrauterine device. One of Dr. Pack’s immediate family members has received personal compensation for serving as an employee of REGENEXBIO. The other authors’ disclosures are listed on the original paper. Dr. Meador has received research support from the National Institutes of Health, Veterans Administration, Eisai, Inc, and Suno Medtronic Navigation, Inc, and the Epilepsy Study Consortium pays Dr. Meador’s university for his research on the Human Epilepsy Project and consultant time related to Eisai, UCB Pharma, and Xenon.

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