A tragic series of events led to a fatal case of transplant-related rabies earlier this year.
Health officials announced Thursday that an organ recipient who underwent transplant surgery in Ohio died of rabies in February. Further investigation revealed that the donor had become infected with the fatal virus after saving a kitten from a skunk.
The unnamed patient, from Michigan, received the donor’s kidney in December 2024, and later developed severe symptoms that prompted hospitalization and "invasive" procedures, the Centers for Disease Control and Prevention (CDC) said.
He reportedly experienced fever, tremors, difficulty swallowing and fear of water and died 51 days after the transplant.
The CDC said the donor, whose donated tissue went to three other recipients, was infected with the silver-haired bat variant of rabies, suggesting the skunk had been infected by a bat.
Records revealed that the organ donor, from Idaho, was scratched on the shin while fending off a skunk that displayed "predatory aggression" six weeks before his death.
"In late October 2024, a skunk approached the donor as he held a kitten in an outbuilding on his rural property," the CDC said. "During an encounter that rendered the skunk unconscious, the donor sustained a shin scratch that bled, but he did not think he had been bitten. According to the family, the donor attributed the skunk’s behavior to predatory aggression toward the kitten."
In the following five weeks, the donor began experiencing hallucinations, trouble swallowing, difficulty walking and a stiff neck, the agency said.
Two days later, he was discovered unresponsive at home after a suspected heart attack, according to health officials. He was reportedly revived at a hospital but was declared brain-dead and removed from life support.
The CDC said his organs were donated after the family documented the skunk encounter in a donor risk assessment. However, health officials noted that the form did not screen for rabies, citing its "rarity in humans."
"In the United States, potential donors’ family members often provide information about a donor’s infectious disease risk factors, including animal exposures," the CDC said. "Rabies is excluded from routine donor pathogen testing because of its rarity in humans in the United States and the complexity of diagnostic testing. In this case, hospital staff members who treated the donor were initially unaware of the skunk scratch and attributed his pre-admission signs and symptoms to chronic comorbidities."
Health officials added that three other patients received corneal tissue from the same infected donor. They all underwent graft removal, received rabies treatment and remained asymptomatic, the CDC reported.
Health officials also reached out to 370 people who could have been in contact with the donor, according to the agency. Forty-six of them were recommended to undergo rabies procedures.
Health officials said the kidney recipient’s death marks the fourth documented case of rabies transmission through an organ transplant in the U.S. since 1978, emphasizing that the risk of such infections remains extremely low.
Transplant teams are now advised to consult public health officials if a potential donor has recent bites or scratches from rabies-susceptible animals, especially if the donor has had unexplained neurological symptoms.
However, "no standard guidance currently exists for addressing reported donor animal exposures by transplant teams," the CDC said.
About 1.4 million Americans receive care for possible rabies exposure annually, and fewer than 10 die from the disease due to effective prevention efforts, according to the agency.
Bonny Chu
https://www.foxnews.com/health/michigan-man-dies-rabies-after-receiving-kidney-from-infected-donor-who-saved-kitten-from-skunk-cdc
A Michigan resident has died of rabies after receiving an organ transplant.
The patient, who received the transplant at an Ohio hospital in December 2024, died of the fatal virus in January 2025, a spokesperson for the Michigan Department of Health and Human Services (MDHHS) confirmed to Fox News Digital.
"The person was a recent organ transplant recipient, and a public health investigation determined they contracted rabies through the transplanted organ," the spokesperson said.
The rabies confirmation was made by the CDC Rabies Laboratory.
The Michigan Department of Health and Human Services has worked closely with the Ohio Department of Health and the Centers for Disease Control and Prevention (CDC) on the investigation, the same source stated.
"Health officials worked together to ensure that people, including healthcare providers, who were in contact with the Michigan individual were assessed for possible exposure to rabies," the MDHHS stated. "Post-exposure preventive care, if appropriate, has been provided."
"There is no threat to the general public."
The organ donor was not a Michigan or Ohio resident, according to health officials. No additional information has been provided about the resident or the donor.
While organs are routinely screened for infectious diseases, cancers, quality and functionality prior to transplant, rabies testing is not typically performed.
"There is currently no country or institution that requires the screening of rabies among donors before organ transplantation surgery," according to information published by the National Institutes of Health.
In 2013, the CDC confirmed the death of four people in Maryland who contracted rabies after receiving organs from the same donor.
In 2004, the agency reported the rabies deaths of three people who received organs from a common infected donor.
What to know about rabies
Rabies is a deadly viral disease that is mainly transmitted to people and pets through bites or scratches from an infected animal, according to the CDC.
The virus affects the central nervous system, ultimately causing brain dysfunction. The infected person may experience anxiety, confusion, agitation and hallucinations, per the health agency.
Rabies is almost always fatal if the infected person does not receive medical attention before symptoms begin.
Around 60,000 people in the U.S. receive medical care after being exposed to rabies, the CDC stated.
Fewer than 10 deaths are reported in the country each year.
Most Americans who contract rabies are infected by bats.
Other animals that commonly carry rabies include raccoons, skunks and foxes.
Melissa Rudy
https://www.foxnews.com/health/patient-dies-rabies-organ-transplant-infected-donor
Tuesday, December 9, 2025
Features affecting treatment decisions and outcome in refractory status epilepticus
Damien C, Torcida Sedano N, Depondt C, Legros B, Gaspard N. Features affecting treatment decisions and outcome in refractory status epilepticus. Epilepsia. 2025 Aug;66(8):2779-2789. doi: 10.1111/epi.18423. Epub 2025 Apr 22. PMID: 40261726.
Abstract
Objective: Refractory status epilepticus (RSE) is associated with worse outcomes than responsive established status epilepticus (SE). Guidelines recommend that refractory convulsive SE should be treated with continuous intravenous anesthetic drugs (CIVADs). Many cases of nonconvulsive SE are not treated with CIVADs, and the use of anesthesia might be associated with increased mortality. The factors leading to the decision to use anesthesia and how these might affect outcome are still largely unknown. Our goal was to identify features of refractory SE associated with treatment choices and outcome. Methods: A single-center, retrospective study was conducted of all consecutive patients with RSE admitted to a tertiary center between January 2015 and December 2020. We collected demographic and clinical variables at SE onset and at time of third-line treatment, including ictal burden during the hour preceding the administration of the third-line treatment. The primary outcome measure was the decision to use CIVADs as third-line treatment. Secondary outcome measures were in-hospital mortality and functional outcome at discharge. Results: One hundred sixty-one RSE episodes were included. Of these, 29 (18%) received CIVADs as third-line treatment and 61 (38%) died. The type of third-line treatment was not associated with mortality. CIVADs were more likely to be used with higher ictal burden, fewer comorbidities, a lower Glasgow Coma Scale (GCS) score at time of third-line administration, and in the absence of history of epilepsy (odds ratio [OR] = 1.03, 0.76, .66, and .25, respectively). Multivariable analyses also identified comorbidities, an acute etiology, and lower GCS score at time of third-line administration as risk factors of mortality (OR = 1.43, .09, .28, and .80, respectively). Ictal burden was not associated with outcome. Significance: Ictal burden, semiology, and consciousness at time of third-line treatment are associated with the decision to use CIVADs in SE. Semiology and consciousness at time of third-line treatment are also associated with mortality.
Cervenka MC. The Refractory Status Epilepticus (RSE) is out of the Barn… the Current State of Refractory Status Epilepticus Management and Outcomes. Epilepsy Currents. 2025;0(0). doi:10.1177/15357597251406105
Commentary
Refractory status epilepticus (RSE), defined as status epilepticus that continues despite adequate doses of one first-line benzodiazepine and one appropriate second-line antiseizure medication, has a high risk of morbidity and mortality. Approaches vary between treating healthcare providers with regard to electroencephalogram (EEG) interpretation, threshold for, and comfort with starting sedating anesthetic medications to treat RSE.
Damien et al examined a retrospective review of a prospective database of 161 adults treated for RSE at Erasme Hospital from 2015 through 2020 to assess management strategies and clinical outcomes. They applied EEG and clinical criteria to quantify ictal burden, used the Charlson comorbidity index to measure comorbidity burden, and the Glasgow Coma Scale score to assess change in neurologic function over time. Status Epilepticus Severity Score (STESS), which includes a composite of level of consciousness, seizure type, age, and seizure history at the onset of status epilepticus, was also used to predict functional outcomes.
The authors found that intravenous anesthetic agents were used third-line in only 29 (18%) of patients, and the mortality rate was 38% overall. Patients with higher comorbidity burden, worse neurologic function at the time of RSE, acute onset, and no prior history of epilepsy were more likely to be treated with anesthetics as a third-line therapy. Nonconvulsive (NC) status epilepticus at onset, higher comorbidity burden, and absence of consciousness (lower modified Rankin scale score) at initiation of an intravenous anesthetic were all associated with poor outcome. Higher STESS was also associated with poor outcome, which helps validate the use of this tool for outcome prediction. Surprisingly, ictal burden at anesthesia initiation and progression to super-RSE (RSE that persists for 24 h or more despite aggressive management or returns after attempting to wean anesthetic agents) were not associated with worse outcome. In addition, when reviewing EEG findings prior to anesthesia initiation, 30% of patients treated did not meet the applied criteria for RSE in the 1 h prior to initiation.
The authors illustrated important study limitations, most notably its retrospective nature. This is particularly true when considering the latter finding that 30% of EEGs did not meet the criteria for RSE before anesthesia initiation. In a real-world scenario, the decision to start anesthetic agents may take place several hours before the initial dose is started, and therefore, evaluating based on only the 1 h immediately preceding initiation may not reflect the EEG findings at the time this decision was reached. Expert EEG interpretation has also been found to be highly subjective, with poor inter- and, at times, intra-rater reliability as well. These observations highlight the dynamic nature of the disease process and difficulty in determining the best time to escalate treatment. The finding that NC RSE was associated with worse outcome supports the need for rapid initiation of long-term, continuously monitored video EEG in order to immediately diagnose and treat this condition, and if unavailable, to immediately transfer a patient to a facility with these capabilities. Intermittent EEG monitoring could delay NC RSE discovery, appropriate treatment escalation, and result in worse outcomes and death.
A subset of patients in the study were conscious when anesthesia was administered, which is a challenging circumstance that healthcare providers, patients, and families can have a difficult time trying to navigate. For example, an asymptomatic patient with EEG findings meeting criteria for electrographic status epilepticus or a patient with epilepsia partialis continua (continuous electroclinical motor seizures with maintained consciousness) may be resistant to consider aggressive therapy. In these cases, the decision regarding whether or not individuals are started on anesthesia can be highly dependent upon the etiology, patient and family preferences, as well as the comfort and experience of the treating team with managing this condition. The optimal approach is unknown, and the study findings in this population may not be easily generalizable to other medical centers.
There are several notable limitations with regard to the study population described. The database from which patients were selected included nearly one year during the COVID-19 pandemic, a time which resulted in healthcare avoidance among patients, a reduction in healthcare resources, increased psychosocial stress, and higher non-COVID death rates overall. It would be interesting to investigate whether this impacted disease severity and comorbidities in patients with RSE, clinical practice in RSE management, and overall outcomes compared to the 5-year interval prior. Finally, individuals with post-anoxic RSE were excluded from the investigation. Studies have previously shown that there is a higher rate of morbidity and mortality in this patient population. However, outcomes may improve with aggressive management and therefore, inclusion of these patients in future studies is warranted.
Overall, the findings of this study support the need for robust long-term EEG monitoring resources to diagnose and treat RSE. The study provides an excellent road map for investigators designing clinical trials to treat RSE when making power calculations based on anticipated outcomes and identifying potential outcome measures to utilize. Innovative and evidence-based treatment strategies are needed to ultimately lead to reductions in morbidity and mortality based on the type and etiology of RSE, as well as patient comorbidities, tailored to the individual and circumstance.
Abstract
Objective: Refractory status epilepticus (RSE) is associated with worse outcomes than responsive established status epilepticus (SE). Guidelines recommend that refractory convulsive SE should be treated with continuous intravenous anesthetic drugs (CIVADs). Many cases of nonconvulsive SE are not treated with CIVADs, and the use of anesthesia might be associated with increased mortality. The factors leading to the decision to use anesthesia and how these might affect outcome are still largely unknown. Our goal was to identify features of refractory SE associated with treatment choices and outcome. Methods: A single-center, retrospective study was conducted of all consecutive patients with RSE admitted to a tertiary center between January 2015 and December 2020. We collected demographic and clinical variables at SE onset and at time of third-line treatment, including ictal burden during the hour preceding the administration of the third-line treatment. The primary outcome measure was the decision to use CIVADs as third-line treatment. Secondary outcome measures were in-hospital mortality and functional outcome at discharge. Results: One hundred sixty-one RSE episodes were included. Of these, 29 (18%) received CIVADs as third-line treatment and 61 (38%) died. The type of third-line treatment was not associated with mortality. CIVADs were more likely to be used with higher ictal burden, fewer comorbidities, a lower Glasgow Coma Scale (GCS) score at time of third-line administration, and in the absence of history of epilepsy (odds ratio [OR] = 1.03, 0.76, .66, and .25, respectively). Multivariable analyses also identified comorbidities, an acute etiology, and lower GCS score at time of third-line administration as risk factors of mortality (OR = 1.43, .09, .28, and .80, respectively). Ictal burden was not associated with outcome. Significance: Ictal burden, semiology, and consciousness at time of third-line treatment are associated with the decision to use CIVADs in SE. Semiology and consciousness at time of third-line treatment are also associated with mortality.
Cervenka MC. The Refractory Status Epilepticus (RSE) is out of the Barn… the Current State of Refractory Status Epilepticus Management and Outcomes. Epilepsy Currents. 2025;0(0). doi:10.1177/15357597251406105
Commentary
Refractory status epilepticus (RSE), defined as status epilepticus that continues despite adequate doses of one first-line benzodiazepine and one appropriate second-line antiseizure medication, has a high risk of morbidity and mortality. Approaches vary between treating healthcare providers with regard to electroencephalogram (EEG) interpretation, threshold for, and comfort with starting sedating anesthetic medications to treat RSE.
Damien et al examined a retrospective review of a prospective database of 161 adults treated for RSE at Erasme Hospital from 2015 through 2020 to assess management strategies and clinical outcomes. They applied EEG and clinical criteria to quantify ictal burden, used the Charlson comorbidity index to measure comorbidity burden, and the Glasgow Coma Scale score to assess change in neurologic function over time. Status Epilepticus Severity Score (STESS), which includes a composite of level of consciousness, seizure type, age, and seizure history at the onset of status epilepticus, was also used to predict functional outcomes.
The authors found that intravenous anesthetic agents were used third-line in only 29 (18%) of patients, and the mortality rate was 38% overall. Patients with higher comorbidity burden, worse neurologic function at the time of RSE, acute onset, and no prior history of epilepsy were more likely to be treated with anesthetics as a third-line therapy. Nonconvulsive (NC) status epilepticus at onset, higher comorbidity burden, and absence of consciousness (lower modified Rankin scale score) at initiation of an intravenous anesthetic were all associated with poor outcome. Higher STESS was also associated with poor outcome, which helps validate the use of this tool for outcome prediction. Surprisingly, ictal burden at anesthesia initiation and progression to super-RSE (RSE that persists for 24 h or more despite aggressive management or returns after attempting to wean anesthetic agents) were not associated with worse outcome. In addition, when reviewing EEG findings prior to anesthesia initiation, 30% of patients treated did not meet the applied criteria for RSE in the 1 h prior to initiation.
The authors illustrated important study limitations, most notably its retrospective nature. This is particularly true when considering the latter finding that 30% of EEGs did not meet the criteria for RSE before anesthesia initiation. In a real-world scenario, the decision to start anesthetic agents may take place several hours before the initial dose is started, and therefore, evaluating based on only the 1 h immediately preceding initiation may not reflect the EEG findings at the time this decision was reached. Expert EEG interpretation has also been found to be highly subjective, with poor inter- and, at times, intra-rater reliability as well. These observations highlight the dynamic nature of the disease process and difficulty in determining the best time to escalate treatment. The finding that NC RSE was associated with worse outcome supports the need for rapid initiation of long-term, continuously monitored video EEG in order to immediately diagnose and treat this condition, and if unavailable, to immediately transfer a patient to a facility with these capabilities. Intermittent EEG monitoring could delay NC RSE discovery, appropriate treatment escalation, and result in worse outcomes and death.
A subset of patients in the study were conscious when anesthesia was administered, which is a challenging circumstance that healthcare providers, patients, and families can have a difficult time trying to navigate. For example, an asymptomatic patient with EEG findings meeting criteria for electrographic status epilepticus or a patient with epilepsia partialis continua (continuous electroclinical motor seizures with maintained consciousness) may be resistant to consider aggressive therapy. In these cases, the decision regarding whether or not individuals are started on anesthesia can be highly dependent upon the etiology, patient and family preferences, as well as the comfort and experience of the treating team with managing this condition. The optimal approach is unknown, and the study findings in this population may not be easily generalizable to other medical centers.
There are several notable limitations with regard to the study population described. The database from which patients were selected included nearly one year during the COVID-19 pandemic, a time which resulted in healthcare avoidance among patients, a reduction in healthcare resources, increased psychosocial stress, and higher non-COVID death rates overall. It would be interesting to investigate whether this impacted disease severity and comorbidities in patients with RSE, clinical practice in RSE management, and overall outcomes compared to the 5-year interval prior. Finally, individuals with post-anoxic RSE were excluded from the investigation. Studies have previously shown that there is a higher rate of morbidity and mortality in this patient population. However, outcomes may improve with aggressive management and therefore, inclusion of these patients in future studies is warranted.
Overall, the findings of this study support the need for robust long-term EEG monitoring resources to diagnose and treat RSE. The study provides an excellent road map for investigators designing clinical trials to treat RSE when making power calculations based on anticipated outcomes and identifying potential outcome measures to utilize. Innovative and evidence-based treatment strategies are needed to ultimately lead to reductions in morbidity and mortality based on the type and etiology of RSE, as well as patient comorbidities, tailored to the individual and circumstance.
Identifying the roles of decision-making and parental anxiety on medication adherence in pediatric epilepsy
Pathways Linking Parental Social Support and Decision-Making Participation to Medication Adherence in Children With Epilepsy: The Moderating Role of Parental Anxiety. Yang C, Huang R, Tao Q, Hao Z, Zhao L, Zhang L. Depress Anxiety. 2025 Sep 16;2025:7159579. doi: 10.1155/da/7159579. PMID: 40995429; PMCID: PMC12457068.
Abstract
Background: Medication adherence among pediatric epilepsy patients is frequently suboptimal, and the complex interplay between parental social support, decision-making participation, treatment satisfaction, and parental anxiety in influencing medication adherence remains underexplored. This study investigates both the direct and indirect pathways linking these factors to medication adherence and examines the mediating role of treatment satisfaction and the moderating role of parental anxiety. Methods: A cross-sectional study was conducted at three medical institutions between January 2020 and June 2024. Data on patient demographics and standardized scales measuring medication adherence, social support, communication and decision-making participation, treatment satisfaction, and parental anxiety were collected. Relationships among these variables were analyzed using structural equation modeling (SEM) and moderation analysis. Results: A total of 1056 patients were included in the study, with a mean age of 8.86 ± 3.99 years; 51.7% were male. Path analysis showed that parental social support (STD = 0.344, p < 0.001), communication and decision-making participation (STD = 0.392, p < 0.001), and treatment satisfaction (STD = 0.090, p < 0.05) had significant positive effects on medication adherence. Parental social support (STD = 0.483, p < 0.001) and communication and decision-making participation (STD = 0.203, p < 0.001) also strongly influenced treatment satisfaction. The indirect effects of social support and decision-making participation on medication adherence, mediated through treatment satisfaction, were statistically significant (p < 0.05). Parental anxiety, as a moderating factor, weakened the positive effects of social support, decision-making participation, and treatment satisfaction on medication adherence (p < 0.05). Conclusion: This study systematically develops an integrated model linking parental social support, communication and decision-making participation, treatment satisfaction, and anxiety to medication adherence in pediatric epilepsy. It highlights the mediating role of treatment satisfaction and the moderating role of parental anxiety. Enhancing parental social support and communication, improving treatment satisfaction, and addressing parental anxiety are key strategies to promote medication adherence.
Fine AL. Support is Critical: Identifying the Roles of Decision-Making and Parental Anxiety on Medication Adherence in Pediatric Epilepsy. Epilepsy Currents. 2025;0(0). doi:10.1177/15357597251406780
Commentary
Medication compliance can be challenging in any chronic pediatric disorder (and non-pediatric disorder) due to a variety of factors, such as challenging child behaviors, independence-seeking behaviors, communication barriers such as low medical literacy or provider communication issues, financial barriers, and others. When the potential consequences of medication noncompliance are breakthrough seizures and status epilepticus, increased hospitalizations, and increased mortality, the importance of medication compliance and reducing the barriers to adherence is dire. Social support can be characterized as the potential or perceived resources that are available or services being provided to an individual. Social support can vary depending on the circumstances (ie, such as caregiver vs patient role) and is typically a combination of resources which may include emotional support, enhanced education/information on the disease state, and practical/financial support.
Yang et al evaluated the impact of social support on communication and decision-making, treatment satisfaction, and caregiver anxiety and the effects on medication adherence in pediatric epilepsy. The authors performed a cross-sectional quantitative study of caregivers of children with epilepsy seen three healthcare facilities in China. The goal was to evaluate how the previously mentioned factors impact adherence, directly and indirectly, and the relationships between these factors by developing a hypothetical path model with medication adherence as the primary outcome variable. Path analysis is a form of multiple regression that entails creation of a path diagram evaluating the relationships between variables. The authors then used structural equation modeling (SEM) to allow for simultaneous analysis of the multiple mediating and moderating effects on medication adherence. The authors used a combination of self-designed scales, that is, Treatment Satisfaction Scale (SAT), Communication and Decision-Making Scale (CDMS), and Adherence to Medication scale (ADH), and available instruments, such as the Generalized Anxiety Disorder-7 (GAD-7) and Perceived Social Support Scale (PSSS).
The study included 1056 patients with a mean age of 8.86 years (sd = 3.99 years). Approximately half (50.5%) of the cohort was newly diagnosed with epilepsy and 98.5% of caregivers were parents. For those patients with established epilepsy, the minimum duration of epilepsy was 3 months per study inclusion criteria, with no information provided on the duration of epilepsy in included patients. Comorbidities were identified in 57.1% of patients (n = 603), including 22% with developmental delay and only a handful patients with ADHD (3.4%, 36 cases), intellectual disability (2.2%, 23 cases), depression or anxiety (0.4%, 4 cases), and autism (0.2%, 2 cases).
Based on scores from caregiver scales, 38.7% (n = 409) of patients exhibited poor treatment adherence, 12.9% (n = 36) of caregivers had low social support, 56.6% (n = 598) had moderate social support, and 30.5% (n = 322) had high social support. Medication adherence demonstrated a significantly positive correlation with satisfaction, social support, and communication/decision-making (p < 0.01 for all correlations). No significant correlation was found with caregiver anxiety (r = -0.058, p > 0.05), which the authors suggested indicated that indirect effects of anxiety were responsible for perceived effects.
Structural equation model analysis demonstrated that social support and communication and decision-making participation significantly improved medication adherence through direct and indirect pathways with direct positive effects seen for both. Satisfaction also significantly promoted medication adherence. Treatment satisfaction partially mediated the relationships between social support, communication and decision-making participation, and medication adherence via significant indirect effects of social support on satisfaction which enhanced medication adherence. Overall, total effects were positive on medication adherence. Caregiver anxiety was shown to significantly negatively moderate the relationships between social support, communication and decision-making participation, and treatment satisfaction and weakened the positive effects of these on medication adherence (Figure 1). Overall, these results demonstrated clear relationships between these factors, with total positive effects of caregiver support, communication and decision-making participation, and treatment satisfaction on medication adherence, while caregiver anxiety negatively impacts these relationships, potentially contributing to reduced medication adherence.
Figure 1. Path relationship results: Solid lines represent significant relationships on path analysis and significant direct effects of perceived social support, communication decision making, and satisfaction on medication adherence. Dashed lines represent significant indirect effects and mediating effects of parental support and communication and decision making on satisfaction with indirect effects on satisfaction positively impacting medication adherence. Dotted lines represent moderating effects of parental anxiety, with “X” representing negative effects, on the relationships between social support, communication decision making, and satisfaction on medication adherence.
The study findings, while not surprising, are important. The personal experience of caregivers of children with chronic medical conditions is impacted by numerous factors including social support, disease burden, medical barriers, caregivers’ coping abilities.7 Given the potential complexity of an individual's epilepsy journey, it is not unexpected that enhancing social support of caregivers improves the overall experience. Qualitative studies have previously identified that for caregiver decision-making in epilepsy important factors include being informed and knowledgeable about epilepsy and therapies, a sense of responsibility, emotional and social support, personal beliefs, and resources.
Some considerations of the study by Yang et al would be the generalizability of the findings to other populations, as there could be cultural and location-specific factors which contributed to their findings. Part of social support can include resources and financial support, which was not really explored in this study. If there are additional stressors due to a lack of financial resources, this could also contribute to increased anxiety and thus weaken the effects seen on medication adherence. It would have been interesting if the authors explored if there were common factors among the patients with the lowest level of social support, which only made up a minority of the caregivers of the included patients.
The authors included patients with a previous diagnosis of epilepsy as well as new onset epilepsy, however as previously noted, the minimum required length of epilepsy history was 3 months, which is still quite early in the potential disease course. One big question is how can these results be applied to patients with severe epilepsies and numerous comorbidities? This study excluded patients who had severe cognitive or developmental concerns including autism, cerebral palsy, or intellectual disability, as well as those with other chronic medical conditions. That would indicate that this study did not really include patients with intractable epilepsy, at least not based on what is reported. This would certainly impact the study findings given that patients with refractory epilepsy likely have more medical complexity and needs, which further could increase caregiver anxiety and an increased need for social support. The rates of comorbidities seen in this cohort was 57.1%, and rates of comorbidities were lower than may be expected, particularly for patients with comorbid ADHD, depression, anxiety, and autism based on prior literature.9 This may skew the sample towards a population that is less impacted by comorbidities and thus could alter generalizability of the study.
This question remains regarding differences between patient and caregiver populations in children with well-controlled epilepsy and in children with refractory epilepsy and developmental and epileptic encephalopathies. Is there better medication adherence with increased medical complexity, or is there an increased impact of social support on medication adherence in a more severely affected population? Future studies could potentially use similar modeling to assess the impact of social support on caregivers of children with intractable epilepsy and treatment adherence. Regardless, this study highlights the importance of assessing support for families and identifying care gaps in order to optimize adherence to therapies for children with epilepsy.
Background: Medication adherence among pediatric epilepsy patients is frequently suboptimal, and the complex interplay between parental social support, decision-making participation, treatment satisfaction, and parental anxiety in influencing medication adherence remains underexplored. This study investigates both the direct and indirect pathways linking these factors to medication adherence and examines the mediating role of treatment satisfaction and the moderating role of parental anxiety. Methods: A cross-sectional study was conducted at three medical institutions between January 2020 and June 2024. Data on patient demographics and standardized scales measuring medication adherence, social support, communication and decision-making participation, treatment satisfaction, and parental anxiety were collected. Relationships among these variables were analyzed using structural equation modeling (SEM) and moderation analysis. Results: A total of 1056 patients were included in the study, with a mean age of 8.86 ± 3.99 years; 51.7% were male. Path analysis showed that parental social support (STD = 0.344, p < 0.001), communication and decision-making participation (STD = 0.392, p < 0.001), and treatment satisfaction (STD = 0.090, p < 0.05) had significant positive effects on medication adherence. Parental social support (STD = 0.483, p < 0.001) and communication and decision-making participation (STD = 0.203, p < 0.001) also strongly influenced treatment satisfaction. The indirect effects of social support and decision-making participation on medication adherence, mediated through treatment satisfaction, were statistically significant (p < 0.05). Parental anxiety, as a moderating factor, weakened the positive effects of social support, decision-making participation, and treatment satisfaction on medication adherence (p < 0.05). Conclusion: This study systematically develops an integrated model linking parental social support, communication and decision-making participation, treatment satisfaction, and anxiety to medication adherence in pediatric epilepsy. It highlights the mediating role of treatment satisfaction and the moderating role of parental anxiety. Enhancing parental social support and communication, improving treatment satisfaction, and addressing parental anxiety are key strategies to promote medication adherence.
Fine AL. Support is Critical: Identifying the Roles of Decision-Making and Parental Anxiety on Medication Adherence in Pediatric Epilepsy. Epilepsy Currents. 2025;0(0). doi:10.1177/15357597251406780
Commentary
Medication compliance can be challenging in any chronic pediatric disorder (and non-pediatric disorder) due to a variety of factors, such as challenging child behaviors, independence-seeking behaviors, communication barriers such as low medical literacy or provider communication issues, financial barriers, and others. When the potential consequences of medication noncompliance are breakthrough seizures and status epilepticus, increased hospitalizations, and increased mortality, the importance of medication compliance and reducing the barriers to adherence is dire. Social support can be characterized as the potential or perceived resources that are available or services being provided to an individual. Social support can vary depending on the circumstances (ie, such as caregiver vs patient role) and is typically a combination of resources which may include emotional support, enhanced education/information on the disease state, and practical/financial support.
Yang et al evaluated the impact of social support on communication and decision-making, treatment satisfaction, and caregiver anxiety and the effects on medication adherence in pediatric epilepsy. The authors performed a cross-sectional quantitative study of caregivers of children with epilepsy seen three healthcare facilities in China. The goal was to evaluate how the previously mentioned factors impact adherence, directly and indirectly, and the relationships between these factors by developing a hypothetical path model with medication adherence as the primary outcome variable. Path analysis is a form of multiple regression that entails creation of a path diagram evaluating the relationships between variables. The authors then used structural equation modeling (SEM) to allow for simultaneous analysis of the multiple mediating and moderating effects on medication adherence. The authors used a combination of self-designed scales, that is, Treatment Satisfaction Scale (SAT), Communication and Decision-Making Scale (CDMS), and Adherence to Medication scale (ADH), and available instruments, such as the Generalized Anxiety Disorder-7 (GAD-7) and Perceived Social Support Scale (PSSS).
The study included 1056 patients with a mean age of 8.86 years (sd = 3.99 years). Approximately half (50.5%) of the cohort was newly diagnosed with epilepsy and 98.5% of caregivers were parents. For those patients with established epilepsy, the minimum duration of epilepsy was 3 months per study inclusion criteria, with no information provided on the duration of epilepsy in included patients. Comorbidities were identified in 57.1% of patients (n = 603), including 22% with developmental delay and only a handful patients with ADHD (3.4%, 36 cases), intellectual disability (2.2%, 23 cases), depression or anxiety (0.4%, 4 cases), and autism (0.2%, 2 cases).
Based on scores from caregiver scales, 38.7% (n = 409) of patients exhibited poor treatment adherence, 12.9% (n = 36) of caregivers had low social support, 56.6% (n = 598) had moderate social support, and 30.5% (n = 322) had high social support. Medication adherence demonstrated a significantly positive correlation with satisfaction, social support, and communication/decision-making (p < 0.01 for all correlations). No significant correlation was found with caregiver anxiety (r = -0.058, p > 0.05), which the authors suggested indicated that indirect effects of anxiety were responsible for perceived effects.
Structural equation model analysis demonstrated that social support and communication and decision-making participation significantly improved medication adherence through direct and indirect pathways with direct positive effects seen for both. Satisfaction also significantly promoted medication adherence. Treatment satisfaction partially mediated the relationships between social support, communication and decision-making participation, and medication adherence via significant indirect effects of social support on satisfaction which enhanced medication adherence. Overall, total effects were positive on medication adherence. Caregiver anxiety was shown to significantly negatively moderate the relationships between social support, communication and decision-making participation, and treatment satisfaction and weakened the positive effects of these on medication adherence (Figure 1). Overall, these results demonstrated clear relationships between these factors, with total positive effects of caregiver support, communication and decision-making participation, and treatment satisfaction on medication adherence, while caregiver anxiety negatively impacts these relationships, potentially contributing to reduced medication adherence.
Figure 1. Path relationship results: Solid lines represent significant relationships on path analysis and significant direct effects of perceived social support, communication decision making, and satisfaction on medication adherence. Dashed lines represent significant indirect effects and mediating effects of parental support and communication and decision making on satisfaction with indirect effects on satisfaction positively impacting medication adherence. Dotted lines represent moderating effects of parental anxiety, with “X” representing negative effects, on the relationships between social support, communication decision making, and satisfaction on medication adherence.
The study findings, while not surprising, are important. The personal experience of caregivers of children with chronic medical conditions is impacted by numerous factors including social support, disease burden, medical barriers, caregivers’ coping abilities.7 Given the potential complexity of an individual's epilepsy journey, it is not unexpected that enhancing social support of caregivers improves the overall experience. Qualitative studies have previously identified that for caregiver decision-making in epilepsy important factors include being informed and knowledgeable about epilepsy and therapies, a sense of responsibility, emotional and social support, personal beliefs, and resources.
Some considerations of the study by Yang et al would be the generalizability of the findings to other populations, as there could be cultural and location-specific factors which contributed to their findings. Part of social support can include resources and financial support, which was not really explored in this study. If there are additional stressors due to a lack of financial resources, this could also contribute to increased anxiety and thus weaken the effects seen on medication adherence. It would have been interesting if the authors explored if there were common factors among the patients with the lowest level of social support, which only made up a minority of the caregivers of the included patients.
The authors included patients with a previous diagnosis of epilepsy as well as new onset epilepsy, however as previously noted, the minimum required length of epilepsy history was 3 months, which is still quite early in the potential disease course. One big question is how can these results be applied to patients with severe epilepsies and numerous comorbidities? This study excluded patients who had severe cognitive or developmental concerns including autism, cerebral palsy, or intellectual disability, as well as those with other chronic medical conditions. That would indicate that this study did not really include patients with intractable epilepsy, at least not based on what is reported. This would certainly impact the study findings given that patients with refractory epilepsy likely have more medical complexity and needs, which further could increase caregiver anxiety and an increased need for social support. The rates of comorbidities seen in this cohort was 57.1%, and rates of comorbidities were lower than may be expected, particularly for patients with comorbid ADHD, depression, anxiety, and autism based on prior literature.9 This may skew the sample towards a population that is less impacted by comorbidities and thus could alter generalizability of the study.
This question remains regarding differences between patient and caregiver populations in children with well-controlled epilepsy and in children with refractory epilepsy and developmental and epileptic encephalopathies. Is there better medication adherence with increased medical complexity, or is there an increased impact of social support on medication adherence in a more severely affected population? Future studies could potentially use similar modeling to assess the impact of social support on caregivers of children with intractable epilepsy and treatment adherence. Regardless, this study highlights the importance of assessing support for families and identifying care gaps in order to optimize adherence to therapies for children with epilepsy.
Monday, December 8, 2025
Chromosome 17p13.3 microdeletions
Inspired by a patient
Abstract
Background: Chromosome 17p13.3 is a region of genomic instability associated with different neurodevelopmental diseases. The malformation spectrum of 17p13.3 microdeletions ranges from an isolated lissencephaly sequence to Miller-Dieker syndrome, while 17p13.3 microduplications result in autism, learning disabilities, microcephaly and other brain malformations. This study aims to provide a more comprehensive delineation of the clinical and genetic characteristics associated with 17p13.3 alterations.
Methods: We retrospectively analyzed the next-generation sequencing (NGS) data of more than 40 thousand patients from January 2016 to December 2021 and identified 38 pediatric patients with copy-number variations (CNVs) or single-nucleotide variations (SNVs) in 17p13.3 region. Published patients with CNVs in the 17p13.3 region were also collected and we performed a Chi-square test to compare the phenotype spectrum of microdeletions and microduplications.
Results: Among the 27 CNV patients, 20 patients with microdeletions and 7 patients with microduplications were found. PAFAH1B1 was the most frequently deleted gene and CRK was the most frequently duplicated gene. Affected genes in 11 SNV patients included PAFAH1B1 and PRPF8. Developmental delay was the most common abnormality detected in the 38 patients (29/38, 76.3%). Of note, Case 10 presented omphalocele and Case 23 presented scoliosis, webbed neck and bone cyst, all of which were unusual variant phenotypes in this region. The Chi-square test revealed that epilepsy, lissencephaly and short stature were statistically significant with microdeletions, while behavioral abnormalities and hand and foot abnormalities were significant with microduplications (p < 0.01).
Conclusions: While PAFAH1B1, YWHAE and CRK are associated with major phenotypes of 17p13.3, RTN4RL1 may be involved in white matter changes and HIC1 might contribute to the occurrence of omphalocele. This study provided a comprehensive understanding of genetic information and phenotype spectrum of the 17p13.3 region.
Emrick LT, Rosenfeld JA, Lalani SR, Jain M, Desai NK, Larson A, Kripps K, Vanderver A, Taft RJ, Bluske K, Perry D, Nagakura H, Immken LL, Burrage LC, Bacino CA, Belmont JW, Network UD, Lee B. Microdeletions excluding YWHAE and PAFAH1B1 cause a unique leukoencephalopathy: further delineation of the 17p13.3 microdeletion spectrum. Genet Med. 2019 Jul;21(7):1652-1656. doi: 10.1038/s41436-018-0358-0. Epub 2018 Dec 20. PMID: 30568308; PMCID: PMC6586530.
Abstract
Purpose: Brain malformations caused by 17p13.3 deletions include lissencephaly with deletions of the larger Miller-Dieker syndrome region or smaller deletions of only PAFAH1B1, white matter changes, and a distinct syndrome due to deletions including YWHAE and CRK but sparing PAFAH1B1. We sought to understand the significance of 17p13.3 deletions between the YWHAE/CRK and PAFAH1B1 loci.
Methods: We analyzed the clinical features of six individuals from five families with 17p13.3 deletions between and not including YWHAE/CRK and PAFAH1B1 identified among individuals undergoing clinical chromosomal microarray testing or research genome sequencing.
Results: Five individuals from four families had multifocal white matter lesions while a sixth had a normal magnetic resonance image. A combination of our individuals and a review of those in the literature with white matter changes and deletions in this chromosomal region narrows the overlapping region for this brain phenotype to ~345 kb, including 11 RefSeq genes, with RTN4RL1 haploinsufficiency as the best candidate for causing this phenotype.
Conclusion: While previous literature has hypothesized dysmorphic features and white matter changes related to YWHAE, our cohort contributes evidence to the presence of additional genetic changes within 17p13.3 required for proper brain development.
Barros Fontes MI, Dos Santos AP, Rossi Torres F, Lopes-Cendes I, Cendes F, Appenzeller S, Kawasaki de Araujo T, Lopes MonlleĆ³ I, Gil-da-Silva-Lopes VL. 17p13.3 Microdeletion: Insights on Genotype-Phenotype Correlation. Mol Syndromol. 2017 Jan;8(1):36-41. doi: 10.1159/000452753. Epub 2016 Nov 25. PMID: 28232781; PMCID: PMC5260540.
Abstract
Microdeletions in the chromosomal region 17p13.3 are associated with neuronal migration disorders, and PAFAB1H1 is the main gene involved. The largest genomic imbalances, including the YWHAE and CRK genes, cause more severe structural abnormalities of the brain and other associated dysmorphic features. Here, we describe a 3-year-old boy with a microdeletion in 17p13.3 presenting with minor facial dysmorphisms, a cleft palate, neurodevelopmental delay, and behavioral disorder with no structural malformation of the brain. The patient was evaluated by a clinician using a standard protocol. Laboratory investigation included GTG-banding, whole-genome AGH, and array-CGH. Whole-genome AGH and array-CGH analysis identified an estimated 2.1-Mb deletion in the 17p13.3 region showing haploinsufficiency of the YWHAE, CRK, H1C1, and OVCA1 genes and no deletion of PAFAH1B1. The complex gene interaction on brain development and function is illustrated in the genotype-phenotype correlation described here. This report reinforces the importance of the 17p13.3 region in developmental abnormalities and highlights the weak implication of the HIC1 and OVCA1 genes in palatogenesis.
Blazejewski SM, Bennison SA, Smith TH, Toyo-Oka K. Neurodevelopmental Genetic Diseases Associated With Microdeletions and Microduplications of Chromosome 17p13.3. Front Genet. 2018 Mar 23;9:80. doi: 10.3389/fgene.2018.00080. PMID: 29628935; PMCID: PMC5876250.
Abstract
Chromosome 17p13.3 is a region of genomic instability that is linked to different rare neurodevelopmental genetic diseases, depending on whether a deletion or duplication of the region has occurred. Chromosome microdeletions within 17p13.3 can result in either isolated lissencephaly sequence (ILS) or Miller-Dieker syndrome (MDS). Both conditions are associated with a smooth cerebral cortex, or lissencephaly, which leads to developmental delay, intellectual disability, and seizures. However, patients with MDS have larger deletions than patients with ILS, resulting in additional symptoms such as poor muscle tone, congenital anomalies, abnormal spasticity, and craniofacial dysmorphisms. In contrast to microdeletions in 17p13.3, recent studies have attracted considerable attention to a condition known as a 17p13.3 microduplication syndrome. Depending on the genes involved in their microduplication, patients with 17p13.3 microduplication syndrome may be categorized into either class I or class II. Individuals in class I have microduplications of the YWHAE gene encoding 14-3-3Īµ, as well as other genes in the region. However, the PAFAH1B1 gene encoding LIS1 is never duplicated in these patients. Class I microduplications generally result in learning disabilities, autism, and developmental delays, among other disorders. Individuals in class II always have microduplications of the PAFAH1B1 gene, which may include YWHAE and other genetic microduplications. Class II microduplications generally result in smaller body size, developmental delays, microcephaly, and other brain malformations. Here, we review the phenotypes associated with copy number variations (CNVs) of chromosome 17p13.3 and detail their developmental connection to particular microdeletions or microduplications. We also focus on existing single and double knockout mouse models that have been used to study human phenotypes, since the highly limited number of patients makes a study of these conditions difficult in humans. These models are also crucial for the study of brain development at a mechanistic level since this cannot be accomplished in humans. Finally, we emphasize the usefulness of the CRISPR/Cas9 system and next generation sequencing in the study of neurodevelopmental diseases.
Monday, December 1, 2025
GLRA1 hyperekplexia
Inspired by a patient
Ferraroli E, Perulli M, Veredice C, Contaldo I, Quintiliani M, Ricci M, Venezia I, Citrigno L, Qualtieri A, Spadafora P, Cavalcanti F, Battaglia DI. Hereditary Hyperekplexia: A New Family and aSystematic Review of GLRA1 Gene-Related Phenotypes. Pediatr Neurol. 2022 Jul;132:45-49. doi: 10.1016/j.pediatrneurol.2022.05.002. Epub 2022 May 17. PMID: 35636282.
Abstract
Hereditary hyperekplexia (HPX) is a genetic neurodevelopmental disorder recently defined by the triad of (1) neonatal hypertonia, (2) excessive startle reflexes, and (3) generalized stiffness following the startle. Defects in GLRA1 are the most common cause of HPX, inherited both in an autosomal dominant and autosomal recessive manner. GLRA1 mutations can also cause milder phenotypes in the startle syndromes spectrum, but the prevalence is uncertain and no clear genotype-phenotype correlation has emerged yet. Moreover, the prevalence of neurodevelopmental outcomes has not been clearly defined. Here we report a new family of patients with a typical HPX phenotype, linked to a novel GLRA1 mutation, inherited with a recessive pattern. We then perform a systematic review of the literature of GLRA1-related HPX, describing the main epidemiological features of 210 patients. We found that GLRA1-related phenotypes do not necessarily fulfill the current criteria for HPX, including also milder and later-onset phenotypes. Among clinical features of the disease, neurodevelopmental issues were reported in a third of the sample; interestingly, we found that these problems, particularly when severe, were more common in homozygous than in heterozygous patients. Additional clinical and preclinical studies are needed to define predictors of adverse neurodevelopmental outcomes and underlying mechanisms.
Thomas RH, Drew CJ, Wood SE, Hammond CL, Chung SK, Rees MI. Ethnicity can predict GLRA1 genotypes in hyperekplexia. J Neurol Neurosurg Psychiatry. 2015 Mar;86(3):341-3. doi: 10.1136/jnnp-2014-307903. Epub 2014 Jun 26. PMID: 24970905.
Abstract
Objectives: Hyperekplexia is predominantly caused by mutations in the Ī±-1 subunit of the inhibitory glycine receptor (GLRA1). Three quarters of cases show autosomal-recessive inheritance.
Methods: We carefully ascertained reports of ethnicity from our hyperekplexia research cohort. These were compared with all published cases of hyperekplexia with an identified genetic cause. Ethnicities were subgrouped as Caucasian, Asian, Arabic, Turkish, Jewish or Afro-American.
Results: We report the ethnicity of 90 cases: 56 cases from our service augmented by 34 cases from the literature. Homozygous deletions of exons 1 to 7 are predominantly seen in people with Turkish backgrounds (n=16/17, p<0.001). In contrast, the dominant point mutation R271 is seen in people of Asian, Caucasian and African-American heritage (n=19) but not in people with Arab or Turkish ethnicities (p<0.001).
Conclusions: Self-declared ethnicity can predict gene-screening outcomes. Cultural practices influence the inheritance patterns and a Caucasian founder is postulated for R271 mutations.
Chung SK, Vanbellinghen JF, Mullins JG, Robinson A, Hantke J, Hammond CL, Gilbert DF, Freilinger M, Ryan M, Kruer MC, Masri A, Gurses C, Ferrie C, Harvey K, Shiang R, Christodoulou J, Andermann F, Andermann E, Thomas RH, Harvey RJ, Lynch JW, Rees MI. Pathophysiological mechanisms of dominant and recessive GLRA1 mutations in hyperekplexia. J Neurosci. 2010 Jul 14;30(28):9612-20. doi: 10.1523/JNEUROSCI.1763-10.2010. PMID: 20631190; PMCID: PMC6632444.
Abstract
Hyperekplexia is a rare, but potentially fatal, neuromotor disorder characterized by exaggerated startle reflexes and hypertonia in response to sudden, unexpected auditory or tactile stimuli. This disorder is primarily caused by inherited mutations in the genes encoding the glycine receptor (GlyR) alpha1 subunit (GLRA1) and the presynaptic glycine transporter GlyT2 (SLC6A5). In this study, systematic DNA sequencing of GLRA1 in 88 new unrelated human hyperekplexia patients revealed 19 sequence variants in 30 index cases, of which 21 cases were inherited in recessive or compound heterozygote modes. This indicates that recessive hyperekplexia is far more prevalent than previous estimates. From the 19 GLRA1 sequence variants, we have investigated the functional effects of 11 novel and 2 recurrent mutations. The expression levels and functional properties of these hyperekplexia mutants were analyzed using a high-content imaging system and patch-clamp electrophysiology. When expressed in HEK293 cells, either as homomeric alpha1 or heteromeric alpha1beta GlyRs, subcellular localization defects were the major mechanism underlying recessive mutations. However, mutants without trafficking defects typically showed alterations in the glycine sensitivity suggestive of disrupted receptor function. This study also reports the first hyperekplexia mutation associated with a GlyR leak conductance, suggesting tonic channel opening as a new mechanism in neuronal ligand-gated ion channels.
Elmslie FV, Hutchings SM, Spencer V, Curtis A, Covanis T, Gardiner RM, Rees M. Analysis of GLRA1 in hereditary and sporadic hyperekplexia: a novel mutation in a family cosegregating for hyperekplexia and spastic paraparesis. J Med Genet. 1996 May;33(5):435-6. doi: 10.1136/jmg.33.5.435. PMID: 8733061; PMCID: PMC1050620.
Abstract
Hyperekplexia is a rare condition characterised by the presence of neonatal hypertonia and an exaggerated startle response. Mutations have been described in GLRA1, the gene encoding the alpha 1 subunit of the glycine receptor, in dominant families with hyperekplexia and in a single sporadic case, thought to represent an autosomal recessive form of the disease. In this study the coding region of the GLRA1 was analysed in eight probands with hyperekplexia by restriction digest and sequencing. Two familial cases were found to possess the previously described G1192A (R271Q) mutation in exon 6. In an additional family in which hyperekplexia cosegregates with spastic paraparesis, a novel A to G transversion at nucleotide 1206 in exon 6 was detected that changes a lysine at amino acid 276 to a glutamate (K276E). In four sporadic cases no mutations were found. In addition, one familial case did not have a mutation in the coding region of the gene.
Ferraroli E, Perulli M, Veredice C, Contaldo I, Quintiliani M, Ricci M, Venezia I, Citrigno L, Qualtieri A, Spadafora P, Cavalcanti F, Battaglia DI. Hereditary Hyperekplexia: A New Family and aSystematic Review of GLRA1 Gene-Related Phenotypes. Pediatr Neurol. 2022 Jul;132:45-49. doi: 10.1016/j.pediatrneurol.2022.05.002. Epub 2022 May 17. PMID: 35636282.
Abstract
Hereditary hyperekplexia (HPX) is a genetic neurodevelopmental disorder recently defined by the triad of (1) neonatal hypertonia, (2) excessive startle reflexes, and (3) generalized stiffness following the startle. Defects in GLRA1 are the most common cause of HPX, inherited both in an autosomal dominant and autosomal recessive manner. GLRA1 mutations can also cause milder phenotypes in the startle syndromes spectrum, but the prevalence is uncertain and no clear genotype-phenotype correlation has emerged yet. Moreover, the prevalence of neurodevelopmental outcomes has not been clearly defined. Here we report a new family of patients with a typical HPX phenotype, linked to a novel GLRA1 mutation, inherited with a recessive pattern. We then perform a systematic review of the literature of GLRA1-related HPX, describing the main epidemiological features of 210 patients. We found that GLRA1-related phenotypes do not necessarily fulfill the current criteria for HPX, including also milder and later-onset phenotypes. Among clinical features of the disease, neurodevelopmental issues were reported in a third of the sample; interestingly, we found that these problems, particularly when severe, were more common in homozygous than in heterozygous patients. Additional clinical and preclinical studies are needed to define predictors of adverse neurodevelopmental outcomes and underlying mechanisms.
Thomas RH, Drew CJ, Wood SE, Hammond CL, Chung SK, Rees MI. Ethnicity can predict GLRA1 genotypes in hyperekplexia. J Neurol Neurosurg Psychiatry. 2015 Mar;86(3):341-3. doi: 10.1136/jnnp-2014-307903. Epub 2014 Jun 26. PMID: 24970905.
Abstract
Objectives: Hyperekplexia is predominantly caused by mutations in the Ī±-1 subunit of the inhibitory glycine receptor (GLRA1). Three quarters of cases show autosomal-recessive inheritance.
Methods: We carefully ascertained reports of ethnicity from our hyperekplexia research cohort. These were compared with all published cases of hyperekplexia with an identified genetic cause. Ethnicities were subgrouped as Caucasian, Asian, Arabic, Turkish, Jewish or Afro-American.
Results: We report the ethnicity of 90 cases: 56 cases from our service augmented by 34 cases from the literature. Homozygous deletions of exons 1 to 7 are predominantly seen in people with Turkish backgrounds (n=16/17, p<0.001). In contrast, the dominant point mutation R271 is seen in people of Asian, Caucasian and African-American heritage (n=19) but not in people with Arab or Turkish ethnicities (p<0.001).
Conclusions: Self-declared ethnicity can predict gene-screening outcomes. Cultural practices influence the inheritance patterns and a Caucasian founder is postulated for R271 mutations.
Chung SK, Vanbellinghen JF, Mullins JG, Robinson A, Hantke J, Hammond CL, Gilbert DF, Freilinger M, Ryan M, Kruer MC, Masri A, Gurses C, Ferrie C, Harvey K, Shiang R, Christodoulou J, Andermann F, Andermann E, Thomas RH, Harvey RJ, Lynch JW, Rees MI. Pathophysiological mechanisms of dominant and recessive GLRA1 mutations in hyperekplexia. J Neurosci. 2010 Jul 14;30(28):9612-20. doi: 10.1523/JNEUROSCI.1763-10.2010. PMID: 20631190; PMCID: PMC6632444.
Abstract
Hyperekplexia is a rare, but potentially fatal, neuromotor disorder characterized by exaggerated startle reflexes and hypertonia in response to sudden, unexpected auditory or tactile stimuli. This disorder is primarily caused by inherited mutations in the genes encoding the glycine receptor (GlyR) alpha1 subunit (GLRA1) and the presynaptic glycine transporter GlyT2 (SLC6A5). In this study, systematic DNA sequencing of GLRA1 in 88 new unrelated human hyperekplexia patients revealed 19 sequence variants in 30 index cases, of which 21 cases were inherited in recessive or compound heterozygote modes. This indicates that recessive hyperekplexia is far more prevalent than previous estimates. From the 19 GLRA1 sequence variants, we have investigated the functional effects of 11 novel and 2 recurrent mutations. The expression levels and functional properties of these hyperekplexia mutants were analyzed using a high-content imaging system and patch-clamp electrophysiology. When expressed in HEK293 cells, either as homomeric alpha1 or heteromeric alpha1beta GlyRs, subcellular localization defects were the major mechanism underlying recessive mutations. However, mutants without trafficking defects typically showed alterations in the glycine sensitivity suggestive of disrupted receptor function. This study also reports the first hyperekplexia mutation associated with a GlyR leak conductance, suggesting tonic channel opening as a new mechanism in neuronal ligand-gated ion channels.
Elmslie FV, Hutchings SM, Spencer V, Curtis A, Covanis T, Gardiner RM, Rees M. Analysis of GLRA1 in hereditary and sporadic hyperekplexia: a novel mutation in a family cosegregating for hyperekplexia and spastic paraparesis. J Med Genet. 1996 May;33(5):435-6. doi: 10.1136/jmg.33.5.435. PMID: 8733061; PMCID: PMC1050620.
Abstract
Hyperekplexia is a rare condition characterised by the presence of neonatal hypertonia and an exaggerated startle response. Mutations have been described in GLRA1, the gene encoding the alpha 1 subunit of the glycine receptor, in dominant families with hyperekplexia and in a single sporadic case, thought to represent an autosomal recessive form of the disease. In this study the coding region of the GLRA1 was analysed in eight probands with hyperekplexia by restriction digest and sequencing. Two familial cases were found to possess the previously described G1192A (R271Q) mutation in exon 6. In an additional family in which hyperekplexia cosegregates with spastic paraparesis, a novel A to G transversion at nucleotide 1206 in exon 6 was detected that changes a lysine at amino acid 276 to a glutamate (K276E). In four sporadic cases no mutations were found. In addition, one familial case did not have a mutation in the coding region of the gene.
Idiopathic intracranial hypertension without papilledema
Inspired by a colleague
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Abstract
Idiopathic intracranial hypertension is characterized by high cerebrospinal fluid pressure with no underlying structural or systemic cause. Idiopathic intracranial hypertension without papilledema, although well-described in adults, is rarely reported in the pediatric population. The usual presentation is similar to that of chronic daily headache, with some features of migraine. However, treatment modalities are different, and specific therapy can lead to significant improvement in symptoms. We describe six children with chronic daily headache, who were diagnosed with idiopathic intracranial hypertension without papilledema. The response to medical management was variable. One child required a lumboperitoneal shunt for persistent signs, with good surgical outcome.
Favoni V, Pierangeli G, Toni F, Cirillo L, La Morgia C, Abu-Rumeileh S, Messia M, Agati R, Cortelli P, Cevoli S. Idiopathic Intracranial Hypertension Without Papilledema (IIHWOP) in Chronic Refractory Headache. Front Neurol. 2018 Jun 26;9:503. doi: 10.3389/fneur.2018.00503. PMID: 29997572; PMCID: PMC6029151.
Abstract
Background: To determine the prevalence of Idiopathic intracranial hypertension without papilledema (IIHWOP) testing revised diagnostic criteria by Friedman in refractory chronic headache (CH) patients.
Methods: This is a prospective observational study. Each patient underwent ophthalmologic evaluation and Optical Coherence Tomography; brain magnetic resonance venography (MRV) and a lumbar puncture (LP) with opening pressure (OP) measurement. CSF withdrawal was performed in patients with CSF OP > 200 mmH20. IIHWOP was defined according Friedman's diagnostic criteria. Effect of CSF withdrawal was evaluated clinically in a 6-month follow-up and with a MRV study at 1 month.
Results: Forty-five consecutive patients were enrolled. Five were excluded due to protocol violations. Analyses were conducted in 40 patients (32 F, 8 M; mean age 49.4 ± 10.8). None had papilledema. Nine patients (22.5%) had OP greater than 200 mmH2O, two of them above 250 mmH2O. Two (5%) had neuroimaging findings suggestive of elevated intracranial pressure. One of them (2.5%) met the newly proposed diagnostic criteria by Friedman for IIHWOP. After CSF withdrawal seven (77.8%) of the nine patients improved. No changes in neuroimaging findings were found.
Conclusions: We found a low prevalence (2.5%) of IIHWOP in refractory CH patients according to current diagnostic criteria. In agreement with Friedman's criteria, our results confirm that a diagnosis of IIHWOP should be based on CSF OP and the combination of neuroradiological findings. However, where to set the CSF OP upper limit in IIHWOP needs further field testing. Although IIHWOP is a rare clinical condition, it should be considered and treated in refractory CH patients.
Sunday, November 23, 2025
Neurelis apology
Lexidrug tells me the price is $439.12 for each dose, or $2,195.60 for a 5 pack. Fortunately, the shelf life is 32-36 months. Given that most of my patients will never actually use a rescue medication, that is a hefty price.
Concentrate (diazePAM Oral) 5 mg/mL (per mL): $5.00
Cheap Diazepam Intensol (5 mg/mL) has been utilized extensively as a rescue medication for seizures, generally given buccally. I have not yet seen evidence for the superiority of Valtoco vs Diazepam Intensol.
Midazolam 10 mg/2 ml (per ml) $0.75 - $3.86
Cheap midazolam has been used extensively as an intranasal or buccal rescue medication for seizures.
Nayzilam per 5 mg $400.15
From Nickels, Katherine C. “Less Effective and More Expensive: Is It Time to Move on From Rectal Diazepam?.” Epilepsy currents vol. 18,1 (2018): 27-28. doi:10.5698/1535-7597.18.1.27: According to this study, the most cost-effective therapy was buccal midazolam, with absolute cost effectiveness of $7.93/SS. Nasal midazolam, nasal lorazepam, and intramuscular midazolam had similar costs, ranging from $13.37/SS to $15.54/SS. The only outlier was rectal diazepam, costing $435.16/SS at the time of their study. Rectal diazepam remained the outlier when incremental effectiveness and willingness to pay were analyzed. The authors determined that, based on efficacy, rectal diazepam would not be cost-effective unless the cost were $6 or less. The current cost of rectal diazepam is approximately $326.
Valtoco and Nayzilam are the current outliers.
I am currently freely prescribing Valtoco and Nayzilam, but I hold my nose when I do so.
Saturday, November 22, 2025
Do classic psychedelics increase the risk of seizures?
Courtesy of a colleague
Soto-Angona Ć, Fortea A, Fortea L, MartĆnez-RamĆrez M, Santamarina E, LĆ³pez FJG, Knudsen GM, Ona G. Do classic psychedelics increase the risk of seizures? A scoping review. Eur Neuropsychopharmacol. 2024 Aug;85:35-42. doi: 10.1016/j.euroneuro.2024.05.002. Epub 2024 Jun 24. PMID: 38917636.
Abstract
Seizures are a concerning adverse event frequently associated with the use of psychedelics, and hence, studies involving these substances tend to exclude patients with past history of epilepsy. This is especially relevant because epileptic seizures are markedly increased in the population suffering from mental disorders, and psychedelic assisted therapy is being researched as a promising treatment for several of them. To determine the extent of the current literature on the relationship between classic psychedelics and seizures, a scoping review was performed using the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews). The search was conducted in PubMed, Web of Science, Google scholar, LILACS and Scielo, and both animal and human models were included. A total of 16 publications on humans, and 11 on animals, were found. The results are heterogeneous, but globally suggest that psychedelics may not increase the risk of seizures in healthy individuals or animals in the absence of other drugs. However, concomitant use of other substances or drugs, such as kambo or lithium, could increase the risk of seizures. Additionally, these conclusions are drawn from data lacking sufficient external validity, so they should be interpreted with caution. Future paths for research and a summary on possible neurobiological underpinnings that might clarify the relationship between classical psychedelics and seizures are also provided.
Soto-Angona Ć, Fortea A, Fortea L, MartĆnez-RamĆrez M, Santamarina E, LĆ³pez FJG, Knudsen GM, Ona G. Do classic psychedelics increase the risk of seizures? A scoping review. Eur Neuropsychopharmacol. 2024 Aug;85:35-42. doi: 10.1016/j.euroneuro.2024.05.002. Epub 2024 Jun 24. PMID: 38917636.
Abstract
Seizures are a concerning adverse event frequently associated with the use of psychedelics, and hence, studies involving these substances tend to exclude patients with past history of epilepsy. This is especially relevant because epileptic seizures are markedly increased in the population suffering from mental disorders, and psychedelic assisted therapy is being researched as a promising treatment for several of them. To determine the extent of the current literature on the relationship between classic psychedelics and seizures, a scoping review was performed using the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews). The search was conducted in PubMed, Web of Science, Google scholar, LILACS and Scielo, and both animal and human models were included. A total of 16 publications on humans, and 11 on animals, were found. The results are heterogeneous, but globally suggest that psychedelics may not increase the risk of seizures in healthy individuals or animals in the absence of other drugs. However, concomitant use of other substances or drugs, such as kambo or lithium, could increase the risk of seizures. Additionally, these conclusions are drawn from data lacking sufficient external validity, so they should be interpreted with caution. Future paths for research and a summary on possible neurobiological underpinnings that might clarify the relationship between classical psychedelics and seizures are also provided.
Thursday, November 20, 2025
Autoimmune autonomic ganglionopathy
An Australian woman has decided to end her life with medical assistance to “die on her own terms” after years of living with a rare and terminal neurological disease.
Annaliese Holland, 25, said she has been ill since she was a child, enduring repeated hospital stays as doctors tried to diagnose an illness that caused chronic pain, nausea and vomiting — and forced her to depend on IV feeding for the past decade, she told News.com.au.
She was diagnosed with autoimmune autonomic ganglionopathy, a rare autoimmune disease in which the body attacks the autonomic ganglia, the nerves responsible for controlling involuntary bodily functions, according to the Cleveland Clinic.
Years before her diagnosis, Holland’s bowels acted as if they were blocked, despite there actually being nothing stopping them.
Feeding tubes proved ineffective as she continued vomiting, and once doctors realized her stomach wasn’t emptying, they placed her on total parenteral nutrition, which supplies nutrients through an IV to bypass digestion.
“Because of the line straight into your bloodstream, if you get an infection, it turns to sepsis really quickly, which is very, very dangerous,” Holland said, adding that she has survived sepsis — a life-threatening reaction in which the body’s response to an infection damages its own tissues and organs — 25 times.
After doctors spent the majority of her young life trying to pinpoint what illness had been plaguing her, it wouldn’t be until Holland turned 18 and was transferred to an adult hospital that she would get an answer.
Holland said she had been told her condition was terminal when she turned 22.
Holland’s medications have weakened her bones to the point of severe osteoporosis, leaving her in constant pain and resulting in four spinal fractures, a fractured sternum, and nearly catastrophic pressure on her heart and lungs.
“I was so miserable,” Holland said. “You can’t change it so you have to just deal with it really. Even though there’s beautiful moments in my days, they are exhausting and long. I’m in chronic debilitating pain.”
Her illness has left her watching life race by from a hospital room, where she spent her 18th and 21st birthdays, as her friends now marry and start families.
“Everyone’s life is moving and I’m just stuck. I’m not living. I’m surviving every day, which is tough,” she said, noting that her disease feels like “walking on a field of landmines.”
“No man wants to date someone dying, I get it.”
Knowing that her life will end, the 25-year-old said she has decided to “die on my own terms” with voluntary assisted dying (VAD) — a legal option in Australia that provides terminally ill patients with self-administered life-ending medication.
She has watched life race ahead from her hospital room — where she spent her 18th and 21st birthdays — while her friends move on to marriages and families.
“Life for me now is getting up each day doing what I need to do medically, taking the painkillers, trying to get through the day, just to go to bed and do it all again,” she said.
“I have the most incredible team of doctors and nurses who have watched what I have been through and I told them I don’t want this anymore.”
While Holland appears at peace with the decision, her parents and sister are shattered by the idea.
“I remember talking to my dad in the kitchen one night and I said, ‘Dad, I’ve had enough.’ And he went, ‘So you’re giving up?’” she said.
She said the turning point for her father, Patrick, came when she was revived by doctors in the hospital and pleaded, “Dad, please let me go. I won’t hate you if you do.”
“I said, ‘If this happens again, I don’t want anything. And please know that in my heart, you letting me go and saying no to treatment … I’m happy with and that’s what I want,’” Holland said, fighting back tears.
“He turned to me and goes, ‘I don’t know how you do it and I totally understand that you’ve had enough.’”
Holland’s mom, Armanda, said she still hopes for a miracle, though she “realistically understands the challenges” her daughter faces.
Knowing that her life will end, the 25-year-old said she has decided to “die on my own terms” with voluntary assisted dying — a legal option in Australia that provides terminally ill patients with self-administered life-ending medication.
Following a three-week evaluation process, Holland was approved for VAD.
“I think it’s so weird to be happy, but I was so happy when I found out I was approved, I was crying,” she recalled.
“It’s hard because for me I am in pain and then I am at peace, but then I put the pain onto my family. You have this battle in your head of not wanting to hurt them so I will put some thought into how it will happen.”
Holland added that she’s “lucky that I do have this choice.”
“It’s one of the bravest things you could ever do, to say I want VAD. It’s not giving up. You’ve had enough and you fought bloody hard.”
Richard Pollina
https://nypost.com/2025/11/20/world-news/terminally-ill-australian-woman-annaliese-holland-to-die-on-own-terms-after-battling-rare-neurological-disease-her-entire-life/
Annaliese Holland, 25, said she has been ill since she was a child, enduring repeated hospital stays as doctors tried to diagnose an illness that caused chronic pain, nausea and vomiting — and forced her to depend on IV feeding for the past decade, she told News.com.au.
She was diagnosed with autoimmune autonomic ganglionopathy, a rare autoimmune disease in which the body attacks the autonomic ganglia, the nerves responsible for controlling involuntary bodily functions, according to the Cleveland Clinic.
Years before her diagnosis, Holland’s bowels acted as if they were blocked, despite there actually being nothing stopping them.
Feeding tubes proved ineffective as she continued vomiting, and once doctors realized her stomach wasn’t emptying, they placed her on total parenteral nutrition, which supplies nutrients through an IV to bypass digestion.
“Because of the line straight into your bloodstream, if you get an infection, it turns to sepsis really quickly, which is very, very dangerous,” Holland said, adding that she has survived sepsis — a life-threatening reaction in which the body’s response to an infection damages its own tissues and organs — 25 times.
After doctors spent the majority of her young life trying to pinpoint what illness had been plaguing her, it wouldn’t be until Holland turned 18 and was transferred to an adult hospital that she would get an answer.
Holland said she had been told her condition was terminal when she turned 22.
Holland’s medications have weakened her bones to the point of severe osteoporosis, leaving her in constant pain and resulting in four spinal fractures, a fractured sternum, and nearly catastrophic pressure on her heart and lungs.
“I was so miserable,” Holland said. “You can’t change it so you have to just deal with it really. Even though there’s beautiful moments in my days, they are exhausting and long. I’m in chronic debilitating pain.”
Her illness has left her watching life race by from a hospital room, where she spent her 18th and 21st birthdays, as her friends now marry and start families.
“Everyone’s life is moving and I’m just stuck. I’m not living. I’m surviving every day, which is tough,” she said, noting that her disease feels like “walking on a field of landmines.”
“No man wants to date someone dying, I get it.”
Knowing that her life will end, the 25-year-old said she has decided to “die on my own terms” with voluntary assisted dying (VAD) — a legal option in Australia that provides terminally ill patients with self-administered life-ending medication.
She has watched life race ahead from her hospital room — where she spent her 18th and 21st birthdays — while her friends move on to marriages and families.
“Life for me now is getting up each day doing what I need to do medically, taking the painkillers, trying to get through the day, just to go to bed and do it all again,” she said.
“I have the most incredible team of doctors and nurses who have watched what I have been through and I told them I don’t want this anymore.”
While Holland appears at peace with the decision, her parents and sister are shattered by the idea.
“I remember talking to my dad in the kitchen one night and I said, ‘Dad, I’ve had enough.’ And he went, ‘So you’re giving up?’” she said.
She said the turning point for her father, Patrick, came when she was revived by doctors in the hospital and pleaded, “Dad, please let me go. I won’t hate you if you do.”
“I said, ‘If this happens again, I don’t want anything. And please know that in my heart, you letting me go and saying no to treatment … I’m happy with and that’s what I want,’” Holland said, fighting back tears.
“He turned to me and goes, ‘I don’t know how you do it and I totally understand that you’ve had enough.’”
Holland’s mom, Armanda, said she still hopes for a miracle, though she “realistically understands the challenges” her daughter faces.
Knowing that her life will end, the 25-year-old said she has decided to “die on my own terms” with voluntary assisted dying — a legal option in Australia that provides terminally ill patients with self-administered life-ending medication.
Following a three-week evaluation process, Holland was approved for VAD.
“I think it’s so weird to be happy, but I was so happy when I found out I was approved, I was crying,” she recalled.
“It’s hard because for me I am in pain and then I am at peace, but then I put the pain onto my family. You have this battle in your head of not wanting to hurt them so I will put some thought into how it will happen.”
Holland added that she’s “lucky that I do have this choice.”
“It’s one of the bravest things you could ever do, to say I want VAD. It’s not giving up. You’ve had enough and you fought bloody hard.”
Richard Pollina
https://nypost.com/2025/11/20/world-news/terminally-ill-australian-woman-annaliese-holland-to-die-on-own-terms-after-battling-rare-neurological-disease-her-entire-life/
Wednesday, November 19, 2025
Clinical, radiologic, and pathologic associations of executive dysfunction in children with focal cortical dysplasia–related epilepsy
Clinical, Radiologic, and Pathologic Associations of Executive Dysfunction in Children With Focal Cortical Dysplasia–Related Epilepsy. Nathan T. Cohen , Hua Xie, Venkata Sita Priyanka Illapani, Sonya M. Leikin, Xiaotong Li, Ana Moreno Chaza,,Chloe Hooker, L. Gilbert Vezina, Chima O. Oluigbo, Hayley J. Loblein, William D. Gaillard, Hayley J. Loblein, William D. Gaillard, Leigh N. Sepeta, and Madison M. Berl. Neurology. December 9, 2025 issue 105 (11) e214352 https://doi.org/10.1212/WNL.0000000000214352
Abstract
Background and Objective
Executive dysfunction (ExD) is a common comorbidity of focal epilepsy. Focal cortical dysplasia (FCD) is the most common lesional cause of epilepsy in children. We aimed to investigate clinical, etiologic (pathology), and anatomic vs functional network associations with ExD in FCD-related epilepsy. FCD lesion-network interactions may underlie ExD. The primary analysis was to evaluate whether FCD colocalization to frontoparietal control network or attention networks is associated with ExD. We also evaluated whether FCD type I pathology is associated with ExD because it is reported to be associated with worse intellectual function.
Methods
Patients with FCD were included from retrospective surgical/radiologic databases at Children's National Hospital from January 2000 to January 2022 if they had preoperative neuropsychological testing. FCD colocalization to the Yeo 7-network atlas was determined. Clinical, radiologic, and pathologic factors were evaluated for association with ExD. The primary outcome measure was ExD measured categorically (ExD/Not ExD) and linearly (Behavior Rating Inventory of Executive Function [BRIEF]-Global Executive Composite [GEC] T-score).
Discussion
These data demonstrate the importance of lesion-network interaction in neuropsychological comorbidity (ExD) in focal epilepsy, unrelated to lesion size or lobar location. FCD colocalization to the Frontoparietal Control network is associated with ExD in a heterogeneous cohort of FCD-related epilepsy. A network-level structure-function correlation is suggested as the most affected processes of cognitive regulation (e.g., planning/organization) are domains regulated by this network. This work contributes toward a more unified theory of focal epilepsy, by beginning to explain common neuropsychological deficits seen across the epilepsies by cortical lesion-network interaction and regardless of lobar location.
Abstract
Background and Objective
Executive dysfunction (ExD) is a common comorbidity of focal epilepsy. Focal cortical dysplasia (FCD) is the most common lesional cause of epilepsy in children. We aimed to investigate clinical, etiologic (pathology), and anatomic vs functional network associations with ExD in FCD-related epilepsy. FCD lesion-network interactions may underlie ExD. The primary analysis was to evaluate whether FCD colocalization to frontoparietal control network or attention networks is associated with ExD. We also evaluated whether FCD type I pathology is associated with ExD because it is reported to be associated with worse intellectual function.
Methods
Patients with FCD were included from retrospective surgical/radiologic databases at Children's National Hospital from January 2000 to January 2022 if they had preoperative neuropsychological testing. FCD colocalization to the Yeo 7-network atlas was determined. Clinical, radiologic, and pathologic factors were evaluated for association with ExD. The primary outcome measure was ExD measured categorically (ExD/Not ExD) and linearly (Behavior Rating Inventory of Executive Function [BRIEF]-Global Executive Composite [GEC] T-score).
Results
Ninety-three patients with FCD (45% female) had preoperative BRIEF-GEC T-scores sampled at 11.4 years (SD 4.5 years). Control network colocalization (odds ratio [OR] 3.6, 95% CI 0.94–13.9, p < 0.05) and FCD type I (OR 4.45, 95% CI 1.39–14.3, p = 0.009) are associated with ExD (BRIEF-GEC T-score ≥65). Control network colocalization is associated with Cognitive Regulation Index (mean difference 8.3, 95% CI 0.7–15.9, p = 0.03) and Plan/Organize subscale (8.4, 95% CI 0.9–16.0, p = 0.028). FCD type I is associated with BRIEF-GEC T-score (8.3, 95% CI 2.3–14.2, p = 0.007), Cognitive Regulation Index (7.1, 95% CI 1.2–13.1, p = 0.019), Working Memory (7.4, 95% CI 1.2–13.6, p = 0.021), Plan/Organize (6.0, 95% CI 0.21–11.8, p = 0.042), Shift (8.1, 95% CI 1.6–14.7, p = 0.015), and Emotional Control (8.5, 95% CI 2.5–14.5, p = 0.006) subscales. These findings were not related to Full Scale IQ. FCD colocalization to attentional network (dorsal or ventral), lobar location, or age seizure onset was not associated with ExD.
Ninety-three patients with FCD (45% female) had preoperative BRIEF-GEC T-scores sampled at 11.4 years (SD 4.5 years). Control network colocalization (odds ratio [OR] 3.6, 95% CI 0.94–13.9, p < 0.05) and FCD type I (OR 4.45, 95% CI 1.39–14.3, p = 0.009) are associated with ExD (BRIEF-GEC T-score ≥65). Control network colocalization is associated with Cognitive Regulation Index (mean difference 8.3, 95% CI 0.7–15.9, p = 0.03) and Plan/Organize subscale (8.4, 95% CI 0.9–16.0, p = 0.028). FCD type I is associated with BRIEF-GEC T-score (8.3, 95% CI 2.3–14.2, p = 0.007), Cognitive Regulation Index (7.1, 95% CI 1.2–13.1, p = 0.019), Working Memory (7.4, 95% CI 1.2–13.6, p = 0.021), Plan/Organize (6.0, 95% CI 0.21–11.8, p = 0.042), Shift (8.1, 95% CI 1.6–14.7, p = 0.015), and Emotional Control (8.5, 95% CI 2.5–14.5, p = 0.006) subscales. These findings were not related to Full Scale IQ. FCD colocalization to attentional network (dorsal or ventral), lobar location, or age seizure onset was not associated with ExD.
Discussion
These data demonstrate the importance of lesion-network interaction in neuropsychological comorbidity (ExD) in focal epilepsy, unrelated to lesion size or lobar location. FCD colocalization to the Frontoparietal Control network is associated with ExD in a heterogeneous cohort of FCD-related epilepsy. A network-level structure-function correlation is suggested as the most affected processes of cognitive regulation (e.g., planning/organization) are domains regulated by this network. This work contributes toward a more unified theory of focal epilepsy, by beginning to explain common neuropsychological deficits seen across the epilepsies by cortical lesion-network interaction and regardless of lobar location.
Laryngeal cleft
A terrified Long Island mom’s quick-thinking but devastatingly painful choice helped save the life of her toddler son over the summer — and eventually revealed the exceptionally rare condition he suffers from.
“Picture breathing through a milkshake straw, then breathing through a regular straw, then trying to breathe through a coffee straw,” Maria Carlin, 36, recently told The Post of her 4-year-old Jack’s harrowing experience in late July.
“We got to a point where I said to myself, ‘It doesn’t get higher-pitched. … I know what comes next.’ [His breathing] just stopped.”
Carlin, a nurse at North Shore University Hospital, got her stricken son — who was previously undiagnosed — into the car and began driving to the medical facility after he had spent the night crying in agony without “a single symptom of anything.”
Jack suddenly lost all of his air halfway into the 10-minute drive, forcing his mom to make to an impossible choice: pull over to give him CPR or keep rushing to the hospital.
Carlin decided to continue to the ER, knowing immediate resuscitation wouldn’t be enough, given Jack would need rapid intubation among other urgent procedures.
“I heard him slump over. I went to look back, and God said, ‘Maria, don’t look back. You made your decision. You’re not going to be able to handle seeing him right now,’ ” she recalled, fighting back tears.
“Knowing that you have a child in the back of your car who’s not breathing and needs CPR and not doing that for them — I don’t wish that scenario on my worst enemy.”
Carlin made the critical decision to drive Jack to the hospital instead of stopping to give him CPR.
Carlin blared her car horn as she pulled up the car to the doors of ER, and a team of doctors and nurses flew into action over Jack, who was now in cardiac arrest and without a heartbeat.
“I just saw this lifeless kid who had no pulse, who looked blue,” said emergency-room Dr. Jennifer Gibb, who rushed to Jack after hearing Carlin “screaming.”
“I didn’t know she was a nurse at the time,” Gibb said of Carlin.
“I heard her saying, ‘Come on, Jack,’ and that’s my son’s name. It sends chills through your spine when you’re helping this little child that could be your own,” said Gibb of her own 11-year-old son.
Jack’s pulse returned after the doctors and nurses worked on him for almost 10 minutes.
“I can’t even explain what that feeling is like when you know that your child’s heart is beating again,” Carlin said.
Jack was transferred to Cohen Children’s Medical Center a few hours later.
“I’ve been working here for 13 years, and I really only had a pediatric arrest like that, maybe about five times,” Gibb said.
Further examinations showed he had a laryngeal cleft, which impacts between 10,000 and 20,000 annual births, according to Northwell.
“It’s an abnormal opening in the back of the voice box that separates the voice box from the esophagus,” said Dr. Lee Smith, Cohen’s chief of pediatric otolaryngology.
Mucus or fluids can block airflow as a result of the “extremely uncommon” occurrence.
The boy’s dire situation was even more incredibly unique, according to Smith, who later performed his corrective surgery with no complications.
“I’ve never seen that before. … This was an extremely unusual and severe presentation,” Smith said of the boy losing lethal amounts of air.
“Picture breathing through a milkshake straw, then breathing through a regular straw, then trying to breathe through a coffee straw,” Maria Carlin, 36, recently told The Post of her 4-year-old Jack’s harrowing experience in late July.
“We got to a point where I said to myself, ‘It doesn’t get higher-pitched. … I know what comes next.’ [His breathing] just stopped.”
Carlin, a nurse at North Shore University Hospital, got her stricken son — who was previously undiagnosed — into the car and began driving to the medical facility after he had spent the night crying in agony without “a single symptom of anything.”
Jack suddenly lost all of his air halfway into the 10-minute drive, forcing his mom to make to an impossible choice: pull over to give him CPR or keep rushing to the hospital.
Carlin decided to continue to the ER, knowing immediate resuscitation wouldn’t be enough, given Jack would need rapid intubation among other urgent procedures.
“I heard him slump over. I went to look back, and God said, ‘Maria, don’t look back. You made your decision. You’re not going to be able to handle seeing him right now,’ ” she recalled, fighting back tears.
“Knowing that you have a child in the back of your car who’s not breathing and needs CPR and not doing that for them — I don’t wish that scenario on my worst enemy.”
Carlin made the critical decision to drive Jack to the hospital instead of stopping to give him CPR.
Carlin blared her car horn as she pulled up the car to the doors of ER, and a team of doctors and nurses flew into action over Jack, who was now in cardiac arrest and without a heartbeat.
“I just saw this lifeless kid who had no pulse, who looked blue,” said emergency-room Dr. Jennifer Gibb, who rushed to Jack after hearing Carlin “screaming.”
“I didn’t know she was a nurse at the time,” Gibb said of Carlin.
“I heard her saying, ‘Come on, Jack,’ and that’s my son’s name. It sends chills through your spine when you’re helping this little child that could be your own,” said Gibb of her own 11-year-old son.
Jack’s pulse returned after the doctors and nurses worked on him for almost 10 minutes.
“I can’t even explain what that feeling is like when you know that your child’s heart is beating again,” Carlin said.
Jack was transferred to Cohen Children’s Medical Center a few hours later.
“I’ve been working here for 13 years, and I really only had a pediatric arrest like that, maybe about five times,” Gibb said.
Further examinations showed he had a laryngeal cleft, which impacts between 10,000 and 20,000 annual births, according to Northwell.
“It’s an abnormal opening in the back of the voice box that separates the voice box from the esophagus,” said Dr. Lee Smith, Cohen’s chief of pediatric otolaryngology.
Mucus or fluids can block airflow as a result of the “extremely uncommon” occurrence.
The boy’s dire situation was even more incredibly unique, according to Smith, who later performed his corrective surgery with no complications.
“I’ve never seen that before. … This was an extremely unusual and severe presentation,” Smith said of the boy losing lethal amounts of air.
Jack is now a happy, healthy pre-K-enrolled kid who, along with his mom, dad and siblings Luke and Emma, makes up a family incredibly grateful to the frontline workers who brought about their happy ending.
“The survival rate of a child going into cardiac arrest outside of a hospital is terrifyingly low,” Carlin said.
“After everything happened, I turned to my husband, and I was just like, ‘We’re going to Disney World. This child is going to experience Disney World.’ “8Jack told The Post he enjoyed his vacation and is happy in pre-K.
“The survival rate of a child going into cardiac arrest outside of a hospital is terrifyingly low,” Carlin said.
“After everything happened, I turned to my husband, and I was just like, ‘We’re going to Disney World. This child is going to experience Disney World.’ “8Jack told The Post he enjoyed his vacation and is happy in pre-K.
The Carlin family just returned from the Happiest Place on Earth, where Jack and his siblings and their dad Stewart got their fill of the magic they deserve after the mid-summer ordeal.
“I really liked the Slinky ride,” Jack told The Post.
“And I love being in school.”
Alex Mitchell
https://nypost.com/2025/11/19/us-news/li-moms-impossible-decision-saves-lifeless-child-and-reveals-exceptionally-rare-condition/
“I really liked the Slinky ride,” Jack told The Post.
“And I love being in school.”
Alex Mitchell
https://nypost.com/2025/11/19/us-news/li-moms-impossible-decision-saves-lifeless-child-and-reveals-exceptionally-rare-condition/
Monday, November 17, 2025
Skeletal muscle MRI patterns in female dystrophinopathy carriers
Vigliano AP, Luce L, Pastor Rueda JM, Chaves H, Mesa L, Carcione M, Mazzanti C, Llames Massini C, Radic CP, Cejas C, Giliberto F. Whole-Body Skeletal Muscle MRI Patterns in Female Dystrophinopathy Carriers. Neurol Genet. 2025 Sep 30;11(5):e200301. doi: 10.1212/NXG.0000000000200301. PMID: 41048923; PMCID: PMC12488845.
Abstract
Background and objectives: Dystrophinopathies are X-linked recessive diseases caused by pathogenic variants in the Duchenne muscular dystrophy (DMD) gene. Some women carrying a single DMD pathogenic variant manifest variable levels of symptomatology. Those who manifest severe and early-onset symptoms are considered to be affected by dystrophinopathy rather than carriers. The aim of this study was to characterize and compare muscle structure between female DMD carriers who were asymptomatic at the time of the study and female control participants using whole-body MRI (WB-MRI) and correlate the findings with clinical and genetic data.
Methods: We conducted a cross-sectional observational study comparing a group of female carriers of DMD pathogenic variants and a group of healthy noncarrier controls. The first group included obligate and genetically confirmed DMD female carriers, not classified as having dystrophinopathy. Women in the healthy group had no family history of DMD or other muscular dystrophies. All individuals underwent WB-MRI, which was evaluated using qualitative grading scales to assess muscle edema, trophism, and fatty infiltration. Neurologic examinations, serum creatine kinase measurement, DMD genetic screening, and X-chromosome inactivation studies were performed on the DMD carriers.
Results: The study included 29 DMD female carriers and 30 healthy noncarrier controls. All DMD carriers showed signs of muscle involvement on MRI, revealing a larger proportion of skeletal muscle involvement in carriers than in controls (85% vs 27% of 48 examined muscles/group of muscles, p < 0.001). Edema, fatty infiltration, and atrophy were more common in DMD carriers (62.5% vs 8%; 81% vs 35%; and 81% vs 25%, respectively, all p < 0.001), particularly in muscles of the calves, thighs, and pelvic region. The most frequently affected muscles were gastrocnemius, gluteus maximus, and soleus. No correlations were found between the MRI results and the clinical and genetic data.
Discussion: Our findings indicate that DMD female carriers who are asymptomatic at the time of our study may be at risk of developing muscle symptoms at a future time. Multidisciplinary surveillance of DMD female carriers will facilitate early detection and management of complications.
Abstract
Background and objectives: Dystrophinopathies are X-linked recessive diseases caused by pathogenic variants in the Duchenne muscular dystrophy (DMD) gene. Some women carrying a single DMD pathogenic variant manifest variable levels of symptomatology. Those who manifest severe and early-onset symptoms are considered to be affected by dystrophinopathy rather than carriers. The aim of this study was to characterize and compare muscle structure between female DMD carriers who were asymptomatic at the time of the study and female control participants using whole-body MRI (WB-MRI) and correlate the findings with clinical and genetic data.
Methods: We conducted a cross-sectional observational study comparing a group of female carriers of DMD pathogenic variants and a group of healthy noncarrier controls. The first group included obligate and genetically confirmed DMD female carriers, not classified as having dystrophinopathy. Women in the healthy group had no family history of DMD or other muscular dystrophies. All individuals underwent WB-MRI, which was evaluated using qualitative grading scales to assess muscle edema, trophism, and fatty infiltration. Neurologic examinations, serum creatine kinase measurement, DMD genetic screening, and X-chromosome inactivation studies were performed on the DMD carriers.
Results: The study included 29 DMD female carriers and 30 healthy noncarrier controls. All DMD carriers showed signs of muscle involvement on MRI, revealing a larger proportion of skeletal muscle involvement in carriers than in controls (85% vs 27% of 48 examined muscles/group of muscles, p < 0.001). Edema, fatty infiltration, and atrophy were more common in DMD carriers (62.5% vs 8%; 81% vs 35%; and 81% vs 25%, respectively, all p < 0.001), particularly in muscles of the calves, thighs, and pelvic region. The most frequently affected muscles were gastrocnemius, gluteus maximus, and soleus. No correlations were found between the MRI results and the clinical and genetic data.
Discussion: Our findings indicate that DMD female carriers who are asymptomatic at the time of our study may be at risk of developing muscle symptoms at a future time. Multidisciplinary surveillance of DMD female carriers will facilitate early detection and management of complications.
Friday, November 14, 2025
Brain-responsive neurostimulation for epilepsy
Nair DR, Laxer KD, Weber PB, Murro AM, Park YD, Barkley GL, Smith BJ, Gwinn RP, Doherty MJ, Noe KH, Zimmerman RS, Bergey GK, Anderson WS, Heck C, Liu CY, Lee RW, Sadler T, Duckrow RB, Hirsch LJ, Wharen RE Jr, Tatum W, Srinivasan S, McKhann GM, Agostini MA, Alexopoulos AV, Jobst BC, Roberts DW, Salanova V, Witt TC, Cash SS, Cole AJ, Worrell GA, Lundstrom BN, Edwards JC, Halford JJ, Spencer DC, Ernst L, Skidmore CT, Sperling MR, Miller I, Geller EB, Berg MJ, Fessler AJ, Rutecki P, Goldman AM, Mizrahi EM, Gross RE, Shields DC, Schwartz TH, Labar DR, Fountain NB, Elias WJ, Olejniczak PW, Villemarette-Pittman NR, Eisenschenk S, Roper SN, Boggs JG, Courtney TA, Sun FT, Seale CG, Miller KL, Skarpaas TL, Morrell MJ; RNS System LTT Study. Nine-year prospective efficacy and safety of brain-responsive neurostimulation for focal epilepsy. Neurology. 2020 Sep 1;95(9):e1244-e1256. doi: 10.1212/WNL.0000000000010154. Epub 2020 Jul 20. PMID: 32690786; PMCID: PMC7538230.
Abstract
Objective: To prospectively evaluate safety and efficacy of brain-responsive neurostimulation in adults with medically intractable focal onset seizures (FOS) over 9 years.
Methods: Adults treated with brain-responsive neurostimulation in 2-year feasibility or randomized controlled trials were enrolled in a long-term prospective open label trial (LTT) to assess safety, efficacy, and quality of life (QOL) over an additional 7 years. Safety was assessed as adverse events (AEs), efficacy as median percent change in seizure frequency and responder rate, and QOL with the Quality of Life in Epilepsy (QOLIE-89) inventory.
Results: Of 256 patients treated in the initial trials, 230 participated in the LTT. At 9 years, the median percent reduction in seizure frequency was 75% (p < 0.0001, Wilcoxon signed rank), responder rate was 73%, and 35% had a ≥90% reduction in seizure frequency. We found that 18.4% (47 of 256) experienced ≥1 year of seizure freedom, with 62% (29 of 47) seizure-free at the last follow-up and an average seizure-free period of 3.2 years (range 1.04-9.6 years). Overall QOL and epilepsy-targeted and cognitive domains of QOLIE-89 remained significantly improved (p < 0.05). There were no serious AEs related to stimulation, and the sudden unexplained death in epilepsy (SUDEP) rate was significantly lower than predefined comparators (p < 0.05, 1-tailed Ļ2).
Conclusions: Adjunctive brain-responsive neurostimulation provides significant and sustained reductions in the frequency of FOS with improved QOL. Stimulation was well tolerated; implantation-related AEs were typical of other neurostimulation devices; and SUDEP rates were low.
Clinicaltrialsgov identifier: NCT00572195.
Classification of evidence: This study provides Class IV evidence that brain-responsive neurostimulation significantly reduces focal seizures with acceptable safety over 9 years.
Geller EB, Skarpaas TL, Gross RE, Goodman RR, Barkley GL, Bazil CW, Berg MJ, Bergey GK, Cash SS, Cole AJ, Duckrow RB, Edwards JC, Eisenschenk S, Fessler J, Fountain NB, Goldman AM, Gwinn RP, Heck C, Herekar A, Hirsch LJ, Jobst BC, King-Stephens D, Labar DR, Leiphart JW, Marsh WR, Meador KJ, Mizrahi EM, Murro AM, Nair DR, Noe KH, Park YD, Rutecki PA, Salanova V, Sheth RD, Shields DC, Skidmore C, Smith MC, Spencer DC, Srinivasan S, Tatum W, Van Ness PC, Vossler DG, Wharen RE Jr, Worrell GA, Yoshor D, Zimmerman RS, Cicora K, Sun FT, Morrell MJ. Brain-responsive neurostimulation in patients with medically intractable mesial temporal lobe epilepsy. Epilepsia. 2017 Jun;58(6):994-1004. doi: 10.1111/epi.13740. Epub 2017 Apr 11. PMID: 28398014.
Abstract
Objective: Evaluate the seizure-reduction response and safety of mesial temporal lobe (MTL) brain-responsive stimulation in adults with medically intractable partial-onset seizures of mesial temporal lobe origin.
Methods: Subjects with mesial temporal lobe epilepsy (MTLE) were identified from prospective clinical trials of a brain-responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2-6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events.
Results: There were 111 subjects with MTLE; 72% of subjects had bilateral MTL onsets and 28% had unilateral onsets. Subjects had one to four leads placed; only two leads could be connected to the device. Seventy-six subjects had depth leads only, 29 had both depth and strip leads, and 6 had only strip leads. The mean follow-up was 6.1 ± (standard deviation) 2.2 years. The median percent seizure reduction was 70% (last observation carried forward). Twenty-nine percent of subjects experienced at least one seizure-free period of 6 months or longer, and 15% experienced at least one seizure-free period of 1 year or longer. There was no difference in seizure reduction in subjects with and without mesial temporal sclerosis (MTS), bilateral MTL onsets, prior resection, prior intracranial monitoring, and prior vagus nerve stimulation. In addition, seizure reduction was not dependent on the location of depth leads relative to the hippocampus. The most frequent serious device-related adverse event was soft tissue implant-site infection (overall rate, including events categorized as device-related, uncertain, or not device-related: 0.03 per implant year, which is not greater than with other neurostimulation devices).
Significance: Brain-responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including patients with unilateral or bilateral MTLE who are not candidates for temporal lobectomy or who have failed a prior MTL resection.
Jobst BC, Kapur R, Barkley GL, Bazil CW, Berg MJ, Bergey GK, Boggs JG, Cash SS, Cole AJ, Duchowny MS, Duckrow RB, Edwards JC, Eisenschenk S, Fessler AJ, Fountain NB, Geller EB, Goldman AM, Goodman RR, Gross RE, Gwinn RP, Heck C, Herekar AA, Hirsch LJ, King-Stephens D, Labar DR, Marsh WR, Meador KJ, Miller I, Mizrahi EM, Murro AM, Nair DR, Noe KH, Olejniczak PW, Park YD, Rutecki P, Salanova V, Sheth RD, Skidmore C, Smith MC, Spencer DC, Srinivasan S, Tatum W, Van Ness P, Vossler DG, Wharen RE Jr, Worrell GA, Yoshor D, Zimmerman RS, Skarpaas TL, Morrell MJ. Brain-responsive neurostimulation in patients with medically intractable seizures arising from eloquent and other neocortical areas. Epilepsia. 2017 Jun;58(6):1005-1014. doi: 10.1111/epi.13739. Epub 2017 Apr 7. PMID: 28387951.
Abstract
Objective: Evaluate the seizure-reduction response and safety of brain-responsive stimulation in adults with medically intractable partial-onset seizures of neocortical origin.
Methods: Patients with partial seizures of neocortical origin were identified from prospective clinical trials of a brain-responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2-6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events. Additional analyses considered safety and seizure reduction according to lobe and functional area (e.g., eloquent cortex) of seizure onset.
Results: There were 126 patients with seizures of neocortical onset. The average follow-up was 6.1 implant years. The median percent seizure reduction was 70% in patients with frontal and parietal seizure onsets, 58% in those with temporal neocortical onsets, and 51% in those with multilobar onsets (last observation carried forward [LOCF] analysis). Twenty-six percent of patients experienced at least one seizure-free period of 6 months or longer and 14% experienced at least one seizure-free period of 1 year or longer. Patients with lesions on magnetic resonance imaging (MRI; 77% reduction, LOCF) and those with normal MRI findings (45% reduction, LOCF) benefitted, although the treatment response was more robust in patients with an MRI lesion (p = 0.02, generalized estimating equation [GEE]). There were no differences in the seizure reduction in patients with and without prior epilepsy surgery or vagus nerve stimulation. Stimulation parameters used for treatment did not cause acute or chronic neurologic deficits, even in eloquent cortical areas. The rates of infection (0.017 per patient implant year) and perioperative hemorrhage (0.8%) were not greater than with other neurostimulation devices.
Significance: Brain-responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including adults with seizures of neocortical onset, and those with onsets from eloquent cortex.
Abstract
Objective: To prospectively evaluate safety and efficacy of brain-responsive neurostimulation in adults with medically intractable focal onset seizures (FOS) over 9 years.
Methods: Adults treated with brain-responsive neurostimulation in 2-year feasibility or randomized controlled trials were enrolled in a long-term prospective open label trial (LTT) to assess safety, efficacy, and quality of life (QOL) over an additional 7 years. Safety was assessed as adverse events (AEs), efficacy as median percent change in seizure frequency and responder rate, and QOL with the Quality of Life in Epilepsy (QOLIE-89) inventory.
Results: Of 256 patients treated in the initial trials, 230 participated in the LTT. At 9 years, the median percent reduction in seizure frequency was 75% (p < 0.0001, Wilcoxon signed rank), responder rate was 73%, and 35% had a ≥90% reduction in seizure frequency. We found that 18.4% (47 of 256) experienced ≥1 year of seizure freedom, with 62% (29 of 47) seizure-free at the last follow-up and an average seizure-free period of 3.2 years (range 1.04-9.6 years). Overall QOL and epilepsy-targeted and cognitive domains of QOLIE-89 remained significantly improved (p < 0.05). There were no serious AEs related to stimulation, and the sudden unexplained death in epilepsy (SUDEP) rate was significantly lower than predefined comparators (p < 0.05, 1-tailed Ļ2).
Conclusions: Adjunctive brain-responsive neurostimulation provides significant and sustained reductions in the frequency of FOS with improved QOL. Stimulation was well tolerated; implantation-related AEs were typical of other neurostimulation devices; and SUDEP rates were low.
Clinicaltrialsgov identifier: NCT00572195.
Classification of evidence: This study provides Class IV evidence that brain-responsive neurostimulation significantly reduces focal seizures with acceptable safety over 9 years.
Geller EB, Skarpaas TL, Gross RE, Goodman RR, Barkley GL, Bazil CW, Berg MJ, Bergey GK, Cash SS, Cole AJ, Duckrow RB, Edwards JC, Eisenschenk S, Fessler J, Fountain NB, Goldman AM, Gwinn RP, Heck C, Herekar A, Hirsch LJ, Jobst BC, King-Stephens D, Labar DR, Leiphart JW, Marsh WR, Meador KJ, Mizrahi EM, Murro AM, Nair DR, Noe KH, Park YD, Rutecki PA, Salanova V, Sheth RD, Shields DC, Skidmore C, Smith MC, Spencer DC, Srinivasan S, Tatum W, Van Ness PC, Vossler DG, Wharen RE Jr, Worrell GA, Yoshor D, Zimmerman RS, Cicora K, Sun FT, Morrell MJ. Brain-responsive neurostimulation in patients with medically intractable mesial temporal lobe epilepsy. Epilepsia. 2017 Jun;58(6):994-1004. doi: 10.1111/epi.13740. Epub 2017 Apr 11. PMID: 28398014.
Abstract
Objective: Evaluate the seizure-reduction response and safety of mesial temporal lobe (MTL) brain-responsive stimulation in adults with medically intractable partial-onset seizures of mesial temporal lobe origin.
Methods: Subjects with mesial temporal lobe epilepsy (MTLE) were identified from prospective clinical trials of a brain-responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2-6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events.
Results: There were 111 subjects with MTLE; 72% of subjects had bilateral MTL onsets and 28% had unilateral onsets. Subjects had one to four leads placed; only two leads could be connected to the device. Seventy-six subjects had depth leads only, 29 had both depth and strip leads, and 6 had only strip leads. The mean follow-up was 6.1 ± (standard deviation) 2.2 years. The median percent seizure reduction was 70% (last observation carried forward). Twenty-nine percent of subjects experienced at least one seizure-free period of 6 months or longer, and 15% experienced at least one seizure-free period of 1 year or longer. There was no difference in seizure reduction in subjects with and without mesial temporal sclerosis (MTS), bilateral MTL onsets, prior resection, prior intracranial monitoring, and prior vagus nerve stimulation. In addition, seizure reduction was not dependent on the location of depth leads relative to the hippocampus. The most frequent serious device-related adverse event was soft tissue implant-site infection (overall rate, including events categorized as device-related, uncertain, or not device-related: 0.03 per implant year, which is not greater than with other neurostimulation devices).
Significance: Brain-responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including patients with unilateral or bilateral MTLE who are not candidates for temporal lobectomy or who have failed a prior MTL resection.
Jobst BC, Kapur R, Barkley GL, Bazil CW, Berg MJ, Bergey GK, Boggs JG, Cash SS, Cole AJ, Duchowny MS, Duckrow RB, Edwards JC, Eisenschenk S, Fessler AJ, Fountain NB, Geller EB, Goldman AM, Goodman RR, Gross RE, Gwinn RP, Heck C, Herekar AA, Hirsch LJ, King-Stephens D, Labar DR, Marsh WR, Meador KJ, Miller I, Mizrahi EM, Murro AM, Nair DR, Noe KH, Olejniczak PW, Park YD, Rutecki P, Salanova V, Sheth RD, Skidmore C, Smith MC, Spencer DC, Srinivasan S, Tatum W, Van Ness P, Vossler DG, Wharen RE Jr, Worrell GA, Yoshor D, Zimmerman RS, Skarpaas TL, Morrell MJ. Brain-responsive neurostimulation in patients with medically intractable seizures arising from eloquent and other neocortical areas. Epilepsia. 2017 Jun;58(6):1005-1014. doi: 10.1111/epi.13739. Epub 2017 Apr 7. PMID: 28387951.
Abstract
Objective: Evaluate the seizure-reduction response and safety of brain-responsive stimulation in adults with medically intractable partial-onset seizures of neocortical origin.
Methods: Patients with partial seizures of neocortical origin were identified from prospective clinical trials of a brain-responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2-6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events. Additional analyses considered safety and seizure reduction according to lobe and functional area (e.g., eloquent cortex) of seizure onset.
Results: There were 126 patients with seizures of neocortical onset. The average follow-up was 6.1 implant years. The median percent seizure reduction was 70% in patients with frontal and parietal seizure onsets, 58% in those with temporal neocortical onsets, and 51% in those with multilobar onsets (last observation carried forward [LOCF] analysis). Twenty-six percent of patients experienced at least one seizure-free period of 6 months or longer and 14% experienced at least one seizure-free period of 1 year or longer. Patients with lesions on magnetic resonance imaging (MRI; 77% reduction, LOCF) and those with normal MRI findings (45% reduction, LOCF) benefitted, although the treatment response was more robust in patients with an MRI lesion (p = 0.02, generalized estimating equation [GEE]). There were no differences in the seizure reduction in patients with and without prior epilepsy surgery or vagus nerve stimulation. Stimulation parameters used for treatment did not cause acute or chronic neurologic deficits, even in eloquent cortical areas. The rates of infection (0.017 per patient implant year) and perioperative hemorrhage (0.8%) were not greater than with other neurostimulation devices.
Significance: Brain-responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including adults with seizures of neocortical onset, and those with onsets from eloquent cortex.
Thursday, November 13, 2025
Decimal point error in a potassium prescription
A 2-year-old boy died in a Florida hospital after a doctor negligently deleted a decimal point in his prescription, resulting in the underweight toddler receiving 10 times the dosage of medicine he should have, a lawsuit alleges.
De’Markus Page “tragically overdosed with potassium” on March 3, 2024, causing him to suffer a massive brain injury and forcing him to spend the next two weeks enduring “a horrific and protracted hospital course” on a ventilator before finally being taken off life support, according to a lawsuit filed by his mother last week.
Mom Dominique Page is suing University of Florida Health and its Shands Teaching Hospital and Clinics, as well as the medical staff that she claims “fumbled” his treatment, including taking 20 minutes to intubate him after he went into cardiac arrest, the Alachua County Circuit Court lawsuit alleges.
De’Markus — who “was suspected of having some level of autism” and was a picky eater — first landed in AdventHealth Ocala Hospital on March 1, 2024, with a virus and dangerously low levels of potassium, Law & Crime first reported, citing the suit.
He was given intravenous fluids to help with his low electrolyte levels and the next morning transferred to Shands Teaching Hospital and Clinics in Gainsville, Fla., “in order to receive the higher level of care he required,” the suit claims.
Shands medical staff found De’Markus weighed just 21 pounds — the 30th percentile of weight for his demographic — and he still had low levels of potassium, the court papers explain.
So the boy was given “electrolyte replacement therapy,” but the next day, Dr. Jiabi Chen “unconscionably” ordered that the boy be given “10 times the level ordered the previous day,” which had “been calculated based on his size, weight, and that day’s lab results,” the filing alleges.
Chen “errantly” ordered the extremely high dosage, “deleting a critical decimal point in the prior day’s dosage of 1.5 mmol — now ordering the liquid supplement to be given at 15 mmol twice a day,” the suit claims.
This was on top of the two other forms of potassium De’Markus was already receiving through IV and Pedialyte, the filing charges.
No one else on the medical team, or the pharmacists, caught the error “despite a Red Flag warning in the hospital’s pharmacy system that alerted them to the excessive dosage,” the court documents claim.
So the toddler received two of the excessive doses, the last being administered at 8:28 p.m. March 3, 2024, the suit alleges. By 9:02 p.m., he went into cardiac arrest caused by the overdose — or hyperkalemic cardiac arrest, the suit alleges.
De’Markus Page was brought to the University of Florida Health, Shands Children Hospital, where medical staff botched his treatment, according to a suit.
The staff bungled the response and carried out “2 to 3 botched attempts” to intubate De’Markus, the court documents claim. And “there was at least twenty minutes that had passed since the Code [Blue] was called, during which time he remained severely deprived of the oxygen necessary to sustain life,” the suit alleges.
De’Markus’ heart eventually spontaneously came back, “but the anoxic damage already done to his brain and other vital organs was catastrophic,” the suit says.
When his blood was drawn, they found elevated potassium and phosphate, the filing claims.
De’Markus was kept alive for the next two weeks while enduring seizures and battling “myriad of ICU-related complications” before he was taken off life support on March 18, 2024, the filing charges.
Dominique, of Marion County, Fla., is suing Shands and University of Florida for at least $50,000 under wrongful death claims and related claims for the pain her son suffered and for her loss of “companionship of her minor child and for mental pain and suffering” she endured.
The Page family lawyer, Jordan Dulcie, called the hospital and its doctors’ actions “grossly negligent” and said they “failed the basic standards of medical care.”
“No parent should have to lose a child like this,” the lawyer continued. “What the family has endured is unimaginable and the worst part is that it was entirely preventable.”
The lawyer said he hopes to bring the case to trial to prevent another family from having to go through what Dominique went through.
The hospital declined to comment on the case but said: “UF Health is committed to protecting the privacy of all patients and their families and follows all state and federal HIPAA regulations. We cannot release information on patients or possible patients and their treatment without consent.”
Chen didn’t immediately return a request for comment Wednesday.
Priscilla DeGregory
https://nypost.com/2025/11/12/us-news/florida-2-year-old-tragically-died-of-potassium-overdose-after-tot-got-10-times-correct-prescription-suit/
SUDEP in children
Whitney R, Keller A, Li SA, Datta AN, MacDonald M, Nabavi Nouri M, Pohl D, Sell E, Ronen GM, Sidhu M, Simard-Tremblay E, Pollanen MS, Donner EJ. Circumstances surrounding sudden unexpected death in epilepsy in children: A national case series. Epilepsia. 2025 Jun;66(6):1988-2000. doi: 10.1111/epi.18339. Epub 2025 Apr 5. PMID: 40186506.
Abstract
Objective: This study was undertaken to understand the circumstances surrounding pediatric sudden unexpected death in epilepsy (SUDEP) and identify clinical factors that may be associated with SUDEP in childhood. Methods: A retrospective case series was conducted. Pediatric SUDEP cases were collected across Canada from the Ontario Forensic Pathology Service, Canadian Pediatric Surveillance Program, and Canadian Pediatric Epilepsy Network. Demographics, epilepsy history, comorbidities, and circumstances surrounding death were analyzed. Results: Forty-nine children with pediatric SUDEP were analyzed; 25 (51%) were females, and the median age at death was 8 years. Six children (12%) were <2 years of age at the time of death. Information on seizure types 6 months before death was known in 35 children. Twenty-two had tonic–clonic seizures within the last 6 months prior to death (63%). Seven children (18%) had no tonic–clonic seizures in their lifetime. Two thirds of children were treated with ≥2 antiseizure medications. Genetic etiologies were most common (55%). Data on global developmental delay (GDD) was known in 46 children: 12 children (26%) had no impairment, and 34 were globally delayed (74%). Children with GDD had earlier age at seizure onset (P < .001); however, epilepsy duration was similar to those without GDD (P = .170). Similar to adult cohorts, death was often unwitnessed (n = 41/46, 89%). Information on recent infection before death was known in 37 children. Seventeen children (46%) had a recent infection. Significance: Our study represents the largest pediatric SUDEP case series to date. SUDEP occurred in children of all ages, including infants, with a spectrum of epilepsies with and without neurodevelopmental impairment. The circumstances around death (ie, timing of death, witnessed/unwitnessed) were similar to previous SUDEP cohorts. A recent infection was often observed, which could decrease seizure threshold and trigger a terminal seizure and may suggest that times of increased seizure risk could warrant heightened surveillance for SUDEP. However, further research is needed to determine the significance of this finding.
Joshi C. In the Quest for Answers: Exploring Circumstances Around Pediatric SUDEP. Epilepsy Currents. 2025;0(0). doi:10.1177/15357597251395592 (commentary on Whitney, et al.)
The American Epilepsy Society and American Academy of Neurology recommend discussing Sudden Unexpected Death in Epilepsy (SUDEP) with every patient as soon as possible—at or after the initial visit—as a best practice recommendation. However, most child neurologists do not follow this practice despite the fact that the risk of SUDEP in pediatric patients is no different than the adult population at approximately 1.2 per 1000 person-years. This deviation from best practice is mostly attributed to lack of sufficient knowledge and lack of a feeling of ethical and moral obligation to be discussing SUDEP with families.
While most epileptologists at tertiary care centers have either had experience with SUDEP or are knowledgeable about it, let us review what is already known about SUDEP:
Childhood Epilepsies are Different From Adult Epilepsies but the Risk of SUDEP is Similar! What are the Specific Risk Factors and How Does Each Increase Risk for SUDEP?
Previous small case series had identified SUDEP risk factors including young age at epilepsy diagnosis, long duration of epilepsy, focal epilepsy, intellectual disability as examples. Subsequently, a systematic review published by the American Academy of Neurology in 2017 clarified risk factors. While high frequency of generalized tonic-clonic seizures (GTC) was the only risk factor identified with a high level of confidence; lack of nighttime supervision and absence of nocturnal listening device were identified risk factors with moderate confidence. In general, methodologic limitations due to small numbers, highly selected populations and differences in definitions of potential risk factors hampered such data pooling. The need for large, high-quality studies to assess risk of SUDEP was unmet till 2020 when Sveinsson et al published their study. These results were obtained from a Swedish population-based case control study of SUDEP-related deaths between July 1, 2006, and December 31, 2011. SUDEP incidence under the age of 16 years was 1.11 per 1000 person-years. Key risk factors included experiencing any GTCs during the preceding year, which contributed to a 27-fold increased risk. Further modeling and logistical regression analysis for the presence of exclusively nocturnal GTCs in the preceding year contributed to a 15-fold increased risk while living alone contributed to a five-fold increased risk. Moreover, the interaction of the combination of living alone and having at least one GTC increased the risk by 67-fold. Previously identified associations of young age at epilepsy onset, longer duration of epilepsy, structural etiology became nonsignificant after controlling for GTC frequency in the above study. While Sveinsson's data identified GTCs as the main culprit, the North American SUDEP Registry data published in 2019 brought attention to the fact that, of 143 patients with known information, 60% had focal epilepsy. Additionally, treatment responsive or benign epilepsy (what would now be classified as self-limited epilepsies) contributed to a sizable minority of SUDEP deaths.
Another systematic analysis of pediatric SUDEP published in 2019 concluded that there is currently insufficient evidence to determine etiology of pediatric SUDEP due to methodological issues of noncomparative studies with a high risk of bias. Moreover, GTCs are not a common feature of pediatric epilepsy—especially in the younger age group. Genetic factors have also been posited as additional risk factors in SUDEP. This hypothesis is supported by the increased incidence of SUDEP in children with epilepsies caused by pathogenic variants in genes including SCN1A, SCN8A, DEPDC5.7
Are Circumstances Around Pediatric SUDEP Different?
This would be a logical question to ask because lack of medication adherence, lack of supervision, living alone, as SUDEP-associated risk factors, are likely less applicable in pediatric epilepsy when compared to adult epilepsy. Authors Whitney and Donner investigated the circumstances surrounding SUDEP in Canadian children using SUDEP-related data from the Ontario forensic pathology service (collected over 3 years between December 2014 and 2017), Canadian pediatric surveillance program (pediatricians were surveyed monthly over 2 years between January 2014 and December 2015) and Canadian pediatric epilepsy network (members completed case report form regarding SUDEP between January 1, 2000 and December 31, 2017). This forms the largest retrospective pediatric case series with 49 definite or probable cases of SUDEP to date.
Key Findings in this Paper Related to Epilepsy
1.
Median age at death was 8 years (range 6 months to 17.9 years)
2.
In the six months prior to death, 63% [22/35] children had either primary generalized or focal to bilateral tonic-clonic seizures.
3.
Seven children [18%] had no documented lifetime history of tonic-clonic seizures.
4.
Three children were seizure-free in the 6 months prior to death [one had juvenile myoclonic epilepsy].
5.
Twenty-seven children [55%] had a genetic or presumed genetic etiology while 12 children [25%] had an unknown etiology.
6.
91% of the children were on antiseizure medications (ASM) at the time of death and only 24% children [5/21] had a history of poor compliance.
7.
Seven children had a dosage reduction [7/34, 47%] or had missed a dose in the 24 h preceding death.
Relevant Medical History
Medical history was extracted from the chart and thus further details regarding severity or classification of comorbidities is not known.
1.
Majority of the children had global developmental delay [46/49, 74%].
2.
Seven children were noted to have a cardiac comorbidity [7/43, 16%].
3.
Nine children had a respiratory comorbidity [9 /36, 25%].
Other Notable Variables
1.
Nine children [9/23, 39%] shared a room with someone.
2.
In seven children [7/17, 41%] regular nocturnal checks were performed and in 2 of the 7 children, listening devices were also used.
3.
93% of the patients were asleep [42/45] and death was unwitnessed in 89% [41/46].
4.
Seventeen children [17/37, 46%] were reported to have recent infection prior to death [“recent” is defined as within the same day or few days—per communication with authors].
Findings in Children <2 years of age
Most patients had global developmental delays, were diagnosed with developmental and epileptic encephalopathy, and were on polytherapy with ASMs at the time of death.
Conclusion and Take-Home Message
Authors who are well-respected in the field have put together the largest case series of pediatric SUDEP. However, this data does not add new knowledge that will help to quantify risk associated with above factors for SUDEP in the next pediatric epilepsy patient that you see. Authors published a retrospective case series built on case report forms submitted across several time spans without a population-based control necessary for comparison or quantification of risk factors associated with pediatric SUDEP.
The circumstances around pediatric SUDEP are not vastly different from those of adult SUDEP in this retrospective sample. One valuable and useful study finding adds justification to the practice of giving patients bridge doses of increased ASM around times of illness/infection—especially in patients with other medical comorbidities. Although granularity regarding significance of medical comorbidities, details regarding infection, type of infection, severity of infection related to baseline infection for that child are lacking in the study, bridge dosing may not be an “overkill.” Close to 50% of those lost to SUDEP in the above case series had a prior infection which in turn could have increased chances of terminal seizures.
By capturing the spectrum of pediatric SUDEP, authors have succeeded in highlighting the shocking reality that no child with epilepsy is risk free when it comes to SUDEP. While much more work is needed to individualize and quantify the risk to the next patient I see in clinic; I must continue to talk about SUDEP to ALL my patients with epilepsy. Without being an alarmist, I must counsel patients that NO seizure is risk-free while trying to reduce the frequency of GTCs as best as I can.
https://journals.sagepub.com/doi/full/10.1177/15357597251395592
Whitney R, Keller A, Li S-A, Datta AN, MacDonald M, Nabavi Nouri M, et al. Circumstances surrounding sudden unexpected death in epilepsy in children: A national case series. Epilepsia. 2025; 66: 1988–2000. https://doi.org/10.1111/epi.18339
Abstract
Objective
This study was undertaken to understand the circumstances surrounding pediatric sudden unexpected death in epilepsy (SUDEP) and identify clinical factors that may be associated with SUDEP in childhood.
Methods
A retrospective case series was conducted. Pediatric SUDEP cases were collected across Canada from the Ontario Forensic Pathology Service, Canadian Pediatric Surveillance Program, and Canadian Pediatric Epilepsy Network. Demographics, epilepsy history, comorbidities, and circumstances surrounding death were analyzed.
Results
Forty-nine children with pediatric SUDEP were analyzed; 25 (51%) were females, and the median age at death was 8 years. Six children (12%) were <2 years of age at the time of death. Information on seizure types 6 months before death was known in 35 children. Twenty-two had tonic–clonic seizures within the last 6 months prior to death (63%). Seven children (18%) had no tonic–clonic seizures in their lifetime. Two thirds of children were treated with ≥2 antiseizure medications. Genetic etiologies were most common (55%). Data on global developmental delay (GDD) was known in 46 children; 12 children (26%) had no impairment, and 34 were globally delayed (74%). Children with GDD had earlier age at seizure onset (p < .001); however, epilepsy duration was similar to those without GDD (p = .170). Similar to adult cohorts, death was often unwitnessed (n = 41/46, 89%). Information on recent infection before death was known in 37 children. Seventeen children (46%) had a recent infection.
Significance
Our study represents the largest pediatric SUDEP case series to date. SUDEP occurred in children of all ages, including infants, with a spectrum of epilepsies with and without neurodevelopmental impairment. The circumstances around death (i.e., timing of death, witnessed/unwitnessed) were similar to previous SUDEP cohorts. A recent infection was often observed, which could decrease seizure threshold and trigger a terminal seizure and may suggest that times of increased seizure risk could warrant heightened surveillance for SUDEP. However, further research is needed to determine the significance of this finding.
Abstract
Objective: This study was undertaken to understand the circumstances surrounding pediatric sudden unexpected death in epilepsy (SUDEP) and identify clinical factors that may be associated with SUDEP in childhood. Methods: A retrospective case series was conducted. Pediatric SUDEP cases were collected across Canada from the Ontario Forensic Pathology Service, Canadian Pediatric Surveillance Program, and Canadian Pediatric Epilepsy Network. Demographics, epilepsy history, comorbidities, and circumstances surrounding death were analyzed. Results: Forty-nine children with pediatric SUDEP were analyzed; 25 (51%) were females, and the median age at death was 8 years. Six children (12%) were <2 years of age at the time of death. Information on seizure types 6 months before death was known in 35 children. Twenty-two had tonic–clonic seizures within the last 6 months prior to death (63%). Seven children (18%) had no tonic–clonic seizures in their lifetime. Two thirds of children were treated with ≥2 antiseizure medications. Genetic etiologies were most common (55%). Data on global developmental delay (GDD) was known in 46 children: 12 children (26%) had no impairment, and 34 were globally delayed (74%). Children with GDD had earlier age at seizure onset (P < .001); however, epilepsy duration was similar to those without GDD (P = .170). Similar to adult cohorts, death was often unwitnessed (n = 41/46, 89%). Information on recent infection before death was known in 37 children. Seventeen children (46%) had a recent infection. Significance: Our study represents the largest pediatric SUDEP case series to date. SUDEP occurred in children of all ages, including infants, with a spectrum of epilepsies with and without neurodevelopmental impairment. The circumstances around death (ie, timing of death, witnessed/unwitnessed) were similar to previous SUDEP cohorts. A recent infection was often observed, which could decrease seizure threshold and trigger a terminal seizure and may suggest that times of increased seizure risk could warrant heightened surveillance for SUDEP. However, further research is needed to determine the significance of this finding.
Joshi C. In the Quest for Answers: Exploring Circumstances Around Pediatric SUDEP. Epilepsy Currents. 2025;0(0). doi:10.1177/15357597251395592 (commentary on Whitney, et al.)
The American Epilepsy Society and American Academy of Neurology recommend discussing Sudden Unexpected Death in Epilepsy (SUDEP) with every patient as soon as possible—at or after the initial visit—as a best practice recommendation. However, most child neurologists do not follow this practice despite the fact that the risk of SUDEP in pediatric patients is no different than the adult population at approximately 1.2 per 1000 person-years. This deviation from best practice is mostly attributed to lack of sufficient knowledge and lack of a feeling of ethical and moral obligation to be discussing SUDEP with families.
While most epileptologists at tertiary care centers have either had experience with SUDEP or are knowledgeable about it, let us review what is already known about SUDEP:
Childhood Epilepsies are Different From Adult Epilepsies but the Risk of SUDEP is Similar! What are the Specific Risk Factors and How Does Each Increase Risk for SUDEP?
Previous small case series had identified SUDEP risk factors including young age at epilepsy diagnosis, long duration of epilepsy, focal epilepsy, intellectual disability as examples. Subsequently, a systematic review published by the American Academy of Neurology in 2017 clarified risk factors. While high frequency of generalized tonic-clonic seizures (GTC) was the only risk factor identified with a high level of confidence; lack of nighttime supervision and absence of nocturnal listening device were identified risk factors with moderate confidence. In general, methodologic limitations due to small numbers, highly selected populations and differences in definitions of potential risk factors hampered such data pooling. The need for large, high-quality studies to assess risk of SUDEP was unmet till 2020 when Sveinsson et al published their study. These results were obtained from a Swedish population-based case control study of SUDEP-related deaths between July 1, 2006, and December 31, 2011. SUDEP incidence under the age of 16 years was 1.11 per 1000 person-years. Key risk factors included experiencing any GTCs during the preceding year, which contributed to a 27-fold increased risk. Further modeling and logistical regression analysis for the presence of exclusively nocturnal GTCs in the preceding year contributed to a 15-fold increased risk while living alone contributed to a five-fold increased risk. Moreover, the interaction of the combination of living alone and having at least one GTC increased the risk by 67-fold. Previously identified associations of young age at epilepsy onset, longer duration of epilepsy, structural etiology became nonsignificant after controlling for GTC frequency in the above study. While Sveinsson's data identified GTCs as the main culprit, the North American SUDEP Registry data published in 2019 brought attention to the fact that, of 143 patients with known information, 60% had focal epilepsy. Additionally, treatment responsive or benign epilepsy (what would now be classified as self-limited epilepsies) contributed to a sizable minority of SUDEP deaths.
Another systematic analysis of pediatric SUDEP published in 2019 concluded that there is currently insufficient evidence to determine etiology of pediatric SUDEP due to methodological issues of noncomparative studies with a high risk of bias. Moreover, GTCs are not a common feature of pediatric epilepsy—especially in the younger age group. Genetic factors have also been posited as additional risk factors in SUDEP. This hypothesis is supported by the increased incidence of SUDEP in children with epilepsies caused by pathogenic variants in genes including SCN1A, SCN8A, DEPDC5.7
Are Circumstances Around Pediatric SUDEP Different?
This would be a logical question to ask because lack of medication adherence, lack of supervision, living alone, as SUDEP-associated risk factors, are likely less applicable in pediatric epilepsy when compared to adult epilepsy. Authors Whitney and Donner investigated the circumstances surrounding SUDEP in Canadian children using SUDEP-related data from the Ontario forensic pathology service (collected over 3 years between December 2014 and 2017), Canadian pediatric surveillance program (pediatricians were surveyed monthly over 2 years between January 2014 and December 2015) and Canadian pediatric epilepsy network (members completed case report form regarding SUDEP between January 1, 2000 and December 31, 2017). This forms the largest retrospective pediatric case series with 49 definite or probable cases of SUDEP to date.
Key Findings in this Paper Related to Epilepsy
1.
Median age at death was 8 years (range 6 months to 17.9 years)
2.
In the six months prior to death, 63% [22/35] children had either primary generalized or focal to bilateral tonic-clonic seizures.
3.
Seven children [18%] had no documented lifetime history of tonic-clonic seizures.
4.
Three children were seizure-free in the 6 months prior to death [one had juvenile myoclonic epilepsy].
5.
Twenty-seven children [55%] had a genetic or presumed genetic etiology while 12 children [25%] had an unknown etiology.
6.
91% of the children were on antiseizure medications (ASM) at the time of death and only 24% children [5/21] had a history of poor compliance.
7.
Seven children had a dosage reduction [7/34, 47%] or had missed a dose in the 24 h preceding death.
Relevant Medical History
Medical history was extracted from the chart and thus further details regarding severity or classification of comorbidities is not known.
1.
Majority of the children had global developmental delay [46/49, 74%].
2.
Seven children were noted to have a cardiac comorbidity [7/43, 16%].
3.
Nine children had a respiratory comorbidity [9 /36, 25%].
Other Notable Variables
1.
Nine children [9/23, 39%] shared a room with someone.
2.
In seven children [7/17, 41%] regular nocturnal checks were performed and in 2 of the 7 children, listening devices were also used.
3.
93% of the patients were asleep [42/45] and death was unwitnessed in 89% [41/46].
4.
Seventeen children [17/37, 46%] were reported to have recent infection prior to death [“recent” is defined as within the same day or few days—per communication with authors].
Findings in Children <2 years of age
Most patients had global developmental delays, were diagnosed with developmental and epileptic encephalopathy, and were on polytherapy with ASMs at the time of death.
Conclusion and Take-Home Message
Authors who are well-respected in the field have put together the largest case series of pediatric SUDEP. However, this data does not add new knowledge that will help to quantify risk associated with above factors for SUDEP in the next pediatric epilepsy patient that you see. Authors published a retrospective case series built on case report forms submitted across several time spans without a population-based control necessary for comparison or quantification of risk factors associated with pediatric SUDEP.
The circumstances around pediatric SUDEP are not vastly different from those of adult SUDEP in this retrospective sample. One valuable and useful study finding adds justification to the practice of giving patients bridge doses of increased ASM around times of illness/infection—especially in patients with other medical comorbidities. Although granularity regarding significance of medical comorbidities, details regarding infection, type of infection, severity of infection related to baseline infection for that child are lacking in the study, bridge dosing may not be an “overkill.” Close to 50% of those lost to SUDEP in the above case series had a prior infection which in turn could have increased chances of terminal seizures.
By capturing the spectrum of pediatric SUDEP, authors have succeeded in highlighting the shocking reality that no child with epilepsy is risk free when it comes to SUDEP. While much more work is needed to individualize and quantify the risk to the next patient I see in clinic; I must continue to talk about SUDEP to ALL my patients with epilepsy. Without being an alarmist, I must counsel patients that NO seizure is risk-free while trying to reduce the frequency of GTCs as best as I can.
https://journals.sagepub.com/doi/full/10.1177/15357597251395592
Whitney R, Keller A, Li S-A, Datta AN, MacDonald M, Nabavi Nouri M, et al. Circumstances surrounding sudden unexpected death in epilepsy in children: A national case series. Epilepsia. 2025; 66: 1988–2000. https://doi.org/10.1111/epi.18339
Abstract
Objective
This study was undertaken to understand the circumstances surrounding pediatric sudden unexpected death in epilepsy (SUDEP) and identify clinical factors that may be associated with SUDEP in childhood.
Methods
A retrospective case series was conducted. Pediatric SUDEP cases were collected across Canada from the Ontario Forensic Pathology Service, Canadian Pediatric Surveillance Program, and Canadian Pediatric Epilepsy Network. Demographics, epilepsy history, comorbidities, and circumstances surrounding death were analyzed.
Results
Forty-nine children with pediatric SUDEP were analyzed; 25 (51%) were females, and the median age at death was 8 years. Six children (12%) were <2 years of age at the time of death. Information on seizure types 6 months before death was known in 35 children. Twenty-two had tonic–clonic seizures within the last 6 months prior to death (63%). Seven children (18%) had no tonic–clonic seizures in their lifetime. Two thirds of children were treated with ≥2 antiseizure medications. Genetic etiologies were most common (55%). Data on global developmental delay (GDD) was known in 46 children; 12 children (26%) had no impairment, and 34 were globally delayed (74%). Children with GDD had earlier age at seizure onset (p < .001); however, epilepsy duration was similar to those without GDD (p = .170). Similar to adult cohorts, death was often unwitnessed (n = 41/46, 89%). Information on recent infection before death was known in 37 children. Seventeen children (46%) had a recent infection.
Significance
Our study represents the largest pediatric SUDEP case series to date. SUDEP occurred in children of all ages, including infants, with a spectrum of epilepsies with and without neurodevelopmental impairment. The circumstances around death (i.e., timing of death, witnessed/unwitnessed) were similar to previous SUDEP cohorts. A recent infection was often observed, which could decrease seizure threshold and trigger a terminal seizure and may suggest that times of increased seizure risk could warrant heightened surveillance for SUDEP. However, further research is needed to determine the significance of this finding.
Monday, November 10, 2025
Scuba diving and epilepsy
Inspired by a patient
Abstract
Recreational scuba diving is a popular sport, and people with epilepsy often ask physicians whether they may engage in diving. Scuba diving is not, however, without risk for anyone; apart from the risk of drowning, the main physiological problems, caused by exposure to gases at depth, are decompression illness, oxygen toxicity, and nitrogen narcosis. In the United Kingdom, the Sport Diving Medical Committee advises that, to dive, someone with epilepsy must be seizure free and off medication for at least 5 years. The reasons for this are largely theoretical. We review the available evidence in the medical literature and diving websites. The risk of seizures recurring decreases with increasing time in remission, but the risk is never completely abolished. We suggest that people with epilepsy who wish to engage in diving, and the physicians who certify fitness to dive, should be provided with all the available evidence. Those who have been entirely seizure-free on stable antiepileptic drug therapy for at least 4 years, who are not taking sedative antiepileptic drugs and who are able to understand the risks, should then be able to consider diving to shallow depths, provided both they and their diving buddy have fully understood the risks.
Smart D, Lippmann J. Epilepsy, scuba diving and risk assessment. Near misses and the need for ongoing vigilance. Diving Hyperb Med. 2013 Mar;43(1):37-41. PMID: 23508661.
Abstract
There is ongoing debate about the safety of scuba diving for individuals with a history of epilepsy. An in-water seizure is highly likely to be fatal. Recommendations for fitness to dive vary with some regarding epilepsy as an absolute contraindication to diving (South Pacific Underwater Medicine Society) and others permitting diving under strict criteria (United Kingdom Sport Diving Medical Committee) with diving to be postponed for a period of three to five years without seizures. Long-term follow up of people with epilepsy shows that at least one-third will have a recurrence and that the risk remains elevated for many years. We present three cases where individuals with a history of epilepsy (or likely epilepsy) almost fell through the cracks of health risk assessment, two with near-fatal consequences. These cases inform the on-going debate about fitness to dive for those with current or past epilepsy, and highlight the importance of education for doctors, dive professionals and divers about the risks associated with epilepsy and diving.
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Google AI
Google AI
Scuba diving with epilepsy is generally not recommended due to the high risk of a fatal seizure underwater. While some diving authorities may allow it after a period of five years with no seizures and after stopping medication, this is only under strict conditions and involves a significant risk that must be accepted by the diver and their buddy. A seizure underwater would likely cause the diver to lose their regulator and drown.
Why scuba diving with epilepsy is dangerous
Seizures underwater are often fatal: A seizure underwater can cause the diver to lose their regulator, leading to drowning.
Triggers in the diving environment: Diving can increase the risk of a seizure due to potential triggers like fatigue, stress, anxiety, sensory deprivation, and nitrogen narcosis.
Medication side effects: Anti-epileptic medications can have sedative effects and may exacerbate nitrogen narcosis or cause it to occur at shallower depths.
Strict conditions for diving
Long seizure-free period: Some authorities may consider allowing a person to dive if they have been seizure-free for at least five years, and are also off all medication.
Medical clearance: It is crucial to consult with a diving doctor and a neurologist to discuss the risks and potential for medical clearance.
Understanding risks: The diver and their buddy must be fully aware of the increased risks involved.
Alternatives to scuba diving
Many other activities are safe and enjoyable for people with epilepsy, as long as precautions are taken and reasonable safety equipment is used.
Examples include biking, contact and non-contact sports, and running.
Why scuba diving with epilepsy is dangerous
Seizures underwater are often fatal: A seizure underwater can cause the diver to lose their regulator, leading to drowning.
Triggers in the diving environment: Diving can increase the risk of a seizure due to potential triggers like fatigue, stress, anxiety, sensory deprivation, and nitrogen narcosis.
Medication side effects: Anti-epileptic medications can have sedative effects and may exacerbate nitrogen narcosis or cause it to occur at shallower depths.
Strict conditions for diving
Long seizure-free period: Some authorities may consider allowing a person to dive if they have been seizure-free for at least five years, and are also off all medication.
Medical clearance: It is crucial to consult with a diving doctor and a neurologist to discuss the risks and potential for medical clearance.
Understanding risks: The diver and their buddy must be fully aware of the increased risks involved.
Alternatives to scuba diving
Many other activities are safe and enjoyable for people with epilepsy, as long as precautions are taken and reasonable safety equipment is used.
Examples include biking, contact and non-contact sports, and running.
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