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.
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