ANKLE2 autosomal recessive congenital microcephaly

Inspired by sibling patients

Fishburn AT, Florio CJ, Lopez NJ, Link NL, Shah PS. Molecular functions of ANKLE2 and its implications in human disease. Dis Model Mech. 2024 Apr 1;17(4):dmm050554. doi: 10.1242/dmm.050554. Epub 2024 May 1. PMID: 38691001; PMCID: PMC11103583.

Abstract

Ankyrin repeat and LEM domain-containing 2 (ANKLE2) is a scaffolding protein with established roles in cell division and development, the dysfunction of which is increasingly implicated in human disease. ANKLE2 regulates nuclear envelope disassembly at the onset of mitosis and its reassembly after chromosome segregation. ANKLE2 dysfunction is associated with abnormal nuclear morphology and cell division. It regulates the nuclear envelope by mediating protein-protein interactions with barrier to autointegration factor (BANF1; also known as BAF) and with the kinase and phosphatase that modulate the phosphorylation state of BAF. In brain development, ANKLE2 is crucial for proper asymmetric division of neural progenitor cells. In humans, pathogenic loss-of-function mutations in ANKLE2 are associated with primary congenital microcephaly, a condition in which the brain is not properly developed at birth. ANKLE2 is also linked to other disease pathologies, including congenital Zika syndrome, cancer and tauopathy. Here, we review the molecular roles of ANKLE2 and the recent literature on human diseases caused by its dysfunction.

Fishburn AT, Florio CJ, Klaessens TN, Prince B, Adia NAB, Lopez NJ, Beesabathuni NS, Becker SS, Cherkashchenko L, Haggard Arcé ST, Hoang V, Shiu TN, Richardson RB, Evans MJ, Rückert C, Shah PS. Microcephaly protein ANKLE2 promotes Zika virus replication. mBio. 2025 Feb 5;16(2):e0268324. doi: 10.1128/mbio.02683-24. Epub 2025 Jan 13. PMID: 39804047; PMCID: PMC11796389.

Abstract

Orthoflaviviruses are positive-sense single-stranded RNA viruses that hijack host proteins to promote their own replication. Zika virus (ZIKV) is infamous among orthoflaviviruses for its association with severe congenital birth defects, notably microcephaly. We previously mapped ZIKV-host protein interactions and identified the interaction between ZIKV non-structural protein 4A (NS4A) and host microcephaly protein ankyrin repeat and LEM domain-containing 2 (ANKLE2). Using a fruit fly model, we showed that NS4A induced microcephaly in an ANKLE2-dependent manner. Here, we explore the role of ANKLE2 in ZIKV replication to understand the biological significance of the interaction from a viral perspective. We observe that ANKLE2 localization is drastically shifted to sites of NS4A accumulation during infection and that knockout of ANKLE2 reduces ZIKV replication in multiple human cell lines. This decrease in virus replication is coupled with a moderate increase in innate immune activation. Using microscopy, we observe dysregulated formation of virus-induced endoplasmic reticulum rearrangements in ANKLE2 knockout cells. Knockdown of the ANKLE2 ortholog in Aedes aegypti cells also decreases virus replication, suggesting ANKLE2 is a beneficial replication factor across hosts. Finally, we show that NS4A from four other orthoflaviviruses physically interacts with ANKLE2 and is also beneficial to their replication. Thus, ANKLE2 likely promotes orthoflavivirus replication by regulating membrane rearrangements that serve to accelerate viral genome replication and protect viral dsRNA from immune detection. Taken together with our previous results, our findings indicate that ZIKV and other orthoflaviviruses hijack ANKLE2 for a conserved role in replication, and this drives unique pathogenesis for ZIKV since ANKLE2 has essential roles in developing tissues.IMPORTANCEZIKV is a major concern due to its association with birth defects, including microcephaly. We previously identified a physical interaction between ZIKV NS4A and host microcephaly protein ANKLE2. Mutations in ANKLE2 cause congenital microcephaly, and NS4A induces microcephaly in an ANKLE2-dependent manner. Here, we establish the role of ANKLE2 in ZIKV replication. Depletion of ANKLE2 from cells significantly reduces ZIKV replication and disrupts virus-induced membrane rearrangements. ANKLE2's ability to promote ZIKV replication is conserved in mosquito cells and for other related mosquito-borne orthoflaviviruses. Our data point to an overall model in which ANKLE2 regulates virus-induced membrane rearrangements to accelerate orthoflavivirus replication and avoid immune detection. However, ANKLE2's unique role in ZIKV NS4A-induced microcephaly is a consequence of ZIKV infection of important developing tissues in which ANKLE2 has essential roles.

Shaheen R, Maddirevula S, Ewida N, Alsahli S, Abdel-Salam GMH, Zaki MS, Tala SA, Alhashem A, Softah A, Al-Owain M, Alazami AM, Abadel B, Patel N, Al-Sheddi T, Alomar R, Alobeid E, Ibrahim N, Hashem M, Abdulwahab F, Hamad M, Tabarki B, Alwadei AH, Alhazzani F, Bashiri FA, Kentab A, Şahintürk S, Sherr E, Fregeau B, Sogati S, Alshahwan SAM, Alkhalifi S, Alhumaidi Z, Temtamy S, Aglan M, Otaify G, Girisha KM, Tulbah M, Seidahmed MZ, Salih MA, Abouelhoda M, Momin AA, Saffar MA, Partlow JN, Arold ST, Faqeih E, Walsh C, Alkuraya FS. Genomic and phenotypic delineation of congenital microcephaly. Genet Med. 2019 Mar;21(3):545-552. doi: 10.1038/s41436-018-0140-3. Epub 2018 Sep 14. PMID: 30214071; PMCID: PMC6986385.

Abstract

Purpose: Congenital microcephaly (CM) is an important birth defect with long term neurological sequelae. We aimed to perform detailed phenotypic and genomic analysis of patients with Mendelian forms of CM.

Methods: Clinical phenotyping, targeted or exome sequencing, and autozygome analysis.

Results: We describe 150 patients (104 families) with 56 Mendelian forms of CM. Our data show little overlap with the genetic causes of postnatal microcephaly. We also show that a broad definition of primary microcephaly -as an autosomal recessive form of nonsyndromic CM with severe postnatal deceleration of occipitofrontal circumference-is highly sensitive but has a limited specificity. In addition, we expand the overlap between primary microcephaly and microcephalic primordial dwarfism both clinically (short stature in >52% of patients with primary microcephaly) and molecularly (e.g., we report the first instance of CEP135-related microcephalic primordial dwarfism). We expand the allelic and locus heterogeneity of CM by reporting 37 novel likely disease-causing variants in 27 disease genes, confirming the candidacy of ANKLE2, YARS, FRMD4A, and THG1L, and proposing the candidacy of BPTF, MAP1B, CCNH, and PPFIBP1.

Conclusion: Our study refines the phenotype of CM, expands its genetics heterogeneity, and informs the workup of children born with this developmental brain defect.

Naveed M, Kazmi SK, Amin M, Asif Z, Islam U, Shahid K, Tehreem S. Comprehensive review on the molecular genetics of autosomal recessive primary microcephaly (MCPH). Genet Res (Camb). 2018 Aug 8;100:e7. doi: 10.1017/S0016672318000046. PMID: 30086807; PMCID: PMC6865151.

Abstract

Primary microcephaly (MCPH) is an autosomal recessive sporadic neurodevelopmental ailment with a trivial head size characteristic that is below 3-4 standard deviations. MCPH is the smaller upshot of an architecturally normal brain; a significant decrease in size is seen in the cerebral cortex. At birth MCPH presents with non-progressive mental retardation, while secondary microcephaly (onset after birth) presents with and without other syndromic features. MCPH is a neurogenic mitotic syndrome nevertheless pretentious patients demonstrate normal neuronal migration, neuronal apoptosis and neural function. Eighteen MCPH loci (MCPH1-MCPH18) have been mapped to date from various populations around the world and contain the following genes: Microcephalin, WDR62, CDK5RAP2, CASC5, ASPM, CENPJ, STIL, CEP135, CEP152, ZNF335, PHC1, CDK6, CENPE, SASS6, MFSD2A, ANKLE2, CIT and WDFY3, clarifying our understanding about the molecular basis of microcephaly genetic disorder. It has previously been reported that phenotype disease is caused by MCB gene mutations and the causes of this phenotype are disarrangement of positions and organization of chromosomes during the cell cycle as a result of mutated DNA, centriole duplication, neurogenesis, neuronal migration, microtubule dynamics, transcriptional control and the cell cycle checkpoint having some invisible centrosomal process that can manage the number of neurons that are produced by neuronal precursor cells. Furthermore, researchers inform us about the clinical management of families that are suffering from MCPH. Establishment of both molecular understanding and genetic advocating may help to decrease the rate of this ailment. This current review study examines newly identified genes along with previously identified genes involved in autosomal recessive MCPH.

103 year old neurologist

Howard Tucker has lived through a World War, the dawn of penicillin and the invention of the MRI—but nothing prepared him for TikTok fame at more than 100 years old. The centenarian doctor-turned-viral-sensation still lectures at Case Western Reserve University—offering both medical insights and life advice in equal doses.

Tucker turns 103 today—and he’s still not ready to fully retire.

Neurologist, Navy veteran, lawyer and part-time lecturer at the School of Medicine, Tucker holds the Guinness World Record as the world’s oldest practicing doctor. Though he stopped treating patients in 2022—he still remembers the exact date, Nov. 15—he remains an active medical educator and is always looking for new opportunities.

“It all fell into place easily,” Tucker said of his long career. “Just things I did as I went. One step at a time. As far as I’m concerned, I’ve lived a pedestrian life.”

Others would disagree. A World War II veteran, Tucker earned his medical degree in 1947 (The Ohio State University College of Medicine), served as chief neurologist for the U.S. Atlantic Fleet during the Korean War and then, after law school at Cleveland State University’s Cleveland–Marshall College of Law, passed the Ohio Bar exam at age 67. His mental acuity still sharp and witty, Tucker continues to consult on medicolegal cases and lecture students at Case Western Reserve, where his seven decades of medical knowledge still resonate.

In 2021, his grandson, Austin, and filmmaker, Taylor Taglianetti, began documenting Tucker’s life in a film called What’s Next?; the pair is currently booking screenings and seeking broader distribution. The documentary’s companion TikTok account—intended mostly to archive footage—took off, attracting more than 100,000 followers. The page has 4.8 million “likes.”

“People want to hear from someone who has truly lived,” Austin Tucker said. “He flips the idea of aging. There are a lot of older adults who want to contribute—and can.”

The project earned a Webby Award in 2025—and a few unforgettable memories, including spending time with Snoop Dogg backstage.

“Grandpa closed down the (Webby) afterparty with Questlove at 2 in the morning,” Austin Tucker said. “It’s hard to put into words how surreal this has all been.”

The digital fame may be new, but Tucker’s message isn’t: Stay curious. Stay engaged. Never stop learning.

Words of wisdom

The elder Tucker reminds his Case Western Reserve medical students not to rely too heavily on technology and to value the patient’s story above all.

“The invention of the CT scan changed everything,” he said, “but you still need to take a good history.”

Tucker credits his own longevity to a combination of genetics (his younger brother turns 100 later this year), regular exercise, curiosity, humor—and a refusal to hate.

“Hatred is devastating to the person who hates,” he said. “Pulse, heart rate, blood pressure all go up. Jealousy is also tremendously unhealthy; just accept yourself as who you are.”

Tucker used to swim a mile each day and jogged regularly; now, he uses a treadmill—the handrails offer security and balance. He occasionally snowshoes with family, including his wife, Sue, of 68 years.

Asked to share his philosophy on living healthy, he doesn’t miss a beat: “Irish playwright Bernard Shaw said the key to longevity is no liquor, no smoking, no caffeine and no red meat. Winston Churchill said he started his day with brandy, smoked between eight and 12 cigars per day and finished his day with red meat. I say—with absolute hubris—that I’m smarter than both of them. Moderation is everything.”

His advice to living a long, rewarding and productive life? “Don’t smoke. Don’t hate,” he said. “And don’t retire unless you absolutely have to; there’s still so much to learn. Why stop now?
https://case.edu/news/his-103rd-birthday-case-western-reserve-university-school-medicines-howard-tucker-has-no-plans-slow-down

EEG abnormalities correlated with developmental delay/intellectual disability in the absence of clinical seizures

Lee YJ, Jo YH, Choi SH, Yoo HW, Jo HY, Park SJ, Park KH, Kong JH, Lee YJ, Nam SO, Kim YM. Is Electroencephalography Useful in Children with Developmental Delays but without Overt Seizures?. Ann Child Neurol. 2024;32(2):105-114.

Abstract

Purpose
Electroencephalography (EEG) is useful for clarifying the association between cortical activity and cognitive processes in children. We investigated whether EEG abnormalities were correlated with developmental delay/intellectual disability (DD/ID) in the absence of clinical seizures.

Methods
We retrospectively identified 166 children with DD/ID who underwent EEG at Pusan National University Hospital between January 2011 and December 2021. We compared clinical characteristics and test results between those with normal and those with abnormal EEGs. Additionally, we analyzed EEG abnormalities in relation to neurodevelopmental disorders, specifically autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD).

Results
Of the 166 patients, 39 (23.5%) displayed abnormal EEGs, while 127 (76.5%) had normal EEGs. Of the former, 25 (64.1%) patients exhibited epileptiform discharges, including 22 (56.3%) with focal and three (7.7%) with generalized discharges. Focal discharges most frequently affected the central area (35.9%). Twenty patients (51.3%) exhibited rhythmic slowing patterns. Epilepsy diagnoses were significantly more common among patients with abnormal EEGs (n=8, 20.5%) than among those with normal EEGs (n=9, 7.1%) (P<0.001). Of 22 patients with ASD, five (12.8%) had abnormal EEGs. Of 13 patients with ADHD, five (36.4%) had abnormal EEGs, all with epileptiform discharges. Two patients with ASD and two with ADHD exhibited rhythmic slowing. Abnormal EEG findings were significantly more common among those with genetic abnormalities compared to genetically normal patients (26 vs. 13, P=0.017).

Conclusion
EEG represents a potential screening tool for children with DD. Abnormal EEG findings are associated with increased epilepsy risk, informing diagnosis and treatment planning.

I remain to be convinced.

Early phenotypic features of beta-propeller protein-associated neurodegeneration

Kim YS, Kim SY, Lee YJ, Oh SH, Choi SM, Lee JH. Early Phenotypic Features of Beta-Propeller Protein-Associated Neurodegeneration: Insights from a Korean Series. J Mov Disord. 2025 Dec 10. doi: 10.14802/jmd.25281. Epub ahead of print. PMID: 41367185.

Abstract

Beta-propeller protein-associated neurodegeneration (BPAN) is a rare X-linked disorder caused by pathogenic variants in WDR45 gene. Early diagnosis remains challenging due to nonspecific presentations in childhood. We report six pediatric patients with BPAN, identified through genetic testing performed during the evaluation of neurodevelopmental disorders. All were female and exhibited early developmental delay, severe language impairment, and varying degrees of motor dysfunction. Seizures occurred in four patients with varying severity. Two patients showed signs of central precocious puberty. Serum neuron-specific enolase was elevated in all tested patients. Brain MRI revealed corpus callosum thinning in all cases. Iron accumulation in the substantia nigra and globus pallidus was observed in only two older patients. WDR45 variants included two nonsense, two splice-site, one in-frame deletion, and one novel frameshift deletion. Our findings highlight early clinical features that may aid in recognizing BPAN prior to the emergence of distinctive MRI abnormalities or degenerative-phase manifestations.

Rabies from kidney transplant

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

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.

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.