Attention-deficit/hyperactivity disorder in children with hearing loss.

OBJECTIVE: To evaluate rates of Attention-Deficit/Hyperactivity Disorder (AD/HD) diagnosis among pediatric patients with normal hearing (NH) and hearing loss (HL) with and without comorbidities. STUDY DESIGN: Retrospective cohort study of NH and HL patients following chart review of all pediatric patients with a history of tympanostomy tube placement treated at the Cleveland Clinic Foundation between 2019 and 2022. METHODS: Patient demographic information, hearing status (type of HL, laterality, severity), and comorbidities including prematurity, genetic syndromes, disorders with neurological impairment, and autism spectrum disorder (ASD) were collected. Rate of AD/HD amongst HL and NH cohorts with and without comorbidities were compared using Fisher's exact test. Covariate-adjusted analysis was also completed (sex, current age, age at tube placement, and OSA). The primary outcome of interest was rates of AD/HD among children with NH and HL, and the secondary outcome of interest was the impact of comorbidities on rates of AD/HD diagnosis in these cohorts. RESULTS: Of the 919 screened patients between 2019 and 2022, there were 778 NH patients and 141 HL patients (80 bilateral, 61 unilateral). HL ranged from mild (n = 110) to moderate (n = 21) to severe/profound (n = 9). Overall, the rate of AD/HD was significantly higher in HL children (12.1% HL vs 3.6% NH, p < 0.001). Of the 919 patients, 157 had comorbidities. In children without comorbidities, HL children still had significantly higher rates of AD/HD compared to NH children (8.0% vs 1.9%, p = 0.02), but there was loss of significance after covariate adjustment (p = 0.72). CONCLUSION: The rate of AD/HD among children with HL (12.1%) is higher than the rate of AD/HD in NH children (3.6%), consistent with previous findings. After excluding patients with comorbidities and adjusting for covariates, there are similar rates of AD/HD between HL and NH patients. Given high rates of comorbidities and AD/HD in HL patients and potential for augmented developmental challenges, clinicians should have a low threshold to refer children with HL for neurocognitive testing, particularly those with any of the comorbidities or covariates described in this study.

Novel Concepts for the Role of Chloride Cotransporters in Refractory Seizures.

Epilepsy is associated with a multitude of acquired or genetic neurological disorders characterized by a predisposition to spontaneous recurrent seizures. An estimated 15 million patients worldwide have ongoing seizures despite optimal management and are classified as having refractory epilepsy. Early-life seizures like those caused by perinatal hypoxic ischemic encephalopathy (HIE) remain a clinical challenge because although transient, they are difficult to treat and associated with poor neurological outcomes. Pediatric epilepsy syndromes are consistently associated with intellectual disability and neurocognitive comorbidities. HIE and arterial ischemic stroke are the most common causes of seizures in term neonates and account for 7.5-20% of neonatal seizures. Standard first-line treatments such as phenobarbital (PB) and phenytoin fail to curb seizures in ~50% of neonates. In the long-term, HIE can result in hippocampal sclerosis and temporal lobe epilepsy (TLE), which is the most common adult epilepsy, ~30% of which is associated with refractory seizures. For patients with refractory TLE seizures, a viable option is the surgical resection of the epileptic foci. Novel insights gained from investigating the developmental role of Cl- cotransporter function have helped to elucidate some of the mechanisms underlying the emergence of refractory seizures in both HIE and TLE. KCC2 as the chief Cl- extruder in neurons is critical for enabling strong hyperpolarizing synaptic inhibition in the brain and has been implicated in the pathophysiology underlying both conditions. More recently, KCC2 function has become a novel therapeutic target to combat refractory seizures.

Targeting ischemia-induced KCC2 hypofunction rescues refractory neonatal seizures and mitigates epileptogenesis in a mouse model.

Neonatal seizures pose a clinical challenge in their early detection, acute management, and long-term comorbidities. They are often caused by hypoxic-ischemic encephalopathy and are frequently refractory to the first-line antiseizure medication phenobarbital. One proposed mechanism for phenobarbital inefficacy during neonatal seizures is the reduced abundance and function of the neuron-specific K+/Cl− cotransporter 2 (KCC2), which maintains chloride homeostasis and promotes GABAergic inhibition upon its phosphorylation during postnatal development. Here, we investigated whether this mechanism is causal and whether it can be rescued by KCC2 functional enhancement. In a CD-1 mouse model of refractory ischemic neonatal seizures, treatment with the KCC2 functional enhancer CLP290 rescued phenobarbital efficacy, increased KCC2 abundance, and prevented the development of epileptogenesis, as quantified by video electroencephalogram monitoring. These effects were prevented by knock-in expression of nonphosphorylatable mutants of KCC2 (S940A or T906A and T1007A), indicating that KCC2 phosphorylation regulates both neonatal seizure susceptibility and CLP290-mediated KCC2 functional enhancement. Our findings therefore validate KCC2 as a clinically relevant target for refractory neonatal seizures and provide insights for future drug development.

TrkB agonists prevent postischemic emergence of refractory neonatal seizures in mice.

Refractory neonatal seizures do not respond to first-line antiseizure medications like phenobarbital (PB), a positive allosteric modulator for GABAA receptors. GABAA receptor-mediated inhibition is dependent upon electroneutral cation-chloride transporter KCC2, which mediates neuronal chloride extrusion and its age-dependent increase and postnatally shifts GABAergic signaling from depolarizing to hyperpolarizing. Brain-derived neurotropic factor-tyrosine receptor kinase B activation (BDNF-TrkB activation) after excitotoxic injury recruits downstream targets like PLCγ1, leading to KCC2 hypofunction. Here, the antiseizure efficacy of TrkB agonists LM22A-4, HIOC, and deoxygedunin (DG) on PB-refractory seizures and postischemic TrkB pathway activation was investigated in a mouse model (CD-1, P7) of refractory neonatal seizures. LM, a BDNF loop II mimetic, rescued PB-refractory seizures in a sexually dimorphic manner. Efficacy was associated with a substantial reduction in the postischemic phosphorylation of TrkB at Y816, a site known to mediate postischemic KCC2 hypofunction via PLCγ1 activation. LM rescued ischemia-induced phospho-KCC2-S940 dephosphorylation, preserving its membrane stability. Full TrkB agonists HIOC and DG similarly rescued PB refractoriness. Chemogenetic inactivation of TrkB substantially reduced postischemic neonatal seizure burdens at P7. Sex differences identified in developmental expression profiles of TrkB and KCC2 may underlie the sexually dimorphic efficacy of LM. These results support a potentially novel role for the TrkB receptor in the emergence of age-dependent refractory neonatal seizures.

Low-Dose Perampanel Rescues Cortical Gamma Dysregulation Associated With Parvalbumin Interneuron GluA2 Upregulation in Epileptic Syngap1+/- Mice.

BACKGROUND: Loss-of-function SYNGAP1 mutations cause a neurodevelopmental disorder characterized by intellectual disability and epilepsy. SYNGAP1 is a Ras GTPase-activating protein that underlies the formation and experience-dependent regulation of postsynaptic densities. The mechanisms that contribute to this proposed monogenic cause of intellectual disability and epilepsy remain unresolved. METHODS: We established the phenotype of the epileptogenesis in a Syngap1+/- mouse model using 24-hour video electroencephalography (vEEG)/electromyography recordings at advancing ages. We administered an acute low dose of perampanel, a Food and Drug Administration-approved AMPA receptor (AMPAR) antagonist, during a follow-on 24-hour vEEG to investigate the role of AMPARs in Syngap1 haploinsufficiency. Immunohistochemistry was performed to determine the region- and location-specific differences in the expression of the GluA2 AMPAR subunit. RESULTS: A progressive worsening of the epilepsy with emergence of multiple seizure phenotypes, interictal spike frequency, sleep dysfunction, and hyperactivity was identified in Syngap1+/- mice. Interictal spikes emerged predominantly during non-rapid eye movement sleep in 24-hour vEEG of Syngap1+/- mice. Myoclonic seizures occurred at behavioral-state transitions both in Syngap1+/- mice and during an overnight EEG from a child with SYNGAP1 haploinsufficiency. In Syngap1+/- mice, EEG spectral power analyses identified a significant loss of gamma power modulation during behavioral-state transitions. A significant region-specific increase of GluA2 AMPAR subunit expression in the somas of parvalbumin-positive interneurons was identified. CONCLUSIONS: Acute dosing with perampanel significantly rescued behavioral state-dependent cortical gamma homeostasis, identifying a novel mechanism implicating Ca2+-impermeable AMPARs on parvalbumin-positive interneurons underlying circuit dysfunction in SYNGAP1 haploinsufficiency.

Sex-Dependent Signaling Pathways Underlying Seizure Susceptibility and the Role of Chloride Cotransporters.

Seizure incidence, severity, and antiseizure medication (ASM) efficacy varies between males and females. Differences in sex-dependent signaling pathways that determine network excitability may be responsible. The identification and validation of sex-dependent molecular mechanisms that influence seizure susceptibility is an emerging focus of neuroscience research. The electroneutral cation-chloride cotransporters (CCCs) of the SLC12A gene family utilize Na+-K+-ATPase generated electrochemical gradients to transport chloride into or out of neurons. CCCs regulate neuronal chloride gradients, cell volume, and have a strong influence over the electrical response to the inhibitory neurotransmitter GABA. Acquired or genetic causes of CCCs dysfunction have been linked to seizures during early postnatal development, epileptogenesis, and refractoriness to ASMs. A growing number of studies suggest that the developmental expression of CCCs, such as KCC2, is sex-dependent. This review will summarize the reports of sexual dimorphism in epileptology while focusing on the role of chloride cotransporters and their associated modulators that can influence seizure susceptibility.