Annals of the Child Neurology Society最新文献

Background

Sudden unexpected death in epilepsy (SUDEP) is the most common cause of epilepsy-related mortality. Although most witnessed SUDEPs follow seizures, mechanisms are uncertain. Investigations into the pathophysiology of SUDEP have relied on models and rare recordings of brain function at the time of the event. The brain-responsive neurostimulation (RNS) device from Neuropace offers a therapeutic option for drug-refractory epilepsy (DRE), enabling the recording of brain activity and the preemptive termination of seizures. Therefore, patients who experience SUDEP while being treated with an RNS device can provide insights into neural activity at the moment of this event.

Objective

We report the history and electrocorticographic (ECoG) recordings of a patient with DRE who experienced SUDEP years after RNS placement.

Patient History

A girl with Phelan–McDermid syndrome and Lennox–Gastaut syndrome had an RNS device implanted at the age of 14 to treat DRE. Initially, electrodes were positioned in the right orbitofrontal (OF) and right premotor frontal regions, with the OF lead later changed to the centromedian thalamic nucleus. At age 19, the patient was found unconscious and in cardiac arrest by her parents. Although spontaneous circulation returned en route to the hospital, the patient did not regain consciousness and died. Subsequent analysis of ECoGs from RNS recordings at the time of death indicated seizure onset in the right premotor frontal cortex, which persisted despite seizure termination attempts by the RNS.

Conclusions

We present a patient with SUDEP associated with the onset of RNS-refractory seizures. The significance of this report is highlighted by the rarity of literature on neuronal function at the time of SUDEP. Moreover, it underscores the potential for devices capable of monitoring ECoG activity to shed light on the mechanisms underlying SUDEP and to inform interventions.

Objective

Dravet syndrome (DS) is an epileptic encephalopathy caused by haploinsufficiency of the SCN1A gene. SCN1A gene deficiency limits the firing rates of fast-spiking inhibitory interneurons, which should reflect in abnormal aggregate network oscillatory electroencephalography (EEG) activity that can be measured by spectral power and phase-amplitude coupling (PAC) analysis. In this retrospective pilot study, we tested whether spectral EEG frequency band power and PAC metrics distinguish children with DS from age-matched controls, an early step toward establishing EEG markers of target engagement by gene or drug therapy.

Methods

EEG data were collected from patients with DS (N = 6) and age-matched control pediatric participants (N = 11) and analyzed for cumulative spectral power and PAC and classification capacity of these metrics, by logistic regression analysis. For this initial spectral and PAC analysis, we focused on sleep EEG, where myogenic artifact is minimal and where δ–γ and θ–γ coupling is otherwise expected to be robust.

Results

Cumulative δ (1– <4 Hz) and θ (4–7 Hz) power was significantly reduced in the DS group, compared with age-matched controls (p = 0.001 and p = 0.02, respectively). The δ power was a stronger classifier of separating DS from controls than θ power, with 87% and 83% accuracy, respectively. The γ power trended toward significant reduction (p = 0.08) in the DS group. We found significantly lower PAC between 1–2 Hz phase and 63–80 Hz amplitude in patients with DS compared with the age-matched controls (p = 0.003), with 78% classification accuracy between groups for PAC.

Interpretation

In this pilot study assessing EEG patterns during sleep, we found lower δ–θ power and PAC in patients with DS versus controls, which may reflect abnormal aggregate macroscale network communication patterns resulting from SCN1A deficiency. These measures may be useful metrics of therapeutic target engagement, particularly if the therapy restores the underlying DS pathophysiology. The sorting capacity of these metrics distinguished patients with DS from patients without DS and may in turn facilitate near-future development of disease and therapy target engagement biomarkers in this syndrome.

The neurology of creativity implies network activity; no singular cerebral area is invoked. A clinician-scientist can develop a creative research project from a single patient, combined with critical scientific alliances, careful observations, and correlations. The developing nervous system poses additional complexity, as changes are expected over time in physiologic circumstances, to which must be added compensatory responses to underlying pathology. The arts represent an especially productive area to study the neurology of creativity, especially with functional imaging, tractography, and intracranial electrophysiology. Music activates widespread bilateral areas, including temporal, orbitofrontal, insular, fusiform, and cerebellar cortex. There are different neuronal clusters for different levels of sound volume, duration, timbre, and pitch. Heschl's gyrus and the arcuate fasciculus correlate with pitch. The orbitofrontal cortex is involved in expectancy generation and appears to be active with no music and then deactivates with music, as if the cortex has an editing function. This appears to correlate with the default mode network being key during improvisation, whereas the central executive network is invoked in effortful, repetitive playing. Furthermore, plasticity is associated with music, from the pathologic development of musicogenic seizures, to protection from musician's dystonia in pianists who begin lessons before age 9 years, to benefits of increased temporal cortex in older adults taking piano lessons after six months. Creativity, reducing negativity bias, and juggling life s priorities are key to countering burnout and building resilience.

Aim

This study analyzed whether retino-dural hemorrhages in infants are markers of the degree of intracranial pathology, rather than evidence of violent shaking.

Methods

Using data from 420 infants with acute intracranial pathologies, comparison of clinical findings is made between cases diagnosed as abusive head trauma (AHT) and four categories: cases where caregivers report no trauma; cases of witnessed or admitted AHT; cases where caregivers report accidental trauma; and witnessed accidents. The data are then controlled for degree of intracranial pathology by only comparing cases in each category that have evidence of hypoxic-ischemic swelling.

Results

Although categories differ in clinical findings when all data are considered, they do not differ when the data are controlled for degree of intracranial pathology.

Conclusions

The data suggest that the clinical findings widely considered to be indicative of shaking are instead markers of the degree of intracranial pathology. Previous results showing differences were driven by selection effects, whereby different categories have different fractions of serious cases. Most notably, caregiver and witnessed reports of accidental head trauma led doctors to explore intracranial pathologies across a broader spectrum of severity, including milder cases, as opposed to situations where no head trauma is reported.

Objective

We present the cases of two sisters, both harboring the same ALDH18A1 gene mutations, who presented with a complex clinical phenotype characterized by spastic paraparesis with ataxia, epileptic encephalopathy, severe psychomotor deficits, and behavioral abnormalities.

Methods

Case description of two sisters with ALDH18A1 gene mutations.

Results

The older patient, a 12-year-old girl, exhibited spastic paraparesis with ataxia, microcephaly, facial dysmorphisms, and severe intellectual disability, with an absence of verbal language. An electroencephalogram (EEG) revealed marked spike-and-wave activation during sleep (SWAS), although no clinically documented seizures were observed. The younger sister, who was 9 years old, displayed a similar clinical presentation, including spastic paraparesis with ataxia, microcephaly, dysmorphisms, however, she displayed slightly more severe intellectual deficits and polymorphic seizures. EEG revealed a SWAS pattern in this case. Magnetic resonance imaging scans in both cases showed only a thin corpus callosum. Whole exome sequencing unveiled the presence of two likely pathogenic variants in compound heterozygosity within the ALDH18A1 gene. Specifically, these variants included the splice site variant c.88 + 1c.88+1G>A of paternal origin and the variant c.1364c.1364T>C (p.Leu455Ser) of maternal origin. Both sisters displayed normal blood levels of ammonia, ornithine, citrulline, arginine, and other amino acids.

Interpretation

These findings were compatible with ALDH18A1-related HSP complicated with a clinical and EEG pattern reminiscent of DEE-SWAS. We present the first report of DEE-SWAS in ALDH18A1-related HSP, expanding the clinical manifestations of this complex neurodevelopmental condition.

Background

Aromatic ʟ-amino acid decarboxylase (AADC) deficiency is a rare, severe neurological disorder caused by pathogenic variants in the dopa decarboxylase (DDC) gene, resulting in a combined deficiency of monoamine neurotransmitters. Clinically, patients present with a range of dysfunctions that impact motor, autonomic, and cognitive development. The constellation of symptoms of AADC deficiency varies among patients, and clinical presentation falls across a wide spectrum. However, most patients with AADC deficiency experience significant impairments when compared with children with normal development, irrespective of genotype, phenotype, or disease severity. Further, AADC deficiency is associated with increased mortality.

Methods

In response to the recent approval of a disease-modifying gene therapy for AADC deficiency, this review presents considerations for the selection of patients for treatment.

Conclusion

Suggested clinical criteria to determine whether a patient is a candidate for gene therapy are: (1) genetically and biochemically confirmed AADC deficiency; (2) lack of achievement of gross motor milestones and/or persistence of clinically significant movement disorders; (3) persistent neurocognitive or systemic symptoms secondary to AADC deficiency despite standard medical therapy; and (4) informed parental/guardian decision and consent to treatment.