In Rett syndrome, a genetic disorder affecting almost exclusively girls, mutations in the MECP2 cause a regression of language and motor skills from 12 to 18 months. The children then generally stabilize, but it is difficult to predict how Rett will ultimately affect them. Some girls develop epilepsy; others have no seizures. Language, cognitive functions and fine motor skills vary considerably.
A recent pilot study conducted by Patrick Davis, MD, PhD, resident in the Department of Neurology at Boston Children’s Hospital, and April Levin MD, researcher and neurologist, suggests that overnight EEG studies may one day help clinicians and families to know what to do. wait and help inform care for girls with Rett syndrome.
“There is a wide range of symptom severity in Rett syndrome,” Davis says. “For example, language development can range from relatively normal to the ability to have simple conversations to no words and no understanding of language. We currently have no reliable way to predict, let alone alter , this developmental trajectory. A biomarker would be a step towards the development of more refined interventions.”
The rhythms of the night
EEG studies in Rett syndrome are not new, but are almost always done while the child is awake. Davis and colleagues Kyle Takach, Kiran Maski, MD, MPH, and April Levin, MD wanted to see what happens to the EEG during sleep.
“Sleep is an active time when the brain is processing new information and rewiring itself to optimize its functioning,” says Davis. “We thought that altered brain activity during sleep might contribute to neurodevelopmental problems in Rett syndrome. There is a rich literature on sleep EEGs, but few studies have looked specifically at Rett syndrome. Rtt.”
The retrospective study analyzed overnight EEG data from 22 girls with Rett syndrome who had clinician-ordered EEGs (most likely to assess seizures) and 25 age-matched controls, developing usually. The researchers tracked the different frequency waves that make up the EEG signal, each created by the collective firing of large groups of neurons.
Specifically, they focused on phase-amplitude coupling, a measure of how slow EEG oscillations, which are important for memory consolidation, are compared to high-frequency waves. This relationship is believed to reflect the quality of integration of brain activity.
And this is where children with Rett syndrome clearly diverged. Typically developing children showed a tight coupling of slow and fast oscillations at the top of the brain, beginning around 12 to 18 months of age. Children with Rett syndrome never developed this feature and instead had clearly different patterns of slow and fast oscillation couplings in various brain locations.
“Just by looking at the sleep EEG, we could predict whether or not a patient had Rett syndrome with 90 percent accuracy,” Davis says. “We also found specific EEG patterns that may correspond to different Rett syndrome subtypes or even help predict clinical severity.”
Long-term goals: Rett syndrome and beyond
Davis points out that this work is only a first pass in a small, select group of patients that needs to be confirmed and expanded. Nor does it prove that altered EEG patterns are the cause of neurodevelopmental regression in Rett syndrome. But Davis is excited about the possibilities the job brings.
“If we can validate our findings in a larger cohort of girls with Rett, it would be interesting to see if noninvasive brain stimulation at night—with a cap worn while sleeping—might improve some EEG biomarkers, and if targeted brain stimulation would improve a child’s developmental trajectory,” he says. “That’s one of our ultimate goals.”
Transcranial magnetic stimulation (TMS) has already been tested in children with epilepsy and has been shown to be safe. It could be an alternative to epilepsy or sleeping pills, which come with many side effects, or be used in combination with medication. Further EEG studies in girls with Rett syndrome could point the way to particular brain circuits to be targeted with brain stimulation.
Davis and colleagues are also interested in nighttime EEGs in children with Rett syndrome who are not epileptic, and in children with other early-onset disorders involving altered sleep dynamics, such as epileptic encephalopathies. , infantile spasms, trisomy 21, and autism spectrum disorders.
“The development of reliable biomarkers is a key step towards identifying the best antiepileptic drugs and developing pharmacological treatments for the cognitive and intellectual symptoms of these disorders,” Davis said. “We believe that overnight EEGs could be the foundation for meaningful translation work.”
Boston Children’s Hospital