Stories about: neurology

Fast brain waves: A better biomarker for epilepsy

EEG and MEG detection of HFOs, fast brain waves associated with epilepsy
Localization of fast brain waves, called HFOs, with scalp EEG (left) and MEG (right). HFOs present a new biomarker for areas of the brain responsible for epileptic seizures.

In the U.S., about one in 100 people have some form of epilepsy. A third of those people have seizures that cannot be controlled with drugs, eventually requiring surgery to remove the area of their brain tissue that is triggering seizure activity.

“If you can identify and surgically remove the entire epileptogenic zone, you will have a patient who is seizure-free,” says Christos Papadelis, PhD, who leads the Boston Children’s Brain Dynamics Laboratory in the Division of Newborn Medicine and is an assistant professor in pediatrics at Harvard Medical School.

Even experts in this field were skeptical for years about the non-invasive detection of HFOs. But now, thanks to our study and other researchers’ work, these people are changing their minds. At present, however, these surgeries are not always successful. Current diagnostics lack the ability to determine precisely which parts of an individual’s brain are inducing his or her seizures, called the epileptogenic zone. In addition, robust biomarkers for the epileptogenic zone have been poorly established.

But now, a team at Boston Children’s Hospital is doing research to improve pre-surgical pinpointing of the brain’s epileptogenic zone. They are using a newly-established biomarker for epilepsy — fast brain waves called high-frequency oscillations (HFOs) — that can be detected non-invasively using scalp electroencephalography (EEG) and magnetoencephalography (MEG).

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Brain ‘connectome’ on EEG could help diagnose attentional disorders

EEG connectome could diagnose attentional disorders ADHD
EEGs shouldn’t just be for epilepsy, say these researchers.

Attention deficit disorder (ADD), with or without hyperactivity, affects up to 5 percent of the population, according to the DSM-5. It can be difficult to diagnose behaviorally, and coexisting conditions like autism spectrum disorder or mood disorders can mask it.

While recent MRI studies have indicated differences in the brains of people with ADD, the differences are too subtle and MRI too expensive to be a practical diagnostic measure. But new research suggests a role for an everyday, relatively cheap alternative: electroencephalography (EEG).

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Patients’ brain tissue unlocks the cellular hideout of Sturge-Weber’s gene mutation

A diagram of the skull and brain showing the leptomeninges, which is affected by Sturge-Weber syndrome
Sturge-Weber syndrome causes capillary malformations in the brain. They occur in the brain’s leptomeninges, which comprise the arachnoid mater and pia mater.

A person born with a port-wine birthmark on his or her face and eyelid(s) has an 8 to 15 percent chance of being diagnosed with Sturge-Weber syndrome. The rare disorder causes malformations in certain regions of the body’s capillaries (small blood vessels). Port-wine birthmarks appear on areas of the face affected by these capillary malformations.

Aside from the visible symptoms of Sturge-Weber, there are also some more subtle and worrisome ones. Sturge-Weber syndrome can be detected by magnetic resonance imaging (MRI). Such images can reveal a telltale series of malformed capillaries in regions of the brain. Brain capillary malformations can have potentially devastating neurological consequences, including epileptic seizures.

Frustratingly, since doctors first described Sturge-Weber syndrome over 100 years ago, the relationship between brain capillary malformations and seizures has remained somewhat unexplained. In 2013, a Johns Hopkins University team found a GNAQ R183Q gene mutation in about 90 percent of sampled Sturge-Weber patients. However, the mutation’s effect on particular cells and its relationship to seizures still remained unknown.

But recently, some new light has been shed on the mystery. At Boston Children’s Hospital, Sturge-Weber patients donated their brain tissue to research after it was removed during a drastic surgery to treat severe epilepsy. An analysis of their tissue, funded by Boston Children’s Translational Neuroscience Center (TNC), has revealed the cellular location of the Sturge-Weber mutation. The discovery brings new hope of finding ways to improve the lives of those with the disorder.

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Antisense drug for spinal muscular atrophy nears the clinic

spinal muscular atrophy Spinraza
Max High of South Carolina was diagnosed with SMA before the age of 1. (Ron Brinson/Flickr)

Update: Nusinersen received FDA approval on December 23, 2016, and will be marketed as Spinraza.

In recent months, two Phase III clinical trials have shown a clear benefit of nusinersen in children with spinal muscular atrophy (SMA), a genetic motor neuron disease that robs children of muscle control and is the leading genetic cause of infant mortality. The ENDEAR trial, involving infants with the more severe SMA Type 1, was first to terminate randomization in August 2016. The CHERISH trial, involving older children with milder Type 2 SMA, was halted on November 8, 2016, because it also met its efficacy target.

Both trials are now open-label, and the FDA has granted nusinersen a priority review. The drug, formerly called SMNRx and now brand-named Spinraza, is an antisense oligonucleotide works by altering gene splicing (see sidebar).

Vector asked Basil Darras, MD, director of the Spinal Muscular Atrophy Program at Boston Children’s Hospital, to put these developments in perspective. Darras is site principal investigator at Boston Children’s for both trials. The hospital was the first in the world to enroll a child with SMA Type 1 in the ENDEAR study, in 2014.

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Sounding out intracranial pressure with a hearing test

Heidary ear ICP measurement croppedBrain tumors, traumatic head injury and a number of brain and nervous system conditions can cause pressure to build up inside the skull. As intracranial pressure (ICP) rises, it can compress the brain and result in swelling of the optic nerves, damaging brain tissue and causing irreversible vision loss.

That’s what nearly happened to a 13-year-old boy who had three weeks of uncontrolled headaches and sudden double vision. His neuro-ophthalmologist at Boston Children’s Hospital, Gena Heidary, MD, PhD, found reduced vision in the right eye, along with poor peripheral vision, an enlarged blind spot and swelling of both optic nerves.

As Heidary suspected, he had idiopathic intracranial hypertension, a condition that can raise ICP both in children and adults. Heidary performed an operation around the optic nerve to relieve the pressure, and vision in the boy’s right eye gradually improved, though not completely. Heidary has had to monitor his ICP ever since to protect his visual system from further irreversible damage.

Unfortunately, such monitoring currently is pretty invasive.

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Intelligent ICU monitoring for patients in status epilepticus: BurSIn

The BurSIn system, in development, interprets EEG data along several key parameters and accurately identifies burst and suppression patterns.
The BurSIn system, in development, interprets EEG data along several key parameters and accurately identifies burst and suppression patterns.

Status epilepticus, a life-threatening form of persistent seizure activity in the brain, is challenging to treat. It requires hospitalization in an intensive care unit, constant monitoring and meticulous medication adjustment. An automated, intelligent monitoring system developed by clinicians and engineers at Boston Children’s Hospital could transform ICU care for this neurological emergency.

Typically, children in status epilepticus are first given powerful, short-acting seizure medications. If their seizures continue, they may need to be placed in a medically induced coma, using long-acting sedatives or general anesthetics. “The goal,” explains biomedical engineer Christos Papadelis, PhD, “is to supply enough sedating medication to suppress brain activity and protect the brain from damage, while at the same time avoiding over-sedation.”

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Mapping the wiring of the developing brain in 3D

Ed. note: Last week we wrote about Jurriaan Peters, MD’s brain network analysis in children with autism. In the second of our two part series on brain mapping, we talk about ways of mapping the brain’s physical wiring.

(AMagill/Flickr)

At the most basic level, the brain is a collection of wires, albeit a really complex one.

But how during development do nerve fibers thread their way through the growing brain and make the right connections?

The answer to that question could reveal more about the nature of conditions like autism spectrum disorders—which, as we reported about a year and a half ago, seem to have their roots in structurally altered brain pathways.

“We know very little about what’s happening in the developing brain in three dimensions,” says Emi Takahashi, PhD, a researcher in the Fetal-Neonatal Neuroimaging & Developmental Science Center (FNNDSC) at Boston Children’s Hospital. “With histology techniques, we can achieve a two-dimensional view over small areas, but it’s hard to know which fiber bundles are growing in which ways during different stages of development in the whole brain.”

But new MRI-based technologies are quickly closing that knowledge gap, giving us our first high-resolution peek into how the developing brain wires itself up.

Using something called high angular resolution diffusion imaging (HARDI) MRI, Takahashi and her colleagues (including neuroradiologist and FNNDSC director P. Ellen Grant, MD) can trace the three-dimensional pathways within the growing brain via stunning images like these:

Courtesy Cerebral Cortex (Takahashi et al., 2012)

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Preventing autism after infant seizures

Early seizures may disrupt circuit formation in babies' brains, leading to autism. But new research suggests that an existing drug can reverse this.

This is the third post in a series about new approaches for seizures and epilepsy. Read the first and second posts.

We already know that there’s some kind of connection between epilepsy and autism: Children who have seizures as newborns not uncommonly develop autism, and studies indicate that about 40 percent of patients with autism also have epilepsy. New research at Boston Children’s Hospital finds a reason for the link, and suggests a way to break it — using an existing drug that’s already been given safely to children.

In the online journal PLoS ONE, Frances Jensen, MD, in the Department of Neurology and the F.M. Kirby Neurobiology Center at Boston Children’s, and lab members Delia Talos, PhD, Hongyu Sun, MD, PhD, and Xiangping Zhou, MD, PhD, showed in a rat model that early-life seizures not only lead to epilepsy later in life, but also produce autistic-like behaviors.

Drilling deeper, they showed that early seizures hyper-activate a group of signaling molecules collectively known as the mTOR pathway.

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Brains, babies and battlefields: Taking pediatric neurocritical care to the bedside

Evacuation of a soldier injured by a roadside bomb, June 17, 2011, Kandahar province of Afghanistan (DVIDSHUB/Flickr)

From the time he was 11, Robert Tasker knew he wanted to be a doctor. The son of a serviceman, he was drawn to battlefield surgery, evacuations and managing traumatic injuries. Instead, he ended up on a different kind of battlefield, where what’s at stake are the highly vulnerable, still developing brains of infants and children – and where it’s critical to be mobile and show up on time.

Tasker directs the Pediatric NeuroCritical Care program at Children’s Hospital Boston, the first of its kind in the world. His goal is to protect brain function not only in children suffering direct head injury, but children undergoing major surgery, children with stroke, children hospitalized for critical illness, children on ventilators, children with nervous-system infections like meningitis and more.

Born in Hong Kong and raised throughout the globe,

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The neurology resident that could

Eye muscles, the nerves that control them, and where things go wrong (click to enlarge)

Elizabeth Engle used to wait in peoples’ driveways until midnight, hoping to enroll them in her genetic studies of eye-movement disorders. She landed there by chance: during her neurology residency, she saw a little boy whose eyes were frozen in a downward gaze. Wanting to find a solution to a disorder that others had written off, she talked her way into the muscular dystrophy genetics lab of Alan Beggs and Lou Kunkel at Children’s.

Why muscular dystrophy? That tragic muscle-weakening disease somehow spares the eye muscles. Engle thought if Beggs and Kunkel took her on, she could answer two questions at once – what was protecting the eye muscles in muscular dystrophy, and what had caused the little boy’s fixed gaze and droopy eyelids. Plus, she needed laboratory training to study the samples she’d started gathering. “I didn’t have a PhD and was never officially trained in the lab,” she once said. “I didn’t even know how to make chemical solutions.”

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