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Advances in Therapeutics, Diagnostics, and Genetic Testing Change the Face of Child Neurology

Article In Brief

Advances in genetics, imaging, multidisciplinary treatment teams, and new therapies have changed the way childhood neurologic disorders such as epilepsy, cerebral palsy, autoimmune encephalitis, and other conditions are treated, pediatric neurologists told Neurology Today.

The field of child neurology has grown by leaps and bounds since Phillip L. Pearl, MD, FAAN, completed an epilepsy fellowship in 1990 and began practicing his specialty.

“When I was in training and started practice, we were mainly ruling out genetic disorders such as Fragile X by obtaining trinucleotide repeat testing and chromosome errors by ordering karyotypes,” recalled Dr. Pearl, director of epilepsy and clinical neurophysiology at Boston Children's Hospital and professor of neurology at Harvard Medical School. “Those tests are ancient by today's standards.”

In the 1990s, Dr. Pearl noted researchers were able to unravel various epilepsy subtypes by identifying putative genetic mutations. Some of the most notable types were the channelopathies—SCNIA to explain Dravet syndrome and KCNQ2 to account for benign familial neonatal seizures. Later, KCNQ2 was recognized as a cause of a severe early onset epileptic encephalopathy.

“We were stuck in the ‘90s with just a few discovered pathogenic gene variants as etiologies for our patients; the information has exploded [since then] over the past two decades,” Dr. Pearl said.

“Our terminology has transformed from syndromic diagnoses of, for example, early myoclonic encephalopathy and Ohtahara syndrome to specific genes,” he added, citing CDKL5 developmental disorder and ARX encephalopathy as well.

“The list goes on, and it is the explosion in genomics, and later proteomics, metabolomics, connectomics, and more of these conceptual ‘omics,’ that have transformed our ability to diagnose and, on the horizon, treat our patients.”

Advances in Imaging

Child neurology has also benefitted from inroads in adult neurologic disease. Imaging techniques have become more sophisticated, and numerous new medications have become available to treat epilepsy, headache, immune-mediated disorders, and genetic conditions.

“The major change has been our ability to recognize the genetic underpinnings of many disorders quickly,” said Anne M. Connolly, MD, FAAN, chief of pediatric neurology at Nationwide Children's Hospital and professor and chair of pediatrics and neurology at the Ohio State University College of Medicine in Columbus. “This has allowed better bench-to- bedside treatment approaches and tighter collaborations between bench and translational researchers.”


“Initially, the focus was on symptomatic therapy, and now we have interventions that can change a child or adults life.”—DR. ANN TILTON

Multidisciplinary Teams

Collaboration also has fostered a team-based multidisciplinary approach to medical management of complex diseases. This allows clinicians to be in close communication with each other and offers the patient convenience in scheduling appointments. For instance, a patient with muscular dystrophy can visit several specialists—a neurologist, physiatrist, pulmonologist, orthopedic surgeon, and an occupational and physical therapist—in the same clinic on one day, said Bruce H. Cohen, MD, FAAN, president of the Child Neurology Society and chair of the AAN Advocacy Committee and board of directors.

However, there is some divergence between child and adult neurology. “The developing brain is uniquely vulnerable to repeated seizures,” said E. Steven Roach, MD, FAAN, professor and associate chair of the department of neurology at the University of Texas at Austin Dell Medical School.

It is well established that prompt treatment is helpful for infantile spasms and other severe epilepsies. But now, there is increasing evidence that presymptomatic management of children at high risk for epilepsy may be effective as well, Dr. Roach said.

A recent study of children with tuberous sclerosis, which is often associated with infantile spasms and other forms of epilepsy, indicated that administration of vigabatrin prior to the onset of clinical seizures led to improvement in long-term cognition and less severe disease. “It seems likely that other disorders with a predictably high epilepsy risk could benefit from a similar approach,” he said.

Among other progress in the last two decades, autoimmune encephalitis has been characterized, and several different autoantibodies have now been documented. Antibody testing is now readily available, and treatment works for many individuals.

“Autoimmune encephalitis is an often-devastating disorder that is more common than viral encephalitis, so being able to diagnose and treat it is a major advance,” said Dr. Roach, whose areas of expertise include stroke in children and selected genetic disorders.


“We were stuck in the ‘90s with just a few discovered pathogenic gene variants as etiologies for our patients; the information has exploded over the past two decades.”—DR. PHILLIP L. PEARL

High- and Low-Tone Muscular Problems

“My career has spanned over 20 years, and I've been fortunate to see significant advances,” said Ann Tilton, MD, FAAN, FANA, professor of neurology and pediatrics at Louisiana State University Health Sciences Center in New Orleans. “It has been really remarkable—the time that I've been in practice.”

In particular, the most recent five to 10 years have seen “incredible breakthroughs,” Dr. Tilton added. “Initially, the focus was on symptomatic therapy, and now we have interventions that can change a child or adult's life.”

Dr. Tilton's areas of expertise range from low-tone to high-tone disorders. She has a longstanding interest in cerebral palsy and other forms of hypertonia and spasticity as well as the other end of the spectrum of tone—low tone and neuromuscular disease. “In those areas alone, we have had significant leaps forward,” she said.

In the care of patients with cerebral palsy, intrathecal baclofen and botulinum toxin have improved patients' lives and outcomes. In addition, tremendous insight has been gained into mimics of cerebral palsy. “With expanded genetic testing, disorders have been identified that closely resemble cerebral palsy but have a genetic origin,” Dr. Tilton said.

More Antiseizure Drugs

Many new antiseizure drugs also have been added to the arsenal of treatment options since Patricia K. Crumrine, MD, FAAN, completed a fellowship in pediatric neurology in 1974. At that time, the only medications were phenytoin, phenobarbital, mysoline, and bromides—and they were not even in frequent use, said Dr. Crumrine, professor of pediatrics at the University of Pittsburgh School of Medicine, where she is a child neurologist/epileptologist focusing her research on the clinical trials of new antiepileptic drugs.

Imaging also posed limitations for diagnostic and monitoring purposes. “MRIs were not available for routine clinical use, and CT scans were just coming into use,” she recalled. “EEG machines were only eight channels of data and were recorded on paper and not digitally as they are today.”

Dr. Crumrine added that “my practice has changed with the use of these newer diagnostic tools and the more advanced treatment options. These have resulted in improved patient outcomes.”

Now, she noted that there is support for ongoing medical research and dissemination of knowledge via many subspecialty meetings at regional, national, and international levels. Furthermore, “patients and their families stimulate and support research with questions and participation in clinical research groups,” Dr. Crumrine said.

Costs of Genetic Testing

Costs for testing also have come down considerably due to “game-changing breakthroughs in rapid and inexpensive genetic testing that has taken the diagnostic odyssey from years to weeks,” said Dr. Cohen, who is director of the NeuroDevelopmental Science Center at Akron Children's Hospital and a professor of pediatrics at Northeast Ohio Medical University in Rootstown.


“Once we have a hypothesis that a patient possibly has a genetic disorder, its much easier, faster, and less expensive, to confirm a definitive diagnosis.”—DR. BRUCE H. COHEN

About 15 years ago, if a neurologist suspected a particular condition, he or she could order specific genetic tests for some, but not all, diseases. The typical genetic test to sequence a single gene would run between $2,000 and $5,000, Dr. Cohen said.

“Now, we can sequence literally thousands of genes at a total cost of around $1,000,” he said. “Once we have a hypothesis that a patient possibly has a genetic disorder, it's much easier, faster, and less expensive, to confirm a definitive diagnosis.”

New life-saving therapies for multiple sclerosis and other diseases have emerged. Although multiple sclerosis is mainly a disease of adults, it can affect children and adolescents. “The new therapies developed in the last five years have, for many patients, turned multiple sclerosis from an incapacitating disease to one where, with therapy, the kids can live normal lives,” Dr. Cohen said.

Progress also has been made in treatments for childhood neurogenetic disorders. All neurogenetic disorders cause a protein to be partially or completely missing. About five years ago, therapies that allow some or complete expression of the missing protein were developed, said Dr. Connolly, a specialist in neuromuscular disorders.

“For children with neuromuscular disorders, we now have the ability to treat the underlying cause. This is true for some forms of muscular dystrophy and spinal muscular atrophy [SMA],” she said, adding that the most severe form of SMA was generally fatal by age 2. “In contrast, now children with SMA treated early with gene replacement have excellent prognoses,” thanks to a gene transfer therapy approved by the US Food and Drug Administration in 2019.

Dr. Connolly's collaborator and mentor, Jerry R. Mendell, MD, FAAN, Curran-Peters Chair of Pediatric Research at Nationwide Children's Hospital, who served from 2004 to 2017 as director of the Center for Gene Therapy at the Research Institute, led both the basic and translational science for SMA, from bench to bedside. “He and collaborators continue to work toward that same goal for children with Duchenne muscular dystrophy,” Dr. Connolly said.

Due to these major advances, more children can be successfully treated. “When I started caring for children with neurogenetic disorders, compassion was often the only tool I had,” said Dr. Connolly, who completed her fellowship training in 1990. “Now, it is possible to give hope to many with previously fatal disorders,” Dr. Connolly said, adding, “We have come a long way.”

Dr. Cohen noted how remarkable it is that specialized treatment for these disorders can begin soon after birth. “Although the final story hasn't been written because it's only been around for a few years, it appears that many of these children can survive with a great quality of life.”

He remains optimistic about what the future has in store. “It's exciting to be in child neurology,” he said, adding that in “five to 10 years, it is possible we will have treatments for hundreds of diseases that aren't available right now.”