​Researchers have linked Nodding syndrome, a devastating form of pediatric epilepsy found in specific areas of east Africa, to a parasitic worm that can cause river blindness. The study, published in Science Translational Medicine, suggests that the mysterious neurological disease may be caused by an autoimmune response to the parasitic proteins.

"This study identifies a cause of Nodding syndrome. But more broadly, these findings provide a novel perspective on epilepsy and suggest that some forms of this neurological disorder may be autoimmune in nature," said Avindra Nath, M.D., clinical director of the NIH's National Institute of Neurological Disorders and Stroke (NINDS).

Nodding syndrome is a form of epilepsy that occurs in children between the ages of 5 and 16 who live in distinct regions of Tanzania, Uganda and the Republic of South Sudan. It is characterized by head nodding, seizures, severe cognitive deterioration and stunted growth. Nodding syndrome may lead to malnutrition and patients have died through seizure-associated traumas such as fatal burns and drowning.

Many studies have reported an association between Nodding syndrome and Onchocerca volvulus, a parasitic worm that can also cause river blindness. The worm is spread by black flies in specific geographic areas, where clusters of Nodding syndrome have been observed. However, it was unclear whether the worm caused this neurological disorder.

In this study, Nath and his colleagues compared serum samples from patients with Nodding syndrome and healthy controls who all lived in the same village in Uganda.

The results showed high levels of antibodies to leiomodin-1 in the samples obtained from patients. In addition, antibody to leiomodin-1 was also present in cerebrospinal fluid of patients with Nodding syndrome. Previous studies have shown leiomodin-1 is found in muscles, but this was the first time researchers saw it in the nervous system.

To confirm that finding, Nath's team examined brain tissue and found leiomodin-1 inside brain cells, notably in regions associated with symptoms of Nodding syndrome. Furthermore, when healthy neurons in a dish were treated with serum from the patients and antibodies against leiomodin-1, they did not survive, but removing the antibodies increased brain cell survival.

In addition, Nath and his group found that antibodies that bind to leiomodin-1 also attach to proteins from Onchocerca volvulus. Structurally, leiomodin-1 was shown to be very similar to specific proteins from that parasite.

The results of this study suggest that Nodding syndrome may be an autoimmune disease, in which the immune system incorrectly attacks the body's own proteins. According to the researchers, the immune system creates antibodies to fight off the parasite following infection with Onchocerca volvulus. However, those antibodies also bind to leiomodin-1, so the immune system - incorrectly - will attack brain cells that contain that protein, which can result in symptoms of Nodding syndrome.

"The findings also suggest that therapies targeting the immune system may be effective treatments against this disorder and possibly other forms of epilepsy," said Nath. "Another huge implication of this study is that exterminating black flies and getting rid of the parasite should stop the disorder from occurring."

More research is needed to learn about the role of leiomodin-1 in healthy people as well as in individuals with epilepsy. For example, one-third of controls also had leiomodin-1 antibodies, but it is unclear whether these individuals may eventually develop Nodding syndrome.

Nath's team is currently developing an animal model of Nodding syndrome to further study the disease and test potential therapies.

This work was supported by the NIH Intramural Program.

Article: Nodding syndrome may be an autoimmune reaction to the parasitic worm Onchocerca volvulus, Tory P. Johnson et al., Science Translational Medicine, doi: 10.1126/scitranslmed.aaf6953, published 15 February 2017.

Following a prolonged epileptic seizures  neural connections of the brain may be rewired in an incorrect way. This may result in seizures that are difficult to control with medication. Mechanisms underlying this phenomenon are not entirely known, which makes current therapies ineffective in some patients.

In a study, published in the Annals of Neurology, researchers at the Neuroscience Center of the University of Helsinki have shown a role for gamma-aminobutyric acid (GABA), a main neurotransmitter in the brain, in the glutamatergic network rewiring in the brain. Rewiring of excitatory glutamatergic neuronal circuits is a major abnormality in epilepsy.

After a prolonged convulsive seizure, instead of the usual inhibitory effect of the transmitter, GABA accelerates brain activity. This, in turn, creates new, harmful neural connections.

Using a rat model of epilepsy they also found that accelerating effect of GABA was blocked for three days with a drug called bumetanide given soon after a seizure. The number of harmful connections detected in the brain was significantly lower two months later. Although there is extensive literature on the role of bumetanide in the acute treatment of seizures, this study has shown for the first time, that bumetanide has a long term effect on the neural network structure of the brain.

Citation

Nazim Kourdougli, Christophe Pellegrino, Juho-Matti Renko, Stanislav Khirug, Geneviève Chazal, Tiina-Kaisa Kukko-Lukjanov, Sari E. Lauri, Jean-Luc Gaiarsa, Liang Zhou, Angélique Peret, Eero Castrén, Raimo K. Tuominen, Valérie Crépel, Claudio Rivera. Depolarizing γ-aminobutyric acid contributes to glutamatergic network rewiring in epilepsy. Annals of Neurology, 2017; 81 (2): 251 DOI: 10.1002/ana.24870

Source: Helsingin yliopisto (University of Helsinki)

Cover: The amount of harmful nerve connections is significantly lower (far right, arrows) when treating with bumetanide after a prolonged convulsive seizure. Credit: Nazin Kourdougli

​Conference Title: 8th National Conference of the Association of Child Neurology " Bridging Advances and Basics in Child Neurology "
Location: New Delhi, India Date: Feb. 3-5, 2017 Hosting Society: Association of Child Neurology
Local Hosts: Dr. Rekha Mittal, Dr. Suvasini Sharma, Dr. Rakesh Jain
Type of meeting: National Conference

Participants: The 8th National conference of the Association of Child Neurology hosted approximately 400 attendees including 275 delegates (child neurologists, adult neurologists, pediatricians and trainees) plus 90 faculty. The delegates originated from all regions of India and included a few delegates from Bangladesh and Nepal. The faculty included 12 international and 78 national faculty. 

Panel of speakers and speaker affiliations: 

1. Linda De Meirleir, Vrie Universiteit Brussels, Brussels, Belgium 
2. Biju Hameed, Bristol Royal Hospital for Children, University of Bristol, Bristol, UK
3. Michael Johnston, Kennedy-Krieger Institute and Children's Hospital and Johns Hopkins Hospital, Baltimore, USA
4. Pratibha Singhi, Advanced Pediatrics Center, Post Graduate Institute of Medical Education and Research, Chandigarh, India
5. Ingrid Tein, Hospital for Sick Children, University of Toronto, Toronto, Canada
6. Jo Wilmshurst, Red Cross Children's Hospital, University of Capetown, Capetown, South Africa 

Topics covered (and speaker)
1. Linda De Meirleir: Pyridoxine dependency and related disorders.
2. Biju Hameed: Rational treatment of epilepsy and newer anti-epileptic drugs (panel discussion)
3. Michael Johnston: Disease modifying treatments for neurogenetic developmental disorders – what does the future hold ?
4. Pratibha Singhi: Dyskinetic cerebral palsy – recent advances in diagnosis and treatment.
5. Ingrid Tein: Metabolic myopathies; Recent advances in the treatment of mitochondrial disorders
6. Jo Wilmshurst: Epilepsy in infants: Treatment guidelines. 

The conference was composed of parallel sessions including the following themes (1) New frontiers in pediatric neurology (2) Hot topics in epilepsy (3) Status epilepticus (4) Bedside clinical neurology (5) Immune mediated and inflammatory disorders (6) Video sessions of autism, reflex seizures, psychogenic seizures and epilepsy mimics in infants (7) Neuromuscular disorders (8) Neurometabolic disorders (9) Recent advances in pediatric neurology (10) Epilepsy (11) Neuro-infections (12) Stroke and headache. 

The common sessions included (1) Panel discussion on the rational treatment of epilepsy and newer anti-epileptic drugs (2) Mechanisms of epilepsy (3) Neurodevelopmental disorders (4) Genetic testing in pediatric neurologic conditions (5) Debate on Neonatal screening (6) Parasomnias (7) Movement disorders (8) Controversies in neurology. There were also poster presentations with a poster competition adjudicated by national faculty and ICNA members. 

Outcomes/Future Plans 

1. The conference stimulated lively interactive academic discussions.
2. Excellent progress was made during the site visit and in the planning of the scientific program for the upcoming ICNC2018 (Nov. 14-18th, 2018) in Mumbai, India with the local organizing committee and executive board of the AOCN. 

Support: 

According to the ICNA policy, the ICNA members supported their own international flights as well as their own accomodations in Mumbai during the ICNC2018 site visit. The ICNA members gratefully acknowledge the support of the AOCN for the internal costs of accomodations and local travel related to the AOCN conference in New Delhi. 

ICNA members received no honoraria. The ICNA members also acknowledge their respective Universities/teaching hospitals for allowing them to use their conference leave time away from service commitments to contribute to the AOCN conference.

Main conference program http://www.childneurocon2017.com/scientific-program/ 

Using magnetic resonance imaging (MRI) in infants with older siblings with autism, researchers from around the country were able to correctly predict 80 percent of those infants who would later meet criteria for autism at two years of age.

The study, published today in Nature, is the first to show it is possible to identify which infants – among those with older siblings with autism – will be diagnosed with autism at 24 months of age. This first-of-its-kind study used MRIs to image the brains of infants, and then researchers used brain measurements and a computer algorithm to accurately predict autism before symptoms set in.

"Our study shows that early brain development biomarkers could be very useful in identifying babies at the highest risk for autism before behavioral symptoms emerge," said senior author Joseph Piven, MD, the Thomas E. Castelloe Distinguished Professor of Psychiatry at the University of North Carolina-Chapel Hill. "Typically, the earliest an autism diagnosis can be made is between ages two and three. But for babies with older autistic siblings, our imaging approach may help predict during the first year of life which babies are most likely to receive an autism diagnosis at 24 months."

This research project included hundreds of children from across the country and was led by researchers at the Carolina Institute for Developmental Disabilities (CIDD) at the University of North Carolina, where Piven is director. The project's other clinical sites included the University of Washington, Washington University in St. Louis, and The Children's Hospital of Philadelphia. Other key collaborators are McGill University, the University of Alberta, the University of Minnesota, the College of Charleston, and New York University.

"This study could not have been completed without a major commitment from these families, many of whom flew in to be part of this," said first author Heather Hazlett, PhD, assistant professor of psychiatry at the UNC School of Medicine and a CIDD researcher. "We are still enrolling families for this study, and we hope to begin work on a similar project to replicate our findings."

People with Autism Spectrum Disorder (or ASD) have characteristic social deficits and demonstrate a range of ritualistic, repetitive and stereotyped behaviors. It is estimated that one out of 68 children develop autism in the United States. For infants with older siblings with autism, the risk may be as high as 20 out of every 100 births. There are about 3 million people with autism in the United States and tens of millions around the world.

Despite much research, it has been impossible to identify those at ultra-high risk for autism prior to 24 months of age, which is the earliest time when the hallmark behavioral characteristics of ASD can be observed and a diagnosis made in most children.

Joe Piven, MD

For this Nature study, Piven, Hazlett, and researchers from around the country conducted MRI scans of infants at six, 12, and 24 months of age. They found that the babies who developed autism experienced a hyper-expansion of brain surface area from six to 12 months, as compared to babies who had an older sibling with autism but did not themselves show evidence of the condition at 24 months of age. Increased growth rate of surface area in the first year of life was linked to increased growth rate of overall brain volume in the second year of life. Brain overgrowth was tied to the emergence of autistic social deficits in the second year.

Previous behavioral studies of infants who later developed autism – who had older siblings with autism –revealed that social behaviors typical of autism emerge during the second year of life.

The researchers then took these data – MRIs of brain volume, surface area, cortical thickness at 6 and 12 months of age, and sex of the infants – and used a computer program to identify a way to classify babies most likely to meet criteria for autism at 24 months of age. The computer program developed the best algorithm to accomplish this, and the researchers applied the algorithm to a separate set of study participants.

The researchers found that brain differences at 6 and 12 months of age in infants with older siblings with autism correctly predicted eight out of ten infants who would later meet criteria for autism at 24 months of age in comparison to those infants with older ASD siblings who did not meet criteria for autism at 24 months.

"This means we potentially can identify infants who will later develop autism, before the symptoms of autism begin to consolidate into a diagnosis," Piven said.

If parents have a child with autism and then have a second child, such a test might be clinically useful in identifying infants at highest risk for developing this condition. The idea would be to then intervene 'pre-symptomatically' before the emergence of the defining symptoms of autism.

Research could then begin to examine the effect of interventions on children during a period before the syndrome is present and when the brain is most malleable. Such interventions may have a greater chance of improving outcomes than treatments started after diagnosis.

Heather Hazlett, PhD

"Putting this into the larger context of neuroscience research and treatment, there is currently a big push within the field of neurodegenerative diseases to be able to detect the biomarkers of these conditions before patients are diagnosed, at a time when preventive efforts are possible," Piven said. "In Parkinson's for instance, we know that once a person is diagnosed, they've already lost a substantial portion of the dopamine receptors in their brain, making treatment less effective."

Piven said the idea with autism is similar; once autism is diagnosed at age 2-3 years, the brain has already begun to change substantially.

"We haven't had a way to detect the biomarkers of autism before the condition sets in and symptoms develop," he said. "Now we have very promising leads that suggest this may in fact be possible."

For this research, NIH funding was provided by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Institute of Mental Health (NIMH), and the National Institute of Biomedical Imaging and Bioengineering. Autism Speaks and the Simons Foundation contributed additional support.

Source: UNC Health Care Press Release

Citation: Hazlett HC, Gu H, Munsell BC, Kim SH, Styner M, Wolff JJ et al. (2017) Early brain development in infants at high risk for autism spectrum disorder. Nature 542 (7641):348-351. DOI: 10.1038/nature21369 PMID: 28202961.

Cover image: A map of significant group differences in surface area from 6 to 12 months. Exploratory analyses were conducted with a surface map containing 78 regions of interest