Subject:  The Pediatric Brain Injury Workshop: Plasticity and Regenerative Therapy

Location:  Houston, Texas

Co-Chairs: Dr. Huda Zoghbi, MD, Professor, Departments of Pediatrics – Neurology and Developmental Neuroscience and Neuroscience; Programs in Cell & Molecular Biology; Developmental Biology; and Translational Biology & Molecular Medicine, Baylor College of Medicine; Director, Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital; Investigator, Howard Hughes Medical Institute

Attendees:  Clinicians, MRI specialists, scientists with expertise in CP, traumatic brain injury, spinal cord injury, animal modeling and stem cells, as well as representatives from Pediatric Brain Foundation and Texas Children’s Hospital.

Recap:  Pediatric Brain Foundation, in collaboration with Texas Children’s Hospital, hosted The Pediatric Brain Injury Workshop: Plasticity and Regenerative Therapy at the Hotel ZaZa in Houston, Texas.  Some of the top scientists and researchers will be in attendance from all over the nation.  By setting the stage for multidisciplinary collaboration, we are giving scientists a format to make sure that our children are getting the science they need.

Scientific highlights of The Pediatric Brain Injury Workshop: Plasticity and Regenerative Therapy

by Donald Marion, MD, Fmr. CNS Science Officer

The static brain injury workshop was held as planned on February 10-12, 2008, and was very successful. In collaboration with Texas Children’s Hospital, CNS Foundation brought together 18 highly productive and innovative clinician/scientists for intense discussions about the most pressing current and future issues to be addressed in order to improve outcomes following cerebral palsy (CP) and periventricular leukomalacia (PVL). The meeting format was unique in that presentations were limited to 12 minutes, and the use of slides was discouraged. In this way we were able to stimulate very informative and spontaneous interactions and the sharing of ideas between all 18 attendees. Moreover, the group included a mix of clinicians, MRI specialists, and basic scientists with expertise in CP, traumatic brain injury, spinal cord injury, animal modeling, and stem cells. Thus, the discussions of pediatric static brain injury covered all aspects of the disease, from etiology to optimal treatment paradigms. Dr. Huda Zoghbi, the meeting co-chair, set the tone by observing that one of the most important current problems is a lack of information about the pathobiology of CP. She suggested that an inadequate understanding of the anatomic, physiologic and metabolic causes of the disease is the most likely reason for failure of past drug and other therapeutic trials.

Major topics of discussion were human diseases most likely to benefit from treatment, optimal animal models of CP, limitations to repair and remodeling including glial responses, and facilitating plasticity and remodeling by stimulating production of endogenous stem cells and exogenous and endogenous axonal outgrow and guidance. In addition, 3 separate sessions were devoted to discussions of the potential for various types of stem cells, including neural progenitor cells, to effectively repair brain tissue or brain circuits damaged as a result of ischemia or CP. Of particular interest were the novel findings of the spinal cord researchers (Reier, Davies) regarding mechanisms for axonal outgrowth through or around glial scar, and especially their most recent findings with the use of decorin, a naturally occurring proteoglycan that promotes axonal growth across the glial scar. Exciting and thought provoking presentations also were provided by the imaging experts (Pautler, Limperopoulos) who suggested ways in which in-utero MRI or MRS imaging of the pregnant mother may soon be possible to non-invasively identify fetal distress, and fetuses at risk for hypoxic-ischemic encephalopathy (HIE) or CP.

By the end of the meeting the attendees reached consensus on the need for better histochemical and histopathologic studies of patients with CP and PVL. Specifically, a brain tissue repository was considered essential in order to answer questions about which brain cells are most vulnerable to PVL, what are the secondary histologic changes, is there significant glial scar and what is it’s composition, and what changes occur in the extracellular matrix. There should be protocols for harvesting and preservation of the tissue included in this Tissue Bank, particularly because specimens will usually be harvested post-mortem. In addition, there is a need to harvest live cells from CSF, serum, and saliva for ex vivo growth and characterization. The attendees also agreed that there is a need for better clinical grading of patients with PVL. Specifically, there needs to be better epidemiologic information about the mothers of these children, better information about genetic predisposition, and a comprehensive study of reasons why some kids with CP do well while others do poorly.

Moreover, there is an urgent need for much better surrogate markers,,molecular, electrophysiologic, radiologic, or others, for predicting the severity of the injury early after birth. The group also recommended standardization of imaging protocols, and of long-term behavioral assessment protocols, to allow for meaningful comparisons of therapeutic trials. The consensus of the basic scientists in the group was that there is no single animal model that reliably replicates all of the characteristics of human CP or PVL. Instead, the group proposed that different animal models were more or less appropriate for different aspects of the diseases. It therefore was recommended that there be a consortium of investigators that used different animal models, thereby allowing for the efficient testing of new concepts or therapies in a variety of models.

While consensus agreement was not reached on all of the details of a therapeutic clinical trial for CP or PVL, some characteristics of the ideal trial were proposed. For example, such a trial would include standardized entry criteria and might require that those enrolled have lactate spikes on their MRS, abnormal signal on DWI, and a negative cranial ultrasound. They would all have a birth weight between 00-1000 grams, and have had at least one dose of antenatal steroids. Long-term outcome studies at a set time point would be planned, and would include standardized cognitive, motor, visual, and hearing tests. The actual therapy being tested would have a robust effect in at least two different animal models, with no significant adverse effects.

Perhaps the most important consequence of the meeting was the introduction of several young neuroscientists from all over the US who had never met. In just the few weeks since the meeting I have received several emails from them describing the details of how they are planning collaborations with individuals they met in Houston for pre-clinical and clinical studies of CP and PVL. In addition, the Houston meeting helped to bring into sharp focus the current and most pressing research problems related to these diseases.”