Shared Learning:
Global Perspective

The AACPDM’s 64th Annual Meeting is designed to provide targeted opportunities for dissemination of information in the basic sciences, prevention, diagnosis, treatment, and technical advances as applied to persons with cerebral palsy and developmental disorders. The program provides a forum for discussion of scientific developments and clinical advances in the care of people with these problems. By presenting forums which foster interdisciplinary communication and interchange among all allied health care professionals concerned with individuals with cerebral palsy and neurodevelopmental disorders, this program’s purpose is to ensure that the qualified personnel have the skills and knowledge derived from practices that have been determined through research and experience to be successful in serving children
with disabilities. The purpose is also to encourage teambuilding within organizations and institutions, encourage multicenter studies, develop information for parents, and find a consensus on the optimal care of various conditions.

The AACPDM’s annual meeting has evolved over time in which it began as a limited event by only inviting physicians who were diplomats of specialty boards into now inviting all health care professionals concerned with the care of patients with cerebral palsy and other childhood onset disabilities, including: Developmental and other Pediatricians, Neurologists, Psychologists, Physiatrists, Orthopedic and Neuro-Surgeons, Physical and Occupational Therapists, Speech and Language Therapists, Orthotists, Rehab Engineers, Kinesthiologists, Nurses, Special Education Teachers, Educators and Administrators, Researchers, and Dieticians.

CPIRF to sponsor Research Panel with a $5,000 Educational Grant, in conjunction with AACPDM

As part of our co-sponsorship of the AACPDM conference, CPIRF will be joining UCP and AACPDM in hosting a CP research panel discussion at the September 22nd conference welcoming session taking place at the Newseum in Washington, DC.

CPIRF Best Scientific Poster Award

Each year, Cerebral Palsy International Research Foundation provides an award for the best scientific poster presentation given at the Annual Meeting. The AACPDM Awards Committee reviews all of the scientific posters and grades each poster per specified criteria noted below:
- Methodology/Hypothesis
- Data Analysis
- Discovery / Interpretation
- Clarity of Writing / Presentation
- Relevance / Significance
- Originality
Each criteria is given a rating of Outstanding, Excellent, Good, Fair, or Poor. Then all of the scores are totaled and averaged. The Award Recipient is selected as highest rated average poster from all committee member ratings.

CEO, Glenn R. Tringali, to Present Goldenson Award to Dr. Terry Sanger

Dr. Terrance Sanger is the 2010 winner of the Isabelle and Leonard H. Goldenson Technology and Rehabilitation Award. This award is presented annually to a scientist for outstanding contributions in the development and use of technology and rehabilitation methodologies that enhance the quality of life for individuals with cerebral palsy and other disabilities and their families. CEO Glenn R. Tringali will be presenting the award to Dr. Sanger during the AACPDM Conference at a ceremony on Friday, September 3, 2010.

See full story of “2010 Goldenson Awards” in “CP In The News”, Featured Stories.

Link to the survey.

Drooling is normal in infants. But a significant proportion of the developmentally disabled population experiences drooling caused primarily by neuromuscular dysfunction that makes it hard to swallow. Cuvposa reduces drooling by lowering the volume of saliva produced.

Glycopyrrolate was approved decades ago to treat peptic ulcers and reduce salivation in patients under anesthesia. Until now, glycopyrrolate has been used on an off-label basis to treat drooling in the developmentally disabled population, but in a different dosage form than the approved product. A drug is said to be used off-label when a physician prescribes its use in a different way than described in the FDA-approved drug label.

In 2001, the FDA held an advisory committee meeting to discuss how best to develop products for drooling with ethically and scientifically sound trials in children who have neurological disorders. Utilizing the advice provided, the FDA has been able to move forward in addressing the needs of this population.

“Cuvposa provides an important therapy for controlling salivation in patients with neurologic disease,” said John Jenkins, M.D., director of the Office of New Drugs in the FDA’s Center for Drug Evaluation and Research. “FDA approval not only ensures that the product meets modern standards for safety, effectiveness, quality and labeling; but, also results in a more suitable dose form for this patient population.”

The FDA drug approval process provides a review of product-specific information that is critical to ensuring the safety and efficacy of a finished drug product. For instance, the applicant must demonstrate that its manufacturing processes can reliably produce drug products of expected identity, strength, quality, and purity. FDA’s review of the applicant’s labeling ensures that health care professionals and patients have the information necessary to understand a drug product’s risks and its safe and effective use.

When used off label, oral tablets of glycopyrrolate had to be crushed to treat drooling in children with neurological disorders. Cuvposa is a flavored oral solution that is easier to administer and provides the optimal dose for each patient.

In clinical trials of Cuvposa glycopyrrolate oral solution, 78 percent of the children on the drug reached clinical improvement in drooling compared with 19 percent of those given an inactive substance (placebo).

Common adverse reactions reported with glycopyrrolate are dry mouth, constipation, flushing, and urinary retention.

Cuvposa (glycopyrrolate) Oral Solution is marketed by Shionogi Pharma Inc. of Osaka, Japan.

Media Inquiries: Elaine Gansz Bobo, 301-796-7567; elaine.bobo@fda.hhs.gov
Consumer Inquiries: 888-INFO-FDA

Drs. Sylvie Girard and Guillaume Sébire, recently published a study in the April 2010 issue of the Journal of Immunology examining the role of maternal bacterial infection and inflammation occurring at the end of gestation. Although it is recognized as an independent risk factor for neuro-developmental disorders such as cerebral palsy, mental deficiency, and autism, it remains unclear whether the inflammation is causal or simply associated with these conditions. The two authors prepared the following literature review regarding maternal infection, inflammation and perinatal brain damage.

The mechanism linking maternal inflammation and fetal brain anomalies is still a controversial matter. In this study, we injected lipopolysaccharide (LPS, also known as endotoxin) from E. coli into the peritoneal space of gravid rats and showed that placental inflammation and the expression of pro-inflammatory cytokines, mainly IL-1beta, can be implicated in perinatal brain damage. The causal link between IL-1 and the altered brain development was documented when an IL-1 receptor antagonist, (L-1Ra) given to the gravida protected her pups (increased survival rate, decreased microglial activation, and preservation of motor functions). Perhaps, the use of IL-1Ra could be a therapeutic strategy to protect against perinatal brain damage arising from pathogen-induced gestational inflammation in humans.

Strength and limitations of the rat model?
An important strength of our animal model is the clinical relevance of the experimental design. We triggered inflammation by exposing the pups prenatally to a relatively low amount of bacterial component (LPS) at the end of the gestation, during a window of high susceptibility of the developing brain (corresponding to the level of brain development of early premature infant in humans, about 26-30 weeks of gestation). However, some limitations of our model need to be taken into account. For example, there are some obvious differences between human and rat brains (i.e. pre- vs post-natal maturation, gyrencephalic vs non-gyrencephalic architecture, amount of white matter…). It is also important to keep in mind that the inflammatory stimulus used (LPS from E. Coli) is a specific Toll-Like receptor4 agonist and therefore results cannot be generalized to other types of in utero infections that might be encountered.

Since LPS results in a broad inflammatory response, how come the IL-1Ra was so effective in minimizing placental and brain damage?
IL-1beta being the cytokine that was early and predominantly expressed within placenta exposed to LPS-induced gestational inflammation, we hypothesized that the IL-1 family might be at the apex of the inflammatory cascade of induction of other cytokines and subsequently to perinatal brain damage. Support for such a concept in human disease comes from gout in adult, and polyarthritis in children. We hypothesized that the cytokines all act together and that stopping one might disrupt the whole system. The powerful IL-1Ra protection we observed on the placenta strongly suggests that the beneficial effects on the pups were, at least in part, mediated by an indirect effect of IL-1 blockage that maintained placental integrity and its neurotrophic functions.

What if IL-1Ra were given postnatally?
Although the therapeutic potential of IL-1Ra in adult brain inflammatory model is increasingly recognized, there are to our knowledge no studies that addressed this issue in the neonatal period. Depending on the developmental time window when the IL-1Ra is administered, the impact could be beneficial without any deleterious impact on brain maturation. However, IL-1 might have physiological effects at this stage of development (e.g. likely role in myelination), so the effect of the IL-1Ra treatment should be carefully assessed both on tissue and on animal behaviour.

How do these results fit with what else has been published?
Others have published reports indicating a potential role of IL-1 in perinatal infectious/inflammatory and/or hypoxic-ischemic (HI) brain damage:

• Cai’s group showed that intra-cerebral injection of IL-1 induced brain damage (2)
• Gressens group showed that systemic IL-1 injection enhanced excitotoxic brain lesions, and the impact of maternal infection on brain development (3,4)
• Hagberg’s group showed that IL-1Ra protected against post-natal HI (5)
• Our group showed in human brain and in preclinical models, the temporal-spatial association between IL-1 expression  and neonatal brain damage (6).

This is just a short overview of the large amount of work that has been done on the role of IL-1 in perinatal brain damage. Thus, our results are in line with what has been hypothesized previously, and helps establish a causal role of IL-1 in the molecular cascade linking gestational inflammation and brain damage in the offspring. Altogether, these data suggest that post-natal IL-1 blockade might add some benefits to the prenatal blockade, not only in the initial inflammatory insult, but also in continued/sustained/prolonged inflammation.  We are currently testing this hypothesis on our preclinical models.

What is the relevancy of this to humans?
The use of IL-1Ra is less broad spectrum than, for example, glucocorticoids which are known to have some deleterious effects of brain development. Thus, a more specific treatment, aiming at one cytokine might be the key to selectively limit the negative effects of inflammation while keeping the likely role of cytokines during this important period of development. In our work, the fact that we studied the impact of IL-1Ra treatment on several end-points, including placenta integrity, cytokines expression, pups’ survival and brain development (i.e. histology and behavioural outcomes) without any short term deleterious effects is encouraging for potential translation. However, attention should be paid to the potential risk of deleterious effects of cytokine blockers, even before preclinical models are considered.

Encouragingly, there has been a recent single case report of IL-1Ra administration throughout pregnancy (as a treatment for Still disease) without any apparent deleterious impact on the fetus, birth and postnatal development so far (7). IL-1Ra is also used to treat cohorts of adults who have gout, and is also used in newborns and infants with inflammatory diseases (e.g. CAPS syndrome, CINCA/NOMID syndrome, Still disease) and seem to be efficient and well tolerated (8-10).

Citations

1. Girard S, Tremblay L, Lepage M, Sébire G. IL-1 receptor antagonist protects against placental and neurodevelopmental defects induced by maternal inflammation. J Immunol 2010;184:3997-4005.
2. Cai Z, Lin S, Pang, Rhodes PG. Brain injury induced by intracerebral injection of interleukin-1beta and tumor necrosis factor-alpha in the neonatal rat. Pediatr. Res 2004;56:377–384.
3. Plaisant F, Dommergues MA, Spedding M, Cecchelli R, Brillault J, Kato G, Muñoz C, Gressens P. Neuroprotective properties of tianeptine: interactions with cytokines. Neuropharmacology 2003;44:801-9.
4. Rousset CI, Chalon S, Cantagrel S, Bodard S, Andres C, Gressens P, Saliba E. 2006. Maternal exposure to LPS induces hypomyelination in the internal capsule and programmed cell death in the deep gray matter in newborn rats. Pediatr. Res. 59:428–433.
5. Hagberg H, Gilland E, Bona E, Hanson LA, Hahin-Zoric M, Blennow M, Holst M, McRae A, Söder O. Enhanced expression of interleukin (IL)-1 and IL-6 messenger RNA and bioactive protein after hypoxia-ischemia in neonatal rats. Pediatr Res 1996;40:603-9.
6. Girard, S., H. Kadhim, A. Larouche, M. Roy, F. Gobeil, and G. Se´bire. Pro-inflammatory disequilibrium of the IL-1 beta/IL-1ra ratio in an experimental model of perinatal brain damages induced by lipopolysaccharide and hypoxiaischemia. Cytokine 2008;43:54–62.
7. Berger CT, Recher M, Steiner U, Hauser TM. A patient’s wish: anakinra in pregnancy. Ann Rheum Dis 2009;68:1794-5.
8. Goldbach-Mansky R. Blocking interleukin-1 in rheumatic diseases. Ann N Y Acad Sci 2009;1182:111-23.
9. Neven B, Marvillet I, Terrada C, Ferster A, Boddaert N, Couloignier V, Pinto G, Pagnier A, Bodemer C, Bodaghi B, Tardieu M, Prieur AM, Quartier P. Long-term efficacy of the interleukin-1 receptor antagonist anakinra in ten patients with neonatal-onset multisystem inflammatory disease/chronic infantile neurologic, cutaneous, articular syndrome. Arthritis Rheum 2010;62:258-67.
10. Miyamae T, Inaba Y, Nishimura G, Kikuchi M, Kishi T, Hara R, Kaneko U, Shinoki T, Imagawa T, Yokokta S. Effect of anakinra on arthropathy in CINCA/NOMID syndrome. Pediatr Rheumatol Online J 2010;8:9.

The CP conferences bring together adults with CP as well as members of the medical profession, social workers and educators who focus on the issues confronting adults with CP. For many adults with CP, as well parents and caregivers, the conferences are the only source of information about living with CP.

The conference takes place from June 25th to June 28th in San Jose.

Read the full brochure here.

Ms. Jacqueline (Jackie) Carmosino

Jackie is based with CEO Glenn R. Tringali in our new office at 186 Princeton Hightstown Road, Building 4, 2nd Floor; Princeton Junction, NJ 08550 which opened on June 1, 2010. The Princeton Junction location will be the CPIRF headquarters and eventually the sole operating office once we complete the transitional process of closing our Washington, DC office on or before September, 2010. (NOTE: Donor contributions and billing inquiries will continue to be processed through our Washington, DC office until such time.)

• At least one small molecule compound with strong evidence of biologic activity in a nervous system disease assay.
• A robust, moderate throughput assay of biological activity suitable for testing compounds generated in an iterative medicinal chemistry effort.
• Secondary bioassays and models sufficient to evaluate the potential of a drug candidate for the intended indication.

To apply, go to
http://grants.nih.gov/grants/guide/rfa-files/RFA-NS-11-002.html
The deadline is August 10, 2010

Contact Dr. Rebecca Farkas at farkasr@ninds.nih.gov or (301) 496-1779
for more information regarding this new initiative

Part One can be found by clicking here…

Leading neuroscientists, clinicians, neurobiologists, and pediatric neurologists came together for a symposium entitled “Injury to the Preterm Brain and Cerebral Palsy” in conjunction with the 37th Annual Meeting of the Child Neurology Society on November 5th, 2008. This symposium was supported by the National Institutes of Health, the Child Neurology Society, the Kennedy Krieger Institute, and the Cerebral Palsy International Research Foundation. Recently a summary of the symposium was published in the Journal of Child Neurology by Michael Babcock, Felina Kostova and Drs. Donna Ferriero, Michael Johnson, Jan Brunstrom, Henrik Hagberg and Bernard Maria. The second session was on molecular mechanisms and animal models of injury to the preterm brain.

Apoptotic Mechanisms of Cell Death in the Immature Brain

Dr. Hagberg of Goteborg University discussed how there is tremendous complexity in the pathophysiology of hypoxic-ischemic (HI) brain injury, one of the most common causes of CP. After the initial injury, there is a regenerative and compensatory response in which mitochondrial respiration and glucose metabolism fully recover in brain tissue. This recovery is often followed by a secondary deterioration that signifies a secondary injury. Dr. Hagberg’s research focuses on apoptotic mechanisms occurring between the first and second injury because it may be the most clinically effective time to initiate therapy.

The intrinsic pathway is a mechanism of apoptosis and is likely responsible for secondary injuries due to a HI event in the premature brain. An internal injury to the cell causes the Bax protein to migrate to the outside of the cell, activating the intrinsic pathway. Once this pathway is activated, the mitochondrial membrane becomes permeable releasing cytochrome 3. The apoptosome is then assembled which activates Caspases 3 and 9, which leads to an expanding cascade of proteolytic activity resulting in digestion of structural proteins in the cytoplasm, degradation of chromosomal DNA, and then phagocytosis of the cell.

Dr. Hagberg is focusing on preventing permeability of the mitochondrial membrane as his therapeutic target. He has found that to block mitochondrial outer membrane permeability and provide neural protection to the immature brain the Bax-dependent channel must be blocked. Caspase -2 is an upstream regulator and has shown in-vitro, that inhibition of caspase -2 can block Bax-dependent mitochondrial outer membrane permeability. Further a selective caspase-2 inhibitor has been developed and has shown neuroprotective effects in animal models of excitotoxicity, hypoxia-ischemia and stroke.

Experimental Models of White Matter Injury

Dr. Steven Back discussed animal models of white matter injury. Much progress has been made in determining triggers of brain injury, the affected cell types and the molecular pathways leading to damage. Current animal models reflect this progress and demonstrate that most common pathology seen in preterm infants is noncystic focal or diffuse white matter lesions. One of the most important mechanisms of injury to white matter in the infant brain is ischemia reperfusion and the preoligodendrocyte, precursor to the myelin producing oligodendrocyte, is the most affected cell type.
Dr. Back has developed a global ischemia model in preterm fetal sheep. At 70% gestation, fetal sheep brain development looks very similar to that of a human fetus at 24 to 28 weeks. Using this model they have demonstrated the diffuse white matter lesions, with little gray matter involvement. With increased ischemia there is damage found in the cortex and basal ganglia, perhaps reflecting the wide spectrum of pathology seen in patients with developmental disorders.

In addition, Dr. Back and colleagues have demonstrated that ischemic injury in fetal sheep white matter injury is not uniform, but varying in severity corresponding to where preoligodendrocytes are more likely to be found. In other words, the topography of white matter injury is related both to the maturational stage and distribution of susceptible cells, and oligodendrocyte maturation confers resistance to injury.

There is a surviving population of preoligodendrocytes after acute-hypoxic injury, however, they do not differentiate to regenerate oligodendrocytes in chronic lesions. This may be due to glial scaring in white matter lesions. Glial scars contain among many things, hyaluronic acid, a molecule known to block maturation of preoligodendrocytes. Further, there is an increase in the number of preoligodendrocytes in chronic lesions, but they appear to have lost functionality and do not mature into myelinating cells even with axons present.

Excitotoxic Mechanisms of White Matter Injury

Dr. Francis Jenkins of Children’s Hospital in Boston discussed the role of excitotoxicity and developmental patterns of neurotransmitter expression as a potential mechanism of pre-term brain injury. Glutamate is the major excitatory neurotransmitter in the brain and glutamate receptors are present in neuronal synapses and on glial cells. The presence of glutamate receptors is developmentally regulated; they first appear on radial glia and subplate neurons, then on preoligodendrocytes , microglia and cortex; and then finally on neuronal synapses at term. Thus this unique pattern of appearance of receptors in the preterm brain potentially provides a window of therapeutic opportunity.

Glutamate receptors are involved in many signaling cascades, particularly for excitatory neurotransmitters involving calcium and downstream signaling cascades. If there is too much excitation, however, these cascades can lead to upregulation of calcium-dependent pathways involved in free radical formation and apoptosis. Many studies have shown a pooling of extracellular glutamate in response to hypoxia/ischemia and infection. In addition, the developing brain has glutamate receptors that have upregulated activity due to importance of excitability in the developing brain. However, this increases the risk of excitotoxicity given the glutamate receptors increased activity and the high levels of extracellular glutamate in response to a hypoxic/ischemic or sepsis event.

Given this, a potential therapeutic target may be glutamate receptor antagonism. Studies have demonstrated that NBQX, an AMPA receptor antagonist, preserved white matter in an animal treated after a hypoxic/ischemic event. NBQX is not currently available for human use, however, another AMPA receptor antagonist, topiramate, has FDA approval and has shown preservation of white matter in treated animals after hypoxia/ischemia. Finally, a NMDA receptor antagonist, being studied in dementia trials, has demonstrated cell survival improvement in animals treated after hypoxia/ischemia and long-term improvement evidenced by a decreased cortical thinning.

Mindy L. Aisen, MD – Medical Director of CPIRF and Rancho Los Amigos Rehabilitation Hospita

CPIRF and Rancho Los Amigos Rehabilitation Rancho Los Amigos National Rehabilitation Center will hold a focused retreat/workshop examining the role of commercially available and emerging technologies for improving motor performance, psycho-social function, cognitive/behavioral function, environmental control and means for extending treatment into the community setting. The neurological conditions to be discussed will be Cerebral Palsy, CP/Autism, Autism spectrum disorders, Stroke, Multiple Sclerosis, Traumatic Brain Injury, PTSD/motor impairments, epilepsy/electrophysiology.

The technologies to be discussed include: robotics, virtual reality, task specific therapy, robotic enhanced socialization, bidirectional broadband communication and monitoring in the community (for health, wellness, safety, continuing rehabilitation), and emerging techniques for using EEG/computer interfaces, and brain computer interfaces.

The  goal is to have industry, academic engineering and clinical researchers present methods and data; then develop cross disciplinary collaborative ideas and dialog to set the stage for new clinical trial development.
The workshop is scheduled for September 2-4, 2010 at the Rancho Los Amigos National Rehabilitation Center in Downey, CA.  The proceedings of the meeting will be published as a supplement to the Journal of Neurorehabilitation and Neural Repair.

Most recently, Mr. Tringali was the Chief Development Officer at the Cancer Research Institute and from 2001-2008, previously served the autism community, first as CEO of the National Alliance for Autism Research prior to leading the organization’s successful merger with Autism Speaks in February, 2006 where he was named Executive Vice President.

CPIRF CEO – Glenn R. Tringali

“I am incredibly honored and excited to be joining the Cerebral Palsy International Research Foundation. The national and global research and education programs we are funding are critically important. With an estimated 1 million children and adults with CP in our country, the need for supporting our efforts has never been greater”.

CPIRF is the nation’s preeminent private organization dedicated to the prevention and treatment of Cerebral Palsy and related developmental disorders. In its fifty-five year history, CPIRF has provided more than $50 million to support research and educational activities in the biomedical and clinical sciences.