The developmental risk associated with exposure to general anesthesia in young children is largely unknown. In an editorial from the FDA published in the New England Journal of Medicine, the authors describe a growing body of evidence suggesting that the developing brain is uniquely vulnerable to anesthetic agents, particularly NmethylDaspartate (NMDA) receptor antagonists (e.g., ketamine) and aminobutyric acid (GABA) agonists (e.g., isoflurane). Studies in rodents and nonhuman primates indicate that prolonged exposure to these anesthetic agents during specific windows of neurodevelopment result in widespread neuronal cell death and long-term cognitive deficits.

Two retrospective cohort studies suggest that the risk associated with exposure to general anesthesia in animals also applies to children. In one study (J Neurosurg Anesthesiol 2009; 21:286), researchers compared 383 children who underwent inguinal hernia repair during the first 3 years of life with 5050 children who did not. Children who underwent surgery were twice as likely as controls to receive diagnoses of developmental or behavioral disorder. In the second study (Anesthesiology 2009; 110:796), investigators examined records of children exposed to one (449 children), two (100 children), or more than two anesthetics (44). The risk of learning disabilities increased with exposure to two or more anesthetics and with greater cumulative exposure to anesthesia.

Comment: Although the exact effects of early exposure to anesthesia in children are still unknown, the potential for an adverse effect on brain development is clear. Therefore, minimizing exposure to anesthetic agents is warranted. Reasonable options include delaying elective procedures until after age 3 years and using regional anesthesia when possible.

— Sandra Juul, MD, PhD

Sandra Juul, MD, PhD, is Professor of Pediatrics in the Division of Neonatology at the University of Washington School of Medicine in Seattle.

Published in Journal Watch Pediatrics and Adolescent Medicine May 4, 2011

Citation(s):

Rappaport B et al. Defining safe use of anesthesia in children. N Engl J Med 2011 Apr 14; 364:1387.

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.

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.

Geron, a pharmaceutical company based in California, announced in January 2009 that they had received clearance from the FDA to begin the first human clinical trial of embryonic stem-cell based therapy in the treatment of acute spinal cord injury. This was planned to be a Phase 1 clinical trial to assess safety and tolerability in patients with subacute (injury occurrence within 7 to 14 days), complete ASIA grade A thoracic spinal cord injury.  However, in subsequent animal studies, an increase of cysts at the site of injury after injection of the Geron product was observed.  Thus, the clinical trial has been postponed until the second half of 2010. Once positive results are obtained in the additional preclinical studies, the clinical trial in humans will begin.  Although the primary endpoint of the trial will be safety, the protocol will include secondary endpoints to assess efficacy, such as improved neuromuscular control or sensation in the trunk or lower extremities. Once safety in this patient population has been established and the FDA reviews clinical data in conjunction with additional data from ongoing animal studies, Geron plans to seek FDA approval to extend the study to increase the dose of GRNOPC1, enroll subjects with complete cervical injuries and expand the trial to include patients with severe incomplete (ASIA grade B or C) injuries to enable access to the therapy for a broad population of spinal cord-injured patients.

Background

The Geron stem-cell based product for spinal cord injury is known as GRNOPC1.  It is a population of living cells containing oligodendrocyte progenitor cells (OPCs) that have been derived from human embryonic stem cells.  OPCs mature into oligodendrocytes, which are naturally occurring cells in the nervous system responsible for the production of myelin (insulating cells that wrap around nerve axons) as well as for the production of neurotrophic factors that support the survival and function of neurons.  Myelin enables the efficient conduction of nerve impulses. Without myelin, the brain and spinal cord cannot function properly.  In most spinal cord injuries there is bruising to the nerve tissue that results in a severe inflammation at the site of injury. This inflammation is very toxic to oligodendrocytes and results in loss of myelin and nerve cells which may result in paralysis below the level of injury.

Geron scientists and scientists from the University of California, Irvine published a paper in Journal of Neuroscience in which they describe their methodology to produce OPCs from animal embryonic stem cells.  These OPCs (GRNOPC1) were then tested in an animal model of spinal cord injury.  This validated animal model, which mimics what occurs in humans after suffering a spinal cord injury, results in a loss of truncal muscle function, bladder control and hind limb function.  Their controlled experiment involved injecting GRNOPC1 at the site of injury within 7 days of contusion.  The treated animals showed both functional (significant hind limb locomotor control) and histological (increased remyelination of axons at injury site) improvement as compared to the control group.  In additional studies, nine months after injury and a subsequent injection of GRNOPC1, the lesion site was filled with GRNOPC1 and myelinated nerve axons crossed the lesion.  Taken together, these findings, that 1)embryonic stem cell derived OPCs were present at the injury site and 2)that there was increased axonal remyelination at the injury site nine months post injury, and 3) there was  functional improvement in the experimental group compared to the control group, are the basis for the clinical trial in humans.

Could be GRNOPC1  be effective for the treatment of motor dysfunction associated with CP?

Human periventricular white matter injury (PWMI) is the predominant form of brain damage and the leading cause of life-long neurological disability from cerebral palsy in survivors of premature birth. The two major causes of PWMI are thought to be: chorioamnionitis, which can induce fetal inflammatory response, and hypoxia/ischemia (H/I),  both of which can cause acute degeneration of oligodendrocyte progenitors (OPCs)resulting in chronic myelination disturbances of neuronal axons. As with spinal cord injury, the loss of myelin causes loss of motor function and control.

The Geron GRNOPC1 SCI protocol requires that the injection be precisely at the point of injury. In cerebral palsy the injury is likely diffuse throughout the brain.  So a major issue would be how to get the OPCs to all of the sites of injury in CP.  Further, Geron has found that the GRNOPC1 product is ineffective 14 days post injury due to scarring around the lesion.  Cerebral palsy may not be diagnosed for up to 2 years post injury.  Geron plans to further study the effectiveness of their human embryonic stem cell derived OPCs in other neurological conditions resulting from white matter injury including Alzheimer’s disease, stroke and multiple sclerosis. There are currently no plans to test this product in cerebral palsy. However, this is a significant advance in the treatment of incurable neurological conditions and the results of this trial may provide important insights on the short and long term effectiveness of stem cell therapy for all neurological conditions. To learn more about Geron and their research program go to http://www.geron.com/products/

Leading neuroscientists, clinicians, radiologists, 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.  The 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 first session was on clinical aspects of injury to the preterm brain.

Current Knowledge of Preterm Injury

Dr. Joseph Volpe of the Children’s Hospital in Boston discussed the current state of knowledge regarding injury to the preterm brain. Of the 60,000 infants born each year in the US weighing less than 1,500 grams, up to 10% develop motor dysfunction and up to 50% have cognitive, behavioral and social deficits. Due to advances in neonatal care, 90% of these extremely low birthweight infants survive.  Periventricular leukomalacia (PVL) is the most common pathology, occurring in up to 50 % of these infants.  PVL has two components, one being a focal component, the other being a diffuse cell-specific  component characterized by injury to the preoligodendrocyte (precursor of the cell responsible for myelinating the neuronal axon), and the occurrence of astrocytosis, and microgliosis (nerve cells that are activated after a CNS injury).  Injury to preoligodendrocytes can result in cell death or loss of cell processes.  After insult, there is a replenishment of preoligodendrocytes that are unable  to mature into oligodendrocytes capable of myelination.

It is believed that there are interacting factors that contribute to PVL  in the premature infant . They include cerebral ischemia, infection and inflammation and a maturation dependent vulnerability of the preoligodendrocyte. Premature infants are susceptible to ischemia because of impaired vascular autoregulation, generating reactive oxygen and nitrogen species. These reactive species accumulate and cause injury in the preoligodendrocytes as they have not yet acquired an antioxidant defense system.  In addition, there is also clearly a link between infection/inflammation and PVL.  Infection and inflammation are associated with release of pathogen-associated molecular products that activate microglia. These activated microglia lead to production of free-radicals that cause injury to the preoligodendrocyte as well.

Thus there are upstream mechanisms of ischemia, reperfusion, and inflammation that activate downstream mechanisms of excitotoxicity (pathological process by which nerve cells are damaged and killed by glutamate and similar substances) and free radical attack that can all potentially be targeted for prevention of injury.  There are many animal studies demonstrating efficacy of various compounds blocking action of reactive species thus preventing injury and many of these appear to be ready for trials in premature infants.

Neuroimaging in Cerebral Palsy

Dr. David Edwards of the Hammersmith Hospital in London, England discussed recent technological advances and clinical usefulness of imaging.  He stated that conventional MRI does not have a lot of value in predicting health outcomes in premature infants.  Another type of imaging, called diffusion tensor imaging (DTI) has shown promise in that it can reveal  the structural integrity of white matter as well as white matter tracts throughout the brain demonstrating connections between various  regions.  Using DTI and tract-based spatial statistics, researchers have demonstrated a good correlation between health outcomes of 2 years old with white matter lesions and measures of microscopic white matter integrity.  DTI has revealed that in children with white matter lesions, not only is there decreased volume of the thalamus, but there is decreased connectivity between the thalamus and the cortex.  It is believed that use of DTI with functional MRI can be combined to give very precise structure-function relationships of various regions of the brain.

Fetal Inflammatory Response

Dr. Olaf Dammann of the University of Hanover in Germany discussed the fetal inflammatory response and brain injury.  It is now believed that premature birth is sometimes the result of some exposure during pregnancy (such as intrauterine infection) and that this exposure causes white matter damage in the infant.  Thus prematurity and cerebral palsy are associated but not necessarily causal in some instances.  In addition, it is now believed that it is not exposure to the pathogen itself that causes the damage, but rather exposure to substances produced by the fetal inflammatory response to the pathogen.

Further, Dr Dammann stated that it is likely that fetal white blood cells are involved in brain injury by going through the fetal blood-brain barrier once activated by cytokines, which in turn, activate microglia and astrocytes that damage the preoligodendrocytes.  He also suggested that brain injury and long-term disability results not just from a single event, but from an ongoing exposure to persistent inflammation as evidenced by the presence of a marker of inflammation present in the blood of children with cerebral palsy at age 10.

January 2010 Fact Sheet

Dolphin Assisted Treatment, Hyperbaric Oxygen Therapy and the Adeli Suit

Dr. Pedro Weisler, a child neurologist at the Nationwide Children’s Hospital in Columbus, OH just published a commentary in Clinical Pediatrics discussing 3 Complimentary and Alternative Medicine  (CAM) treatments for children with developmental disorders. The following are highlights from his paper.

1. )  CAM is defined as “ a group of diverse medical and health care systems, practices and products that are not presently considered to be part of conventional medicine”.

2. )  For the most part CAM treatments “ are based on anecdotal evidence and at times rather unusual ideas about the biology of the condition to which they are being applied”.
3. )  In 2002, Americans spent more than $34 billion for CAM treatments.
4. )  Dolphin- Assisted Therapy (DAT) for treatment of mental retardation

• A researcher has postulated that the ultrasound produced by dolphins has a ‘positive effect on the brain’s psycho-neuro-immunological alpha state’ and that the ultrasonic energy may cause neuronal migration and other cellular changes in living tissue.
• Studies to evaluate these claims don’t exist
• The cost of a 4-day DAT program is approximately $4,500.

5. )  Hyperbaric Oxygen Therapy (HBOT) for the treatment of cerebral palsy

• HBOT is the therapeutic use of oxygen at concentrations higher than normal air
• HBOT has proven efficacy for the treatment of carbon monoxide poisoning, decompression sickness and would healing
• The biological premise that HBOT is useful for the treatment of CP is based on the theory that exposure to high levels of pressurized oxygen can heal or reactivate damaged neurons.
• In most cases, the underlying cause for CP is periventricular leukomalacia, an injury of white matter in the brain. White matter is produced by oligodendrocytes, a glial cell, not a neuron, so the hypothetical basis for HBOT treatment is not defensible.
• No well-designed, controlled clinical study has shown that HBOT is more effective for the treatment of CP than exposure to pressurized air
• Reports of the benefits of HBOT on improving CP-related symptoms are from testimonials, single patient studies or poorly designed experiments from HBOT facilities
• The cost of a typical 40 session treatment is $4000.

6. )  Adeli Suit (AST) for the treatment of cerebral palsy

• The Adeli Suit was first designed for Russian Cosmonauts to counter the effects of weightlessness (loss of muscular fitness and decreased bone density)
• The AST technique uses an intensive exercise protocol paired with putting on the suit for 1 month
• The most recent clinical study comparing the Adeli suit with the use of a standard neurodevelopmental treatment found no difference in improvement of CP-related symptoms although both treatment groups did show greater than expected improvement
• The authors of the study concluded that the children with CP benefitted because they received intensive therapy, irrespective of type, for 1 month and because of the increased involvement of their families in their treatment.
• The cost of a 28 day AST treatment is $4000.00.

7. )  Conclusion: There is no good clinical evidence to support the use of these 3 alternative treatments for cerebral palsy. With regard to DAT and HBOT, there is no underlying biological basis that supports their use in the treatment of mental retardation and cerebral palsy, respectively. What is becoming clear, is that parental involvement, combined with intensive, physical therapy has beneficial effects on children with CP.

General

Cause

Diagnosis and Treatment

Prevention

Technical

Federal funding (National Institutes of Health) into the prevention and treatment of cerebral palsy is very low when compared to other childhood conditions. The disparity becomes readily apparent when examined on an annual funding per new case basis. For instance, NIH funding for cerebral palsy was $29 million dollars in FY 2009 and is projected to be $29 million in FY 2010  (NIH RePORT, 2009).  Estimates of CP prevalence in the western world range from 2 to 4.4 cases per 1000 live births; and is widely believed to be increasing.  Given that there were over 4 million lives births in the US in 2005 (CDC, 2006), a reasonable estimate of the number of new cases of cerebral palsy diagnosed each year is 12,000.  Thus, on an annual basis $2400 Federal research dollars are spent for every new case of cerebral palsy.  In comparison, $93 million Federal dollars were spent on cystic fibrosis research and it is projected that $94 million Federal dollars will be spent in FY10.  In the US, there were an estimated 0.3 new cases of cystic fibrosis per 1000 live births  (National Heart Lung and Blood Institute), resulting in 4000 new cases annually.  Thus, $23,000 Federal research dollars were spent for every new case of cystic fibrosis last year, a 10-fold difference over that spent for CP research.  Go to the NIH RePORT website to see Federal funding amounts for various conditions.  HYPERLINK “http://report.nih.gov/rcdc/categories/” http://report.nih.gov/rcdc/categories/

Many childhood health conditions have been able to obtain support from the general public to support research activities.  The US Cystic Fibrosis Foundation provides $85 million annually in research support, and the Juvenile Diabetes Foundation, $156 million.  Our foundation, the Cerebral Palsy International Research Foundation is the only Foundation in the US entirely devoted to research for the prevention and treatment of cerebral palsy. Unfortunately, our  entire research budget in FY09 was only $1.6 million. Clearly, for advances in prevention and treatment of one the most common disabling conditions of childhood, cerebral palsy, more money is needed to fund the research that must to be done to decrease the number of new cases of cerebral palsy, to develop early treatments that might prevent or lessen the disability associated with brain injury and to improve motor and cognitive function in children and adults with CP.  So what can YOU do? Write your Congressman and alert them to this funding disparity! Donate to CPIRF what you can so that we can continue to fund more and better research for CP! We are the only private foundation in the US solely devoted to CP research.

Human periventricular white matter injury (PWMI) is the predominant form of brain damage and the leading cause of life-long neurological disability from cerebral palsy in survivors of premature birth. The two major causes of PWMI are thought to be: chorioamnionitis, which can induce fetal inflammatory response, and hypoxia/ischemia (H/I), which both can cause acute degeneration of oligodendrocyte progenitors resulting in chronic myelination disturbances of neuronal axons and subsequent loss of motor control.

Recently , there has been much discussion of how cell-based therapies may used for regeneration of damaged neuronal tissue. In particular, cell based therapies may help repair/regenerate damaged neurological tissue by becoming neurons or glial cells (oligodendrocytes and astrocytes) and integrating into the neuronal network, restoring tissue by promoting activation of endogenous stem cells or by preventing tissue damage by changing body’s immune response.

Neural stem cells (NSCs) are found in the subventricular zone (SVZ) of the brain and give rise to three major cell types: neurons, astrocytes and oligodendrocytes. In development, neuroblasts from the SVZ migrate to the olfactory bulbs and a separate lineage of glioblasts migrate throughout the forebrain. While the neuroblast marker Doublecortin (Dcx) is necessary for embryonic cortical migration, it is unknown whether it is necessary for migration towards neonatal H/I lesions. Scientists are currently studying how neural stem cells respond to neo-natal hypoxia/ischemia and their potential role in repairing tissue resulting tissue damage. The researchers hypothesize that the SVZ derived stem cells redirect their migration toward brain areas injured by H/I; that SVZ NSCs expand lineage restrictions following H/I; and that Doublecortin is necessary for SVZ neuronal migration in response to H/I. This study may provide an important understanding of SVZ cell behavior in response to neonatal H/l and serve as a starting point for developing strategies to harness endogenous NSCs for repair/regeneration of damaged nerve tissue.

In addition, scientists are evaluating the role of vascular endothelial growth factor (VEGF) on neural progenitor cell proliferation and differentiation after a perinatal H/I injury. Previous research indicates although the SVZ expands in size after H/I injury, there is a shift in the production of astrocytes and oligodendrocytes. VEGF, a key mediator of tissue repair after ischemia, is rapidly induced after H/I injury and increases the specification of astrocytes rather than oligodendrocytes from bipotential glial progenitors in vitro. These researchers hypothesize that VEGF isoforms cause an aberrant shift in the proliferation and differentiation of SVZ progenitors towards astrocytic phenotypes instead of a more appropriate oligodendrocyte lineage after H/I injury. They propose to evaluate a particular isoform of VEGF that they believe will stimulate mainly oligodendrocyte production in response to a perinatal H/I injury and perhaps lead to a therapy that will stimulate endogenous neural stem cells to expand the production of oligodendrocytes for myelin repair.

Scientists are also evaluating the effects exogenous neural stem cells implanted into the SVZ of a developing brain after H/I injury. They propose to implant adult neural stem cells into the lateral ventricle or injured cortex at 24 hours and 7 days post injury. The location, cell type, and degree of differentiation of the transplanted stem cells will be analyzed 7 to 14 days post transplant. Axonal tracing studies will also be performed to begin to understand the physiologic activity of the implanted cells.

Finally, researchers are evaluating transplantation of oligodendrocyte precursors (OPCs) as a potential repair strategy in both acquired (CP) and congenital disorders of myelination. They propose to transplant genetically engineered oligodendrocyte precursors (pre OLs) into a model of congenital leukodystrophy, a condition characterized by progressive degeneration of the myelin sheath. Their previous work has demonstrated that Dlx homeobox transcription factors act as repressors of oligodendrocyte formation and maturation during embryogenesis. Cells for transplantation will be generated by using conditional Dlx2 knockout mice with loss of Dlx2 function in postnatal SVZ progenitors. The researchers hypothesize that the loss of Dlx function in the pre OLs will result in enhancement of their maturation and increased myelination of axons, and possibly a new therapeutic strategy for treatment of white matter pathology.

These studies demonstrate that, while in its infancy, cell therapies for the treatment of cerebral palsy hold great promise for a condition that has proven very difficult to prevent or cure.

October 2009 Fact Sheet

They enlisted 2,241 women diagnosed as being at high risk for going into premature labor between weeks 24 and 31 of their term. The women were randomized to receive either an intravenous infusion of magnesium sulfate solution, or a placebo that looked exactly the same. The infusions were started just before delivery was thought to be starting, at a dose rate of 6 grams over 20 to 30 minutes. This was then followed by a maintenance infusion at a dose rate of 2 grams an hour. If delivery did not take place within 12 hours, the infusion was stopped and started again later, when it looked like delivery was about to take place again.

The results showed that:

There was no significant difference in the risk of infant death between the magnesium sulfate and placebo group.

However, moderate or severe cerebral palsy occurred about half as often in the magnesium sulfate group (1.9 per cent) than in the placebo group (3.5 per cent).

This is an extremely important finding. This may well change the way obstetrical medicine is practiced, and MUCH MORE RESEARCH IS NECESSARY to determine HOW and WHY magnesium sulfate appears to be neuroprotective, if it may be useful in different doses, at different times during pregnancy and delivery and even in the growing infant and child.

UCP Research and Educational Foundation is very proud that the seminal work for this discovery was supported by our Foundation 13 years ago during the brilliant leadership of Dr. Murray Goldstein Medical Director, Jack Hausman Chairman of the Board and Leonard Goldenson, Vice-Chairman of the Board.  High quality research supported today will pay off in our lifetime!!