A growing body of evidence suggests that the developing brain is uniquely vulnerable to anesthetic agents.

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.

April 2010 Fact Sheet

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/

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.

December 2009 Fact Sheet

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.

October 2009 Fact Sheet

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

Under the Food and Drug Administration Amendments Act of 2007 (FDAAA), gave FDA authority to require safety labeling changes.  The FDA review for safety of BOTOX started February 2008, the conclusion of this review was introduced by implementation of a Risk Evaluation and Mitigation Strategy (REMS) that includes a BOTOX®/BOTOX® Cosmetic Medication Guide to provide to patients being administered BOTOX. The REMS has been implemented to ensure that the benefits of BOTOX®/BOTOX® Cosmetic treatment outweigh the potential risks of BOTOX®/BOTOX® Cosmetic treatment.  The goals of the BOTOX®/ BOTOX® Cosmetic REMS are to:

• Minimize the risks of medication errors related to the lack of interchangeability of BOTOX®/ BOTOX® Cosmetic Units with those of licensed botulinum toxins of other manufacturers
• Inform prescribers and patients about the potential occurrence of spread of toxin effect beyond the injection site

The strategy requires that an FDA-Approved Patient Medication Guide for BOTOX® be sent to health care providers who are administering Botox and to patients each time Botox is administered.

Non-Interchangeability of Botulinum Toxin A products
Because the potency units of BOTOX®/BOTOX® Cosmetic Units are specific to the preparation and assay method utilized, it is not interchangeable with other Botulinum Toxin A products such as DYSPORT ^TM manufactured by the Ipsen Group.  To address this issue, Allergan, in conjunction with the FDA and the United States Adopted Names Council, has adopted the established the name onabotulinumtoxinA that is specific to BOTOX® . This uniquely established nonproprietary name replaces the previous common terms Botulinum Toxin Type A and differs from the established name for DYSPORT™ (abobotulinumtoxinA) .

Distant Spread of Toxin Effects
Postmarketing reports indicate that the effects of  BOTOX®/BOTOX® Cosmetic and all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects. These may include asthenia, generalized muscle weakness, diplopia, blurred vision, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence, and breathing difficulties. These symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be life threatening and there have been reports of death. Therefore patients, care-givers, and/or parents must be vigilant about be on the alert for these symptoms. The risk is probably greatest in children treated for spasticity but symptoms can also occur in adults treated for spasticity and other conditions, particularly in those patients who have underlying conditions that would predispose them to these symptoms. In unapproved uses, including spasticity in children and adults, and in approved indications, cases of spread of toxin effect have occurred at doses comparable to those used to treat cervical dystonia and at lower doses. The REMS requires a periodic evaluation on its’ effectiveness. The timeline for evaluation is 18month, 3years, or 7 years. FDA may eliminate the REMS requirement if after 3 years if it is managed well.

CPIRF Scientific Advisory Council member, Dr. Nigel Paneth will lead a statewide team of researchers from Michigan who will utilize the state’s archive of newborn blood spots to help them uncover causes of cerebral palsy. The research team’s work is being funded by a $1.9 million grant from the National Institute of Neurological Disorders and Stroke as part of the federal American Recovery and Reinvestment Act. Partners include the Michigan State University, University of Minnesota, the University of Michigan and Helen DeVos Children’s Hospital and the Mary Free Bed Hospital in Grand Rapids.

Read more about the study here

Recent Developments in Healthcare for CP: Implications and Opportunities for Orthotics

A conference convened by the International Society for Prosthetics and Orthotics (ISPO) reviewed the evidence for the physical management of cerebral palsy (CP). Papers presented at the meeting included a global health perspective, definition and classification of CP, classification of gait in CP, and reviews of physiotherapy, occupational therapy and medical, surgical and orthotic management. Small group and plenary discussions resulted in wide ranging conclusions and recommendations.

The report of the conference, titled Recent Developments in Healthcare for Cerebral Palsy: Implications and Opportunities for Orthotics, is available free of charge at www.ispoweb.org The report contains the background to the conference, manuscripts of all the papers, and the conclusions and recommendations. Notwithstanding the focus on implications for orthotics, the content provides a valuable resource for anyone providing or researching health services for people with CP.

The ISPO intends to use the report as an educational resource for further instructional courses and disseminate the information as broadly as possible with the aim of improving the health care of people with CP worldwide.

Nathan Baker is proof positive that kids with disabilities can compete in sports.

Nathan Baker and Coach Mike Miragliuolo :

Nathan Baker was a participant in a study conducted by Dr. Deborah Thorpe at the University of North Carolina at Chapel Hill and funded by the Cerebral Palsy International Research Foundation. Dr. Thorpe’s study compared the efficacy of treadmill training versus aquatic therapy in improving quality of life and motor function in children with cerebral palsy aged 12-19 years of age.

From Nathan’s Mom…

We are so thankful for the research funds that the Cerebral Palsy International Research Foundation contributed to Dr. Deborah Thorpe of the University of North Carolina School of Medicine, Division of Physical Therapy. Nathan’s physical therapist, Cathy Howes (also UNC Hospitals), recommended us for the study. We soon discovered that Nathan would be in the treadmill portion of Dr. Thorpe’s study and this meant that he would be on the treadmill for 3 times a week for 40 minutes at each session. Nathan decided to combine this study participation with physical fitness work he needed to do for his Boy Scout Personal Fitness merit badge.

Dr. Thorpe, Nathan, and I were amazed at Nathan’s progress on the treadmill as he participated in this study. He increased his speed to 4 mph and higher and was able to sustain this pace for the two 20 minute sessions. As Nathan’s participation in this study was coming to completion, Dr. Thorpe began to educate us on how important it is for individuals with CP to exercise throughout their lives so they can ward off loss of function as they age. She also inspired Nathan to inquire about Cross Country or Track opportunities at his school.

Nathan inquired about Track at his middle school and was not enthusiastically received. We found some coaches are unwilling or fearful to include those with disabilities in physical endeavors. Other coaches will embrace the idea and know the benefit it can bring to all members of the team as they learn lessons of perseverance and “heart” from those with disabilities.

We decided to be persistent and inquired about Cross Country as Nathan was making plans to enter High School. Coach Mike Miragliuolo urged Nathan to join his team at Green Hope High School. He promised Nathan that if he was willing to attend practices and put in the effort, he would be part of the team. Nathan began his workouts with the team that summer. North Carolina is gruelingly hot and humid in the summer and the municipal park where the high school team often trains has some challenging terrain for a person with motor disabilities to navigate.

Coach’s first goal for Nathan was to be able to run 3 miles without stopping to walk. The first two weeks were daunting. Nathan grew discouraged. Coach began to reconsider what was possible and offered Nathan the opportunity to remain as part of the team in a support role(help with water/towels, etc.). Nathan “dug in” and founded it within his character to continue to try and by the time the team was ready for its first meet, Nathan could run 3 miles. He ran this first 5 K with a time of 33:55. The lead runner’s time was 19:08. Nathan’s current personal record for the 5K has improved to 24:18.

Nathan discovered a fountain of inspiration:
1) others inspire him to run his best with their cheering and 2) he inspires others to run because “if I can run, so can others with CP”. Nathan became an advocate for people with disabilities to exercise and he challenges those without disabilities to join him as well.

Read more about Nathan Baker and the Green Hope, NC running team in an article in USA Today.

http://www.usatoday.com/sports/preps/xcountry/2008-10-14-big-teams_N.htm

The New England Journal of Medicine just published a study on the medical and social problems of adults (20-36 years old) who were born alive (and without congenital anomalies) in Norway between 1967 and 1983. The authors state:

“Advances in perinatal care have increased the number of premature babies who survive. There are concerns, however, about the ability of these children to cope with the demands of adulthood.”

Here are some of the most important points:

1.The risk of serious medical disabilities such as cerebral palsy, mental retardation, and disorders of psychological development, behavior, and emotion, as well as of other major disabilities such as blindness or low vision, hearing loss, and epilepsy increased markedly with decreasing gestational age. We also observed a significant association of autism-spectrum disorders with very low gestational age, but these findings were based on a very small number of cases in the lowest gestational-age groups.

2. At 19 to 35 years of age, nearly 1 of 9 persons who had been born at 23 to 27 weeks of gestation received a disability pension, as compared with 1 of 12 who had been born at 28 to 30 weeks, 1 of 24 born at 31 to 33 weeks, 1 of 42 born at 34 to 36 weeks, and 1 of 59 born at term.

3. There were progressively higher risks of cerebral palsy, mental retardation and autism with decreasing gestational age.

4. Among those who did not have medical disabilities, the gestational age at birth was associated with the education level attained, income, receipt of Social Security benefits, and the establishment of a family, but not with rates of unemployment or criminal activity.

5. Babies born between 23-27 weeks were 78 times more likely to have CP than those born at term.

6. Babies born <28 weeks were 9.7 times as likely to develop Autism Spectrum Disorder.

Moster D, Lie RT, Markestad T. Long-Term Medical and Social Consequences of Preterm Birth. NEJM 359:262-273.