March 2010 Fact Sheet

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.

Below you’ll find a list of fact sheets we have been accumulating for more than a decade on Cerebral Palsy Research. The articles are laid out first by category then subdivided with the most recent at the top of each category.
Look out for new fact sheets every month!

General

Cause

Diagnosis and Treatment

Prevention

Technical

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

Dr John Thorp, an OB-GYN the University of North Carolina (UNC) at Chapel Hill conducted a large clinical trial at 20 different sites to examine the effect of magnesium sulfate on the rate of stillbirth or infant death, and the rate of moderate or severe cerebral palsy at or after the age of 2 years.

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!!

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.

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.

By Dr. Deborah Thorpe

Sixty percent of persons with cerebral palsy (CP) in the United States are over the age of fifteen¹ with life expectancies reaching those of the unaffected population but still strongly related to degree of severity. Cooper et. al. ²in a study on physical activity and health among people with disabilities found that activity level was highly correlated with years of survival in adults with CP. Several investigators ^{3, 4, 5, 6, 7} have concluded that there is evidence that adults with cerebral palsy might not be engaging in sufficient physical activity to produce the improvements in fitness that would be required to experience associated health benefits. van der Slot 7 measured physical activity in adults with hemiplegic CP using an Activity Monitor and found these adults participated to a similar degree as their healthy comparisons. However, more severely impaired adults with cerebral palsy (GMFCS Levels 2-5) that have severe activity limitations most likely develop secondary conditions that lead to decreased health benefits. ⁸ In adults with CP, Johnson et, al. ⁹ found total energy expenditure (TEE) to be highly variable and a significant predictor of ambulatory status in adults with CP.

A few studies ^{10, 11, 12, 13} have addressed progressive resistive strength training on land in adults with CP with significant improvements in muscle strength, walking velocity, and gross motor abilities. Work has begun to validate the use of water as an optional exercise medium to land in this population. ^{14, 15, 16, 17} Utilizing the beneficial properties of water such as buoyancy, neutral warmth, and variable resistance and eliminating the negative effects of gravity, persons with cerebral palsy can optimize their full movement potential in an aquatic environment while maintaining joint integrity.

Unnithan and colleagues ¹⁸ designed a combination of aerobic and strength interval training for 14-18 year olds with CP and found significant improvements in work economy which may have implications for increasing physical activity levels in this population. It has been only recently that therapists and researchers have looked beyond the limitations of the disease and discovered that many children and adults with CP can train at near-normal intensity levels (70-85% of maximum heart rate). ^{10, 11, 13, 14, 15}

There is no information on the impact of exercise and fitness on health outcomes such as body fat, blood lipids, and blood pressure in adults with CP ¹⁹ and no idea if improvements in physical fitness will have similar benefits as in the general population. Future research should include identifying specific types (strengthening, aerobic, flexibility), combinations and doses of exercise and physical activity for adults with CP. Specific physiologic parameters need to be identified that will provide the most reliable and valid information in order to discern fitness need and change. In order to develop physical activity interventions based on individual needs that promote strengthening and aerobic conditioning but also maintain optimal nutritional status valid methods to determine total energy expenditure (TEE) need to be identified. Finally, comprehensive investigations of physical activity are needed to determine the relationships between physical activity, participation, HRQL and psychosocial functioning.