May 2010 Fact Sheet

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.

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.

Date:
Jan 01, 2008

Most children with CP are now surviving into adulthood and they face unique physical and medical problems related to their underlying condition. Indeed, aging adults with CP experience an early decline in function which is multi-factorial and poorly documented. This is complicated by the fact that as teenagers with CP transition into adulthood, they experience a precipitous loss of educational and state provided medical services. Society needs to address these issues from a standpoint of best care, continuity of care, and prevention of early loss in function as the adult with CP is a growing population due to improved survival of low birth weight infants and concomitant increasing longevity.

Epidemiology of Cerebral Palsy: Cerebral palsy (CP) is a non-progressive neurodevelopmental condition initiated early in life that persists into adulthood. Though the exact number of children and adults living with CP in the US is unknown, the population is increasing due to improvements in the survival of low birthweight infants (Colver, Pharoah, Vincer, Odding, Uldall). 87 to 93% of children born with CP now survive into adulthood (Hutton, Evans, Nielson) and a reasonable estimate is that 700,000 children and adults up to age 50 are living with CP in the US.

Complications of Aging with CP: Adults with CP experience musculoskeletal problems and loss of function that non-disabled adults do not experience until much later (IOM). A study indicated that 75% of individuals with CP stopped walking by age 25 due to fatigue and walking inefficiency (Murphy). Another study on young adults with CP found clinical evidence of arthritis in 27 % of subjects vs. 4% in the general population (Cathels). These challenges result in chronic immobility, harming bone health. Elevated fracture rates in adults with CP are not well documented, however, documentation in children with CP (Munns), men surviving spinal cord injury (Bauman, 2001A) and stroke survivors (Sahin, Sato) does exist. Immobilization not only elevates fracture risk but also the risk for metabolic syndrome (Zderic).

Long term outcomes in the adult of current clinical practice in children with CP: The long-term impact of interventions used to treat children with CP has not been well studied. Spasticity, the most often treated condition, is managed with physical therapy, chemodenervation using botulinum toxin A or phenol, continuous intrathecal baclofen, neurosurgical procedures, such as selective dorsal rhizotomy and placement of Baclofen pumps, and orthopedic surgeries such as tendon transfers and osteotomies (Paul), but there is little scientific evidence supporting effectiveness of these treatments, particularly over the long term.

Cutting Edge Technologies in Neurorehabilitation: There is considerable evidence that the adult human brain is capable of significant recovery (plasticity) with the appropriate frequency and timing of treatments. Cutting edge therapies have shown promise in adult patients after stroke or spinal cord injury and in children with CP. Task specific training has shown to improve walking ability (Schindl, Maltais, McNevin). Neuromuscular electrical stimulation has shown improvements in muscle strength (Stackhouse ). Virtual reality therapy has improved upper and lower limb function when used in conjunction with neurorehabilitation modalities (Henderson, Stewart, Crosbie, Bryanton). Vibration therapy has been shown to decrease spasticity (Ahlborg, 2006) allow postponement of surgical interventions (Semler), and reduce the age related deterioration of body composition in animal models (Rubin).

Summary

There is an urgent need for more scientific research into the magnitude of the secondary musculoskeletal and neuromuscular complications in the adult with cerebral palsy. Clinicians who treat children with cerebral palsy may need to re-evaluate treatment choices with long-term health outcomes in mind. From what we have learned about plasticity in the adult stroke population, it may be possible that the adult with CP may gain new motor skills from the appropriate task specific rehabilitative techniques, or at the least, prevent/mitigate the secondary complications.

REFERENCES
Ahlborg L, Andersson C, Julin P. Whole-Body Vibration Training Compared with Resistance Training: Effect on Spasticity, Muscle Strength and Motor Performance in Adults with Cerebral Palsy. J Rehabil Med. 2006; 38: 302-308.
Bauman WA, Spungen AM. (2001A) Body composition in aging: adverse changes in able-bodied persons and in those with spinal cord injury. Top Spinal Cord Inj Rehabil. 6: 22-36.
Bryanton C, Bosse J, Brien M, McLean J, McCormick A, Sveistrup H. (2006) Feasibility, motivation, and selective motor control: virtual reality compared to conventional home exercise in children with cerebral palsy. Cyberpsychol. Behav. 9(2):123-8.
Cathels BA, Reddihough DS. (1993). The health care of young adults with cerebral palsy. Med J Aust. 159:444-446.
Sahin L, Ozoran K, Gunduz OH, Ucan H. Yucel M. (2001) Bone mineral density in patients with stroke. Am J Phys Med Rehabil. 80: 592-596.
Colver AF, Gibson M, Hey EN, Jarvis SN, Mackie PC, and Richmond S. (2000) Increasing rates of cerebral palsy across the severity spectrum in north-east England 1964-1993. The North of England Collaborative Cerebral Palsy Survey. Arch. Dis Child Fetal Neonatal Ed. 83 (1):F7-F12.
Crosbie JH, Lennon S, Basford JR, McDonough SM. (2007) Virtual reality in stroke rehabilitation: still more virtual than reality. Disabil Rehabil 29(14):1139-46.
Evans PM, Evans SJ, Alberman E. (1990) Cerebral Palsy: why we must plan for survival. Arch. Dis Child. 65(12):1329-33.
Henderson A, Korner-Bitensky N, and Levin M, (2007) Virtual reality in stroke rehabilitation: a systematic review of its effectiveness for upper limb motor recovery. Top Stroke Rehabil. 14(2):52-61.
Hutton JL, Cooke T, Pharoah PO. Life expectancy in children with cerebral palsy. (1994) BMJ;309(6952):431-5.
IOM (Institute of Medicine). 2007. The Future of Disability in America. Washington, DC. National Academy Press. Maltais D, Bar-Or O, Pierrynowski M, Galea V. (2003) Repeated treadmill walks affect physiologic responses in children with cerebral palsy. Med Sci Sports Exerc. 35(10):1653-1661
McNevin NH, Coraci L, Schafer J. (2000) Gait in adolescent cerebral palsy: the effect of partial unweighting. Arch Phys Med Rehabil 81:525-528
Munns CFJ, Cowell CT (2005) Prevention and treatment of osteoporosis in chronically ill children. J Musculoskelet Neuronal Interact. 5(3):262-272.
Murphy KP, Molnar GE, Lankasky K. (1995) Medical and functional status of adults with cerebral palsy. Dev. Med. Child. Neurol. 37:1075-1084.
Nielson JD, Uldall PV, Rasmussen S, Topp MW. (2002) Survival of children born with cerebral palsy. Children born 1971-1986. Ugesker Laeger. 164(48):5640-3.
Odding E, Roebroeck ME, Stam HJ. (2006) The epidemiology of cerebral palsy: incidence, impairments and risk factors. Disabil Rehabil. 28 (4):183-91.
Paul SM, Siegel KL, Malley J, Jaeger R. (2007) Evaluating interventions to improve gait in cerebral palsy: a meta analysis of spatiotemporal measures. Dev. Med Child Neurol.49:542-549.
Pharoah, PO, Platt, MJ, and Cooke, T. (1996) The changing epidemiology of cerebral palsy. Arch Dis Child Fetal Neonatal Ed. 75(3):F169-73.
Rubin CT, Capilla E, Luu YK, Crawford H, Nolan DJ, Mittal V, Rosen CJ, Pessin JE, Judex S. Adipogenesis is inhibited by brief, daily exposure to high frequency, extremely low-magnitude mechanical signals. PNAS. 2007; 104:17879-17884.
Sato Y, Kuno H, Asoh T, Honda Y, Oizumi K. (1998). Effect of immobilization on vitamin D status and bone mass in chronically disabled hospitalized disabled stroke patients. Age and Aging. 1998; 28: 265-269.
Schindl MR, Forstner C, Kern H, Hesse S. (2000) Treadmill training with partial body weight support in nonambulatory patients with cerebral palsy. Arch Phys Med Rehabil 81:301-306
Stackhouse SK, Binder-Macleod SA, Stackhouse CA, McCarthy JJ, Prosser LA and Lee SC. (2007) Neuromuscular Electrical Stimulation versus Volitional Isometric Strength Training in Children with Spastic Diplegic Cerebral Palsy: A Preliminary Study. Neurorehabil Neural Repair. Nov-Dec 21(6):475-485.
Semler O, Fricke O, Vezyroglou K, Stark C, Schoenau E. Preliminary results on the mobility after whole body vibration in immobilized children and adolescents. J Musculoskelet Neuronal Interact. 2007; 7: 77-81.
Stewart JC, Yeh SC, Jung Y, Yoon H, Whitford M, Chen SY, Li L, McLaughlin M, Rizzo A, Winstein CJ. (2007) Intervention to enhance skilled arm and hand movements after stroke: A feasibility study using a new virtual reality system. J Neuroengineering Rehabil (4):21
Uldall P, Michelson SI, Topp M, Madsen M, (2001). The Danish Cerebral Palsy Registry. A registry on a specific impairment. Dan Med Bull. 48(3):161-3.
Vincer MJ, Allen AC, Joseph KS, Stinson DA, Scott H, Wood E. (2006) Increasing prevalence of cerebral palsy among very preterm infants: a population-based study. Pediatrics. 118(6):e1621-6.
Zderic TW, Hamilton MT. (2006) Physical inactivity amplifies the sensitivity of skeletal muscle to the lipid-induced downregulation of lipoprotein lipase activity. J Appl Physiol. 100(1): 249-57.

Date:

Nov 01, 2007

Basic research into the causes of cerebral palsy has revealed that gender may influence the pathogenesis of developmental brain injury. Sex differences in the immature brain appear to be strongly influenced by intrinsic differences between male and female cells due to their distinct chromosomal complements. These cellular differences could be associated with the different patterns of brain injury observed in males and females and might be important for designing future trials of neuroprotective agents.

Males have a higher incidence than females of several brain-based developmental disabilities including mental retardation, autism, attention deficit hyperactivity disorder and cerebral palsy. A recent analysis of a European database of 4500 children with cerebral palsy found that the incidence of CP was 30% higher in males than females. This same study showed that the risk of cerebral palsy for male babies is 16 times higher than females for those with birth weights are below the 3rd percentile and 4 times higher for those with birth weights over the 97th percentile. In another recent study of the incidence of neurological and developmental disability after extremely preterm birth, males had significantly increased incidence of severe disability, cerebral palsy, and low scores of cognitive function at 6 years of age compared with females. Further evidence of greater biological vulnerability in the male infant versus the female infant includes a higher incidence of preterm birth, mortality due to prematurity, stillbirth and intraventricular hemorrhage (neo-natal stroke).

Studies have reported gender-based brain structure differences in children born very prematurely. Premature males have significantly less white matter than age/sex-matched controls while there is no difference in white matter volume between premature females and age/sex-matched controls. In contrast, premature females who had an intraventricular hemorrhage (IVH) had less grey matter than controls while males with IVH did not. This suggests that the adverse effects of preterm birth and IVH on the developing brain are strongly influenced by their interaction with sex-specific differences in normal brain development.

Evidence is accumulating to suggest the cellular pathways leading to neuronal death after an infant brain injury are different in males and females and that this is influenced by the sex chromosomes, not sex hormones as it may be later in life. Thus, an intervention found to be efficacious in preventing neuronal damage after an insult in infant males may not confer the same protection in infant females. For example, a recent study showed that the clinically approved glutamate antagonist dextromethorphan is protective against ischemia in male but not female infant rats, while another study showed that erythropoietin is more effective in female than in male pups subjected to hypoxia-ischemia. Thus, it is prudent when designing future pre-clinical and clinical trials of neuroprotective agents that study subjects be stratified by sex so as not to mask a potential beneficial effect.

* Johnston, MV and Hagberg, H. Sex and the pathogenesis of cerebral palsy. Dev. Med. & Child Neurol. 2007, 49:74-78

Date:
Oct 01, 2005

SUMMARY:

Cells destined to become neurons and those destined to become oligodendrocytes generate different isoprostanes when challenged by hypoxia/ischemia. In this autopsy study, the authors found that the oligodendrocyte isoprostane was elevated in the area of periventricular leucomalacia while the neuron isoprostane was not. In babies dying after perinatal hypoxia/ischemia the neuron isoprostane was expressed.

This Research Fact sheet is a bit technical so I will start with some explanations. It is well known that the most common form of cerebral palsy is spastic diplegia. Spastic diplegia occurs almost exclusively in premature children and is associated with a pathological change in the cerebral white matter called periventricular (around the ventricles) leucomalacia (white matter disease) abbreviated PVL.

The white matter of the brain consists of the long nerve cell processes called axons connecting one part of the brain with another and an insulating material called myelin which gives the white matter its distinctive color. Myelin is made by special cells called oligodendrocytes. Cells that will mature into oligodendrocytes are especially prevalent during the period of fetal life when PVL may develop. When oligodendrocyte precursors become hypoxic (shortage of oxygen) or ischemic (interruption of blood supply) they express a substance called F2-isoprostane while nerve cells precursors produce the closely related F4-isoprostane.

There is a great deal of interest in two related questions. Is PVL primarily the result of injury to developing nerve cells or to the cells destined to produce myelin? Is the injury primarily due to hypoxia/ischemia or is it the result of inflammation. Many would argue that both must be present to produce PVL.

This month we report on an autopsy study designed to address these questions1 . The authors studied the isoprostanes expressed in the brains of 33 babies who had died of various causes and had come to autopsy at one of 2 medical centers in the United States. Of these infants, 10 had PVL. Five had hypoxic/ischemic injury at the time of birth but did not have PVL. Eighteen infants with neither condition served as controls.

They found that the F2-isoprostane was elevated in areas of PVL while F4-isoprostane was not. This elevation of F2-isoprostane was not found in the brains of the control babies or in the brains of those who suffered hypoxic/ischemic insults at birth.

They conclude that the occurrence of PVL in preterm infants is related to hypoxic injury to the cells that were destined to differentiate into oligodendrocytes. The role of inflammation was not addressed.

COMMENT:

These findings suggest that hypoxia/ischemia is important to the development of PVL and that oligodendrocytes are the principle target. Since the babies were not evaluated for possible inflammatory changes, their data does not exclude a critical role for this factor as well.

1Back SA et al. Selective vulnerability of preterm white matter to oxidative damage defined by F2-isotopes. Annals of Neurology 2005; 58:108-120.

© UCP Research & Educational Foundation, October 2005

Date:
Mar 01, 2005

SUMMARY:

Hemiplegic cerebral palsy usually results from occlusion of a cerebral artery during the perinatal period producing a stroke in the infants brain. There are many risk factors for these strokes. Most children who suffer perinatal stroke will have several risk factors. When only one risk factor is present, the child usually develops normally.

Unfortunately, the medical and common term “stroke” includes two rather different types of disorder: hemorrhage and infarction1. The former term is self explanatory. Infarction, however, is a more technical term used to denote a process of tissue injury most often caused by the interruption of arterial blood flow to some part of an organ, in this case the brain. Such arterial occlusion is the most common cause of “stroke” in the elderly as well as hemiparetic cerebral palsy. These children are weak and spastic on one side of the body. Characteristically the arm is more affected than the leg.

Lee and her colleagues studied the incidence and causes of perinatal cerebral infarction confirmed by either MRI or CT scan among nearly 200,000 infants born in the Kaiser Permanente Medical Care Program of northern California between the years of 1997 and 2000, an incidence of 20/100,000 live births. They compared these children to a well selected control panel of 120 children without perinatal stroke.

Among the strengths of this study is their careful selection of patients including their insistence of imaging criteria characteristic of major artery occlusion. On the other hand, this might have excluded children with less severe brain injury. The study did not address the outcome of these children although is seems clear that all would have some degree of impairment.

Several risk factors were seen in the infants who suffered strokes. Strokes were more common among first born children and children of mothers with a history of infertility or preeclampsia. Risk factors during labor and delivery included emergency cesarean section, prolonged rupture of membranes, prolonged second stage labor, and vacuum extraction. Factors specific to the infant include heart anomalies, chorioamnionitis (inflammation of the placenta), and umbilical cord abnormalities. Many infants had more than one of these risk factors. 86% of infants with perinatal stroke had at least one compared to 59% of the controls; 25% had two or more compared to 25% of controls; 60% had 3 or more compared to 6% of the controls; and 31% had 4 or more risk factors compared with 2% of controls.

COMMENT:

This study emphasizes the multifactoral causes of this form of cerebral palsy. It is impressive that more than half of the controls had at least one risk factor for perinatal stroke but did not suffer one. This speaks well of the hardiness of the infant. It is similar to data being published on premature infants where the majority do not display cerebral palsy.

1 Lee J, Croen LA, Yoshida CK et al. Maternal and infant characteristics associated with perinatal arterial stroke in the infant. JAMA. 2005; 293(6):723-729

© UCP Research & Educational Foundation, March 2005

Date:
Dec 01, 2004

It is becoming increasingly recognized that either maternal or fetal infection is a major element in the cause of Cerebral Palsy. This process may also affect the premature newborn as demonstrated by a recent study performed by Stoll and her colleagues at the NIH National Institute of Child Health and Human Development.1

The authors identified 6093 children born between 1993 and 2001 included in the data base of the Institute. These children weighed less than 1000 gm (a bit over 2 pounds), survived, and were available for study when they were between 18 and 22 months corrected gestational age. Children who had shunts placed in the ventricles of their brains to drain fluid or had major malformations of the brain were excluded.

Nearly two of three children in their study acquired some type of infection during their newborn period. Over 40% of those with some sort of infection developed brain injury resulting in cerebral palsy, cognitive impairments, or both. For cerebral palsy alone, 16% of children who acquired any kind of infection in the post natal period developed cerebral palsy while only 8% of those without infection developed cerebral palsy. Children with infection in their blood (sepsis), infection associated bowel disease, and meningitis were especially at risk. The forms of Cerebral Palsy were not specified in this study.

Comment:

This study is most interesting taken in the context of the present attention to the role of maternal and placental infection and inflammation on the occurrence of Cerebral Palsy. It shows that newborn children with acquired infections, not caused by infection of the mother or of the placenta, are also prone to develop Cerebral Palsy and cognitive defects. It is worth noting that the infection need not affect the brain directly. The chemicals (cytokines) released by the infant to fight infection may be the source of the injury. Adult neurologists may see an analogy between the white matter injury seen in these infants and those seen in multiple sclerosis where it is believed that the inflammatory process begins outside of the brain and is then carried into it in a number of possible ways.

1Stoll, B.J., et al. Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection. JAMA, Nov 17 2004; 292 (19):2357-2401

© UCP Research & Educational Foundation, December 2004

Date:
Jun 02, 2003

Athetoid cerebral palsy is a form of CP that is characterized by uncontrolled movements of the trunk of the body, arms, and/or legs. In years past, it was often due to a large increase in the amount of a body chemical—bilirubin—in the blood of the newborn infant. This increase results in yellowing of the infant’s skin called jaundice. It also injures essential parts of the brain controlling the coordination of movements, the basal ganglia and the cerebellum. The brain injury is called Kernicterus and was a major cause of athetoid cerebral palsy.

There are a number of reasons for an increase in blood bilirubin in the newborn infant; among these are a genetic factor preventing adequate bilirubin clearance from the infant’s blood; the effect of certain medications; an infection causing increased destruction of infant red blood cells (a product of red blood cell destruction is bilirubin) and Rh factor blood incompatibility between the mother and the infant resulting in increased infant red blood cell destruction. In the past, Rh blood factor incompatibility was a major cause of Kernicterus.

With increased knowledge about blood types and Rh factors, improved methods of prevention were discovered. Also, methods for early detection of increased bilirubin and treatment were developed and applied; this later included photo (light) therapy and when necessary, an exchange blood transfusion. With control of the Rh factor incompatibility, the occurrence of new cases of Kernicterus almost disappeared and with that, the occurrence of athetoid CP diminished.

However, there are new preliminary reports of an increased occurrence of high levels of bilirubin in the blood of newborns leading to jaundice and the development of Kernicterus1. These reports have resulted in the government’s Center for Disease Control and Prevention (CDC) increasing its surveillance of newborns at risk of these disorders and stimulated other agencies to investigate the possible causes and develop even better methods of treatment.

The UCP Research and Educational Foundation is monitoring this situation and will report on it as new information becomes available. Hopefully, the reason for the increase in blood bilirubin levels in the newborn can be brought under control. In any case, one additional infant with Kernicterus is one too many.

1Bhutani, V.K. et al. Hyperbilirubinemia and Kernicterus; Epidemiology, Etiology and Therapy. Ped Acad Societies Abstracts. May 2003: 398A

UCP Research & Educational Foundation, June 2003

Date:

Jul 02, 2001

Stroke in childhood (SIC) can cause the disabilities usually identified with the occurrence of cerebral palsy: loss of muscle control and difficulty with speech and swallowing; it also can result in a seizure disorder such as epilepsy. SIC like cerebral palsy results in lifelong disabilities. Unlike stroke in adults, SIC is rarely caused by arterial atherosclerosis (plaque occluding an artery); it generally is caused by other types of injury to the arteries supplying blood to the brain. One potential risk factor for SIC is chickenpox, a common infectious disease of children.

In order to evaluate the relationship of chickenpox to SIC, two clinical research teams in Canada (Toronto and Hamilton) studied a group of young children (ages 6 months to 10 years) who had experienced a stroke due to lack of arterial blood to the brain (arterial ischemic stroke) during the period January 1992 to January 1999.1 The children studied were divided into two groups: those who had a history of chickenpox infection within 12 months of their stroke and those who did not. 31% of the children had a history of chickenpox in the preceding 1-11 months, with the average being 5.2 months. The children who had chickenpox were more likely to have hemiparesis (poor muscle control on one side of the body) and less likely to have seizures than the non-chickenpox group. The specific areas of the brain injured (basal ganglia), the type of arterial injury (large vessel occlusion) and the site of arterial injury were distinctive in the chickenpox-stroke group. The clinical neurological symptoms were essentially the same in both groups of children. The occurrence of subsequent strokes was more common in the chickenpox group (45%) than in the other group (20%), an important personal and public health finding.

As compared to SIC in non-measles related children, there was a 3 fold increase in the occurrence of SIC in children who had chickenpox within 12 months of the stroke; however, chickenpox related SIC is still relatively uncommon occurring in Canada in 1 out of 15,000 children. The reasons for both the occurrence of chickenpox related stroke and for its low occurrence are unknown. The authors suggest the reasons may be related to a child’s specific immune system response to infection or to a particular type (strain) of chickenpox virus. Prevention of chickenpox related SIC by use of an available vaccine against chickenpox needs to be considered, but is probably not a priority public health measure (having to vaccinate 15,000 children to prevent one case). However, the authors suggest the use of long-term therapy with aspirin for children who have had a stroke in order to prevent subsequent strokes.

Comment:

In many instances, cerebral palsy is the result of stroke: stroke in the fetus during pregnancy; stroke at the time of delivery; stroke in the early years of life. By stroke we mean brain damage due to an inadequate blood or oxygen supply to the brain or due to hemorrhage in the brain. These can occur in fetal life, in infancy and in childhood. We label the consequence, cerebral palsy. Cerebral palsy certainly can have other causes such as maternal illness or infant brain infection, but damage to the blood vessels of the developing and young brain is probably a major cause. Our Foundation is trying to influence the nation’s stroke research experts, who generally only think about adult stroke, to also give serious attention to stroke in the fetus, infant and child. We need their expertise to prevent stroke related cerebral palsy and to more adequately treat its consequences. Stroke occurs at all ages and because in children we call its consequences cerebral palsy, should not interfere with their giving it the attention it requires.

1Askalan, R. et al. Chickenpox and Stroke in Childhood; A Study of Frequency and Causation. Stroke 2001;32: 1257-1261

Date:
Jun 01, 2001

The occurrence of jaundice in the newborn infant is an unusual but not rare event; particularly in the premature. Experts in the field recently published a comprehensive article reviewing the present status of knowledge about this area.

Jaundice is a yellowish-coloring of the skin, white of the eyes (sclera) and deeper body tissues (e.g. brain) due to an increase of bilirubin in the blood. Bilirubin is a normal product of the metabolic breakdown by the liver of the hemoglobin released from red blood cells when they die, thus the term Ahyperbilirubinemia (hyper = high; bilirubin; emia = in the blood; high blood levels of bilirubin). The presence for a short period of time of modest jaundice in the newborn is a physiologic (Anormal) occurrence because the destruction of red blood cells in the newborn occurs at a more rapid rate than later in life. However, a prominent increase of red blood cell destruction such as seen in the Rh factor disorder (incompatible maternal – infant blood types) or due to an improper processing of bilirubin by the liver or its excretion into the gut can lead to high levels of blood bilirubin resulting in the presence of jaundice.

The infant brain is particularly vulnerable to high levels of blood bilirubin and there can be a generalized adverse brain reaction to it (an encephalopathy) or damage to specific brain areas. When the basal ganglia of the brain — the brain area controlling the coordination of muscle movement is damaged, a pathology called kernicterus occurs. Kernicterus is a very serious developmental brain disorder. In the past it was often due to Rh blood maternal-child incompatibilities that resulted in a severe movement disorder of infants. Since Rh factor incompatibility is now relatively rare, the occurrence of kernicterus has significantly diminished.

The level of bilirubin in the blood of the newborn can now be relatively easily measured, so treatment of neonatal jaundice can be initiated easily and brain damage prevented. The most common form of treatment is phototherapy –placing the infant under strong lights which convert the bilirubin to a form that can be easily eliminated by the infant. There are also other forms of therapy that can be used in very severe cases; one example is blood replacement.

There are many causes of increased or prolonged jaundice in the newborn including increased destruction of circulating red blood cells in the newborn, genetic enzyme defects, complications of pregnancy, birth trauma, newborn infection, administration of specific drugs and low intake of breast milk. In regard to low intake of breast milk — usually due to poor feeding — an increase in the number of breast feedings and supplemental feedings can be effective in reducing the jaundice, particularly during treatment by phototherapy.

The present practice of the early discharge of infants from a hospital can result in poor detection of jaundice of the newborn. It is generally recommended that all infants who are discharged from the hospital 48 hours or less after delivery should be examined within 2 to 3 days after discharge.

Comment:

A mild degree of jaundice shortly after birth is a physiologic process that disappears. However, the more severe forms of jaundice need immediate attention to prevent permanent brain damage. Now that there are methods available to accurately measure the level of bilirubin in the infant’s blood and very useful methods of therapy to reduce pathological levels of bilirubin, neonatal jaundice should no longer be an important clinical problem. However, in those infants in which there is a continuing increased destruction of red blood cells or a poor ability to convert the resulting bilirubin to an innocuous form, the reasons for the problem need to be specifically addressed and treated. All infants need to be evaluated within 48 hours after delivery whether still in the hospital or at home to ascertain whether they are jaundiced and if so, the degree and cause of the jaundice. In nearly all instances, brain damage can be prevented by early diagnosis and prompt therapy. There are isolated reports of a recent increase in the occurrence of neonatal jaundice. Whether these are due to early discharge from the hospital of newborns or some other factor are under investigation.

UCP Research & Educational Foundation, June 2001