Prenatal Origin of Hemiparetic Cerebral Palsy: How Often and Why?

ALLEN C. CROCKER, MD

Children's Hospital

300 Longwood Avenue

Boston, Massachusetts 02115

Prenatal Originof Hemiparetic

Cerebral Palsy: How Often

and Why?

“¿Th@eprenatalperiodis dangerous: antenatal mor tality is around 70%. Postnatal major or minor problems resulting from prenatal disturbances afflict nearly 10% of those who survive embryonic and fetal life. The nervous system is often a target. Statistical data suggest that 25% of conceptions are affected by developmental disturbances of the central nervous system. . .“‘

The first report concerning prenatal brain dam age may have come from the neuropathologic investigations of Virchow in 1868.2 Since then there has been a slow accumulation of neuropatho logic25 and clinical6'7 evidence that some brain dis orders, including some cases of hemiparetic cerebral palsy, have their origins prenatally. With the ad vent of neuroimaging the pace at which such evi dence has been reported has accelerated.@'2 The description by Scher and colleagues'3 of six full term neonates with intracranial lesions dated by ultrasonography to pathologic processes occurring before the onset of labor is an example of the application of neuroimaging techniques to the ques tion of when cerebral lesions originate.

Christensen and Melchior'@pointed out that “¿Any post-mortem study of neuropathology in hemiple

gics is bound to be unrepresentative as most of

these patients survive for a long time.―An impor tant advantage of neuroimaging, and especially of

ultrasonography, is that it provides a noninvasive, apparently risk-free, and widely applicable ap proach to obtaining information on brain structure relatively near to the time of presumed pathoge netic events.14

This commentary touches briefly on hemiparetic cerebral palsy, on what fraction of it occurs pre natally, and on a little of what we know about the mechanisms by which it may arise.

HEMIPARETICCEREBRALPALSY

Hemiparesis, or unilateral spastic paresis usually affecting the arm more than the leg, is the disability in 20% to 40% of children with cerebral palsy. The birth weight distribution in hemiparetic cerebral palsy is less skewed toward low weight than in other forms of cerebral palsy (Grether JK, Cummins 5K, Nelson KB, unpublished data),'5 although during recent years the prevalence of hemiplegia has in creased in infants oflow birth weight.16 Unlike most other forms of cerebral palsy, congenital hemipa resis is associated with lower socioeconomic status12―7;that association, in turn, may be related to higher parity and to prior reproductive losses,'2 although it is not known how these factors are connected.

HOW OFTEN IS HEMIPARETICCEREBRAL

PALSY DUE TO PRENATALINJURY?

Unfortunately, most reports documenting the prenatal occurrence of hemiparesis and of other forms of cerebral palsy are not informative as to what fraction of the disorder is due to problems arising before birth, because these reports do not contain information on the number of cases of the disorder arising in the same population that were not prenatal in origin.

Two studies of early onset hemiparesis in Swed ish populations offer evidence that disability arose prenatally in a majority of the children who were born at term.'8―9In preterm infants, hemiparesis

often may be related to early postnatal events or to

an interaction between prenatal and perinatal fac

Studies are now in progress of imaging in preterm babies in population-based studies. It is reasonable to hope that in the near future there will be imaging studies that sample populations of full-term babies as well, with later ascertainment of neurologic sta

tus in those children. Such studies will provide

information on the proportion of infants with later neurologic disabilities who have prenatal brain le sions evident by neonatal ultrasonographic exami nations.

REFERENCES

1. Taylor AB, Epstein SG, Crocker AC. Health care for chil then with special needs. In: Schlesinger MJ, Eisenberg L, eds. Children in a Changing Health System: Assessments and ProposaLcfor Reform. Baltimore, MD: Johns Hopkins Uni versity Press; 1990:27—48

2. Perrin JM, Stein REK. Reinterpreting disability: changes in Supplementary Security Income for children. Pediatrics.

1991;88:1047—1051

lization may account for the excess of left-brain lesions.

Strokes that begin in the first days after birth2426 may be the results of sepsis, disseminated intravascular coagulation, sinus thrombosis, em bolization, or unknown factors.2426 Barmada et a!. mention the potential relevance of “¿procedures such as arterial catheterization, surgery, or massive antibiotic treatment which predispose to throm botic complications.―24

In some children with early hemiparesis, imaging reveals irregular enlargements of the lateral ventri des, other lesions, or no apparent abnormality. The irregular ventricular enlargements may be evidence of white matter necroses in perinatal life. Such features are attributed by a number of authors to perinatal hypoxia or ischemia.'9 But markers of infection appear at least as prominent as markers of perfusion failures in the histories of infants with white matter necroses: Leviton and Paneth'4 point out that the correlates of white matter necroses, where known, often are not factors commonly linked with hypoxia or ischemia such as fetal heart rate abnormalities or low Apgar scores, but include increasing maternal age and housing density (an indicator of low socioeconomic status), congenital malformations, placental vascular anastomoses, maternal and intra-amniotic infection, and twin ning.

The association of prenatal brain damage with twinning is of special interest, because the preva lence of cerebral palsy was six times higher in twins than singletons in a population-based study of re cent North American births (Grether et al, unpub lished data). Ten percent of the cerebral palsy in that cohort was in twins. Twins tend to be low in birth weight and have an excess of congenital anomalies and of obstetric complications including cord entanglement. Shunts through anastomotic vascular connections between twins may produce the transfusion syndrome. Antenatal necrosis of cerebral white matter in twins was associated with polyhydramnios, intrauterine death of one twin, and placental vascular connections, the last-men tioned being the most important factor.27 When one of a pair of twins dies, disruption of the surviving co-twin may occur due to release of thromboplastic substances or to embolization, shifts in hemody namics, or other mechanisms. When this occurs early in gestation, before 16 weeks, microgyria and neuronal heterotopia in the surviving twin may result.m Mild vaginal bleeding may be the only clinical evidence of the disappearance of one twin.29 Death of a twin later in gestation can produce destructive lesions in the brain, kidneys, gut, skin, and other tissues of the surviving neonate.3°Twin

1060

PEDIATRICSVol.88 No.5 NOVEMBER1991

WHAT ARE THE POSSIBLEPRENATAL

CAUSESOF HEMIPARESIS?

Evrard et al' summarized prenatal brain-building as follows: the major steps of the first half of gestation are formation and multiplication of neu rons, their migration, and the regional development of the cerebral vesicles. In the second half of ges tation, growth and arborization of neuronal proc esses, development of synaptic connections, and myelination and gliogenesis occur. The major le sional mechanisms of the second half of gestation are residual disturbances of histogenesis, interfer ence with circulation of spinal fluid leading to hy drocephalus, ischemias, infection, trauma, and mi nor cortical disturbances of growth and differentia tion.

Given the complexity of the processes of gener ating a nervous system, and the dependence of each stage upon the successful completion of the one preceding it, there are many opportunities for de velopment to go wrong. Confident identification of the mechanism by which brain maldevelopment or damage occurs is not necessarily easy, even by means of neuropathologic investigation: “¿Thesame cause may lead to different types of lesions, and morphologically identical lesions may be due to different causes. In addition, cause and pathogen esis of fetal brain lesions are often speculative.2'

In the brains of children with hemiparesis, whether investigated by neuropathology or neu roimaging, there are sometimes wedge-shaped le

sions suggestingvascularocclusions.Later findings

on computed tomography suggestive of infarction are considerably more common in children with hemiparetic cerebral palsy than in those with other forms of cerebral palsy.22 Underlying the vascular occlusions (in utero strokes) may be aberrant de velopment of blood vessels, abnormality of blood constituents, vasculopathies, embolic or thrombotic disorders secondary to maternal diseases or those of the fetus or placenta. Perfusion failures may be secondary to maternal disease, cardiovascular col lapse, or serious hypoxemia through mechanisms including anaphylaxis, shock of any etiology, or gas intoxicatiOn. Direct trauma may involve the fetus, and some authors consider the possibility that trauma without direct injury to the fetus may pro duce enough release of maternal catecholamines to affect the fetus via vasoconstriction. A variety of disorders of the placenta and cord can affect the fetal brain.23

Many series of cases through several decades have demonstrated that congenital hemiparesis more often affects the right side of the body than the left (Grether et al, unpublished work), and some authors have considered the possibility that embo

at Viet Nam:AAP Sponsored on September 1, 2020

www.aappublications.org/news

ning ascertained by ultrasonography early in preg nancy is more frequent than at the time of deliv ery,3' so the explanatory power of the pathogenetic mechanisms in twins may be greater than is evident based on the prevalence of twinning at birth.

The chief point for this discussion is that there are clearly a variety of known mechanisms by which fetal brain injury can occur, and presumably many more awaiting discovery.

CONCLUSION

“¿Considerwhat must be accomplished during the course of fetal brain development. In effect, in a few months the entire work of hundreds of millions of years of evolution must be reachieved. . . . Tens of billions of neurons must be born. . . . These new cells must find their way to their anatomical desti nations, sometimes moving over substantial dis tances in an embryo that is constantly changing in form. . . Once the cell is fixed in place, the axon must find its way to its own destination. . . . They must not only get where they are going and make a connection, but they must avoid making any num ber of other connections that they might wrongly make in places they pass. Each nerve cell must develop one or more of at least a dozen neurotrans mitters. . . “¿32The product of that miracle is the most complicated object in the known universe, a human brain.

In this “¿Decadeof the Brain,―we can anticipate the emergence of a great deal more information about how the nervous system develops, prenatally and thereafter, and how and when that develop ment can go awry. That information will come from laboratories, clinics, and nurseries. Neuroimaging of the infant brain, a subject now producing a rich harvest in journals of pediatrics, neurology, radio!-ogy, and obstetrics, will contribute important new information about the processes of brain develop ment in our species, the timing of derailment from the normal course of brain development, and some aspects of pathogenesis. Neuropathology and the enormous flowering of new approaches in the basic and clinical neurosciences will help in explication of the mechanisms of maldevelopment and early injury. And we can hope that identification of mechanisms will allow us to develop strategies to prevent at least some of the problems leading to prenatal damage of the developing human brain.

KARIN B. NELSON, MD

National Institute of Neurological Disorders and Stroke

Department of Health and Human Services

National Institutes of Health Federal Building, Room 700 Bethesda, Maryland 20892

REFERENCES

1. Evrard P, de Saint-Georges P, Kadhim HJ, Gadisseux J-F.

Pathology ofprenatal encephalopathies. In: Child Neurology

and Developmental Disabilities. Baltimore, MD: Paul H. Brookes; 1989:153

2. Squier M, Keeling JW. The incidence of prenatal brain injury. NeuropatholAppl NeurobioL 1991;17:29-38 3. Malamud N, Itabashi HH, Castor J, Messinger HB. An

etiologic and diagnostic study of cerebral palsy. J Pediotr. 1964;65:270—293

4. Michaelis R, Rooschuz B, Dopfer R. Prenatal origin of congenital spastic hemiparesis. Early Hum Dev. 1980;4:

243—255

5. Christensen E, Melchior J. Cerebral Palsy—A Clinical and

Neuropathological Study. London: Heinemann Medical

Books; 1967. Clinics in Developmental Medicine No. 25 6. Haar F, Dyken P. Hereditary nonprogressive athetotic hem

iplegia: a new syndrome. Neurology. 1977;27:849—854

7. Zonana J, Adomato BT, Glass ST, Webb MJ. Familial porencephaly and congenital hemiplegia. J Pediatr.

1986;109:671—674

8. Claeys V, Deonna T, Chrzanowski R. Congenital hemipa

resis: the spectrum of lesions. Helu Paediatr Acto.. 1983;

38:439—455

9. Cohen ME, Duffner PK. Prognostic indicators in hemipa retic cerebral palsy. Ann NeuroL 1981;9:353—357 10. Kotlarek F, Rodewig R, Brull D, Zeumer H. Computed

tomographic findings in hemiparesis in childhood and their relation to etiology and prognosis. Neuropediatrics. 1981;12:101—109

11. Bejar R, Wozniak P, Allard M, et al. Antenatal origin of

neurologicdamage in newborn infants. Am J ObstetGynecoL

1988;159:357—363

12. Wildund L-M, Uvebrant P, Flodmark 0. Computed tomog raphy as an adjunct in etiological analysis of hemiplegic

cerebral palsy. I: Children born preterm. Neumpediatrics.

1991;22:50—56

13. Scher MS, Belfar H, Martin J, Painter MJ. Destructive brain lesions of presumed fetal onset: antepartum causes of

cerebral palsy. Pediatrics. 1991;88:898—906

14. Leviton A, Paneth N. White matter damage in preterm newborns—an epidemiologic perspective. Early Hum Deu. 1990;24:1—22

15. Pharoah POD, Cooke T, Rosenbloom L, Cooke RWI. Effects of birth weight, gestational age, and maternal obstetric

history on birth prevalence ofcerebral palsy. Arch Dis Child. 1987;62:1035—1040

16. Pharoah POD, Cook T, Cooke RWI, Rosenbloom L. Birth weight specific trends in cerebral palsy. Arch Dis Child. 1990;65:602—606

17. Dowding VM, Barry C. Cerebral palsy: social class differ

ences in prevalence in relation to birthweight and severity of disability. J Epidemiol Community Health.

1990;44:191-195

18. Hagberg B, Hagberg G. Prenatal and perinatal risk factors in a survey of 681 Swedish cases. In: Stanley F, Alberman E, eds. The Epidemiology of the Cerebral Palsies. Philadel phia, PA: Lippincott Co; 1984:131—132.Clinics in Develop mental Medicine No.87

19. Wiklund L-M, Uvebrant P. Hemiplegic cerebral palsy: cor relation between CT morphology and clinical findings. Dev Med Child NeuroL 1991;33:512—523

20. Powell TG, Pharoah P9D, Cooke RWI, Rosenbloom L

Cerebral palsy in low-birthweight infants. I. Spastic hemi

plegia: associations with intrapartum stress. Dev Med Child NeuroL 1988;30:11—18

Biol Neonate. 1986;50:61—74

22. Taudorf K, Meichior JC, Pedersen H. CT findings in spastic cerebral palsy, clinical, aetiological and prognostic aspects. Neuropediatrics. 1984;15:120—124

23. Benirshke K. Pathology ofthe Human Placenta. 2nd ad. New York; Springer-Verlag-,1990

24. Barmada MA, Moossy J, Shuman RM. Cerebral infarcts with arterial occlusion in neonates. Ann NeuroL 1979; 6:495—502

25. Ment LR, Duncan CC, Ehrenkranz RA. Perinatal cerebral infarction. Ann NeuroL 1984;16:559-568

26. Levy SR, Abroms IF, Marshall PC, Rosquete EE. Seizures and cerebral infarction in the full-term newborn. Ann Neu roL 1985;17:366—370

27. Bejar R, Vigliocco G, Gramajo H, et al. Antenatal origin of neurologic damage in newborn infants. II. Multiple gesta

tions. Am J Obstet GynecoL 1990;162:1230—1236

28. Barth, PG. Disorders of neuronal migration. Can J Neurol

Sci.1987;14:1—6

29. Gindoff PR, Yeh M-N, Jewelewicz R. The vanishing sac

syndrome, ultrasound evidence of pregnancy failure in mul

tiple gestations, induced and spontaneous. J Reprod Med. 1986;31:322—325

30. Patten RM, Mack LA, Nyberg DA, Filly RA. Twin emboli zation syndrome: prenatal sonographic detection and signif icance. Radiology. 1989;173:685—689

31. Landy HJ, Weiner S, Corson SL, Batzer FR, Bolognese RJ. The “¿vanishingtwin―:ultrasonographic assessment of fetal disappearance in the first trimester. Am J Obstet GynecoL

1986;155:14—19

32. Konners M. The Tangled Wing. New York: Henry Holt & Co; 1982:70

1062

PEDIATRICSVol.88 No.5 NOVEMBER1991

PROGRESS IN PEDIATRIC PHARMACOLOGY

The survey by the Pharmaceutical Manufacturers Association has identified 114 drugs and vaccines that are being developed specifically for pediatric use...

. The 114 medicines involve 127 clinical testing research projects, since some

are being tested for more than one use. An example is Prokine, a colony stimulating factor being tested by Hoechst-Roussel and Immunex for two kinds of blood disorders, for cancer, and for bone marrow transplantation.

. 56 companies are involved in these research projects, a very broad base of

companies that again, I think, reflects the strong research capabilities of the private sector.

I Nearly two-thirds of the projects are in the final stages of development: 45

are in the Phase III human clinical tests and another 35 are at the Food and Drug Administration for review.

. Fully a quarter of our research projects—32 to be exact—are for rare diseases

and are designated as orphan drugs on the chart.

Gerald J. Mossinghoff, President, Pharmaceutical Manufacturers Association. Press Briefing. New York, NY: October 24, 1990

NOTED BY J.F.L., MD

at Viet Nam:AAP Sponsored on September 1, 2020

www.aappublications.org/news

1991;88;1059

Pediatrics

KARIN B. NELSON

Prenatal Origin of Hemiparetic Cerebral Palsy: How Often and Why?

Services

Updated Information &

http://pediatrics.aappublications.org/content/88/5/1059

including high resolution figures, can be found at:

Permissions & Licensing

http://www.aappublications.org/site/misc/Permissions.xhtml

entirety can be found online at:

Information about reproducing this article in parts (figures, tables) or in its

Reprints

http://www.aappublications.org/site/misc/reprints.xhtml

1991;88;1059

Pediatrics

KARIN B. NELSON

Prenatal Origin of Hemiparetic Cerebral Palsy: How Often and Why?

http://pediatrics.aappublications.org/content/88/5/1059

the World Wide Web at:

The online version of this article, along with updated information and services, is located on

American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 1991 by the been published continuously since 1948. Pediatrics is owned, published, and trademarked by the Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has

at Viet Nam:AAP Sponsored on September 1, 2020

www.aappublications.org/news