Perspectives On Animal Research
Volume 1, Supplement
An Evaluation of Ten Randomly-Chosen Animal Models
of Human Disease
Vitamin A Deficiency Hydrocephalus (Rabbits)(1)
Description of the Model:
Hydrocephalus is generally divided into two types: obstructive hydrocephahis resulting from obstruction of the flow of cerebrospinal fluid CSF) within the ventricular system; and communicating hydrocephalus due to either overproduction or inadequate absorption of CSF. Prior to the development of shunts, congenital hydrocephalus in human infants was a devastating condition with a poor prognosis.(2) Congenital hydrocephalus remains a clinical challenge due to potentially irreversible in utero damage, shunt complications, and shunt failures.
One of the earliest animal models of this disease was developed by J.W.
Muilen and his co-workers in the 1950s.(3-7) Newberne reviewed this model
of congenital communicating hydrocephalus in 1975. Investigators deprived
female rabbits of vitamin A, causing hydrocephalus in the offspring.
The researchers based their methodology on observations that vitamin
A-deficient diets caused hydrocephalus in newborn animals of many species.
Newberne concluded, "...the vitamin A-deficient rabbit provides
a readily available model that is predictable and one that yields highly
reproducible results."(1)
Criterion I: Concordance between the Animal Model
and the Human Disease
Clinical Manifestations:
Newberne noted the clinical similarity of hydrocephalus in newborn babies and in the rabbits:
Signs and symptoms of vitaritin A-deficiency hydrocephalus in the newborn rabbit are essentially the same as those observed in the human infant, If present at birth, there is a distinct bulging over the frontal lobes of the brain and a genera] distortion of the shape of the head.(1)
Pathogenesis:
While the gross clinical presentation of vitamin A-deficiency hydrocephalus in the rabbit and human congenital communicating hydrocephalus contain similar elements, there are fundamental differences in pathophysiology. Our literature review did not reveal a single case of congenital hydrocephalus due to maternal vitamin A deficiency, even though vitamin A deficiency is a worldwide health problem and a leading cause of blindness. While there have been a few case reports of hydrocephalus in children with a diet deficient in vitamin A(8,9) or poor absorption of vitamin A,(10,11) it does not appear that humans are susceptible to congenital vitamin A-deficiency hydrocephalus. In the experimental rabbits, there appears to be a developmental defect of the CSF production and/or absorption system. Such an etiology is probably different from postnatal vitamin A-deficiency hydrocephalus in human newborns -- itself a rare cause of hydrocephalus. Giroud doubted that a deficiency of vitamin A causes teratogenicity in humans:
In other species, particularly in the rabbit, the teratogenic action of vitamin A deficiency was also observed. In humans only one case seems to have been quoted and it is open to question since Venkatachalam et al. did not notice any repercussions in mothers very poor in vitamin A.(12)
Giroud continued:
...the questions of nutrition of the embryo is not completely solved ... the problem is complicated by interferences with genetic conditions: it is the reason why the translation of results from one species to another and to humans remains difficult.(12)
While there is controversy over the etiology of hydrocephalus in both animals and in man, it appears that the cause of hydrocephalus in the experimental rabbits is different from any mechanism in humans. Millen and Dickson observed, "Up to the present, evidence from experiments on rabbits and other animals points to an overactivity of the choroid plexuses, unaccompanied by gross histological changes as the most probable cause of the condition.(7) On the other hand, Kennedy noted that in human infants, "The primary defect in communicating hydrocephalus is an impairment in the resorptive mechanism of cerebrospinal fluid."(13) Wilson, in reviewing human brain development, concurred, "Although excessive production of cerebrospinal fluid has been cited as a possible cause of hydrocephalus, the increased CSF pressure and enlargement of the ventricles most often appear to be caused by blockage in CSF circulation or absorption."(14) Indeed, Minns et al. found that, in hydrocephalic infants, "The rate of production of CSF ... may vary by a factor of 10 over a 1-hour period, although the average rate of CSF production remains within previously established normal limits."(15)
There is some evidence from studies of human tissues that hypovitaminosis A may cause increased mucopolysaccharide concentration in the dura, and this may impede CSF absorption.(10) In 1966, Danes and Beam found that the addition of vitamin A to cultured fibroblasts from patients with Hurler syndrome decreased cellular mucopolysaccharide content.(16) Three years later, Cousins et al. reported that vitamin A-deficient calves had markedly increased mucopolysaccharide concentration in the tentonum cerebelli dura.(7) A 1970 study by Harrington and Newberne using the rabbit model of congenital hydrocephalus did not report changes in mucopolysaccharides, but it is unclear if biochemical studies were done.(8) In 1956, Millen and Woollam found, "In none of the hydrocephalic young (rabbits) examined after death was any congenital abnormality discovered other than the presence of hydrocephalus. There was no evidence of bony overgrowth in the skull."(6) Thus, while mucopolysaccharide accumulation may explain hydrocephalus in some animals and in human infants fed a vitamin A-deficient diet, the authors were unable to locate evidence that this was the etiology in the experimental rabbit model of hydrocephalus.
Criterion II: Citations
We located 29 articles in the Science Citation Index from 1961 to 1988,
which cited at least one of the original papers describing this animal model
of congenital communicating hydrocephalus.(3-7) (See
Appendix A.) Of these, five were studies that involved human patients.
None credited the animal model with an important clinical insight.
1. In 1961, Bass and Fisch reported two cases of increased intracranial pressure and bulging fontanel in infants fed a low vitamin A diet.(11) They cited Millen et al.(4) when noting that, "Little is known as to the specific action of vitamin A in spite of much experimental work on animals."(11) Thus, they concluded that the animal model had not yielded significant insight into the pathophysiology of hydrocephalus.
2. Pitt and Samson compared the dietary history of 99 mothers who bore children with birth defects to 99 control mothers.(19) The only data relevant to this review of hydrocephalus were 13 cases of spina bifida, which could be associated with hydrocephalus. They found, "The absence of positive significant differences (between the two groups of mothers) in the mongoloid and spina bifida groups is worthy of comment."(19) Pitt and Samson cited several papers, including Mullen et al.,(3) when they noted that maternal dietary deficiencies can cause congenital defects in many different animals, including hydrocephalus in the rabbit.
3. Feldman and Schlezinger reported two cases of benign intracranial hypertension associated with hypervitaminosis A in two adults.(20) When they remarked that both hypo- and hypervitaminosis A caused hydrocephalus in newborn animals, they cited papers by Millen and co-workers. They did not comment further on the vitamin A deficiency.
4. Keating and Feigin reported two 4-month old infants with cystic fibrosis and signs of intracranial hypertension felt to be caused by poor intestinal absorption of vitamin A.(21) They cited the work of Millen et al.(4) as evidence for one of three possible theories explaining the association of increased intracranial pressure and hypovitaminosis A. They commented, "...Millen et al. suggested that the elaboration of cerebrospinal fluid was increased beyond the absorptive capacity."(21) The two other theories were also derived from animal studies. This paper indicated that animal research has yielded several theories about the cause of hydrocephalus. None of the theories were relevant to Keating and Feigin's conclusion that, "Prompt recognition of this syndrome and appropriate therapy with vitamin A may prevent blindness or death and obviate the necessity to perform a number of potentially hazardous procedures..." (21) It is important to note that investigators who reported hydrocephalus in children with vitamin A-deficient diets encouraged vitamin A therapy before the development of this animal model.(8,9)
5. Abernathy also reported a case of cystic fibrosis secondary hypovitaminosis A and increased CSF pressure.(10) He cited Mullen et al.(4) in the following passage:
In 1940, Moore and Sykes described the development of increased intracranial pressure in young calves kept on a carotene-deficient diet. By 1956, this had also been demonstrated in young rabbits, pigs, chickens, and the offspring of vitamin A-deficient sheep.(10)
Abernathy did not credit the rabbit model with inspiring any clinical insight. He noted only that it was one of several examples of hydrocephalus secondary to vitamin A deficiency in animals.
Criterion III: Historical Impact
Because hydrocephalus can be a manifestation of many different pathological processes, there have been few general reviews. Two recent reports on the diagnosis and management of fetal hydrocephalus using human patients failed to mention research with the rabbit animal model in their review of the literature. (22,23) Of these two papers, only one by Chervenak et al. cited any animal study. This involved in utero diagnosis of hydrocephalus in rhesus monkeys.(23)
Ring-Mrozik and Angerpointner did an extensive historical review of hydrocephalus. Their major focus was on surgical management of the condition. Of 249 references, none involved the rabbit model. (24)
Despite the enthusiasm of the original investigators who developed and studied this animal model in the 1950s and 1960s, there has been little subsequent interest, except the 1970 study by Harrington and Newberne.(18) In a 1985 review entitled "Animal models of hydrocephalus: recent developments," Hockwald also failed to cite research with the rabbit model among his 105 references.(25)
Conclusions:
A wide range of anatomical or physiological defects can cause hydrocephalus in newborn humans. While there have been a few reports that a vitamin A-deficient diet can reversibly elevate CSF pressure, it is uncertain whether there has been even a single case of congenital hydrocephalus secondary to maternal vitamin A deprivation in man, despite the worldwide prevalence of vitamin A deficiency. While the etiology of hydrocephalus is unclear in both experimental animals and in man, it appears that rabbits suffer from a teratogenic effect secondary to vitamin A deficiency, and human beings do not. Thus, it is unclear whether or not the rabbit model has any relevance to congenital communicating hydrocephalus, except insofar as both rabbits and humans have similar gross clinical presentations and elevation of CSF pressure. Presumably due to differences in pathophysiology, none of the five clinical studies that cited this research credited the animal model with any important insights. Similarly, two clinical articles, a historical review, and even a recent review of the experimental literature did not cite this animal model.
References:
1. Newberne PM: Vitamin A deficiency hydrocephaly, model no.38 in Jones TC, Hackel DB, Migaki G (eds): Handbook: Animal Models of Human Disease, Fasc 3. Washington DC, Armed Forces Institute of Pathology, 1974.
2. Behrman RE, Vaughan VC: Nelson Textbook of Pediatrics, 13th Ed. Philadelphia, WB Saunders, 1987, pp 1304-1306
3. Millen JW, Woollam DHM, Lamming GE: Hydrocephalus associated with deficiency of vitamin A. Lancet 1953;2:1234-1236.
4. Millen JW, Woollam DHM, Lamming GE: Congenital hydrocephalus due to experimental hypovitaminosis A. Lancet 1954;2:679-683.
5. Lamming GE, Woollam DHM, Mullen JW: Hydrocephalus in young rabbits associated with maternal vitamin A deficiency. Br J Nutr 1954;8:363-369.
6. Millen SW, Woollam DHM: The effect of the duration of vitamin A deficiency in female rabbits upon the incidence of hydrocephalus in their young. J Neurol Neurosurg Psychiat 1956;19:17-20.
7. Millen JW, Dickson AD: The effect of vitamin A upon the cerebrospinal fluid pressures of young rabbits suffering from hydrocephalus due to maternal hypovitaminosis A. Br J Nutr 1957;11:440-446.
8. Blackfan JD, Wolbach SB: Vitamin A deficiency in infants; clinicRi and pathological study. I Pediat 1933;3:679-706.
9. Cornfield D, Cooke RE: Vitamin A deficiency: case report. Pediatrics 1952;10:33-39.
10. Abernathy RS: Bulging fontanelle as presenting sign in cystic fibrosis. Am J Dis Child 1976;130:1360-1362.
11. Bass MH, Fisch GR: Increased intracranial pressure with bulging fontanel. Neurology 1961;11:1091-1094.
12. Giroud A: Nutrition of the embryo. Fed Proc 1968;27:163-184.
13. Shozo I (ed): Hydrocephalis. Princeton, Excerpta Medica, 1986.
14. Wilson DB: Embryonic development of the head and neck: part 5, the brain and cranium. Head Neck Surg 1980;2312-320.
15. Minns RA, Brown JK, Engelman HM: CSF production rate: 'real time' estimation. Z Kinderrchir 1987;42(supp I):36-40.
1& Danes BS, Beam AG: Hurler's syndrome: effect of retinal (vitamin A alcohol) on cellular mucopolysaccharides in cultured human skin fibroblasts. J Exp Med 1966;124:1181-1198.
17. Cousins RJ, Eaton HD, Rousseau JE Jr., et al.: Biochemical constituents of the dura mater in vitamin A deficiency. J Nutr 1969;97:409-418.
18. Harrington DD, Newberne PM: Correlation of maternal blood levels of vitamin A at conception with the incidence of hydrocephaluis in newborn rabbits: an experimental animal model. Lab An Care 1970;20:675-680.
19. Pitt DB, Samson PE Congenital malfonnations and maternal diet. Aust An Med 1961;10:268-273.
20. Feldman MH, Schlezinger NS: Benign intracranial hypertension associated with hypervitaminosis A. Arch Neurol 1970;22:1-7.
21. Keating JP, Ralph RD: Increased intracranial pressure associated with probable vitamin A deficiency in cystic fibrosis. Pediatrics 197046:41-46.
2L Pretorius DH, Davis K, Manco-Johnson ML, Manchester D, Meier PR, Clewell WH: Clinical course of fetal hydrocephalus: 40 cases. Am J Roenigenol 1985;144:827-831.
23. Chervenak FA, Berkowitz RL., Tortora M, Hobbins JC: The management of fetal hydrocephalus. Am J Obstet Gynecol 1985;l51:933-942.
24. Ring-Mrozik F, Angerpointner TA: Historical aspects of hydrocephalus. Prog Pediac Surg 1986;2th158-187.
25. Hockwald GM: Animal models of hydrocephalus: recent developments. Proc Soc Exp Biol Med 1985;178:l-11.