- Email: [email protected]
A Poison Tree
947
these aims requires well-planned research by scientists and clinicians working together. For this reason the academic environment of IVF should be preserved in institutions already undertaking this The considerable research. advantages for medicine of this association have already reproductive been seen in obstetrics and gynaecology, and in endocrinology and diagnostic ultrasonography and it is likely that there will be many more benefits from this research in the future. Ethical guidelines in clinical practice and research are gradually being established worldwide, as is the appropriate legislation to protect patients and their children in the context of gamete donation and embryo cryopreservation.17,18 It is essential that the medical and scientific community contribute to this process if reasonable, ethical, and compassionate rules and regulations are to be achieved.
A Poison Tree A STRANGE form of motoneurone disease (MND) called lytico (Spanish, paralytico) has been recognised for several hundred years by the Chamorros, the indigenous population of the tropical volcanic island of Guam, three thousand miles west of Hawaii.1-3 A similar illness occurs in two small villages in the Kii peninsula of Japan, in Western New Guinea, and among the inhabitants of Groote Eylandt, off the coast of north-eastern Australia.4 The worldwide incidence of MND is about 1 in 100 000, but in Guam the illness, which is also accompanied by symptoms of parkinsonism and dementia, is, or was until lately, much more common.5 Dr Kulch’s survey of Guam in 1954 showed an incidence of 200 per 100 000, but this had fallen dramatically to 30 per 100 000 by 1980.6 A survey reported in 1979 showed that neuropathological changes-cerebral atrophy, degeneration of the substantia nigra, and prominent neurofibrillary tangles-resembling those of MND in Guam, also occur in nearly half of all Chamorros aged 40 years arid older who have no clinical evidence of the disease.7 Is this strange disorder genetic or environmental in 17. Robertson JA. Ethical and legal issues in cryopreservation of human embryos. Fertil Steril 1987; 47: 371-81. 18. Jansen R. The clinical impact of in vitro fertilization. Part 2. Regulation, money and research. Med J Aust 1987; 146: 362-66. 1. Brody JA, Kurland LT. Amyotrophic lateral sclerosis and parkinsonism-dementia in Guam. In Spillane JD, ed. Tropical neurology. London: Oxford University Press, 1973: 355-75. 2. Kurland LT, Choi NS, Sayre GP. Implications of incidence and geographic patterns on the classification of amyotrophic lateral sclerosis. In. Norris FH Jr, Kurland LT, eds Motor neuron diseases. New York: Grune & Stratton, 1969: 28. 3. Elizan TS, Hirano A, Abrams BM, Read RL, Van Nuis C, Kurland LT. Amyotrophic lateral sclerosis and parkinsonism-dementia complex of Guam: Neurological reevaluation. Arch Neurol 1966; 14: 356-68. 4. Gajdusek DC. Foci of motor neuron disease in high incidence in isolated populations of East Asia and the Western Pacific. In: Rowland P, ed. Human motor neuron diseases. New York: Raven, 1982: 363-93. 5. Juergens SM, Kurland LT, Okazaki H, Mulder DW. ALS in Rochester, Minnesota: 1925-1977. Neurology (Minneap) 1980; 30: 463-70. 6. Kurland LT, Molgaard CA. Guamanian ALS: hereditary or acquired? In Rowland LP, ed Human motor neuron diseases. New York: Raven, 1982: 165-71. 7. Anderson FH, Richardson EP Jr, Okazaki H, Brody JA Neurofibrillary degeneration on Guam: frequency in Chamorros and non-Chamorros with no known neurological disease. Brain 1979; 102: 65-77.
origin? After the ceding of Guam to the United States in 1898, death certificates frequently mentioned "progressive muscular atrophy", which was initially thought to be hereditary.3 However, the decline in incidence of the disease over the past 30 years has challenged this view. A condition somewhat similar to MND, with cramp, spasticity, and paralysis in the legs is caused by eating the drought-resistant pea, Lathyrus sativus, in lean monsoon seasons in central India.8 Last year, the likely toxin was identified as p-Noxalyl-amino alanine (BOAA), which causes motor tract damage in monkeys similar to that seen in MND.9 Does a comparable plant toxin cause MND in Guam? There, cycads-palm-like plants, some over 40 feet tall, whose pithy stem is a source of sago-have been under suspicion for many years.2 Cycad was the main source of edible starch among the Chamorros before and during the 1939-45 war.10 However, cycad production is arduous and the plant is eaten less frequently since the population has become Americanised. One has to sally forth into the boondocks, cut the nuts from the trees, carry them back, soak them for seven days while changing the water daily, dry them out, and grind them into flour. This lengthy preparation is needed to get rid of poisonous cycasin, which is converted to a methylating agent, methylazomethanol (MAM), one of the most toxic and carcinogenic substances in naturey,12 MAM will cause, as well as cerebellar necrosis in mice and dogs, microcephaly and retinal damage, but does not produce the typical features of motoneurone disease in small animals .13-17 However, cycad extracts also contain an unusual non-protein aminoacid, ex-amino- &bgr;-methylaminoproprionic acid (synonym, p-N-methyIamino-L-alanine or BMAA), which is chemically similar to BOAA. Spencer and his colleagues fed BMAA to cynomolgus monkeys, and found after 2-12 weeks that it caused a condition strongly resembling Guam MND-parkinsonism.18 The animals had wrist drop, clumsiness, muscle 8. Dastur DK.
Lathyrism.
Some aspects of the disease in man and animals. World Neurol
1962; 3: 721-30. 9. Spencer PS, Roy DN, Ludolph A, Hugon J, Dwivedi MP, Schaumbaurg HH Lathyrism: evidence for the role of the neuroexcitatory aminoacid BOAA Lancet 1986; ii: 1066-67. 10 Kurland LT. An appraisal of the neurotoxicity of cycad and the etiology of
11
amyotrophic lateral sclerosis on Guam. Sixth International Cycad Conference, Chicago, April, 1972. Fed Proc 1972; 31: 1540-42. O’Gara RW, Brown JM, Whiting MG. Induction of hepatic and renal tumors by topical application of aqueous extract of cycad nut to artificial skin ulcers in mice. Third conference on the toxicity of cycads, Chicago, April 7, 1964. Fed Proc 1964;
23: 1383. 12. Hirono I. Carcinogenicity and neurotoxicity of cycasin with special reference to species differences. Fed Proc 1972; 31: 1493-97 13. Hirono I, Shibuya C, Hayashi K. Induction of a cerebellar disorder with cycasin in newborn mice and hamsters Proc Soc Exp Biol Med 1969; 131: 593. 14. Jones M, Yang M, Mickelsen O. Effects of methylazoxy methanol glucoside and methylazoxy acetate on the cerebellum of postnatal Swiss albino mouse. Fed Proc 1972, 31: 1508-11. 15. Spatz M, Laqueur GL. Chemical induction of microencephaly in two strains of rats. Part 1. Proc Soc Exp Biol Med 1968; 129: 705. 16. Sanger VL, Yang M, Mickelsen O. Cycasin-induced central nervous system lesions in postnatal mice. Fed Proc 1972; 31: 1524-28. 17 Griffin G, Cork LC, Troncoso JC, Price DL. Experimental neurotoxic disorders of motor neurons: neurofibnllary pathology In: Rowland LP, ed. Human motor neuron diseases. New York: Raven, 1982: 419-33. 18 Spencer PS, Nunn PB, Hugon J, et al. Guam amyotrophic lateral sclerosisparkinsonism-dementia linked to a plant excitant neurotoxin. Science 1987; 237: 517-22.
948
weakness, wasting, and prolonged administration,
and, with more expressionless face and blank stare, a crouched posture, and a bradykinetic shuffling gait. The features of parkinsonism responded to levodopa. There were electrophysiological and pathological signs of both upper and lower motor neuron damage. Much evidence now links MNDparkinsonism in Guam to BMAA intake, although as yet the extrapyramidal and Alzheimer-type features of the human disease have not been mirrored exactly in animals, and the occasional time lapse of up to 30 years tremor, an
between residence in Guam and disease onset has not been explained. How may BMAA destroy nerve cells? It has been suggested that BMAA or an active metabolite may act like certain excitotoxic aminoacids and some glutamate receptor agonists, which kill neurons with excessive and sustained firing, leading to enhanced calcium entry and cell damage.19 Thus, for example, glutamate or aspartate receptor agonists will damage cortical neurons, and, on the other hand, the Nmethyl-D-aspartate (NMDA) receptor antagonist MK801, which selectively blocks one population of glutamate receptors, 20 may possibly prevent BMAA toxicity in monkeys.18 Eating cycads is not the usual cause of MND or parkinsonism worldwide, for these plants have a very limited geographic range. However, there are many other poisonous plants that damage the central nervous system-eg, the yellow star thistle in Sacramento, which causes parkinsonism in horses, although its active toxin has not been identified.21 Other environmental factors may increase glutamate toxicity and endogenous excitatory aminoacids may themselves be toxic.22,23 Indeed, Charing Cross neuroscientists have shown high levels of glutamate and aspartate as well as glycine in the cerebrospinal fluid in MND.24 Glycine enhances glutamate toxicity.25 Spencer’s work raises many fundamental questions, not least the possibility that nerve loss in Huntington’s chorea, parkinsonism, and Alzheimer’s disease, as well as in MND, is related to abnormal or excessive stimulation of different receptor types. The time has come to follow Meldrum’s suggestion of a therapeutic trial of excitatory aminoacid antagonists such as MK801 in these and other chronic neurological disorders.26 19. Chase
RA, Pearson S, Nunn PB, Lantos PL. Comparative toxicity of alpha- and beta-N-oxalyl-L-alpha, beta-diaminoproprionic acids to rat spinal cord. Neurosci Lett 1985; 55: 89-94
Wong EHF, Kemp JA, Priestly T The anticonvulsant MK801 is a potent N-methyl-D-aspartate antagonist. Proc Natl Acad Sci USA 1986, 83: 7104-08. 21. Cordy DR Nigropallidal encephalomalacia in horses. J Neuropath Exp Neurol 1954; 20.
13: 330-42. 22.
Beal MF, Kowall NW, Ellison DW, Mazurek MF, Swartz KJ, Martin JB. Replication of the neurochemical characteristics of Huntington’s disease by quinolinic acid.
Nature 1986; 321: 168-71. 23. Plaitakis A, Berl S, Yahr MD. Abnormal glutamate metabolism in an adult-onset degenerative neurological disorder Science 1982; 216: 193-96 24. de Belleroche J, Recordati A, Clifford Rose F Elevated levels of ammo acids in the CSF of motor neurone disease patients. Neurochem Pathol 1984, 2: 1-6 25. Johnson JW, Ascher P. Glycine potentiates the NMDA response m cultured mouse brain neurons Nature 1987, 325: 529-31. 26. Meldrum B Possible therapeutic application of antagonists of excitatory ammo acid neurotransmitters. Clin Sci 1985; 68: 113-22.
WHAT CAN BE DONE FOR NIGHT WAKING IN CHILDREN? MANY aspects of night waking are uncertain, including its defmition.1 In practice it concerns children who regularly disturb their parents’ sleep.2 In British samples it is most common in one to two year olds, when roughly 25% wake three or more nights a week, but in some countries (for unknown reasons) the prevalence is higher throughout the preschool years .2-1 The mean persistence is unclear because while one-third or more are still waking one year later,3-5 up to half of these may have stopped and restarted.4 Since we do not know why some parents cope and others do not,3,10 it is not surprising that the efficacy of most forms of treatment is unclear. 3,4 Recommended management includes alleviating medical causes such as methylxanthine or anticonvulsant therapy, otitis media, and cow’s milk allergy; changing the domestic routine, reducing daytime naps, and introducing solids if appropriate; sedatives, for the child or the mother; and modification. 11-14 behaviour behaviour Formerly, modification meant leaving the child to cry, but today other methods are preferred--eg, changing the parents’ response more gradually, rewarding the child for not disturbing its parents, and introducing consistency and a bedtime ritua1.4,12 In preschool children with various degrees of night waking, four to eight weeks’ therapy has been followed by improvement in 77-90% and complete resolution in over 50%, lasting up to six months;4,15-18 none of the studies was controlled, however. The response may be less rapid in children over 18 months,16 and the treatment less effective if there is marital discord or the father is not involved.15 Medication is widely resorted to.1o In two samples of children, aged 14 and 15 months, respectively,5,6 13-16% had been given drugs, including mild analgesics, for night waking. In an inner-city survey, general practitioners had in one year prescribed "sleep medicine" to 7 % of the preschool children under their care.19 Ounsted and Simons reported 1 Van Tassel EB. The relative influence of child and environmental characteristics
on
sleep disturbances in the first and second years of life. J Dev Behav Pediatr 1985; 6: 81-86. 2. Ounsted MK, Simons CD. The first born child: toddlers
problems. Dev Med Child Neurol 1978; 20: 710-19. 3. Jenkins S, Owen C, Bax M, Hart H. Continuities of common behaviour problems in preschool children. J Child Psychol Psychiatry 1984; 25: 75-89. 4. Richman N, Douglas J, Hunt H, Lansdown R, Levere R. Behavioural methods in the treatment of sleep problems—a pilot study. J Child Psychol Psychiatry 1985; 26: 581-90. 5. Bernal JF. Night waking in infants during the first fourteen months. Dev Med Child Neurol 1973; 15: 760-9. 6 Blurton-Jones N, Ferreira MCR, Farquar Brown M, McDonald L. The association between perinatal factors and later night waking Dev Med Child Neurol 1978; 20: 427-34. 7 Klackenberg G. Sleep behaviour studied longitudinally. Data from four to sixteen years on duration, night awakening, and bed sharing. Acta Paediatr Scand 1982; 71: 501-06. 8. Beltramini AU, Hertzig ME. Sleep and bedtime behavior in preschool-aged children Pediatrics 1983; 71: 153-58. 9 Basler K, Largo RH, Molinari L. Die Entwicklung des Schlafverhaltens in den ersten funf Lebensjahren. Helv Paediatr Acta 1980; 35: 211-23. 10. Chavin W, Tinson S. Children with sleep difficulties. Health Visitor 1980; 53:477-80. 11. Valman HB. ABC of 1 to 7 (revised). Sleep problems. Br Med J 1987, 294: 828-30. 12. Bax MCO Sleep disturbance in the young child. Br Med J 1980; 280: 1177-79. 13. Illingworth RS. The normal child. Some problems of the early years and their treatment, 8th ed. Edinburgh Churchill Livingstone, 1983. 14. Kahn A, Mozin MJ, Casimir G, Montauk L, Blum D Insomnia and cows milk allergy in infants. Pediatrics 1985; 76: 880-84. 15. Jones DPH, Verduyn CM. Behavioural management of sleep problems. Arch Dis Child 1983, 58: 442-44. 16. Bidder RT, Gray OP, Howells PM, Eaton MP. Sleep problems in preschool children. community clinics. Child Care Health Dev 1986, 12: 325-37. 17. Sanger S, Weir K, Churchill E. Treatment of sleep problems: the use of behavioural modification techniques by health visitors Health Visitor 1981; 54: 421-4 18. Largo RH, Hunziker UA. A developmental approach to the management of children with sleep disturbances in the first three years of life. Eur JPediart 1984; 142: 170-73. 19. Bax M, Hart H Health needs of preschool children. Arch Dis Child 1976, 51: 848-52
these aims requires well-planned research by scientists and clinicians working together. For this reason the academic environment of IVF should be preserved in institutions already undertaking this The considerable research. advantages for medicine of this association have already reproductive been seen in obstetrics and gynaecology, and in endocrinology and diagnostic ultrasonography and it is likely that there will be many more benefits from this research in the future. Ethical guidelines in clinical practice and research are gradually being established worldwide, as is the appropriate legislation to protect patients and their children in the context of gamete donation and embryo cryopreservation.17,18 It is essential that the medical and scientific community contribute to this process if reasonable, ethical, and compassionate rules and regulations are to be achieved.
A Poison Tree A STRANGE form of motoneurone disease (MND) called lytico (Spanish, paralytico) has been recognised for several hundred years by the Chamorros, the indigenous population of the tropical volcanic island of Guam, three thousand miles west of Hawaii.1-3 A similar illness occurs in two small villages in the Kii peninsula of Japan, in Western New Guinea, and among the inhabitants of Groote Eylandt, off the coast of north-eastern Australia.4 The worldwide incidence of MND is about 1 in 100 000, but in Guam the illness, which is also accompanied by symptoms of parkinsonism and dementia, is, or was until lately, much more common.5 Dr Kulch’s survey of Guam in 1954 showed an incidence of 200 per 100 000, but this had fallen dramatically to 30 per 100 000 by 1980.6 A survey reported in 1979 showed that neuropathological changes-cerebral atrophy, degeneration of the substantia nigra, and prominent neurofibrillary tangles-resembling those of MND in Guam, also occur in nearly half of all Chamorros aged 40 years arid older who have no clinical evidence of the disease.7 Is this strange disorder genetic or environmental in 17. Robertson JA. Ethical and legal issues in cryopreservation of human embryos. Fertil Steril 1987; 47: 371-81. 18. Jansen R. The clinical impact of in vitro fertilization. Part 2. Regulation, money and research. Med J Aust 1987; 146: 362-66. 1. Brody JA, Kurland LT. Amyotrophic lateral sclerosis and parkinsonism-dementia in Guam. In Spillane JD, ed. Tropical neurology. London: Oxford University Press, 1973: 355-75. 2. Kurland LT, Choi NS, Sayre GP. Implications of incidence and geographic patterns on the classification of amyotrophic lateral sclerosis. In. Norris FH Jr, Kurland LT, eds Motor neuron diseases. New York: Grune & Stratton, 1969: 28. 3. Elizan TS, Hirano A, Abrams BM, Read RL, Van Nuis C, Kurland LT. Amyotrophic lateral sclerosis and parkinsonism-dementia complex of Guam: Neurological reevaluation. Arch Neurol 1966; 14: 356-68. 4. Gajdusek DC. Foci of motor neuron disease in high incidence in isolated populations of East Asia and the Western Pacific. In: Rowland P, ed. Human motor neuron diseases. New York: Raven, 1982: 363-93. 5. Juergens SM, Kurland LT, Okazaki H, Mulder DW. ALS in Rochester, Minnesota: 1925-1977. Neurology (Minneap) 1980; 30: 463-70. 6. Kurland LT, Molgaard CA. Guamanian ALS: hereditary or acquired? In Rowland LP, ed Human motor neuron diseases. New York: Raven, 1982: 165-71. 7. Anderson FH, Richardson EP Jr, Okazaki H, Brody JA Neurofibrillary degeneration on Guam: frequency in Chamorros and non-Chamorros with no known neurological disease. Brain 1979; 102: 65-77.
origin? After the ceding of Guam to the United States in 1898, death certificates frequently mentioned "progressive muscular atrophy", which was initially thought to be hereditary.3 However, the decline in incidence of the disease over the past 30 years has challenged this view. A condition somewhat similar to MND, with cramp, spasticity, and paralysis in the legs is caused by eating the drought-resistant pea, Lathyrus sativus, in lean monsoon seasons in central India.8 Last year, the likely toxin was identified as p-Noxalyl-amino alanine (BOAA), which causes motor tract damage in monkeys similar to that seen in MND.9 Does a comparable plant toxin cause MND in Guam? There, cycads-palm-like plants, some over 40 feet tall, whose pithy stem is a source of sago-have been under suspicion for many years.2 Cycad was the main source of edible starch among the Chamorros before and during the 1939-45 war.10 However, cycad production is arduous and the plant is eaten less frequently since the population has become Americanised. One has to sally forth into the boondocks, cut the nuts from the trees, carry them back, soak them for seven days while changing the water daily, dry them out, and grind them into flour. This lengthy preparation is needed to get rid of poisonous cycasin, which is converted to a methylating agent, methylazomethanol (MAM), one of the most toxic and carcinogenic substances in naturey,12 MAM will cause, as well as cerebellar necrosis in mice and dogs, microcephaly and retinal damage, but does not produce the typical features of motoneurone disease in small animals .13-17 However, cycad extracts also contain an unusual non-protein aminoacid, ex-amino- &bgr;-methylaminoproprionic acid (synonym, p-N-methyIamino-L-alanine or BMAA), which is chemically similar to BOAA. Spencer and his colleagues fed BMAA to cynomolgus monkeys, and found after 2-12 weeks that it caused a condition strongly resembling Guam MND-parkinsonism.18 The animals had wrist drop, clumsiness, muscle 8. Dastur DK.
Lathyrism.
Some aspects of the disease in man and animals. World Neurol
1962; 3: 721-30. 9. Spencer PS, Roy DN, Ludolph A, Hugon J, Dwivedi MP, Schaumbaurg HH Lathyrism: evidence for the role of the neuroexcitatory aminoacid BOAA Lancet 1986; ii: 1066-67. 10 Kurland LT. An appraisal of the neurotoxicity of cycad and the etiology of
11
amyotrophic lateral sclerosis on Guam. Sixth International Cycad Conference, Chicago, April, 1972. Fed Proc 1972; 31: 1540-42. O’Gara RW, Brown JM, Whiting MG. Induction of hepatic and renal tumors by topical application of aqueous extract of cycad nut to artificial skin ulcers in mice. Third conference on the toxicity of cycads, Chicago, April 7, 1964. Fed Proc 1964;
23: 1383. 12. Hirono I. Carcinogenicity and neurotoxicity of cycasin with special reference to species differences. Fed Proc 1972; 31: 1493-97 13. Hirono I, Shibuya C, Hayashi K. Induction of a cerebellar disorder with cycasin in newborn mice and hamsters Proc Soc Exp Biol Med 1969; 131: 593. 14. Jones M, Yang M, Mickelsen O. Effects of methylazoxy methanol glucoside and methylazoxy acetate on the cerebellum of postnatal Swiss albino mouse. Fed Proc 1972, 31: 1508-11. 15. Spatz M, Laqueur GL. Chemical induction of microencephaly in two strains of rats. Part 1. Proc Soc Exp Biol Med 1968; 129: 705. 16. Sanger VL, Yang M, Mickelsen O. Cycasin-induced central nervous system lesions in postnatal mice. Fed Proc 1972; 31: 1524-28. 17 Griffin G, Cork LC, Troncoso JC, Price DL. Experimental neurotoxic disorders of motor neurons: neurofibnllary pathology In: Rowland LP, ed. Human motor neuron diseases. New York: Raven, 1982: 419-33. 18 Spencer PS, Nunn PB, Hugon J, et al. Guam amyotrophic lateral sclerosisparkinsonism-dementia linked to a plant excitant neurotoxin. Science 1987; 237: 517-22.
948
weakness, wasting, and prolonged administration,
and, with more expressionless face and blank stare, a crouched posture, and a bradykinetic shuffling gait. The features of parkinsonism responded to levodopa. There were electrophysiological and pathological signs of both upper and lower motor neuron damage. Much evidence now links MNDparkinsonism in Guam to BMAA intake, although as yet the extrapyramidal and Alzheimer-type features of the human disease have not been mirrored exactly in animals, and the occasional time lapse of up to 30 years tremor, an
between residence in Guam and disease onset has not been explained. How may BMAA destroy nerve cells? It has been suggested that BMAA or an active metabolite may act like certain excitotoxic aminoacids and some glutamate receptor agonists, which kill neurons with excessive and sustained firing, leading to enhanced calcium entry and cell damage.19 Thus, for example, glutamate or aspartate receptor agonists will damage cortical neurons, and, on the other hand, the Nmethyl-D-aspartate (NMDA) receptor antagonist MK801, which selectively blocks one population of glutamate receptors, 20 may possibly prevent BMAA toxicity in monkeys.18 Eating cycads is not the usual cause of MND or parkinsonism worldwide, for these plants have a very limited geographic range. However, there are many other poisonous plants that damage the central nervous system-eg, the yellow star thistle in Sacramento, which causes parkinsonism in horses, although its active toxin has not been identified.21 Other environmental factors may increase glutamate toxicity and endogenous excitatory aminoacids may themselves be toxic.22,23 Indeed, Charing Cross neuroscientists have shown high levels of glutamate and aspartate as well as glycine in the cerebrospinal fluid in MND.24 Glycine enhances glutamate toxicity.25 Spencer’s work raises many fundamental questions, not least the possibility that nerve loss in Huntington’s chorea, parkinsonism, and Alzheimer’s disease, as well as in MND, is related to abnormal or excessive stimulation of different receptor types. The time has come to follow Meldrum’s suggestion of a therapeutic trial of excitatory aminoacid antagonists such as MK801 in these and other chronic neurological disorders.26 19. Chase
RA, Pearson S, Nunn PB, Lantos PL. Comparative toxicity of alpha- and beta-N-oxalyl-L-alpha, beta-diaminoproprionic acids to rat spinal cord. Neurosci Lett 1985; 55: 89-94
Wong EHF, Kemp JA, Priestly T The anticonvulsant MK801 is a potent N-methyl-D-aspartate antagonist. Proc Natl Acad Sci USA 1986, 83: 7104-08. 21. Cordy DR Nigropallidal encephalomalacia in horses. J Neuropath Exp Neurol 1954; 20.
13: 330-42. 22.
Beal MF, Kowall NW, Ellison DW, Mazurek MF, Swartz KJ, Martin JB. Replication of the neurochemical characteristics of Huntington’s disease by quinolinic acid.
Nature 1986; 321: 168-71. 23. Plaitakis A, Berl S, Yahr MD. Abnormal glutamate metabolism in an adult-onset degenerative neurological disorder Science 1982; 216: 193-96 24. de Belleroche J, Recordati A, Clifford Rose F Elevated levels of ammo acids in the CSF of motor neurone disease patients. Neurochem Pathol 1984, 2: 1-6 25. Johnson JW, Ascher P. Glycine potentiates the NMDA response m cultured mouse brain neurons Nature 1987, 325: 529-31. 26. Meldrum B Possible therapeutic application of antagonists of excitatory ammo acid neurotransmitters. Clin Sci 1985; 68: 113-22.
WHAT CAN BE DONE FOR NIGHT WAKING IN CHILDREN? MANY aspects of night waking are uncertain, including its defmition.1 In practice it concerns children who regularly disturb their parents’ sleep.2 In British samples it is most common in one to two year olds, when roughly 25% wake three or more nights a week, but in some countries (for unknown reasons) the prevalence is higher throughout the preschool years .2-1 The mean persistence is unclear because while one-third or more are still waking one year later,3-5 up to half of these may have stopped and restarted.4 Since we do not know why some parents cope and others do not,3,10 it is not surprising that the efficacy of most forms of treatment is unclear. 3,4 Recommended management includes alleviating medical causes such as methylxanthine or anticonvulsant therapy, otitis media, and cow’s milk allergy; changing the domestic routine, reducing daytime naps, and introducing solids if appropriate; sedatives, for the child or the mother; and modification. 11-14 behaviour behaviour Formerly, modification meant leaving the child to cry, but today other methods are preferred--eg, changing the parents’ response more gradually, rewarding the child for not disturbing its parents, and introducing consistency and a bedtime ritua1.4,12 In preschool children with various degrees of night waking, four to eight weeks’ therapy has been followed by improvement in 77-90% and complete resolution in over 50%, lasting up to six months;4,15-18 none of the studies was controlled, however. The response may be less rapid in children over 18 months,16 and the treatment less effective if there is marital discord or the father is not involved.15 Medication is widely resorted to.1o In two samples of children, aged 14 and 15 months, respectively,5,6 13-16% had been given drugs, including mild analgesics, for night waking. In an inner-city survey, general practitioners had in one year prescribed "sleep medicine" to 7 % of the preschool children under their care.19 Ounsted and Simons reported 1 Van Tassel EB. The relative influence of child and environmental characteristics
on
sleep disturbances in the first and second years of life. J Dev Behav Pediatr 1985; 6: 81-86. 2. Ounsted MK, Simons CD. The first born child: toddlers
problems. Dev Med Child Neurol 1978; 20: 710-19. 3. Jenkins S, Owen C, Bax M, Hart H. Continuities of common behaviour problems in preschool children. J Child Psychol Psychiatry 1984; 25: 75-89. 4. Richman N, Douglas J, Hunt H, Lansdown R, Levere R. Behavioural methods in the treatment of sleep problems—a pilot study. J Child Psychol Psychiatry 1985; 26: 581-90. 5. Bernal JF. Night waking in infants during the first fourteen months. Dev Med Child Neurol 1973; 15: 760-9. 6 Blurton-Jones N, Ferreira MCR, Farquar Brown M, McDonald L. The association between perinatal factors and later night waking Dev Med Child Neurol 1978; 20: 427-34. 7 Klackenberg G. Sleep behaviour studied longitudinally. Data from four to sixteen years on duration, night awakening, and bed sharing. Acta Paediatr Scand 1982; 71: 501-06. 8. Beltramini AU, Hertzig ME. Sleep and bedtime behavior in preschool-aged children Pediatrics 1983; 71: 153-58. 9 Basler K, Largo RH, Molinari L. Die Entwicklung des Schlafverhaltens in den ersten funf Lebensjahren. Helv Paediatr Acta 1980; 35: 211-23. 10. Chavin W, Tinson S. Children with sleep difficulties. Health Visitor 1980; 53:477-80. 11. Valman HB. ABC of 1 to 7 (revised). Sleep problems. Br Med J 1987, 294: 828-30. 12. Bax MCO Sleep disturbance in the young child. Br Med J 1980; 280: 1177-79. 13. Illingworth RS. The normal child. Some problems of the early years and their treatment, 8th ed. Edinburgh Churchill Livingstone, 1983. 14. Kahn A, Mozin MJ, Casimir G, Montauk L, Blum D Insomnia and cows milk allergy in infants. Pediatrics 1985; 76: 880-84. 15. Jones DPH, Verduyn CM. Behavioural management of sleep problems. Arch Dis Child 1983, 58: 442-44. 16. Bidder RT, Gray OP, Howells PM, Eaton MP. Sleep problems in preschool children. community clinics. Child Care Health Dev 1986, 12: 325-37. 17. Sanger S, Weir K, Churchill E. Treatment of sleep problems: the use of behavioural modification techniques by health visitors Health Visitor 1981; 54: 421-4 18. Largo RH, Hunziker UA. A developmental approach to the management of children with sleep disturbances in the first three years of life. Eur JPediart 1984; 142: 170-73. 19. Bax M, Hart H Health needs of preschool children. Arch Dis Child 1976, 51: 848-52