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EXTRAPYRAMIDAL DISEASES AND DEMENTIA
1199 GLUTAMIC-ACID DECARBOXYLASE ACTIVITY
*
t
6 cases, 83:!: 10 years. 8 cases, with little or no cerebrovascular disease (Dr J. A. N. Corsellis, personal communication). Values in parentheses are the range
(1 standard deviation). t, §, If Significance, P < 0-001,
·
<
0-01, and
<
0-02, respectively.
therapy -with neuroleptics can elicit an akinetic-rigid parkinsonian syndrome. To this we must now add the finding9 that therapy with levodopa in elderly patients afflicted with senile dementia (and exhibiting only minor extrapyramidal signs) can result in some improvement in while
biopsy: cryostat section, haematoxylin and eosin. Vacuoles are present in about half the fibres in this field. Other stains show the vacuoles are filled with lipid and occur predominantly in type-I fibres. Scale mark 50 jjun. Muscle
-
electroencephalogram
was
mildly abnormal
and
an
electro-
myogram showed slight myopathic changes. Lipid droplets were visible in many neutrophils in the peripheral blood.
A muscle biopsy (left quadriceps) showed abundant lipid droplets in the predominating type-I fibres (see accompanying figure) which also stained red with the modified trichrome
method. Fibre diameters were normal and there were no central nuclei. The muscle camitine concentration was 2-61 iJ.mol per g. dry weightcompared with control values of 11-6, 13-4, and 15-7 iJ.mol per g. in normal muscle. Serum-camitine has not yet been assayed.
The patient was given high doses of a proprietary compound water-soluble vitamin preparation, with additional hydroxocobalamin, choline, and biotin with dubious Medium-chain clinical and no biochemical benefit. mouth too nauseating, but a clinical triglycerides by proved trial of a low-fat diet (20 g.) is now in progress, and so far, after 8 weeks, he has gained weight with cessation of nausea, and has become more active. A trial of DL-carnitine, for which some therapeutic success has been claimed,ó is also planned. We are dubious of the value of corticosteroids in this condition.g Hospital for Sick Children, and National Hospital for Nervous Diseases, London WC1.
DIANE P. L. SMYTH B. D. LAKE J. MACDERMOT J. WILSON.
EXTRAPYRAMIDAL DISEASES AND DEMENTIA SIR,-Drachman and Stahl 9 cited clinical evidence to’ support the view that senile dementia and Parkinson’s disease represent two ends of a spectrum rather than unrelated disease entities. The clinical, pharmacological, morphological, and neurochemical data that we shall briefly review not only add weight to their argument but also suggest that the spectrum could be broadened to include at least some dyskinesias (i.e., Huntington’s chorea) at one end and cases of Parkinson’s disease with dementia at the other. Dementia is the decisive clinical feature of Alzheimer’s disease and senile dementia, it almost always occurs in at least the terminal stages of Huntington’s chorea, and it is often associated with Parkinson’s disease. Many pharmacological studies show that, while levodopa often alleviates
parkinsonian signs, 8. 9.
the treatment
can
lead
to
dyskinesia;
Marquis, N. R., Fritz, I. B. Lipid. Res. 1964, 5, 184. Drachman, D. A., Stahl, S. Lancet, April 5, 1975, p. 809.
intellect. At the morphological level, atrophy of specific regions of the basal ganglia are diagnostic of Huntington’s chorea and parkinsonism. Although the analogous histopathological hallmarks of senile dementia and Alzheimer’s disease occur in the cortex and hippocampus, morphological changes have also been recorded in basal ganglia.110 Pioneer neurochemical studies by Hornykiewicz et al.ll have established that the metabolism of the neurotransmitters dopamine and y-aminobutyric acid (G.A.B.A.) is defective in parts of the basal ganglia in parkinsonism. Other investigations 12,13 suggest that the metabolism of G.A.B.A. is impaired in basal ganglia in Huntington’s chorea. Similar studies on basal ganglia in senile dementia show that the activities of both the key enzyme (see accompanying table) in G.A.B.A. biosynthesis and levodopa decarboxylase and concentration of the major metabolite of dopamine, are quite markedly reduced from the level in aged-matched controls.14,15 In view of the global impairment in intellect it is not surprising that, in contrast to Huntington’s chorea and parkinsonism, in senile dementia the defect in glutamic-acid decarboxylase activity is also evident in other regions including cortical grey matter and thalamus (see table). Of particular interest are our findings in a case of parkinsonism with dementia. The glutamicacid decarboxylase activity in this brain, although much reduced in cortex and thalamus, was almost undetectable in caudate nucleus and substantia nigra. Although dopamine metabolism is clearly affected in parkinsonism and senile dementia there is convincing evidence that the metabolism of G.A.B.A. is widely, if not universally, impaired in dementias where the causative factor is so far unrecognised. It has been postulated that neurological diseases of this type (abiotrophies 16) are caused by an unidentified essential defect of vital endurance leading to cellular death. Though it is clearly too early to conclude that the essential or primary defect in these dementias occurs in G.A.B.A.-ergic neuronesl7 the finding of Pearce, J. Eur. Neurol. 1974, 12, 94. Lloyd, K. G., Davidson, L., Hornykiewicz, O. Advances in Neurology: Progress in the Treatment of Parkinsonism; vol. 3. New York, 1973. 12. Perry, T. C., Hansen, S., Kloster, M. New Engl. J. Med. 1973, 288, 337. 13. Bird, E. D., Iversen, L. L. Brain, 1974, 97, 457. 14. Bowen, D. M., Flack, R. H. A., White, P., Smith, C. B., Davison, " A. N. Lancet, 1974, ii, 1247. 15. Gottfries, C. G., Gottfries, R., Roos, B. E. Br. J. Psychiat. 1969, 115, 563. 16. Br. med. J. 1974, i, 337. 17. Roberts, E. Biochem. Pharm. 1974, 23, 2637.
10. 11.
1200 metabolism in all of these diseases suggests that only limited benefit will ensue from levodopa therapy in patients afflicted with " abiotrophic dementias ".
impaired
G.A.B.A.
Miriam Marks Department of
Neurochemistry, Institute of Neurology, National Hospital, Queen Square,
DAVID M. BOWEN ALAN N. DAVISON.
London WC1N 3BG.
DOWN SYNDROME IN INDIA
SIR,-In a worldwide study of congenital malformations organised by the World Health Organisation no cases of Down syndrome were reported from India among 59,689 births in Bombay and Calcutta. There were no cases in 4141 births to Indian mothers in Kuala Lumpur, and only
ADRENAL SUPPRESSION BY CLOBETASOL
PROPIONATE SIR,—Until recently we have assumed that normal skin
constitutes an effective barrier to the absorption of corticosteroids. Application of potent steroids to diseased skin may produce transient suppression of pituitary-adrenal function, but the efficiency of the barrier increases with clinical improvement. Adrenal function recovers despite continuing steroid application. The increasingly effective combination of potent steroids and scientifically optimal bases threatens this physiological safety valve. We found that two of our topical corticosteroid preparations caused important adrenal suppression when applied to normal
1 affected child
was born to 3119 Indian mothers in In Singapore. all, there was only 1 child with Down to born 66,000 Indian mothers. These observasyndrome
FREQUENCY
OF
DOWN
SYNDROME
IN
SURVEYS
OF
NEWBORNS
IN INDIA
generated an impression that the frequency of Down syndrome in India is extremely low. This, however, is contrary to clinical experience of most paediatricians in India. Over 125 patients with Down syndrome have been evaluated in the genetics clinic in our hospital over a 4-year period. In the neonatal unit of our hospital, 4 infants with Down syndrome (confirmed by cytogenetic studies) have been detected among 3236 live births, giving a frequency of 1 per 809 live births (1-24 per 1000). Information from other Indian surveys of consecutive newborns gives a mean frequency of 1 per 1215 births (0-82 per 1000), with a range from 0-26 to 1-6 per 1000 births (see table). Excluding the data from Madras, which appears to have a low incidence, the mean frequency is 1-19 per 1000 births from among 35,325 births (range 0-73 to 1-6). The combined results of 9 surveys in Europe, North America, and Australiagave an average of 1 per 663 births (1-51 per 1000 births), with a range of 1-15 to 1-9 per 1000 births.
. &mid ot;
tions
5 chromosomal surveys of newborns in the U.K. and North America yielded a mean of 1-0 per 1000 births, with a range of 0 among 2081 births in London, Ontario, to 1-5 per 1000 births in Edinburgh. The frequency of Down syndrome, therefore, does not appear to be very different in various parts of the world. Genetics and Neonatal Unit, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi 110016, India.
Fluocinonide 0-05% gel
Because of the potential risks we abandoned the development of these preparations. Reports suggesting that clobetasol propionate (’Der-
skin.
movate ’) has systemic effects 2,3led us to compare its systemic effect with that of two fluocinonide products (’Lidex’ cream andTopsyn ’ gel). Nine healthy male volunteers were admitted to hospital. 15 g. of the topical preparation was applied to the trunk, beginning in the evening and twice daily thereafter for a total of nine applications. There was never any occlusion by plastic film. Three volunteers were treated with each of the preparations. Plasma was obtained at 7.30 A.M. daily for 6 days and again on the 1 lth day, and cortisol levels were determined by the competitive protein-binding method of Murphy et al.4 Mean plasma-cortisol levels are shown in the accompanying figure. Complete suppression of plasma-cortisol levels was already evident 9-5 hours after the first application of clobetasol propionate and continued throughout the period of application. Sparkes and Wilson,5 in discussing adrenal suppression, state that " It is not expected that clobetasol propionate will behave differently " from other steroids. We
ISHWAR C. VERMA MEHARBAN SINGH.
1. Stevenson, A. C., Johnston, H. A., Stewart, M. I. P., Golding, D. R. Bull. Wld Hlth Org. 1966, 34, suppl. 1. 2. Ghosh, S., Bali, L. Ind. J. Child Hlth, 1963, 12, 448. 3. Khanna, K. K., Prasad, L. S. N. Ind. J. Pediat. 1967, 34, 63. 4. Aiyar, R. R., Agarwal, J. R. Ind. Pediat. 1969, 6, 729. 5. Raju, V. B. Personal communication. 6. Tibrewala, N. S., Pai, P. M. Ind. Pediat. 1974, 11, 403. 7. Hamerton, J. L. Human Cytogenetics; vol. II, p. 201. New York, 1971. 8. Hamerton, J. L., Ray, M., Abbot, J., Williamson, C., Ducasse, G. C. Can. med. Ass. J. 1972, 106, 776.
Average values 3 normal males per preparation Clobetasol propionate 0’05% ointment Fluocinonide 0’05% cream
cannot
agree.
Clinical Pharmacology Unit 404B, Hospital General de Mexico, Mexico City, Mexico.
E. ORTEGA.
Institute of Clinical Medicine,
Syntex Research, Palo Alto, California, U.S.A.
K. H. BURDICK E. J. SEGRE.
1. Lancet, 1967, ii, 1078. 2. Feiwel, M., Kelly, W. J. ibid. 1974, ii, 112. 3. Tan, R. Proc. R. Soc. Med. 1974, 67, 31. 4. Murphy, B. E. P., Engelberg, W, Pattee, C. J. J. clin. Endocr. Metab. 1963, 23, 293. 5. Sparkes, C. G., Wilson, L. Br. J. Derm. 1974, 90, 197.
*
t
6 cases, 83:!: 10 years. 8 cases, with little or no cerebrovascular disease (Dr J. A. N. Corsellis, personal communication). Values in parentheses are the range
(1 standard deviation). t, §, If Significance, P < 0-001,
·
<
0-01, and
<
0-02, respectively.
therapy -with neuroleptics can elicit an akinetic-rigid parkinsonian syndrome. To this we must now add the finding9 that therapy with levodopa in elderly patients afflicted with senile dementia (and exhibiting only minor extrapyramidal signs) can result in some improvement in while
biopsy: cryostat section, haematoxylin and eosin. Vacuoles are present in about half the fibres in this field. Other stains show the vacuoles are filled with lipid and occur predominantly in type-I fibres. Scale mark 50 jjun. Muscle
-
electroencephalogram
was
mildly abnormal
and
an
electro-
myogram showed slight myopathic changes. Lipid droplets were visible in many neutrophils in the peripheral blood.
A muscle biopsy (left quadriceps) showed abundant lipid droplets in the predominating type-I fibres (see accompanying figure) which also stained red with the modified trichrome
method. Fibre diameters were normal and there were no central nuclei. The muscle camitine concentration was 2-61 iJ.mol per g. dry weightcompared with control values of 11-6, 13-4, and 15-7 iJ.mol per g. in normal muscle. Serum-camitine has not yet been assayed.
The patient was given high doses of a proprietary compound water-soluble vitamin preparation, with additional hydroxocobalamin, choline, and biotin with dubious Medium-chain clinical and no biochemical benefit. mouth too nauseating, but a clinical triglycerides by proved trial of a low-fat diet (20 g.) is now in progress, and so far, after 8 weeks, he has gained weight with cessation of nausea, and has become more active. A trial of DL-carnitine, for which some therapeutic success has been claimed,ó is also planned. We are dubious of the value of corticosteroids in this condition.g Hospital for Sick Children, and National Hospital for Nervous Diseases, London WC1.
DIANE P. L. SMYTH B. D. LAKE J. MACDERMOT J. WILSON.
EXTRAPYRAMIDAL DISEASES AND DEMENTIA SIR,-Drachman and Stahl 9 cited clinical evidence to’ support the view that senile dementia and Parkinson’s disease represent two ends of a spectrum rather than unrelated disease entities. The clinical, pharmacological, morphological, and neurochemical data that we shall briefly review not only add weight to their argument but also suggest that the spectrum could be broadened to include at least some dyskinesias (i.e., Huntington’s chorea) at one end and cases of Parkinson’s disease with dementia at the other. Dementia is the decisive clinical feature of Alzheimer’s disease and senile dementia, it almost always occurs in at least the terminal stages of Huntington’s chorea, and it is often associated with Parkinson’s disease. Many pharmacological studies show that, while levodopa often alleviates
parkinsonian signs, 8. 9.
the treatment
can
lead
to
dyskinesia;
Marquis, N. R., Fritz, I. B. Lipid. Res. 1964, 5, 184. Drachman, D. A., Stahl, S. Lancet, April 5, 1975, p. 809.
intellect. At the morphological level, atrophy of specific regions of the basal ganglia are diagnostic of Huntington’s chorea and parkinsonism. Although the analogous histopathological hallmarks of senile dementia and Alzheimer’s disease occur in the cortex and hippocampus, morphological changes have also been recorded in basal ganglia.110 Pioneer neurochemical studies by Hornykiewicz et al.ll have established that the metabolism of the neurotransmitters dopamine and y-aminobutyric acid (G.A.B.A.) is defective in parts of the basal ganglia in parkinsonism. Other investigations 12,13 suggest that the metabolism of G.A.B.A. is impaired in basal ganglia in Huntington’s chorea. Similar studies on basal ganglia in senile dementia show that the activities of both the key enzyme (see accompanying table) in G.A.B.A. biosynthesis and levodopa decarboxylase and concentration of the major metabolite of dopamine, are quite markedly reduced from the level in aged-matched controls.14,15 In view of the global impairment in intellect it is not surprising that, in contrast to Huntington’s chorea and parkinsonism, in senile dementia the defect in glutamic-acid decarboxylase activity is also evident in other regions including cortical grey matter and thalamus (see table). Of particular interest are our findings in a case of parkinsonism with dementia. The glutamicacid decarboxylase activity in this brain, although much reduced in cortex and thalamus, was almost undetectable in caudate nucleus and substantia nigra. Although dopamine metabolism is clearly affected in parkinsonism and senile dementia there is convincing evidence that the metabolism of G.A.B.A. is widely, if not universally, impaired in dementias where the causative factor is so far unrecognised. It has been postulated that neurological diseases of this type (abiotrophies 16) are caused by an unidentified essential defect of vital endurance leading to cellular death. Though it is clearly too early to conclude that the essential or primary defect in these dementias occurs in G.A.B.A.-ergic neuronesl7 the finding of Pearce, J. Eur. Neurol. 1974, 12, 94. Lloyd, K. G., Davidson, L., Hornykiewicz, O. Advances in Neurology: Progress in the Treatment of Parkinsonism; vol. 3. New York, 1973. 12. Perry, T. C., Hansen, S., Kloster, M. New Engl. J. Med. 1973, 288, 337. 13. Bird, E. D., Iversen, L. L. Brain, 1974, 97, 457. 14. Bowen, D. M., Flack, R. H. A., White, P., Smith, C. B., Davison, " A. N. Lancet, 1974, ii, 1247. 15. Gottfries, C. G., Gottfries, R., Roos, B. E. Br. J. Psychiat. 1969, 115, 563. 16. Br. med. J. 1974, i, 337. 17. Roberts, E. Biochem. Pharm. 1974, 23, 2637.
10. 11.
1200 metabolism in all of these diseases suggests that only limited benefit will ensue from levodopa therapy in patients afflicted with " abiotrophic dementias ".
impaired
G.A.B.A.
Miriam Marks Department of
Neurochemistry, Institute of Neurology, National Hospital, Queen Square,
DAVID M. BOWEN ALAN N. DAVISON.
London WC1N 3BG.
DOWN SYNDROME IN INDIA
SIR,-In a worldwide study of congenital malformations organised by the World Health Organisation no cases of Down syndrome were reported from India among 59,689 births in Bombay and Calcutta. There were no cases in 4141 births to Indian mothers in Kuala Lumpur, and only
ADRENAL SUPPRESSION BY CLOBETASOL
PROPIONATE SIR,—Until recently we have assumed that normal skin
constitutes an effective barrier to the absorption of corticosteroids. Application of potent steroids to diseased skin may produce transient suppression of pituitary-adrenal function, but the efficiency of the barrier increases with clinical improvement. Adrenal function recovers despite continuing steroid application. The increasingly effective combination of potent steroids and scientifically optimal bases threatens this physiological safety valve. We found that two of our topical corticosteroid preparations caused important adrenal suppression when applied to normal
1 affected child
was born to 3119 Indian mothers in In Singapore. all, there was only 1 child with Down to born 66,000 Indian mothers. These observasyndrome
FREQUENCY
OF
DOWN
SYNDROME
IN
SURVEYS
OF
NEWBORNS
IN INDIA
generated an impression that the frequency of Down syndrome in India is extremely low. This, however, is contrary to clinical experience of most paediatricians in India. Over 125 patients with Down syndrome have been evaluated in the genetics clinic in our hospital over a 4-year period. In the neonatal unit of our hospital, 4 infants with Down syndrome (confirmed by cytogenetic studies) have been detected among 3236 live births, giving a frequency of 1 per 809 live births (1-24 per 1000). Information from other Indian surveys of consecutive newborns gives a mean frequency of 1 per 1215 births (0-82 per 1000), with a range from 0-26 to 1-6 per 1000 births (see table). Excluding the data from Madras, which appears to have a low incidence, the mean frequency is 1-19 per 1000 births from among 35,325 births (range 0-73 to 1-6). The combined results of 9 surveys in Europe, North America, and Australiagave an average of 1 per 663 births (1-51 per 1000 births), with a range of 1-15 to 1-9 per 1000 births.
. &mid ot;
tions
5 chromosomal surveys of newborns in the U.K. and North America yielded a mean of 1-0 per 1000 births, with a range of 0 among 2081 births in London, Ontario, to 1-5 per 1000 births in Edinburgh. The frequency of Down syndrome, therefore, does not appear to be very different in various parts of the world. Genetics and Neonatal Unit, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi 110016, India.
Fluocinonide 0-05% gel
Because of the potential risks we abandoned the development of these preparations. Reports suggesting that clobetasol propionate (’Der-
skin.
movate ’) has systemic effects 2,3led us to compare its systemic effect with that of two fluocinonide products (’Lidex’ cream andTopsyn ’ gel). Nine healthy male volunteers were admitted to hospital. 15 g. of the topical preparation was applied to the trunk, beginning in the evening and twice daily thereafter for a total of nine applications. There was never any occlusion by plastic film. Three volunteers were treated with each of the preparations. Plasma was obtained at 7.30 A.M. daily for 6 days and again on the 1 lth day, and cortisol levels were determined by the competitive protein-binding method of Murphy et al.4 Mean plasma-cortisol levels are shown in the accompanying figure. Complete suppression of plasma-cortisol levels was already evident 9-5 hours after the first application of clobetasol propionate and continued throughout the period of application. Sparkes and Wilson,5 in discussing adrenal suppression, state that " It is not expected that clobetasol propionate will behave differently " from other steroids. We
ISHWAR C. VERMA MEHARBAN SINGH.
1. Stevenson, A. C., Johnston, H. A., Stewart, M. I. P., Golding, D. R. Bull. Wld Hlth Org. 1966, 34, suppl. 1. 2. Ghosh, S., Bali, L. Ind. J. Child Hlth, 1963, 12, 448. 3. Khanna, K. K., Prasad, L. S. N. Ind. J. Pediat. 1967, 34, 63. 4. Aiyar, R. R., Agarwal, J. R. Ind. Pediat. 1969, 6, 729. 5. Raju, V. B. Personal communication. 6. Tibrewala, N. S., Pai, P. M. Ind. Pediat. 1974, 11, 403. 7. Hamerton, J. L. Human Cytogenetics; vol. II, p. 201. New York, 1971. 8. Hamerton, J. L., Ray, M., Abbot, J., Williamson, C., Ducasse, G. C. Can. med. Ass. J. 1972, 106, 776.
Average values 3 normal males per preparation Clobetasol propionate 0’05% ointment Fluocinonide 0’05% cream
cannot
agree.
Clinical Pharmacology Unit 404B, Hospital General de Mexico, Mexico City, Mexico.
E. ORTEGA.
Institute of Clinical Medicine,
Syntex Research, Palo Alto, California, U.S.A.
K. H. BURDICK E. J. SEGRE.
1. Lancet, 1967, ii, 1078. 2. Feiwel, M., Kelly, W. J. ibid. 1974, ii, 112. 3. Tan, R. Proc. R. Soc. Med. 1974, 67, 31. 4. Murphy, B. E. P., Engelberg, W, Pattee, C. J. J. clin. Endocr. Metab. 1963, 23, 293. 5. Sparkes, C. G., Wilson, L. Br. J. Derm. 1974, 90, 197.