492 and presumed high-altitude pulmonary oedema before evacuation from about 5000 m down to Pheriche where we examined her. One of the women, who had gross anasarca (and pulmonary rales), said that this cedema occurred every time she went to high altitude, but never when she was in a cold environment at sea-level. 8 of our group had cerebellar symptoms and signs, in 3 cases severe with very marked ataxia, and retinal haemorrhages were seen in 2. Choking of the optic disc was thought to be present in 2 others. We conclude that peripheral oedema is indeed common in newcomers at high altitudes; that it may not be confined to exposed parts but be generalised; that it is probably more common in women than in men (the male/female ratio of trekkers as a whole was 7/3 but of those with peripheral œdema, 3/7); that in women it is not related to the menstrual cycle; and that in both sexes it is not necessarily a benign sign but may accompany signs of pulmonary and possibly cerebral oedema of high altitude. We are investigating this phenomenon in far greater detail. All we know from previous cases is that it does not seem to be associated with increased proteinuria, and it is relieved on return to sea-level, often after two or three days delay, by a considerable and spontaneous diuresis. ness

Department of Medicine,

Rush-Presbyterian-St. Lukes Medical Center, Chicago 60612, U.S.A.

PETER HACKETT

DRUMMOND RENNIE

hydrocephalus (compensatory), macrogyria, and vascular disorders (table). Neuronal degeneration in the cerebral cortex was the most frequent histopathologic finding (8 out of 18 cases). In the 3 mildly retarded cases (of the total of 18), "neuronophagia" in the cerebral cortex was reported in 2 (1 case with nodular ectopia and microgyria and 1 with eosinophilia of neurons). None of the 3 mildly retarded cases had inclusion bodies (compared with 4 among the 15 other cases) or neurofibrillary tangles (compared with 3 of 15 other cases). Clues to possible causal mechanisms may be suggested bv these data. Meningeal fibrosis, for example, is a common finding in the profoundly and severely retarded, and suggests previous meningitis. Viral encephalitis may have been an agent in some cases, as suggested by the finding of depigmentation of substantia nigra and lesions of the brainstem (table); histologically, neurofibrillary tangles were reported in 3 of 8 severely retarded cases. Evidence of injury and destructive changes is provided by the frequent finding of gliotic encephalopathy, which probably reflects late fetal or perinatal events.3 In the mildly retarded, the group of main interest here, perhaps nearly all of the gross findings (table) can be attributed cedema. Cerebral herniations and cerebellar pressure cones, flattened gyri, and narrowed ventricles with increased intracranial pressure, are associated with generalised œdema.6 Fishman’sclassification of brain oedema, based on that of Klatzo,8 to

6. 7. 8.

Bakay, L., Lee, J. C. Cerebral Edema. Springfield, Illinois, Fishman, R. A. New Engl. J. Med. 1975, 293, 706. Klatzo, I. J. Neuropath. 1967, 26, 1.

1965.

POST-MORTEM NEUROPATHOLOGY IN A MENTALLY RETARDED POPULATION

SIR,—Many gross and histological studies of neuropathology in the mentally retarded have been reported, 1-4 but there have been few detailed reports on neuropathological findings by level of retardation, and these have included only a small number of mildly retarded cases. Such studies may provide clues to causation or to the possible time at which developmental or environmental agents operated. Records of deaths among patients at an institution for the mentally retarded (the Ontario Hospital School, Orillia, Ontario, Canada) were available from 1958 to 1973. The total population varied from about 2900 to 2100 per year; 707 patients died during this period. Necropsy reports were obtained for 237 of the 246 performed, and neuropathological reports were obtained for 199. Analysis is limited to 138 "unclassified" cases4 since neuropathological findings in classified syndromes have been reported extensively. Reporting of gross neuropathological findings was compared by level of retardation (excluding 6 cases of uncertain level); histopathological findings were available for only 18 cases. In almost all cases (97.8%) at least one gross abnormality or noteworthy condition was reported (table). In general, the frequency of most conditions decreases from the "idiot" (profoundly retarded) level to the higher grades of retardation. The grosser defects, such as porencephaly, micrencephaly, and agenesis (or atrophy) or cerebral cortex and subcortical whitematter, are relatively more frequent in the lower grades, suggesting that severe retardation is often associated with events occurring before birth. Although porencephaly was once regarded as a perinatal lesionit seems to result from events late in fetal life. Noteworthy exceptions to the general pattern are the high frequency of hydrocephalus (compensatory), oedema, herniations, and macrogyria and other anomalies of shape and surface, in the higher grades. Among the mildly retarded, the most frequent findings were oedema, herniations, 1. Crome, L. Br. med. J. 1960, i, 897. 2. Palo, J., Lydecken, K., Kivalo, E. Am. J. ment. Defic. 1967, 71, 401. 3. Crome, L., Stern, J. Pathology of Mental Retardation. London, 1972. 4. Jellinger, K. in The Brain in Unclassified Mental Retardation (edited by J. B. Cavanagh); p. 293. London, 1972. 5. Levine, D. N., Fisher, M. A., Caviness, V. S., Jr. Acta neuropath. 1974, 29, 99.

GROSS NEUROPATHOLOGICAL FINDINGS IN

UNCLASSIFIED* CASES,

BY LEVEL OF RETARDATION

*Excludes "classified" cases-i.e., those with a clinical history of hrvrocephalus, metabolic disorders, postencephalitic tuberous sclerosis, neurofibromatosis, Down syndrome, Lejeune srI!drome, and Cockayne syndrome.

encephalopathy,

493

categories (vasogenic, cytotoxic, and interstitial). Cytotoxic oedema is due to hypoxia, and seems to characterise the cedema found in 1 mildly retarded case. This patient involves three

(male, age fifteen years at

at

death) had hemiplegia and

"anoxia

birth"; cerebellar cell loss and demyelination, and cerebral

cortical neuronophagia with eosinophilia were reported. Brain herniation is most likely to occur with vasogenic cedema, which is related to brain tumour, infarction, contusion, lead encephalopathy, and purulent meningitis.7 Among the mildly retarded, no tumours were reported; meningeal changes suggestive of meningitis were reported in 1 case, but there was no oedema. Infarction may have been involved in 1 case (male, age thirteen years); in the clinical history, the encephalopathy was attributed to postnatal vascular occlusion. The probable cause

vasogenic oedema could not be determined in most mildly retarded (or other) cases. It is not known whether the œdema was causally related to retardation or occurred in persons already retarded. Oedema could have occurred, for example, as a result of head injuries in retarded persons with epilepsy ; clinical records of 5 of the 10 mildly retarded with cedema, but only 2 of the 6 with herniations, mentioned epilepsy.

We believe that the

potential advantages of the quaternary high enough to warrant further investigations, aimed at clarifying their pharmacological effects compared with those of the tertiary analogues. neuroleptics

are

Parliament

of the

Further studies on oedema in the retarded may be warranted; detailed clinical histories, including electroencephalographic findings, would be needed. more

This work

was

supported

in part

by a grant from

the University of assistant professor in of Waterloo.

Waterloo, Ontario, Canada, received while I the Department of Kinesiology,

University

was

Birth Defects Institute,

State Department of Health, Albany, N.Y., U.S.A.

GERHARD LANGER HO SAM AHN JAMES M. PEREL MAYNARD H. MAKMAN EDWARD J. SACHAR

Department of Psychiatry, University College of Physicians and Surgeons New York, N.Y. 10032, U.S.A., and Department of Biochemistry and Pharmacology, A. Einstein College of Medicine, Bronx, N.Y. Columbia

New Dental and

Optical Charges Details were given in answer to a written question in the House of Commons on Feb. 17 of the increased charges for dental and optical treatment which the Chancellor of the Exchequer announced in July as part of the savings in public expenditure. Mr DAVID ENNALS, Secretary of State for Social Services, said that the charge for most courses of dental treatment would be increased from 3-50 to 5; this was a maximum charge, and patients who required only a small amount of treatment would pay less than this. The charges for the supply of dentures (present maximum, £ 12) would be: Synthetic resin

ANTHONY P. POLEDNAK*

dentures *Present address:

Radiological and Environmental Research Division, Argonne Illinois 60439, U.S.A.

National Laboratory, Argonne,

Bearing 1, 2, or 3 teeth Bearing 4-8 teeth Bearing more than 8 teeth Maximum for

more

than

one

Perphenazine-N-dimethyldichloride, prochlorperazine-Ndimethyldichloride, and haloperidol-N-methylchloride were synthesised by the method of Huang et al.4 Authenticity was proved by elemental analysis, and purity was established by spectroscopic techniques. The method for the adenylcyclase assay has been described previously.’ Although intravenous injections of perphenazine 0.5mg and prochlorperazine 2. 0 mg resulted in prompt release of prolactin in five male volunteers, injections of equimolar doses of the quaternary ammonium salts of these drugs did not release human prolactin. Also in contrast to their tertiary analogues, the quaternary neuroleptics did not block dopamine-sensitive adenylcylase activity in striatal homogenates of the cebus monkey. 1

Fog, R. L., Randrup, A., Pakkenberg,

H.

Psychopharmacologia, 1968, 12,

428. 2. Kebabian,

J. W., Petzold, G. W., Greengard, P. Proc. nat. Acad. Sci. U.S.A. 1972, 69, 2145. 3 Kleinberg, D. L., Noel, G. L., Frantz, A. G.J. clin. Endocr. Metab. 1971, 33, 873. 4. Huang, C. L., Mir, G. M., Yeh, J. Z. J. pharm. Sci. 1970, 59, 976. 5 Ahn, H. S., Mishra, R. K., Demirjan, C., Makman, M. H. Brain Res. 1976, 116, 437.

/;

/:

10 11 12

15 16 17

20

30

den-

ture

NO EFFECTS OF QUATERNARY NEUROLEPTICS ON HUMAN PROLACTIN AND ADENYLCYCLASE SIR,—Quaternary ammonium salts of neuroleptic drugs cannot penetrate the blood/brain barrier in significant amounts. Thus they could be valuable tools for evaluating possible psychotropic effects of neuroleptics which might be triggered by the action of the drugs on structures outside the blood/brain barrier. Quaternary neuroleptics are roughly equipotent to their tertiary, conventional counterparts in behavioural tests in rats after microinjections into the central nervous system.’ Conventional tertiary neuroleptics inhibit dopamine-sensitive adenylcyclase activity2 and release prolactin in man,3 but are their quaternary counterparts equally effective?

Metal dentures and bridges

The charges for crowns, inlays, pinlays, and gold fillings would be £10 for each tooth restored, with a maximum of C30 if more than 3 teeth were restored; there would also be a maximum of C30 for a combination of any of these items of treatment. The special charges for particular high-cost items of treatment, such as crowns (which figured in about 3% of courses of treatment) had been introduced with reluctance, but this was the only way to keep the ordinary maximum charge down to a level which would not deter people from seeking

regular treatment. Optical charges would be raised from 2-25 to 2 90 for each single-vision lens, from 4-25 to £5.50 for each fused glass bifocal lens, and from ,5 to 6-15 for any other type of lens (including solid glass or plastic bifocals). Regulations implementing these proposals would be laid before Parliament to come into effect on April 1; the last increases in dental and optical charges came into effect on Jan. 1,1976. -

Blood for Private Patients

In answer to questions from Mr LAURIE PAVITT in the House of Commons on Feb. 8 concerning the use by private patients of blood collected by the National Blood Transfusion Service Mr ROLAND MOYLE, Minister of State, Department of Health and Social Security, said that no separate financial or administrative arrangements applied to blood used by private patients in N.H.S. hospitals. Daily charges were inclusive of accommodation and all services. Where blood was supplied to a private hospital or nursing home, no charge was made for the blood itself, but if circumstances justified, a charge might be made for the pathological and other services involved. Senior officials of the National Blood Transfusion Service were employees of the N.H.S. authorities. No instructions issued by the Department of Health barred them from serving on the board of directors of a private hospital or of organisations pro-

viding private-patient hospital cover.