- Email: [email protected]
EARLY TRAUMATIC EPILEPSY
1209 LENGTH OF STAY OF
while
51 PATIENTS WITH DEPRESSION OR MANIA
were receiving lithium carbonate. The favourable in the 51 Camberwell patients seems to be a consequence of the exclusion of patients who had been admitted only once or not at all during 1965 and 1966 (see accompanying figure). The data on the length of stay are presented in the accompanying table. The division into subgroups of depression had perforce to depend on the final diagnosis reached by different psychiatrists, but whatever their shortcomings these data show that the patients with reactive depression had a worse prognosis than did those patients with endogenous or unspecified depression. The average length of stay of patients with endogenous depression during 1965 and 1966 was 146.6 days (73-3 days per year) and during 1967 and 1968 72’4 (36-2 days per year). Therefore, these patients stayed 74’2 days less during the latter period. This result is statisti-
they
outcome
cally significant (p < 002). These data are presented to show that the remarkable results of Baastrup and Schou could possibly have been arrived at by the design of the experiment. This would not be harmful if psychiatrists viewed the use of lithium only with cautious optimism, but many still seem to have an unjustified conviction of its prophylactic value. Institute of Psychiatry, London S.E.5.
B. M. SARAN.
ORAL CONTRACEPTIVES AND DEPRESSION SIR,-In 1967 two correspondents 12 pointed out the possible association of depression with the taking of oral contraceptives, and later the same year Daly et awl. suggested some possible reasons for this. I should like to suggest a further possible explanation for the precipitation or aggravation of depression in certain women taking oral contraceptives. Dewhurst ’has postulated that a dysfunction of tryptophan metabolism is implicated in the onset of certain types of depression, and it has also been suggested that one of the mechanisms involved is a shift of tryptophan metabolism from the serotonin pathway to the kynurenine pathway.5-7 Price et a].’ have shown that the use of steroid hormones for ovulation control results in a disturbance of tryptophan metabolism along the kynurenine pathway. Similar disturbances occur during pregnancy, just before menstruation, and with the administration of cortisone.5 Since cortisone, oral contraceptives, and pregnancy all have in common the possibility of 1. Tharkudas, H. Lancet, 1967, i, 1164. 2. McGregor, C. M. ibid. p. 1231. 3. Daly, R. J., Kane, F. J., Jr., Ewing, J. A. ibid. 1967, ii, 444. 4. Dewhurst, W. G. Nature, Lond. 1968, 218, 1130. 5. Green, A. R., Curzon, G. ibid. 1968, 220, 1095. 6. Mandell, A. J., Spooner, C. E. Science, N.Y., 1968, 162, 1442. 7. Lapin, L. P., Oxenkrug, G. F. Lancet, Jan. 18, 1969, p. 132. 8. Price, J. M., Thornton, M. J., Mueller, L. M. Am. J. clin. Nutr.
20, 452.
1967,
severe depression in susceptible patients, and are also known to upset tryptophan metabolism, then, if tryptophan metabolism is shown to be associated with control of mood, it would be more credible that these effects are mediated in some way through an upset of tryptophan metabolism than to believe that this is just mere coincidence. The fact that progestogens given alone do not cause this disturbance of tryptophan metabolism9 and are also reported not to cause depression 10 would lend weight to this view. Whereas the disturbance of tryptophan metabolism by hydrocortisone is supposedly caused by the activation of tryptophan pyrollase5 oral contraceptives (and presumably pregnancy and menstruation) apparently create a functional deficiency of pyridoxine, for the disturbance of tryptophan metabolism along the kynurenine pathway is corrected by giving supplementary pyridoxine.8 Apparently the steroid hormones have the effect of loosening the binding of some pyridoxine to its enzyme. Since the decarboxylation of tryptophan to tryptamine and serotonin is also dependent on pyridoxine it would be interesting to know whether giving supplemental pyridoxine would protect patients on oral contraceptives from becoming depressed. In this regard one patient in her 4th month of pregnancy had her symptoms of depression and irritability completely resolved five days after starting on pyridoxine 50 mg. daily. Similarly, another young woman who became extremely irritable and difficult to live with during the second half of her menstrual cycle ceased to have these episodes soon after starting on pyridoxine. These are only straws in the wind, but it does seem that the matter merits further investigation.
precipitating
Madison, Wisconsin,
FRANK WINSTON.
U.S.A.
EARLY TRAUMATIC EPILEPSY
SIR,-Of the patients described by Professor Jennett (May 24, p. 1023), how many had their first fits within 1 week after blunt head injuries: 273 (tables II, III) or 331 (table v) ? How many in weeks 2-8: 66 (tables 11, III) or 41 (table v) ? How many in weeks 1-8: 331 (the opening words of the paper), 339 (paragraph 3, tables 11, III), 372 (table v) ? Granted, one can guess, by weighing evidence, which the correct figures probably are; but who wants that task ? In table vi where do all those patients with " No early epilepsy " come from ? Table iv shows that, of patients having their first fits in weeks 2-8, 41 were followed up for 4 years, and, of those having them more than 3 months after injury, 158 were followed up for 4 years, making a total of only 199 (or 223 even if 24 with missile injuries are added). Those followed up for
if
more
than 4 years,
as
in table vi, should therefore be
anything fewer than 199. How can they be 240 ? Why are patients who had their first fits up to
8 weeks after injury, and those who had them more than 3 months after injury, selected for discussion ? Why exclude the period from 9 to 12 weeks ? Or was it included for the purposes of table vi only, and is that how the figure 240 is reached ? London S.W.20. JOHN PENMAN.
** This letter has been shown to Professor Jennett, who writes as follows: Dr. Penman is correct in one point; 331 in the summary should read 339. As for the rest of his comments I can only regret the unhappy outcome of my attempt to make an argument clear by omitting details which seemed irrelevant to the main theme. I can, however, assure him that each table is internally consistent. But attempts to compare different tables can lead only to confusion; thus tables n and ill include all cases in a consecutive series, table iv is limited to cases followed for 4 years, whilst table v excludes those with "
9. Brown, R. R., Rose, P. P., Price, J. M., Wolff, H. Proc. N. Y. Acad. Sci. (in the press). 10. Carranza-Acevedo, J. Lancet, 1967, ii, 104.
1210 insufficient details about the type of fit but includes some additional cases for which this information was available. Table vi is designed to support the assertion that patients with
early epilepsy are much more likely to develop further (i.e., late) seizures than those who are free of epilepsy in the first week, but it puzzles Dr. Penman; perhaps this is because it includes a large series of patients whose characteristic was that they did not have early epilepsy. Of these 240 patients 222 had no epilepsy at any time, and so are not represented in any of the preceding tables, which deal solely with patients who did have epilepsy at some time after the injury."-ED. L. THYROXINE IN BLOOD AND TISSUES SIR,-In discussing the evidenceagainst the " classical " view of thyroxine metabolism, Dr. Hoffenberg and Miss Black (May 31, p. 1095) suggest that the reported difference in
rats of disappearance of radiothyroxine from plasma and whole-body might be explained within the framework of the classical " model. They suggest that retention of label as free iodide might explain the divergence. This seems unlikely, because the animals were on a high-iodide diet and radioiodide would be expected to be rapidly eliminated. The fact that the whole-body activity (see accompanying figure) extrapolates to 95% dose at zero time, gives an indication that contamination of the radiothyroxine by radioiodide was of the order of 5%. They also suggest that faecal retention of labelled thyroxine might account for the divergence of whole-body and plasma activity. We have repeatedly measured the rate of disappearance of radiothyroxine from the intestinal tract, by serial measurements in rats of the entire intestinal tract and contents using a large-well scintillation counter. Typical results are seen in the figure. Had the divergence of the whole-body slope from that of the plasma been due to fsecal retention, the rate of disappearance from the intestine would have had to be slower "
1.
Harland, W. A., Orr, J. S. J. Physiol., Lond. 1969, 200, 297.
than for the whole body. In fact it is somewhat faster. Therefore the suggested deduction of non-exchangeable dose within the gut from the whole-body activity would result in an increased prolongation of whole-body half-time. Dr. Hoffenberg and Miss Black also present data on thyroxine disappearance from whole body and plasma in the rabbit. They suggest that, although the plasma and wholebody curves diverge at first, after a few days they become roughly parallel. Brown-Grant,2in discussing certain aspects of the " classical " view of thyroxine metabolism, has pointed out that " the use of blood radioactivity levels to estimate the half-life is based, theoretically, on the assumption that hormone in the vascular compartment is in equilibrium with hormone throughout the T3 or T4 distribution space of the body, or at least equilibrates with it with a time constant that is negligibly small compared with the tl in the body ". The data presented by Dr. Hoffenberg and Miss Black show that, in the rabbit, plasma and whole-body radiothyroxine curves do not become parallel for several days. It is clear therefore that in this case the time constant of equilibration is very far from being negligibly small compared with the tin the body. with the These data, like ours, are therefore " classical " view. Pathology Department, University of Glasgow, Western Infirmary, Glasgow, and W. A. HARLAND Department of Clinical Physics and J. S. ORR. Bioengineering, Glasgow
incompatible
TREATMENT OF INSULINOMA WITH STREPTOZOTOCIN SiR,—The paper of Dr. Murray-Lyon and his colleagues3 prompts us to report briefly on another case of malignant metastatic insulinoma, which was apparently successfully treated with streptozotocin 4 months ago. The patient, a 55-year-old man, was first seen in September, 1968. He had been having repeated hypoglycaemic crises for a year. His general condition was still good (77 kg. bodyweight for 170 cm. height). Physical examination was negative except for gross hepatic enlargement. Fasting glycxmia levels ranged between 30 and 50 mg. per 100 ml., and high seruminsulin levels (100 microunits per ml. or more by radio-
immunoassay) were repeatedly observed. Serum-alkalinephosphatase was raised at 250 and 500 Bessey-Lowry units (normal values 26-106 units). Serum transaminases, glutamicoxaloacetic (G.O.T.) and glutamic-pyruvic (G.P.T.), reached 180 BLOOD-GLUCOSE, IMMUNOREACTIVE INSULIN
(I.R.I.),
G.O.T., G.P.T., AND
ALKALINE PHOSPHATASE IN PATIENT WITH MALIGNANT METASTATIC
INSULINOMA TREATED WITH STREPTOZOTOCIN
and 275 Wroblewsky units respectively (normal 5-30 units). Liver scan (l98Au) and hepatic phlebography (through umbilical vein) showed three large filling defects. Laparoscopy showed disseminated metastases of varying sizes: biopsy was consistent with a primary islet-cell carcinoma. Treatment with diazoxide (400-1000 mg. per day) and chlorothiazide (1 g. per day) controlled the hypoglycxmic crises only temporarily. After a week, the recurrence of hypoglycaemic attacks, associated with water retention and gastrointestinal distress, forced us to stop the diazoxide. Since the patient’s general condition had very rapidly deteriorated, it was decided to try streptozotocin. On Dec. 15, 1-5 g. was given
Days Disappearance curves of radiothyroxine from whole body, intestines plus contents, and plasma in rats. Each point is the mean of 5 observations (±S.E.M.)
2. 3.
Brown-Grant, K. ibid. 1967, 191, 167. Murray-Lyon, I. M., Eddleston, A. L. W. F., Williams, R., Brown, M., Hogbin, B. M., Bennett, A., Edwards, J. C., Taylor, K. W. Lancet, 1968, ii, 895.
while
51 PATIENTS WITH DEPRESSION OR MANIA
were receiving lithium carbonate. The favourable in the 51 Camberwell patients seems to be a consequence of the exclusion of patients who had been admitted only once or not at all during 1965 and 1966 (see accompanying figure). The data on the length of stay are presented in the accompanying table. The division into subgroups of depression had perforce to depend on the final diagnosis reached by different psychiatrists, but whatever their shortcomings these data show that the patients with reactive depression had a worse prognosis than did those patients with endogenous or unspecified depression. The average length of stay of patients with endogenous depression during 1965 and 1966 was 146.6 days (73-3 days per year) and during 1967 and 1968 72’4 (36-2 days per year). Therefore, these patients stayed 74’2 days less during the latter period. This result is statisti-
they
outcome
cally significant (p < 002). These data are presented to show that the remarkable results of Baastrup and Schou could possibly have been arrived at by the design of the experiment. This would not be harmful if psychiatrists viewed the use of lithium only with cautious optimism, but many still seem to have an unjustified conviction of its prophylactic value. Institute of Psychiatry, London S.E.5.
B. M. SARAN.
ORAL CONTRACEPTIVES AND DEPRESSION SIR,-In 1967 two correspondents 12 pointed out the possible association of depression with the taking of oral contraceptives, and later the same year Daly et awl. suggested some possible reasons for this. I should like to suggest a further possible explanation for the precipitation or aggravation of depression in certain women taking oral contraceptives. Dewhurst ’has postulated that a dysfunction of tryptophan metabolism is implicated in the onset of certain types of depression, and it has also been suggested that one of the mechanisms involved is a shift of tryptophan metabolism from the serotonin pathway to the kynurenine pathway.5-7 Price et a].’ have shown that the use of steroid hormones for ovulation control results in a disturbance of tryptophan metabolism along the kynurenine pathway. Similar disturbances occur during pregnancy, just before menstruation, and with the administration of cortisone.5 Since cortisone, oral contraceptives, and pregnancy all have in common the possibility of 1. Tharkudas, H. Lancet, 1967, i, 1164. 2. McGregor, C. M. ibid. p. 1231. 3. Daly, R. J., Kane, F. J., Jr., Ewing, J. A. ibid. 1967, ii, 444. 4. Dewhurst, W. G. Nature, Lond. 1968, 218, 1130. 5. Green, A. R., Curzon, G. ibid. 1968, 220, 1095. 6. Mandell, A. J., Spooner, C. E. Science, N.Y., 1968, 162, 1442. 7. Lapin, L. P., Oxenkrug, G. F. Lancet, Jan. 18, 1969, p. 132. 8. Price, J. M., Thornton, M. J., Mueller, L. M. Am. J. clin. Nutr.
20, 452.
1967,
severe depression in susceptible patients, and are also known to upset tryptophan metabolism, then, if tryptophan metabolism is shown to be associated with control of mood, it would be more credible that these effects are mediated in some way through an upset of tryptophan metabolism than to believe that this is just mere coincidence. The fact that progestogens given alone do not cause this disturbance of tryptophan metabolism9 and are also reported not to cause depression 10 would lend weight to this view. Whereas the disturbance of tryptophan metabolism by hydrocortisone is supposedly caused by the activation of tryptophan pyrollase5 oral contraceptives (and presumably pregnancy and menstruation) apparently create a functional deficiency of pyridoxine, for the disturbance of tryptophan metabolism along the kynurenine pathway is corrected by giving supplementary pyridoxine.8 Apparently the steroid hormones have the effect of loosening the binding of some pyridoxine to its enzyme. Since the decarboxylation of tryptophan to tryptamine and serotonin is also dependent on pyridoxine it would be interesting to know whether giving supplemental pyridoxine would protect patients on oral contraceptives from becoming depressed. In this regard one patient in her 4th month of pregnancy had her symptoms of depression and irritability completely resolved five days after starting on pyridoxine 50 mg. daily. Similarly, another young woman who became extremely irritable and difficult to live with during the second half of her menstrual cycle ceased to have these episodes soon after starting on pyridoxine. These are only straws in the wind, but it does seem that the matter merits further investigation.
precipitating
Madison, Wisconsin,
FRANK WINSTON.
U.S.A.
EARLY TRAUMATIC EPILEPSY
SIR,-Of the patients described by Professor Jennett (May 24, p. 1023), how many had their first fits within 1 week after blunt head injuries: 273 (tables II, III) or 331 (table v) ? How many in weeks 2-8: 66 (tables 11, III) or 41 (table v) ? How many in weeks 1-8: 331 (the opening words of the paper), 339 (paragraph 3, tables 11, III), 372 (table v) ? Granted, one can guess, by weighing evidence, which the correct figures probably are; but who wants that task ? In table vi where do all those patients with " No early epilepsy " come from ? Table iv shows that, of patients having their first fits in weeks 2-8, 41 were followed up for 4 years, and, of those having them more than 3 months after injury, 158 were followed up for 4 years, making a total of only 199 (or 223 even if 24 with missile injuries are added). Those followed up for
if
more
than 4 years,
as
in table vi, should therefore be
anything fewer than 199. How can they be 240 ? Why are patients who had their first fits up to
8 weeks after injury, and those who had them more than 3 months after injury, selected for discussion ? Why exclude the period from 9 to 12 weeks ? Or was it included for the purposes of table vi only, and is that how the figure 240 is reached ? London S.W.20. JOHN PENMAN.
** This letter has been shown to Professor Jennett, who writes as follows: Dr. Penman is correct in one point; 331 in the summary should read 339. As for the rest of his comments I can only regret the unhappy outcome of my attempt to make an argument clear by omitting details which seemed irrelevant to the main theme. I can, however, assure him that each table is internally consistent. But attempts to compare different tables can lead only to confusion; thus tables n and ill include all cases in a consecutive series, table iv is limited to cases followed for 4 years, whilst table v excludes those with "
9. Brown, R. R., Rose, P. P., Price, J. M., Wolff, H. Proc. N. Y. Acad. Sci. (in the press). 10. Carranza-Acevedo, J. Lancet, 1967, ii, 104.
1210 insufficient details about the type of fit but includes some additional cases for which this information was available. Table vi is designed to support the assertion that patients with
early epilepsy are much more likely to develop further (i.e., late) seizures than those who are free of epilepsy in the first week, but it puzzles Dr. Penman; perhaps this is because it includes a large series of patients whose characteristic was that they did not have early epilepsy. Of these 240 patients 222 had no epilepsy at any time, and so are not represented in any of the preceding tables, which deal solely with patients who did have epilepsy at some time after the injury."-ED. L. THYROXINE IN BLOOD AND TISSUES SIR,-In discussing the evidenceagainst the " classical " view of thyroxine metabolism, Dr. Hoffenberg and Miss Black (May 31, p. 1095) suggest that the reported difference in
rats of disappearance of radiothyroxine from plasma and whole-body might be explained within the framework of the classical " model. They suggest that retention of label as free iodide might explain the divergence. This seems unlikely, because the animals were on a high-iodide diet and radioiodide would be expected to be rapidly eliminated. The fact that the whole-body activity (see accompanying figure) extrapolates to 95% dose at zero time, gives an indication that contamination of the radiothyroxine by radioiodide was of the order of 5%. They also suggest that faecal retention of labelled thyroxine might account for the divergence of whole-body and plasma activity. We have repeatedly measured the rate of disappearance of radiothyroxine from the intestinal tract, by serial measurements in rats of the entire intestinal tract and contents using a large-well scintillation counter. Typical results are seen in the figure. Had the divergence of the whole-body slope from that of the plasma been due to fsecal retention, the rate of disappearance from the intestine would have had to be slower "
1.
Harland, W. A., Orr, J. S. J. Physiol., Lond. 1969, 200, 297.
than for the whole body. In fact it is somewhat faster. Therefore the suggested deduction of non-exchangeable dose within the gut from the whole-body activity would result in an increased prolongation of whole-body half-time. Dr. Hoffenberg and Miss Black also present data on thyroxine disappearance from whole body and plasma in the rabbit. They suggest that, although the plasma and wholebody curves diverge at first, after a few days they become roughly parallel. Brown-Grant,2in discussing certain aspects of the " classical " view of thyroxine metabolism, has pointed out that " the use of blood radioactivity levels to estimate the half-life is based, theoretically, on the assumption that hormone in the vascular compartment is in equilibrium with hormone throughout the T3 or T4 distribution space of the body, or at least equilibrates with it with a time constant that is negligibly small compared with the tl in the body ". The data presented by Dr. Hoffenberg and Miss Black show that, in the rabbit, plasma and whole-body radiothyroxine curves do not become parallel for several days. It is clear therefore that in this case the time constant of equilibration is very far from being negligibly small compared with the tin the body. with the These data, like ours, are therefore " classical " view. Pathology Department, University of Glasgow, Western Infirmary, Glasgow, and W. A. HARLAND Department of Clinical Physics and J. S. ORR. Bioengineering, Glasgow
incompatible
TREATMENT OF INSULINOMA WITH STREPTOZOTOCIN SiR,—The paper of Dr. Murray-Lyon and his colleagues3 prompts us to report briefly on another case of malignant metastatic insulinoma, which was apparently successfully treated with streptozotocin 4 months ago. The patient, a 55-year-old man, was first seen in September, 1968. He had been having repeated hypoglycaemic crises for a year. His general condition was still good (77 kg. bodyweight for 170 cm. height). Physical examination was negative except for gross hepatic enlargement. Fasting glycxmia levels ranged between 30 and 50 mg. per 100 ml., and high seruminsulin levels (100 microunits per ml. or more by radio-
immunoassay) were repeatedly observed. Serum-alkalinephosphatase was raised at 250 and 500 Bessey-Lowry units (normal values 26-106 units). Serum transaminases, glutamicoxaloacetic (G.O.T.) and glutamic-pyruvic (G.P.T.), reached 180 BLOOD-GLUCOSE, IMMUNOREACTIVE INSULIN
(I.R.I.),
G.O.T., G.P.T., AND
ALKALINE PHOSPHATASE IN PATIENT WITH MALIGNANT METASTATIC
INSULINOMA TREATED WITH STREPTOZOTOCIN
and 275 Wroblewsky units respectively (normal 5-30 units). Liver scan (l98Au) and hepatic phlebography (through umbilical vein) showed three large filling defects. Laparoscopy showed disseminated metastases of varying sizes: biopsy was consistent with a primary islet-cell carcinoma. Treatment with diazoxide (400-1000 mg. per day) and chlorothiazide (1 g. per day) controlled the hypoglycxmic crises only temporarily. After a week, the recurrence of hypoglycaemic attacks, associated with water retention and gastrointestinal distress, forced us to stop the diazoxide. Since the patient’s general condition had very rapidly deteriorated, it was decided to try streptozotocin. On Dec. 15, 1-5 g. was given
Days Disappearance curves of radiothyroxine from whole body, intestines plus contents, and plasma in rats. Each point is the mean of 5 observations (±S.E.M.)
2. 3.
Brown-Grant, K. ibid. 1967, 191, 167. Murray-Lyon, I. M., Eddleston, A. L. W. F., Williams, R., Brown, M., Hogbin, B. M., Bennett, A., Edwards, J. C., Taylor, K. W. Lancet, 1968, ii, 895.