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ACUTE INFECTIOUS LYMPHOCYTOSIS
1257 Abnormal development of the central nervous system after treatment by ovulation stimulants might be fortuitous. It might be related to the underlying infertility, which is not uncommonly associated, in the same patient, with other forms of reproductive failure. A possible teratogenic effect of anti-nauseant treatment cannot be ruled out. We think, however, that the possibility of a causal relationship between ovulation-stimulating treatment and C.N.S. abnormality should not be dismissed lightly. If additional evidence is found for this hypothesis the question arises whether, in case 1, the ovum was damaged before implantation or even before fertilisation. We shall be interested to hear of any similar observations. Patient 1 was under the care of Mr H. Agar, and patient 2 under the care of Mr R. T. Sears, who kindly gave permission to use the clinical notes. Department of Pathology, City Hospital, Nottingham. Department of Pathology, The Maternity Hospital at Leeds.
Wood
Cottage, Chilworth, Surrey.
GERALD A. MACGREGOR.
ACUTE INFECTIOUS LYMPHOCYTOSIS
H. G. KOHLER.
SIR,-Hepatitis-associated antigen (H.A.A.) has been more often among patients with various forms of malignancies, such as leukaemia and Hodgkin’s disease, than among the general population. 1-4 To the best of our knowledge, no such studies have been carried out in patients with Burkitt’s lymphoma. Our results in 5 patients with this found
were:
N.P.
=
Not
performed.
SIR,—Since the first description of acute infectious lymphocytosis by Smith in 1941, sporadic cases and groups of cases have been reported from all over the world. Although the cause remains unknown, recent evidence suggests a relationship between certain viruses and infectious lymphocytosis. We describe a case of acute infectious lymphocytosis associated with a significant rise of serumneutralising-antibody to Coxsackie B6 virus. A
14-month-old girl was seen at the Korle Bu Teaching because of fever, vomiting, and anorexia cf two days’ duration. She was febrile (101°F, 38.3 °C), and the throat and tonsils were highly inflamed but without exudates. The liver, spleen, and peripheral lymph-nodes were not enlarged. The
Hospital
(1) Chronic active hepatitis.
The presence of H.A.A. in 4 of these patients may be of interest. None of our patients had a blood-transfusion or chemotherapy before testing. Permission for needle biopsy of the liver was obtained in 2 of these patients; it showed chronic active hepatitis in one and focal hepatitis in the other. NAMIK CEVIK Department of Pædiatrics, Hacettepe University, Ankara, Turkey.
lomas have healed.’ The immune response to the sarcoid 1, agent locally sometimes leads to hypoparathyroidism and possibly later to malignancy.6 The case of parathyroid cancer following excision of a parathyroid adenoma, reported from Professor Dent’s unit,’may also be an example of the mechanism,8 and conceivably sarcoidosis might have caused both the parathyroid adenoma and the cervical cancer in an earlier case of theirs.9 Less ingenuity will be required when the whole story is told.
JENNIFER L. DYSON.
HEPATITIS-ASSOCIATED ANTIGEN AND BURKITT’S LYMPHOMA
condition
sarcoidosis and parathyroid disease has been noticed occasionally with interest, 1and sarcoid infiltration possibly causes tertiary hyperparathyroidism 3 long after the granu-
AYSEL PIRNAR BURHAN SAY.
(2) Focal hepatitis.
white-cell count cytes). On the
97,000 per c.mm. (85% mature lymphofollowing day diarrhoea began. No shigella, salmonella, or pathogenic Escherichia coli were isolated from culture of a rectal swab, and no ova or parasites were found in a stool specimen. Bone-marrow aspiration showed normal myeloid and erythroid maturation with a slight increase in eosinophilic granulocytes. Megakaryocytes were adequate in numbers. The’most striking feature of the marrow aspirate was the great increase in mature small lymphocytes. No abnormal cells were present. Subsequent white and differential counts were: was
LOCALISATION OF PARATHYROID TUMOURS
SIR The selective assays performed by Mr Davies team (May 19, p. 1079) were evidently very valuable. Perhaps the procedure would need to be done still less often if the past history of the patient was fully available. and his
For the tumours to be anticipated, more needs to be learnt about the earlier pathology. Already the combination of Blumberg, B. S., Gertsley, B. J. S., Hungerford, D. A., London, W. T., Sutnick, A. I. Ann. intern. Med. 1967, 66, 924. 2. Sutnick, A. I., London, W. T., Levine, P. H., Blumberg, B. S. Lancet, 1971, i, 1200. 3. Blumberg, B. S., Sutnick, A. I., London, W. T. Bull. N.Y. Acad. Med. 1968, 44, 1566. 4. Blumberg, B. S., Alter, H. J., Visnich, S. J. Am. med. Ass. 1965, 191, 541. 1.
The fever subsided within 48 hours and the diarrhoea with treatment of symptoms. 1. Davies, D. R., Dent, C. E. Br. med. J. 1968, ii, 395. 2. MacGregor, G. A. ibid. 1969, i, 385. 3. MacGregor, G. A. Lancet, 1969, i, 730. 4. MacGregor, G. A. ibid. May 19, 1973, p. 1133. 5. MacGregor, G. A. ibid. 1970, ii, 1257. 6. MacGregor, G. A. ibid. 1972, ii, 931. 7. Davies, D. R., Dent, C. E., Ives, D. R. Br. med. J. 8. MacGregor, G. A. ibid. 1971, i, 348. 9. Dent, C. E., Watson, L. C. A. ibid. 1964, ii, 218.
improved
1973, i, 397.
1258 Acute and convalescent sera from the patient (taken 10 days were examined for neutralising antibody to various enteroviruses and adenoviruses. These included poliovirus serotypes 1, 2, 3; Coxsackie group B (serotypes 1-6); echoviruses (serotypes 4, 5, 6, 7, 9, 11, and 20); and adenoviruses (serotypes 2, 4, 7, 14, and 21). Fourfold increase in reciprocal neutralisingantibody titres was demonstrable for polio 2, echo 6, adeno 7, and adeno 21. However, a 64-fold titre increase was demonstrated for Coxsackie B6 (reciprocal titre acute serum 4, convalescent serum 256). This was considered highly significant and suggestive of recent or intercurrent infection with Coxsackie B6.
apart)
Very few virus studies have been reported in acute infectious lymphocytosis. Olson and others1 were able to associate adenoviruses in 4 of their reported cases which presented with a pertussis-like disease without isolation or serological evidence of infection with Bordetella pertlissis. Poliovirus type 2 has also been isolated in a patient who presented with lymphocytosis and mild neurological deficit. Horwitz and Moorehave associated an untyped enterovirus resembling Coxsackie A subgroup in an outbreak of acute infectious lymphocytosis at a state school for mentally retarded children. The highly significant rise of neutralising antibody to Coxsackie B6 virus in the cases reported above, together with the few reported virus studies, suggest that acute infectious lymphocytosis is probably associated with a number of enteroviruses. In our patient, upper respiratory infection, diarrhœa, and lymphocytosis associated with significant rise in titre to Coxsackie B6 strongly suggest a causal relationship. University of Ghana Medical School, P.O. Box 4236, Accra, Ghana.
F. K. NKRUMAH P. A. K. ADDY.
PLASMA-NORTRIPTYLINE LEVELS IN DEPRESSION
SIR,—Åsberg et al.described nortriptyline plasma levels and their relation to its therapeutic effect in 29 depressed patients in hospital. Amelioration, as determined by the arithmetic difference between initial scores and the twoweek scores, was plotted against plasma concentration, and a curvilinear relationship was described, so that least improvement occurred at the lowest and highest plasma concentrations. They postulate, in explanation of this that finding, tricyclic antidepressants may have a dual action: at lower plasma levels drug action is ineffective. At middle levels monoamine uptake is blocked, causing increased available monamines at the reception site with clinical benefit. At higher plasma levels a phenothiazinelike blockade of the monoaminergic receptor occurs which might account for poorer antidepressant action. The purpose of this letter is to use these data to examine more closely the relationships among therapeutic effects, plasma levels, and dosage. Asberg et al. did not define completely their drug regimen. They state that nortriptyline was given in dosages varying from 25 to 75 mg. three times daily after a placebo period of four to seven days; that the dose was kept constant for each patient during the study, and the individual dosage levels were chosen without regard to severity of depression. It is not stated what did determine choice of dosage. We have correlated their dosage (mg. per kg.) with the baseline depression scores. The low correlation (r= -002) supports their contention that dosage 1. 2. 3. 4.
was not
assigned by severity.
Olson, L. C., Miller, G., Hanshaw, J. B. Lancet, 1964, i, 20. van der Kley, T. M. Maandschr. Kindergeneesk. 1954, 22, 321. Horwitz, M. S., Moore, G. T. New Engl. J. Med. 1968, 279, 399. Asberg, M., Cronholm, B., Sjoqvist, F., Tuck, D. Br. med. J. 1971, iii, 331.
Plasma-nortriptyline levels
and deviation
scores.
We examined the relationship of initial to final scores and found it sufficiently linear to obtain covariance deviation scores for further analyses-i.e., a change score uncorrelated with initial position. The accompanying figure shows the relationship of deviation scores to nortriptyline plasma concentration. The curvilinear relationship is similar to that found by Asberg et al. when they plotted amelioration (arithmetic difference) against plasma concentration, and thus supports their analysis. A crucial clinical question is whether the curvilinear relationship of amelioration to plasma concentration also holds for amelioration to dose. We examined this in two ways, using the amelioration score (arithmetic difference of final minus initial score) and the covariance deviation scores.
The Pearson correlation of dose to the arithmetic amelioration score is 0-12; the correlation of dose to the covariance deviation score is 0-04. The scattergrams do not indicate a non-linear correlation. We conclude that the curvilinear relationship between plasma level and improvement does not mean that the clinician need be wary of low or high dosages of nortriptyline. If anything, the dose/effect relationship seems to indicate that routine dosage over 75 mg. per day is unwarranted. However, without data giving both dosage by weight and the patient’s weight, this remains inferential. A study5 boy the same group, using a similar design, replicates the observation that high blood levels are associated with therapeutic refractoriness. However, these data do not lend themselves to the type of analysis we did from their first paper. Since dose is constant, it cannot be related to severity; and the baseline depression scores are not given because the final score was used as the outcome measure.
Unfortunately, the two studies provide different optinortriptyline blood levels, so that, at present, blood levels cannot be used predictively. However, the authors report the very interesting finding that, of 7 non-responders with a plasma-nortriptyline concentration above 170 ng. per ml., 5 were well and discharged within a week after reduction of dosage. This suggests that with patients for
mum
5.
Kragh-Sørensen, P., 1973, p. 113.
Åsberg, M., Eggert-Hanse, C. Lancet, Jan. 20,
Wood
Cottage, Chilworth, Surrey.
GERALD A. MACGREGOR.
ACUTE INFECTIOUS LYMPHOCYTOSIS
H. G. KOHLER.
SIR,-Hepatitis-associated antigen (H.A.A.) has been more often among patients with various forms of malignancies, such as leukaemia and Hodgkin’s disease, than among the general population. 1-4 To the best of our knowledge, no such studies have been carried out in patients with Burkitt’s lymphoma. Our results in 5 patients with this found
were:
N.P.
=
Not
performed.
SIR,—Since the first description of acute infectious lymphocytosis by Smith in 1941, sporadic cases and groups of cases have been reported from all over the world. Although the cause remains unknown, recent evidence suggests a relationship between certain viruses and infectious lymphocytosis. We describe a case of acute infectious lymphocytosis associated with a significant rise of serumneutralising-antibody to Coxsackie B6 virus. A
14-month-old girl was seen at the Korle Bu Teaching because of fever, vomiting, and anorexia cf two days’ duration. She was febrile (101°F, 38.3 °C), and the throat and tonsils were highly inflamed but without exudates. The liver, spleen, and peripheral lymph-nodes were not enlarged. The
Hospital
(1) Chronic active hepatitis.
The presence of H.A.A. in 4 of these patients may be of interest. None of our patients had a blood-transfusion or chemotherapy before testing. Permission for needle biopsy of the liver was obtained in 2 of these patients; it showed chronic active hepatitis in one and focal hepatitis in the other. NAMIK CEVIK Department of Pædiatrics, Hacettepe University, Ankara, Turkey.
lomas have healed.’ The immune response to the sarcoid 1, agent locally sometimes leads to hypoparathyroidism and possibly later to malignancy.6 The case of parathyroid cancer following excision of a parathyroid adenoma, reported from Professor Dent’s unit,’may also be an example of the mechanism,8 and conceivably sarcoidosis might have caused both the parathyroid adenoma and the cervical cancer in an earlier case of theirs.9 Less ingenuity will be required when the whole story is told.
JENNIFER L. DYSON.
HEPATITIS-ASSOCIATED ANTIGEN AND BURKITT’S LYMPHOMA
condition
sarcoidosis and parathyroid disease has been noticed occasionally with interest, 1and sarcoid infiltration possibly causes tertiary hyperparathyroidism 3 long after the granu-
AYSEL PIRNAR BURHAN SAY.
(2) Focal hepatitis.
white-cell count cytes). On the
97,000 per c.mm. (85% mature lymphofollowing day diarrhoea began. No shigella, salmonella, or pathogenic Escherichia coli were isolated from culture of a rectal swab, and no ova or parasites were found in a stool specimen. Bone-marrow aspiration showed normal myeloid and erythroid maturation with a slight increase in eosinophilic granulocytes. Megakaryocytes were adequate in numbers. The’most striking feature of the marrow aspirate was the great increase in mature small lymphocytes. No abnormal cells were present. Subsequent white and differential counts were: was
LOCALISATION OF PARATHYROID TUMOURS
SIR The selective assays performed by Mr Davies team (May 19, p. 1079) were evidently very valuable. Perhaps the procedure would need to be done still less often if the past history of the patient was fully available. and his
For the tumours to be anticipated, more needs to be learnt about the earlier pathology. Already the combination of Blumberg, B. S., Gertsley, B. J. S., Hungerford, D. A., London, W. T., Sutnick, A. I. Ann. intern. Med. 1967, 66, 924. 2. Sutnick, A. I., London, W. T., Levine, P. H., Blumberg, B. S. Lancet, 1971, i, 1200. 3. Blumberg, B. S., Sutnick, A. I., London, W. T. Bull. N.Y. Acad. Med. 1968, 44, 1566. 4. Blumberg, B. S., Alter, H. J., Visnich, S. J. Am. med. Ass. 1965, 191, 541. 1.
The fever subsided within 48 hours and the diarrhoea with treatment of symptoms. 1. Davies, D. R., Dent, C. E. Br. med. J. 1968, ii, 395. 2. MacGregor, G. A. ibid. 1969, i, 385. 3. MacGregor, G. A. Lancet, 1969, i, 730. 4. MacGregor, G. A. ibid. May 19, 1973, p. 1133. 5. MacGregor, G. A. ibid. 1970, ii, 1257. 6. MacGregor, G. A. ibid. 1972, ii, 931. 7. Davies, D. R., Dent, C. E., Ives, D. R. Br. med. J. 8. MacGregor, G. A. ibid. 1971, i, 348. 9. Dent, C. E., Watson, L. C. A. ibid. 1964, ii, 218.
improved
1973, i, 397.
1258 Acute and convalescent sera from the patient (taken 10 days were examined for neutralising antibody to various enteroviruses and adenoviruses. These included poliovirus serotypes 1, 2, 3; Coxsackie group B (serotypes 1-6); echoviruses (serotypes 4, 5, 6, 7, 9, 11, and 20); and adenoviruses (serotypes 2, 4, 7, 14, and 21). Fourfold increase in reciprocal neutralisingantibody titres was demonstrable for polio 2, echo 6, adeno 7, and adeno 21. However, a 64-fold titre increase was demonstrated for Coxsackie B6 (reciprocal titre acute serum 4, convalescent serum 256). This was considered highly significant and suggestive of recent or intercurrent infection with Coxsackie B6.
apart)
Very few virus studies have been reported in acute infectious lymphocytosis. Olson and others1 were able to associate adenoviruses in 4 of their reported cases which presented with a pertussis-like disease without isolation or serological evidence of infection with Bordetella pertlissis. Poliovirus type 2 has also been isolated in a patient who presented with lymphocytosis and mild neurological deficit. Horwitz and Moorehave associated an untyped enterovirus resembling Coxsackie A subgroup in an outbreak of acute infectious lymphocytosis at a state school for mentally retarded children. The highly significant rise of neutralising antibody to Coxsackie B6 virus in the cases reported above, together with the few reported virus studies, suggest that acute infectious lymphocytosis is probably associated with a number of enteroviruses. In our patient, upper respiratory infection, diarrhœa, and lymphocytosis associated with significant rise in titre to Coxsackie B6 strongly suggest a causal relationship. University of Ghana Medical School, P.O. Box 4236, Accra, Ghana.
F. K. NKRUMAH P. A. K. ADDY.
PLASMA-NORTRIPTYLINE LEVELS IN DEPRESSION
SIR,—Åsberg et al.described nortriptyline plasma levels and their relation to its therapeutic effect in 29 depressed patients in hospital. Amelioration, as determined by the arithmetic difference between initial scores and the twoweek scores, was plotted against plasma concentration, and a curvilinear relationship was described, so that least improvement occurred at the lowest and highest plasma concentrations. They postulate, in explanation of this that finding, tricyclic antidepressants may have a dual action: at lower plasma levels drug action is ineffective. At middle levels monoamine uptake is blocked, causing increased available monamines at the reception site with clinical benefit. At higher plasma levels a phenothiazinelike blockade of the monoaminergic receptor occurs which might account for poorer antidepressant action. The purpose of this letter is to use these data to examine more closely the relationships among therapeutic effects, plasma levels, and dosage. Asberg et al. did not define completely their drug regimen. They state that nortriptyline was given in dosages varying from 25 to 75 mg. three times daily after a placebo period of four to seven days; that the dose was kept constant for each patient during the study, and the individual dosage levels were chosen without regard to severity of depression. It is not stated what did determine choice of dosage. We have correlated their dosage (mg. per kg.) with the baseline depression scores. The low correlation (r= -002) supports their contention that dosage 1. 2. 3. 4.
was not
assigned by severity.
Olson, L. C., Miller, G., Hanshaw, J. B. Lancet, 1964, i, 20. van der Kley, T. M. Maandschr. Kindergeneesk. 1954, 22, 321. Horwitz, M. S., Moore, G. T. New Engl. J. Med. 1968, 279, 399. Asberg, M., Cronholm, B., Sjoqvist, F., Tuck, D. Br. med. J. 1971, iii, 331.
Plasma-nortriptyline levels
and deviation
scores.
We examined the relationship of initial to final scores and found it sufficiently linear to obtain covariance deviation scores for further analyses-i.e., a change score uncorrelated with initial position. The accompanying figure shows the relationship of deviation scores to nortriptyline plasma concentration. The curvilinear relationship is similar to that found by Asberg et al. when they plotted amelioration (arithmetic difference) against plasma concentration, and thus supports their analysis. A crucial clinical question is whether the curvilinear relationship of amelioration to plasma concentration also holds for amelioration to dose. We examined this in two ways, using the amelioration score (arithmetic difference of final minus initial score) and the covariance deviation scores.
The Pearson correlation of dose to the arithmetic amelioration score is 0-12; the correlation of dose to the covariance deviation score is 0-04. The scattergrams do not indicate a non-linear correlation. We conclude that the curvilinear relationship between plasma level and improvement does not mean that the clinician need be wary of low or high dosages of nortriptyline. If anything, the dose/effect relationship seems to indicate that routine dosage over 75 mg. per day is unwarranted. However, without data giving both dosage by weight and the patient’s weight, this remains inferential. A study5 boy the same group, using a similar design, replicates the observation that high blood levels are associated with therapeutic refractoriness. However, these data do not lend themselves to the type of analysis we did from their first paper. Since dose is constant, it cannot be related to severity; and the baseline depression scores are not given because the final score was used as the outcome measure.
Unfortunately, the two studies provide different optinortriptyline blood levels, so that, at present, blood levels cannot be used predictively. However, the authors report the very interesting finding that, of 7 non-responders with a plasma-nortriptyline concentration above 170 ng. per ml., 5 were well and discharged within a week after reduction of dosage. This suggests that with patients for
mum
5.
Kragh-Sørensen, P., 1973, p. 113.
Åsberg, M., Eggert-Hanse, C. Lancet, Jan. 20,