- Email: [email protected]
X-CHROMOSOME ACTIVITY IN LYMPHOCYTES
258
important clue to the metabolism of IgG into the pathogenesis of D.S.
or
provide insight
MEAN VALUES FOR SOME PLATELET-FUNCTION TESTS IN
10 PATIENTS
WILLEBRAND’S DISEASE,
27 CONTROLS, 10 PATIENTS
AND
WITH PORTSMOUTH SYNDROME
It should be appreciated that failure to find raised IgA or IgM in newborns with D.S. weighs against the hypothesis of persistence of a foetal infection in these infants, but does not eliminate the possibility that these infants had experienced a transient foetal infection. MICHAEL E. MILLER Department of Pediatrics, WILLIAM J. MELLMAN University of Pennsylvania, FRANK A. OSKI School of Medicine, GERTRUDE KOHN. Philadelphia, Pennsylvania.
PLATELETS: A PORTSMOUTH SYNDROME? SIR,-Dr. Hirsh and his colleagues (July 1, p. 18) describe a patient with a haemorrhagic diathesis whose platelet-rich plasma (P.R.P.) showed no aggregation on the addition of collagen. The P.R.P. of most people will respond to a suspension of collagen, but I have recorded no response to collagen in 2 people, who had no hxmorrhagic diathesis, in less than 100 controls. The accompanying figure shows tracings of the most usual type of response and tracings from these 2 people; these
WITH VON
Figures in parentheses in last column are the is excluded. * Theoretical mean: not assayed. t Significant difference from controls r<0<01. 1 Significant difference from controls, r<0<05.
means
if 1
atypical patient
abnormal collagen response is supported by the finding that in the controls there was a significant relation between the collagen " delay " and the slope of the adrenaline response. None of the other indices measured distinguished this group (or the group with von Willebrand’s disease) from the controls. Thus a 5th attribute-namely, a poor response to collagen-can be added to the definition of the syndrome. There was some overlap between individual results in the three groups, and a clear distinction was evident only on studying the groups as a whole. If the patients with Portsmouth syndrome had a mild form of von Willebrand’s disease, which initially seemed possible, then all their results should have been intermediate between those found in patients with von Willebrand’s disease and in normals. This seems most unlikely, since the von Willebrand’s disease patients responded normally to collagen and adrenaline, while the Portsmouth syndrome group responded abnormally to collagen and perhaps to adrenaline. The patient of Dr.Hirsh and his colleagues probably has the mild rather indefinite syndrome. Dr. Hardisty and Mr. Hutton3 describe another selected group of patients who also had a poor response to collagen. Perhaps these two reports and mine are all concerned with a roughly similar abnormality. same
This study will be reported in greater detail elsewhere. The statistical analysis was carried out by Mr. M. J. R. Healy of the Medical Research Council Clinical Research Centre, to whom I am most grateful. This work was carried out during the tenure of grants from the Wellcome Trust and the British Heart Foundation which Effect of
are
collagen and A.D.P.
on
P.R.P.
of citrated plasma with 400,000-450,000 platelets per stirred at 37°C. An equal amount of collagen was added to each. A.D.P., final concentration Mx 10-7, was added as shown. Bottom tracing: usual type of result. Top two tracings: results in the 2 controls described in the text.
Samples
Central Laboratory, Portsmouth and Isle of Wight Ar
c.mm. were
responses
important colleagues
It thus becomes to know how many normals Dr. Hirsh and his have studied with their technique.
were
repeatable on subsequent days.
I have collected 10 selected
patients who all have: (1) history bleeding; (2) moderately prolonged bleeding-time; (3) moderately abnormal platelet loss when tested in my glassbead column 1; and (4) normal plasma-antihasmophilic-globulin levels. I have tentatively called this the " Portsmouth syndrome ". A variety of aggregation tests2 were carried out on these 10 patients, 10 patients with von Willebrand’s disease, and 27 controls. Of the 19 indices of platelet function studied, only the significant ones and the adenosine diphosphate (A.D.P.) slope " are reported in the accompanying table. The response by the 10 patients with Portsmouth syndrome to a crude tendon extract (collagen) was found to be significantly less than normal. If 1 patient who could have a different syndrome was excluded from this group, then the adrenaline response was also significantly decreased. The probable abnormality of adrenaline response and its association with an of
"
1. 2.
O’Brien, J. R., Heywood, J. B. J. clin. Path. 1967, 20, 56. O’Brien, J. R., Heywood, J. B., Heady, J. A. Thromb. Diath. hœmorrh. 1966, 16, 752.
gratefully acknowledged. Pathological Service, Portsmouth.
J. R. O’BRIEN.
X-CHROMOSOME ACTIVITY IN LYMPHOCYTES SiR,-The report of Dr. Pegoraro and his colleagues (April 8, p. 781) prompts us to further remarks on the Lyon hypothesis and the genetic activity of the X chromosome. The Lyon hypothesis has been generally accepted because it can evidently clear up some questions in human genetics and is apparently considered no longer as a hypothesis but as proven. Thus
findings like R.N.A. synthesis by chromosomes, which are not in accordance with the hypothesis, are attributed to technical inadequacies.4 Clinical and biochemical findings suggest a repression of the genetic activity of the sex-chromatinforming X chromosome.5 These findings, however, do not suffice for the assumption of complete and constant inactivation. It has been assumed, owing to the frequency of occurrence of sex chromatin in tissue-culture cells, that all cells do not show inactivation.Our findings on R.N.A. synthesis of prophase chromosomes in female lymphocytes (Feb. 18, p. 385) permit the conclusion that inactivation of the X chromosome is incom3. 4. 5.
Hardisty, R. M., Hutton, R. A. Lancet, 1967, i, 983. Comings, D. E. Cytogenetics, 1966, 5, 247. Davidson, R. G., Nitowsky, H. M., Childs, B. Proc. U.S.A. 1963, 50, 481. 6. Therkelsen, A. J. Lancet, 1964, i, 987.
natn.
Acad. Sci.
259 does not exist, or that activity varies during the cell In the prophase of human lymphocytes we found the late-replicating X chromosome to be heterochromatic in only a few mitoses, as it is in most female cells in culture during interphase in the sex chromatin-in which genetic activity is repressed by heterochromatinisation.’ It has also been shown that cells in culture are chromatin-negative for a certain time after Mitosis.Thus heterochromatinisation is present only in a certain phase of the cell cycle and possibly not in cells with a short cell cycle,9 as apparently is the case in most blood-cells in culture. The differential condensation behaviour of the sex chromosome favours the assumption of a cell-cycle-dependent alteration of genetic activity, the occurrence of inactivation depending on the duration of the cell cycle. Cell-cycledependent inactivity concerns only the long arm of the X chromosome.1o All findings strongly support the above-
plete
or
cycle.
mentioned assumption of Therkelsen.6s For these reasons, late D.N.A. replication is not necessarily identical with inactivity, but rather suggests cell-cycledependent chromosomal activity. Therefore I think that not only the term " inactive " but also the term " heterochromatic " should not be applied to late-replicating X chromosomes, because neither term fully corresponds to the circumstances. This study was done for the Association of Society of Radiation Research for Hacmatology. Hæmatology Institute of the Society of Radiation Research in Association with EURATOM, Munich, Germany.
EURATOM and the
F. BACK.
RECURRENT APHTHOUS ULCERS SIR,-Iread with interest the article by Dr. Bishop and his co-workers.11 Previous workers had claimed that oestrogen could not be shown to have such a beneficial effect on oral lesions.12 Pregnancy, however, has long been associated with freedom from attacks of aphthous ulceration, and I have shown that oestrogenic anovulants have the same desirable effect.13 The more cestrogenic the anovulant, the more effective it is. However, I have observed successful remission in patients taking anovulants containing less than the 0-2 mg. ethinylcestradiol which your contributors found to be the minimum effective dose. This may be due to an cestrogenic contribution from the breakdown of the progestogen, or it could be that the endogenous cestrogen is not quite sufficient to produce full mucosal maturation without an exogenous boost. Indication that the anovulant was the therapeutic agent was provided by the recurrence of the ulceration in a few patients who ceased taking oral contraceptives before a planned pregnancy. All these patients whom I have seen during or since their pregnancy state that they were free from ulceration again whilst pregnant. A study of Papanicolaou-stained smears from the buccal mucosa shows the rationale of this treatment. Main and Ritchie 14 showed the existence of a cornification cycle in the oral mucosa of normal young women, and Morley 15 showed that a neutrophil cycle can be demonstrated in the healthy individual. Neutrophils become more plentiful in the smear as the cornification index falls. Their scarcity accounts for the aphthous ulceration associated with cyclical neutropenia.16 This occurs mainly premenstrually, when the mucosa relies most on the neutrophils to provide a defence mechanism, since the other defence mechanism, the cornification (or 7. Frenster, J. H., Allfrey, V. G., Mirsky, A. E. Proc. natn. Acad. Sci. U.S.A. 1963, 50, 1026. 8. Demars, R. Science, N.Y. 1964, 146, 424. Hbsli, P. Acta anat. 1963,
55,370. 9. Therkelsen, A. J., Lamm, L. U. Expl Cell Res. 1967, 44, 636. 10. Back, F. Unpublished. 11. Bishop, P. M. F., Harris, P. W. R., Trafford, J. A. P. Lancet, 1967, i, 1345. 12. Silverman, S., Jr., Shouse, C. J. Oral Therap. Pharmac. 1966, 3, 87. 13. Carruthers, R. Aust. dent. Y. 1967, 12, 279. 14. Main, D. M. G., Ritchie, G. M. Br.J. Derm. 1967, 79, 20. 15. Morley, A. A. Lancet, 1966, ii, 1220. 16. Baikie, A. G., Amerena, V. C., Morley, A. A. ibid. 1967, i, 45.
maturation) of are
squames, is at its lowest level.
Patients who
taking oestrogen show more neutrophils and do not show such striking depressions
pregnant or who
are
in buccal smears, of the cornification index. Is this the mechanism which Dr. Bishop and his co-workers were seemingly seeking ? Department of Dermatology, General Hospital, RONALD CARRUTHERS. Launceston, Tasmania.
METHOTREXATE IN MENINGEAL LEUKÆMIA SIR,-As the median survival in acute leukaemia of children has increased, consequent upon improvements in both specific antileukxmic treatment and supportive therapy, so involvement of the central nervous system by the leukxmic process has become a more common problem. In contrast, clinical evidence of neurological involvement is still uncommon in adults with acute leukxmia, and this is probably to be related to the infrequency of response to chemotherapy in the disease as it occurs in older persons.! The median survival of untreated cases of any age is about 2-2 months 2: very few cases of meningeal involvement occur within this period in children 34 or adults.5 The incidence of this complication in adults may be expected to increase if improvements in therapy, either specific or supportive, lead to better survival times in that age-group. Thus it may be important to emphasise that intrathecal methotrexate may be effective in the treatment of adults with meningeal leukaemia just as it is in children. We know of reports of five adults with acute leukaemia in whom meningeal involvement has been so treated,5-8 and we have recently treated a sixth patient. A woman aged 52 was seen with bronchopneumonia and anxmia. The white blood-cell (w.B.C.) count was 68,000 per c.mm., 89% of which were immature cells. Acute granulocytic leukaemia was diagnosed on the findings in the peripheral blood and bone-marrow. She was treated for 4 weeks with a combination of vincristine, methotrexate, mercaptopurine, and prednisolone until marrow hypoplasia developed. Treatment was continued with prednisolone alone and a satisfactory remission attained. 12 weeks after presentation, maintenance treatment with mercaptopurine was begun, and prednisolone was discontinued over the next 6 weeks. Marrow hypoplasia recurred 20 weeks after presentation when mercaptopurine was discontinued and treatment with prednisolone reinstituted. 27 weeks after her first presentation, while taking 40 mg. of prednisolone daily, she developed mild headaches. These worsened over the next 2 weeks and visual blurring developed, but there was no nausea, vomiting, or papillcedema at any time. Lumbar puncture showed the cerebrospinal-fluid pressure to be 200 mm. of water; the fluid contained 110 mg. of protein per 100 ml. and 500 white cells per c.mm.. In Romanowskystained preparations numerous blast cells were seen. The patient was given three doses of 15 mg. of methotrexate intrathecally at intervals of 12 and 7 days. Thoracic herpes zoster developed 3 days after the first injection. Headache improved at once and remitted completely after the third injection. At that time the cell count in the cerebrospinal fluid had fallen to 70 per c.mm. Symptoms have not recurred and now, 46 weeks after presentation and 19 weeks after the first clinical evidence of meningeal involvement, she is well and receiving
mercaptopurine
as an
outpatient.
Thus methotrexate, which is usually ineffective in the systemic treatment of acute leukaemia in adults,9may produce remission of the meningeal syndrome when given intrathecally. This is particularly important in view of the severe and often 1. Medical Research Council. Br. med. J. 1963, i, 7. 2. Tivey, H. Ann. N. Y. Acad. Sci. 1954, 60, 322. 3. Shaw, R. K., Moore, E. W., Freireich, E. J., Thomas, L. B. Neurology, Minneap. 1960, 10, 823. 4. Pierce, M. I. Pediat. Clins N. Am. 1962, 9, 425. 5. Spiers, A. S. D., Clubb, J. S. Med. J. Aust. 1966, i, 930. 6. Shanbrom, E., Miller, S., Fairbanks, V. F. New Engl. J. Med. 1961, 265, 169. 7. Baker, G. P., Oliver, R. A. M. Lancet, 1962, i, 837. 8. Macdougall, R. W. A. J. neurol. Sci. 1964, 1, 291. 9. Burchenal, J. H. Bull. N.Y. Acad. Med. 1954, 30, 429.
important clue to the metabolism of IgG into the pathogenesis of D.S.
or
provide insight
MEAN VALUES FOR SOME PLATELET-FUNCTION TESTS IN
10 PATIENTS
WILLEBRAND’S DISEASE,
27 CONTROLS, 10 PATIENTS
AND
WITH PORTSMOUTH SYNDROME
It should be appreciated that failure to find raised IgA or IgM in newborns with D.S. weighs against the hypothesis of persistence of a foetal infection in these infants, but does not eliminate the possibility that these infants had experienced a transient foetal infection. MICHAEL E. MILLER Department of Pediatrics, WILLIAM J. MELLMAN University of Pennsylvania, FRANK A. OSKI School of Medicine, GERTRUDE KOHN. Philadelphia, Pennsylvania.
PLATELETS: A PORTSMOUTH SYNDROME? SIR,-Dr. Hirsh and his colleagues (July 1, p. 18) describe a patient with a haemorrhagic diathesis whose platelet-rich plasma (P.R.P.) showed no aggregation on the addition of collagen. The P.R.P. of most people will respond to a suspension of collagen, but I have recorded no response to collagen in 2 people, who had no hxmorrhagic diathesis, in less than 100 controls. The accompanying figure shows tracings of the most usual type of response and tracings from these 2 people; these
WITH VON
Figures in parentheses in last column are the is excluded. * Theoretical mean: not assayed. t Significant difference from controls r<0<01. 1 Significant difference from controls, r<0<05.
means
if 1
atypical patient
abnormal collagen response is supported by the finding that in the controls there was a significant relation between the collagen " delay " and the slope of the adrenaline response. None of the other indices measured distinguished this group (or the group with von Willebrand’s disease) from the controls. Thus a 5th attribute-namely, a poor response to collagen-can be added to the definition of the syndrome. There was some overlap between individual results in the three groups, and a clear distinction was evident only on studying the groups as a whole. If the patients with Portsmouth syndrome had a mild form of von Willebrand’s disease, which initially seemed possible, then all their results should have been intermediate between those found in patients with von Willebrand’s disease and in normals. This seems most unlikely, since the von Willebrand’s disease patients responded normally to collagen and adrenaline, while the Portsmouth syndrome group responded abnormally to collagen and perhaps to adrenaline. The patient of Dr.Hirsh and his colleagues probably has the mild rather indefinite syndrome. Dr. Hardisty and Mr. Hutton3 describe another selected group of patients who also had a poor response to collagen. Perhaps these two reports and mine are all concerned with a roughly similar abnormality. same
This study will be reported in greater detail elsewhere. The statistical analysis was carried out by Mr. M. J. R. Healy of the Medical Research Council Clinical Research Centre, to whom I am most grateful. This work was carried out during the tenure of grants from the Wellcome Trust and the British Heart Foundation which Effect of
are
collagen and A.D.P.
on
P.R.P.
of citrated plasma with 400,000-450,000 platelets per stirred at 37°C. An equal amount of collagen was added to each. A.D.P., final concentration Mx 10-7, was added as shown. Bottom tracing: usual type of result. Top two tracings: results in the 2 controls described in the text.
Samples
Central Laboratory, Portsmouth and Isle of Wight Ar
c.mm. were
responses
important colleagues
It thus becomes to know how many normals Dr. Hirsh and his have studied with their technique.
were
repeatable on subsequent days.
I have collected 10 selected
patients who all have: (1) history bleeding; (2) moderately prolonged bleeding-time; (3) moderately abnormal platelet loss when tested in my glassbead column 1; and (4) normal plasma-antihasmophilic-globulin levels. I have tentatively called this the " Portsmouth syndrome ". A variety of aggregation tests2 were carried out on these 10 patients, 10 patients with von Willebrand’s disease, and 27 controls. Of the 19 indices of platelet function studied, only the significant ones and the adenosine diphosphate (A.D.P.) slope " are reported in the accompanying table. The response by the 10 patients with Portsmouth syndrome to a crude tendon extract (collagen) was found to be significantly less than normal. If 1 patient who could have a different syndrome was excluded from this group, then the adrenaline response was also significantly decreased. The probable abnormality of adrenaline response and its association with an of
"
1. 2.
O’Brien, J. R., Heywood, J. B. J. clin. Path. 1967, 20, 56. O’Brien, J. R., Heywood, J. B., Heady, J. A. Thromb. Diath. hœmorrh. 1966, 16, 752.
gratefully acknowledged. Pathological Service, Portsmouth.
J. R. O’BRIEN.
X-CHROMOSOME ACTIVITY IN LYMPHOCYTES SiR,-The report of Dr. Pegoraro and his colleagues (April 8, p. 781) prompts us to further remarks on the Lyon hypothesis and the genetic activity of the X chromosome. The Lyon hypothesis has been generally accepted because it can evidently clear up some questions in human genetics and is apparently considered no longer as a hypothesis but as proven. Thus
findings like R.N.A. synthesis by chromosomes, which are not in accordance with the hypothesis, are attributed to technical inadequacies.4 Clinical and biochemical findings suggest a repression of the genetic activity of the sex-chromatinforming X chromosome.5 These findings, however, do not suffice for the assumption of complete and constant inactivation. It has been assumed, owing to the frequency of occurrence of sex chromatin in tissue-culture cells, that all cells do not show inactivation.Our findings on R.N.A. synthesis of prophase chromosomes in female lymphocytes (Feb. 18, p. 385) permit the conclusion that inactivation of the X chromosome is incom3. 4. 5.
Hardisty, R. M., Hutton, R. A. Lancet, 1967, i, 983. Comings, D. E. Cytogenetics, 1966, 5, 247. Davidson, R. G., Nitowsky, H. M., Childs, B. Proc. U.S.A. 1963, 50, 481. 6. Therkelsen, A. J. Lancet, 1964, i, 987.
natn.
Acad. Sci.
259 does not exist, or that activity varies during the cell In the prophase of human lymphocytes we found the late-replicating X chromosome to be heterochromatic in only a few mitoses, as it is in most female cells in culture during interphase in the sex chromatin-in which genetic activity is repressed by heterochromatinisation.’ It has also been shown that cells in culture are chromatin-negative for a certain time after Mitosis.Thus heterochromatinisation is present only in a certain phase of the cell cycle and possibly not in cells with a short cell cycle,9 as apparently is the case in most blood-cells in culture. The differential condensation behaviour of the sex chromosome favours the assumption of a cell-cycle-dependent alteration of genetic activity, the occurrence of inactivation depending on the duration of the cell cycle. Cell-cycledependent inactivity concerns only the long arm of the X chromosome.1o All findings strongly support the above-
plete
or
cycle.
mentioned assumption of Therkelsen.6s For these reasons, late D.N.A. replication is not necessarily identical with inactivity, but rather suggests cell-cycledependent chromosomal activity. Therefore I think that not only the term " inactive " but also the term " heterochromatic " should not be applied to late-replicating X chromosomes, because neither term fully corresponds to the circumstances. This study was done for the Association of Society of Radiation Research for Hacmatology. Hæmatology Institute of the Society of Radiation Research in Association with EURATOM, Munich, Germany.
EURATOM and the
F. BACK.
RECURRENT APHTHOUS ULCERS SIR,-Iread with interest the article by Dr. Bishop and his co-workers.11 Previous workers had claimed that oestrogen could not be shown to have such a beneficial effect on oral lesions.12 Pregnancy, however, has long been associated with freedom from attacks of aphthous ulceration, and I have shown that oestrogenic anovulants have the same desirable effect.13 The more cestrogenic the anovulant, the more effective it is. However, I have observed successful remission in patients taking anovulants containing less than the 0-2 mg. ethinylcestradiol which your contributors found to be the minimum effective dose. This may be due to an cestrogenic contribution from the breakdown of the progestogen, or it could be that the endogenous cestrogen is not quite sufficient to produce full mucosal maturation without an exogenous boost. Indication that the anovulant was the therapeutic agent was provided by the recurrence of the ulceration in a few patients who ceased taking oral contraceptives before a planned pregnancy. All these patients whom I have seen during or since their pregnancy state that they were free from ulceration again whilst pregnant. A study of Papanicolaou-stained smears from the buccal mucosa shows the rationale of this treatment. Main and Ritchie 14 showed the existence of a cornification cycle in the oral mucosa of normal young women, and Morley 15 showed that a neutrophil cycle can be demonstrated in the healthy individual. Neutrophils become more plentiful in the smear as the cornification index falls. Their scarcity accounts for the aphthous ulceration associated with cyclical neutropenia.16 This occurs mainly premenstrually, when the mucosa relies most on the neutrophils to provide a defence mechanism, since the other defence mechanism, the cornification (or 7. Frenster, J. H., Allfrey, V. G., Mirsky, A. E. Proc. natn. Acad. Sci. U.S.A. 1963, 50, 1026. 8. Demars, R. Science, N.Y. 1964, 146, 424. Hbsli, P. Acta anat. 1963,
55,370. 9. Therkelsen, A. J., Lamm, L. U. Expl Cell Res. 1967, 44, 636. 10. Back, F. Unpublished. 11. Bishop, P. M. F., Harris, P. W. R., Trafford, J. A. P. Lancet, 1967, i, 1345. 12. Silverman, S., Jr., Shouse, C. J. Oral Therap. Pharmac. 1966, 3, 87. 13. Carruthers, R. Aust. dent. Y. 1967, 12, 279. 14. Main, D. M. G., Ritchie, G. M. Br.J. Derm. 1967, 79, 20. 15. Morley, A. A. Lancet, 1966, ii, 1220. 16. Baikie, A. G., Amerena, V. C., Morley, A. A. ibid. 1967, i, 45.
maturation) of are
squames, is at its lowest level.
Patients who
taking oestrogen show more neutrophils and do not show such striking depressions
pregnant or who
are
in buccal smears, of the cornification index. Is this the mechanism which Dr. Bishop and his co-workers were seemingly seeking ? Department of Dermatology, General Hospital, RONALD CARRUTHERS. Launceston, Tasmania.
METHOTREXATE IN MENINGEAL LEUKÆMIA SIR,-As the median survival in acute leukaemia of children has increased, consequent upon improvements in both specific antileukxmic treatment and supportive therapy, so involvement of the central nervous system by the leukxmic process has become a more common problem. In contrast, clinical evidence of neurological involvement is still uncommon in adults with acute leukxmia, and this is probably to be related to the infrequency of response to chemotherapy in the disease as it occurs in older persons.! The median survival of untreated cases of any age is about 2-2 months 2: very few cases of meningeal involvement occur within this period in children 34 or adults.5 The incidence of this complication in adults may be expected to increase if improvements in therapy, either specific or supportive, lead to better survival times in that age-group. Thus it may be important to emphasise that intrathecal methotrexate may be effective in the treatment of adults with meningeal leukaemia just as it is in children. We know of reports of five adults with acute leukaemia in whom meningeal involvement has been so treated,5-8 and we have recently treated a sixth patient. A woman aged 52 was seen with bronchopneumonia and anxmia. The white blood-cell (w.B.C.) count was 68,000 per c.mm., 89% of which were immature cells. Acute granulocytic leukaemia was diagnosed on the findings in the peripheral blood and bone-marrow. She was treated for 4 weeks with a combination of vincristine, methotrexate, mercaptopurine, and prednisolone until marrow hypoplasia developed. Treatment was continued with prednisolone alone and a satisfactory remission attained. 12 weeks after presentation, maintenance treatment with mercaptopurine was begun, and prednisolone was discontinued over the next 6 weeks. Marrow hypoplasia recurred 20 weeks after presentation when mercaptopurine was discontinued and treatment with prednisolone reinstituted. 27 weeks after her first presentation, while taking 40 mg. of prednisolone daily, she developed mild headaches. These worsened over the next 2 weeks and visual blurring developed, but there was no nausea, vomiting, or papillcedema at any time. Lumbar puncture showed the cerebrospinal-fluid pressure to be 200 mm. of water; the fluid contained 110 mg. of protein per 100 ml. and 500 white cells per c.mm.. In Romanowskystained preparations numerous blast cells were seen. The patient was given three doses of 15 mg. of methotrexate intrathecally at intervals of 12 and 7 days. Thoracic herpes zoster developed 3 days after the first injection. Headache improved at once and remitted completely after the third injection. At that time the cell count in the cerebrospinal fluid had fallen to 70 per c.mm. Symptoms have not recurred and now, 46 weeks after presentation and 19 weeks after the first clinical evidence of meningeal involvement, she is well and receiving
mercaptopurine
as an
outpatient.
Thus methotrexate, which is usually ineffective in the systemic treatment of acute leukaemia in adults,9may produce remission of the meningeal syndrome when given intrathecally. This is particularly important in view of the severe and often 1. Medical Research Council. Br. med. J. 1963, i, 7. 2. Tivey, H. Ann. N. Y. Acad. Sci. 1954, 60, 322. 3. Shaw, R. K., Moore, E. W., Freireich, E. J., Thomas, L. B. Neurology, Minneap. 1960, 10, 823. 4. Pierce, M. I. Pediat. Clins N. Am. 1962, 9, 425. 5. Spiers, A. S. D., Clubb, J. S. Med. J. Aust. 1966, i, 930. 6. Shanbrom, E., Miller, S., Fairbanks, V. F. New Engl. J. Med. 1961, 265, 169. 7. Baker, G. P., Oliver, R. A. M. Lancet, 1962, i, 837. 8. Macdougall, R. W. A. J. neurol. Sci. 1964, 1, 291. 9. Burchenal, J. H. Bull. N.Y. Acad. Med. 1954, 30, 429.