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INTRATHECAL METHOTREXATE
571
speculate that an effect of the XYY chromosome configuration in this case may have been to delay and alter epiphyseal growth, resulting in his excessive height and skeletal deformity. In this context the delayed age of puberty is of interest, and possibly this may be a more general effect of the XYY syndrome. Chromosome studies on patients presenting with epiphyseal growth abnormalities may
may therefore be of value. My thanks are due to Dr. D. R. Coles and Mr. A. C. H. Ratliff for permission to publish this report. Bristol Royal Infirmary,
E. R. WILLIAMS.
Bristol BS2 8HW.
suggests that it was most probably a consequence of the drug itself. In most instances the symptoms began 2-4 hours after the instillation and lasted 12-24 hours. Temperatures in most cases rose to 101-103°F (38-2-39-3°C). In a few of our children, the reactions followed a previous uneventful instillation of methotrexate. This apparent " chemical meningitis " has not been prevented by omission of the chemical preservative from the diluent or by the use of different lots of methotrexate. Analysis of earlier lots of this drug by the manufacturer did not reveal any pyrogens. Further studies of potency and search for degradation products and impurities are in progress.
RECURRENT LARYNGEAL NERVE AT THYROIDECTOMY
SIR,-Your editorial (Feb. 21, p. 398) pointing out the importance of avoiding injury to the recurrent laryngeal nerve at thyroidectomy is welcome. I cannot express an opinion as to whether identifying the nerve at operation and stimulating it, as is so strongly advocated by Mr. Victor Riddell,l is effective or not in achieving this end, but his figures are convincing and are supported by rational arguments. As a laryngologist, however, I should like to emphasise the seriousness of permanent bilateral recurrentlaryngeal-nerve palsy; it is an avoidable complication, and its treatment is not wholly satisfactory. The laryngologist can offer some help by a permanent tracheostomy, or by arytenoidectomy with lateral repositioning of the vocal cord. The drawbacks of a permanent tracheostomy are obvious, and arytenoidectomy, while giving considerable relief in most cases, has to be a compromise between increasing the airway and harming the voice. If, after thyroidectomy, the vocal cords are found to be adducted, and tracheostomy has to be done, it is worth looking for the nerves at the same time, since in a few cases a repairable injury may be found.2 Avoiding damage is, of course, preferable, and any technique that increases the safftv of the
nerves
is
to
be encouraged.
London W.1.
ROLAND S. LEWIS.
INTRATHECAL METHOTREXATE SIR,-Over the past year we have seen an increase in the frequency of febrile reactions to intrathecal methotrexate in children with meningeal leukxmia. Discussion of this problem with colleagues and a review of the literature suggested that our experience was not being shared by others. In one series of 51 patients treated this way only 7 had fever or headache.3 We were, therefore, interested in the report (Jan. 31, p. 249) by Dr. Rosner and his colleagues of cases resembling those seen by us. We have attempted a follow-up and analysis of our patients from Sept. 1, 1969 to Feb. 1, 1970. 20 prophylactic instillations of intrathecal methotrexate were given to 8 children with acute lymphocytic leukaemia. In all patients but 2, prophylactic therapy was decided upon after an initial attack of meningeal leukaemia in the hope of reducing the otherwise high recurrence-rate. Reactions occurred after 18 of 20 instillations, and consisted of fever (12 times), headache (14 times), and vomiting (12 times). On only 2 occasions were no reactions observed. Headache alone developed on 3 occasions. The infrequency of this symptom after lumbar puncture in children, and its association with vomiting and/or fever in most of our cases 1. 2.
Riddell, V. Br. J. Surg. 1970, 57, 1. Doyle, P. J., Brummett, R. E., Ewerts,
E. C.
Laryngoscope, 1967, 77,
1245.
3.
Sullivan, M. P., Vietti, T. J., Fernbach, D. J., Griffith, K. M., Haddy, T. B., Watkins, W. L. Blood, 1969, 34, 301.
Physicians who choose this drug for prophylaxis of meningeal infiltration in the well child with leukxmia should alert the parents to the possibility of such reactions. The methotrexate analyses were arranged Lederle Laboratories, Pearl River, N.Y. St.
by Mr. L. S. Carr,
Christopher’s Hospital for Children and
Department of Pediatrics, Temple University Health Sciences Center, 2600 N. Lawrence Street, Philadelphia, Pennsylvania 19133.
J. LAWRENCE NAIMAN LOTHAR M. RUPPRECHT GULTEN TANYERI PHILIP PHILIPPIDIS.
NORMAL SERUM AND RED-CELL FOLATE LEVELS IN A CHILD WITH CŒLIAC DISEASE SIR,-McNeish and Willoughby1 have suggested that a normal whole-blood folate (w.B.F.) level may be used with confidence to exclude a clinical diagnosis of coeliac disease in childhood. All 30 children with coeliac disease in their series had low w.B.F. (less than 60 ng. per ml.) and serumfolate levels (less than 6 ng. per ml.) compared with a control group of 20 children with normal values. Coeliac disease was diagnosed on jejunal biopsy by the presence of " subtotal villous atrophy ". The whole-blood folate is liable to be low in any severe anaemia, because most of the folate is in the red blood-cells. For this reason the red-cell folate is a more specific test of folate deficiency. We wish to record the case of an 11-year-old girl with untreated coeliac disease and normal serum and red-cell folate levels. The patient was investias one of a series (to be published) of currently untreated children who, at one time or another, had been diagnosed as having coeliac disease on clinical, radiological, or biochemical grounds, but who had never had an intestinal biopsy. The patient, born Jan. 11, 1958, was bottle-fed until 6 months, when she was weaned on to cereals and solids. At this time her growth-rate declined, and she became difficult to feed. Over the ensuing months the stools became frothy, pale, and offensive, with 2-4 motions a day. The parents also reported abdominal distension and frequent vomiting. At the age of 2 years, she was investigated and found to have steatorrhoea and a dilated jejunum. A gluten-free diet was instituted for 6 months, and resulted in improvement in the stools and vomiting but only minimal weight-gain. A hypochromic anaemia (haemoglobin 7-6 g. The diet was per 100 ml.) was treated with oral iron. abandoned after 6 months, and from the age of 3 the patient remained on a normal diet, including bread and cereals; she is at present asymptomatic, with 2 normal On physical examination she is bowel actions a day. normal except for her short stature (129 cm., below 3rd percentile); she is a little overweight (39-5 kg., above 75 percentile). Barium follow-through examination of the small intestine showed dilatation of several loops of jejunum and ileum. A jejunal-biopsy specimen showed flat mucosa
gated
1.
McNeish,
A.
S., Willoughby, M. L. N. Lancet, 1969, i, 442.
speculate that an effect of the XYY chromosome configuration in this case may have been to delay and alter epiphyseal growth, resulting in his excessive height and skeletal deformity. In this context the delayed age of puberty is of interest, and possibly this may be a more general effect of the XYY syndrome. Chromosome studies on patients presenting with epiphyseal growth abnormalities may
may therefore be of value. My thanks are due to Dr. D. R. Coles and Mr. A. C. H. Ratliff for permission to publish this report. Bristol Royal Infirmary,
E. R. WILLIAMS.
Bristol BS2 8HW.
suggests that it was most probably a consequence of the drug itself. In most instances the symptoms began 2-4 hours after the instillation and lasted 12-24 hours. Temperatures in most cases rose to 101-103°F (38-2-39-3°C). In a few of our children, the reactions followed a previous uneventful instillation of methotrexate. This apparent " chemical meningitis " has not been prevented by omission of the chemical preservative from the diluent or by the use of different lots of methotrexate. Analysis of earlier lots of this drug by the manufacturer did not reveal any pyrogens. Further studies of potency and search for degradation products and impurities are in progress.
RECURRENT LARYNGEAL NERVE AT THYROIDECTOMY
SIR,-Your editorial (Feb. 21, p. 398) pointing out the importance of avoiding injury to the recurrent laryngeal nerve at thyroidectomy is welcome. I cannot express an opinion as to whether identifying the nerve at operation and stimulating it, as is so strongly advocated by Mr. Victor Riddell,l is effective or not in achieving this end, but his figures are convincing and are supported by rational arguments. As a laryngologist, however, I should like to emphasise the seriousness of permanent bilateral recurrentlaryngeal-nerve palsy; it is an avoidable complication, and its treatment is not wholly satisfactory. The laryngologist can offer some help by a permanent tracheostomy, or by arytenoidectomy with lateral repositioning of the vocal cord. The drawbacks of a permanent tracheostomy are obvious, and arytenoidectomy, while giving considerable relief in most cases, has to be a compromise between increasing the airway and harming the voice. If, after thyroidectomy, the vocal cords are found to be adducted, and tracheostomy has to be done, it is worth looking for the nerves at the same time, since in a few cases a repairable injury may be found.2 Avoiding damage is, of course, preferable, and any technique that increases the safftv of the
nerves
is
to
be encouraged.
London W.1.
ROLAND S. LEWIS.
INTRATHECAL METHOTREXATE SIR,-Over the past year we have seen an increase in the frequency of febrile reactions to intrathecal methotrexate in children with meningeal leukxmia. Discussion of this problem with colleagues and a review of the literature suggested that our experience was not being shared by others. In one series of 51 patients treated this way only 7 had fever or headache.3 We were, therefore, interested in the report (Jan. 31, p. 249) by Dr. Rosner and his colleagues of cases resembling those seen by us. We have attempted a follow-up and analysis of our patients from Sept. 1, 1969 to Feb. 1, 1970. 20 prophylactic instillations of intrathecal methotrexate were given to 8 children with acute lymphocytic leukaemia. In all patients but 2, prophylactic therapy was decided upon after an initial attack of meningeal leukaemia in the hope of reducing the otherwise high recurrence-rate. Reactions occurred after 18 of 20 instillations, and consisted of fever (12 times), headache (14 times), and vomiting (12 times). On only 2 occasions were no reactions observed. Headache alone developed on 3 occasions. The infrequency of this symptom after lumbar puncture in children, and its association with vomiting and/or fever in most of our cases 1. 2.
Riddell, V. Br. J. Surg. 1970, 57, 1. Doyle, P. J., Brummett, R. E., Ewerts,
E. C.
Laryngoscope, 1967, 77,
1245.
3.
Sullivan, M. P., Vietti, T. J., Fernbach, D. J., Griffith, K. M., Haddy, T. B., Watkins, W. L. Blood, 1969, 34, 301.
Physicians who choose this drug for prophylaxis of meningeal infiltration in the well child with leukxmia should alert the parents to the possibility of such reactions. The methotrexate analyses were arranged Lederle Laboratories, Pearl River, N.Y. St.
by Mr. L. S. Carr,
Christopher’s Hospital for Children and
Department of Pediatrics, Temple University Health Sciences Center, 2600 N. Lawrence Street, Philadelphia, Pennsylvania 19133.
J. LAWRENCE NAIMAN LOTHAR M. RUPPRECHT GULTEN TANYERI PHILIP PHILIPPIDIS.
NORMAL SERUM AND RED-CELL FOLATE LEVELS IN A CHILD WITH CŒLIAC DISEASE SIR,-McNeish and Willoughby1 have suggested that a normal whole-blood folate (w.B.F.) level may be used with confidence to exclude a clinical diagnosis of coeliac disease in childhood. All 30 children with coeliac disease in their series had low w.B.F. (less than 60 ng. per ml.) and serumfolate levels (less than 6 ng. per ml.) compared with a control group of 20 children with normal values. Coeliac disease was diagnosed on jejunal biopsy by the presence of " subtotal villous atrophy ". The whole-blood folate is liable to be low in any severe anaemia, because most of the folate is in the red blood-cells. For this reason the red-cell folate is a more specific test of folate deficiency. We wish to record the case of an 11-year-old girl with untreated coeliac disease and normal serum and red-cell folate levels. The patient was investias one of a series (to be published) of currently untreated children who, at one time or another, had been diagnosed as having coeliac disease on clinical, radiological, or biochemical grounds, but who had never had an intestinal biopsy. The patient, born Jan. 11, 1958, was bottle-fed until 6 months, when she was weaned on to cereals and solids. At this time her growth-rate declined, and she became difficult to feed. Over the ensuing months the stools became frothy, pale, and offensive, with 2-4 motions a day. The parents also reported abdominal distension and frequent vomiting. At the age of 2 years, she was investigated and found to have steatorrhoea and a dilated jejunum. A gluten-free diet was instituted for 6 months, and resulted in improvement in the stools and vomiting but only minimal weight-gain. A hypochromic anaemia (haemoglobin 7-6 g. The diet was per 100 ml.) was treated with oral iron. abandoned after 6 months, and from the age of 3 the patient remained on a normal diet, including bread and cereals; she is at present asymptomatic, with 2 normal On physical examination she is bowel actions a day. normal except for her short stature (129 cm., below 3rd percentile); she is a little overweight (39-5 kg., above 75 percentile). Barium follow-through examination of the small intestine showed dilatation of several loops of jejunum and ileum. A jejunal-biopsy specimen showed flat mucosa
gated
1.
McNeish,
A.
S., Willoughby, M. L. N. Lancet, 1969, i, 442.