Failure of Strychnine Treatment during the Neonatal Period in Three Finnish Children with Nonketotic Hyperglycinemia

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1166 PEDIATRICS Vol. 65 No. 6 June 1980

Failure

of Strychnine

Treatment

during

the

Neonatal

Period

in Three

Finnish

Children

with

Nonketotic

Hyperglycinemia

Lennart

von

Wendt, MD, Seppo Simil#{228},MD,

Anna-Liisa Saukkonen, MD, and Maila Koivisto, MD

From the Department of Paediatrics, University of Oulu, Oulu, Finland

ABSTRACT. Three Finnish infants with a severe

neo-natal-onset-type of nonketotic hyperglycinemia were

treated with strychnine nitrate in a daily dosage of 0.2 to

0.9 mg/kg, given orally in four doses. In order to lower

the plasma and CSF-glycine concentrations concomitant

exchange transfusions (200 to 300 mi/kg of heparinized

blood) were carried out in two of these infants. Although the strychnine therapy was started at ages 15, 40, and 62

hours, the strychnine produced no clinical effect, and the exchange transfusion caused only a transient decrease in the plasma glycine level. Despite treatment, the clinical course was the same as in the majority of children with the severe form of the disease-all died within the first ten days of life. Impressive effects of strychnine treatment initiated in two infants at ages 5 and 6#{189}months, and given in addition to sodium benzoate and anticonvulsants, have been reported. These cases, however, probably rep-resent a less severe type of nonketotic hyperglycinemia.

Nevertheless, the therapeutic failure in the present cases probably indicates that strychnine treatment does not solve the therapeutic problems of severe forms of NKH.

Pediatrics 65:1 166-i 169, 1980; nonketotic hyperglycine-mia, glycine, strychnine.

Nonketotic hyperglycinemia (NKH) is a rare dis-order of glycine metabolism with autosomal reces-sive inheritance.’ Since 1965, when the first cases were recognized, nearly 100 patients with this dis-ease have been reported in the literature, including 22 Finnish infants.23 The biochemical defect

con-sists of a blocking of glycine degradation via serine, leading to an accumulation of glycine in the body fluids of the patient.4’5 The pathognomic laboratory findings in these patients thus include hyperglycin-uria, with clearly elevated concentrations of plasma

Received for publication July 16, 1979; accepted Oct 1, 1979. Reprint requests to (L.v.W.)Department of Paediatrics, Univer-sity of Oulu, SF-90220 Oulu 22 Finland.

glycine (700 to 2,000 zmoles/1iter, normal = 204 ±

83 tmoles/liter) and CSF glycine (73 to 342 jzmoles/ liter, normal = 4.0 ± 2.1 tmoles/liter. Metabolic

acidosis, ketosis, and osteoporosis, which are all common features of secondary or ketotic hypergly-cinemia, are not observed. The newborn infant with NKH generally appears healthy at birth, but glycine concentrations start to rise immediately and neu-rologic symptoms are usually observed during the first days oflife.’ In most ofthe children the clinical condition deteriorates rapidly, leading to death in early infancy. The survivors have, with few excep-tions, suffered severe psychomotor retardation.7’9”#{176} In spite of numerous therapeutic trials, promising results have been obtained in only two recent cases, in which strychnine was administered in addition to sodium benzoate and an anticonvulsant.”2

In our study of three Finnish infants, all born in 1979, strychnine therapy was commenced immedi-ately after confirmation of diagnosis. Informed pa-rental consent was obtained before using this

ex-perimental treatment, which in two cases also in-cluded exchange transfusions. At this early stage of the disease the central nervous system had probably not yet suffered any severe damage; therefore,

op-timal conditions for successful therapy should have been ensured.

MATERIALS AND METHODS

In order to reach a diagnosis of NKH as rapidly as possible, the initial glycine determinations were performed colorimetrically.’3 These specimens, as well as the amniotic fluid samples (N = 20) of the

control pregnancies were also examined in auto-matic amino acid analyzers (JEOL JLC-6AH and JEOL JLC-5AH)’4 using the standard method of the manufacturer. Urinary organic acids were mea-sured as trimethylsilyl (TMS) and o-methoxine-TMS derivatives using gas-liquid chromatography

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TABLE. Essential Clinical Features of Three Cases of Nonketotic Hyperglycinemia Treated with Strychnine in the Neonatal Period

Case 2

II/(V)

Normal, 40th wk

9/9

3,300 gm/SO cm 220 7hr 15 hr 1,260/265 Final outcome day

Death at age 9 days

SPECIAL ARTICLES 1167

(Carlo Erba, model 2403T). Strychnine nitrate was given orally as an aqueous solution (0.1 mg/nil). The exchange transfusions were performed using heparinized blood of the infant’s blood group.

CASE REPORTS

Case 1

Patient J.H. was the first child of healthy, unrelated parents. There was no family history ofmetabolic disease.

With the exception of a high-pitched cry, this girl was

considered healthy immediately after birth, but lethargy,

hypotonia, and nursing difficulties were observed at the

age of 8 hours. The rapid progression of symptoms led to

a suspicion of metabolic disease, and NKH was diagnosed

at the age of 40 hours.

On arrival at our hospital, at age 62 hours, the infant was already severely hypotonic and gave only crude, weak reactions to external stimuli. No tendon reflexes could be elicited and there was a partial absence of primitive reflexes. An EEG recorded on admission revealed

mod-erate depression of cortical activity. In order to enhance the expected favorable effect of strychnine treatment,

which was started at 62 hours of age, two exchange transfusions were performed (see Table). The lowest

re-corded plasma glycine level after the exchange transfu-sion was 940 tmoles/liter, and the preexchange level was

reached in six hours. No beneficial effect of this combined therapy was observed. Respiratory depression developed

on the fifth day, and the EEG finding deteriorated rap-idly, revealing isoelectricity four hours before the death

of the infant at 6 days of age. Autopsy findings were within normal limits.

Case 2

Infant J.M. was the second live born child of healthy, unrelated parents, after they had experienced three mis-carriages and the birth of a son who died of NKH at 3 weeks of age. This child appeared neurologically normal after birth, but his cry was high-pitched. Because of the positive family history of NKH, glycine concentrations were determined at regular intervals after birth. The plasma glycine levels were 465 tmoles/liter at birth, 415 moles/liter at 2 hours, 595 tmoles/liter at 6 hours, 1,160

jmoles/liter at 10 hours, and 1,560 moles/liter at 15 hours of age, at which stage CSF glycine was 265 moles/ liter. Hypotonia and lethargy were observed at the age of

7 hours; by the time of diagnosis the primitive reflexes

were still present, but reactions for external stimuli were

clearly depressed. Strychnine treatment was started as

soon as the diagnosis had been confirmed, and exchange

transfusions were performed every six hours during the

first day of treatment. After one day of this combined treatment, the clinical condition and EEG finding mdi-cated no positive effects, and the exchange transfusions were discontinued (see Table ). Following a steady down-ward course in the disease, this boy died at the age of 5 days. No specific findings were revealed at autopsy.

Case 3

R.S. was the sixth child of healthy parents, who were second cousins. Two children in this family had died of

Parity

Gestation and delivery

Apgar score (1 min/5 miii) Weight/length at birth

Glycine concentration in amniotic fluid (tmoles/liter)

Neurologic symptoms first observed

(age)

Diagnosis of NKH established (age) Glycine concentrations at time of

di-agnosis (plasma/CSF in moles/ liter)

Ketoacidosis and metabolic acidosis

Blood ammonia concentration

(jimoles/liter) Therapy Strychnine Exchange transfusion Case 1 I/(II)

Normal, 38th wk

9/10

3,880 grn/53 cm

Not measured 8hr 40 hr 1,300/65 Absent 136-153 0.2-0.3 mg/kg/day, orally, divided in 4 doses 62 hr to 6th day

200 nil/kg,

per-formed twice (66 hr and 80 hr)

Death at age 6 days

Absent

48-105

0.2-0.3 mg/kg/day, orally, divided in 4 doses 15 hr to 5th

300 mi/kg, per-formed every 6 hr during first day (17 to 41 hr)

Death at age 5 days

Case 3 VI/(VI)

Threatened premature labor, 37th wk

8/9

2,630 gm/49 cm 325 7hr 32 hr 735/110 Absent 65-106

0.2-0.9 mg/kg/day,

or-ally, divided in 4 doses 40 hr to 9th day

Not performed

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1168 STRYCHNINE TREATMENT

NKH during the neonatal period, both also had bilateral clubfoot. During her sixth pregnancy the mother suffered from premature uterine contractions and received treat-ment with isoxsuprine. This boy was born in the 37th week of pregnancy. Bilateral clubfoot and cleft palate were observed at birth, but neurologically the child ap-peared normal until the age of 7 hours when lethargy and nursing difficulties were noticed. The first EEG, recorded at 12 hours of age, revealed a partial burst suppression

pattern, and laboratory analysis confirmed the diagnosis

at age of 32 hours. On arrival at our hospital at age 40 hours this infant was hypotonic and responses to external stimuli were weak, but the Moro reflex was still positive. Strychnine was initially administered at a dosage of 0.2

mg/kg/day, but this was later increased to 0.9 mg/kg/ day. No favorable effect of this treatment was observed, and the child died at the age of9 days. With the exception of the malformations noted above, autopsy findings were normal.

DISCUSSION

As strychnine, administered in addition to

so-dium benzoate and anticonvulsants in two infants from the ages of 5 and 6#{189}months,”2 caused con-siderable improvement of the clinical condition, an even more pronounced effect was expected of strychnine therapy commenced in the newborn pe-riod. The favorable effect of sodium benzoate, re-ported in a number of patients with NKH, is most probably due to a lowering of plasma and to a limited extent a lowering of CSF-glycine levels.’5 This can be more efficiently achieved by exchange transfusions, which were therefore carried out in two of the present cases in order to create optimal conditions for strychnine therapy. In contrast to most other patients with NKH,’6 these infants de-veloped myoclonic seizures only transiently and, therefore, anticonvulsant treatment was not

clini-cally indicated.

Benzodiazepines have been shown to interact with central nervous system glycine receptors,’7 and a combination therapy consisting of strychnine, so-dium benzoate, and a benzodiazepine, through some as yet unknown mechanism, might be of special advantage in the treatment of NKH. However, it seems justified to conclude that the administration of strychnine probably does not alter the prognosis for neonates suffering from the severe type of the disease, which fulminates in the immediate

post-natal period. As strychnine failed to provide protec-tion against neurologic symptoms during experi-mentally induced hyperglycinemia in animals,’ it is obvious that this therapy does not definitely settle the therapeutic problems of NKH, although it may well be of considerable benefit, especially if insti-tuted at an early stage in less fuhninant cases of the disease.

The patients in whom the favorable effect was

observed did not show life-threatening symptoms in the neonatal period; therefore, they obviously represent a less severe form of the disease.

NKH is still an intractable disease and thus a reliable method for prenatal diagnosis would be of value. Although the glycine concentration of the amniotic fluid (see Table) during the last phase of pregnancy (220 zmoles/liter and 325 moles/liter) is clearly higher than in healthy Finnish parturients (134 ± 47 .tmoles/liter),’4 these concentrations probably only reflect the heterozygote state of the mother, since high amniotic glycine levels (185 moles/liter and 295 tmoles/liter) also were noted when healthy infants were born to Finnish NKH families.

Further studies of strychnine therapy in the treatment of various types of NKH are required before the definite value of this therapy can be judged. The highest strychnine dosage (0.9 mg/kg! day) used in this experimental approach is equal to that used by Gitzelinann et al,’2 but a gradual increase of the dosage to even higher levels might well enhance the therapeutic effect, especially if the initial reaction is favorable.

ACKNOWLEDGMENTS

This study was supported by grants from the Alma and K. A. Sneilman Foundation, FinSka L#{228}kars#{228}llskapet

So-ciety, and Oulu Medical Research Foundation.

REFERENCES

1. Nyhan W: Nonketotic hyperglycinemia, in Stanbury J,

Wyn-gaarden J, Fredrickson D (eds): The Metabolic Basis of

Inherited Disease, ed 4. New York, McGraw-Hill Book Co,

1978, pp 518-527

2. v Wendt L, Hirvasniemi A, Simil#{228}5: Nonketotic

hypergly-cinemia: A genetic study of 13 Finnish families. Clin Genet

15:411, 1979

3. v Wendt L: Experimental hyperglycinaemia-an evaluation of the efficacy of strychnine therapy in nonketotic hypergly-cinaemia. JMent Defic Res 23:195, 1979

4. Ando T, Nyhan W, Gerritsen T, et al: Metabolism of glycine

in the nonketotic form of hyperglycinemia. Pediatr Res 2:

254, 1968

5. de Groot CJ, Troelstra JA, Hommes FA: Nonketotic

hyper-glycinemia: An invitro study ofthe glycine-serine conversion in liver ofthree patients and the effect ofdietary methionine.

Pediatr Res 4:238, 1970

6. v Wendt L, Simil#{228}5, Hirvasniemi A, et al: Altered levels of various amino acids in blood plasma and cerebrospinal fluid

of patients with nonketotic hyperglycinemia.

Neuropadia-trie 9:360, 1978

7. Holmgren G, Blomquist H: Non-ketotic hyperglycinemia in two sibs with mild psycho-neurological symptoms. Neuro-padiatrie 8:67, 1977

8. Perry Th, Urquhart N, Hansen S: Studies of the glycine cleavage enzyme system in brain from infants with glycine encephalopathy. Pediatr Res 12:1192, 1977

9. Bank W, Morrow G: A familial spinal cord disorder with hyperglycinaemia. Arch Neurol 27:136, 1973

10. Frazier D, Summer G, Chamberlin H: Hyperglycinuria and hyperglycinemia in two siblings with mild developmental

delays. Am J Dis Child 132:777, 1978

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SPECIAL ARTICLES I 169 11. Arneson D, Chien L, Chance P, et al: Strychnine therapy in 15. Krieger I, Winbauni E, Eisenbrey A: Cerebrospinal fluid

nonketotic hyperglycinemia. Pediatrics 63:369, 1979 glycine in nonketotic hyperglycinaemia: Effect of treatment

12. Gitzehnann R, Steinmann B, Otten A, et al: Nonketotic with sodium benzoate and a ventriculum shunt. Metabolism

hyperglycinemia treated with strychnine, a glycine receptor 26:517, 1977

antagonist. Helv Paediatr Acta 32:517, 1977 16. v Wendt L, Simil#{227}5, Hirvasniemi A, et al: Nonketotic

13. Sardesai W, Provido H: The determination of glycine in hyperglycinaemia: A clinical analysis of 19 Finnish patients. biological fluids. Clin Chim Acta 29:67, 1970 Monogr Hum Genet 9:58, 1978

14. Yl#{246}staloP, Tuderman L, Kuutti E, et al: Amino acid com- 17. Young A, Zukin 5, Snyder 5: Interaction of benzodiazepines position of amniotic fluid in hepatosis of pregnancy, pre- with central nervous system glycine receptors: Possible eclampsia and Rh-incompatibility. Br J Obstet Gynaecol 82: mechanisms of action. Proc Nati Acad Sci USA 71:2246,

786, 1975 1974

THE ATTENDING PHYSICIAN: PRIVILEGE AND PITFALLS

The goals of medical education today, both at the undergraduate and graduate levels, are thwarted by a multitude of forces. Medical school enrollments are increasing. Academic and administrative demands on the faculty abound. Fi-nancial difficulties plague the institutions. The public is dissatisfied with and distrustful of the profession. House staff clamors for more tolerable working conditions. Within this milieu patients must be cared for and trainees instructed. Central to the successful provision of quality medical education and patient care

stands the attending physician. His strengths, however, have become dissipated

out of need for self-preservation in the pursuit of more tangible, more remuner-ative activities.

As attending physicians for students and house officers, through discussions with students from visiting medical schools, and from interviewing applicants for house staff training, we have identified several problems. Students and house officers are rarely counseled about their performance, whether good or bad. Often the student reaches the threshold of graduation unable to gather data adequately, perform a physical examination, or apply pathophysiological prim-ciples. Similarly, the house officer whose clinical skills are inadequate and who is often inconsiderate of patients or other members of the health care team reaches certification for board examinations without objective evidence that any of these deficiencies have been addressed by attending faculty.

Who is responsible to counsel, direct, and guide the trainee? It surely is, as always has been, the attending physician. How and why is he failing?

We believe he too often sees his role as an entertainer, one who passes through the wards on a regularly scheduled basis to scatter “pearls” and speak eruditely of topics that are interesting, but not always relevant to patient care. He assumes that house staff and students will manage diagnostic and therapeutic problems adequately, acquire appropriate and timely consultations, and attend to the personal needs of the patient and family while maintaining a deep commitment to work ethic. He fails to oversee house staff decisions in the outpatient clinic and emergency room. He frequently is not available to be consulted or to offer advice. Is it a wonder that the house staff members believe that the attending does not care?

Submitted by Lewis A. Barness, MD

From the Journal ofthe American Medical Association, Jan 18, 1980 (243:235, 1980).

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1980;65;1166

Pediatrics

Lennart von Wendt, Seppo Similä, Anna-Liisa Saukkonen and Maila Koivisto

Children with Nonketotic Hyperglycinemia