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DMSO

Dimethy Sulfoxide Therapy in Severe Retardation in Down Syndrome Children*

Part 1

Manuel J. Aspillaga, Ghislaine Morizon, and Isabel Avendano

Department of Genetics
Calvo Mackenna Children`s Hospital
Santiago, Chile

Mila Sanchez

Quilpué Hospital
Quilpué, Chile

Lucila Capdeville

Department Of Neuropsychiatry
Manuel Arriaran Children`s Hospital
Santiago, Chile

Introduction

Since ancient times medical science has been preoccupied with improving the prognosis of brain-damaged individuals. One of the many types of mental retardation is Down's Syndrome, known better today as trisomy of chromosome 21. Much has been written about various treatments of this condition with medical, kenetic, pedagogical, and even surgical procedures. The results up till now have not been very satisfactory. The discovery of dimethyl sulfoxide (DMSO) and of its clinical application for almost a decade brings new hope to these patients. Its great power to penetrate and diffuse without causing cellular alterations, and its capacity to potentiate pharmaceutically active substances dissolved in it, make this an ideal vehicle for reducing the required dosage of many drugs. This enhances their therapeutic value, while diminishing the possibilities of side effects. The penetrating power of DMS0 allows such amino acids as 4-aminobutyric acid (GABA), 7-amino-8-hydroxbutyric acid (GABOB), and acetylglutamine, all of them important components of the Kregs-Henseleit cycle, to penetrate the meninges and thus to activate the neuronal function suppressed in many mental retardation syndromes. We might presume that the earlier the therapy is administered, the greater the possibility of improvement will be, as at the early stages the neuronal change is in full development. Investigation of this idea is the purpose of this work and the topic of the exposition.

Method

    A group of childíen with trisomy-21 were clinically diagnosed, and the diagnosis was confirmed by dermatoglyphics. As in this disease various groups can be distinguished according to the type of chromosomal aberration, and in some types spontaneous favorable evolution has been known, we considered it indispensable, in view of their rapid neurological development, to distinguish by means of a karvogram those children of less than 3½ years of age who had only a partial trisomy-21 and mosaics with a high percentage on normal cells, and not to treat these children. We started with 64 mongoloid patients. HaIf of them were treated One treated child and 8 controls quit the experience. The remaining 55 children with trisomy-21 were separated into two groups. Of those Iess than 3½ years of age, 15 were treated, while 13 were controls. In the older group (up to 14 years of age), 16 were treated and 11 were controls. This division was made as both groups are considered representative, the first being formed by children in the period of the development of the central nervous system, and the second by children that are only in the learning stage.

Sex

    In the group of children less than 3½ years of age, 7 of the treated children and 9 of the controls were masculine; 8 treated children and 4 controls were female. In the group over 3½ years of age, 10 treated children and 6 controls were males, and 6 treated children and 5 controls were females; thus there was a slightly higher number of male children. The following factors were considered important in the anamnesis; the social stratum, the age of the mother, the number of children and the mongoloid child's order of birth in each family, prematurity and also whether or not the child was desired, as this consideration more or less implies the collaboration of the parents during the treatment. The background information on the children is given in Table 1. A thorough pediatric examination was performed the beginning of the clinical work in order to discover other antecedent, such as malformations that could interfere in the treatment, and the nutritional condition and dermatoglyphics of the child and his parents. The patients were also submitted to neurological, psychological, ophthalmologic, and cardiologic examinination by specialists. Thereafter the pediatrician examined all the patients of both groups monthly and bimonthly; the other examininations were repeated every 6 months. In cases of severe infectious pathology the treatment was suspended for a short period, but only during the acute stage of the infection. It was established as a basic condition that the patient had not received any previous treatment (other than dietary indications, vitamin therapy, and/or necessary surgical operations). In both groups the parents were motivated to cooperate, and it was recommended that kinesitherapy be practiced according to the individual need of each chud. The economic factor was eliminated by providing the medication without cost.

    The DMSO and amino acids were administered by intramuscular injections, with a different rhythm in each of the two groups. In those aged less than 3½ years, the injections were applied every other day in series of 90 days, which were alternated with a month's rest. Ml received a minimum of 3 series. Several of them have continued with support treatment of 2 injections a week. During the rest periods the medication was administered in capsules that contained GABA, GABOB, acetylglutamine, and arginine, but not DMSO.

    For the children of less than 3½ years of age the dosage of the 5 cc ampule of 5% DMSO associated with GABA (5 mg), GABOB (10 mg), and l-acetylgltamine (10 mg) was adjusted in relation to body weight. Those that weighed less than 8 kg were administered 0.5 cc, those between 8 and 11 kg 1 cc, and those that weighed more than 11 kg 2 cc. Placebos were not used in injections, because the strong alliaceous ordor exhaled by patients who receive DMSO injections gives them away, and thus eliminates the first prerequisite for a double-blind trial. The children aged more than 3 ½ years received daily injections for periods of 20 days, alternated with 20-day pauses during which the above mentioned capsules were administered. For all of these children the dosage was intramuscular injections of 5 cc, and 2 capsules daily during the pauses from the injections. They received in all a total of 5 series of 20 injections each.

    The psychometric examination of those aged less that 3½ years were done according to Geseil; we calculated the development quotient (the relation of motor, adaptive, language, and social development to chronological age). We considered only increases of over 10 points as clinical improvement, since lesser variations could be due to a fault in the examination, imputable to the criterium of each investigator. The intelligence quotient was not measured, as the first years of life the functions of the nervous system are different, and the children act by habit and instinctive reactions rather than by application of conscious reactions or intelligence. The neurological development was explored fundamentally by observing sense organs, reflexes, statics, coordination, muscular tone, and sfincter control. A classiflcation of deficient was given if the fúnction looked for was frankly abnormally low; moderate, when it was acceptable and usefull and good if it was within the normal limits. The ophthalmologic examination was directed at checking up and/or treating malformations, disturbances of refraction, and other complications. The cardiologist checked the course of preexistíng cardiopatholgy.

    Psychometric measurements were practiced on children of more than 3 ½ years, with special tests for mongoloids such as the Binet-Kulman test, and everv 40 days the intelligence quotient was computed according to the Geselí, Wieneland, and Binet tests. More laboratory studies such as the hemogram, urine analysis, flocculation tests to measure hepatic ffinction, and tests of aminoaciduria and aminoacidemia were done on this group.

    Photographs were taken at the beginning of treatment, during treatment, and at the end of the treatment in an attempt to capture the psychic state and preponderant physical features of the patient. Movies were taken of some of the patients at different stages of treatment.

Table 1

Background Information on Children with Trisomy-21;
24 Controls and 31 Treated with DMSO-Amino Acid Therapy

Group

Sex
Male/ Female

Cases of
Malnutrition

Social Class
Lower/ Middle/ Upper

Prematurity

Order
of
Birth
1 >7

Number
of
Siblings
1 >7

Maternal
Age
<20 >40

Between 6 months and 3½ years

             

controls

9 / 4

1

1 / 10 / 2

3

5 / 1

5 / 1

- / -

treated between 3 and 14 years

7 / 8

1

2 / 12 / 1

2

7 / 3

7 / 3

4 / 5

controls

6 / 5

-

- / 11 / -

-

1 / 3

1 / 3

1 / 1

treated

10 / 6

-

2 / 13 / 1

-

3 / 2

1 / 2

- / 1

Results

    An attempt was made to diminish the existing differences between the treated and control groups such as age, nutritional and social conditions, and also the karyogram for those aged less than 3½ years. Ml corresponded to the standard trisomy, except for one control, who had a mosaic with 12% normal cells in a peripheral blood leukocyte culture. After a few months this child achieved better results than any other in his group.

    The dermatoglyphics in both control groups, as well as in the treated groups, where characteristic; and the Turpin and Lejeune index was over 5 in all children. With respect to sex, even though there were more males in both groups, this apparently did no have any influence on the results. The malnutrition observed in two children under 3 ½ years of age was mild; one was in the control group, the other in the treated group. Both recovered rapidly. Among the patients over 3½ years of age, there was neither malnutrition nor obesity.

    The other factors analyzed as antecedents were as follows:

    Social-economic Condition. This was very similar for both series of children. In general all belonged economically to the middle class. Of those aged less than 3½ years, among those treated, we had on extreme case of a prematurely born child, a carrier of a congenital cataract, whose mother was less than 20 years of age. The other children, both controls and treated, of poor economic backgrounds did not seem to be influenced by this handicap. At the other extreme, there were three children of economically well-situated mothers. The two controls showed parameters slightly higher than the rest of their groups the third was treated, but did not show a superior development. In the older group the influence of this factor was not noticed.

    Prematurity. As a rule, this was regarded as important only in the patients younger than 3½ years of age. There were 3 cases in each group. In the control group, one premature child had a more retarded evolution. This child also had very accentuated bilateral palpebral ptosis which made his vision difficult, and he had a congenital cardiopathy. The others evolved in the same way as the rest of their groups. In the treated group, one child who had congenital amblyopia due to a bilateral cataract had a very retarded evolution. There was only one child whose birth had not been desired by his parents. His results were no worse than those of the rest of the group, however.

    Birth Order of Siblings. We noticed only one case in which a patient`s being the seventh child had an unfavorable influence (this was in the group over 3½ years of age). The only son did not have any advantage. With reference to the total number of siblings the above is confirmed, as the trisomy-21 nearly always occurred in the last child.

    Age of the Mother. In the group less than 3 ½ years of age that were treated with DMSO and amino acids, 4 had mothers less than 20 years of age. Only one (the carrier of the congenital cataract) had a deficient evolution. Among those over 3½ years of age, there was one control case whose mother was under 20, and this child did not show a difference ftom the rest. A maternal age of over 40 did not influence any of the cases.

    Infections of the respiratory tract were frequent in both groups. Both groups also had summer diarrheas, which however, did not influence their evolution.

    In both groups of children under 3½ years of age, during the observation period, the body weight, height, and rhythm of cranial growth were commonly found to coincide with the patterns known for this pathology. Between the second and third year, the appearance of a moderate nasal bridge and a decrease of the epicanthus and of the obliquity of the palpebral fissune were observed. In the majority, macroglossia diminished or disappeared. Hair became more abundant and the neck became thinner. The thorax became more normal, with the increase of abdominal muscular tone, and the umbilical hernias were less frequent. Also some cases of squint improved, and voices became higher. On the other hand, in neither group were there rnodifications of the cranial form, denture, narrowness of the auditive canal, or of cardiac or respiratory frequency. There was no visceromegaly; cryptorchism and onthopedic defects did not modify. The cardiopathies (interauricular or interventricular communication) continued on the same course. The pulmonary hypertension present in one treated child showed a discrete improvement during the observation period, and did not appear to influence the evolution. Among the preexisting eye trouble, we found refraction defects and strabismus in both groups. Medical or surgical treatment was performed in the control case with bilateral palpebral ptosis and in the treated child with the preexistent bilateral central cataract, as well as in all the other cases when necessary. One case of 8 g-hemoglobin anemia had to be treated with translúsions before treatment was begun.

    In general, the control group under 3½ years of age was better than it should be (because of their trisomy, and according to class descriptions). The social strata of two of these cases could have influenced the results. In the older children the physical examination did not show ostensible somatic changes, apart from the improvement in the expression, mimetic capacity and psychic states of those treated with DMSO. Serious malformations were not found. The audigram gave normal results for all the children.

    The initial ocular examination revealed peripheral point-form crystalline opacity and some refraction defects in three controls. Among those treated, the initial examination showed four opacities of the type described, two cases of myopia, and one of astigmatism. In both groups the appropriate glasses were prescribed, Fundus of the eye was normal in all patients, and showed no modification or complications during treatment.

    With respect to the psychometric results of the study, the development of those less than 3½ years of age was calculated in accordance with Gesell's development quotient. The results are shown in Figure 1.

Continue, Part II