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A double blind trial of bromocriptine in the Rett syndrome
A Double Blind Trial of Bromocriptine the Rett Syndrome
• In
Michele Zappella, MD
Ten girls affected by the Rett syndrome (RS) were treated with bromocriptine in a double blind trial. Two girls showed considerable improvements in gross and fine motor development, in cognitive and social activities, and in their autonomy after four months of treatment. Minimal improvements were seen in one girl, but the others showed no positive change. Key words: Rett syndrome (RS), bromocriptine. ZappellaM. A double blind trial of bromocriptine in the Rett syndrome. Brain Dev 1990;12:148-50
In previous papers it was reported that bromocriptine can be of some benefit in some girls affected by Rett syndrome (RS) [1, 2] _ However, no double blind trial was conducted to confirm this. In addition, previous papers noted only the effects of this drug on some symptoms of this condition and, although definite improvements in locomotor abilities had been observed, no developmental scale was used to better assess the progress. A therapeutic project was therefore set up, combining the administration of bromocriptine in a double blind trial with evaluation of a child's condition through the use of the Po~tage Guide to Early Education [3], which is currently used in our Department for assessing young handicapped children. METHODS Ten girls affected by RS were the subjects of the present study. Their ages ranged from 3 years 5 months to 14 years 10 months (mean, 8 years 1 month). Before treatment was begun, each girl was evaluated according to the assessment charts of the Portage Guide as to items concerning autonomy, motor, social and cognitive development. Language development, as assessed with these charts, was not considered, but words which the child would utter were simply counted. The same evaluation
From the Department of Child Neurology and Psychiatry, Regional Hospital, Siena. Correspondence address: Dr. Michele Zappella, Department of Child Neurology and Psychiatry, Regional Hospital, USL 30, Via Mattioli 10, 53100 Siena, Italy.
was repeated after two months of treatment or placebo administration, and after two subsequent months of treatment. The girls were divided into two groups: group A (cases 1 to 5) and group B (cases 6 to 10). In group A, bromocriptine was given for four months, while in group B, a placebo was given for the first two months. This project was approved by the Ethical Commission of the Tuscan Region in which our hospital is situated. With informed consent of the parents, treatment was started with the administration of Parlodel (Sandoz) pills (2.5 mg of bromocriptine) at the dosage of a quarter of a pill two times a day for a girl aged 3 years 5 months, a quarter of a pill three times a day for girls aged 5 years, half a pill twice a day for two girls aged, respectively, 6 and 9 years, and half a pill three times a day for those older than 10 years. The parents and the doctor were not aware whether these pills contained bromocriptine or the placebo. Every girl underwent a complete blood count, and evaluation of transaminases and blood pressure before starting the treatment and every two months until the trial was completed. Apart from cases 2, 4 and 7, who were taking different kinds of antiepileptic drugs, the other girls were having no other pharmacological treatment. RESULTS Table 1 summarizes the results of this trial. It is evident that the placebo did not cause any change in the girls' behaviour and only one girl in group B showed some moderate improvement after the administration of bromocriptine. On the contrary, two girls in group A showed impressive improvements for every scale, which was more
Table 1 Behavioural changes in girls treated with bromocriptine and placebo Case no Age
3 Sy1m
4 SySm
S Sy6m
6
llyllm
2 6y 10m
2m 4m
10+ 10+
1+ 13+
1+
Auton
2m 4m
1+ 4+
4+
4+
Cognit
2m 4m
4+ 4+
1+ 2+
2+
2m 4m
2+ 2+
9+
2m 4m
17+ 20+
2+ 28+
2m 4m
8 10
Motor
Social Total Words
1
Onset of disease
2y
Ambulant
+
Sy8m
9y8m
7
8 3ySm
14y 10m
9
10 13y 1m
8m
ly
9m
ly 3m
7+
ly 6m
ly 2m
8m
ly
ly
+
+
+
+
+
+
'>.'
Cases 1-5 comprise group A, cases 6-10 comprise group B. Numbers with a + indicate the numbers of items of the Portage Guide for Early Education which were gained after, respectively, 2 and 4 months of treatment (or placebo for those in group B after the first two months). 2m: after 2 months of treatment (or placebo for those in group B), 4m: after 4 months of treatment (or after 2 months of treatment in group B), m: months, y: years.
pronounced· for the motor one, case 1 improving in 10 items in the first two months, namely learn to climb on a chair, remove 1" pegs from a pegboard, put them in, build a tower of 12 cubes alone, squat and return to the standing position and push and pull toys while walking. The same girl improved in 4 items on the cognitive scale in the same period of time, namely place 5 round pegs in a pegboard on request, match objects with pictures of the same objects, point to named pictures and turn pages of a book to find them. Case 2 showed more rapid improvement in the second two months of treatment, when she improved in 13 items on the motor scale, namely, among other things, walk upstairs with alternating placement of the feet and run around with coordinated, alternating arm movements. She became more sociable and autonomous, but on the cognitive scale she improved in only 2 items. In point of fact, the improvements these two girls made in a few months in terms of developmental items corresponded to improvements which normal children make in much longer periods of time. In addition, their sleep became regular, their attention and exploration improved, and their "hand-washing" stereotypic activities decreased, and periods of relaxation of up to half an hour were often seen almost daily. Some minor improvement was also seen in case 6. In contrast, no noticeable progress was observed in the remaining 7 girls, 3 of whom were reported to be more tense, while another one (case 8) had frequent bouts of vomiting after the onset of treatment, which was soon
stopped. No other negative side effects were noticed, and the results of laboratory tests as well as evaluation of blood pressure were normal. • DISCUSSION The present results confirm the results of previously reported studies on the efficacy of bromocriptine in some girls affected by the RS. Although little change was observed in group B, which underwent the placebo trial, the rapid and important progress in two cases in group A suggests that bromocriptine can be of help in some girls affected by this syndrome. An intriguing aspect of this postive result is the surprisingly rapid improvement in some items. For example, case 1 was able, after two months ofbromocriptine treatment, to build a tower of 12 cubes, whereas previously she should not put one cube on top of another. According to Illingworth [4], a child of 15 months is able to build a tower of 2 cubes, whereas a child of three years can build a tower of 9 cubes: in that item she therefore improved in two months of treatment to the same extent as normal children do in 20 months or more. There were no particular features in cases 1 and 2 with which one could distinguish them from other girls in the group, except slightly greater motor ability of their hands: before treatment each of them could hold an object like a glass or a cube for a few seconds. In addition, the onset of disease was reported to be as late as 1 year and a half or 2 years of age. It may well be that for the efficacy of this
Zappella: Rett syndrome - bromocriptine 149
dopaminergic agonist drug, a situation is required where damage to the dopaminergic system is not as profound as in most girls affected by this syndrome. A useful comparison can be drawn between RS girls treated with bromocriptine and pediatric patients affected by "akynetic mutism" treated with the same drug. Akynetic mutism shows some "functional" similarity to RS in that affected patients are in a state of silent, immobile wakefulness, when they can, for example, watch television or follow objects with the eyes. It has been observed that children affected by akynetic mutism following a variety of disorders, like diffuse meningoencephalitis or viral encephalitis, intraventricular meningioma or traumatic head injury, can recover from their mutism and unresponsiveness to pain after a few days of treatment with bromocriptine [5]. On the contrary, bromocriptine failed to reverse akynetic mutism in a patient with diffuse leUkoencephalopathy, probably because the dopamine terminals were diffusely damaged [6]. It is therefore possible to infer in both cases, in RS and in akynetic mutism patients, that the positive effects of this dopaminergic agonist drug are related to its positive action on some preserved dopamine terminals. These data favour the view of the existance of an impaired central dopa-
150 Brain & Development, Vol 12, No 1, 1990
minergic tone in RS and are consistent with the results of the neurophysiological studies reported by Nomura and Segawa [7].
REFERENCES 1. Zappella M, Genazzani A. Girls with Rett syndrome treated with bromocriptine (letter). Wien Klin Wochenschr 1986; . 98:780. 2. Zappella M, Genazzani A, Facchinetti F, Hayek G. Bromocriptine in Rett syndrome. Brain Dev (Tokyo) (submitted for publ). 3. Shearer MS, Shearer DE. The Portage Project: a model for early childhood education. Exceptional Children 1972;38: 210-7. 4. Il1ingworth RS. The development of the infant and young child. Edinburgh· London: Livingstone, 1960. S. Echiverry HC, Tatum WO, Merens TA, Coker SB. Akinetic mutism: pharmacological probe of the dopaminergic mesencephalofrontal activating system. Pediatr Neurol 1988;4: 228-30. 6. Devinsky 0, Lemann W, Evans A. Akinetic mutism in a bone marrow transplant recipient following total body irradiation and amphotericin B chemoprophylaxis: a PET and neuropathologic study. Arch Neurol 1987;44:414-7. 7. Nomura Y, Segawa M. Anatomy of Rett syndrome. Am J Med Genet 1986;24:289-303.
• In
Michele Zappella, MD
Ten girls affected by the Rett syndrome (RS) were treated with bromocriptine in a double blind trial. Two girls showed considerable improvements in gross and fine motor development, in cognitive and social activities, and in their autonomy after four months of treatment. Minimal improvements were seen in one girl, but the others showed no positive change. Key words: Rett syndrome (RS), bromocriptine. ZappellaM. A double blind trial of bromocriptine in the Rett syndrome. Brain Dev 1990;12:148-50
In previous papers it was reported that bromocriptine can be of some benefit in some girls affected by Rett syndrome (RS) [1, 2] _ However, no double blind trial was conducted to confirm this. In addition, previous papers noted only the effects of this drug on some symptoms of this condition and, although definite improvements in locomotor abilities had been observed, no developmental scale was used to better assess the progress. A therapeutic project was therefore set up, combining the administration of bromocriptine in a double blind trial with evaluation of a child's condition through the use of the Po~tage Guide to Early Education [3], which is currently used in our Department for assessing young handicapped children. METHODS Ten girls affected by RS were the subjects of the present study. Their ages ranged from 3 years 5 months to 14 years 10 months (mean, 8 years 1 month). Before treatment was begun, each girl was evaluated according to the assessment charts of the Portage Guide as to items concerning autonomy, motor, social and cognitive development. Language development, as assessed with these charts, was not considered, but words which the child would utter were simply counted. The same evaluation
From the Department of Child Neurology and Psychiatry, Regional Hospital, Siena. Correspondence address: Dr. Michele Zappella, Department of Child Neurology and Psychiatry, Regional Hospital, USL 30, Via Mattioli 10, 53100 Siena, Italy.
was repeated after two months of treatment or placebo administration, and after two subsequent months of treatment. The girls were divided into two groups: group A (cases 1 to 5) and group B (cases 6 to 10). In group A, bromocriptine was given for four months, while in group B, a placebo was given for the first two months. This project was approved by the Ethical Commission of the Tuscan Region in which our hospital is situated. With informed consent of the parents, treatment was started with the administration of Parlodel (Sandoz) pills (2.5 mg of bromocriptine) at the dosage of a quarter of a pill two times a day for a girl aged 3 years 5 months, a quarter of a pill three times a day for girls aged 5 years, half a pill twice a day for two girls aged, respectively, 6 and 9 years, and half a pill three times a day for those older than 10 years. The parents and the doctor were not aware whether these pills contained bromocriptine or the placebo. Every girl underwent a complete blood count, and evaluation of transaminases and blood pressure before starting the treatment and every two months until the trial was completed. Apart from cases 2, 4 and 7, who were taking different kinds of antiepileptic drugs, the other girls were having no other pharmacological treatment. RESULTS Table 1 summarizes the results of this trial. It is evident that the placebo did not cause any change in the girls' behaviour and only one girl in group B showed some moderate improvement after the administration of bromocriptine. On the contrary, two girls in group A showed impressive improvements for every scale, which was more
Table 1 Behavioural changes in girls treated with bromocriptine and placebo Case no Age
3 Sy1m
4 SySm
S Sy6m
6
llyllm
2 6y 10m
2m 4m
10+ 10+
1+ 13+
1+
Auton
2m 4m
1+ 4+
4+
4+
Cognit
2m 4m
4+ 4+
1+ 2+
2+
2m 4m
2+ 2+
9+
2m 4m
17+ 20+
2+ 28+
2m 4m
8 10
Motor
Social Total Words
1
Onset of disease
2y
Ambulant
+
Sy8m
9y8m
7
8 3ySm
14y 10m
9
10 13y 1m
8m
ly
9m
ly 3m
7+
ly 6m
ly 2m
8m
ly
ly
+
+
+
+
+
+
'>.'
Cases 1-5 comprise group A, cases 6-10 comprise group B. Numbers with a + indicate the numbers of items of the Portage Guide for Early Education which were gained after, respectively, 2 and 4 months of treatment (or placebo for those in group B after the first two months). 2m: after 2 months of treatment (or placebo for those in group B), 4m: after 4 months of treatment (or after 2 months of treatment in group B), m: months, y: years.
pronounced· for the motor one, case 1 improving in 10 items in the first two months, namely learn to climb on a chair, remove 1" pegs from a pegboard, put them in, build a tower of 12 cubes alone, squat and return to the standing position and push and pull toys while walking. The same girl improved in 4 items on the cognitive scale in the same period of time, namely place 5 round pegs in a pegboard on request, match objects with pictures of the same objects, point to named pictures and turn pages of a book to find them. Case 2 showed more rapid improvement in the second two months of treatment, when she improved in 13 items on the motor scale, namely, among other things, walk upstairs with alternating placement of the feet and run around with coordinated, alternating arm movements. She became more sociable and autonomous, but on the cognitive scale she improved in only 2 items. In point of fact, the improvements these two girls made in a few months in terms of developmental items corresponded to improvements which normal children make in much longer periods of time. In addition, their sleep became regular, their attention and exploration improved, and their "hand-washing" stereotypic activities decreased, and periods of relaxation of up to half an hour were often seen almost daily. Some minor improvement was also seen in case 6. In contrast, no noticeable progress was observed in the remaining 7 girls, 3 of whom were reported to be more tense, while another one (case 8) had frequent bouts of vomiting after the onset of treatment, which was soon
stopped. No other negative side effects were noticed, and the results of laboratory tests as well as evaluation of blood pressure were normal. • DISCUSSION The present results confirm the results of previously reported studies on the efficacy of bromocriptine in some girls affected by the RS. Although little change was observed in group B, which underwent the placebo trial, the rapid and important progress in two cases in group A suggests that bromocriptine can be of help in some girls affected by this syndrome. An intriguing aspect of this postive result is the surprisingly rapid improvement in some items. For example, case 1 was able, after two months ofbromocriptine treatment, to build a tower of 12 cubes, whereas previously she should not put one cube on top of another. According to Illingworth [4], a child of 15 months is able to build a tower of 2 cubes, whereas a child of three years can build a tower of 9 cubes: in that item she therefore improved in two months of treatment to the same extent as normal children do in 20 months or more. There were no particular features in cases 1 and 2 with which one could distinguish them from other girls in the group, except slightly greater motor ability of their hands: before treatment each of them could hold an object like a glass or a cube for a few seconds. In addition, the onset of disease was reported to be as late as 1 year and a half or 2 years of age. It may well be that for the efficacy of this
Zappella: Rett syndrome - bromocriptine 149
dopaminergic agonist drug, a situation is required where damage to the dopaminergic system is not as profound as in most girls affected by this syndrome. A useful comparison can be drawn between RS girls treated with bromocriptine and pediatric patients affected by "akynetic mutism" treated with the same drug. Akynetic mutism shows some "functional" similarity to RS in that affected patients are in a state of silent, immobile wakefulness, when they can, for example, watch television or follow objects with the eyes. It has been observed that children affected by akynetic mutism following a variety of disorders, like diffuse meningoencephalitis or viral encephalitis, intraventricular meningioma or traumatic head injury, can recover from their mutism and unresponsiveness to pain after a few days of treatment with bromocriptine [5]. On the contrary, bromocriptine failed to reverse akynetic mutism in a patient with diffuse leUkoencephalopathy, probably because the dopamine terminals were diffusely damaged [6]. It is therefore possible to infer in both cases, in RS and in akynetic mutism patients, that the positive effects of this dopaminergic agonist drug are related to its positive action on some preserved dopamine terminals. These data favour the view of the existance of an impaired central dopa-
150 Brain & Development, Vol 12, No 1, 1990
minergic tone in RS and are consistent with the results of the neurophysiological studies reported by Nomura and Segawa [7].
REFERENCES 1. Zappella M, Genazzani A. Girls with Rett syndrome treated with bromocriptine (letter). Wien Klin Wochenschr 1986; . 98:780. 2. Zappella M, Genazzani A, Facchinetti F, Hayek G. Bromocriptine in Rett syndrome. Brain Dev (Tokyo) (submitted for publ). 3. Shearer MS, Shearer DE. The Portage Project: a model for early childhood education. Exceptional Children 1972;38: 210-7. 4. Il1ingworth RS. The development of the infant and young child. Edinburgh· London: Livingstone, 1960. S. Echiverry HC, Tatum WO, Merens TA, Coker SB. Akinetic mutism: pharmacological probe of the dopaminergic mesencephalofrontal activating system. Pediatr Neurol 1988;4: 228-30. 6. Devinsky 0, Lemann W, Evans A. Akinetic mutism in a bone marrow transplant recipient following total body irradiation and amphotericin B chemoprophylaxis: a PET and neuropathologic study. Arch Neurol 1987;44:414-7. 7. Nomura Y, Segawa M. Anatomy of Rett syndrome. Am J Med Genet 1986;24:289-303.