Bromocriptine in the Rett Syndrome Michele Zappella, MD, Andrea Genazzani, MD, Fabio Facchinetti, MD and Giuseppe Hayek, MD
Twelve typical cases of the Rett syndrome and one forme fruste were treated with bromocriptine for six months and then had a washout for two months followed by resumption of the bromocriptine treatment. During the first bromocriptine treatment there were improvements in communication and relaxation in some of the girls: a more regular sleep pattern was observed in 4 and a more varied facial expression in 8, and 4 girls began to utter a few words. The bouts of hyperpnea disappeared in 5 and grinding of the teeth in 3. There was also a reduction in stereo typic hand activities in 5 girls and signs of improved motor abilities in 3. The washout caused a general decrease in the positive effects of the previously administered bromocriptine and resumption of the treatment with this drug led to less marked improvement. Metoc!opramide was tested in all the girls before the treatment, and it was noted that, while endorphins were hyporesponsive, prolactin was hyperresponsive. This test was repeated two months after the bromocriptine treatment had been performed and, while ~-lipotropin remained unchanged, ~-endorphin showed increased responsiveness. Key words: Rett syndrome (RS), ~-lipotropin (BLPH), ~-endorphin (BEP), prolactin (PRL). Zappella M, Genazzani A, Facchinetti F, Hayek G. Bromocriptine in the Rett syndrome. Brain Dev 1990;12:221-5
It has already been reported that bromocriptine may be
beneficial in girls affected by the Rett syndrome (RS), in that it induces more relaxation, more communication and improved locomotor abilities in some of them [1,2] . These data favour the view of the existence of an impaired central dopaminergic tone in this syndrome and are consistent with other observations, which support similar conclusions from neuropathological [3] and neurophysiological [4, 5] points of view. On the other hand, from a behavioural point of view, RS shows features of a communication disorder in which several symptoms, such as staring, social withdrawal, bouts of hyperpnea and even wringing and washing hands movements, can eventually be reduced for very short periods of time, if, for example, people relate to such cases in highly expressive ways and in a face to face position or if external requests are decreased and sources of keen interest (stories, music, etc) presented [6]. As a consequence, if a drug has an effect on these symptoms, it is possible that the latter From the Department of Child Neurology and Psychiatry, Regional Hospital, Siena (MZ, GH); Department of Gynecology and Obstetrics, University of Modena, Modena (AG, FF). Received for publication: January 6, 1989. Accepted for pUblication: October 11, 1989. Correspondence address: Dr. Michele Zappella, Department of Child Neurology and Psychiatry, Regional Hospital, USL 30, Via Mattioli 10,53100 Siena, Italy.
can be increased or diminished, according to the relational strategies which are used with these patients. A therapeutic project was therefore set up, combining the administration of bromocriptine with appropriate advice to parents as to how they could relate to their daughters in a way which could foster communication.
METHODS Subjects Thirteen cases of RS were the subjects of the present study. Their ages ranged from 3 to 14 years. They showed symptoms which agreed with the criteria established at the second Vienna conference on RS [7] with the exception of case 1, who is better defined as a forme fruste: she did not show head growth deceleration and was not clearly ataxic, and midline stereotypic hands activities were not seen as frequently as usual in this condition. Also, cases 8 and 13 did not show head growth deceleration, but otherwise presented a full clinical picture of the syndrome. Case 8 was able to utter some words, whereas all the other girls were unable to utter a single word. Cases 2 and 5 were not ambulant. Before the treatment was begun, each patient was videotaped for ten minutes with her mother and for ten minutes with a physiotherapist. In both situations she was offered standard objects (a doll, a rattle, small cubes,
etc), and encouraged to walk around and to go up and down stairs. Data regarding her status were collected both on direct observation and from her parents. The data included ones on sleep, facial expression, spoken words, bouts of hyperpnea, grinding of the teeth, stereo typic hand activities and motor abilities, such as going up and down stairs. The same evaluation and videotape assessment were repeated at the end of the treatment (after six months) and, subsequently, after a washout and after two months of further treatment with bromocriptine. No formal developmental test was given to these girls, because of the severity of their expressive and praxic handicaps. The scoring was conducted in the following way (see
Table 1): sleep, evaluated on the basis of parents' reports; +, regular, -, irregular with frequent night awakening. Facial expression, scored from +++ to -, according to patients'videotapes; +++, looks at and reacts normally to people, hugs and kisses the parents, ++, looks at people, but remains at times a little vacant, shows at least three of the following expressions, "joy," "serious intent," "surprise," "dismay," "smiling," "laughing," "rage" and "weeping," +, frequently avoids people's faces, looks only occasionally at them and shows two expressions among those listed above, -, maintains one expression and avoids looking at people most of the time. Words; +, present, -, absent. Bouts of hyperpnea ("ventilation"); +, ventila-
Table 1 Effects of bromocriptine in the cases under study Case number
1
2
3
4
5
6
7
8
9
10
11
12
13
Age (years:months) Weight (kg)
3:9 15
4:1 15
5:0 15
5:5
5:9 14
6:11 25
7:5 30
8:3 28
8:6 15
10:11 30
11:5 20
12:6 25
14:4 53
+ +
+
+
+
+
+
+ +
+ +
+ +
+
+
+
+ +
+
+
+ ++
+ +
+ +
+ +
+
+ +
+ +
+
+
+ +
+ +
+ +
A) Before treatment Sleep Facial expression Words Ventilation Teeth movements Hand activities Going up/down stairs B) After treatment Sleep Facial expression Words Ventilation Teeth movements Hand activities Going up/down stairs C) After washout Sleep Facial expression Words Ventilation Teeth movements Hand activities Going up/down stairs D) Resumption of therapy after washout Sleep Facial expression Words Ventilation Teeth movements Hand activities Going up/down stairs
+ + +
+
+ +++ + + + ++ +
+ ++ + + + ++
+ ++ + + +
+
+ ++ + + +
+ +
+ +
13
+ +
+ + + +
+
+
+ +++ + + + ++ +
+ +++ + + + + +
+ ++
+
+ +++ +
+ ++
+
+
+
+ +
+
+
+
+
+
+
+
+ +++ +
+ ++
+
+
+
+ +
+
+
+
+
+
+
+
+ +++ + + + + +
+ + +
+
+ ++ + + + +
+ ++ + + +
+
+ +
+
+ +
+ +
+ +
+
Ventilation: +, no hyperpnea; -, hyperpnea present. Teeth movements: +, normal teeth movements; -, grinding of the teeth present. Hand activities: -, continuous stereotypic hand activiteis; + (or ++ or +++), reduced stereo typic hand activities.
222 Brain & Development, Vol 12, No 2,1990
tion normal and therefore bouts of hyperpnea absent, -, present. Grinding of the teeth ("teeth movements"); +, absent, -, present. Stereotypic hands activities, scored from +++ to -; +++, stereotypic hands activities never observed, ++, intervals of half an hour or more free from them, +, intervals of 3 minutes or more free from them, -, continuously present. Going up and down stairs alone; +, present, -, absent. Before the treatment was begun the parents were advised to frequently hold their daughters in their laps in a face to face position, and to talk to them "as if they could understand": this possibility had to be considered, because the miserable, hypomimic appearance of their faces could not be assumed to signify a lack of comprehension. The girls were also told stories from picture books and heard them on cassette. It was recommended that they also listen to music. The parents were encouraged to guide their hands in possible new patterns of movement, to support them in moving around and, if possible, to get them to go up and down stairs. Every girl was assessed with the metoc1opramide test [5] before the treatment, and this assessment was repeated after two months of therapy with bromocriptine. With informed consent of the parents, an Lv. line was placed into the forearm vein at 9.00 AM after bed rest. Thirty minutes after the venipuncture, 10 mg of metoc1opramide (plasil, Lepetit) was given as a bolus, and heparinized blood samples were taken before, and then 30 and 60 minutes later. {3-Lipotropin (BLPH), {3-endorphin (BEP) and prolactin (PRL) were measured in all samples taken before and after two months of treatment. Prolactin was measured by means of a radioimmunoassay (RIA) directly in plasma samples using materials from Radim (Rome I). BLPH and BEP were extracted from 3 m1 of plasma with silicic acid, and then chromatographed on a Sephadex G-75 column (1.5 45 cm) eluted with 0.1 M acetic acid, 0.01% bovine serum albumin, in order to separate the 2 peptides, as previously reported [6]. The BLPH and BEP RIAs were performed using anti N-terminal BLPH and anti C-terminal BEP sera (CH Li, San Francisco, Ca). Highly purified BLPH from the same source and synthetic BEP (Organon, Oss, The Netherlands) were used as a standard and for labelling iodine, respectively. The details of the RIAs were reported previously [6] . 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 2.5 mg per day in two refracted doses given with the main meals for girls weighing up to 25 kg, whereas those weighing more were given 5 mg per day. The girls were given a quarter of a pill at the start, which was subsequently increased every four days to the final dosage. After six months the treatment was interrupted for a period of two months
and subsequently resumed for the same period of time. RESULTS Table 1 summarizes the main data obtained during this treatment. There are two sets of interesting data: those on single items and those on individual girls. Sleep improved in 4 cases with the bromocriptine treatment, a reversal to the previous frequent night awakenings being observed in 1 case with the washout and subsequent improvement after resumption of the treatment. The improvement in facial expression was perhaps the most positive and frequent, since it improved in 8 girls with the bromocriptine treatment, but deteriorated in 4 of them with the washout: only 2 of the latter were able to regain the previous rich facial expression when the therapy with bromocriptine was resumed. There were 4 girls who started to utter a few words [2-10] with the bromocriptine treatment, but this ability was lost in 2 of them with the washout and regained subsequently in only 1. Bouts of hyperpnea disappeared in 5 girls with the treatment, but they reappeared when the treatment was interrupted, and continued to be present in most cases on resumption of the therapy. Grinding of the teeth disappeared with the therapy in 3, and appeared again with the washout in one of them and then disappeared again on resumption of the treatment. Stereotypic hand activities were considerably reduced by the treatment in 5 cases, but the washout caused deterioration in all of them and resumption of the therapy caused minor improvement in only 2 of them. In case 1, apparently a "forme fruste" of RS, the treatment was followed by the appearance of a new ability as to the use of the hands, she successfully built a tower of three cubes. In all the other girls no improvement in the use of the hands was observed, even if they were more relaxed and less involved in stereotypic activities. Another striking effect of bromocriptine administration was improved motor ability in the lower limbs in 3 girls, who became able to go up and down stairs alone: in one of them this ability was lost with the washout and was not regained when the treatment was started again. Table 1 (Section B) presents the data obtained after two months of treatment: the data were identical after six months with the exception of those for hand activities, for which only cases 2 and 7 showed again more frequent stereotypic behaviour (scores of +). Fig 1 shows the response of BLPH and BEP in the metoc1opramide test before and after the bromocriptine treatment. The mean (± SD) basal levels of BEP (3.9 ± 2.5 fmol/rnl) and BLPH (6.2 ± 4.0 fmol/ml) were unchanged by the therapy (3.8 ± 2.1 and 4.2 ± 3.4, respectively), while the PRL basal values were significantly suppressed (1.1 ± 0.4, p
Twelve typical cases of the Rett syndrome and one forme fruste were treated with bromocriptine for six months and then had a washout for two months followed by resumption of the bromocriptine treatment. During the first bromocriptine treatment there were improvements in communication and relaxation in some of the girls: a more regular sleep pattern was observed in 4 and a more varied facial expression in 8, and 4 girls began to utter a few words. The bouts of hyperpnea disappeared in 5 and grinding of the teeth in 3. There was also a reduction in stereo typic hand activities in 5 girls and signs of improved motor abilities in 3. The washout caused a general decrease in the positive effects of the previously administered bromocriptine and resumption of the treatment with this drug led to less marked improvement. Metoc!opramide was tested in all the girls before the treatment, and it was noted that, while endorphins were hyporesponsive, prolactin was hyperresponsive. This test was repeated two months after the bromocriptine treatment had been performed and, while ~-lipotropin remained unchanged, ~-endorphin showed increased responsiveness. Key words: Rett syndrome (RS), ~-lipotropin (BLPH), ~-endorphin (BEP), prolactin (PRL). Zappella M, Genazzani A, Facchinetti F, Hayek G. Bromocriptine in the Rett syndrome. Brain Dev 1990;12:221-5
It has already been reported that bromocriptine may be
beneficial in girls affected by the Rett syndrome (RS), in that it induces more relaxation, more communication and improved locomotor abilities in some of them [1,2] . These data favour the view of the existence of an impaired central dopaminergic tone in this syndrome and are consistent with other observations, which support similar conclusions from neuropathological [3] and neurophysiological [4, 5] points of view. On the other hand, from a behavioural point of view, RS shows features of a communication disorder in which several symptoms, such as staring, social withdrawal, bouts of hyperpnea and even wringing and washing hands movements, can eventually be reduced for very short periods of time, if, for example, people relate to such cases in highly expressive ways and in a face to face position or if external requests are decreased and sources of keen interest (stories, music, etc) presented [6]. As a consequence, if a drug has an effect on these symptoms, it is possible that the latter From the Department of Child Neurology and Psychiatry, Regional Hospital, Siena (MZ, GH); Department of Gynecology and Obstetrics, University of Modena, Modena (AG, FF). Received for publication: January 6, 1989. Accepted for pUblication: October 11, 1989. Correspondence address: Dr. Michele Zappella, Department of Child Neurology and Psychiatry, Regional Hospital, USL 30, Via Mattioli 10,53100 Siena, Italy.
can be increased or diminished, according to the relational strategies which are used with these patients. A therapeutic project was therefore set up, combining the administration of bromocriptine with appropriate advice to parents as to how they could relate to their daughters in a way which could foster communication.
METHODS Subjects Thirteen cases of RS were the subjects of the present study. Their ages ranged from 3 to 14 years. They showed symptoms which agreed with the criteria established at the second Vienna conference on RS [7] with the exception of case 1, who is better defined as a forme fruste: she did not show head growth deceleration and was not clearly ataxic, and midline stereotypic hands activities were not seen as frequently as usual in this condition. Also, cases 8 and 13 did not show head growth deceleration, but otherwise presented a full clinical picture of the syndrome. Case 8 was able to utter some words, whereas all the other girls were unable to utter a single word. Cases 2 and 5 were not ambulant. Before the treatment was begun, each patient was videotaped for ten minutes with her mother and for ten minutes with a physiotherapist. In both situations she was offered standard objects (a doll, a rattle, small cubes,
etc), and encouraged to walk around and to go up and down stairs. Data regarding her status were collected both on direct observation and from her parents. The data included ones on sleep, facial expression, spoken words, bouts of hyperpnea, grinding of the teeth, stereo typic hand activities and motor abilities, such as going up and down stairs. The same evaluation and videotape assessment were repeated at the end of the treatment (after six months) and, subsequently, after a washout and after two months of further treatment with bromocriptine. No formal developmental test was given to these girls, because of the severity of their expressive and praxic handicaps. The scoring was conducted in the following way (see
Table 1): sleep, evaluated on the basis of parents' reports; +, regular, -, irregular with frequent night awakening. Facial expression, scored from +++ to -, according to patients'videotapes; +++, looks at and reacts normally to people, hugs and kisses the parents, ++, looks at people, but remains at times a little vacant, shows at least three of the following expressions, "joy," "serious intent," "surprise," "dismay," "smiling," "laughing," "rage" and "weeping," +, frequently avoids people's faces, looks only occasionally at them and shows two expressions among those listed above, -, maintains one expression and avoids looking at people most of the time. Words; +, present, -, absent. Bouts of hyperpnea ("ventilation"); +, ventila-
Table 1 Effects of bromocriptine in the cases under study Case number
1
2
3
4
5
6
7
8
9
10
11
12
13
Age (years:months) Weight (kg)
3:9 15
4:1 15
5:0 15
5:5
5:9 14
6:11 25
7:5 30
8:3 28
8:6 15
10:11 30
11:5 20
12:6 25
14:4 53
+ +
+
+
+
+
+
+ +
+ +
+ +
+
+
+
+ +
+
+
+ ++
+ +
+ +
+ +
+
+ +
+ +
+
+
+ +
+ +
+ +
A) Before treatment Sleep Facial expression Words Ventilation Teeth movements Hand activities Going up/down stairs B) After treatment Sleep Facial expression Words Ventilation Teeth movements Hand activities Going up/down stairs C) After washout Sleep Facial expression Words Ventilation Teeth movements Hand activities Going up/down stairs D) Resumption of therapy after washout Sleep Facial expression Words Ventilation Teeth movements Hand activities Going up/down stairs
+ + +
+
+ +++ + + + ++ +
+ ++ + + + ++
+ ++ + + +
+
+ ++ + + +
+ +
+ +
13
+ +
+ + + +
+
+
+ +++ + + + ++ +
+ +++ + + + + +
+ ++
+
+ +++ +
+ ++
+
+
+
+ +
+
+
+
+
+
+
+
+ +++ +
+ ++
+
+
+
+ +
+
+
+
+
+
+
+
+ +++ + + + + +
+ + +
+
+ ++ + + + +
+ ++ + + +
+
+ +
+
+ +
+ +
+ +
+
Ventilation: +, no hyperpnea; -, hyperpnea present. Teeth movements: +, normal teeth movements; -, grinding of the teeth present. Hand activities: -, continuous stereotypic hand activiteis; + (or ++ or +++), reduced stereo typic hand activities.
222 Brain & Development, Vol 12, No 2,1990
tion normal and therefore bouts of hyperpnea absent, -, present. Grinding of the teeth ("teeth movements"); +, absent, -, present. Stereotypic hands activities, scored from +++ to -; +++, stereotypic hands activities never observed, ++, intervals of half an hour or more free from them, +, intervals of 3 minutes or more free from them, -, continuously present. Going up and down stairs alone; +, present, -, absent. Before the treatment was begun the parents were advised to frequently hold their daughters in their laps in a face to face position, and to talk to them "as if they could understand": this possibility had to be considered, because the miserable, hypomimic appearance of their faces could not be assumed to signify a lack of comprehension. The girls were also told stories from picture books and heard them on cassette. It was recommended that they also listen to music. The parents were encouraged to guide their hands in possible new patterns of movement, to support them in moving around and, if possible, to get them to go up and down stairs. Every girl was assessed with the metoc1opramide test [5] before the treatment, and this assessment was repeated after two months of therapy with bromocriptine. With informed consent of the parents, an Lv. line was placed into the forearm vein at 9.00 AM after bed rest. Thirty minutes after the venipuncture, 10 mg of metoc1opramide (plasil, Lepetit) was given as a bolus, and heparinized blood samples were taken before, and then 30 and 60 minutes later. {3-Lipotropin (BLPH), {3-endorphin (BEP) and prolactin (PRL) were measured in all samples taken before and after two months of treatment. Prolactin was measured by means of a radioimmunoassay (RIA) directly in plasma samples using materials from Radim (Rome I). BLPH and BEP were extracted from 3 m1 of plasma with silicic acid, and then chromatographed on a Sephadex G-75 column (1.5 45 cm) eluted with 0.1 M acetic acid, 0.01% bovine serum albumin, in order to separate the 2 peptides, as previously reported [6]. The BLPH and BEP RIAs were performed using anti N-terminal BLPH and anti C-terminal BEP sera (CH Li, San Francisco, Ca). Highly purified BLPH from the same source and synthetic BEP (Organon, Oss, The Netherlands) were used as a standard and for labelling iodine, respectively. The details of the RIAs were reported previously [6] . 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 2.5 mg per day in two refracted doses given with the main meals for girls weighing up to 25 kg, whereas those weighing more were given 5 mg per day. The girls were given a quarter of a pill at the start, which was subsequently increased every four days to the final dosage. After six months the treatment was interrupted for a period of two months
and subsequently resumed for the same period of time. RESULTS Table 1 summarizes the main data obtained during this treatment. There are two sets of interesting data: those on single items and those on individual girls. Sleep improved in 4 cases with the bromocriptine treatment, a reversal to the previous frequent night awakenings being observed in 1 case with the washout and subsequent improvement after resumption of the treatment. The improvement in facial expression was perhaps the most positive and frequent, since it improved in 8 girls with the bromocriptine treatment, but deteriorated in 4 of them with the washout: only 2 of the latter were able to regain the previous rich facial expression when the therapy with bromocriptine was resumed. There were 4 girls who started to utter a few words [2-10] with the bromocriptine treatment, but this ability was lost in 2 of them with the washout and regained subsequently in only 1. Bouts of hyperpnea disappeared in 5 girls with the treatment, but they reappeared when the treatment was interrupted, and continued to be present in most cases on resumption of the therapy. Grinding of the teeth disappeared with the therapy in 3, and appeared again with the washout in one of them and then disappeared again on resumption of the treatment. Stereotypic hand activities were considerably reduced by the treatment in 5 cases, but the washout caused deterioration in all of them and resumption of the therapy caused minor improvement in only 2 of them. In case 1, apparently a "forme fruste" of RS, the treatment was followed by the appearance of a new ability as to the use of the hands, she successfully built a tower of three cubes. In all the other girls no improvement in the use of the hands was observed, even if they were more relaxed and less involved in stereotypic activities. Another striking effect of bromocriptine administration was improved motor ability in the lower limbs in 3 girls, who became able to go up and down stairs alone: in one of them this ability was lost with the washout and was not regained when the treatment was started again. Table 1 (Section B) presents the data obtained after two months of treatment: the data were identical after six months with the exception of those for hand activities, for which only cases 2 and 7 showed again more frequent stereotypic behaviour (scores of +). Fig 1 shows the response of BLPH and BEP in the metoc1opramide test before and after the bromocriptine treatment. The mean (± SD) basal levels of BEP (3.9 ± 2.5 fmol/rnl) and BLPH (6.2 ± 4.0 fmol/ml) were unchanged by the therapy (3.8 ± 2.1 and 4.2 ± 3.4, respectively), while the PRL basal values were significantly suppressed (1.1 ± 0.4, p
![[Molecular mechanism in Rett syndrome].](/assets/img/hold.png)
