Sleep Problems in Individuals with Angelman Syndrome
Presentations at the 1st World Conference IASO - Tampere, Finland, 4-8 July, 2000
Presented by: By Joseph Wagstaff University of Virginia School of Medicine, Charlottesville, VA, USA
Note: For more details and related figures, see: Irina V. Zhdanova, Richard J. Wurtman, Joseph Wagstaff: Effects of a Low Dose of Melatonin on Sleep in Children with Angelman Syndrome. Journal of Pediatric Endocrinology and Metabolism, 1999 Jan-Feb, 12(1):57-67. http://chem-faculty.ucsd.edu/harvey/wagstaffsleep
Thank you very much for inviting me to talk about sleep problems in Angelman syndrome. I should tell you from the outset that I am primarily a geneticist. I began to work on sleep problems in Angelman syndrome because many of the families with Angelman children in the area around Boston began telling me about melatonin in 1995, saying how much better their children were sleeping since they were taking Melatonin than they had before. At that timeI did not even remember what melatonin was from medical school so I began to educate myself a little bit about melatonin. We then did a study at Boston Children's Hospital several years ago.
Today I am going to summarize work from other people about sleep problems in Angelman syndrome, then give a brief summary of the study that we did at Boston Children's Hospital. I think that we should have a lot of time for questions and answers and exchange between you and me and also exchange between different people in the audience.
I think that this is a very difficult problem for Angelman individuals themselves and for their families. There really is no clear, good answer for the problem that is applicable for every Angelman person at all times of their lives, but this is really an important problem and something that I would hope that other people would begin to do more research on. Dr. Saitoh gave a report yesterday of his research in Japan on the use of Melatonin in Angelman syndrome and I would hope that even more people would begin to work on Melatonin and other ways of coping with the sleep problems in Angelman syndrome.
Sleep disturbances affect the great majority of Angelman individuals at some time during their lives. Jill Clayton -Smith in a clinical review of Angelman syndrome in 1993 reported that approximately 90 per cent of Angelman individuals in her study had sleep disturbance at some point in their lives. The sleep disturbance was usually worst between two years of age and six years of age.
Ellie Smith and collaborators in 1996 reported that 86 per cent of deletion Angelman individuals had sleep disturbance with the typical pattern being sleep limited to a two to three hour period with several two to three hour periods at night. Nine out of the twelve patients that they reported at that time showed an improvement in their sleep problems at six to eight years of age. There have been only a small number reports of treatment in AS of sleep disturbances. First, before going into one of those reports, just a few words about sleep and epilepsy. There is an observation that the onset of the sleep disorder in AS usually between two and three years of age sometimes appears to coincide with the onset of clinical seizures. The reason for this relationship between the onset of seizures and the onset of the sleep disorder is not clear. One possibility is that epileptic discharges may prevent the normal transition between sleep stages that is required for a normal night's sleep. It's also known that sleep deprivation can increase the occurrence of abnormal epileptiform changes in an awake EEG. It definitely appears that a period of sleep deprivation can lead to a worsening of seizures in individuals with AS.
The first treatment report of the sleep problem in AS was a behavioral-pharmacological protocol reported by Summers et al in 1992. Their program for improving the sleep of an Angelman individual included not allowing sleep during the daytime, providing no fluids by mouth after 7.30 pm, giving diphenhydramine (Benadryl) half a milligram per kilogram one hour before bedtime, and regularity in time of putting the child to bed each night. In this study during a short period of follow-up they found that sleep improved from 3.2 hours per day at the baseline to 7.1 hours a day after going through this for a period of several weeks. As I said, however, there is no long-term follow up of the sleep in this child, and there are many anecdotal reports of diphenhydramine effect wearing off after a very short period of time in AS children as well as in other individuals.
As I said earlier, interest in the Angelman community and my own personal interest in Melatonin started around 1995. First, what is Melatonin? It's a substance produced by the pineal gland within the brain, its chemical name is N-acetyl-5-methoxytryptamine and it is produced from the neurotransmitter Serotonin. In humans it affects circadian rhythms which is why many of us have used it to deal with the jet lag that has accompanied getting to Finland, and it also affects sleep. This is the chemical structure of Melatonin (Slide). It binds to proteins that are in the membranes of brain cells called melatonin receptors and binding the melatonin to these receptors leads to a number of effects. The melatonin cycling is responsible for the seasonality of reproduction in other species that only reproduce during certain times of the year. It is responsible for the daily or circadian rhythms that we all undergo. There are other effects of melatonin on physiology of the retina. Melatonin also has what are called hypnotic effects that are independent of its effects on the circadian rhythm. Hypnotic effect is a medical term meaning the effect causing someone to feel sleepy, and melatonin, even in very low doses, produces feelings of sleepiness in individuals.
So the study that I did, which was in collaboration with Drs. Zhdanova and Wurtman at the Massachusetts Institute of Technology, involved 13 patients between the ages of two and ten. Twelve of these had chromosome 15 deletion and one had paternal UPD 15. 9 were female, 4 were male, and they included one pair of identical twins with Angelman deletion. All had seizure disorder, and they were on a variety of medications including Valproate, Clonopin, Tranxene, Neurontin, and Mebaral. The basic structure of the study was that the children underwent a period where their baseline sleep behavior was observed and this was measured using a device called an actigraph that measures the number of movements per minute as a kind of indicator of activity, inactivity, sleep and awake states.
We also measured the body's own production of melatonin by sampling blood every hour determining the concentration of melatonin in the blood. As you can see (Slide), this is a normal melatonin curve in an AS child. This child had very close to zero levels of melatonin until approximately 8 in the evening, 20:00 hours, then the melatonin level began to rise slowly reaching the peak of approximately 60 picograms per milliliter at 1 AM, decreasing back down to a base line level by 7 or 8 am the next morning. So this is the normal pattern and actually the peak level of melatonin when he was not taking Melatonin was within the range of the general population for children of this age. This is a recording of his activity during a 4-day period: one 24-hour period, the next 24-hour period, so forth. These go from 7.30 pm, 19:30 hours, at this tick mark to 19:30 hours 24 hours later. And as you can see there's high level of activity around the clock 24 hours per day with no indication of long pauses that would correspond to sleep in the pre-melatonin situation. After doing these baseline measurements we then gave the child 0.3 mg of melatonin at 7.30 pm, or 19:30 hours. The new blood levels of melatonin with the additional melatonin raised his levels to approximately 160 picograms per ml. at 11 pm which then again came down and joined the normal curve about 3 am, and came down to a normal base line. The same patient taking the 0.3 mg of Melatonin now had a very different activity/rest-pattern with a long period of approximately 8 hours with almost no movements recorded, then normal movements during the daytime hours, again a period with no movements, then normal movements during the daytime hours and so forth for four 24-hour periods.
We saw similar results to these in twelve out the thirteen children who were involved in the study with increases in their blood melatonin levels and also significant decreases in their nighttime movement when they were taking the melatonin. One out of the thirteen did not show any increase in the blood melatonin levels taking the 0.3 mg of melatonin, and also did not show any improvement in the sleep/wake pattern. One aspect of the study that I should mention is that because we were doing this extensive blood sampling in association with measuring the activity levels this was an open study without a placebo control. All of the children within the study received the 0.3 mg of Melatonin, and I think we naively felt that children with AS would probably not be very susceptible to a placebo effect. However, I think that there have been studies in other children with developmental disorders since that time, with significant placebo effects even in children with developmental impairments. These may be due to effects on the child's perceptions of what's going on, or to effects on the parents' perception of what's going on, or other care takers, but I think studies of this sort in the future should probably include also a placebo control group and investigators should be blinded to the group that patients fall into. This is the plan for the proposed study of folic acid and betaine, discussed by Dr. Beaudet. This is a summary of the effects of 0.3 mg of melatonin on the body movements during the expected sleep period which was eight hours after the administration of melatonin. At the base line the value was over 100 and with 0.3 mg the amount of movement during the expected sleep period was reduced very, very dramatically which coincided with parental perceptions that these children were sleeping much better.
All of these are data that I have shown previously. Dr.. Saitoh's work presented yesterday provides some extension of this I think that many children with AS now are taking Melatonin and are sleeping better. As I said earlier, we still do not have a clear idea of why it's working, but I think that it clearly does have benefit for some individuals with AS in improving their sleep, and also in improving their daytime attentiveness and behavior.
That's all I have to say right now. Thank you very much.
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