The Green Leaflet - Selected Articles
UPDATE ON TOURETTE SYNDROME RESEARCH
By: Paul Sandor, M.D., F.R.C.P. (C)
It is heartening that every year a larger number of scientific articles appear in various journals regarding different aspects of Tourette Syndrome and related disorders. The task of reviewing the progress of research in the area of Tourette Syndrome, however, becomes more difficult by the year. I will attempt to provide you with an overview of progress in imaging, genetics and pharmacotherapy,
Using Magnetic Resonance Imaging (MRI) technique which produces very detailed pictures of various brain structures, two groups have recently shown that several structures located deep in the middle of the brain (caudate, putamen) were smaller in patients with Tourette Syndrome compared to controls. In addition, these brain structures were larger on the left side as compared to the right in the controls but in Tourette Syndrome patients, this expected lack of symmetry was not present. These observations were made in a group of adults by Dr. Peterson et al. at Yale and in children by Drs. Singer et al. from Johns Hopkins University. This report, for the first time, documented a measurable anatomical difference between individuals with Tourette Syndrome and those without the condition. Unfortunately, the method works well only in a group of subjects, it cannot be yet applied for diagnostic purposes to any one individual. One possible explanation for these observations may be that there are subtle abnormalities in the process of brain development and maturation. Depending on the extent of this developmental abnormality, the Tourette Syndrome may be more or less severe and indeed may or may not be associated with one or several or the other associated disorders.
Consistent with the observations about the structure of the brain, there are now reports of Positron Emission Tomography (PET) and Single Phototon Emission Computerized Tomography (SPECT) techniques applied to patients with Tourette Syndrome. These techniques examine the brain activity as reflected in the volume of blood flow in different parts of the brain. Consistent with the previous structural studies, the blood flow to the caudate on the left side appears to be decreased compared to the right side. This is different from the controls where the blood flow is essentially equal on both sides of the brain. The PET study by Dr. Braun et al. from National Institute of Mental Health (NIMH) and SPECT study by Dr. Moriarity et al. from Queen Square, London support our understanding of Tourette Syndrome as a biologically determined condition with a genetic factor disturbing the normal development of the brain which then leads to various behavioural disturbances. It has been long accepted that understanding of Tourette Syndrome must involve understanding how the dopamine system is disturbed. Another type of SPECT imaging study by Dr. Malison et al. from Yale suggests that the dopamine system in Tourette patients is over-active. This is, of course, consistent with the observation that medications which block dopamine effects, such as Haloperidol® and Pimozide®, generally produce reduction in symptoms in patients with Tourette Syndrome.
It is now estimated that the Tourette Syndrome gene predisposing to the condition may be present in one out of every 200 people in the general population. This makes it a very common problem. Fortunately, the symptoms tend to be mild in the large majority of those who have the gene. Nevertheless, one of the most direct ways of trying to understand the disorder and finding better treatment for it may come from detecting the Tourette Syndrome gene or genes. Finding such a gene would probably lead to development of a blood test which would allow determining who does and who does not have Tourette Syndrome. In the long run, understanding the genetic basis of Tourette Syndrome would allow us to develop more direct and more effective methods of treatment. The genetic consortium supported by Tourette Syndrome Foundation of Canada (TSFC) and Tourette Syndrome Association (TSA) has attempted a search for the TS gene which used large families with many members who had Tourette Syndrome. This study has now excluded more than 90% of the DNA as a possible site for the TS gene. The failure to find the gene so far may be due to the fact that it may be hiding in the remaining few percent of the DNA which has not yet been examined. There could be other reasons for lack of success so far. It is possible that abnormality in any one of several major genes may all lead to Tourette Syndrome. On the other hand, it is possible that simultaneous disturbance in several different minor genes is required to produce Tourette Syndrome as suggested by Dr. Comings.
Paradoxically, the genetic studies on twins with Tourette Syndrome provide the evidence that there may be important environmental factors which interact with the genetic predisposition to produce Tourette Syndrome. In order to overcome many of these factors, a new approach was developed for identifying the TS gene. This is based on collecting several hundred small families with at least two siblings, each of whom have Tourette Syndrome. The Tourette Syndrome genetic consortium is now in the process of collecting such families both in North America and Europe. Once the clinical information and the blood for the DNA have been collected, the analysis using several hundred available genetic markers will proceed.
Recently Grice and colleagues from Yale published a report suggesting that a particular form of subtype of dopamine receptor (D4) may be associated with the presence of Tourette Syndrome. This is in contrast with other published papers which seemingly excluded the involvement of D4. Obviously further work will be required to clarify whether D4 abnormalities may be responsible for at least some of the cases of Tourette Syndrome. Another interesting development is a case report by Boghosian-Se11 and colleagues (City of Hope) who found a family in which the presence of tics in various members of the family is associated with a chromosomal abnormality (translocation). In the near future, we can look forward to further information examining this region of the DNA in other TS families.
For many years, the mainstay of treatment for patients with Tourette Syndrome included Clonidine®, Haloperidol®; and Pimozide®;. Although dopamine receptor blockers Haloperidol® and Pimaride® can be very helpful in many patients, they are sometimes associated with adverse effects. There are anectodal reports that Risperidone® is effective in treating symptoms of Tourette Syndrome and less likely to produce some of the adverse effects such as restlessness and tremors. We can look forward next year to the results of a study conducted by Drs. Dion and Chouinard which will provide much needed information about the effectiveness and adverse effects of this promising new treatment in patients with Tourette Syndrome. Risperidone® differs from Haloperidol® and Pimozide® in that it not only blocks dopamine receptors but also Type B serotonin receptors. One possible adverse effect that one ought to be aware of is that in some individuals, the serotonin blockade may increase the intensity of obsessive-compulsive symptoms.
A substantial number of patients with Tourette Syndrome also have Obsessive-Compulsive Disorder (OCD). The symptoms of OCD generally improve with serotonin re--uptake inhibitors (SSRI's). However, there have been case reports of patients in whom such medications made the tics worse.
Clonidine® has been known to be helpful in about one-third of the patients with Tourette Syndrome. Dr. Comings reported very good results with the Clonidine® patch (not yet available in Canada), however, this work has not been reproduced by other groups to date. Recently a report appeared of another agent, Guanafacine®, which has a very similar mechanism of action, e.g., it stimulates the alpha-2-adernergic receptors just like Clonidine®. An uncontrolled study in ten children with Tourette Syndrome and Attention Deficit Hyperactivity Disorder (ADHD) was reported as helpful and reasonably well tolerated by Hunt et al. They did note, however, sedation, fatigue, headaches and dizziness among some of their subjects. These are similar to adverse effects noted with Clonidine®. In any case, these are very preliminary results and it is unclear whether this agent has anything more to offer than Clonidine® or stimulants in the management of comorbid ADHD and TS.
The use of stimulants in patients with Tourette Syndrome remains somewhat controversial. Although there have been several reports in earlier literature that stimulants tend to increase the frequency and intensity of tics in children with Tourette Syndrome, more recent evidence suggests that this may be the case in only 25% of those tested. Interestingly, Gadow et al. reported last year the results of a placebo controlled Ritalin® study in 34 children with ADHD and TS. In this group, Ritalin® was effective in suppressing the symptoms of ADHD and it had minimal effect on the severity of the tic disorder. Although there was a slight increase in the frequency of motor tics, there was in fact a decrease in vocal tics during treatment with Ritalin®. This study accords with the current experience that for many children with Tourette Syndrome, treatment with stimulants can be both safe and effective.
Tourette Syndrome is a complex disorder which is biologically determined but modulated by psychological and social factors. For the minority of Tourette Syndrome patients who require intervention, an individually tailored management combining medications, psychological and behavioural measures as well as adjustments in their school or work environment may be required to produce the best results. The rapidly accumulating knowledge produced by the explosion of research interest in this area will allow us to provide increasingly more effective and successful treatment for patients with Tourette Syndrome.