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  • Study: Relationships Between TS and Other Disorders

    ScienceDirect
    Tourette's Syndrome

    Current Biology, Volume 16, Issue 12, Pages R443-R444
    G. Jackson


    The Relationship Between Tourette Syndrome, Attention Deficit Hyperactivity Disorder, and Stimulant Medication: A Critical Review

    Gerald Erenberg MD, a,

    Department of Neurology, Section of Child Neurology, Cleveland Clinic Foundation, Cleveland, OH.

    Available online 10 June 2006.

    The relationship between tic disorders and attention deficit hyperactivity disorder (ADHD) is of great clinical importance because both disorders can lead to emotional, social, and academic difficulties. To further complicate this interrelationship is the concern that the use of psychostimulant medication to treat ADHD will help the hyperactivity and attention problems but will lead to the onset of tics or will worsen preexisting tics. The first part of this review investigates how often Tourette syndrome (TS) is associated with ADHD and finds that ADHD has been reported in 35% to 90% of children with TS. The second part of the review looks at whether the ADHD seen in TS is the same as in children who do not have tics. Recent studies lead to the conclusion that the ADHD seen in TS is the same, although the attentional difficulties seen in TS are influenced also by the distraction of the tics themselves as well as by internal distractions such as is seen in comorbid anxiety or obsessive-compulsive behavior. The final part of the review investigates the question of whether psychostimulants worsen or cause tics. Twenty-two studies were found that investigated this possible relationship. Earlier studies were confounded by the natural pattern seen in TS in which tics spontaneously wax and wane in occurrence, intensity, and frequency. More recent double-blind, placebo-controlled studies have shown that psychostimulants are equally effective in improving ADHD symptoms whether the disorder is associated with tics or not. When group data are analyzed, there is no significant increase in tics when psychostimulants are used in patients with tics compared with controls. Individual patients, however, may experience an increase in tics. This increase is not appreciated in analysis of group data. In conclusion, it is medically appropriate to provide treatment with psychostimulant medication in persons with tics where the ADHD symptoms are significantly disturbing their quality of life.

    The disorder that now carries his name was first described in 1885. In this first report, Tourette described the obsessive compulsive problems seen in persons with tics, but he did not describe the symptoms of attention deficit hyperactive disorder (ADHD) as being one of the associated features. The reports that followed initially focused entirely on the presence of tics. Tourette syndrome (TS) was thought to be a rare disorder until the 1980s. In 1965, Kelman1 summarized the 44 cases that were then in the world literature, and hyperkinesis was mentioned in 4 of them. A review of 29 patients reported by Sweet and associates2 in 1973 reported that 2 of their 29 TS patients had minimal cerebral dysfunction, an earlier name for ADHD. And, in 1977, Golden3 reported 15 children with TS and found school problems in 11 and hyperactivity in 5.

    All studies since 1980 have found a high incidence of ADHD in children with Tourette syndrome. The incidence is highest in clinic-referred populations and has ranged from 35% to 90%. The occurrence of ADHD in nonreferred TS patients is still uncertain. A population-based study from Sweden was published in 2000. A birth cohort born in 1985 was reevaluated at 11 years of age. Five of the 435 children were found to have TS via screening, and 1 of these 5 had ADHD.


    Is the ADHD Seen in TS the Same as the ADHD Seen in Children Who Do Not Have Tics?

    There have been an increasing number of studies that have looked at the relationship between ADHD and TS. Before 1995, however, the studies that compared children with TS with those with ADHD did not divide the TS patients into 2 groups (ie, those with TS and ADHD and those with TS and no ADHD). A report from Yale published in 1982 compared perceptual, motor, and neuromaturational competence in 4 groups: TS, ADD only, ADD and epilepsy, and controls. The TS group differed only slightly from controls, and the ADD-only and the ADD-and-epilepsy groups did much worse. Silverstein and colleagues studied adults comparing attentional ability in 3 groups: TS, ADHD, and controls. The worst performance on attentional tasks was seen in the TS group with active tics and/or obsessive compulsive symptoms.

    Harris and coworkers16 compared executive function (EF) in 3 groups: TS only (ADHD now selected out), ADHD only, and TS + ADHD. EF was significantly worse in the TS + ADHD group than in the TS-only group, and EF was worse in the ADHD-only group compared with the TS-only group. A study from Johns Hopkins published in 1996 compared 3 groups of TS patients: TS only, TS + ADHD, and TS + possible ADHD. Learning disabilities were present in 23% of the total sample but were not present in any of the TS-only group.

    Spencer and associates compared 5 groups: TS only, TS + ADHD, ADHD only, psychiatric referrals, and controls. Obsessive-compulsive disorder (OCD) and phobias were seen in the TS groups, but other behavioral disorders occurred equally in the TS-only and the ADHD-only groups. The worst overall psychosocial outcome was seen in the TS + ADHD group. A study from UCLA compared 4 groups: TS only, TS + ADHD, ADHD only, and controls. Impairment in sustained attention was found in the TS + ADHD and the ADHD-only groups but not in the TS-only group.

    Other studies have looked at the relationship of tics, ADHD, and other possible comorbid features of TS such as aggressive behavior, rage attacks, OCD, anxiety, oppositional behavior, conduct problems, and social functioning. Pierre and coworkers compared ADHD only and ADHD with mild tics and found no differences. But those with ADHD and more severe tics had higher rates of anxiety as well as aggressive and oppositional behaviors.

    Budman and associates studied 12 children presenting with TS and rage. All had comorbid ADHD and OCD but only mild tics. They concluded that rage is based on comorbid conditions and not TS. Stephens and Sandor studied aggressive behavior in 3 groups: TS only, TS + ADHD, and controls. Aggressive behavior and conduct disorder was seen more frequently in the TS patients with comorbid ADHD or OCD, but the TS-only group was no different than the control group.

    Three groups were compared in a study by Carter and coworkers: TS only, TS + ADHD, and controls. Tic severity was not associated with social, behavioral, or emotional functioning. The TS + ADHD group showed more externalizing and internalizing behavior problems as well as poorer social adaptation. The TS-only group was the same as the control group except for a higher level of internalizing symptoms.

    Finally, a study published in 2003 by Sukhodolsky and associates compared 207 patients divided into 4 groups. The TS-only and the control groups had the same incidence of problems with aggression, delinquent behavior, and conduct problems. The incidence was much higher in the TS + ADHD group and was at the same level seen in the ADHD-only groups.

    In conclusion, it appears that the ADHD seen in TS is the same as the ADHD seen in persons who do not have TS. But in those with TS, their ability to maintain attention is influenced by factors beyond those seen in persons with only ADHD. These include distraction from the tics themselves, distraction from attempts being made to inhibit the tics, and internal distractions from anxiety and obsessive compulsive traits. TS only, with no comorbid emotional difficulties, is not associated with a higher incidence of behavior problems. And tic severity is not directly linked to the occurrence of behavior problems except as a direct reaction to the social and emotional burden of the tics themselves. ADHD, when present as a comorbid condition, is what contributes the most to the increased incidence of school problems, social difficulties, rage attacks, and presence of other emotional disorders.


    Do Psychostimulants Worsen Tic Disorders?

    There is now general agreement that the symptoms of ADHD are present before the appearance of tics in persons with TS and associated ADHD. There is also much evidence that psychostimulants improve the symptoms of ADHD equally well in persons with ADHD whether these symptoms appear in isolation or as part of the TS complex. For several decades, however, there has been debate as to whether the psychostimulants can lead to tics in those who would not otherwise experience them or whether they can lead to an increase in tics in persons in whom the tics are preexistent.

    After the report of a single case by Golden in 1974, there were several reports of individual cases or small series of children who experienced the onset of tics or a worsening of tics at some time after psychostimulants were started. Such occurrences were reported with methylphenidate (MPH), dextroamphetamine, and pemoline. In 1983, an influential report by Lowe and coworkers described 15 children who developed tics while on psychostimulants. Around that time and apparently based on that report, the Food and Drug Administration required the Physicians Desk Reference to begin listing contraindications to the use of psychostimulants. They were not to be used in persons with tics or who had a first-degree relative with tics. They were also to be discontinued in any person who developed tics while receiving a psychostimulant.

    A review of the literature from 1977 to 2003 found 22 studies that attempted to answer the question of what is the relationship between tics and psychostimulants. Eight of them were retrospective studies. In general, the earlier studies were all retrospective and usually based on chart review of clinic referred patients.

    In 5 chart review studies, an increase in tics was reported in 16% to 100% of patients with preexisting tics after being treated with psychostimulants. Prospective studies, 0% to 80% had an increase in tics (0% increase was reported in 5 of the 14 studies). In these studies, some patients reported a decrease in tics, some had an increase in tics at lower but not higher doses, and some had an increase only at higher doses.

    Ten studies are important enough to warrant individual reporting. The first was a 1985 study by Price and associates. In this study, 6 pairs of monozygotic twins with TS were identified. Only 1 of each twin set had been exposed to psychostimulants, but each twin eventually was diagnosed with TS. In the same year, Erenberg and his associates reviewed the charts of 200 consecutive children with TS, of whom 48 had been exposed to psychostimulants. Nine of the 48 had been exposed before the start of their tics, but only 4 of the 9 were still on psychostimulants when their tics developed. In the 39 with preexisting tics, the tics increased in 11, decreased in 2, and were unchanged in 22.

    Gadow and Sverd published prospective, acute, and long-term studies in 1989, 1995, and 1999. The first study only had 4 subjects, all with TS + ADHD and all treated with MPH at various dosages or with a placebo. Three of the 4 experienced increased tics at lower but not higher doses. The second study enrolled 34 children and found no increase in tics over 6 weeks when compared with placebo. The last study was a 2-year follow-up study of the same 34 children. Group data showed no increase in tics severity or frequency compared with their tic activity while on placebo in the initial study.

    Three studies followed children with or without ADHD but without tics. A retrospective study of 124 children treated with psychostimulants for treatment of ADHD and followed for 2 years showed that 11 of the group (9%) had developed tics. The tics developed in 1 of the 11 in less than 1 week. They started in 1 to 6 months in 3 patients, in 6 to 12 months in 2, and after 12 months in 4. A second study reevaluated 2 groups 4 years after they had first been enrolled. Tics had developed in 34% of the 128 children with ADHD, and the rate of onset of tics did not differ by the presence or absence of exposure to psychostimulants. In comparison, only 6% of a control group had developed tics over the same 4 years. The third study prospectively followed 91 children with ADHD with or without tics. The treated group was given low-dose MPH. Analysis showed that MPH did not lead to more tics than placebo in both those with and without tics (ie, the treated group and the placebo group had equal numbers of those who developed tics or who had worsening of preexisting tics).

    A prospective, double-blind placebo-controlled study was reported from the National Institutes of Health by Castellanos and coworkers. Twenty children participated and received MPH, dextroamphetamine, or placebo in a crossover design. Tics increased in 3 of the 20 while on all doses of both medications. Overall, tics were the same when on MPH as when on placebo but were increased when on dextroamphetamine. Thirteen subjects went on to a 6- to 36-month open label follow-up study. Three of the 13 dropped out because of increased tics. Six of the other 8 were on MPH and experienced a decrease in tics while on treatment compared with baseline, but 4 of the 5 on dextroamphetamine had more tics than at baseline.

    Perhaps the most important study was the one performed by the Tourette Syndrome Study Group and published in 2002. This National Institute of Health?funded multicenter study enrolled 136 children who were divided into 4 treatment groups: MPH alone, clonidine alone, MPH + clonidine, and placebo. At the end of 16 weeks, there was no difference in the percentage of children who had experienced an increase in tics. No matter which treatment group they were in, 20% to 26% of the study subjects had experienced an increase in tics during the time of the study.

    In conclusion, psychostimulants are useful in treating ADHD whether it is associated with TS or not. This benefit does not diminish with length of treatment. Interpretation of studies about the role of psychostimulants and tics is difficult because the ADHD is present before the onset of tics and treatment may have begun before the full natural history of the disorder was obvious. In addition, the frequency and severity of tics will naturally fluctuate independent of external influences such as the administration of medication.

    The studies reported previously indicate that, when analyzing group data, the use of psychostimulants do not lead to a significant increase in the causation of tics or to an increase in tics in those where tics preexist. Some studies do show, however, that there may be individual patients who experience an increase in tics when treated with psychostimulants. As a guide, it would appear appropriate to consider a possible cause-and-effect relationship in any patient who experiences an increase in tics within 4 weeks of starting therapy. The optimal approach would be to discontinue the psychostimulant and rechallenge the patient at a future time. When tics are caused by medication, it is not known how long it will take for the tics to return to baseline after the treatment is stopped. There are also no studies that have investigated whether antitic medications have the same effect on tics that may be caused by medication compared with tics unrelated to their use.


    Summary

    ADHD is a frequent comorbidity in persons with TS. Studies have now shown that many of the behavioral disturbances seen in TS are actually caused by the ADHD and not the TS itself. When the ADHD symptoms have a significantly negative effect on the child?s quality of life, it is medically appropriate to consider a trial of treatment with psychostimulant medication. The ADHD symptoms respond equally well in children with ADHD whether or not the disorder is associated with TS. For the vast majority of TS patients, the psychostimulants do not lead to an increase in tics beyond that seen caused by the natural variability of the disorder.

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