Tourette Syndrome: Lessons from a Model

Neal R. Swerdlow
1999 CNS Spectrums  
guest editor Biological models allow investigators to extrapolate from simple to complex systems, to generate and test hypotheses, and to grasp schema that are within range of our intellect, as we reach to conceptualize things beyond this range. Tourette Syndrome (TS) is a model neuropsychiatric disorder 12 that seems tantalizing in its simplicity. The genetic basis is stronger than any common neuropsychiatric disorder other than Huntington's disease. The age of onset and sex distribution of TS
more » ... are strong clues that neurodevelopmental and hormonal processes are causative in TS. Emerging evidence suggests a role of epigenetic factors, such as hypoxia, or environmental factors, such as Group A Streptococcal infections, 3 in the etiology of at least some cases of TS, again making TS an ideal model for nature/nurture interactions in the pathogenesis of brain disorders. The clinical presentation and responsivity to dopamine antagonists provide strong clues that the critical substrates of TS fall within the basal ganglia-a system implicated in an increasing number of neuropsychiatric disorders, and perhaps the one most studied and best understood in the neuropsychiatric literature. The familial and phenomenologic links to obsessive-compulsive disorder (OCD) have led many to conceptualize tics in TS as "movement-equivalents" of obsessions and compulsions, and the apparent connections with OCD and attention-deficit/hyperactivity disorder (ADHD) raise hope that by solving the TS model, we will understand a family of disorders that collectively affects close to 10% of the population. By all accounts, the TS model should be readily solvable, like a practice question before the really tough questions on an exam. Phrases like "imminent" and "forthcoming" are frequently found in editorials and epilogues to describe the timetable for solving this model. However, while these two issues of CNS Spectrums are testimony to the fact that we have made great strides, you will find no definitive answer here. And the reason that we have no answer yet is that TS is a very complex disorder. It is not Huntington's disease, and it is almost certainly not transmitted via simple autosomal dominant inheritance. Environmental influences relevant to some TS-like conditions (eg, PANDAS 3 ) may not be relevant to more common forms of TS. Evidence for a primary dopaminergic pathology in TS is slim, and no replicated findings support a simple basal ganglia lesion in this disorder. Neuroimaging studies reveal more differences than similarities between patterns of regional brain metabolism in TS and OCD. The argument, therefore, that TS is a simple part of the obsessive-compulsive spectrum, cousin to compulsive gambling, shopping, and body building, becomes less convincing under the light of data. So, what are we learning from the TS model? First, we are learning that simple assumptions do not always apply to complex conditions. For example, the simplest assumption that TS is a tic disorder promotes further assumptions about brain mechanisms and about associations with other disorders and treatments. But as individuals with TS can tell you-and two superbly enlightening personal accounts can be found in the self-assessment reports by Bliss 4 and Hollenbeck 5 -TS is not just a disorder of tics: it is a disorder of sensations, and it has an internal life invisible to the external world. Information of this type from individuals with TS prompted the landmark descriptions by Cohen and Leckman 6 of the unseen TS, of premonitory urges and relentless building pressures. And yet, the undoing of this one assumption-that TS is just a tic disorderand the implications of this new information, are only slowly being integrated into the neurobiological models of this disorder. Second, we are learning that complex neuropsychiatric disorders must be studied via seamless integration across and within disciplines. Perhaps the most fascinating sociological model generated by this disorder exists at the interface of medical and scientific specialties. Psychiatrists and neurologists grapple for a common nosology, for uniform diagnostic criteria, and more fundamentally, with the true definition of a "disorder." Neurobiologists, comfortable with formalin, lab benches, and pipettes, struggle to become discerning consumers of the clinical literature, lest they formulate and test scientific hypotheses-spending years and countless precious dollars-based on clinical dogma that crumbles when critically probed. Geneticists, experts in statistical models and the intricacies of allele sorting, run head-on into an elusive and often uncertain clinical phenotype, expressed differently across and within families, across diagnosticians, across continents and cultures. The search for a TS cure has made us all much smarter-clinicians and basic scientists Dr. Swerdlow is associate professor in the
doi:10.1017/s1092852900000778 fatcat:bjddh2socjhsdofvybd2wvhuga