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Thus, a young woman describes her ex-boyfriend who had Tourette syndrome (TS), the impact of which caused their breakup. TS affects approximately 1 in 100 Americans and is marked by a fluctuating course of multiple motor and phonic tics, which can have devastating social, physical, and psychological consequences for the patient.
Thus, a young woman describes her ex-boyfriend who had Tourette syndrome (TS), the impact of which caused their breakup. TS affects approximately 1 in 100 Americans and is marked by a fluctuating course of multiple motor and phonic tics,1,2 which can have devastating social, physical, and psychological consequences for the patient.
TS commonly first appears as tics between the ages of 7 and 15 years and is more common in boys, explained Shubhangi Chitnis, MD, assistant professor of pediatric neurology at West Virginia University School of Medicine in Morgantown. Typically, TS intensifies during adolescence and subsides by adulthood, but a small group of persons-fewer than 20%-remain afflicted into their adult years.1,2
DOPAMINE MAY BE CAUSAL
Evidence collected by Harvey Singer, MD, of the Division of Pediatric Neurology at Johns Hopkins University School of Medicine in Baltimore, suggests that TS is caused by a defect involving the dopamine system and its effect on the corticostriatothalamocortical circuits.3,4
"Dopaminergic neurons directly influence cortical and striatal neurons as well as presynaptic glutamatergic corticostriatal terminals that synapse in the striatum. Whether dopamine's influence is inhibitory or excitatory depends on the type of receptors it interacts with," Singer explained.4 Dopamine can either depress or potentiate corticostriatal transmissions.5 Its effect on the resting potentials of striatal neurons could account for the waxing and waning pattern of tics noted in persons with TS.6
Most dopamine innervation to the cortex is in the frontal region, especially the striatum.7,8 Gilbert and colleagues9 report that the brain of adults with TS is structured differently from that of others in that it has fewer D2 receptors in extrastriatal regions. The TS-affected brain also has reduced distribution volume ratio values in the orbitofrontal and motor cortex, hippocampus, anterior cingulate gyrus, and mediodorsal thalamus, suggesting reduced D2 or D3 receptor density. In his view, the thalamus may play a crucial role in sensory, cognitive, limbic, and behavioral difficulties in TS.
Singer and his group also are studying the brain structure of patients with TS. In 1 study, the team performed a postmortem analysis of brain tissue to determine whether the defect might be located in the frontal lobe.10 "The frontal lobe is integral to the circuits that connect cortical regions to basal ganglia, and it is a site where tics and associated comorbidities could originate," explained Dustin Yoon, a teaching assistant at Johns Hopkins and the study's lead author.
The investigators analyzed tissue samples for several neurochemical markers: dopamine (D1, D2), serotonin (5HT-1A), a-adrenergic (a2A) receptors, dopamine transporter (DAT), and vesicular docking and release proteins.10 While the sample size was small-3 patients with TS and 3 matched controls-DAT and D2 receptor densities were consistently increased in 5 of 6 frontal regions in all the patients with TS. Density values for persons with TS versus controls ranged from 133% to 276% for DAT, and from 132% to 182% for the D2 receptor.10
"We found that the actual density of DAT and D2 exceeded 150% of control values. A lot of things can contribute to this. It may be that patients with TS have an intrinsic regulatory defect that causes receptor density to increase, or there may be frontal dopaminergic hyperinnervation from the ventral tegmental area," explained Yoon. But he and his colleagues cautioned that their findings must be considered within the context of the effect of medications on the brain. "Treatment with neuroleptics- including dopamine antagonists-increases D2 dopamine receptors in the striatum. It's entirely possible that our findings were the result of patients being treated chronically with neuroleptics," Yoon said.
OTHER POSSIBLE CAUSES
The uncontrollable urge to perform a tic suggests that TS might be related to the inability to effectively regulate-or gate-sensory information. Effective gating requires the body to sustain neural oscillations in the basal ganglia and cortex that work to filter out motor, somatic, and perceptual stimuli from the surrounding environment. In this model, TS can be seen as a condition in which the ability to ignore constant environmental stimuli is impaired.
In support of this theory, studies have shown that persons with TS are deficient in a key γ-aminobutyric acidergic interneuron that orchestrates filtering oscillations.2 Loss of these cells in the dorsal lateral striatum can lead to tics; losses in other striatal areas can contribute to comorbidities seen in TS, such as obsessive-compulsive disorder (OCD) and attention-deficit hyperactivity disorder (ADHD).2 Deficiency of γ-aminobutyric acidergic interneurons also explains why persons with TS are often disinhibited.11
A problem with the oscillatory system also may contribute to tha- lamocortical dysrhythmia.12 Resolving this dysrhythmia would ease tics and might explain why deep brain stimulation (DBS) directed at either the midline thalamic nuclei or the internal globus pallidus alleviates symptoms in some patients.13
Some investigators think that serotonin plays a role in TS, although the mechanism of action is unclear.14 Studies have shown decreased levels of serum serotonin and tryptophan in affected patients.15 Levels of serotonin metabolites (5-hydroxyindoleacetic acid) also are diminished in the basal ganglia and cerebrospinal fluid of persons with TS.16
Generally speaking, treatment is recommended when tics are causing pain; are jeopardizing safety; or are compromising the patient's physical, mental, or social quality of life or ability to function educationally and professionally.17
Several medications are available, but those recommended as first-line treatment-clonidine and guanfacine-are not necessarily the strongest, according to Gilbert. "The Tourette Syndrome Association's medical board has found dopamine-blocking agents-haloperidol, pimozide [Orap], and risperidone [Risperdal]-to be the most compelling.18 But the problem with these medications is that they cause bothersome adverse effects. Patients don't appreciate the weight gain, sedation, and anxiety that can accompany treatment. So, while these drugs might look really good on paper, they're not the most palatable choice at the clinical level," Gilbert explained. He also pointed out that second- and third-line medication choices depend on the patient's tolerance. His recommendation is to individualize treatment.
Chitnis starts his patients with clonidine, 0.1 mg/d, which is titrated upward as needed. Patients who do not respond are switched to guanfacine, starting at 1 mg/d and titrated as necessary to control tics. "Haloperidol is another option, but I rarely resort to it," Chitnis said.
Gilbert advises physicians to be realistic with the patient and family about expectations. "Persons who want to try medical treatment can expect to have their tics reduced to some extent, but those tics are not going to be totally eliminated," Gilbert said. Chitnis added that he will "always treat the patients who are suffering from social or functional impairment as a result of their tics. But I must be honest here: I find that the success rate of treatment is low."
DEEP BRAIN STIMULATION
DBS has been found useful for treatment of many movement disorders, including dystonia and Parkinson disease.19 Early reports also indicate that DBS works for adults with OCD and TS, although more study is needed. "DBS is used at my facility for adults who have movement disorders, but we don't use it in children, nor are we using it for TS," explained Chitnis.
In DBS, electrodes are surgically implanted in the brain near the known or suspected site of an abnormality, making implantation for TS challenging because the precise site of abnormality is not known. (Most reported cases of DBS have targeted the centromedian-parafascicular complex of the thalamus, the internal segment of the globus pallidus, or the anterior limb of the internal capsule.19)
When the electrodes are in place, the battery-powered implanted pulse generator (IPG) to which they are connected is inserted either beneath the patient's clavicle or in his abdomen. The IPG, which must be expertly calibrated, sends electrical impulses to the brain to modify neural activity. Perfecting the calibration can take up to a year and is one of the drawbacks of DBS use. Other potential problems include manic conversion and sudden exacerbation of symptoms when DBS is discontinued. The IPG batteries also need to be replaced every 3 to 5 years.
Although DBS has been used successfully in persons with movement disorders, only about 10 published reports of DBS in persons with TS exist.20 Joohi Shahed, MD, assistant professor of neurology and an associate at the Parkinson's Disease Center and Movement Disorders Clinic at Baylor College of Medicine in Houston, reported good results with bilateral DBS of the globus pallidus interna in a 15-year-old boy with severe symptoms (including coprolalia, screaming, grabbing others, self-injury, anxiety, depression, and impulsivity) that had not responded to pharmacotherapy.20
"We found that comorbidities and quality of life improved considerably. On follow-up testing, this patient had improvement in verbal reasoning, psychomotor speed, mental flexibility, and visual perception," said Shahed.
In its guidelines,19 the Tourette Syndrome Association recommends DBS as an option for patients with severe tics that persist despite adequate trials of 3 different classes of medications. The guidelines also recommend that before performing a DBS procedure, the psychological condition of the patients be evaluated to rule out OCD, ADHD, and mood disorders, and that physicians get a sense about whether the patient is capable of taking care of himself after surgery.19
The guidelines recommend standard neuroimaging mapping with MRI 1 month before the procedure. They also recommend that patients be followed up at 3, 6, and 12 months after surgery, then annually thereafter, to evaluate long-term effects of DBS.19
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Mink JW, Walkup J, Frey KA, et al. Patient selection and assessment recommendations for deep brain stimulation in Tourette syndrome.
Shahed J, Poysky J, Kenney C, et al. GPi deep brain stimulation for Tourette syndrome improves tics and psychiatric comorbidities.