Deep brain stimulation for treatment of refractory Tourette syndrome: long-term follow-up.

BACKGROUND: Eighteen patients with severe and refractory Tourette Syndrome underwent bilateral thalamic deep brain stimulation. The surgical procedures and stimulation processes of the cohort were reported in 2008; the 2 year follow-up was reported in 2009. The aim of the research is the assessment of long-term outcome (5-6 years) on tics, obsessional behaviours, anxiety, mood, and on the overall general health of the patients and their general satisfaction. METHOD: In this study, all 18 of the original patients will be discussed, pre- and post-DBS, according to our protocol using standardized objective schedules, as well as the clinical impressions of both clinicians and patients. As there were no substantial nor statistical differences on measures of cognitive functioning between pre-DBS and 2 year follow-up, we decided not to continue this aspect of the formal assessment, particularly as there were also no clinical indications. RESULTS: At 5-6 year follow-up, there was a significant reduction in tic severity (p < 0.001), and significant improvements in obsessive compulsive behaviours (p = 0.003), anxiety (p < 0.001) and depressive (p < 0.001) symptoms. Patients, in general, required less medication for tics, co-morbid conditions and/or co-existent psychopathologies. The long-term outcome/satisfaction were not unanimous between patients and the medical team. CONCLUSIONS: At long-term follow-up, DBS was very successful in terms of a significant improvement in tics and also a significant reduction in the potentially disabling symptoms of obsessionality, anxiety and depression. However, compared with our more positive overall results at 2 years, these later results demonstrate long-term difficulties as follows: non-compliance, long-term complications , and the differences in the opinions between the (a) medical, (b) the surgical teams and (c) the post-DBS patients as to their outcome/satisfaction with the procedures. Our experience highlights the need for controlled studies, for long-term follow up, and the need to improve the selection of patients for DBS.

Chronic alcohol exposure during critical developmental periods differentially impacts persistence of deficits in cognitive flexibility and related circuitry.

Cognitive flexibility in decision making depends on prefrontal cortical function and is used by individuals to adapt to environmental changes in circumstances. Cognitive flexibility can be measured in the laboratory using a variety of discrete, translational tasks, including those that involve reversal learning and/or set-shifting ability. Distinct components of flexible behavior rely upon overlapping brain circuits, including different prefrontal substructures that have separable impacts on decision making. Cognitive flexibility is impaired after chronic alcohol exposure, particularly during development when the brain undergoes rapid maturation. This review examines how cognitive flexibility, as indexed by reversal and set-shifting tasks, is impacted by chronic alcohol exposure in adulthood, adolescent, and prenatal periods in humans and animal models. We also discuss areas for future study, including mechanisms that may contribute to the persistence of cognitive deficits after developmental alcohol exposure and the compacting consequences from exposure across multiple critical periods.

Quality of life in young people with treatment-responsive epilepsy: A controlled study.

OBJECTIVE: Quality of life (QoL) has been shown to be lower in individuals with epilepsy than the general public. However, few studies have investigated the QoL of individuals with well-controlled epilepsy. This study investigated the effects of epilepsy on QoL in persons with treatment-responsive seizures, beyond factors directly related to the presence of seizures. METHODS: Fifty young patients with controlled epilepsy and 102 healthy controls completed a generic, multidimensional, self-report QoL instrument, along with standardized scales assessing anxiety, depression, and other emotional or behavioral difficulties. RESULTS: Young people with epilepsy reported increased anxiety (P=0.037) and more emotional and behavioral difficulties (P<0.001). Though there were was no difference between the groups in Total QoL score, treatment-responsive epilepsy was associated with lower QoL within the Self domain (P=0.016). CONCLUSIONS: Epilepsy may exert a negative influence on QoL in relation to thoughts and feelings about the self in the context of complete seizure remission. Future research should investigate the therapeutic value of interventions targeting detrimental changes to self-perception in young people living with controlled epilepsy.

Adults with Tourette's syndrome with and without attention deficit hyperactivity disorder.

OBJECTIVE: Comorbidity between Tourette's syndrome (TS) and attention deficit hyperactivity disorder (ADHD) is high. In children, those with both TS+ADHD fare less well than those with TS-only on measures of both psychopathology and behaviour. The objective of this study was to document such measures in adult patients. METHOD: Eighty adults with TS-only were compared to 64 with TS+ADHD using a clinical interview and standardised measures of depression, anxiety and obsessionality. RESULTS: The two groups were no different on measures of TS severity. TS+ADHD patients had significantly more depression, anxiety, obsessive-compulsive behaviour and maladaptive behaviours than patients with TS-only. There were also significant differences in the incidence of copro- and echo-phenomena and family history of ADHD. CONCLUSION: The finding of increased overall behavioural difficulties and psychopathology in adult patients with TS+ADHD when compared with TS-only is in agreement with previous findings in children with TS. Appropriate treatment of ADHD in TS patients during childhood may prevent many behavioural problems in adulthood.

Deep brain stimulation in 18 patients with severe Gilles de la Tourette syndrome refractory to treatment: the surgery and stimulation.

BACKGROUND: There have been several reports of successful deep brain stimulation (DBS) for the treatment of severe Gilles de la Tourette syndrome (GTS). METHOD: 18 cases of GTS who were resistant to at least 6 months of standard and innovative treatments, as well as to psychobehavioural techniques, underwent DBS. DBS was placed bilaterally in the centromedian-parafascicular (CM-Pfc) and ventralis oralis complex of the thalamus. Patients were evaluated after surgery, with immediate and formal assessments at least every 3 months, including "on-off" and "sham off" in the first nine patients. RESULTS: All patients responded well to DBS, although to differing degrees. The duration of follow-up assessments ranged from 3 to 18 months. The comorbid symptoms of obsessive-compulsive behaviour, obsessive-compulsive disorder, self-injurious behaviours, anxiety and premonitory sensations decreased after treatment with DBS. There were no serious permanent adverse effects. CONCLUSIONS: DBS is a useful and safe treatment for severe GTS. The results of ours and previous DBS reports suggest that the CM-Pfc and ventralis oralis complex of the thalamus may be a good DBS target for GTS.

Anti-basal ganglia antibodies and Tourette's syndrome: a voxel-based morphometry and diffusion tensor imaging study in an adult population.

Anti-basal ganglia antibodies (ABGAs) have been suggested to be a hallmark of autoimmunity in Gilles de la Tourette's syndrome (GTS), possibly related to prior exposure to streptococcal infection. In order to detect whether the presence of ABGAs was associated with subtle structural changes in GTS, whole-brain analysis using independent sets of T(1) and diffusion tensor imaging MRI-based methods were performed on 22 adults with GTS with (n = 9) and without (n = 13) detectable ABGAs in the serum. Voxel-based morphometry analysis failed to detect any significant difference in grey matter density between ABGA-positive and ABGA-negative groups in caudate nuclei, putamina, thalami and frontal lobes. These results suggest that ABGA synthesis is not related to structural changes in grey and white matter (detectable with these methods) within frontostriatal circuits.

Beck Depression Inventory is a useful screening tool for major depressive disorder in Gilles de la Tourette syndrome.

This study determined the prevalence of and factors associated with comorbid major depressive disorder (MDD) in patients with Gilles de la Tourette syndrome (GTS). How a simple self-report instrument, the Beck Depression Inventory (BDI), correlates with clinical assessment of comorbid MDD in this population was assessed. In a continuous sample of 114 adult patients with GTS, assessed clinically using the Diagnostic and Statistical Manual of Mental Disorders-IV criteria, 26 (23%) patients met criteria for MDD; more severe tics as measured with the Yale Global Tic Severity Scale, conduct disorder in childhood or higher age at the time of assessment were associated with MDD. The BDI score had a high negative predictive value for diagnosis of MDD, but a low positive predictive value. Using the BDI as a screening tool for comorbid MDD in patients with GTS is suggested.

Excitability of motor cortex inhibitory circuits in Tourette syndrome before and after single dose nicotine.

The pathophysiology underlying the involuntary tics of Gilles de la Tourette syndrome (GTS) remains unknown. Here we used transcranial magnetic stimulation (TMS) to examine the excitability of two different inhibitory systems in the human motor cortex: short interval intracortical inhibition (SICI) and short interval afferent inhibition (SAI) in 10 healthy non-smoking controls and eight untreated non-smoking patients with GTS. Compared with the healthy control group, both SICI (measured at a range of conditioning intensities) and SAI were reduced in patients. This is consistent with the suggestion that reduced excitability of cortical inhibition is one factor that contributes to the difficulty that patients have in suppressing involuntary tics. In addition, the reduced SAI indicates that impaired intracortical inhibition may not be limited to the motor cortex but also involves circuits linking sensory input and motor output. A single dose of nicotine reduced tic severity as assessed by blind video scoring in the majority of patients. In addition, it abolished the difference between patients and controls in SICI and SAI. There was no effect of nicotine, and no difference between controls and patients in measures of motor or SICI threshold. This indicates that cholinergic input can modulate the efficiency of SICI and SAI differently in GTS and healthy controls.

A functional neuroanatomy of tics in Tourette syndrome.

BACKGROUND: Tics are involuntary, brief, stereotyped motor and vocal behaviors often associated with irresistible urges. They are a defining symptom of the classic neuropsychiatric disorder, Tourette syndrome (TS), and constitute an example of disordered human volition. The neural correlates of tics are not well understood and have not been imaged selectively. METHODS: Event-related [(15)O]H(2)O positron emission tomography techniques combined with time-synchronized audio and videotaping were used to determine the duration of, frequency of, and radiotracer input during tics in each of 72 scans from 6 patients with TS. This permitted a voxel-by-voxel correlational analysis within Statistical Parametric Mapping of patterns of neural activity associated with the tics. RESULTS: Brain regions in which activity was significantly correlated with tic occurrence in the group included medial and lateral premotor cortices, anterior cingulate cortex, dorsolateral-rostral prefrontal cortex, inferior parietal cortex, putamen, and caudate, as well as primary motor cortex, the Broca's area, superior temporal gyrus, insula, and claustrum. In an individual patient with prominent coprolalia, such vocal tics were associated with activity in prerolandic and postrolandic language regions, insula, caudate, thalamus, and cerebellum, while activity in sensorimotor cortex was noted with motor tics. CONCLUSIONS: Aberrant activity in the interrelated sensorimotor, language, executive, and paralimbic circuits identified in this study may account for the initiation and execution of diverse motor and vocal behaviors that characterize tics in TS, as well as for the urges that often accompany them. Arch Gen Psychiatry. 2000;57:741-748

Subthreshold rTMS over pre-motor cortex has no effect on tics in patients with Gilles de la Tourette syndrome.

OBJECTIVE: A previous study showed no effect of 1Hz repetitive transcranial magnetic stimulation (rTMS) on tics in Gilles de la Tourette Syndrome (GTS). We modified the rTMS protocol in order to investigate some of the possible methodological reasons for the negative outcome in that study. METHODS: In a single blinded placebo-controlled cross-over study in five GTS patients without obsessive compulsive disorder we probed whether longer trains (1800 stimuli) of 1 Hz pre-motor cortex rTMS at 80% of active motor threshold and application to both hemispheres can improve tics in GTS. This was measured with the Yale Global Tic severity rating scale, the MOVES self-rating scale and video analysis. RESULTS: We found no significant effect of either left pre-motor cortex stimulation alone, or left pre-motor followed by right pre-motor cortex stimulation. CONCLUSIONS: These results suggest that the rTMS protocol used in this study is not useful for the treatment of tics in GTS. SIGNIFICANCE: rTMS protocols need to be modified substantially in order to explore their potential for the treatment of tics in GTS.

Soluble adhesion molecules in Gilles de la Tourette's syndrome.

To investigate the immune-mediated response in TS, and its relationship with streptococcal infection, we measured serum levels of soluble intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin in patients with TS, compared to healthy and diseased controls. Soluble VCAM-1 and sE-selectin were significantly elevated in children and adults with TS, and sVCAM-1 was higher among anti-basal ganglia antibodies (ABGA)-positive adults with TS. No correlation of adhesion molecule levels to clinical severity or anti-streptococcal antibodies was observed. Children with Sydenham's chorea and paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) showed an increased level of sICAM-1, but not sVCAM-1 and sE-selectin. These results provide initial evidence for a role of adhesion molecules and systemic inflammation in TS, and support the hypothesis of an ongoing immune-mediated process in this condition.

Gilles de la Tourette syndrome in a cohort of deaf people.

We present six patients with Gilles de la Tourette syndrome (TS) who are also deaf. TS has been observed previously, but rarely reported in deaf people, and to date, so called "unusual" phenomenology has been highlighted. TS occurs almost worldwide and in all cultures, and the clinical phenomenology is virtually identical. In our cohort of deaf patients (we suggest another culture) with TS, the phenomenology is the same as in hearing people, and as in all other cultures, with classic motor and vocal/phonic tics, as well as associated phenomena including echo-phenomena, pali-phenomena and rarer copro-phenomena. When "words" related to these phenomenon (e.g. echolalia, palilalia, coprolalia or mental coprolalia) are elicited in deaf people, they occur usually in British Sign Language (BSL): the more "basic" vocal/phonic tics such as throat clearing are the same phenomenologically as in hearing TS people. In our case series, there was a genetic predisposition to TS in all cases. We would argue that TS in deaf people is the same as TS in hearing people and in other cultures, highlighting the biological nature of the disorder.

Neuroreceptor subunit genes and the genetic susceptibility to Gilles de la Tourette syndrome.

Segregation studies have shown that Gilles de la Tourette Syndrome (GTS) is probably transmitted as an autosomal dominant gene disorder and can therefore be studied by classical linkage analysis to identify susceptibility loci. Many neurotransmitter systems have been implicated in the etiology of GTS. Most recently the alpha-1 subunit of the glycine receptor etiologically responsible for hyperekplexia has been hypothesized as the cause of the susceptibility to GTS. Because of this and the high concentration of other neuroreceptor genes at 5q33-35, it was decided to study this region and the associated gene cluster on chromosome 4p12-16 in a large British kindred multiply affected with GTS and chronic motor tics. The genotypes of the microsatellite markers at these loci were determined by polymerase chain reaction. The allele data were analyzed using both parametric and nonparametric methods. Approximate multipoint maps were constructed across the regions of interest using FASTLINK. All of the lod scores produced were negative, showing no evidence of linkage to GTS in the family studied. The multipoint maps showed good exclusion across these regions. The glycine receptor gene responsible for hyperekplexia and the other neuroreceptor genes examined in this paper are not involved in the etiology of GTS in this large pedigree.

The genetic susceptibility to Gilles de la Tourette syndrome in a large multiple affected British kindred: linkage analysis excludes a role for the genes coding for dopamine D1, D2, D3, D4, D5 receptors, dopamine beta hydroxylase, tyrosinase, and tyrosine hydroxylase.

Segregation analyses have shown that Gilles de la Tourette Syndrome (GTS) is transmitted as an autosomal dominant gene disorder indicating that classical linkage analysis should be able to identify susceptibility loci. Previous studies of GTS have included investigations of neuroreceptor function, neurotransmitters, and their metabolites as well as neurotransmitter-related enzymes in an attempt to determine the pathophysiology of GTS. The neurotransmitter systems most often thought to be involved in GTS include those involving adrenaline, noradrenaline, and dopamine. We have carried out research to test the hypothesis that genes encoding proteins in the catecholamine pathways may contribute to the genetic etiology of GTS. Polymorphic markers at or near the D1, D2, D3, D4, D5 neuroreceptor gene loci as well as at the genes encoding dopamine beta hydroxylase (DBH), tyrosinase (TY) and tyrosine hydroxylase (TH) were studied in one large multiple affected pedigree. The linkage results of this investigation exclude a major role of these candidate genes in the etiology of GTS in the pedigree.

Exclusion of the 5-HT1A serotonin neuroreceptor and tryptophan oxygenase genes in a large British kindred multiply affected with Tourette's syndrome, chronic motor tics, and obsessive-compulsive behavior.

OBJECTIVE: Previous studies have demonstrated a relationship between obsessive-compulsive disorder or behavior and Gilles de la Tourette syndrome. It has been hypothesized that the serotonergic system is implicated in the etiology of obsessive-compulsive disorder. Therefore, the authors investigated whether genetic variation in a serotonergic receptor and a modifying enzyme were associated with Tourette's syndrome. METHOD: A linkage analysis using DNA and blood group markers was carried out in a large British kindred multiply affected with Tourette's syndrome, chronic motor tics, and obsessive-compulsive behavior. RESULTS: There was no evidence to support the hypothesis that genetic variation in the serotonin 5-HT1A receptor and tryptophan oxygenase genes causes susceptibility to Tourette's syndrome and chronic multiple tics. CONCLUSIONS: The results eliminate two possible candidate genes from having a role in the pathophysiology of Tourette's syndrome.

Obsessions in obsessive-compulsive disorder with and without Gilles de la Tourette's syndrome.

OBJECTIVE AND METHOD: Although obsessive-compulsive disorder commonly occurs in many patients with Gilles de la Tourette's syndrome, little is known about the obsessions and compulsions of Tourette's syndrome and whether they differ from those seen in pure obsessive-compulsive disorder. The authors prospectively studied 10 subjects with obsessive-compulsive disorder and 15 subjects with obsessive-compulsive disorder and comorbid Tourette's syndrome by using the Yale-Brown Obsessive Compulsive Scale, the Leyton Obsessional Inventory, and a new questionnaire designed to emphasize the differences in symptoms between these two groups. RESULTS: Subjects with comorbid obsessive-compulsive disorder and Tourette's syndrome had significantly more violent, sexual, and symmetrical obsessions and more touching, blinking, counting, and self-damaging compulsions. The group with obsessive-compulsive disorder alone had more obsessions concerning dirt or germs and more cleaning compulsions. The subjects who had both disorders reported that their compulsions arose spontaneously, whereas the subjects with obsessive-compulsive disorder alone reported that their compulsions were frequently preceded by cognitions. CONCLUSIONS: There are phenomenologic differences between obsessive-compulsive disorder and obsessive-compulsive disorder with comorbid Tourette's syndrome that may reflect differential involvement of neurochemical and neuroanatomic pathways.

Sex of parent transmission effect in Tourette's syndrome: evidence for earlier age at onset in maternally transmitted cases suggests a genomic imprinting effect.

Parent of origin effects caused by genomic imprinting may influence the phenotypic expression of a number of heritable human disorders. To test this phenomenon in Tourette's syndrome (TS), we studied 437 first degree relatives systematically ascertained through 57 probands. We compared age at onset, age at diagnosis, and phenotypic expressions as observed in the diagnosis of TS, chronic motor tics, and obsessive compulsive behavior in the offspring of affected males with the offspring of affected females. Of the 437 subjects, 16.7% had matrilineal inheritance and 13.9% had patrilineal inheritance, as determined by family history methodology. Chi-square analysis of the different phenotypic expressions and sex of the transmitting parent failed to provide evidence of significant group differences. We found no significant differences in the age at diagnosis either. However, the maternally transmitted offspring showed a significantly earlier age at onset. This points to a parent of origin effect on the putative TS gene that could be explained by meiotic events or even intrauterine environmental influences. These findings may help explain the hitherto conflicting reports about the nature of genetic transmission in TS, and suggest a need to re-examine family data separately for maternally and paternally transmitted cases, taking into account the possible role of imprinting.

A volumetric MRI study of Gilles de la Tourette's syndrome.

The neuroanatomic or neuropathologic basis of Gilles de la Tourette's syndrome (GTS) remains unknown. Recent studies have suggested abnormalities of cerebral asymmetry and basal ganglia volumes. We studied 17 patients with GTS and eight normal controls using volumetric MRI techniques for measuring the caudate nucleus, amygdala, and corpus callosum. One subject with GTS was subsequently excluded because he was left handed. No absolute differences in caudate nucleus volumes between patient and control groups were evident. There was an increase in corpus callosum (CC) cross-sectional area and a loss of the normal asymmetry of the caudate nucleus in the patient group. A loss of the normal correlation between cross-sectional area of the CC and whole brain index (WBI) in the patient group also was found. The amygdala measurements had a poor interrater reliability.

Bilineal transmission in Tourette's syndrome families.

We assessed the frequency of bilineal (from maternal and paternal sides) transmission of Tourette's syndrome (TS) in two groups of pedigrees: (1) 39 high-density families in which five or more relatives were reported to have TS, and (2) the families of 39 consecutively ascertained probands referred for evaluation of TS. We used two designations for the TS phenotype (tics, tics or obsessive-compulsive behavior [OCB]), and we attempted to verify bilineal transmission with direct examinations. For the high-density pedigrees, bilineal transmission was evident in 33% (considering tics) and 41% (considering tics or OCB) of families, which was confirmed by examination in 77% of the kindreds. For the consecutive pedigrees, bilineal transmission was seen in 15% (tics) and 26% (tics or OCB) of families, which was verified by examination in 66% of the kindreds. Both parents of the proband were affected (tics or OCB) in 38% of the high-density pedigrees and 10% of the consecutive pedigrees. For the high-density families only, the frequency of bilineal transmission appeared to be related to the proband's severity of TS, and for both pedigree groups, the frequency of both parents being affected was higher in families in which the proband's symptoms were most severe. Our findings support the contention that bilineal transmission and homozygosity are common in TS. These genetic phenomena might play a role in determining severity of illness and may explain current difficulties in localizing the gene defect by linkage analysis.