deletions | additions       diff --git a/Treatment.md b/Treatment.md  index 3e87c61..77df3bd 100644  --- a/Treatment.md  +++ b/Treatment.md 
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\citet{26002052} reported a carefully designed, thoughtful pilot study of glutamatergic modulators as tic treatment. Twenty-three children with TS completed a double-blind, parallel group study involving 6 weeks of placebo, D-serine (up to 30 mg/kg/day), or riluzole (up to 200 mg/day). Total tic scores from the YGTSS improved by 25-38% in each group, without significant group differences. Although power was limited by the small sample size, this null result argues against eager pursuit of glutamatergic medications for TS at this juncture.   A meta-analysis of 22 randomized, controlled trials (RCTs) involving 2,385 children with ADHD found no causal relationship between stimulants and onset of tics \cite{26299294}. \citep{26299294}.  Rather, tics were associated with ADHD itself (5.7% in the psychostimulant groups and 6.5% in the placebo groups). This summary of previous evidence hopefully can further reassure patients and prescribers that stimulants do not cause tics. The evidence for this conclusion is strongest for methylphenidate (19 of the 22 trials), and in a large RCT in children with TS and ADHD, tics _improved_ significantly with methylphenidate \cite{11865128}. \citep{11865128}.  In this meta-analysis, results were similar for the 3 trials involving amphetamines, but tic severity did increase in 12 adults after a single intravenous dose of 0.3mg/kg D-amphetamine \cite{23876376}. \citep{23876376}.  Four patients with treatment-refractory TS were studied in [an an  early report](http://www.webcitation.org/query?url=http%3A%2F%2Fir.catalystpharma.com%2Freleasedetail.cfm%3FReleaseID%3D919254&date=2016-05-09) report  of results using vigabatrin, a  medication from the GABA-aminotransferase inhibitor class. class \citep{vigabatrinPR}.  One patient had a clinically significant reduction in tics while two others had tic reduction of approximately 25% but did not report subjective clinical improvement. ### Neurosurgery 
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Fourteen patients were randomly allocated to DBS on-stimulation or off-stimulation conditions for the first 3 months after DBS leads were placed in the GPi (globus pallidus, pars interna), followed by a switch to the other condition for another 3 months \citep{25882029}. Ratings were collected blind to stimulation status. Thirteen patients completed assessments in both blinded periods. This was followed by open-label stimulation adjustments for both groups. Total YGTSS scores were 15% lower at the end of the on-stimulation period compared with the off-stimulation period (p=0.048). Three serious adverse events occurred (two infections with the DBS hardware and one episode of hypomania during the blinded stimulation on condition). This study is important as it provides evidence of efficacy in an on *vs* off stimulation, randomized, controlled design.   A case study raised the issue of temporary DBS treatment \citep{26290773}. The patient started having simple motor tics at the age of 7 followed by vocal and complex motor tics two years later. The patient also had ADHD and learning difficulties. Thalamic DBS surgery was provided when he developed continuous motor and vocal tics that resulted in his leaving school at the age of 17. A year after surgery his YGTSS score had decreased by 58%. Three years after the surgery the tic severity increased and the IPG was replaced, again followed by improved tic severity. When the patient was 23 it was noticed that the IPG was not operational, yet there had not been any increase in the patient's symptoms. After the device was left off for 2 years and the patient remained stable clinically, the decision was made to remove the device and the patient was still stable 8 months later. This case raises important questions discussed in the consensus statement \citep{25476818}, but without adequate controls, controls  it is impossible to know whether DBS was the cause of tic improvement. \citet{26180116} reviewed electrophysiological data obtained in nonhuman primate models of TS and in Parkinson disease, with the hope of identifying possible mechanisms to account for the efficacy of high-frequency GPi DBS in both a hyper- and a hypokinetic movement disorder. This article focuses on the possibility that excessive synchrony and pathological low-frequency oscillations (LFO) impair activation in the motor regions that receive input from the basal ganglia. There is also some evidence that synchronous oscillatory activity and excess LFO contribute to TS. DBS effectiveness is considered to occur because population-scale firing rates are maintained allowing proper encoding of desired movement. When used with Parkinson patients, DBS suppresses excess LFO in the GPE in addition to the GPI. GPI-DBS is theorized to suppress the phasic activations in the GPe and phasic inhibitions in the GPi for TS patients. It is hypothesized that in both medical conditions aberrant output is minimized while the population-averaged firing rate is maintained.  
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Lisanby and colleagues reported a careful, randomized controlled trial of repetitive transcranial magnetic stimulation (rTMS) aimed at supplementary motor area (SMA) in 20 adults with TS \citep{25912296}. There were suggestions of improvement, but on average, patients in the sham treatment group improved almost as much as those in the active treatment group. However, rTMS most effectively stimulates superficial regions of cortex, and an Israeli group employed this coil in an open-label study of 12 patients with treatment-refractory TS \citep{25342253}. The patients as a whole did not improve significantly, but a _post hoc_ analysis showed benefit in the 6 patients who also had OCD, and the treatment was well tolerated. A double blind, sham-controlled study in TS patients with OCD will be needed to confirm efficacy.  A review discusses the possible relevance of neurofeedback for the treatment of Tourette syndrome and suggests that it may be most useful to treat TS children and adults who also have ADHD \citep{25616186}. \citet{26074752} summarize evidence suggesting that autonomic dysfunction may have a role in both epilepsy and Tourette Syndrome. This article also summarizes attempts to use electrodermal activity (EDA) biofeedback to treat both conditions and describes the challenges that are presented by TS in using this type of intervention. EDA biofeedback, which consisted of 12 sessions over 4 weeks, produced at least a 50% reduction in seizures in more than half of the epileptic subjects and also produced changes in Contingent Negative Variation, which is modulated by changes in peripheral autonomic activity. Based on seizure diaries that were kept by a subset of the patients, these improvements were maintained over a period of years. These results were replicated in a 2014 study by another research group. In contrast, when a similar EDA biofeedback protocol was used with TS subjects \cite{24674962}, \citep{24674962},  TS patients in the active and sham biofeedback groups were not able to reduce their sympathetic activity. Despite this, both the active-biofeedback and sham-control groups had significant decreases in tic frequency and obsessive-compulsive disorder symptoms, plus improvements in quality of life related to OCD symptoms. Cranial electrical stimulation has been used over 40 years to treat symptoms such as anxiety, depression, assaultiveness and insomnia. (See \citet{23538086} insomnia (see \citep{23538086}  for a review.) review).  An open label trial of cranial electrical stimulation (CES) treatment was provided to 42 children with TS who were less than 12 years old \citep{25546850}. The patients applied electrodes to their earlobes when they went to bed so that they could receive the treatment on a daily basis for 24 weeks. Treatment was provided for 60 minutes and they could go to sleep if they wanted. Only one child dropped out before the completion of the study. The mean YGTSS score significantly decreased from 26.3 when they were initially seen to 11.4 after 24 weeks of treatment. These results must be viewed as preliminary, since an RCT is required to rule out spontaneous improvement.  Functional MRI scanning was an  optional part of this study,  andonly  8 subjects completed the scans before and after treatment. Independent component analysis with hierarchical partner matching was used to examine functional connectivity among regions within the cortico-striato-thalamo-cortical circuit circuit,  followed by Granger causality to examine effective connectivity. After the CES treatment this subsample had stronger functional activity and connectivity in the anterior cingulate cortex, caudate and posterior cingulate cortex and weaker activity in the supplementary motor area.These results must be viewed as preliminary, since an RCT is required to rule out spontaneous improvement.    Another treatment undergoing initial efficacy testing is an oral orthotic device with which some patients have reported success. The rationale and design of the study, and initial safety results, were reported at the London meeting \citep{orthotic:London}, and efficacy testing continues (see [the trial summary at ClinicalTrials.gov](https://clinicaltrials.gov/ct2/show/NCT02067819)).