In 2000, Kwak and colleagues described the results of a longitudinal follow-up study, which included 35 (30 male and 5 female) TS patients with a mean age of 23.3±15.5 years.43 All patients received intramuscular botulinum toxin injection and there were total 115 treatment sessions. Twenty-nine patients experienced improvement in tics following injection and 23 patients had marked relief in premonitory discomfort. No severe complications were reported with the exception of neck weakness in 4 patients, ptosis in 2 patients, generalized weakness in 1 patient, nondisabling dysphagia in 2 patients, fatigue in 1 patient and nausea/vomiting in 1 patient. Although this was an open label evaluation and, as such, subject to biases, the findings of this study supports the use of botulinum toxin as a safe and effective treatment for tics.
In 2010, Rath and colleagues evaluated the short-term and long-term treatment effects of botulinum toxin type A in 15 consecutive patients (18 tics) with simple motor tics.44 Short-term efficacy was reported in 89% patients (16/18 tics), and long-term efficacy was reported in 66.66% patients (12/18 tics). Premonitory urge decreased following treatment in all patients and disappeared in 2 patients. None of the patients had serious adverse effects. The authors concluded that botulinum toxin type A appears a safe and effective treatment for simple motor tics and retains its efficacy over long-term.
In 2008 Aguirregomozcorta and colleagues reported complete resolution of cervical dystonic tics in a 42 year male with TS, 2 months following 300 units of botulinum toxin type A injected bilaterally to the sternocleidomastoid muscle (50 U) and to the splenium capitis (100 U).46 Srirompotong and colleagues in 2007 reported complete disappearance of ear wiggling tics 9 days following 40 units of botulinum toxin type A injection in the pinna muscle (ie, the auricularis anterior and superior).47
In 1964, Stevens reported the outcomes of prefrontal lobotomy done on a 37-year-old man who had extreme disability because of his motor and vocal tics.57 After 2 years follow-up patient demonstrated improvement in his symptoms, which persisted for 6 years. But, due to confounding use of neuroleptics the effect of surgery in symptoms was not fully evident.
Targeting the corticostriatal hyperactivity by thalamotomy has also been tried in patients with TS. Hassler and Dieckmann63 reported 70% to 100% subjective improvement in tics in 3 patients who underwent bilateral thalmotomy targeting rostral intralaminar and medial nuclei. Contrary to Hassler, Cappabianca et al64 reported only temporary and slight reduction in tics and compulsions. Nonreversible disabling complications were reported by Leckman et al65 in a patient who underwent bilateral cingulotomies and infrathalamic lesionectomy. The patient developed dysarthria, dysphagia, gait and hand-writing difficulties, mild hemiparesis, abnormal extraocular movements, axial rigidity, and bradykinesia post operatively.
Lesional surgery resulted in improvement in symptoms for some patients, but was associated with a number of permanent and disabling side effects. Most of these reports do not mention details regarding impedance measurements, depth recordings, or postoperative imaging thus raising concerns about the real target localization. With the advent of alternative functional surgical options like DBS, lesional surgery is gradually becoming obsolete.
The age of patients undergoing DBS has ranged from 12 to 60 years. There was a clear male dominance with most case series and reports having more male subjects with TS undergoing DBS.
The most commonly used targets have been the thalamic region followed by pallidal targets. In the thalamus, CM-Pf region is the most widely studied target. Servello et al,92 evaluated the effect of CM-Pf stimulation in 36 subjects and reported improvement in YGTSS by 47% over a follow-up period ranging from 3 to 48 months. In a recent study of 48 patients who underwent DBS for TS, authors reported that 27 of the 37 patients had 78% reduction in YGTSS score.122
Most of the studies published in literature reported beneficial effect of DBS in TS, but of these only 6 were randomized controlled studies. Houeto et al,70 conducted the first prospective double-blind study of one patient who underwent bilateral CM-Pf thalamic and bilateral anteromedial GPi lead implantation. The tic severity was assessed using the YGTSS and Rush Video-Based Tic Rating Scale (RVBTS) in various phases including sham stimulation. After 2 months of bilateral thalamic stimulation, a 65% reduction in the YGTSS and a 77% improvement on RVBTS was observed. When bilateral GPi stimulation was used, a 65% reduction in the YGTSS and a 67% improvement in the RVBTS were reported. When combined thalamic and GPi stimulations were tried, there was remission of self-injurious behavior and a 70% reduction in YGTSS, which persisted for 2 years. One month after the stimulation was stopped (during sham stimulation), the tics and panic attacks progressively returned.70 In another randomized, double-blinded trial of bilateral thalamic CM-Pf in 5 patients, Maciunas et al74 demonstrated 40% to 67% mean motor tic reduction and 21% to 70% mean vocal tic reduction using the modified Rush Video-based Tic Rating Scale (mRVTRS) in the stimulation state.
Welter and colleagues in a double-blind, randomized cross-over trial studied the effect of high frequency stimulation of the CM-Pf and/or the ventromedial GPi in 5 patients and recorded improvement in the YGTSS score from 65% to 96%with bilateral GPi stimulation. A less robust reduction of 30% to 64% was noted with CM-Pf stimulation. When combined GPi and thalamic stimulation was tried the improvement ranged from 43% to 76%.81
In 2011, Ackermans and colleagues in a randomized double-blind cross-over trial studied the effect of DBS stimulation in Cm-Spv-Voi of thalamus in 6 patients. When tic severity was compared between on and off state, a significant 37% improvement in YGTSS was reported.103
In a recent double-blind multicenter parallel-group trial evaluating efficacy of anteromedial GPi-DBS in 16 patients of TS, no significant reduction in tic severity was reported between the sham and active stimulation groups during the 3 month double-blind period. There was no reduction in depression, anxiety and other neuropsychological measures.131
The prospective international DBS database and registry is the largest registry of patients of medically refractory TS, who underwent DBS implantation at 31 institutions in 10 countries around the world. Over a period of 4 years the registry reported 185 patients of TS who underwent DBS. The mean total YGTSS improved from 75.01 to 41.19 at 1 year, which is almost an improvement of 45.1% after DBS.135
In a meta-analysis Baldermann and colleagues included 57 studies (156 cases) and concluded that overall, DBS resulted in a significant improvement of 52.68% in the YGTSS. Significant YGTSS reductions were seen after stimulation of the thalamus, the posteroventrolateral part and the anteromedial part of the GPi, the ALIC and nucleus accumbens; however, there was no significant difference between these targets.141
Most of the randomized double-blind trials of DBS have their own inherent fallacies. Data collected from multiple centers have several limitations including different surgical techniques and treatment approaches that can affect results. In RCTs where unblinded adjustment of parameters were done, patients may have known whether they were actually in ON or OFF stimulation phase of the trial and thus bringing in bias. Similarly in the sham arm, the duration of the stimulation effects from the previous stimulation phase could have led to a carryover effect and the possibility of a placebo effect must also be considered, particularly in a population known to be suggestible.
Different paradigms of DBS stimulation have been studied and their safety and efficacy have been evaluated. Okun and colleagues tested the efficacy of scheduled, rather than the classic continuous, DBS paradigm with target of 50% improvement in the YGTSS total score to prove its efficacy. Six-month data revealed that reductions in the YGTSS total score did not achieve the prestudy criterion of a 50% improvement on scheduled stimulation settings.109 One of the most promising paradigms is that of adaptive DBS, which will be a closed-loop system designed to measure and analyze local field potentials recorded by DBS electrodes reflecting the patient’s clinical condition and give feedback so as to modify online stimulation settings.142
The adverse effects may be categorized as related to surgery, hardware and stimulation effects. The adverse effects related to surgery and hardware include hematoma at tip of electrodes, intracranial haemorrhage, lead breakage, poor wound healing, infections in the battery pouch, and abdominal hematoma.76,89,95,99 In the International Deep Brain Stimulation Database and Registry, the overall adverse event rate was 35.4% with intracranial hemorrhage occurring in 1.3%, and infection in 3.2%.135 The most common stimulation-induced adverse effects were dysarthria (10 [6.3%]) and paresthesia (13 [8.2%]). Servello and colleagues evaluated the rates of hardware and infection related complications during DBS for different disorders.99 A much higher rate of DBS related infection in TS is reported compared with DBS in other disorders, which may be because of the associated compulsive behaviors.95 Some specific adverse effects like lead fracture due to head-snapping tics was reported because of the comorbidity associated with the disease, which may add further challenges.80
The adverse effects related to stimulation are weight loss, mood changes, changes in sexual behavior, psychiatric symptoms including psychosis, depression, hypomania, and decreased energy levels.76,80,99 The side effects related to stimulation varied according to the target of DBS. Gaze and visual disturbances were associated with CM-Spv-Voi of the thalamus.68
When the Ventral Anterior and Ventrolateral Motor part of the thalamus was stimulated the eye disturbances became less, but there were mood deterioration and stimulation-dependent dysarthria.135 Pallidal stimulation-have been linked with memory and behavioural disturbances.135,128 Stimulation of the ALIC/Nac region has been associated with side effects related to mood and affect of patients.70
Although there is lack of large randomized controlled studies assessing efficacy of DBS in TS, the evidence from current literature suggest that DBS may be considered as one of the therapeutic options in patients with medically refractory TS. European clinical guidelines for DBS in TS and other tic disorders patients classified the recommendations as undisputed for treatment resistant severe tics with no major depression.54 They have also highlighted debatable issues where no equivocal recommendations can be given, like minimum age, duration of severe tics, definition of treatment resistance, and which target should be selected. New advances in stimulation paradigm can make this procedure safer and produce better clinical outcomes. A large multicentric randomized double-blind trial with large number of patients will further test its efficacy and also the side effect profile of this procedure. There are still questions like the best target for stimulation, which needs to addressed in trials with high-quality design with minimal bias. The prohibitive cost and the limited availability of centers with this facility are also important concerns which lead to less use of this therapeutic modality.
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