Introduction
Methods
Review of the literature (based on search of studies on DBS between 1970 and August 2021)
Authors | Numbers of patients* | Target | Duration (months) | Mean tic improvement (according to YGTSS)** | ||
---|---|---|---|---|---|---|
Double-blind controlled study part | Open uncontrolled study part | Double-blind controlled study part | Open uncontrolled study part | |||
Houeto et al. [25] | 1/1 | CM-Pf, internal part of the GPi | 11 | 24 | Tic reduction of 59–70% depending on target Mean tic reduction of 41.25 according to YGTSS-TTS | “Improvement” (no data shown) |
Maciunas et al. [26] | 5/5 | Bilateral thalamic stimulation | 1 | 3 | Mean tic reduction of 2.4 according to YGTSS-TTS | Improvement in 3/5 patients Mean tic reduction of 9.0 according to the YGTSS-TTS at the 3-Month follow-up Mean overall reduction of 38.8 (44%) according to YGTSS-GS at 3 months compared with the preoperative score |
Welter et al. [27] | 3/3 | GPi and thalamic stimulation | 8 | 20–60 | Tic improvement ranging from 30 to 96% according to YGTSS-TTS | Tic improvement ranging from 74 to 82% according to YGTSS-TTS |
Ackermans et al. [31] | 6/6 | Thalamic stimulation | 6 | 12 | Significant improvement (p = 0.046) of 37% according to YGTSS-TTS Mean YGTSS-TTS improvement of 15.5 | Significant improvement (p = 0.028) of 49% according to YGTSS-TTS Mean YGTSS-TTS improvement of 20.7 |
Kefalopoulou et al. [30] | 13/15 | GPi | 6 | 8–36 | Significant tic improvement according to YGTSS-TTS (p = 0.048) Mean improvement in YGTSS-TTS of 12.4 | Significant improvement according to YGTSS-TTS (p < 0.0001) Mean improvement in YGTSS-TTS of 36.3 |
Welter et al. [29] | 16/16 | GPi | 3 | 6 | No significant improvement (p = 0.39) Mean reduction of 1.2 according to YGTSS-TTS | Significant improvement (no p shown) Mean reduction of 30.3 according to YGTSS-TTS |
Müller-Vahl et al. [28] | 10/10 | GPi vs thalamic stimulation | 9 | 6–89.9 | Significant tic reduction at group level, after GPi—but not thalamic—DBS compared to baseline No effects on premonitory urges and psychiatric comorbidities Inconsistent or negative findings when comparing targets directly | At group level, no improvement of tics, comorbidities, and quality of life Single patients benefitted continuously from thalamic DBS At last follow-up 89.9 months (mean) after surgery, 50% of patients had discontinued DBS |
Baldermann et al. [32] | 8/8 | Thalamic stimulation | 48 h of ON followed by 48 h sham stimulation at 6 and 12 months | 12 | Significant tic reduction according YGTSS (p = 0.001) YGTSS tic scores were significantly decreased with active stimulation by 26% compared to discontinued stimulation after 6 months and by 44% after 12 months | YGTSS tic scores decreased significantly from baseline to 6 months (p < 0.001) and twelve months (p = 0.001) but not from 6 months to 12 months (p = 1.0) |
Single case reports | ||
---|---|---|
N of studies | N (patients) | References |
35 | 1 |
Case series | ||
---|---|---|
N of studies | N of patients (range) | References |
25 | 2–55 |
Open uncontrolled studies | ||
---|---|---|
N of studies | N of patients (range) | References |
28 | 1–123 |
Randomized controlled trials
Authors | Study type | N* | Comorbidities assessed | Results of the double blind phase | Results of the open label phase |
---|---|---|---|---|---|
Houeto et al. [25] | RCT | 1/1 | Depression, anxiety, impulsivity | Range of change of − 8 to 60% in depression (MADRS) Range of change of 0 to + 110% in anxiety (BAI) Range of change of –14 to 55% in Impulsivity (BIS) Reduction of self-injurious behavior | Improvement of self-injurious behavior |
Maciunas et al. [26] | RCT | 5/5 | Depression, anxiety, OCD | Trends towards improvements in depression (BDI, HAM-D), OCD (Y-BOCS), and anxiety (HAM-A) | A non-significant trend for decreased verbal fluency, memory, and sustained attention and reaction time at the 3-month follow-up compared with levels at the preoperative assessment BDI-2,HAM-D, HAM-A, and Y-BOCS showed a trend toward improved mood, reduced anxiety, and fewer obsessions and compulsions |
Welter et al. [27] | RCT | 3/3 | Depression, anxiety, OCD | Improvement during both pallidal and thalamic stimulation in 2/2 patient with depression (MADRS) Improvement of anxiety in 2/2 patients with anxiety (BAI) No change in OCD (0/0) (no scale used) | A dramatic reduction in self-injurious behavior and impulsiveness |
Ackermans et al. [31] | RCT | 6/6 | Depression, anxiety, OCD, ADHD, self-injurious behaviors | No effect on any comorbidities (Y-BOCS, CAARS, BAI, BDI) | No effect on any comorbidities (Y-BOCS, CAARS, BAI, BDI) |
Kefalopoulou et al. [30] | RCT | 13/15 | Depression, anxiety, OCD | No improvement of depression (p = 0.127, BDI) No improvement of anxiety (p = 0.352, STAI) No improvement of OCD (p = 0.979, Y-BOCS) | Significant improvement of mood (BDI) Modest, non-significant effects in OCD (Y-BOCS) and anxiety (STAI) |
Welter et al. [29] | RCT | 16/16 | Depression, anxiety, OCD | No improvement of depression (p = 0.25, MADRS and p = 0.08, HAM-D) No improvement of OCD (p = 0.25, Y-BOCS) No improvement of anxiety (p = 0.91, BAS) | Significant changes between inclusion and the end of the open-label period in anxiety (MADRS, HADS) No significant changes in depression (BAS, HADS) and OCD (Y-BOCS) |
Müller-Vahl et al. [28] | RCT | 10/10 | OCD, ADHD, depression, anxiety | No effect on any comorbidities (Y-BOCS, CAARS, BAI, BDI) | OCD completely remitted (Y-BOCS) None of the patients exhibited a reduction in CAARS values of ≥ 30% at any follow-up visit Due to incompliance, only incomplete data were available without convincing evidence suggesting changes in mood No changes in anxiety (STAI) |
Baldermann et al. [32] | RCT | 8/8 | Depression, OCD, anxiety, ADHD | Not assessed | Significant improvement of OCD, depression and anxiety |
Baldermann et al. [36]** | M | 156 | Depression, OCD | Median reduction of 31.25% in OCD (Y-BOCS) Median reduction of 38.89% in depression (BDI) | Median reduction of 31.25% in OCD (Y-BOCS) Median reduction of 38.89% in depression (BDI) |
Coulombe et al. [35]** | M | 58 | Depression, anxiety, OCD | Range of change of − 75 to + 100% in OCD (Y-BOCS) Range of change of − 2.6 to + 58% in anxiety (STAI) Range of change of − 80 to + 100% in depression (HAM-D) | Range of change of − 75 to + 100% in OCD (Y-BOCS) Range of change of − 2.6 to + 58% in anxiety (STAI) Range of change of − 80 to + 100% in depression (HAM-D) |
The International Deep Brain Stimulation Database and Registry
Meta-analyses
Retrospective analysis on long-term follow-up
Target selection
Adverse events
Study | Type of the study | Number of patients included | Total number of different AEs | Stimulation-related AEs* | Procedure-related AEs* | Absolute number of infections |
---|---|---|---|---|---|---|
Baldermann et al. [36] | M | 156 | Not reported | Number of events not reported, descriptive results: gaze disturbances, mood deterioration, dysarthria, psychotic symptoms, erectile dysfunction, memory impairment, anxiety, weight gain, agitation, tiredness, nausea, hypotonia, impulsivity, dizziness, poor balance, speech problems, worsening of tics, hypomania, suicide attempt, apathy | Not reported | Not reported |
Coulombe et al. [35] | M | 58 | 16 | N = 16, tension headache, worsening of preexisting tremor, transient blurring of vision, dizziness, decreased memory, seizure-like episode, suicidal thoughts, decline of attention and mental flexibility, neck tightness, paraesthesias, headedness, parkinsonism, increased OCD, anxiety, agitation, disturbance of eye mobility, dysarthria, nausea, lead removal | N = 8, infection, hematoma, wound revision, subcutaneous hydrops, hardware malfunction, lead tip cyst, lead fracture | N = 3 |
Houeto et al. [25] | RCT | 1/1* | 5 | N = 5, paraesthesias in the contralateral half of the tongue, contraction of the contralateral half of the body, nausea, hypotonia, and anxiety | N = 0 | N = 0 |
Maciunas et al. [26] | RCT | 5/5* | 4 | N = 2, acute psychosis, recurrence of tics | N = 0 | N = 0 |
Welter et al. [27] | RCT | 3/3* | 6 | N = 6, lethargy, transientcheiro-oral or arm paresthesias, nausea, vertigo, anxiety, libido decrease | N = 0 | N = 0 |
Ackermans et al. [31] | RCT | 6/6* | 9 | N = 5, lack of energy, nystagmus, blurred vision, fixation problem, impaired vertical gaze | N = 3, parenchymal hemorrhage, infection, varying motor and psychiatric symptoms (lethargy, binge eating, dysarthria, apathy, gait disturbances and frequent falls) | N = 1 |
Kefalopoulou et al. [30] | RCT | 13/15* | 23 | N = 19, deterioration of condition, hypomania, increased anxiety, insomnia, irritability, tiredness, headaches, mood deterioration, emotional lability, upper-respiratory tract infection, abdominal rush, panic attacks, mild dysarthria, lower limb dyskinesia | N = 7, battery infection, prolonged pain around IPG, keloid scar, burr-hole cap discomfort, connection cable discomfort, upper-respiratory tract infection | N = 2 |
Welter et al. [29] | RCT | 16/16* | 29 | N = 15, increase in tic severity and anxiety, depression, transient loss of balance, nausea and vertigo, sleep disorder, falls, dysarthria, abnormal movements resembling dyskinesia, weight gain | N = 14, infection leading to removal of stimulator and electrodes, misplacement of electrode, serious suffusion around head scar, device migration, headache, asthenia, hardware-related pain, | N = 6 |
Müller-Vahl et al. [28] | RCT | 10/10* | 20/16 | N = 31, headache, dizziness, paraesthesia, teeth gnashing, tremor of extremities, tiredness, double vision, dystonic movements of the hand, speech blockade, increase of tics, dysphoria, sleeping problems, deterioration of OCD | N = 5, cable dysfunction, superficial wound infection, chronic infections of stimulator’s area (subclavical region) | N = 4 |
Baldermann et al. [32] | RCT | 8/8 | 12 | N = 6, Increase in self-injurious behaviors, increased irritability, dysarthria, micrographia | N = 2, postoperatively measured increased impedances, discomfort with cable | N = 0 |
Recommendations from recently published guidelines
Results of the ESSTS survey
Future developments
Updated recommendations of the ESSTS DBS guidelines group
Clinical problem | Suggestions | Rationale |
---|---|---|
Age limit | No age limit is recommended | In 2006, an expert group [132] recommended an age limit of 25 years (with rare potential exceptions). However, during the last decades, 58 patients younger than 25 years have received DBS [35]. Since then, different age limits (18 or 21 years) have been suggested by different groups [133]. In 2015, in their updated recommendations Schrock et al. [129] suggested that there should be no age limit, but the decision should be taken individually. Although in the majority of patients tics improve during the course of the disease, it is unclear, whether, when and to what extent severely affected patients may await a significant improvement. Since, there is no evidence that DBS is less efficacious in children, adolescents and young adults with TS—although direct comparisons are missing—evidence is missing justifying any age limit |
Functional “tic-like” movement disorder | The diagnosis of a functional “tic-like” movement disorder must be excluded. In particular, co-occurrence of tics and functional “tic-like” movements should be taken into consideration before making the diagnosis of “otherwise treatment-refractory” TS | The diagnosis of a functional movement disorder with “tic-like movements” must be excluded. From clinical experience it can be assumed that the prevalence of functional tic-like movements is increasing and/or physicians are increasingly aware of this phenomenon. Most of these patients present with severe and complex symptoms that do not respond to anti-tic treatments (including antipsychotics and behavioral therapy), and, therefore, might be erroneously misdiagnosed with severe and “treatment-refractory” TS. In addition, there is increasing evidence that in some patients with confirmed TS, in addition, functional tic-like movements coexist. In the literature, this phenomenon has also been described as “tic attacks” [134], since functional tic-like movements may resemble TS-related tic exacerbations. Accordingly, it has been speculated that inconsistent data on DBS in TS might at least in part be influenced by results obtained from patients who suffer—in addition or solely—from functional ‘tic-like’ movements [135, 136] |
Primary treatment goal | The reduction of tics—and not the improvement of comorbidities—should be the primary goal of DBS | Only limited data is available regarding efficacy of DBS on psychiatric comorbidities in TS. While there seems to be some beneficial effect on comorbid depression, effects on OCS and OCD varied, and there seems to be no effect on anxiety and ADHD. Therefore, best possible treatment of psychiatric comorbidities should be established prior to surgery |
Treatment refractoriness | Most authors suggest to assume ‘‘treatment refractoriness’’, if behavioral interventions as well as pharmacotherapy with 3 different drugs including both a typical and an atypical antipsychotic in adequate dosage over an adequate period of time do not result in a significant tic reduction or lead to unbearable AEs | There is no generally accepted definition available for ‘‘treatment refractoriness’’ in TS. Although different patients may respond in a different way to different antipsychotics, three different drugs seem to be adequate to determine treatment refractoriness. Since clonidine is less commonly used in Europe compared to the USA and many European experts are convinced that clonidine is only effective in case of comorbid ADHD and in these cases less effective compared to antipsychotics, we believe that treatment with clonidine must not be undertaken to determine ‘‘treatment refractoriness’’. Although several other drugs have been recommended for the treatment of tics, in Europe none of these drugs is approved or can be recommended without reservation. Although haloperidol is the only drug that is formally licensed in many European countries for the indication tics and TS, due to relevant AEs it can no longer be recommended without restrictions. Since treatment strategies also depend on availability and approval in respective countries, we recommend not to stick to a specific number of different treatments before DBS, but suggest to use at least three different drugs before considering DBS |
Target | Altogether eight different targets have been suggested for DBS in TS. Based on current knowledge most experts recommend to use either thalamus (CM–Pf and/or CM–Pf/Voi) or GPi (postero-ventrolateral or anteromedial) | Currently, there are no generally accepted predictors known suggesting superiority of one target over another one. Recommendation for use of thalamus and GPi DBS is largely based on the fact that these targets have been used much more common compared to all other targets. It has been speculated that different targets might be comparable effective, since they may form a common network involved in TS |
Number of electrodes and targets | In the vast majority of patients, bilateral stimulation at one target has been performed. Only in single cases unilateral DBS at one target or simultaneous stimulation at two targets has been performed. | Bilateral stimulation at one target is the standard procedure in TS. However, simultaneous implantation of 4 electrodes at two targets has alternatively been suggested to increase options for stimulation without further surgery. If tics mainly occur on one body part, (contralateral) unilateral DBS can be taken into consideration |