Domenico Servello

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.

Microvascular decompression for trigeminal neuralgia: comments on a series of 250 cases, including 10 patients with multiple sclerosis

OBJECTIVE To examine surgical findings and results of microvascular decompression (MVD) for trigeminal neuralgia (TN), including patients with multiple sclerosis, to bring new insight about the role of microvascular compression in the pathogenesis of the disorder and the role of MVD in its treatment. METHODS Between 1990 and 1998, 250 patients affected by trigeminal neuralgia underwent MVD in the Department of Neurosurgery of the “Istituto Nazionale Neurologico C Besta” in Milan. Limiting the review to the period 1991–6, to exclude the “learning period” (the first 50 cases) and patients with less than 1 year follow up, surgical findings and results were critically analysed in 148 consecutive cases, including 10 patients with multiple sclerosis. RESULTS Vascular compression of the trigeminal nerve was found in all cases. The recurrence rate was 15.3% (follow up 1–7 years, mean 38 months). In five of 10 patients with multiple sclerosis an excellent result was achieved (follow up 12–39 months, mean 24 months). Patients with TN for more than 84 months did significantly worse than those with a shorter history (p<0.05). There was no mortality and most complications occurred in the learning period. Surgical complications were not related to age of the patients. CONCLUSIONS Aetiopathogenesis of trigeminal neuralgia remains a mystery. These findings suggest a common neuromodulatory role of microvascular compression in both patients with or without multiple sclerosis rather than a direct causal role. MVD was found to be a safe and effective procedure to relieve typical TN in patients of all ages. It should be proposed as first choice surgery to all patients affected by TN, even in selected cases with multiple sclerosis, to give them the opportunity of pain relief without sensory deficits.

Thalamic deep brain stimulation for treatment-refractory Tourette syndrome: two-year outcome.

Background: Eighteen patients with severe and refractory Tourette syndrome (TS) underwent bilateral thalamic deep brain stimulation (DBS). Objective: To assess the long-term outcome on tics, behavioral symptoms, and cognitive functions in the largest case series of thalamic DBS for TS to date. Methods: In this prospective cohort study, 15 of the original 18 patients were evaluated before and after surgery according to a standardized protocol that included both neuropsychiatric and neuropsychological assessments. Results: In addition to marked reduction in tic severity (p = 0.001), 24-month follow-up ratings showed improvement in obsessive-compulsive symptoms (p = 0.009), anxiety symptoms (p = 0.001), depressive symptoms (p = 0.001), and subjective perception of social functioning/quality of life (p = 0.002) in 15 of 18 patients. There were no substantial differences on measures of cognitive functions before and after DBS. Conclusions: At 24-month follow-up, tic severity was improved in patients with intractable Tourette syndrome (TS) who underwent bilateral thalamic deep brain stimulation. Available data from 15 of 18 patients also showed that neuropsychiatric symptoms were improved and cognitive performances were not disadvantaged. Controlled studies on larger cohorts with blinded protocols are needed to verify that this procedure is effective and safe for selected patients with TS. Level of evidence: This study provides class IV evidence that bilateral thalamic deep brain stimulation reduces global tic severity measured 24 months after implantation in patients with severe intractable Tourette syndrome.

Deep brain stimulation and cognitive functions in Parkinson's disease: A three-year controlled study

There is debate over the cognitive and behavioral effects of deep brain stimulation (DBS) of the subthalamic nucleus (STN) in advanced Parkinsons disease (PD). To evaluate these effects, we performed a prospective, naturalistic controlled, 3‐year follow‐up study. A total of 65 PD patients were enrolled, of whom 32 underwent STN‐DBS (PD‐DBS) and 33, even though eligible for this treatment, declined surgery and chose other therapeutic procedures (PD‐control). Motor and neuropsychological functions were assessed in all the subjects at baseline (T0) and 36 months (T36). The PD‐DBS patients were also evaluated at 1, 6, 12, and 24 months after surgery (T1, T6, T12, and T24). At T1, compared with T0, the PD‐DBS patients recorded worse logical executive function task and verbal fluency (FAS) scores, whereas their performance of memory tasks remained stable. At T12, their cognitive profile had returned within the pre‐DBS range, thereafter remaining stable until T36. FAS scores at T36 were significantly worse in the PD‐DBS compared with the PD‐control patients. This is the first long‐term naturalistic controlled study of cognitive functions in PD patients submitted to STN‐DBS. Our results confirm previous reports of a worsening of verbal fluency after DBS, but show that STN‐DBS seems to be relatively safe from a cognitive standpoint, as the short‐term worsening of frontal‐executive functions was found to be transient.

Tourette's Syndrome and Role of Tetrabenazine Review and Personal Experience

Gilles de la Tourette’s syndrome (Tourette’s syndrome; TS) is an inherited tic disorder commonly associated with other neurobehavioural conditions such as attention-deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD). While the clinical presentation of TS and other features of this disorder have been well characterized, the genetic and neurobiological basis of the disease remains incompletely elucidated. The suggestion of a central role of dopamine in the aetiology of TS has been made on the basis of experimental studies, evidence from neuroimaging studies and the therapeutic response patients with TS have to agents that antagonize or interfere with putative dopaminergic pathways. Tetrabenazine is such an agent; it depletes presynaptic dopamine and serotonin stores and blocks postsynaptic dopamine receptors. In clinical studies, tetrabenazine has been found to be effective in a wide range of hyperkinetic movement disorders, including small numbers (<50) of patients with TS in some studies. Results of a retrospective chart review enrolling only patients with TS (n = 77; mean age ≈15 years) showed that 2 years’ treatment with tetrabenazine resulted in an improvement in functioning and TS-related symptoms in over 80% of patients, findings that suggest that treatment with tetrabenazine may have long-term benefits. The authors’ experience with 120 heavily co-medicated patients with TS confirms these findings. Long-term (mean 19 months) tetrabenazine treatment resulted in a Clinical Global Impressions of Change scale rating of ‘improved’ in 76% of patients. Such findings are promising and suggest that tetrabenazine may be suitable as add-on therapy in patients for whom additional suppression of tics is required.

Subthalamic Local Field Beta Oscillations during Ongoing Deep Brain Stimulation in Parkinson's Disease in Hyperacute and Chronic Phases

In the past years, local field potential (LFP) signals recorded from the subthalamic nucleus (STN) in patients undergoing deep brain stimulation (DBS) for Parkinson’s disease (PD) disclosed that DBS has a controversial effect on STN beta oscillations recorded 2–7 days after surgery for macroelectrode implantation. Nothing is known about these DBS-induced oscillatory changes 30 days after surgery. We recorded STN LFPs during ongoing DBS in 7 patients with PD, immediately (hyperacute phase) and 30 days (chronic phase) after surgery. STN LFP recordings showed stationary intranuclear STN beta LFP activity in hyperacute and chronic phases, confirming that beta peaks were also present in chronic recordings. Power spectra of nuclei with significant beta activity (54% of the sample) showed that it decreased significantly during DBS (p = 0.021) under both recording conditions. The time course of beta activity showed more evident DBS-induced changes in the chronic than in the hyperacute phase (p = 0.014). DBS-induced changes in STN beta LFPs in patients undergoing DBS in chronic phase provide useful information for developing a new neurosignal-controlled adaptive DBS system.

De novo and rescue DBS leads for refractory Tourette syndrome patients with severe comorbid OCD: a multiple case report

Invasive treatment for Gilles de la Tourette syndrome has shown interesting results in a number of published reports; it seems to be evolving into a promising therapeutic procedure for those patients demonstrating disabling clinical pictures who are refractory to conservative treatments. There are important issues concerning the stimulated brain target, with different nuclei currently under investigation. Our group asked in this pilot study whether Tourette syndrome could be treated by tailoring specific brain targets for specific symptoms. Deep brain stimulation for Tourette syndrome may thus in the future be tailored and patient specific, utilizing specific target regions for individual clinical manifestations. In our early experience we did not adequately address non-motor clinical symptoms as we only used a thalamic target. More recently in an obsessive compulsive disease cohort we have had success in using the anterior limb of the internal capsule and nucleus accumbens region as targets for stimulation. We therefore explored the option of a “rescue” procedure for our Tourette patients with persistent obsessive-compulsive disorder following ventralis oralis/centromedianus-parafascicularis (Vo/CM-Pf) deep brain stimulation. Following two cases where rescue anterior limb of internal capsule/nucleus accumbens leads were employed, we performed two additional procedures (anterior limb of the internal capsule plus ventralis oralis/centromedianus-parafascicularis and anterior limb of the internal capsule alone) with some mild improvement of comorbid obsessive–compulsive disorder, although the number of observations in this case series was low. Overall, the effects observed with using the anterior limb of the internal capsule either alone or as a rescue were less than expected. In this report we detail our experience with this approach.

Multiple-source current steering in subthalamic nucleus deep brain stimulation for Parkinson's disease (the VANTAGE study): a non-randomised, prospective, multicentre, open-label study

BACKGROUND High-frequency deep brain stimulation (DBS) with a single electrical source is effective for motor symptom relief in patients with Parkinsons disease. We postulated that a multiple-source, constant-current device that permits well defined distribution of current would lead to motor improvement in patients with Parkinsons disease. METHODS We did a prospective, multicentre, non-randomised, open-label intervention study of an implantable DBS device (the VANTAGE study) at six specialist DBS centres at universities in six European countries. Patients were judged eligible if they were aged 21-75 years, had been diagnosed with bilateral idiopathic Parkinsons disease with motor symptoms for more than 5 years, had a Hoehn and Yahr score of 2 or greater, and had a Unified Parkinsons disease rating scale part III (UPDRS III) score in the medication-off state of more than 30, which improved by 33% or more after a levodopa challenge. Participants underwent bilateral implantation in the subthalamic nucleus of a multiple-source, constant-current, eight-contact, rechargeable DBS system, and were assessed 12, 26, and 52 weeks after implantation. The primary endpoint was the mean change in UPDRS III scores (assessed by site investigators who were aware of the treatment assignment) from baseline (medication-off state) to 26 weeks after first lead implantation (stimulation-on, medication-off state). This study is registered with ClinicalTrials.gov, number NCT01221948. FINDINGS Of 53 patients enrolled in the study, 40 received a bilateral implant in the subthalamic nucleus and their data contributed to the primary endpoint analysis. Improvement was noted in the UPDRS III motor score 6 months after first lead implantation (mean 13·5 [SD 6·8], 95% CI 11·3-15·7) compared with baseline (37·4 [8·9], 34·5-40·2), with a mean difference of 23·8 (SD 10·6; 95% CI 20·3-27·3; p<0·0001). One patient died of pneumonia 24 weeks after implantation, which was judged to be unrelated to the procedure. 125 adverse events were reported, the most frequent of which were dystonia, speech disorder, and apathy. 18 serious adverse events were recorded, three of which were attributed to the device or procedure (one case each of infection, migration, and respiratory depression). All serious adverse events resolved without residual effects and stimulation remained on during the study. INTERPRETATION The multiple-source, constant-current, eight-contact DBS system suppressed motor symptoms effectively in patients with Parkinsons disease, with an acceptable safety profile. Future trials are needed to investigate systematically the potential benefits of this system on postoperative outcome and its side-effects. FUNDING Boston Scientific.

Long-Term, Post-Deep Brain Stimulation Management of a Series of 36 Patients Affected With Refractory Gilles de la Tourette Syndrome

Objectives:  This study aimed to assess the long‐term results of deep brain stimulation (DBS) for patients affected with Gilles de la Tourette syndrome, documenting refractoriness to conservative treatments.

Conflict-dependent dynamic of subthalamic nucleus oscillations during moral decisions.

Although lesional, neuroimaging, and brain stimulation studies have provided an insight into the neural mechanisms of judgement and decision-making, all these works focused on the cerebral cortex, without investigating the role of subcortical structures such as the basal ganglia. Besides being an effective therapeutic tool, deep brain stimulation (DBS) allows local field potential (LFP) recordings through the stimulation electrodes thus providing a physiological “window” on human subcortical structures. In this study we assessed whether subthalamic nucleus LFP oscillations are modulated by processing of moral conflictual, moral nonconflictual, and neutral statements. To do so, in 16 patients with Parkinsons disease (8 men) bilaterally implanted with subthalamic nucleus (STN) electrodes for DBS, we recorded STN LFPs 4 days after surgery during a moral decision task. During the task, recordings from the STN showed changes in LFP oscillations. Whereas the 14–30 Hz band (beta) changed during the movement executed to perform the task, the 5–13 Hz band (low-frequency) changed when subjects evaluated the content of statements. Low-frequency band power increased significantly more during conflictual than during nonconflictual or neutral sentences. We conclude that STN responds specifically to conflictual moral stimuli, and could be involved in conflictual decisions of all kinds, not only those for moral judgment. LFP oscillations provide novel direct evidence that the neural processing of conflictual decision-making spreads beyond the cortex to the basal ganglia and encompasses a specific subcortical conflict-dependent component.