Randomized double-blind sham-controlled trial of thalamic versus GPi stimulation in patients with severe medically refractory Gilles de la Tourette syndrome.

BACKGROUND: There are still no sufficient data regarding the use of deep brain stimulation (DBS) in Gilles de la Tourette syndrome (GTS) and no agreement on optimal target. OBJECTIVE: To compare efficacy and safety of bilateral DBS of thalamus (centromedian-ventro-oral internus, CM-Voi) versus posteroventral lateral globus pallidus internus (pvl GPi)) versus sham stimulation, and baseline in severe medically refractory GTS. METHODS: In this randomized double-blind sham stimulation-controlled trial (RCT), 10 patients (3 women, mean age = 29.4 ± 10.2 SD, range 18-47) underwent three blinded periods each lasting three months including (i) sham, (ii) pvl GPi (on-GPi), and (iii) thalamic stimulation (on-thal) followed by an open uncontrolled long-term follow-up (up to 9 years) with individually determined target and stimulation settings. RESULTS: Nine patients completed the RCT. At group level, on-GPi - but not on-thal - resulted in a significant tic reduction compared to baseline, but had no effect on premonitory urges and psychiatric comorbidities. Direct comparisons of targets resulted in inconsistent or negative (compared to sham) findings. During follow-up, we found no improvement of tics, comorbidities, and quality of life at group level, however, single patients benefitted continuously from thalamic DBS. At last follow-up 89.9 months (mean) after surgery, 50% of patients had discontinued DBS. Hardware infections occurred in 3/10 patients. CONCLUSION: Our data suggest that the initial effect of pvl GPi DBS is superior to thalamic (CM-Voi) DBS. While half of the patients discontinued treatment, single patients benefitted from thalamic DBS even after years. It is likely that outcome is influenced by various factors beyond the mere change in tic severity.

The anterior and posterior pedunculopontine tegmental nucleus are involved in behavior and neuronal activity of the cuneiform and entopeduncular nuclei.

Loss of cholinergic neurons in the mesencephalic locomotor region, comprising the pedunculopontine nucleus (PPN) and the cuneiform nucleus (CnF), is related to gait disturbances in late stage Parkinson's disease (PD). We investigate the effect of anterior or posterior cholinergic lesions of the PPN on gait-related motor behavior, and on neuronal network activity of the PPN area and basal ganglia (BG) motor loop in rats. Anterior PPN lesions, posterior PPN lesions or sham lesions were induced by stereotaxic microinjection of the cholinergic toxin AF64-A or vehicle in male Sprague-Dawley rats. First, locomotor activity (open field), postural disturbances (Rotarod) and gait asymmetry (treadmill test) were assessed. Thereafter, single-unit and oscillatory activities were measured in the non-lesioned area of the PPN, the CnF and the entopeduncular nucleus (EPN), the BG output region, with microelectrodes under urethane anesthesia. Additionally, ECoG was recorded in the motor cortex. Injection of AF64-A into the anterior and posterior PPN decreased cholinergic cell counts as compared to naive controls (P<0.001) but also destroyed non-cholinergic cells. Only anterior PPN lesions decreased the front limb swing time of gait in the treadmill test, while not affecting other gait-related parameters tested. Main electrophysiological findings were that anterior PPN lesions increased the firing activity in the CnF (P<0.001). Further, lesions of either PPN region decreased the coherence of alpha (8-12 Hz) band between CnF and motor cortex (MCx), and increased the beta (12-30 Hz) oscillatory synchronization between EPN and the MCx. Lesions of the PPN in rats had complex effects on oscillatory neuronal activity of the CnF and the BG network, which may contribute to the understanding of the pathophysiology of gait disturbance in PD.

Human hypothalamus shows differential responses to basic motivational stimuli--an invasive electrophysiology study.

The hypothalamus supports basic motivational behaviours such as mating and feeding. Recording directly from the posterior inferior hypothalamus in a male patient receiving a deep brain stimulation (DBS) electrode for the alleviation of cluster headache, we tested the hypothalamic response to different classes of motivational stimuli (sexually relevant: pictures of dressed and undressed women; pictures of food) and pictures of common objects as control. Averaged local field potentials (LFP) to sexually relevant stimuli were characterized by a biphasic significantly enhanced response (relative to objects; bootstrapping statistics) with a first phase starting at around 200 ms and a second phase peaking at around 600 ms. Sexually relevant stimuli also showed a greatly enhanced positivity relative to other stimulus classes in surface event-related potentials in a group of 11 male control participants. It is suggested that the hypothalamus is involved in the recruitment of attentional resources by sexually relevant stimuli reflected in this surface positivity. In a second session, the response to food stimuli relative to objects was tested in two states: after fasting for 14 h, LFPs to food and object stimuli showed significant differences in between 300 and 850 ms, which disappeared after a full high-calorie meal, thus replicating classic studies in monkeys [Rolls et al., Brain Res (1976) 111:53-66]. The current data are the first to demonstrate hypothalamic responses to the sight of motivational stimuli in man and thus shows that recording from DBS electrodes might provide important information about the cognitive functions of subcortical structures.

Deep brain stimulation for dystonia: outcome at long-term follow-up.

OBJECTIVE: Deep brain stimulation (DBS) has emerged as a useful therapeutic option for patients with insufficient benefit from conservative treatment. METHODS: Nine patients with chronic DBS who suffered from cervical dystonia (4), generalized dystonia (2), hemidystonia (1), paroxysmal dystonia (1) and Meige syndrome (1) were available for formal follow-up at three years postoperatively, and beyond up to 10 years. All patients had undergone pallidal stimulation except one patient with paroxysmal dystonia who underwent thalamic stimulation. RESULTS: Maintained improvement was seen in all patients with pallidal stimulation up to 10 years after surgery except in one patient who had a relative loss of benefit in dystonia ratings but continued to have improved disability scores. After nine years of chronic thalamic stimulation there was a mild loss of efficacy which was regained when the target was changed to the pallidum in the patient with paroxysmal dystonia. There were no major complications related to surgery or to chronic stimulation. Pacemakers had to be replaced within 1.5 to 2 years, in general. CONCLUSION: DBS maintains marked long-term symptomatic and functional improvement in the majority of patients with dystonia.

Health-related quality of life in segmental dystonia is improved by bilateral pallidal stimulation.

In contrast to generalized dystonia, reports on the effectiveness of pallidal stimulation on quality of life in patients with segmental dystonia are sparse to date. In ten patients with idiopathic segmental dystonia we prospectively evaluated the effect of pallidal stimulation on quality of life using the SF-36 questionnaire. Parallel to the improvement of motor scores, total SF-36 scores and physical and mental health subscores improved significantly at follow-up to a mean of 17 months postoperatively. Thus, pallidal stimulation should be recognized as a promising treatment option in patients with segmental dystonia.

Chronic spinal cord stimulation in medically intractable orthostatic tremor.

BACKGROUND: Orthostatic tremor with its sense of unsteadiness when standing may have a devastating effect on affected persons. Currently, there are no other treatment options in those who do not respond or who do not tolerate medical treatment. OBJECTIVES: To report on a pilot study on spinal cord stimulation in medically intractable orthostatic tremor. METHODS: Chronic spinal cord stimulation (SCS) was performed in two patients with medically-intractable orthostatic tremor via quadripolar plate electrodes implanted at the lower thoracic spine. The electrodes were connected to implantable pulse generators. RESULTS: Subjective and objective improvement of unsteadiness was achieved within a frequency range of 50 to 150 Hz, and occurred in the presence of stimulation-induced paraesthesia. With optimized stimulation settings polygraphic electromyelogram (EMG) recordings continued to show the typical 14-16 Hz EMG activity. The beneficial effect of SCS was maintained at long-term follow-up. CONCLUSIONS: The results of this pilot study indicate that SCS may be an option in patients with otherwise intractable orthostatic tremor.

Risperidone-responsive segmental dystonia and pallidal deep brain stimulation.

A 67-year-old man with risperidone-responsive segmental dystonia underwent bilateral deep brain stimulation (DBS) of the globus pallidus internus. Prospectively, the authors assessed the Burke-Fahn-Marsden Dystonia Rating Scale in medication (M) and stimulation (S) "on"/"off" states. With DBS at 9 months, the score improved by 86% to 8.5 in M-"on"/S-"on" and 12.5 in M-"off"/S-"on." Studies of the effects of DBS and concomitant medication may be warranted in selected patients treated by DBS for dystonia.

Differential modulation of subcortical target and cortex during deep brain stimulation.

The combination of electrical deep brain stimulation (DBS) with functional imaging offers a unique model for tracing brain circuitry and for testing the modulatory potential of electrical stimulation on a neuronal network in vivo. We therefore applied parametric positron emission tomography (PET) analyses that allow characterization of rCBF responses as linear and nonlinear functions of the experimentally modulated stimulus (variable stimulator setting). In patients with electrodes in the thalamic ventrointermediate nucleus (VIM) for the treatment of essential tremor (ET) here we show that variations in voltage and frequency of thalamic stimulation have differential effects in a thalamo-cortical circuitry. Increasing stimulation amplitude was associated with a linear raise in rCBF at the thalamic stimulation site, but with a nonlinear rCBF response in the primary sensorimotor cortex (M1/S1). The reverse pattern in rCBF changes was observed with increasing stimulation frequency. These results indicate close connectivity between the stimulated nucleus (VIM) and primary sensorimotor cortex. Likewise, stimulation parameter-specific modulation occurs at this simple interface between an electrical and a cerebral system and suggests that the scope of DBS extends beyond an ablation-like on-off effect: DBS could rather allow a gradual tuning of activity within a neuronal circuit.

Effect of chronic pallidal deep brain stimulation on off period dystonia and sensory symptoms in advanced Parkinson's disease.

OBJECTIVE: To investigate the efficacy of chronic pallidal deep brain stimulation (DBS) on off period dystonia, cramps, and sensory symptoms in advanced Parkinson's disease (PD). METHODS: 16 patients (6 women, 10 men; mean age at surgery 65 years) suffering from advanced PD were followed up prospectively for one year after implantation of a monopolar electrode in the posteroventral lateral globus pallidus internus. Unilateral DBS was performed in 9 patients. 10 patients had bilateral procedures (contemporaneous bilateral surgery in 7 and staged bilateral surgery in 3 instances). The decision whether to perform unilateral or bilateral surgery depended on the clinical presentation of the patient. Patients were formally assessed preoperatively, at 3-5 days, 3 months, and 12 months after surgery. RESULTS: In patients who underwent unilateral surgery, pain was present in 7 (78%), off dystonia in 5 (56%), cramps in 6 (67%), and dysaesthesia in 4 (44%). In patients who underwent bilateral surgery, pain was present in 7 (70%), off dystonia in 6 (60%), cramps in 7 (70%), and dysaesthesia in 4 (40%). With unilateral DBS, contralateral off period dystonia was improved by 100% at 1 year postoperatively, pain by 74%, cramps by 88%, and dysaesthesia by 100%. There was less pronounced amelioration of ipsilateral off period dystonia and sensory symptoms. With bilateral DBS, total scores for dystonia were improved by 86%, for pain by 90%, for cramps by 90%, and for dysaesthesia by 88%. The benefit appeared early at the first evaluation 3-5 days after surgery and was stable throughout the follow up period. CONCLUSIONS: Pallidal DBS yields major improvement of off period dystonia, cramps, and sensory symptoms in patients with advanced PD.

Deep brain stimulation of the centre median-parafascicular complex in patients with movement disorders.

The centre median-parafascicular (CM-Pf) complex of the thalamus is considered to be a possible target for deep brain stimulation (DBS) in patients with movement disorders. In a prospective study on the effect of CM-Pf DBS versus somatosensory thalamic DBS on chronic neuropathic pain, three of 12 patients had additional movement disorders. Bifocal quadripolar electrodes were implanted by computed tomography guided stereotactic surgery under local anaesthesia contralaterally to the side of the pain for test stimulation. Two of the three patients with movement disorders had permanent implantation of CM-Pf electrodes. During test stimulation of the left CM-Pf complex for several days, a 67 year old woman received no benefit with respect to the neuropathic pain, but the choreoathetotic movements of her right foot ceased. As the pain syndrome was not improved, she decided not to have permanent implantation. A 74 year old man with postzoster neuralgia and allodynia enjoyed excellent relief from his pain with chronic CM-Pf DBS. In addition, improvement in the tremor at rest was noted. A 72 year old man had sustained reduction in his stump dyskinesias. Further evaluation of the possible role of the "forgotten" central and medial thalamic nuclei in the treatment of movement disorders may be warranted.

Pallidal deep brain stimulation in patients with cervical dystonia and severe cervical dyskinesias with cervical myelopathy.

OBJECTIVES: Surgical treatment of complex cervical dystonia and of cervical dyskinesias associated with cervical myelopathy is challenging. In this prospective study, the long term effect of chronic pallidal stimulation in cervical dystonia and on combining the technique with spinal surgery in patients with severe cervical dyskinesias and secondary cervical myelopathy is described. METHODS: Eight patients with a history of chronic dystonia who did not achieve adequate benefit from medical treatment or botulinum toxin injection participated in the study. Five patients had complex cervical dystonia with tonic postures and phasic movements. Three patients had rapidly progressive cervical myelopathy secondary to severe cervical dyskinesias and dystonia in the context of a generalised movement disorder. Quadripolar electrodes were implanted in the posteroventral lateral globus pallidus internus with stereotactic CT and microelectrode guidance. In the three patients with secondary cervical myelopathy, spinal surgery was performed within a few weeks and included multilevel laminectomies and a four level cervical corporectomy with spinal stabilisation. RESULTS: Improvement of the movement disorder was noted early after pallidal surgery, but the full benefit could be appreciated only with a delay of several months during chronic stimulation. Three months after surgery, patients with cervical dystonia had improved by 38% in the severity score, by 54% in the disability score, and by 38% in the pain score of a modified version of the Toronto western spasmodic torticollis rating scale. At a mean follow up of 20 months, the severity score had improved by 63%, the disability score by 69%, and the pain score by 50% compared with preoperatively. There was also sustained amelioration of cervical dyskinesias in the three patients who underwent spinal surgery. Lead fractures occurred in two patients. The mean amplitude needed for chronic deep brain stimulation was 3.8 V at a mean pulse width of 210 micros, which is higher than that used for pallidal stimulation in Parkinson's disease. CONCLUSIONS: Chronic pallidal stimulation is effective for complex cervical dystonia and it is a useful adjunct in patients with cervical dyskinesias and secondary cervical myelopathy who undergo spinal surgery.

Deactivation of thalamocortical activity is responsible for suppression of parkinsonian tremor by thalamic stimulation: a 99mTc-ECD SPECT study.

Four patients with Parkinson's disease (PD) achieved excellent improvement of their unilateral tremor by chronic deep brain stimulation (DBS) of the contralateral ventral intermediate (Vim) nucleus of the thalamus. Repeated measurements of cerebral blood flow were obtained 14 days apart off and on stimulation using 99mTc-ECD SPECT. Subjects were scanned at rest and the data were compared with those of normal healthy volunteers. During stimulation, there were highly significant deactivations in the motor area and supplementary motor area on the electrode side and in the prefrontal area and the anterior cingulum bilaterally. No cerebellar deactivation was detected. We conclude that the mechanism responsible for suppression of parkinsonian tremor by thalamic stimulation is deactivation of thalamocortical activity.

Concepts and methods in chronic thalamic stimulation for treatment of tremor: technique and application.

OBJECTIVE: To rationalize the technique and reduce the costs associated with chronic deep brain stimulation of the thalamus for treatment of refractory tremor. METHODS: The efficacy and safety of a modification in surgical techniques was prospectively assessed in 94 patients with tremor. Bilateral electrodes were implanted in 29 patients, and 65 patients received unilateral implants. Forty-five patients had Parkinson's disease tremor, 42 patients had essential tremor, and 7 patients had kinetic tremors of different causes. In all instances, intraoperative stimulations to analyze the thresholds of intrinsic and extrinsic responses were performed directly with the implanted leads. The electrodes were repositioned until satisfactory results were achieved. The pulse generators were implanted directly after the first step in the same operative session. Patients were not subjected to interoperative test stimulation trials. RESULTS: Postoperative improvement of tremor at a mean follow-up of 11.9 months was rated as excellent in 47 patients (50%), marked in 37 patients (39%), moderate in 8 patients (9%), and minor in 2 patients (2%). There was no persistent morbidity related to surgery. In patients with Parkinson's disease, the symptomatic improvement of tremor was rated as excellent in 51% of patients, marked in 36%, moderate in 11%, and minor in 2%. In patients with essential tremor, symptomatic outcome was classified as excellent in 57% of patients, marked in 36%, moderate in 5%, and minor in 2%. Six of the seven patients with kinetic tremor achieved marked symptomatic improvement, and one patient experienced moderate improvement. Forty patients experienced stimulation-related side effects. Side effects were mild in general, and they were reversible with a change in electrical parameters. They occurred more frequently in patients who had bilateral stimulation. CONCLUSION: Excellent to marked improvement of tremor is achieved in the majority of patients with physiological target determination via implanted leads in thalamic deep brain stimulation. Interoperative test stimulation trials are unnecessary. Modifications in technique may help to reduce the costs of the related hospital stay.

Chronic thalamic stimulation for treatment of dystonic paroxysmal nonkinesigenic dyskinesia.

The authors report the effect of chronic stimulation of the ventrointermediate (Vim) thalamus for treatment of dystonic paroxysmal nonkinesigenic dyskinesias (PNKD). A 37-year-old patient had a 4-year history of severe and painful PNKD of the right arm. Chronic stimulation through a stereotactically implanted monopolar electrode in the left Vim resulted in a decrease of the frequency, duration, and intensity of the dystonic paroxysmal movement disorder. The benefit of stimulation has been maintained over 4 years of follow-up.

Long-term follow-up study of chronic globus pallidus internus stimulation for posttraumatic hemidystonia.

The authors report the first case of chronic globus pallidus internus (GPi) stimulation for treatment of medically intractable hemidystonia for which long-term follow-up data are available. The patient had developed left-sided low-frequency tremor and hemidystonia after a severe head trauma sustained at 15 years of age. He experienced relief of the tremor but not of the hemidystonia after a thalamotomy was performed in the right hemisphere 3 years postinjury. When the patient was 24 years old, the authors performed a magnetic resonance-guided stereotactic implantation of a monopolar electrode in the right-sided posteroventral GPi. Chronic deep brain stimulation resulted in remarkable improvement of dystonia-associated pain, phasic dystonic movements, and dystonic posture, which was accompanied by functional gain. Postoperative improvement was sustained after 4 years of follow up. Chronic GPi stimulation appears to be a valuable treatment option for posttraumatic dystonia.

Bilateral stimulation of globus pallidus internus for treatment of cervical dystonia.

In three selected patients with severe complex cervical dystonia, continuous bilateral stimulation of the globus pallidus internus was associated with improvement of cervical dystonia, dystonia-associated pain, and functional disability.

Cerebral arteriovenous malformations and movement disorders.

A series of six patients with movement disorders associated with cerebral arteriovenous malformations (AVM) is reported. The AVMs were classified according to the Spetzler-Martin classification as grade V (one patient), grade IV (four patients), and as grade III (one patient). One patient had action-induced hemidystonia caused by a contralateral frontoparietal AVM which compressed the putamen and was supplied partially by enlarged lenticulostriate arteries. Two patients presented with unilateral cortical tremor associated with contralateral high-frontal cortical/subcortical AVMs sparing the basal ganglia. Another patient developed hemidystonia and hemichorea-hemiballism after bleeding of a contralateral temporooccipital AVM and subsequent ischemia. Two patients had focal dystonia after thalamic and basal ganglia hemorrhage from AVMs. Five patients were operated on. The movement disorder was abolished in one patient postoperatively. Different mechanisms were identified that are relevant for the development of AVM-related movement disorders: mass effect, diaschisis, local parenchymal altered cerebral blood flow, and hemorrhagic or ischemic structural lesions.

Expression of major histocompatibility complex antigens in squamous cell carcinomas of the head and neck: effects of interferon gene transfer.

The effect of retroviral-mediated interferon-gamma (IFN-gamma) gene transfer on major histocompatibility complex (MHC) class I and II antigen expression was investigated in 13 head and neck squamous carcinoma cell lines. Six cell lines exhibited increased MHC class I expression, and 10 exhibited increased MHC class II expression after IFN-gamma gene transfer. Differences in MHC antigen expression between parental and transduced cell lines were significant (P = 0. 002) only for cell lines that upregulated MHC class II expression. After incubation in medium containing 100 U/mL recombinant IFN-gamma, or in medium from IFN-gamma retrovirus-transduced NIH 3T3 cells, 12 cell lines significantly upregulated MHC class I expression, and 9 significantly upregulated MHC class II expression. Only cell lines that exhibited increased MHC class II expression after retroviral transduction also upregulated class II expression with exogenous IFN-gamma treatment. Thus some head and neck squamous carcinoma cell lines can upregulate MHC class I and II expression after exogenous application of either IFN-gamma or IFN-gamma retroviral transduction. These are promising findings for head and neck cancer immunotherapy and gene therapy.