Effectiveness and safety of safinamide in routine clinical practice in a Belgian Parkinson's disease population: an open-label, levodopa add-on study.

BACKGROUND: Safinamide is a recent multimodal antiparkinsonian drug that inhibits monoamine oxidase B and modulates the glutamatergic system with positive effects on motor and nonmotor symptoms of Parkinson's disease (PD). This post-hoc analysis of the European SYNAPSES study provides first-time data on the use of safinamide in routine clinical practice in Belgium. OBJECTIVE: To describe the efficacy and safety of safinamide in Belgian PD patients in real-life conditions. METHODS: Post-hoc analysis of the Belgian cohort from the European SYNAPSES trial, which was an observational, multicenter, retrospective-prospective cohort study. Patients were followed up to 12 months. Analyses were performed in the overall population and according to different criteria such as the age limit (> 75 years), presence or absence of relevant comorbidities, presence or absence of psychiatric conditions such as depression and anxiety, patients on levodopa monotherapy or levodopa in combination with other treatments, patients on rasagiline before inclusion or not. RESULTS: Of the 172 patients included, 29.2% were > 75 years, 58.9% had relevant comorbidities and 32.7% had psychiatric conditions. Almost all the patients reported motor (98.8%) or non-motor (86.3%) symptoms. During the study, 36.3% of patients reported drug-related reactions. The adverse drug reactions were those already described in the patients' information leaflet. The majority were mild or moderate and completely resolved and no differences were detected between the subgroups of patients. Almost 35% of the patients demonstrated a clinically significant improvement in the UPDRS and 50% of the patients with wearing-off at baseline, did not report wearing-off anymore after one year of treatment. Patients under levodopa monotherapy compared to patients receiving levodopa combined with other antiparkinsonian treatments benefit more from safinamide treatment. Patients switched from rasagiline to safinamide seemed also to benefit more from safinamide treatment. CONCLUSION: The study confirms the excellent safety and efficacy profile of safinamide, particularly in more vulnerable groups of patients such as the elderly and patients with significant comorbidities or psychiatric conditions such as depression or anxiety.

Subcortical Stimulation with Tip of Ultrasound Aspirator.

BACKGROUND: During resection of intrinsic brain tumors in eloquent areas, particularly under awake mapping, subcortical stimulation is mandatory to avoid irreversible deficits by damaging white fiber tracts. The current practice is to alternate between subcortical stimulation with an appropriate probe and resection of tumoral tissue with an ultrasound aspiration device. Switching between different devices induces supplementary movement and possible tissue trauma, loss of time, and inaccuracies in the localization of the involved area. OBJECTIVE: To use one device for both stimulation as well as a resecting tool. METHODS: The tip of different ultrasound aspiration devices is currently used for monopolar current transmission (e.g., for vessel coagulation in liver surgery). We use the same circuitry for monopolar subcortical stimulation when connected with the usual stimulator devices. RESULTS: We have applied this method since 2004 in over 500 patients during tumor resection with cortical and subcortical stimulation, mostly with awake language and motor monitoring. CONCLUSION: A method is presented using existing stimulation and wiring devices by which simultaneous subcortical stimulation and ultrasonic aspiration are applied with the same tool. The accuracy, safety, and speed of intrinsic intracranial lesion resection can be improved when subcortical stimulation is applied.

Intestinal levodopa infusion: the Belgian experience.

Data concerning efficacy, safety, and patient satisfaction of levodopa/carbidopa intestinal gel (LCIG, Duodopa, AbbVie, Wavre, Belgium) infusion in routine clinical practice were needed to maintain reimbursement of the drug in Belgium. Patients with advanced Parkinson's disease in 27 neurology centers across Belgium were included. Of 100 patients who underwent naso-intestinal (NI) evaluation with LCIG, 67 received permanent treatment with LCIG via percutaneous endoscopic gastrostomy and jejunal tube (PEG/J). Efficacy was evaluated at baseline (on levodopa) and during a follow-up (FU) visit (on LCIG) using the Unified Parkinson's Disease Rating Scale (UPDRS) IV. Patient appraisal of the Duodopa system was evaluated using a visual analog scale for therapy compliance, user-friendliness, and global appreciation. Safety was assessed by reporting suspected adverse drug reactions (ADRs) and medical device-related complaints. FU evaluations were conducted in 37 patients. Significant improvement at FU was observed for motor complications (UPDRS IV) as the mean change from baseline to FU was -6.3 (95 % CI -8.1 to -4.5). Patient appraisal showed high scores for hospital delivery, user-friendliness, and patient global appreciation, as well as family appreciation of the system on daily life. Few ADRs and system malfunctions were reported, with no unexpected ADRs. In conclusion, the symptoms and impact of Parkinsonism improved markedly when LCIG PEG/J was initiated.

Selecting deep brain stimulation or infusion therapies in advanced Parkinson's disease: an evidence-based review.

Motor complications in Parkinson's disease (PD) result from the short half-life and irregular plasma fluctuations of oral levodopa. When strategies of providing more continuous dopaminergic stimulation by adjusting oral medication fail, patients may be candidates for one of three device-aided therapies: deep brain stimulation (DBS), continuous subcutaneous apomorphine infusion, or continuous duodenal/jejunal levodopa/carbidopa pump infusion (DLI). These therapies differ in their invasiveness, side-effect profile, and the need for nursing care. So far, very few comparative studies have evaluated the efficacy of the three device-aided therapies for specific motor problems in advanced PD. As a result, neurologists currently lack guidance as to which therapy could be most appropriate for a particular PD patient. A group of experts knowledgeable in all three therapies reviewed the currently available literature for each treatment and identified variables of clinical relevance for choosing one of the three options such as type of motor problems, age, and cognitive and psychiatric status. For each scenario, pragmatic and (if available) evidence-based recommendations are provided as to which patients could be candidates for either DBS, DLI, or subcutaneous apomorphine.

Double-blind clinical trial of thalamic stimulation in patients with Tourette syndrome.

Deep brain stimulation of the thalamus has been proposed as a therapeutic option in patients with Tourette syndrome who are refractory to pharmacological and psychotherapeutic treatment. Patients with intractable Tourette syndrome were invited to take part in a double-blind randomized cross-over trial assessing the efficacy and safety of stimulation of the centromedian nucleus-substantia periventricularis-nucleus ventro-oralis internus crosspoint in the thalamus. After surgery, the patients were randomly assigned to 3 months stimulation followed by 3 months OFF stimulation (Group A) or vice versa (Group B). The cross-over period was followed by 6 months ON stimulation. Assessments were performed prior to surgery and at 3, 6 months and 1 year after surgery. The primary outcome was a change in tic severity as measured by the Yale Global Tic Severity Scale and the secondary outcome was a change in associated behavioural disorders and mood. Possible cognitive side effects were studied during stimulation ON at 1 year postoperatively. Interim analysis was performed on a sample of six male patients with only one patient randomized to Group B. Tic severity during ON stimulation was significantly lower than during OFF stimulation, with substantial improvement (37%) on the Yale Global Tic Severity Scale (mean 41.1 ± 5.4 versus 25.6 ± 12.8, P = 0.046). The effect of stimulation 1 year after surgery was sustained with significant improvement (49%) on the Yale Global Tic Severity Scale (mean 42.2 ± 3.1 versus 21.5 ± 11.1, P = 0.028) when compared with preoperative assessments. Secondary outcome measures did not show any effect at a group level, either between ON and OFF stimulation or between preoperative assessment and that at 1 year postoperatively. Cognitive re-assessment at 1 year after surgery showed that patients needed more time to complete the Stroop Colour Word Card test. This test measures selective attention and response inhibition. Serious adverse events included one small haemorrhage ventral to the tip of the electrode, one infection of the pulse generator, subjective gaze disturbances and reduction of energy levels in all patients. The present preliminary findings suggest that stimulation of the centromedian nucleus-substantia periventricularis-nucleus ventro-oralis internus crosspoint may reduce tic severity in refractory Tourette syndrome, but there is the risk of adverse effects related to oculomotor function and energy levels. Further randomized controlled trials on other targets are urgently needed since the search for the optimal one is still ongoing.

Brain activation associated with deep brain stimulation causing dissociation in a patient with Tourette's syndrome.

Dissociation involves a disruption in the integrated functions of consciousness, memory, identity, or perception of the environment. Attempts at localizing dissociative responses have yielded contradictory results regarding brain activation, laterality, and regional involvement. Here, we used a single-day split-dose activation paradigm with single photon emission computed tomography and 99m-Tc ethylcysteinatedimer as a brain perfusion tracer in a patient with Tourette's syndrome undergoing bilateral high-frequency thalamic stimulation for the treatment of tics who developed an alternate personality state during right thalamic stimulation. We documented increased regional cerebral blood flow in bilateral prefrontal and left temporal brain areas during the alternate identity state. We conclude that our findings support the temporal lobe as well as the frontolimbic disconnection hypotheses of dissociation.

Deep brain stimulation in Tourette's syndrome: two targets?

In this report, we describe the effects of bilateral thalamic stimulation in one patient and of bilateral pallidal stimulation in another patient. Both patients suffered from intractable Tourette's syndrome (TS). Any conservative treatment had failed or had been stopped because of unbearable side effects in the 2 patients. In both cases, there was no comorbidity except for associated behavioral symptoms (compulsions). Electrodes were implanted at the level of the medial part of the thalamus (centromedian nucleus, the substantia periventricularis, and the nucleus ventro-oralis internus) in one patient and in the posteroventral part of the globus pallidus internus (GPi) in the other patient. In both cases, deep brain stimulation (DBS) resulted in a substantial reduction of tics and compulsions. These data show that bilateral DBS of the thalamus as well as of the GPi can have a good effect on tics and behavioral symptoms in patients suffering from intractable TS.

Long-term effects of bilateral subthalamic nucleus stimulation in advanced Parkinson disease: a four year follow-up study.

In this study we aimed to investigate the effects of bilateral STN HFS in patients with advanced Parkinson disease (PD) at long-term, with a minimum follow-up of 4 years. Twenty patients (15 men, five women) were included, with a mean age of 60.9+/-8.1 years. Surgery was performed under local anesthesia. The target was defined on computerized tomography (CT). At 3 months, significant improvements were found on the total Unified Parkinson disease rating scale (UPDRS) III (motor) score, in the medication. off (from 42.3+/-9.3 to 19.5+/-6.4), as well as the medication on (from 18.6+/-12.1 to 10.1+/-5.9) phase. The UPDRS IVa (dyskinesias) and IVb (motor fluctuations) scores decreased significantly. At long-term follow-up, there were still significant improvements on the total UPDRS III motor score (from 42.3+/-9.3 to 24.2+/-13.2), as well as in all motor subscores, in the off phase, during stimulation. In the on phase, the only significant improvement was seen for rigidity. Complications included hypomania to mania in four patients. Our results indicate that HFS STN results in long-lasting improvement of the motor symptoms, ADL activities and functional performance in patients suffering from advanced PD. The stimulation induced behavioural changes need special consideration.

Long-term motor effect of unilateral pallidal stimulation in 26 patients with advanced Parkinson disease.

OBJECT: The aim of this study was to evaluate the long-term effects of unilateral pallidal stimulation on motor function in selected patients with advanced Parkinson disease (PD). METHODS: The authors enrolled 26 patients with idiopathic PD in whom there was an asymmetric distribution of symptoms and, despite optimal pharmocological treatment, severe response fluctuations and/or dyskinesias. After the patient had received a local anesthetic agent, a quadripolar electrode (Medtronic model 3387) was implanted at the side opposite the side affected or, if both sides were affected, the side contralateral to the more affected side. No serious complications occurred. After 3 months, the total Unified PD Rating Scale (UPDRS) Part III score decreased by 50.7% while patients were in the off-medication state (from 26.5 +/- 9.2 to 13.1 +/- 6.1) and by 55.4% while they were in the on-medication state (from 10.6 +/- 6.3 to 4.7 +/- 4.4). Only during the on state was the contralateral effect clearly more pronounced. The UPDRS Part IVa score decreased by 75% (from 3.7 +/- 2.5 to 0.9 +/- 1.1) and the UPDRS Part IVb score by 54.7% (from 3.3 +/- 1.3 to 1.5 +/- 1.3). At long-term follow-up review (32.7 +/- 10.7 months), there was an 8.3% increase in the UPDRS Part III score while patients were in the off state (from 26.5 +/- 9.2 to 28.7 +/- 7.6) and a 40.2% increase in this score while patients were in the on state (from 10.6 +/- 6.3 to 14.9 +/- 5.1). The UPDRS Part IVa score decreased by 28.1% (from 3.7 +/- 2.5 to 2.7 +/- 2.3) and the UPDRS Part IVb score increased by 3.5% (from 3.3 +/- 1.3 to 3.4 +/- 1.6). CONCLUSIONS: Based on these unsatisfactory results at long-term review, the authors conclude that unilateral pallidal stimulation is not an effective treatment option for patients with advanced PD.

Bilateral high-frequency stimulation of the subthalamic nucleus in patients with multiple system atrophy--parkinsonism. Report of four cases.

The aim of this study was to investigate the effect of high-frequency stimulation (HFS) of the subthalamic nucleus (STN) in patients with a subtype of multiple system atrophy (MSA) in which levodopa-unresponsive MSA parkinsonism (MSA-P) is predominant. After a local anesthetic was administered, electrodes were stereotactically implanted bilaterally into the STN in four patients with MSA-P and predominantly akinetorigid symptoms. Unified Parkinson's Disease Rating Scale (UPDRS) scores were evaluated preoperatively, at 1 month, and at long-term follow up. At 1 month the median decrease in the UPDRS III motor score was 22 on the 56-point scale (decreases of 16, 13, 29, and 15 points compared with baseline for Cases 1, 2, 3, and 4, respectively). This was mainly due to an improvement in rigidity and akinesia. The median decrease in the UPDRS II score was 11 on the 52-point scale (respective decreases of 5, 7, 13, and 9 points). At 2 years (mean follow up 27 months) there was a median decrease in the UPDRS III score of 12 (respective decreases of 18, 13, 21, and 9 points), and in the UPDRS II score of 5 (with respective decreases of 2, 2, 17, and 2), both compared with the stimulation off state. At long-term follow up there was an increase in the individual Schwab and England scores of 10 to 15% in the stimulation on compared with the stimulation off condition. There was a beneficial effect of STN HFS in these four patients on both a short-term and a long-term basis. A larger prospective study is justified.

Chronic bilateral thalamic stimulation: a new therapeutic approach in intractable Tourette syndrome. Report of three cases.

Based on the results of thalamotomies described by Hassler in 1970, the authors performed bilateral thalamic high-frequency stimulation (HFS) in three patients with intractable Tourette syndrome (TS). In this report they describe the long-term effects. Three male patients (42, 28, and 45 years of age) had manifested motor and vocal tics since early childhood. The diagnosis of TS was made according to the criteria of the Tourette Syndrome Classification Study Group. Any drug or alternative treatment had been either ineffective or only temporarily effective in all three patients. There was no serious comorbidity. The target for stimulation was chosen at the level of the centromedian nucleus, substantia periventricularis, and nucleus ventrooralis internus. After 2 weeks of test stimulation, the pulse generators were implanted. After a follow-up period of 5 years in the patient in Case 1, 1 year in the patient in Case 2, and 8 months in the patient in Case 3, all major motor and vocal tics had disappeared and no serious complications had occurred. When stimulation was applied at the voltage necessary to achieve an optimal result on the tics, a slight sedative effect was noted in all three patients. In the patients in Cases 1 and 3 there were stimulation-induced changes in sexual behavior. Chronic thalamic HFS may be an effective and safe treatment for medically intractable TS in adult patients. Unwanted stimulation-induced side effects may occur.

Case-control study of environmental risk factors for Parkinson's disease in Belgium.

The aetiology of Parkinson's disease (PD) is unknown and said to be multifactorial. We report on a retrospective epidemiological case control study, performed in Flanders during a 3-year period, investigating known and potential environmental risk factors for PD by means of questionnaires. We investigated 423 prevalent patients and 205 spouse-controls. We found familial occurrence in 15% of the patients, a mean age of onset of 58 years, and a clear male preponderance (male/female ratio 1.53). Our results suggest more nulliparity among female PD patients (95% CI: 1.08-5.76). We found a discrete clustering of patients in areas with intensive metallurgic frequently employed in metallurgy than controls (95% CI: 1.04-9.20). Furthermore, patients were clearly more exposed to zinc (95% CI: 1.51-90.90) and toluene (95% CI: 1.03 58.82). Male patients report more prostatectomy-surgery (95% CI: 1.54-17.24).