Long-term effect of bilateral STN-DBS on non-motor symptoms in Parkinson's disease: A four-year observational, prospective study.

BACKGROUND: Several studies have shown beneficial effects of bilateral stimulation of the subthalamic nucleus (STN-DBS) on motor as well as on non-motor symptoms (NMS) up to 36 months post-surgery in advanced Parkinson's disease (PD) patients. We set to explore the long-term effect of STN-DBS on NMS in a four-year follow-up, prospective, observational study. METHODS: Forty patients were enrolled and assessed at baseline. Twenty-eight were followed-up at 6, 12, 24, 36 and 48 months after the operation. The effect of post-operative time on NMS was analyzed by six-level repeated measures ANOVA. In a post-hoc analysis the follow-up scores were compared to baseline using a paired t-test. RESULTS: The following scores stayed improved up to 24 months after surgery, presented as baseline/24 months, p-value (t-test): total Non-Motor Symptoms Scale score (54.0 ± 5.6/44.9 ± 5.0, p = 0.029), Hamilton Anxiety Scale (14.3 ± 1.3/11.3 ± 1.2, p = 0.019) and PDQ39 (53.4 ± 4.5/40.2 ± 2.9, p = 0.012). PD Sleep Scale 2 remained improved throughout the study (17.4 ± 2.0/12.8 ± 1.3 at 48 months, p = 0.032), while Beck Depression Inventory only at six months post-surgery (9.5 ± 1.2/6.7 ± 0.7 at 6 months, p = 0.006). Montreal Cognitive Assessment remained stable up to 24 months and then declined at 36 months (26.3 ± 0.5/25.4 ± 0.5 at 36 months, p = 0.003), Starkstein Apathy Scale deteriorated throughout the study (7.6 ± 0.7/12.7 ± 0.9 at 48 months, p = 0.006). CONCLUSIONS: We observed beneficial effect of STN-DBS in several but not all domains of NMS at least up to 24 months post-op in advanced PD. Further long-term studies on larger cohorts of PD patients and longer follow-up need to be conducted to better understand the long-term effect of STN-DBS on NMS.

Neurogeriatrics-a vision for improved care and research for geriatric patients with predominating neurological disabilities.

Geriatric medicine is a rapidly evolving field that addresses diagnostic, therapeutic and care aspects of older adults. Some disabilities and disorders affecting cognition (e.g. dementia), motor function (e.g. stroke, Parkinson's disease, neuropathies), mood (e.g. depression), behavior (e.g. delirium) and chronic pain disorders are particularly frequent in old subjects. As knowledge about these age-associated conditions and disabilities is steadily increasing, the integral implementation of neurogeriatric knowledge in geriatric medicine and specific neurogeriatric research is essential to develop the field. This article discusses how neurological know-how could be integrated in academic geriatric medicine to improve care of neurogeriatric patients, to foster neurogeriatric research and training concepts and to provide innovative care concepts for geriatric patients with predominant neurological conditions and disabilities.

Improving the Standard for Deep Brain Stimulation Therapy: Target Structures and Feedback Signals for Adaptive Stimulation. Current Perspectives and Future Directions.

Deep brain stimulation (DBS) is an established therapeutic option for the treatment of various neurological disorders and has been used successfully in movement disorders for over 25 years. However, the standard stimulation schemes have not changed substantially. Two major points of interest for the further development of DBS are target-structures and novel adaptive stimulation techniques integrating feedback signals. We describe recent research results on target structures and on neural and behavioural feedback signals for adaptive deep brain stimulation (aDBS), as well as outline future directions.

Occupancy of pramipexole (Sifrol) at cerebral dopamine D2/3 receptors in Parkinson's disease patients.

Whereas positron emission tomography (PET) with the antagonist ligand [(18)F]fallypride reveals the composite of dopamine D2 and D3 receptors in brain, treatment of Parkinson's disease (PD) patients with the D3-prefering agonist pramipexole should result in preferential occupancy in the nucleus accumbens, where the D3-subtype is most abundant. To test this prediction we obtained pairs of [(18)F]fallypride PET recordings in a group of nine PD patients, first in a condition of treatment as usual with pramipexole (ON-Sifrol; 3 × 0.7 mg p.d.), and again at a later date, after withholding pramipexole 48-72 h (OFF-Sifrol); in that condition the serum pramipexole concentration had declined by 90% and prolactin levels had increased four-fold, in conjunction with a small but significant worsening of PD motor symptoms. Exploratory comparison with historical control material showed 14% higher dopamine D2/3 availability in the more-affected putamen of patients OFF medication. On-Sifrol there was significant (p Ë‚ 0.01) occupancy at [(18)F]fallypride binding sites in globus pallidus (8%) thalamus (9%) and substantia nigra (19%), as well as marginally significant occupancy in frontal and temporal cortex of patients. Contrary to expectation, comparison of ON- and OFF-Sifrol results did not reveal any discernible occupancy in nucleus accumbens, or elsewhere in the extended striatum; present methods should be sensitive to a 10% change in dopamine D2/3 receptor availability in striatum; the significant findings elsewhere in the basal ganglia and in cerebral cortex are consistent with a predominance of D3 receptors in those structures, especially in substantia nigra, and imply that therapeutic effects of pramipexole may be obtained at sites outside the extended striatum.

Pallidal neurostimulation in patients with medication-refractory cervical dystonia: a randomised, sham-controlled trial.

BACKGROUND: Cervical dystonia is managed mainly by repeated botulinum toxin injections. We aimed to establish whether pallidal neurostimulation could improve symptoms in patients not adequately responding to chemodenervation or oral drug treatment. METHODS: In this randomised, sham-controlled trial, we recruited patients with cervical dystonia from centres in Germany, Norway, and Austria. Eligible patients (ie, those aged 18-75 years, disease duration ≥3 years, Toronto Western Spasmodic Torticollis Rating Scale [TWSTRS] severity score ≥15 points) were randomly assigned (1:1) to receive active neurostimulation (frequency 180 Hz; pulse width 120 µs; amplitude 0·5 V below adverse event threshold) or sham stimulation (amplitude 0 V) by computer-generated randomisation lists with randomly permuted block lengths stratified by centre. All patients, masked to treatment assignment, were implanted with a deep brain stimulation device and received their assigned treatment for 3 months. Neurostimulation was activated in the sham group at 3 months and outcomes were reassessed in all patients after 6 months of active treatment. Treating physicians were not masked. The primary endpoint was the change in the TWSTRS severity score from baseline to 3 months, assessed by two masked dystonia experts using standardised videos, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00148889. FINDINGS: Between Jan 19, 2006, and May 29, 2008, we recruited 62 patients, of whom 32 were randomly assigned to neurostimulation and 30 to sham stimulation. Outcome data were recorded in 60 (97%) patients at 3 months and 56 (90%) patients at 6 months. At 3 months, the reduction in dystonia severity was significantly greater with neurostimulation (-5·1 points [SD 5·1], 95% CI -7·0 to -3·5) than with sham stimulation (-1·3 [2·4], -2·2 to -0·4, p=0·0024; mean between-group difference 3·8 points, 1·8 to 5·8) in the intention-to-treat population. Over the course of the study, 21 adverse events (five serious) were reported in 11 (34%) of 32 patients in the neurostimulation group compared with 20 (11 serious) in nine (30%) of 30 patients in the sham-stimulation group. Serious adverse events were typically related to the implant procedure or the implanted device, and 11 of 16 resolved without sequelae. Dysarthria (in four patients assigned to neurostimulation vs three patients assigned to sham stimulation), involuntary movements (ie, dyskinesia or worsening of dystonia; five vs one), and depression (one vs two) were the most common non-serious adverse events reported during the course of the study. INTERPRETATION: Pallidal neurostimulation for 3 months is more effective than sham stimulation at reducing symptoms of cervical dystonia. Extended follow-up is needed to ascertain the magnitude and stability of chronic neurostimulation effects before this treatment can be recommended as routine for patients who are not responding to conventional medical therapy. FUNDING: Medtronic.

Effects of acoustic stimuli used for vestibular evoked myogenic potential studies on the cochlear function.

OBJECTIVE: To study if acoustic stimuli used for vestibular evoked myogenic potential (VEMP) studies can damage the cochlea. STUDY DESIGN: Prospective diagnostic study. SETTING: Academic tertiary referral center. METHODS: In 30 young healthy adults aged between 20 and 35 years without any audiovestibular disorders, cVEMP studies were performed in a standard setting (tone burst, 500 Hz, 133 dB SPL, stimuli rate 200). Before and after acoustic stimulation for the cVEMP examination, the cochlear function was measured using pure tone audiometry and distortion product otoacoustic emissions (DPOAE). Additionally, the subjects were asked about ear symptoms. RESULTS: In all subjects, cVEMP could be recorded. Eight (27%) of them reported subjective hearing symptoms direct after the VEMP examination. All were again free of complaints on the next day. Hearing thresholds did not deteriorate in pure tone audiometry. DPOAE levels decreased on the exposed side in the high-frequency range (4,000-6,000 Hz). The subjects with subjective ear symptoms had a stronger level decrease. In a follow-up measurement 24 hours later, the DPOAE levels showed recovery. CONCLUSION: Acoustic stimuli used to elicit VEMP were found to have an adverse effect on the cochlear function. A clinically relevant hearing loss was not found in our study in healthy adults. Subjective auditory symptoms were reversible within 24 hours. Nevertheless, the stimulus levels and the number of repetitions should be kept as low as possible.

Detection of substantia nigra echogenicities in 3D transcranial ultrasound for early diagnosis of Parkinson disease.

Parkinson's disease (PD) is a neurodegenerative movement disorder caused by decay of dopaminergic cells in the substantia nigra (SN), which are basal ganglia residing within the midbrain area. In the past two decades, transcranial B-mode sonography (TCUS) has emerged as a viable tool in differential diagnosis of PD and recently has been shown to have promising potential as a screening technique for early detection of PD, even before onset of motor symptoms. In TCUS imaging, the degeneration of SN cells becomes visible as bright and hyper-echogenic speckle patches (SNE) in the midbrain. Recent research proposes the usage of 3D ultrasound imaging in order to make the application of the TCUS technique easier and more objective. In this work, for the first time, we propose an automatic 3D SNE detection approach based on random forests, with a novel formulation of SNE probability that relies on visual context and anatomical priors. On a 3D-TCUS dataset of 11 PD patients and 11 healthy controls, we demonstrate that our SNE detection approach yields promising results with a sensitivity and specificity of around 83%.

Dynamic visual cueing in combination with treadmill training for gait rehabilitation in Parkinson disease.

Various cueing techniques as well as treadmill training have been shown to be effective in the gait rehabilitation of patients with Parkinson disease. We present a novel setup combining both dynamic visual cueing and body weight-supported treadmill training. A nonambulatory patient with Parkinson disease received six training sessions. Continuous improvement of gait parameters was observed throughout the course of training. When comparing cued and noncued conditions in individual training sessions, it was found that step length was larger and that gait symmetry was enhanced in the cued condition. At the end of the training period, the patient was capable of walking short distances with a walking frame. In conclusion, dynamic visual cueing in combination with body weight-supported treadmill training seems to be a promising treatment strategy for patients with Parkinson disease, even in the case of severe impairment.

Midbrain segmentation in transcranial 3D ultrasound for Parkinson diagnosis.

Ultrasound examination of the human brain through the temporal bone window, also called transcranial ultrasound (TC-US), is a completely non-invasive and cost-efficient technique, which has established itself for differential diagnosis of Parkinson's Disease (PD) in the past decade. The method requires spatial analysis of ultrasound hyperechogenicities produced by pathological changes within the Substantia Nigra (SN), which belongs to the basal ganglia within the midbrain. Related work on computer aided PD diagnosis shows the urgent need for an accurate and robust segmentation of the midbrain from 3D TC-US, which is an extremely difficult task due to poor image quality of TC-US. In contrast to 2D segmentations within earlier approaches, we develop the first method for semi-automatic midbrain segmentation from 3D TC-US and demonstrate its potential benefit on a database of 11 diagnosed Parkinson patients and 11 healthy controls.

Health-related quality of life and its determinants in Parkinson's disease: results of an Italian cohort study.

Parkinson's disease (PD) is a common neurodegenerative disorder with a progressive disabling course. Health-related quality of life (HrQoL) in Italian patients with PD has not been evaluated. The objective of this study was to evaluate HrQol of an Italian cohort of PD patients and to provide a comprehensive analysis of HrQoL determinants. We performed a cross-sectional survey of 70 outpatients with idiopathic PD recruited in the department of Neurology, Napoli University, Italy. Clinical data included the Unified PD Rating Scale (UPDRS), motor and non-motor symptoms. The generic instrument EuroQol (EQ-5D and EQ-VAS) was used to evaluate HrQol. Factors influencing HrQol were assessed by multivariate regression analysis. Severe problems in at least one dimension of the EQ-5D were experienced by 60% of PD patients versus 4.7% in general Italian population. The dimensions most affected were mobility, pain/discomfort and anxiety/depression with only 17.4%, 18.8% and 17.4% of patients, respectively, reporting no problems in these dimensions. The mean EQ-VAS score was 54.20 ± 18.38. Independent determinants of reduced HrQoL were increased UPDRS scores, motor fluctuations, dyskinesias, depression and dementia. PD strongly affects HrQol in Italian patients. The results of this study should be considered in the development of national healthcare programmes aimed at improvement of the HrQoL in Italian patients with PD. In particular, these programmes should concentrate not only on motor but also on non-motor manifestations of PD.

Costs of Parkinson's disease and antiparkinsonian pharmacotherapy: an Italian cohort study.

OBJECTIVE: Antiparkinsonian pharmacotherapy is costly and the determinants of drug costs in Parkinson's disease (PD) have been poorly investigated. The objective of this study was to investigate the costs of PD and antiparkinsonian drugs in an Italian cohort of patients and identify cost-driving factors of drug therapy. METHODS: Seventy outpatients with idiopathic PD were recruited in the Department of Neurology, Napoli University, Italy. Data on resource utilization were collected for 6 months using a bottom-up approach. Clinical status was evaluated using the Unified Parkinson's Disease Rating Scale. Direct and indirect costs were calculated from the societal perspective (figures of year 2009). Independent determinants of total costs and costs of antiparkinsonian drugs were identified using multivariate regression analysis. RESULTS: The total costs of PD were EUR 8,640 (95% CI: EUR 6,700-11,240) per patient over a 6-month period. Direct costs accounted for 70% of the total costs. Antiparkinsonian drugs (EUR 1,450; 95% CI: EUR 1,220-1,760) were the primary component of costs paid by the health insurance (39.6%) and one of the most expensive components of the direct costs (24.0%). The highest copayments made by patients were for antiparkinsonian drugs and medical equipment (58%). Independent determinants of the increased costs of antiparkinsonian pharmacotherapy were younger age and occurrence of motor fluctuations. CONCLUSIONS: Antiparkinsonian pharmacotherapy is one of the major cost components of PD-related costs for health insurance. It imposes a considerable economic burden on patients and their families as well.

Increased alpha-synuclein aggregation following limited cleavage by certain matrix metalloproteinases.

Recent evidence indicates that protein aggregation and in particular the formation of toxic protein oligomers is a key mechanism in synucleinopathies such as Parkinson's disease (PD). Post mortem brain tissue studies as well as animal studies furthermore suggest that matrix metalloproteinases (MMPs) are also involved in the pathogenesis of PD. We used confocal single molecule spectroscopy to characterize the influence of MMPs and other proteases on the aggregation of alpha-synuclein. These studies were complemented by the characterization of alpha-synuclein fragment patterns generated by these proteases using gel electrophoresis and mass spectrometry. Limited digestion by MMP-1 and MMP-3, but not by MMP-9, increased the tendency of alpha-synuclein to aggregate. Proteinase K and Trypsin did not increase the level of de novo aggregation of alpha-synuclein. SDS-PAGE as well as MALDI-ToF analysis of limitedly digested alpha-synuclein demonstrate that all proteases generate different fragments of alpha-synuclein. We provide mass spectrometry data of proteolytic alpha-synuclein fragments and propose specific cleavage sites for MMP-1 and MMP-9 in alpha-synuclein. We furthermore found four additional cleavage sites of MMP-3 that had not been described previously. In order to increase aggregation of alpha-synuclein, specific cleavage between the highly charged C-terminal domain and the aggregation-prone NAC domain of alpha-synuclein seems to be crucial. Our findings obtained in vitro in a well-characterized model of pathological alpha-synuclein aggregation indicate that MMP-1 and MMP-3 may also influence pathogenesis of PD in vivo by generation of specific aggregation-enhancing alpha-synuclein fragments resulting from limited proteolysis.

The influence of caloric nystagmus on flash evoked transient and steady-state potentials.

OBJECTIVE: Caloric stimulation leads to a reduction of the cerebral blood flow in the visual cortex. This reduction has been attributed to the suppression of visual input caused by nystagmus induced by caloric stimulation. We investigated the influence of caloric stimulation on transient flash and steady-state flash visual evoked potentials. METHODS: Visual evoked potentials to 1 and 10 Hz flash stimulation were recorded in 12 normal subjects at baseline, during nystagmus induced by caloric stimulation with cold water, and after the cessation of nystagmus. RESULTS: Neither the amplitude of the transient flash visual evoked potentials (1 Hz stimulation) nor the amplitude of the steady-state flash visual evoked potentials (10 Hz stimulation) was influenced by caloric stimulation compared to baseline. CONCLUSIONS: The deactivation of the visual cortex by caloric stimulation does not seem to affect transient flash or steady-state flash visual evoked potentials. Reduction of cerebral blood flow in the visual cortex does not affect the processing of visual qualities (e.g., luminance and pattern). SIGNIFICANCE: Caloric stimulation does not reduce the amplitudes of transient flash or steady-state flash visual evoked potentials.