Long-term efficacy of deep brain stimulation for essential tremor: An observer-blinded study.

OBJECTIVE: Deep brain stimulation (DBS) of the ventral intermediate thalamic nucleus (Vim) is established for medically refractory severe essential tremor (ET), but long-term efficacy is controversial. METHODS: Twenty patients with ET with DBS had standardized video-documented examinations at baseline, in the stimulation-on condition at short term (13.1 ± 1.9 months since surgery, mean ± SEM), and in the stimulator switched on and off (stim-ON/OFF) at long term; all assessments were done between 32 and 120 months (71.9 ± 6.9 months) after implantation. The primary outcome was the Tremor Rating Scale (TRS) blindly assessed by 2 trained movement disorder neurologists. Secondary outcomes were TRS subscores A, B, and C; Archimedes spiral score; and activities of daily living score. At long-term follow-up, tremor was additionally recorded with accelerometry. The rebound effect after switching the stimulator off was assessed for 1 hour in a subgroup. RESULTS: Tremor severity worsened considerably over time in both in the nonstimulated and stimulated conditions. Vim-DBS improved the TRS in the short term and long term significantly. The spiral score and functional measures showed similar improvements. All changes were highly significant. However, the stimulation effect was negatively correlated with time since surgery (ρ = -0.78, p < 0.001). This was also true for the secondary outcomes. Only one-third of the patients had a rebound effect terminated 60 minutes after the stimulator was switched off. Long-term worsening of the TRS was more profound during stim-ON than in the stim-OFF condition, indicating habituation to stimulation. CONCLUSION: Vim-DBS loses efficacy over the long term. Efforts are needed to improve the long-term efficacy of Vim-DBS. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with medically refractory severe ET, the efficacy of Vim-DBS severely decreases over 10 years.

Assessment of Head Tremor with Accelerometers Versus Gyroscopic Transducers.

BACKGROUND: Accelerometers and gyroscopes are used commonly in the assessment of hand tremor, but their validity in the assessment of head tremor has not been studied. We hypothesized that gyroscopy would be superior to accelerometry because head tremor is rotational motion, and gyroscopes record rotational motion, free of gravitational artifact. We also hypothesized a strong logarithmic relationship between 0 to 4-point tremor ratings and the transducer measures of tremor amplitude, similar to those previously reported for hand tremor. METHODS: Head tremor was recorded for 1 minute in each of the five head positions used in the Essential Tremor Rating Assessment Scale, using a triaxial accelerometer and triaxial gyroscope mounted at the vertex of the head. Mean and maximum 3-second burst displacement tremor and rotation tremor were computed by spectral analysis. The minimum detectable change for the transducers was estimated using the residual mean squared error from repeated-measures analysis of variance. RESULTS: Tremor displacement and rotation (T) were logarithmically related to tremor ratings (tremor rating score; TRS): log(T) = α TRS + ß, where α ≈ 0.47 for displacement and ≈0.64 for rotation, and ß ≈ -1.8 and -1.4. Tremor ratings correlated more strongly with gyroscopy (r = 0.83-0.87) than with accelerometry (r = 0.71-0.75). Minimum detectable change (percent reduction) was approximately 66% of the baseline geometric mean. CONCLUSIONS: Gyroscopic transducers are superior to accelerometry for assessment of head tremor. Both measures of head tremor are logarithmically related to tremor ratings. The minimum detectable change of the transducer measures is comparable to those previously reported for hand tremor.

Functional impact of different muscle localization techniques for Botulinum neurotoxin A injections in clinical routine management of post-stroke spasticity.

BACKGROUND: Treatment options for spasticity include intramuscular botulinum neurotoxin A (BoNT-A) injections. Both ultrasound (US) or electromyographic (EMG) guided BoNT-A injections are employed to isolate muscles. To date, most studies have included patients naïve to BoNT-A or following a prolonged wash out phase. OBJECTIVE: To determine the impact of US/EMG guided BoNT-A injections on function in outpatients with spasticity receiving an established re-injection regime. METHODS: Thirty patients post-stroke were investigated in a single-blinded, randomized controlled trial using a cross-over design for the EMG and US and a parallel design for the control group. The Modified Ashworth (MAS), Disability Assessment (DAS), Quality of Life (EQ-5D), self-rating scale and Barthel Index were assessed pre- and post-BoNT-A injections of upper limb muscles by a to the injection technique blinded person. RESULTS: MAS improved in arm, finger and upper limb 4 weeks after BoNT-A treatment. The improvement showed no significant differences between the three injection techniques. Barthel Index, DAS and EQ-5D remained unchanged in all groups. CONCLUSIONS: This pilot study questions the impact of the instrumental guided injection techniques on everyday functionality in a routine clinical setting with established re-injection intervals. Larger trials are warranted with patients who are under long-term treatment on a regular basis.

Beamformer source analysis and connectivity on concurrent EEG and MEG data during voluntary movements.

Electroencephalography (EEG) and magnetoencephalography (MEG) are the two modalities for measuring neuronal dynamics at a millisecond temporal resolution. Different source analysis methods, to locate the dipoles in the brain from which these dynamics originate, have been readily applied to both modalities alone. However, direct comparisons and possible advantages of combining both modalities have rarely been assessed during voluntary movements using coherent source analysis. In the present study, the cortical and sub-cortical network of coherent sources at the finger tapping task frequency (2-4 Hz) and the modes of interaction within this network were analysed in 15 healthy subjects using a beamformer approach called the dynamic imaging of coherent sources (DICS) with subsequent source signal reconstruction and renormalized partial directed coherence analysis (RPDC). MEG and EEG data were recorded simultaneously allowing the comparison of each of the modalities separately to that of the combined approach. We found the identified network of coherent sources for the finger tapping task as described in earlier studies when using only the MEG or combined MEG+EEG whereas the EEG data alone failed to detect single sub-cortical sources. The signal-to-noise ratio (SNR) level of the coherent rhythmic activity at the tapping frequency in MEG and combined MEG+EEG data was significantly higher than EEG alone. The functional connectivity analysis revealed that the combined approach had more active connections compared to either of the modalities during the finger tapping (FT) task. These results indicate that MEG is superior in the detection of deep coherent sources and that the SNR seems to be more vital than the sensitivity to theoretical dipole orientation and the volume conduction effect in the case of EEG.

Multi-modal causality analysis of eyes-open and eyes-closed data from simultaneously recorded EEG and MEG.

Owing to the recent advances in multi-modal data analysis, the aim of the present study was to analyze the functional network of the brain which remained the same during the eyes-open (EO) and eyes-closed (EC) resting task. The simultaneously recorded electroencephalogram (EEG) and magnetoencephalogram (MEG) were used for this study, recorded from five distinct cortical regions of the brain. We focused on the 'alpha' functional network, corresponding to the individual peak frequency in the alpha band. The total data set of 120 seconds was divided into three segments of 18 seconds each, taken from start, middle, and end of the recording. This segmentation allowed us to analyze the evolution of the underlying functional network. The method of time-resolved partial directed coherence (tPDC) was used to assess the causality. This method allowed us to focus on the individual peak frequency in the 'alpha' band (7-13 Hz). Because of the significantly higher power in the recorded EEG in comparison to MEG, at the individual peak frequency of the alpha band, results rely only on EEG. The MEG was used only for comparison. Our results show that different regions of the brain start to `disconnect' from one another over the course of time. The driving signals, along with the feedback signals between different cortical regions start to recede over time. This shows that, with the course of rest, brain regions reduce communication with each another.

The central oscillatory network of orthostatic tremor.

Orthostatic tremor (OT) is a movement disorder of the legs and trunk that is present in the standing position but typically absent when sitting. The pathological central network involved in orthostatic tremor is still unknown. In this study we analyzed 15 patients with simultaneous high-resolution electroencephalography and electromyography recording to assess corticomuscular coherence. In 1 patient we were able to simultaneously record the local field potential in the ventrolateral thalamus and electroencephalography. Dynamic imaging of coherent source analysis was used to find the sources in the brain that are coherent with the peripheral tremor signal. When standing, the network for the tremor frequency consisted of unilateral activation in the primary motor leg area, supplementary motor area, primary sensory cortex, two prefrontal/premotor sources, thalamus, and cerebellum for the whole 30-second segment recorded. The source coherence dynamics for the primary leg area and the thalamic source signals with the tibialis anterior muscle showed that they were highly coherent for the whole 30 seconds for the contralateral side but markedly decreased after 15 seconds for the ipsilateral side. The source signal and the recorded thalamus signal followed the same time frequency dynamics of coherence in 1 patient. The corticomuscular interaction in OT follows a consistent pattern with an initially bilateral pattern and then a segregated unilateral pattern after 15 seconds. This may add to the feeling of unsteadiness. It also makes the thalamus unlikely as the main source of orthostatic tremor.

Corticomuscular coherence in asymptomatic first-degree relatives of patients with essential tremor.

BACKGROUND: Essential tremor (ET) follows an autosomal dominant type of inheritance in the majority of patients, yet its genetic basis has not been identified. Its exact origin is still elusive, but coherence measurements between electromyography tremor bursts and electroencephalography unequivocally demonstrate a correlation. METHODS: We tested these measurements in 37 healthy first-degree relatives (children) of patients with essential tremor (ET) and a group of 37 age-matched and sex-matched controls. Pooled coherence spectra of the maximally coherent electroencephalogram electrodes were computed for ET relatives and controls. RESULTS: The maximal coherence and its frequency were significantly higher in ET relatives than in controls during the pinch grip task and during slow hand movements. Electromyography amplitude (root-mean-square) was slightly but significantly greater in ET relatives, whereas 2-Hz to 40-Hz power and spectral peak frequency were not different. CONCLUSIONS: The presymptomatic alteration in corticomuscular interaction may reflect a role of genetic factors.

The natural history of multiple system atrophy: a prospective European cohort study.

BACKGROUND: Multiple system atrophy (MSA) is a fatal and still poorly understood degenerative movement disorder that is characterised by autonomic failure, cerebellar ataxia, and parkinsonism in various combinations. Here we present the final analysis of a prospective multicentre study by the European MSA Study Group to investigate the natural history of MSA. METHODS: Patients with a clinical diagnosis of MSA were recruited and followed up clinically for 2 years. Vital status was ascertained 2 years after study completion. Disease progression was assessed using the unified MSA rating scale (UMSARS), a disease-specific questionnaire that enables the semiquantitative rating of autonomic and motor impairment in patients with MSA. Additional rating methods were applied to grade global disease severity, autonomic symptoms, and quality of life. Survival was calculated using a Kaplan-Meier analysis and predictors were identified in a Cox regression model. Group differences were analysed by parametric tests and non-parametric tests as appropriate. Sample size estimates were calculated using a paired two-group t test. FINDINGS: 141 patients with moderately severe disease fulfilled the consensus criteria for MSA. Mean age at symptom onset was 56·2 (SD 8·4) years. Median survival from symptom onset as determined by Kaplan-Meier analysis was 9·8 years (95% CI 8·1-11·4). The parkinsonian variant of MSA (hazard ratio [HR] 2·08, 95% CI 1·09-3·97; p=0·026) and incomplete bladder emptying (HR 2·10, 1·02-4·30; p=0·044) predicted shorter survival. 24-month progression rates of UMSARS activities of daily living, motor examination, and total scores were 49% (9·4 [SD 5·9]), 74% (12·9 [8·5]), and 57% (21·9 [11·9]), respectively, relative to baseline scores. Autonomic symptom scores progressed throughout the follow-up. Shorter symptom duration at baseline (OR 0·68, 0·5-0·9; p=0·006) and absent levodopa response (OR 3·4, 1·1-10·2; p=0·03) predicted rapid UMSARS progression. Sample size estimation showed that an interventional trial with 258 patients (129 per group) would be able to detect a 30% effect size in 1-year UMSARS motor examination decline rates at 80% power. INTERPRETATION: Our prospective dataset provides new insights into the evolution of MSA based on a follow-up period that exceeds that of previous studies. It also represents a useful resource for patient counselling and planning of multicentre trials.

Source analysis of beta-synchronisation and cortico-muscular coherence after movement termination based on high resolution electroencephalography.

We hypothesized that post-movement beta synchronization (PMBS) and cortico-muscular coherence (CMC) during movement termination relate to each other and have similar role in sensorimotor integration. We calculated the parameters and estimated the sources of these phenomena.We measured 64-channel EEG simultaneously with surface EMG of the right first dorsal interosseus muscle in 11 healthy volunteers. In Task1, subjects kept a medium-strength contraction continuously; in Task2, superimposed on this movement, they performed repetitive self-paced short contractions. In Task3 short contractions were executed alone. Time-frequency analysis of the EEG and CMC was performed with respect to the offset of brisk movements and averaged in each subject. Sources of PMBS and CMC were also calculated.High beta power in Task1, PMBS in Task2-3, and CMC in Task1-2 could be observed in the same individual frequency bands. While beta synchronization in Task1 and PMBS in Task2-3 appeared bilateral with contralateral predominance, CMC in Task1-2 was strictly a unilateral phenomenon; their main sources did not differ contralateral to the movement in the primary sensorimotor cortex in 7 of 11 subjects in Task1, and in 6 of 9 subjects in Task2. In Task2, CMC and PMBS had the same latency but their amplitudes did not correlate with each other. In Task2, weaker PMBS source was found bilaterally within the secondary sensory cortex, while the second source of CMC was detected in the premotor cortex, contralateral to the movement. In Task3, weaker sources of PMBS could be estimated in bilateral supplementary motor cortex and in the thalamus. PMBS and CMC appear simultaneously at the end of a phasic movement possibly suggesting similar antikinetic effects, but they may be separate processes with different active functions. Whereas PMBS seems to reset the supraspinal sensorimotor network, cortico-muscular coherence may represent the recalibration of cortico-motoneuronal and spinal systems.

Continuous theta-burst stimulation of the primary motor cortex in essential tremor.

OBJECTIVE: We investigated whether essential tremor (ET) can be altered by suppressing the corticospinal excitability in the primary motor cortex (M1) with transcranial magnetic stimulation. METHODS: 10 Patients with ET and 10 healthy controls underwent transcranial continuous theta-burst stimulation (cTBS) of the left primary motor hand area at 80% (real cTBS) and 30% (control cTBS) of active motor threshold in two separate sessions at least one week apart. Postural tremor was rated clinically and measured accelerometrically before and after cTBS. Corticospinal excitability was assessed by recording the motor evoked potentials (MEP) from the first dorsal interosseous muscle. RESULTS: Real cTBS but not control cTBS reduced the tremor total power assessed with accelerometry. This beneficial effect was subclinical as there were no significant changes in clinical tremor rating after real cTBS. Relative to control cTBS, real cTBS reduced corticospinal excitability in the stimulated primary motor cortex only in healthy controls but not in ET patients. CONCLUSION: Real cTBS has a beneficial effect on ET. Since cTBS did not induce a parallel reduction in corticospinal excitability, this effect was not mediated by a suppression of the corticospinal motor output. SIGNIFICANCE: "Inhibitory" cTBS of M1 leads to a consistent but subclinical reduction in tremor amplitude.

The phenomenology of parkinsonian tremor.

The definition of Parkinsonian tremor covers all different forms occurring in Parkinson's disease. The most common form is rest tremor, labelled as typical Parkinsonian tremor. Other variants cover also postural and action tremors. Data support the notion that suppression of rest tremor may be more specific for PD tremors. Several differential diagnoses like rest tremor in ET, dystonic tremor, psychogenic tremor and Holmes' tremor may be misinterpreted as PD-tremor. Tests and clinical clues to separate them are presented.

Levetiracetam in primary orthostatic tremor: a double-blind placebo-controlled crossover study.

BACKGROUND: In a double-blind crossover study we evaluated the antitremor effect of a 4-week treatment with either escalating dosages of levetiracetam or placebo in orthostatic tremor. METHODS: Twelve patients with orthostatic tremor participated in the study. Primary end point was improvement in stance duration. Secondary end points were total track length of the sway path and tremor total power. The patients' impression of impairment was assessed by a visual analog scale and quality of life by the SF-36. RESULTS: We found no significant effect of dosage or treatment on stance duration (P = .175), total track length (P = .690), total power (P = .280), or visual analog scale (P =.735). Neither was SF-36 differentially changed by levetiracetam or placebo (SF-36, Physical Component Summary: P = .079; SF-36, Mental Component Summary: P = .073). Side effects like dizziness, fatigue, or nausea were only mild to moderate. CONCLUSIONS: Levetiracetam is ineffective in the treatment of orthostatic tremor.

Excessive daytime sleepiness in multiple system atrophy (SLEEMSA study).

BACKGROUND: Sleep disorders are common in multiple system atrophy (MSA), but the prevalence of excessive daytime sleepiness (EDS) is not well known. OBJECTIVE: To assess the frequency and associations of EDS in MSA. DESIGN: Survey of EDS in consecutive patients with MSA and comparison with patients with Parkinson disease (PD) and individuals without known neurologic disease. SETTING: Twelve tertiary referral centers. PARTICIPANTS: Eighty-six consecutive patients with MSA; 86 patients with PD matched for age, sex, and Hoehn and Yahr stage; and 86 healthy subject individuals matched for age and sex. MAIN OUTCOME MEASURES: Epworth Sleepiness Scale (ESS), modified ESS, Sudden Onset of Sleep Scale, Tandberg Sleepiness Scale, Pittsburgh Sleep Quality Index, disease severity, dopaminergic treatment amount, and presence of restless legs syndrome. RESULTS: Mean (SD) ESS scores were comparable in MSA (7.72 [5.05]) and PD (8.23 [4.62]) but were higher than in healthy subjects (4.52 [2.98]) (P < .001). Excessive daytime sleepiness (ESS score >10) was present in 28% of patients with MSA, 29% of patients with PD, and 2% of healthy subjects (P < .001). In MSA, in contrast to PD, the amount of dopaminergic treatment was not correlated with EDS. Disease severity was weakly correlated with EDS in MSA and PD. Restless legs syndrome occurred in 28% of patients with MSA, 14% of patients with PD, and 7% of healthy subjects (P < .001). Multiple regression analysis (with 95% confidence intervals obtained using nonparametric bootstrapping) showed that sleep-disordered breathing and sleep efficiency predicted EDS in MSA and amount of dopaminergic treatment and presence of restless legs syndrome in PD. CONCLUSIONS: More than one-quarter of patients with MSA experience EDS, a frequency similar to that encountered in PD. In these 2 conditions, EDS seems to be associated with different causes.

Treatment of patients with essential tremor.

Essential tremor is a common movement disorder. Tremor severity and handicap vary widely, but most patients with essential tremor do not receive a diagnosis and hence are never treated. Furthermore, many patients abandon treatment because of side-effects or poor efficacy. A newly developed algorithm, based on the logarithmic relation between tremor amplitude and clinical tremor ratings, can be used to compare the magnitude of effect of available treatments. Drugs with established efficacy (propranolol and primidone) produce a mean tremor reduction of about 50%. Deep brain stimulation (DBS) in the thalamic nucleus ventrointermedius or neighbouring subthalamic structures reduces tremor by about 90%. However, no controlled trials of DBS have been done, and the best target is still uncertain. Better drugs are needed, and controlled trials are required to determine the safety and efficacy of DBS in the nucleus ventrointermedius and neighbouring subthalamic structures.