Double lesion MRgFUS thalamotomy for essential tremor: 4.5-year outcomes and framework for assessing loss of efficacy and tremor progression.

BACKGROUND: The essential tremor (ET) course to 54 months post-unilateral VIM/PSA magnetic resonance-guided focused ultrasound (MRgFUS) in the treated arm (TA) and non-treated arm (NTA) of 12 patients is reported. METHODS: Tremor severity was rated using Bain Findley spirography (BFS) scores in the TA and NTA. We divided follow-up into 'Early' (0-6 months) and 'Late' (6-54 months) phases, to minimise the effect of peri-lesion oedema resolution on the latter. RESULTS: The mean baseline BFS score was 6.2 in TA and 5.7 in the NTA. After unilateral VIM/PSA MRgFUS, mean BFS improved in TA at all subsequent time points (p < 0.001), with no significant differences between BFS scores at consecutive assessments or between 1 and 54 months, while the NTA BFS scores worsened between 12 and 24 months (p < 0.003). Three patients showed worsening of their TA BFS scores and an increasing NTA-TA BFS difference, indicating slower tremor worsening in TA compared to NTA, whilst one patient showed a greater rate of worsening in the TA compared to NTA BFS. CONCLUSION: After 54 months, the beneficial effect of MRgFUS is usually maintained with any worsening of BFS scores in TA slower than in NTA. Loss of treatment benefit is rare.

Tremor assessment scales before, during and after MRgFUS for essential tremor - results, recommendations and implications.

BACKGROUND: neurosurgical interventions such as MR-guided focused ultrasound (MRgFUS) are increasingly deployed for treatment of essential tremor. OBJECTIVE: to make recommendations for monitoring treatment effects during and after MRgFUS based on our investigation of correlations between different scales of tremor severity. METHODS: twenty-five clinical assessments were collected from thirteen patients before and after unilateral MRgFUS sequential lesioning of the thalamus and posterior subthalamic area for alleviating essential tremor. Scales included Bain Findley Spirography (BFS), Clinical Rating Scale for Tremor (CRST), Upper Extremity Total Tremor Score (UETTS) and Quality of Life of Essential Tremor (QUEST), and were documented at baseline, while lying in the scanner with stereotactic frame attached (BFS), and at 24-month follow-up. RESULTS: the four different scales of tremor severity all correlated significantly. BFS and CRST showed a strong correlation of 0.833 (p < 0.001). BFS, UETTS and CRST correlated moderately with QUEST (ρ = 0.575-0.721, p < 0.001). BFS and UETTS correlated significantly with all CRST subparts, with the strongest correlation between UETTS and CRST part C (ρ = 0.831, p < 0.001). Moreover, BFS drawn sitting upright in an outpatient setting correlated with spirals drawn in a supine position on the scanner bed with the stereotactic frame attached. CONCLUSION: we recommend a combination of BFS & UETTS for intraoperative assessment of awake essential tremor patients and BFS & QUEST for pre-operative and follow-up assessments, as these scale sets are quick and simple to collect and provide meaningful information whilst meeting the practical constraints of intraoperative assessment.

The diagnostic value of clinical neurophysiology in hyperkinetic movement disorders: A systematic review.

INTRODUCTION: To guide the neurologist and neurophysiologist with interpretation and implementation of clinical neurophysiological examinations, we aim to provide a systematic review on evidence of electrophysiological features used to differentiate between hyperkinetic movement disorders. METHODS: A PRISMA systematic search and QUADAS quality evaluation has been performed in PubMed to identify diagnostic test accuracy studies comparing electromyography and accelerometer features. We included papers focusing on tremor, dystonia, myoclonus, chorea, tics and ataxia and their functional variant. The features were grouped as 1) basic features (e.g., amplitude, frequency), 2) the influence of tasks on basic features (e.g., entrainment, distraction), 3) advanced analyses of multiple signals, 4) and diagnostic tools combining features. RESULTS: Thirty-eight cross-sectional articles were included discussing tremor (n = 28), myoclonus (n = 5), dystonia (n = 5) and tics (n = 1). Fifteen were rated as 'high quality'. In tremor, the basic and task-related features showed great overlap between clinical tremor syndromes, apart from rubral and enhanced physiological tremor. Advanced signal analyses were best suited for essential, parkinsonian and functional tremor, and cortical, non-cortical and functional jerks. Combinations of electrodiagnostic features could identify essential, enhanced physiological and functional tremor. CONCLUSION: Studies into the diagnostic accuracy of electrophysiological examinations to differentiate between hyperkinetic movement disorders have predominantly been focused on clinical tremor syndromes. No single feature can differentiate between them all; however, a combination of analyses might improve diagnostic accuracy.

Which disease features run in essential tremor families? A systematic review.

Essential tremor is a common and highly heritable movement disorder. It is largely unknown, however, to what extent family members share overlapping symptoms. Such knowledge would be useful, as it may lead to the definition of familial essential tremor phenotypes, which will aid the ongoing search for genotypes. Also, this information can be used by clinicians in patient counselling. Therefore, we conducted a systematic review to provide an overview of the evidence on which essential tremor features run in families, to assess the literature's strengths and weaknesses, and to provide recommendations for future studies. PubMed was searched resulting in 460 titles: sixteen articles ultimately proved fit for inclusion. The results are represented in line with the Axis 1 classification of tremor as published in the latest Consensus Statement. In summary, we found varying levels of positive evidence for familial aggregation of age at onset, disease progression, alcohol responsiveness, parkinsonism and dystonia. Evidence on midline tremor was conflicting. The evidence on familial clustering was negative for cerebellar signs and action tremor asymmetry. Although the level of evidence is modest, it seems that some disease features are indeed familial, while other features are not. We discuss complicating factors, such as state-vs-trait dependency of characteristics, the place of familial dystonia, and the development of diagnostic criteria for essential tremor over time. In the future, comprehensive replication studies are needed, with the addition of several characteristics that have not been investigated so far, as the next step towards discovery of essential tremor phenotypes.

Wavelet coherence analysis: A new approach to distinguish organic and functional tremor types.

OBJECTIVE: To distinguish tremor subtypes using wavelet coherence analysis (WCA). WCA enables to detect variations in coherence and phase difference between two signals over time and might be especially useful in distinguishing functional from organic tremor. METHODS: In this pilot study, polymyography recordings were studied retrospectively of 26 Parkinsonian (PT), 26 functional (FT), 26 essential (ET), and 20 enhanced physiological (EPT) tremor patients. Per patient one segment of 20 s in duration, in which tremor was present continuously in the same posture, was selected. We studied several coherence and phase related parameters, and analysed all possible muscle combinations of the flexor and extensor muscles of the upper and fore arm. The area under the receiver operating characteristic curve (AUC-ROC) was applied to compare WCA and standard coherence analysis to distinguish tremor subtypes. RESULTS: The percentage of time with significant coherence (PTSC) and the number of periods without significant coherence (NOV) proved the most discriminative parameters. FT could be discriminated from organic (PT, ET, EPT) tremor by high NOV (31.88 vs 21.58, 23.12 and 10.20 respectively) with an AUC-ROC of 0.809, while standard coherence analysis resulted in an AUC-ROC of 0.552. CONCLUSIONS: EMG-EMG WCA analysis might provide additional variables to distinguish functional from organic tremor. SIGNIFICANCE: WCA might prove to be of additional value to discriminate between tremor types.

How typical are 'typical' tremor characteristics? Sensitivity and specificity of five tremor phenomena.

INTRODUCTION: Distinguishing between different tremor disorders can be challenging. Some tremor disorders are thought to have typical tremor characteristics: the current study aims to provide sensitivity and specificity for five 'typical' tremor phenomena. METHODS: Retrospectively, we examined 210 tremor patients referred for electrophysiological recordings between January 2008 and January 2014. The final clinical diagnosis was used as the gold standard. The first step was to determine whether patients met neurophysiological criteria for their type of tremor. Once established, we focused on 'typical' characteristics: tremor frequency decrease upon loading (enhanced physiological tremor (EPT)), amplitude increase upon loading, distractibility and entrainment (functional tremor (FT)), and intention tremor (essential tremor (ET)). The prevalence of these phenomena in the 'typical' group was compared to the whole group. RESULTS: Most patients (87%) concurred with all core clinical neurophysiological criteria for their tremor type. We found a frequency decrease upon loading to be a specific (95%), but not a sensitive (42%) test for EPT. Distractibility and entrainment both scored high on sensitivity (92%, 91%) and specificity (94%, 91%) in FT, whereas a tremor amplitude increase was specific (92%), but not sensitive (22%). Intention tremor was a specific finding in ET (85%), but not a sensitive test (45%). Combination of characteristics improved sensitivity. CONCLUSION: In this study, we retrospectively determined sensitivity and specificity for five 'typical' tremor characteristics. Characteristics proved specific, but few were sensitive. These data on tremor phenomenology will help practicing neurologists to improve distinction between different tremor disorders.

Cerebellar Atrophy in Cortical Myoclonic Tremor and Not in Hereditary Essential Tremor-a Voxel-Based Morphometry Study.

Essential tremor (ET) presumably has a cerebellar origin. Imaging studies showed various cerebellar and also cortical structural changes. A number of pathology studies indicated cerebellar Purkinje cell pathology. ET is a heterogeneous disorder, possibly indicating different underlying disease mechanisms. Familial cortical myoclonic tremor with epilepsy (FCMTE), with evident Purkinje cell degeneration, can be an ET mimic. Here, we investigate whole brain and, more specifically, cerebellar morphological changes in hereditary ET, FCMTE, and healthy controls. Anatomical magnetic resonance images were preprocessed using voxel-based morphometry. Study 1 included voxel-wise comparisons of 36 familial, propranolol-sensitive ET patients, with subgroup analysis on age at onset and head tremor, and 30 healthy controls. Study 2 included voxel-wise comparisons in another nine ET patients, eight FCMTE patients, and nine healthy controls. Study 3 compared total cerebellar volume between 45 ET patients, 8 FCTME patients, and 39 controls. In our large sample of selected hereditary ET patients and ET subgroups, no local atrophy was observed compared to healthy controls or FCMTE. In ET patients with head tremor, a volume increase in cortical motor regions was observed. In FCMTE, a decrease in total cerebellar volume and in local cerebellar gray matter was observed compared to healthy controls and ET patients. The current study did not find local atrophy, specifically not in the cerebellum in hereditary ET, contrary to FCMTE. Volume increase of cortical motor areas in ET patients with head tremor might suggest cortical plasticity changes due to continuous involuntary head movements.

Muscle co-activity tuning in Parkinsonian hand movement: disease-specific changes at behavioral and cerebral level.

We investigated simple directional hand movements based on different degrees of muscle co-activity, at behavioral and cerebral level in healthy subjects and Parkinson's disease (PD) patients. We compared "singular" movements, dominated by the activity of one agonist muscle, to "composite" movements, requiring conjoint activity of multiple muscles, in a center-out (right hand) step-tracking task. Behavioral parameters were obtained by EMG and kinematic recordings. fMRI was used to investigate differences in underlying brain activations between PD patients (N = 12) and healthy (age-matched) subjects (N = 18). In healthy subjects, composite movements recruited the striatum and cortical areas comprising bilaterally the supplementary motor area and premotor cortex, contralateral medial prefrontal cortex, primary motor cortex, primary visual cortex, and ipsilateral superior parietal cortex. Contrarily, the ipsilateral cerebellum was more involved in singular movements. This striking dichotomy between striatal and cortical recruitment vs. cerebellar involvement was considered to reflect the complementary roles of these areas in motor control, in which the basal ganglia are involved in movement selection and the cerebellum in movement optimization. Compared to healthy subjects, PD patients showed decreased activation of the striatum and cortical areas in composite movement, while performing worse at behavioral level. This implies that PD patients are especially impaired on tasks requiring highly tuned muscle co-activity. Singular movement, on the other hand, was characterized by a combination of increased activation of the ipsilateral parietal cortex and left cerebellum. As singular movement performance was only slightly compromised, we interpret this as a reflection of increased visuospatial processing, possibly as a compensational mechanism.

Limited correlations between clinician-based and patient-based measures of essential tremor severity.

INTRODUCTION: We investigated the relation between changes in clinician-based and patient-based measures of tremor severity, within the Fahn-Tolosa-Marin Tremor Rating Scale (TRS) and Visual Analogue Scale (VAS) in essential tremor patients. METHODS: Thirty-seven patients were assessed twice: on- and off-medication. Clinician-based, objective TRS assessments, consisting of part A (postures/movements) and part B (tremor-inducing tasks) were conducted by a blinded assessor using video-tapes. Patients completed TRS part C (limitations in activities of daily life) and indicated subjective tremor severity using VAS. RESULTS: Patients' total TRS and VAS scores improved on-medication (both p < 0.001). Mean improvement was 6.3 (sd 5.4) points on the total TRS and 2.3 (sd 2.3) points on the VAS score. Within the TRS, we found moderate correlations between changes in clinician-based TRS-B and patient-based TRS-C scores (ρ = 0.387, p = 0.011), but not between changes in clinician-based TRS-A and TRS-C scores (ρ = 0.128, p = 0.232). Moreover, changes in subjective VAS scores correlated with changes in total TRS (ρ = 0.422, p = 0.007), changes in TRS-C scores (ρ = 0.367, p = 0.015) and, more weakly, with changes in TRS-B scores (ρ = 0.281, p = 0.049), but again: not with changes in TRS-A scores (ρ = -0.008, p = 0.482). DISCUSSION: We found no correlation between changes in clinician-based TRS-A, and patient-based measures TRS-C or VAS scores, and a weak correlation between clinician-based TRS-B and VAS scores. The limited correlations between changes in clinician-based and patient-based measures of tremor severity suggest that the different scales measure different aspects of tremor severity and support the additional use of subjective patient-based assessments in clinical practice and clinical trials.

Rhythmic finger tapping reveals cerebellar dysfunction in essential tremor.

INTRODUCTION: Cerebellar circuits are hypothesized to play a central role in the pathogenesis of essential tremor. Rhythmic finger tapping is known to strongly engage the cerebellar motor circuitry. We characterize cerebellar and, more specifically, dentate nucleus function, and neural correlates of cerebellar output in essential tremor during rhythmic finger tapping employing functional MRI. METHODS: Thirty-one propranolol-sensitive essential tremor patients with upper limb tremor and 29 healthy controls were measured. T2*-weighted EPI sequences were acquired. The task consisted of alternating rest and finger tapping blocks. A whole-brain and region-of-interest analysis was performed, the latter focusing on the cerebellar cortex, dentate nucleus and inferior olive nucleus. Activations were also related to tremor severity. RESULTS: In patients, dentate activation correlated positively with tremor severity as measured by the tremor rating scale part A. Patients had reduced activation in widespread cerebellar cortical regions, and additionally in the inferior olive nucleus, and parietal and frontal cortex, compared to controls. CONCLUSION: The increase in dentate activation with tremor severity supports involvement of the dentate nucleus in essential tremor. Cortical and cerebellar changes during a motor timing task in essential tremor might point to widespread changes in cerebellar output in essential tremor.

Usefulness of intermuscular coherence and cumulant analysis in the diagnosis of postural tremor.

OBJECTIVE: To investigate the potential value of two advanced EMG measures as additional diagnostic measures in the polymyographic assessment of postural upper-limb tremor. METHODS: We investigated coherence as a measure of dependency between two EMG signals, and cumulant analysis to reveal patterns of synchronicity in EMG activity in muscle pairs. Eighty datasets were analyzed retrospectively, obtained from four groups: essential tremor (ET), Parkinson's disease (PD), enhanced physiological tremor (EPT), and functional tremor (FT). RESULTS: Intermuscular coherence was highest in the PD group (0.58), intermediate in FT (0.43) and ET (0.40), and weakest in EPT (0.16) (p=0.002). EPT patients could be distinguished by low coherence: coherence <0.18 in the wrist+elbow extensors differentiates EPT in this sample with a sensitivity of 86% and specificity of 84%. Cumulant analysis showed predominantly alternating activity between wrist and elbow extensor in ET patients, while a more synchronous pattern was predominant in PD, EPT and FT (p=0.008). EMG activity in wrist and elbow flexors tended to be more synchronous in PD (p=0.059). CONCLUSION: Our results suggest that coherence and cumulant analysis may be of additional value in the diagnostic work-up of postural tremor. SIGNIFICANCE: These additional measures may be helpful in diagnosing difficult tremor cases.