The Conundrum of Dystonia in Essential Tremor Patients: How does One Classify these Cases?

Background: The relationship between essential tremor (ET) and dystonia has been long debated and the boundaries between these disorders remain unclear. Here, we highlight the diagnostic uncertainty that can arise when observing dystonic postures in patients who have received ET diagnoses. Methods: An international panel of seven movement disorders neurologists from five countries reviewed the clinical history and videotaped neurological examinations of five individuals diagnosed with ET who also had various features of dystonia on neurological examination. Experts were instructed to assign diagnoses and provide their rationale for diagnostic assignments. Results: The five cases each exhibited a variety of abnormal postures. These were observed by all experts, and interpreted as dystonic postures by six experts. According to six of seven experts, all five cases had ET. One expert classified all cases as dystonic tremor rather than ET. One case had cervical dystonia, and five of seven experts assigned dual diagnoses of ET and dystonia in that case. The assignment of dystonia diagnoses was variable among the other four cases, with two to three experts assigning this diagnosis in each case, underscoring differences in diagnostic interpretation of dystonic postures on examination. Conclusions: This study draws attention to some of the differences between experts in assigning diagnoses of ET or dystonia to individuals with ET and abnormal postures. The goal here was not necessarily to build consensus, but to raise issues, highlight areas of uncertainty, and identify areas of common vs. differentiated thought. Several questions for additional research were also raised.

Problems and controversies in tremor classification.

The Consensus Statement on the Classification of Tremors, from the Task Force of the International Parkinson's and Movement Disorder Society was published in 2018 in response to advances in the understanding of essential tremor (ET), tremor associated with dystonia and other monosymptomatic and indeterminate tremors. This was a revision of the previous 1998 Consensus Statement. A number of problems arise from this classification and, in this manuscript, we highlight several of these. These problems relate to the definition of tremor, the definition of ET, the proposal of the term 'essential tremor plus', issues related to orthostatic tremor (OT) including the proposal of the term 'orthostatic tremor plus', and the absence of a hierarchy of terms used to classify tremor. Among the proposals we make is that the definition of tremor should acknowledge that tremor is a symptom, ET should be redefined, severity is an important characteristic for classifying and diagnosing tremor, the terms 'essential tremor plus' and 'orthostatic tremor plus' should be abandoned, and classification of tremor requires rules for creating a hierarchy of terminology. "This article is part of the Special Issue "Tremor" edited by Daniel D. Truong, Mark Hallett, and Aasef Shaikh".

Tremor and Dysmetria in Multiple Sclerosis: A Neurophysiological Study.

Objective: The mechanisms contributing to the pathogenesis of tremor and/or dysmetria in multiple sclerosis (MS) are poorly understood. Abnormal oscillations within the olivo-cerebello-thalamo-cortical networks are believed to play an important part in tremor aetiology, but could also contribute to intention dysmetria due to disruptions in motor timing. Conversely, delayed central motor conduction times are a common feature of ataxias, but could also contribute to the expression of dysmetria in MS. This study examined the roles of central conduction delays in the manifestation of tremor and/or dysmetria in MS. Methods: Twenty-three individuals with MS participated: 8 with no movement disorder, 6 with tremor, 4 with pure dysmetria and 5 with both tremor and dysmetria. Median nerve somatosensory evoked potentials (SEPs), transcranial magnetic stimulation (TMS) over the motor cortex and cervical spine, stretch reflexes were used assess sensory and motor conduction times. Results: Central, but not peripheral, sensory conductions time were significantly delayed in participants with dysmetria, regardless of the presence of tremor. Similarly, the TMS evoked muscles responses and the long-latency component of stretch reflexes were significantly delayed in those with dysmetria, but not pure tremor. Conclusion: Dysmetria in MS is associated with delays in central conduction of sensory or motor pathways, or both, likely leading to disruption of muscle activation timing and terminal oscillations that contribute to dysmetria. Significance: The presence of dysmetria in MS is associated with decreased conduction velocities in central sensory and/or motor pathways likely reflects greater demyelination of these axons compared to those with no movement disorder or pure tremor.

A Population Model of Deep Brain Stimulation in Movement Disorders From Circuits to Cells.

For more than 30 years, deep brain stimulation (DBS) has been used to target the symptoms of a number of neurological disorders and in particular movement disorders such as Parkinson's disease (PD) and essential tremor (ET). It is known that the loss of dopaminergic neurons in the substantia nigra leads to PD, while the exact impact of this on the brain dynamics is not fully understood, the presence of beta-band oscillatory activity is thought to be pathological. The cause of ET, however, remains uncertain, however pathological oscillations in the thalamocortical-cerebellar network have been linked to tremor. Both of these movement disorders are treated with DBS, which entails the surgical implantation of electrodes into a patient's brain. While DBS leads to an improvement in symptoms for many patients, the mechanisms underlying this improvement is not clearly understood, and computational modeling has been used extensively to improve this. Many of the models used to study DBS and its effect on the human brain have mainly utilized single neuron and single axon biophysical models. We have previously shown in separate models however, that the use of population models can shed much light on the mechanisms of the underlying pathological neural activity in PD and ET in turn, and on the mechanisms underlying DBS. Together, this work suggested that the dynamics of the cerebellar-basal ganglia thalamocortical network support oscillations at frequency range relevant to movement disorders. Here, we propose a new combined model of this network and present new results that demonstrate that both Parkinsonian oscillations in the beta band and oscillations in the tremor frequency range arise from the dynamics of such a network. We find regions in the parameter space demonstrating the different dynamics and go on to examine the transition from one oscillatory regime to another as well as the impact of DBS on these different types of pathological activity. This work will allow us to better understand the changes in brain activity induced by DBS, and allow us to optimize this clinical therapy, particularly in terms of target selection and parameter setting.

Traditional Trial and Error versus Neuroanatomic 3-Dimensional Image Software-Assisted Deep Brain Stimulation Programming in Patients with Parkinson Disease.

BACKGROUND: Programming deep brain stimulation (DBS) settings in patients with Parkinson disease (PD) is challenging and time consuming because of the vast number of possible parameter combinations. This results in long sessions that can be exhausting for the patients and physicians. GUIDE (Boston Scientific) is a 3-dimensional neuroanatomic visual software that precisely visualizes the location of the DBS electrode in the subthalamic nucleus (STN). The objective of this paper is to compare the duration and clinical effects of traditional trial and error versus GUIDE-assisted DBS programming in 10 patients with PD treated with STN DBS. METHODS: For each patient, neurostimulation parameters were selected with GUIDE to create a stimulation field encompassing the dorsal part of the STN. On programming day, each patient was assessed with both traditional and GUIDE approaches using a crossover design. For GUIDE-assisted sessions, the patients were programmed directly with the DBS settings obtained with the stimulated field model, and if necessary, parameters were adjusted to achieve optimal clinical response. Clinical improvement was assessed with Unified Parkinson's Disease Rating Scale scores for limb bradykinesia, tremor, and rigidity. RESULTS: In 7 patients, DBS settings obtained with GUIDE led to suboptimal clinical improvement and mild adjustments were required. After these adjustments, the magnitude of clinical improvement with the 2 approaches was comparable (P = 0.8219). Programming time with GUIDE was significantly shorter than with the traditional programming approach (P < 0.0001). CONCLUSIONS: Visualization of stimulation fields with GUIDE provides useful information to achieve a clinical improvement comparable with that obtained with the traditional trial and error approach, but with shorter and more efficient programming sessions.

Sleep problems and hypothalamic dopamine D3 receptor availability in Parkinson disease.

OBJECTIVE: To investigate the relationship between hypothalamic D3 dopamine receptor availability and severity of sleep problems in Parkinson disease (PD). METHODS: Twelve patients were assessed with PET and the high-affinity dopamine D3 receptor radioligand [11C]-propyl-hexahydro-naphtho-oxazin ([11C]-PHNO). Severity of sleep problems was rated with appropriate subitems of the Unified Parkinson's Disease Rating Scale part I (patient questionnaire) and the Epworth Sleepiness Scale. RESULTS: We found that lower dopamine D3 receptor availability measured with [11C]-PHNO PET was associated with greater severity of excessive daytime sleepiness but not with problems of falling asleep or insomnia. CONCLUSION: In our cohort of patients with PD, the occurrence of excessive daytime sleepiness was linked to reductions in hypothalamic dopamine D3 receptor availability. If these preliminary findings are confirmed in larger cohorts of patients with polysomnographic characterization, selective pharmacologic modulation of the dopaminergic D3 system could be used to increase daytime alertness in patients with PD.

Transducer-based evaluation of tremor.

The International Parkinson and Movement Disorder Society established a task force on tremor that reviewed the use of transducer-based measures in the quantification and characterization of tremor. Studies of accelerometry, electromyography, activity monitoring, gyroscopy, digitizing tablet-based measures, vocal acoustic analysis, and several other transducer-based methods were identified by searching PubMed.gov. The availability, use, acceptability, reliability, validity, and responsiveness were reviewed for each measure using the following criteria: (1) used in the assessment of tremor; (2) used in published studies by people other than the developers; and (3) adequate clinimetric testing. Accelerometry, gyroscopy, electromyography, and digitizing tablet-based measures fulfilled all three criteria. Compared to rating scales, transducers are far more sensitive to changes in tremor amplitude and frequency, but they do not appear to be more capable of detecting a change that exceeds random variability in tremor amplitude (minimum detectable change). The use of transducer-based measures requires careful attention to their limitations and validity in a particular clinical or research setting. © 2016 International Parkinson and Movement Disorder Society.

Proposing a Parkinson's disease-specific tremor scale from the MDS-UPDRS.

BACKGROUND: This article proposes an International Parkinson and Movement Disorder Society (MDS)-UPDRS tremor-based scale and describes its measurement properties, with a view to developing an improved scale for assessing tremor in Parkinson's disease (PD). METHODS: This was a cross-sectional, multicenter study of 435 PD patients. Rasch analysis was performed on the 11 MDS-UPDRS tremor items. Construct validity, precision, and test-retest reliability were also analyzed. RESULTS: After some modifications, which included removal of an item owing to redundancy, the obtained MDS-UPDRS tremor scale showed moderate reliability, unidimensionality, absence of differential item functioning, satisfactory convergent validity with medication, and better precision than the raw sum score. However, the scale displayed a floor effect and a need for more items measuring lower levels of tremor. CONCLUSIONS: The MDS-UPDRS tremor scale provides linear scores that can be used to assess tremor in PD in a valid, reliable way. The scale might benefit from modifications and studies that analyze its responsiveness.

Reversing the polarity of bipolar stimulation in deep brain stimulation for essential tremor: a theoretical explanation for a useful clinical intervention.

The quadripolar electrodes used for deep brain stimulation are designed to give flexibility in contact configuration, optimize therapeutic effect, and minimize side-effects. A patient with essential tremor did not tolerate a bipolar setting due to the emergence of a pulling sensation in her face. However, when the polarity of the contacts was reversed, a 70% higher voltage was tolerated. Using an electric field model, we predicted that this effect was due to the proximity of the topmost contact to the internal capsule. Post-operative imaging supported this prediction. These results demonstrate how a multi-disciplinary approach allows us to optimize parameter settings.

Motor phenotype and magnetic resonance measures of basal ganglia iron levels in Parkinson's disease.

BACKGROUND: In Parkinson's disease the degree of motor impairment can be classified with respect to tremor dominant and akinetic rigid features. While tremor dominance and akinetic rigidity might represent two ends of a continuum rather than discrete entities, it would be important to have non-invasive markers of any biological differences between them in vivo, to assess disease trajectories and response to treatment, as well as providing insights into the underlying mechanisms contributing to heterogeneity within the Parkinson's disease population. METHODS: Here, we used magnetic resonance imaging to examine whether Parkinson's disease patients exhibit structural changes within the basal ganglia that might relate to motor phenotype. Specifically, we examined volumes of basal ganglia regions, as well as transverse relaxation rate (a putative marker of iron load) and magnetization transfer saturation (considered to index structural integrity) within these regions in 40 individuals. RESULTS: We found decreased volume and reduced magnetization transfer within the substantia nigra in Parkinson's disease patients compared to healthy controls. Importantly, there was a positive correlation between tremulous motor phenotype and transverse relaxation rate (reflecting iron load) within the putamen, caudate and thalamus. CONCLUSIONS: Our findings suggest that akinetic rigid and tremor dominant symptoms of Parkinson's disease might be differentiated on the basis of the transverse relaxation rate within specific basal ganglia structures. Moreover, they suggest that iron load within the basal ganglia makes an important contribution to motor phenotype, a key prognostic indicator of disease progression in Parkinson's disease.

What is It? Difficult to Pigeon Hole Tremor: a Clinical-Pathological Study of a Man with Jaw Tremor.

BACKGROUND: The phenomenology of tremor is broad and its classification is complicated. Furthermore, the full range of tremor phenomenology with respect to specific neurological and neurodegenerative diseases has not been fully elaborated. CASE REPORT: This right-handed man had a chief complaint of jaw tremor, which began approximately 20 years prior to death at age 101 years. He had been diagnosed with essential tremor (ET) by a local doctor. His examination at age 100 years was notable for marked jaw tremor at rest in the absence of other clear features of parkinsonism, mild kinetic tremor of the hands and, in the last year of life, a score of 22/41 on a cognitive screen. A senior movement disorder neurologist raised doubt about the "ET" diagnosis. The history and videotaped examination were reviewed by three additional senior tremor experts, who raised a number of diagnostic possibilities. A complete postmortem examination was performed by a senior neuropathologist, and was notable for the presence of tufted astrocytes, AT8-labeled glial cytoplasmic inclusions, and globose neuronal tangles. These changes were widespread and definitive. A neuropathological diagnosis of progressive supranuclear palsy was assigned. DISCUSSION: This case presents with mixed and difficult to clinically classify tremor phenomenology and other neurological findings. The postmortem diagnosis was not predicted based on the clinical features, and it is possible that it does not account for all of the features. The case raises many interesting issues and provides a window into the complexity of the interpretation, nosology, and classification of tremor phenomenology.

48, XXYY syndrome associated tremor.

48, XXYY syndrome is a form of sex chromosome aneuploidy that affects between 1 in 18 000 to 1 in 40 000 males. It is not inherited and is diagnosed by karyotyping. It has similarities to 47, XXY Klinefelter's syndrome, with tall stature, micro-orchidism, hypergonadotropic hypogonadism and infertility in males. However, patients with 48, XXYY syndrome also commonly have dental problems, tremor, attention deficit disorder, learning difficulties, allergies and asthma. The tremor is typically reported as an intention tremor (in 71% of patients XXYY aged >20 years with 48), which becomes more common with age and worsens over time.

SPG11 Presenting with Tremor.

BACKGROUND: Hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurological diseases, which typically present with progressive lower extremity weakness and spasticity causing progressive walking difficulties. Complicating neurological or extraneurological features may be present. CASE REPORT: We describe a 19-year-old male who was referred because of an action tremor of the hands; he later developed walking difficulties. Callosal atrophy was present on his cerebral magnetic resonance imaging scan, prompting genetic testing for SPG11, which revealed homozygous mutations. DISCUSSION: The clinical features, differential diagnosis and management of SPG11, the most common form of autosomal recessive complicated HSP with a thin corpus callosum are discussed.

Orthostatic tremor.

Orthostatic tremor is characterised by a feeling of unsteadiness that is accompanied by a high frequency (13-18 Hz) tremor of the legs when standing, and which is relieved by sitting or walking. We describe a typical patient whose condition gradually progressed so that eventually he could no longer stand still. We discuss the clinical features, management and pathogenesis, and highlight the need for awareness of this condition because the diagnosis is often missed or delayed.

Automatic classification of 123I-FP-CIT (DaTSCAN) SPECT images.

INTRODUCTION: We present a method of automatic classification of I-fluoropropyl-carbomethoxy-3ß-4-iodophenyltropane (FP-CIT) images. This technique uses singular value decomposition (SVD) to reduce a training set of patient image data into vectors in feature space (D space). The automatic classification techniques use the distribution of the training data in D space to define classification boundaries. Subsequent patients can be mapped into D space, and their classification can be automatically given. METHODS: The technique has been tested using 116 patients for whom the diagnosis of either Parkinsonian syndrome or non-Parkinsonian syndrome has been confirmed from post I-FP-CIT imaging follow-up. The first three components were used to define D space. Two automatic classification tools were used, naïve Bayes (NB) and group prototype. A leave-one-out cross-validation was performed to repeatedly train and test the automatic classification system. Four commercially available systems for the classification were tested using the same clinical database. RESULTS: The proposed technique combining SVD and NB correctly classified 110 of 116 patients (94.8%), with a sensitivity of 93.7% and specificity of 97.3%. The combination of SVD and an automatic classifier performed as well or better than the commercially available systems. CONCLUSION: The combination of data reduction by SVD with automatic classifiers such as NB can provide good diagnostic accuracy and may be a useful adjunct to clinical reporting.