Features of “ET plus” correlate with age and tremor duration: “ET plus” may be a disease stage rather than a subtype of essential tremor

BackgroundEssential tremor (ET) is characterized by considerable clinical heterogeneity. In 2018, the term “ET plus” was introduced to mark a potential stratification point for dividing ET into subtypes – ET vs ET plus (i.e., ET cases with neurological features other than action tremor). However, as ET progresses, patients often develop increasingly severe tremor, spread of tremor, tremor under different activation conditions, and other features. Given this situation, ET plus may represent a disease stage rather than a disease classification or subtype. In theory, if the defining characteristics of a disease subtype fluctuate with age or disease duration, it raises the distinct possibility the “subtype” is a disease stage.MethodsA cohort of 241 prospectively enrolled ET cases underwent a detailed motor and cognitive assessment in which the features of ET plus including cerebellar signs (intention tremor, tandem gait difficulty), rest tremor, dystonia, and cognitive performance were evaluated. We determined whether these features of ET plus correlated with action tremor duration and age.ResultsWe demonstrated that numerous ET plus features were significantly correlated with both age and action tremor duration (numerous p values < 0.05). The same relationships were observed in a series of sensitivity analyses.ConclusionWe observed that the component parts of ET plus are highly age- and stage-dependent. These features are yearly-changing features conditional on a demographic and disease stage variable. These data support the notion that ET plus may represent a disease stage rather than a distinct disease subtype or disease classification.     

Head tremor in essential tremor: “Yes–yes”, “no–no”, or “round and round”?

IntroductionEssential tremor (ET) is a common yet frequently misdiagnosed movement disorder. One contributing factor may be the dearth of studies that focus on the nuances of clinical phenomenology. A clinical feature that has received relatively little attention is head tremor. Indeed, there is no consensus regarding the predominant direction of head tremor in ET, and no study has examined the clinical correlates of directionality.MethodsWe identified 51 ET cases with head tremor enrolled in a clinical-epidemiological study of ET at Columbia University. Each had a videotaped neurological examination. Videotapes were viewed and coded by a movement disorders neurologist for head tremor direction (“no–no”, “yes–yes”, or mixed) and continuity (continuous, intermittent, or rare). Direction was correlated with a wide range of clinical features.ResultsFourteen cases (27.5%) had “no–no” tremor, 9 (17.6%) had “yes–yes” tremor, and 28 (54.9%) had a mixed tremor. Mixed and “yes–yes” cases were older (p = 0.004) and had a longer tremor duration (p = 0.018) than “no–no” cases. Tremor severity (arms) was higher for mixed cases than for “yes–yes” and “no–no” cases (p = 0.04). More mixed cases had continuously present tremor while more “no–no” cases had rare head tremor (p < 0.001).ConclusionsHead tremor in ET seems to start as an infrequent tremor in one direction (esp. “no–no”) and becomes more frequent while acquiring additional directionality and a mixed phenotype as the disease progresses. These findings add to our understanding of the clinical spectrum of ET.     

Essential tremor: Is the word “essential” really essential?

Essential tremor (ET) is among the common movement disorders. A surge in research in recent years has considerably improved our understanding of disease etiology and pathogenesis, and its associated clinical phenomenology and natural history. With this progress have emerged a multitude of new questions and conundrums and newly proposed terminologies. Amidst these various related discussions, it is worth revisiting the essence of the nomenclature, “essential tremor”, to assess how well it continues to fit the growing understanding of this entity.Here we revisit the historical underpinnings of the nomenclature, its accuracy, pitfalls of eliminating the word, and advantages of removing the word. There are two primary historical bases for using the word “essential”: (i) idiopathic or unclear etiology, (ii) a unitary (single-featured) trait perceived as a constitutional feature. Numerous studies indicate that ET is neither truly idiopathic nor is fully isolated, making the use of “essential” technically incorrect. There are pitfalls and advantages of eliminating the term “essential” and both are succinctly described in this article. Yet in the absence of any flawless alternatives at present, we conclude that it is preferable for now to persist with “essential” tremor, thereby respecting the historical continuity of this one-and-a-half-century old nomenclature.     

Functional movement disorders

Functional movement disorders (FMD) represent a complex and disabling entity characterized by a broad range of clinical symptoms not explained by a classical neurological disease. In 2013, the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) added a clinical criterion based on incongruence and inconsistency, supported by recent literature highlighting the role of “positive clinical signs”. These clinical signs allow a “rule-in” procedure in making a diagnosis of FMD so that the diagnosis is no longer a “rule-out” or “by default” diagnosis made after exclusion of other neurological conditions. This review summarizes current evidence on common clinical features and highlights bedside signs in FMD, such as tremor, dystonia, myoclonus and parkinsonism. Tics, chorea and hemiballism are also briefly discussed.     

Anti-Tremor Action of Subtype Selective Positive Allosteric Modulators of GABAA Receptors in a Rat Model of Essential Tremors

The Cerebellum - Essential tremor (ET) is among the most prevalent neurological disorders and the most common cause of abnormal tremors. It is characterized by postural and action tremors ranging...     

Factor structure of motor signs in essential tremor

Motor signs in essential tremor (ET) are varied. Patients may have limb tremors, including postural, kinetic (e.g. writing, pouring), and rest tremors, head tremor, voice tremor, or chin tremor. Factor analysis allows one to determine whether these signs fall into a smaller number of discrete domains. Such an analysis has not been performed on a group of ET cases. ET cases (n = 168) were recruited from the Neurological Institute of New York and a videotaped examination was performed. A factor analysis was performed on 17 motor items. Four distinct factors emerged, explaining 68.7% of the total variance. These were factor I (action tremor in the dominant arm), factor II (action tremor in the nondominant arm), factor III (tremor at rest) and factor IV (chin tremor, head tremor, and voice tremor). The demonstration of these four factors will be of potential use for pathological and genetic studies as well as interventional studies, as will be discussed.     

Tremor

Tremor is one of the most frequent neurological signs; the diagnosis is mainly clinical. The most frequent tremor is essential tremor, which manifests itself as a postural and kinetic tremor. Tremor may occur not only in the hands, but also in the head and voice. Parkinsonian tremor is a tremor at rest; the legs and face are frequently involved. Orthostatic tremor mainly manifests itself in the legs and gives rise to postural instability. Dystonic tremor is an action tremor of the affected region of the body. Drug therapy mostly depends on the clinical manifestation. Postural and action tremors respond to beta blockers, primidone, some antiepileptics and benzodiazepines. Classical rest tremors are improved by dopaminergic substances or anticholinergics. Dystonic tremor may be successfully treated by injecting botulinum toxin. Orthostatic tremor responds to gabapentin or benzodiazepines in some patients. In patients with severely disability, implantation of thalamic stimulation electrodes may be considered.     

Bayesian Interpretation of Essential Tremor Plus

Essential tremor (ET) plus is a new tremor classification that was introduced in 2018 by a task force of the International Parkinson and Movement Disorder Society. Patients with ET plus meet the criteria for ET but have one or more additional systemic or neurologic signs of uncertain significance or relevance to tremor (“soft signs”). Soft signs are not sufficient to diagnose another tremor syndrome or movement disorder, and soft signs in ET plus are known to have poor interrater reliability and low diagnostic sensitivity and specificity. Therefore, the clinical significance of ET plus must be interpreted probabilistically when judging whether a patient is more likely to have ET or a combined tremor syndrome, such as dystonic tremor. Such a probabilistic interpretation is possible with Bayesian analysis. This review presents a Bayesian analysis of ET plus in patients suspected of having ET versus a dystonic tremor syndrome, which is the most common differential diagnosis in patients referred for ET. Bayesian analysis of soft signs provides an estimate of the probability that a patient with possible ET is more likely to have an alternative diagnosis. ET plus is a distinct tremor classification and should not be viewed as a subtype of ET. ET plus covers a more-comprehensive phenotyping of people with possible ET, and the clinical interpretation of ET plus is enhanced with Bayesian analysis of associated soft signs.     

Is essential tremor a single entity?

Essential tremor (ET) is a frequent movement disorder. The new tremor classification has subdivided ET into the classical form with bilateral action tremor of the hands with or without involvement of further tremor locations and without any other explaining signs or symptoms for the tremor and into ‘ET plus’ which comes additionally with further neurological signs of unknown origin. This will provide a better foundation for subclassifying the condition. The immediate cause of ET is a preformed oscillating network within the central nervous system as revealed with electrophysiological methods. The reason why this network is getting into the tremor mode is unclear. Pathology has so far not convincingly proved neurodegeneration for the condition but possibly adaptive changes of the brain particularly in the cerebellum are likely. Genetics have not yet provided insight into the molecular causes of the condition but several genetic diseases presenting with an ET syndrome have been uncovered. Treatment options cover medication (propranolol, primidone, topiramate) and surgical interventions with deep brain stimulation, gamma‐knife surgery and the recently introduced magnetic resonance imaging guided focused ultrasound lesioning. Further progress is awaited from the better integration of large prospective cohort assessment and basic science studies on the possible etiologies. In particular, aging‐related tremor may explain a large number of the patients seen in clinical practice. Currently ET is considered a clinically relatively uniform condition with presumably various underlying etiologies.     

Predictive value of nigrostriatal dysfunction in isolated tremor: A clinical and SPECT study

The overlap among tremor disorders is wide and complex because essential tremor patients may present resting tremor coexisting with postural tremor, while postural may coexist with resting tremor in Parkinson's disease. We investigated dopamine transporter binding in 61 subjects presenting with isolated atypical tremors defined as unilateral either postural, resting, or mixed (i.e. resting and postural) tremor, without rigidity or bradykinesia, by means of 123I‐FPCIT SPECT imaging at baseline. Patients were followed‐up clinically for 28.4 ± 7.2 months. Twenty‐five patients with baseline normal SPECT continued to present only tremor at follow‐up. Among 36 patients with abnormal SPECT, 23 (64%) developed PD, while the remaining 13 continued to present only tremor at follow‐up. The value of 123I‐FPCIT SPECT in predicting the evolution to PD was very high in a way independent from the first clinical presentation of tremor (Rest tremor, P = 0.015; Mixed tremor, P = 0.015; Postural tremor, P = 0.039; chi‐square test). Our data suggest that the clinical presentation of isolated tremors is insufficient to allow a precise early‐stage diagnosis, whereas the detection of presynaptic nigrostriatal dopaminergic dysfunction could lead to diagnosis of atypical tremor disorders at a very early stage. We suggest this disorder to be labeled as “isolated tremor with dopaminergic presynaptic dysfunction.” © 2008 Movement Disorder Society     

Tremor disorders: Identification and treatment

Tremor, one of the most common neurological disorders, may be defined simply as a rhythmic and sinusoidal movement. The abundant array of tremors may be classified along multiple axes, and this results in a nosology which can be confusing to the novice. In general, however, all tremors may be simply classified as either rest tremors or action tremors. This review focuses on some of the more common tremor disorders as well as those that are most relevant to clinical psychiatrists. The most common cause of rest tremor is Parkinson's disease, treated with levodopa, amantadine, and anticholinergic agents. The most common cause of action tremor is physiologic tremor and essential tremor, treated with propranolol and primidone. The major indications for treating tremor are social embarrassment or functional disability.     

Writing tremor: its relationship to benign essential tremor.

Nine patients with tremor on writing and one patient with tremor only on swinging a golf club were investigated. None of the patients had any other neurological symptoms or signs. The frequency of the tremor ranged from 5 to 6 Hz. Rapid passive supination or pronation of the forearm by a torque motor evoked a short burst of alternating tremor in seven patients. The tremor was improved by alcohol or propranolol in six patients. These characteristics of writing tremor (and of other isolated action tremors) suggest that it is a variant of benign essential tremor.     

Is essential tremor predominantly a kinetic or a postural tremor? A clinical and electrophysiological study

Both postural and kinetic tremors may occur in essential tremor (ET), however the relative contribution of each is not clear. ET has been variably defined with respect to kinetic and postural tremors. To examine the relative severity of postural and kinetic tremors in ET, 50 ET cases from a clinic and 55 from a community underwent a videotaped tremor examination. Kinetic and postural tremors were rated using a validated clinical rating scale (score range, 0-3). Thirty-one cases also underwent accelerometry to precisely quantify tremor amplitude. In clinic cases, the mean postural tremor rating was 1.25 (S.D., 0.89). The mean kinetic tremor rating was 52% higher (1.90; S.D., 0.57; P < 0.001). The community cases had similar characteristics. Sixty percent of the 105 cases had postural tremor ratings scoring 0 or 1 (no tremor or low amplitude, intermittent tremor). In clinic cases, the mean amplitude of postural tremor during tremor analysis was 0.51 mm (S.D., 0.66 mm), and the mean amplitude of kinetic tremor was 2.91 mm (S.D., 2.11 mm; P < 0.01). Similar values were obtained for community cases. These quantitative data suggest that kinetic tremor is more severe than postural tremor in ET. The majority of cases had mild or absent postural tremor. Despite this, ET is defined only as a postural tremor in many studies. Our data argue for a more consistent inclusion of kinetic tremor in diagnostic criteria for ET.     

Serpentine tongue in long-term metoclopramide treatment

A 57-year-old woman with gastrointestinal disturbances was treated with metoclopramide (30 mg per day). After 3 months of therapy, “serpentine tongue” dyskinesia occurred without further neurological signs. The patient was investigated for metabolic disorders, acanthocytosis, central or peripheral nervous system damage (by 1.5 T MRI and electrophysiological studies), and paraneoplastic syndromes (by tumor marker analysis and whole-body ¹⁸F-FDG PET/CT scan). By exclusion the involuntary movement was considered drug-induced.“Serpentine tongue” should describe a dystonia that is strictly isolated to the tongue with different clinical features from the typical tongue protrusion dystonia.     

Essential tremor: phenotypes

Classically, essential tremor (ET) was defined by the Movement Disorder Society Consensus Statement on Tremor (1998) as "a bilateral, largely symmetric postural or kinetic tremor involving hands and forearms that is visible and persistent". Additional or isolated tremor of the head may occur but in the absence of abnormal posture. Duration is more than 5 years and the neurological examination is normal, with exception of the cogwheel phenomenon. In the last years ET has evolved into two different meanings. First of all, the classical ET, as a monosymptomatic disorder, and second, a heterogeneous disorder, the Essential Tremors, or a family of diseases. Nowadays, ET can be classified with both motor and non-motor elements. Tremor may occur also in the legs, feet, trunk, jaw, chin, tongue, and voice. Although postural and kinetic tremors are the main features of ET, intentional tremor and tremor at rest may also occur in some patients. Other motor features described in patients with ET are gait ataxia, postural instability and eye-motion abnormalities. Non-motor features include cognitive (memory and executive problems and dementia), psychiatric (anxiety, depression and social phobia), and sensory abnormalities (olfactory deficits, hearing loss).     

A new twist for stopping the shakes? Revisiting GABAergic therapy for essential tremor.

Aside from physiological tremor, essential tremor (ET) is by far the most common cause of tremor in humans, affecting large numbers of individuals in every human population. The crude prevalence of ET has been conservatively estimated to be between 0.4% and 3.9%, although some estimates of the prevalence of ET among the elderly are higher than 20%. Essential tremor is the most prevalent adult-onset movement disorder, and is also regarded as one of the most common neurological disorders of adults, with a prevalence that is similar to or greater than that of stroke, Alzheimer disease, migraine headache, and lumbosacral pain syndromes. Essential tremor is as much as 20 times more prevalent than Parkinson disease.     

X-Linked Parkinsonism: Phenotypic and Genetic Heterogeneity

X-linked parkinsonism encompasses rare heterogeneous disorders mainly inherited as a recessive trait, therefore being more prevalent in males. Recent developments have revealed a complex underlying panorama, including a spectrum of disorders in which parkinsonism is variably associated with additional neurological and non-neurological signs. In particular, a childhood-onset encephalopathy with epilepsy and/or cognitive disability is the most common feature. Their genetic basis is also heterogeneous, with many causative genes and different mutation types ranging from “classical” coding variants to intronic repeat expansions. In this review, we provide an updated overview of the phenotypic and genetic spectrum of the most relevant X-linked parkinsonian syndromes, namely X-linked dystonia-parkinsonism (XDP, Lubag disease), fragile X-associated tremor/ataxia syndrome (FXTAS), beta-propeller protein-associated neurodegeneration (BPAN, NBIA/PARK-WDR45), Fabry disease, Waisman syndrome, methyl CpG-binding protein 2 (MeCP2) spectrum disorder, phosphoglycerate kinase-1 deficiency syndrome (PGK1) and X-linked parkinsonism and spasticity (XPDS). All clinical and radiological features reported in the literature have been reviewed. Epilepsy occasionally represents the symptom of onset, predating parkinsonism even by a few years; action tremor is another common feature along with akinetic-rigid parkinsonism. A focus on the genetic background and its pathophysiological implications is provided. The pathogenesis of these disorders ranges from well-defined metabolic alterations (PGK1) to non-specific lysosomal dysfunctions (XPDS) and vesicular trafficking alterations (Waisman syndrome). However, in other cases it still remains poorly defined. Recognition of the phenotypic and genetic heterogeneity of X-linked parkinsonism has important implications for diagnosis, management, and genetic counseling. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society     

Limb positioning and magnitude of essential tremor and other pathological tremors

We examined the influence of maintaining different postural configurations of the upper extremity on the magnitude of tremor in patients with essential tremor and with postural tremor from a variety of other neurological disorders. Patients maintained postures requiring different angles of forward flexion in the sagittal plane, of horizontal flexion, and of elbow extension. The tremor of patients diagnosed with essential tremor was either unaffected or affected only little by changes in limb position. In contrast, patients with pathological tremors, of the cerebellar postural, parkinsonian, and other types, exhibited positional dependence of their tremor. When there was positional dependence of tremor, it was always largest when the hands were near the nose or chin. These observations suggest a practical method for assistance with the clinical discrimination of essential tremor from other postural tremors.     

Trunk and head tremor as isolated manifestations of dystonia

Five patients presenting with isolated tremors of the trunk or neck are described. Their clinical features were similar to seven other patients who presented with head tremor, or arm and head tremor, but then eventually developed obvious torticollis, sometimes with arm dystonia. We conclude that isolated tremor of the trunk or head, especially of slow frequency (2-5 Hz), and in the case of the head in a "no-no" direction, may be the initial manifestation of focal dystonia.