Diagnosis Versus Classification of Essential Tremor: A Research Perspective

Roberto Erro; Marina Picillo; Maria Teresa Pellecchia; Paolo Barone

doi:10.14802/jmd.23020

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Viewpoint Diagnosis Versus Classification of Essential Tremor: A Research Perspective: Roberto Erro, Marina Picillo, Maria Teresa Pellecchia, Paolo Barone; Journal of Movement Disorders 2023;16(2):152-157.
DOI: https://doi.org/10.14802/jmd.23020
Published online: May 24, 2023

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Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, Neuroscience Section, University of Salerno, Baronissi, Italy

Corresponding author: Roberto Erro, MD, PhD Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, Neuroscience Section, University of Salerno, Via Allende 43, Baronissi 84081, Italy / Tel: +39-089969119 / E-mail: rerro@unisa.it

• Received: January 23, 2023 • Revised: March 17, 2023 • Accepted: April 7, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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DIAGNOSTIC VERSUS CLASSIFICATION CRITERIA
ET-PLUS: A DIFFERENT ENTITY OR A SUBGROUP OF ET?
A RESEARCH PERSPECTIVE
Notes
Acknowledgments
REFERENCES

The majority of tremor syndromes are conditions with poorly understood etiology and heterogeneity in presentation, natural history, and outcomes [1]. Few of them, with the exception of Parkinson’s disease (PD) and a few others [2], have a single clinical, laboratory, pathological, or radiological marker that might serve as a “gold standard” for diagnosis and/or classification. Therefore, the development of criteria for both clinical practice and research purposes is an important milestone for the field [3]. Theoretically, the application of suggested criteria should lead to the identification of diagnostic biomarkers and tremor etiology, which in turn might lead to a reappraisal of the existing classification and/or diagnostic criteria. However, such an ideal process did not occur in the tremor field; we use essential tremor (ET), which is arguably the most common tremor syndrome [4], as an example. After decades of extensive research on ET, there is no consensus on its prevalence, phenotypical features, natural history or pathological findings [5-11]. One explanation for such inconsistencies is likely the inclusion of different disorders under the ET umbrella [5,12,13]. due to its loosely defined boundaries, which calls into question the existing criteria for ET and their (differential) application in clinical practice and for research purposes. In this piece, we argue that diagnostic and classification criteria have conceptual and operational differences, which has important research implications, especially in the field of ET, where there is the most disagreement.

DIAGNOSTIC VERSUS CLASSIFICATION CRITERIA

Diagnosis can be defined as the identification of the cause or nature (i.e., etiology) of a syndrome by evaluation of its signs and symptoms as well as from the results of supportive tests in any individual patient. In the absence of gold standards, determining a diagnosis involves estimation of the probability of a suspected condition. Accordingly, diagnostic criteria represent a set of clinical features and/or tests to aid this process in clinical practice and to eventually guide therapeutic decisions. Such criteria should generally be broad enough to account for the clinical heterogeneity of the disease, with the aim of accurately identifying as many people with the condition as possible. Conversely, classification criteria represent standardized definitions that are primarily meant to establish well-defined and relatively homogeneous cohorts of patients (ideally with a given diagnosis) for subsequent clinical research. Contrary to diagnostic criteria, they are not designed to be sensitive but rather to identify the majority of patients with key shared features of the condition (i.e., designed for high specificity), which makes them unsuitable for use in clinical practice. Validated classification criteria can ensure critical interpretation of study findings and comparisons of results among studies, although they might restrict the external validity of individual studies. Therefore, diagnostic and classification criteria have different intrinsic features and objectives (Table 1).

Where disease etiology is robustly defined, such as in PD, diagnostic and classification criteria may theoretically overlap and be used interchangeably, with classification criteria potentially serving a diagnostic role, provided that acceptable internal and external validity for diagnosis is achieved in a given population. Nonetheless, this has not been even formally applied in PD, where clinical heterogeneity is well established and classification schemes, including tremor/postural-instability subtyping or more recent nonmotor subtyping proposals, clearly diverge from diagnostic criteria [14]. However, new classification (i.e., subtyping) criteria are beginning to be used in experimental trials to analyze different PD subgroups [15].

The same argument applies to ET [5], which has no clearly identified etiology; moreover, because the clinical features of any disease presenting with the core phenotype of action tremor of the arms (i.e., with ET according to the new classification scheme) are likely to be different among patients, classification criteria cannot be 100% accurate, resulting in potential misclassification of a subset of patients when regarding classification and diagnostic criteria as fully equivalent.

In 2018, the Tremor Task Force of the International Parkinson’s and Movement Disorders Society (IPMDS) published the new tremor classification system [1], the primary purpose of which was to classify patients with various tremor syndromes (i.e., to propose classification criteria). However, it was further intended to “serve as a tool for clinical diagnosis” (i.e., to be used as a set of diagnostic criteria). As previously mentioned, such ambivalence might not be entirely logically sound and can represent a source of ambiguity, especially with regard to the newly proposed construct of ET-plus, as described below.

ET-PLUS: A DIFFERENT ENTITY OR A SUBGROUP OF ET?

One of the main departures from previous classification schemes in the 2018 consensus statement is the introduction of a newly defined entity (ET-plus) that shares the core phenotype of ET but is also characterized by rest tremor and/or additional soft signs that do not suffice to make an alternative syndrome classification or diagnosis [1]. ET and ET-plus share a name and are presented in the same paragraph as well as in the same box in Figure 3 of the consensus statement [1], which hints that ET-plus represents a classification subgroup of ET. We interpret the heart of this proposal as intending to deal with the heterogeneity in ET as it was formerly conceived. Although its definition has not been firmly grounded on any biological markers, it still has the merit of serving its implicit aim, that is, to separate groups of “pure” ET and ET-plus in the hope that research on the former would identify some genetic, pathophysiologic or pharmacotherapeutic markers that could eventually be further tested in the latter. Although some would see this as an attempt to actually remove that very heterogeneity from ET, to cordon those patients off and to place them in another category [16], this is the exact purpose of classification criteria, that is, to introduce stratification among patients with a given diagnosis, albeit performed on clinical grounds.

One of the major criticisms of ET-plus is that as ET progresses, patients accumulate additional clinical features such as mild gait impairment and soft cognitive deficits; thus, ET-plus might represent only a state condition rather than a trait condition [17]. If true, this would undermine the stratification of ET patients into pure and plus forms, as suggested by the consensus statement. However, accumulating data indicate that ET-plus does not simply represent more advanced forms of ET [18-20]. Nonetheless, the use of the current criteria for both diagnostic and classification purposes remains unclear. In fact, a literature search for original articles adopting the new classification scheme revealed that ET-plus was either considered an exclusion criterion [21], merged with ET [22], or considered a different “phenotype” of ET [23]. While some would argue that these approaches might depend on the research question, we believe this further reflects the uncertainty about ET-plus because it is not clear whether it is intended as a different entity or a subgroup of ET. Such ambiguity is also present in ongoing trials testing experimental drug treatments for ET. For instance, the published protocols of the trials testing the experimental drugs SAGE-324 and CAD-1883 (available from ClinicalTrials.gov) do not mention whether the presence of soft signs should be considered an exclusion criterion, with the inclusion criteria strictly mirroring the definition of ET according to the new classification. Conversely, the study protocol of the trial testing the experimental drug PRAX-944 clearly mentions that “it is acceptable for patients to have one or more ET plus signs including mild dystonic posturing, mild rest tremor in the context of advanced ET […], intention tremor, mild increase in tandem gait difficulties”, which suggests that the classification criteria are intended as diagnostic criteria (Table 1).

A RESEARCH PERSPECTIVE

The importance of correctly interpreting the value of diagnostic and classification criteria is not merely a semantic exercise. There are similar debates in other fields of medicine [24,25], and perhaps the most well-known example of divergent diagnostic and classification criteria is that of diabetes. It is clear that diagnostic and classification criteria have different intrinsic features and different purposes (Table 1). With this in mind, we deem a point of clarification necessary and further propose adding granularity to the current classification [26]. This would not detract from the diagnosis of ET and therefore would not hinder the putative reasons for retaining the label of ET, that is, to ensure coverage of symptomatic anti-tremor treatments and to support patient advocacy groups [27]. Similarly, our proposal would not conflict with the current IPMDS tremor consensus [1]: indeed, the initial stratification (i.e., classification) of ET patients into pure and plus forms seems a good starting point for advancing research in this field.

We therefore suggest that the diagnosis of ET should be performed using the core criteria of the new scheme (i.e., action tremor of the upper limbs of at least 3 years duration) in the absence of neurological signs that would lead to diagnosis of a combined tremor syndrome. We recommend that this definition, lacking the distinction of “pure” and “plus” forms, should be adopted in clinical practice for diagnostic purposes. At the current stage, in fact, there is no evidence that an explicit diagnosis of pure ET or ET-plus has any pragmatic consequences in terms of management and prognostic counseling. One might argue that the 3-year duration criterion is arbitrary, as it might leave some “ET-looking” patients under the undefined rubric of indeterminate tremor for some time. However, in the TITAN study (i.e., the only available, large, prospective study started after the release of the IPMDS tremor consensus [18]), only 15 patients out of nearly 680 patients recruited in the first year of activities, were diagnosed with isolated segmental action tremor or indeterminate tremor because of the 3-year criterion, representing approximately 3% of the entire group of ET/ET-plus, which suggests that this might be a more theoretical than practical concern. Obviously, patients should be followed up long after the 3-year time point since the possibility of transitioning across diagnostic entities is possible. Patients may have an ET diagnosis for decades before developing additional movement disorders: these patients will be reclassified as having a combined tremor with antecedent ET, as per consensus [1]. Longitudinal studies on this topic might help to resolve the debate regarding the controversial relationship between antecedent ET and subsequent PD [28].

Lumping together ET and ET-plus patients might further serve some specific purposes from the research standpoint. In fact, from an epidemiological perspective, if one aims to address the “true” prevalence of the disorder, these subgroups should be considered together [29]. Conversely, we deem it unwise to adopt the diagnostic level of criteria, that is, combining ET and ET-plus into a single category, in other research settings because this approach would grossly reduce the external validity of any research, hampering the comparability across studies and undermining the validity of the results. As mentioned above, accumulating data indicate that ET and ET-plus have different clinical features in terms of age at onset and clinical progression [18-20]; therefore, when attempting to identify physiologic and etiologic correlates of either syndrome, the two subgroups should be separated and explored individually. One might further argue that the current classification criteria, which are relatively simple, might not yield a homogeneous group of patients. In fact, there is likely heterogeneity within the group of “pure” ET, for example, between early-onset and late-onset patients who show different clinical features and progression [30], as there is within the group of ET-plus [20,31]. One way to explore this within-group heterogeneity is to increase the complexity of classification criteria (Figure 1), for instance, incorporating clinical features that are deemed to influence the phenotype of ET, including age at onset, family history or the phenomenology of tremor [26,30,32]. Such deep phenotyping collects more fine-grained details about disease manifestations, ultimately facilitating the identification of nonclinical markers of such heterogeneity [33]. Obviously, future empirical research is needed to determine whether the suggested features, including tremor phenomenology, are useful anchors to sensibly stratify patients. Initial data indicate that tremor phenomenology might reflect the underlying circuitry involved in the generation of involuntary movements and, in turn, might be exploited to predict treatment response to neuromodulation. For instance, Schreglmann et al. [34] used phase-locked, transcranial electrical stimulation of the cerebellum as a therapeutic tool for ET. In their sample, however, two subgroups were identified (e.g., responders and nonresponders) that were different in terms of tremor phenomenology; the nonresponders displayed asymmetrical, irregular and coarse tremors [34]. This example highlights the importance of classification criteria that allow inferring pathophysiology and predict treatment outcomes within the ET population.

Likewise, we recommend increased granularity in the definition of ET-plus, that is, to consider adding a specific feature to the core phenotype of ET to fully explore the value of this new construct [20,31,35]. For instance, it is possible that subtle dystonia and questionable bradykinesia might identify different groups of ET-plus patients [20,36]. As mentioned above, this hypothesis should be tested in longitudinal studies that can validate (or reject) some of the proposed clinical anchors to subclassify ET and ET-plus. Longitudinal studies are also needed to settle the debate of whether some features of ET-plus represent late complications or coexisting symptoms of “pure” ET. Neurophysiological anchors might distinguish between subgroups of patients and make classification criteria less dependent on clinical features, including phenomenology, which are more prone to disagreement.

There is no doubt that the new classification scheme has renewed interest in tremor research, but it has also generated an enlightening debate, with supporters and detractors disputing the legitimacy of defining ET as a syndrome and of the construct of ET-plus [16,17,26,27,37-40]. It is beyond the scope of this piece to contribute to this debate; nevertheless, we aimed to clarify that the diagnosis and classification of any condition, including ET, are not equivalent. An effort should be made to promote and homogenize the use of the current classification scheme to ensure comparable results across studies.

Notes

Ethics Statement

The ethical approval is not required for this manuscript. Informed patient consent was not necessary or acquired for this work.

Conflicts of Interest

Roberto Erro receives royalties from the following publications: Case Studies in Movement Disorders—Common and Uncommon Presentations (Cambridge University Press, 2017) and Paroxysmal Movement Disorders (Springer, 2020). He has received consultancies from SANOFI and honoraria for speaking from the International Parkinson’s Disease and Movement Disorders Society. Marina Picillo is supported by the Michael J Fox Foundation for Parkinson’s research. Paolo Barone received consultancies as a member of the advisory board for Zambon, Lundbeck, UCB, Chiesi, Abbvie, and Acorda. Maria Teresa Pellecchia has no conflicts of interest.

Funding Statement

None

Author Contributions

Conceptualization: Roberto Erro. Writing—original draft: Roberto Erro. Writing—review & editing: all authors.

Acknowledgments

We thank Susan Ainscough for editing the text.

Figure 1.

From diagnostic to classification criteria for the essential tremor (ET) spectrum. The figure summarizes our interpretation of the International Parkinson’s and Movement Disorders Society (IPMDS) criteria for ET (depicted in the box) regarding their use for diagnostic or classification purposes and further shows our proposal of subclassifying both pure ET and ET-plus by incorporating additional clinical factors that might increase the likelihood of finding physiologic and/or etiologic markers.

Table 1.

The main differences between diagnostic and classification criteria and implications for essential tremor

	Diagnostic criteria	Classification criteria	Implications for ET
Aims	To establish the diagnosis of a condition in clinical practice	To define a homogeneous group of patients for research purposes	Diagnostic and classification criteria for ET are to be used in different settings and for different purposes, that is for clinical practice and for research
The starting point	Suspicion of a condition	Established diagnosis of a condition	Classification criteria are used (for research purposes) in patients with a given diagnosis of ET, whereas diagnostic criteria have to be applied in patients with no diagnosis or in whom a former diagnosis (for instance of isolated head tremor) has to be reconsidered
Differential diagnosis	Always considered	Not considered	Diagnostic criteria need to include items to exclude alternative conditions (for instance task-specific tremors) whereas classification criteria do not require such items since the diagnosis of ET is already established
Sensitivity/specificity	They favor sensibility over specificity, which should be however high	High specificity is required, even if some loss in sensitivity	Diagnostic criteria do not weigh the heterogeneity of ET and therefore include both “pure” and “plus” forms; conversely, classification criteria are meant to create more homogenous (i.e., specific) subgroups of patients
External validity	Need to be broad and must reflect possible different features and severity of a disease (heterogeneity).	Need to define (relatively) homogenous groups that can be compared across studies and populations	The criteria that suffice to make the diagnosis of ET are too broad to identify homogenous groups of patients. ET patients might be instead classified into more homogenous groups (for instance, young- and late-onset patients) to facilitate research efforts into the discovery of pathophysiologic and etiologic correlates.
Presence of a “gold standard”	For disease with a gold standard, diagnostic and classification criteria can be very similar. For diseases without gold standard, development of diagnostic criteria poses significant challenges	Classification criteria are possible for disease with and without true “gold standards”	Until a gold standard for the diagnosis of ET is identified, diagnostic and classification criteria of ET have to be divergent to favor sensitivity and specificity, respectively.
Patients’ outcomes	Diagnostic criteria are for diagnosis, and therefore, have implications for treatment (as well as for billing and reimbursement)	Classification criteria have no treatment implications for patients and no/little impact on billing and reimbursement	Clinical management of ET patients will remain the same, regardless of their belonging to specific ET subgroups (pure vs. plus forms, young vs. late- onset, etc.)

ET, essential tremor.

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