University of Groningen Objective and subjective movement symptoms in (functional) tremor Kramer, Gerrit

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University of Groningen

Objective and subjective movement symptoms in (functional) tremor

Kramer, Gerrit

DOI:

10.33612/diss.136731740

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Publication date: 2020

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Kramer, G. (2020). Objective and subjective movement symptoms in (functional) tremor. University of Groningen. https://doi.org/10.33612/diss.136731740

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CHAPTER 7

GENERAL DISCUSSION AND

FUTURE PERSPECTIVES

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Functional movement disorders (FMDs) are characterized by an impairment in explicit movement control[1,2], leading to symptoms like tremor, dystonia and myoclonus[3]. The problem is thought to arise from a higher hierarchical level in the brain[2], that is, a problem in brain function rather than structure[4]. Due to the nature of this disorder, test results are typically negative and therefore, FMD is often disregarded as stress-related or psychiatric[5]. This view was fuelled by a study showing that patients with a functional tremor (FT), a subtype of FMD, dramatically overestimated their tremor duration compared to patients with an organic tremor (OrgT), such as Parkinsonian or dystonic tremor[6].

The idea that FMD is mainly a psychological problem, however, faces serious critique. Given the extensive heterogeneity in patients with FMD, it seems unlikely that a simplistic “it’s all due to stress” is true for all patients with FMD[7,8]. Many studies suggest that psychological factors are only relevant in a subset of patients with FMD[9], and their relevance is often comparable to that in patients with an organic movement disorder[10,11]. The list of similarities between patients with FMD and those with organic movement disorders is impressive[12]. Therefore, it seems unlikely that psychological factors play an important causative role in every individual patient with FMD. Typical case-control studies are not able to investigate individual differences, especially within a heterogenous sample, and do not distinguish between cause and consequence[13]. Idiographic research, the study of individual patients, can provide this information and was employed in the current thesis. Such a study requires an extensive time series of data on symptoms and potential contributing factors.

In this thesis, tremor was studied, as this symptom can be assessed simultaneously both objectively and subjectively. The use of objective assessment methods fits with the current emphasis on studying FMD using positive criteria[7]. Objective tremor symptoms were first analysed in the clinical environment, before long-term symptom assessment (in the natural home environment) was employed. In the final study, the influence of psychological factors on objective and subjective movement disorder symptoms was studied, thereby answering some of the questions regarding the presumed psychological aetiology in patients with FMD.

Diagnosis of functional tremor

The diagnosis of functional movement disorders is currently mainly dependent on clinical assessment[14]. However, this clinical assessment does not always provide a definitive diagnosis. For example, the feature of distraction that is thought to be typical for FT can sometimes also be present in patients with essential tremor[15]. Also, many typical signs of certain tremor types are specific, but not sensitive, thereby limiting diagnostic certainty in a proportion of patients[16]. Additional neurophysiological assessment can aid in the diagnosis, as shown by a test battery to enhance diagnostic certainty in patients with FT[17]. A previously conducted study from our centre suggested the potential of an additional approach: coherence analysis of tremulous muscle activity. This technique can be used to discriminate between enhanced physiological tremor and other tremor types[18]. However, this coherence analysis was not successful in distinguishing FT from OrgT[18]. This might be due to the single estimate provided by this standard coherence

GENERAL DISCUSSION AND FUTURE PERSPECTIVES

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analysis, and therefore, small variations in coherence over time might not have been detected. In

chapter 2, wavelet coherence analysis was employed, which enables the detection of changes

in coherence over time[19]. In this study, FT was characterized by high average coherence with frequent short interruptions and irregularities over time. These short interruptions and irregularities argue against a stable tremor generator, as is the case in Parkinson’s disease[20], but instead may fit with a more complex brain network disorder in FT[21]. A decision tree was provided to distinguish between FT and OrgT. A clear advantage of this study design was the analysis of tremor without the use of specific tasks during the recordings, as is the case in most other electrophysiological tests in tremor[17]. These electrophysiological tests help to obtain positive features in establishing the diagnosis of FT/FMD, which is currently more and more emphasized[8].

Long-term assessment of subjective and objective tremor symptoms

The aforementioned electrophysiological testing still only provides a snapshot of the patient’s condition as this test typically takes around 30 minutes. The method is thus not able to provide information regarding daily fluctuations in tremor symptoms, for example due to influence of stress. The long-term assessments that are needed for such an analysis are the subject of the remaining part of this thesis.

Long-term assessment can be characterized according to two main categories: objective methods, by using a transducer, and subjective methods, e.g. by using some form of self-report. Both have been studied for over 30 years[22] but are not routinely used in clinical practice. In

Chapter 3 we reviewed the currently available methods to assess movement disorder symptoms

in the home environment. In short, subjective methods remained the most widely adopted long-term assessment methods. The main subjective measures were the ON/OFF diary to detect medication response in patients with Parkinson’s disease and fall diaries. Interestingly, most studies employing a combination of objective and subjective methods showed remarkable differences between both approaches. Therefore, a better understanding is necessary regarding which information is provided by subjective and objective assessment. Only one objective measure, accelerometry to study tremor, provided sufficiently reliable results; this method was used in the subsequent part of the thesis.

In the final three studies of this thesis (chapter 4-6), a cohort of 17 patients with FT and 27 with OrgT were studied for 30 days in their home environment. They wore an accelerometer to objectively record tremor during day time and completed a web-based diary five times a day.

First in chapter 4, the minimum assessment time required to obtain reliable tremor estimates was calculated. A method was used that previously enabled to determine the number of assessment days to obtain reliable daily activity measures[23]. Already one assessment day provided an acceptable estimate of most tremor characteristics. However, three days provided good to excellent estimates of tremor percentage and tremor frequency variability, and therefore, this assessment period is recommended for clinical applications. These findings are in line with a similar study on long-term EMG analysis in patients with tremor, which also studied patients for three days[24]).

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Subsequently, in chapter 5, the level of subjective and objective tremor symptoms in patients with FT and OrgT was assessed. As a previous study detected a dramatic subjective overestimation of objective tremor duration, especially in patients with FT (compared to OrgT)[6], this study aimed to replicate and validate these results. These previous findings, if true, would have major consequences for both clinical practice and scientific research: patients with FT would have almost no objectively quantifiable tremor, but rather only perceive they have tremor. In contrast with the aforementioned study, a considerable level of objective tremor duration in patients with FT was detected. Moreover, level of subjective tremor symptoms was similar between tremor groups, as was the association between subjective and objective tremor symptoms. These results implicate that (patients with) FT and OrgT are more similar than previously thought and argue against the idea of FT being mainly a problem of perception[25].

Influence of psychopathology on tremor symptoms in patients with

functional or organic tremor

The final chapter (Chapter 6) tested the long-held hypothesis of a strong influence of psychological factors in patients with FMD. The influence of daily stress was studied, as expressed with the variable of negative affect, on objective and subjective tremor symptoms in individual patients with a FT or OrgT. Vector autoregressive modelling was used to study the temporal association between negative affect and tremor symptoms. This method enables to study both contemporaneous and time-lagged associations.

On the contemporaneous level, there was a clear association between negative affect and subjective tremor symptoms, and, to a lesser extent, also objective tremor symptoms. These contemporaneous associations were not statistically significant different between patients with FT and those with OrgT. Time-lagged associations were mixed and only present in some of the patients, and again, these associations were similar in patients with FT or OrgT. These findings argue for a similar role of psychological factors in fluctuations in objective and subjective tremor symptoms in patients with FT and OrgT.

Methodological aspects and limitation

The studies in the current thesis all used novel methods with often relatively small patient groups. This provided new insights, but generalizability of the studies remains unknown. In the first study, objective positive criteria (tremor stability characteristics) were employed to differentiate between tremor groups. As this was a pilot study, the findings have to be reproduced in a larger, preferably prospective, sample. Furthermore, electrical muscle activity was only measured for 20 seconds; a future study should consider the use of longer segments, possibly even long-term assessment as was used in the rest of this thesis.

In the final three studies of this thesis, a group of patients with FT or OrgT was monitored for a relatively long study period, 30 days, during which they had to complete a web-based diary five times a day. This provided a unique insight in the influence of daily fluctuations of negative affect on tremor symptoms and vice versa. Due to the large number of data points per participant, it

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was possible to analyse this relationship on the individual level, thereby providing more insight in causality than the traditional case-control study would provide. However, this study design comes with its own limitations. First, many potential participants declined to participate, due to the expected study burden, and therefore, these studies contained a selection of motivated participants. Second, patients with FT and OrgT reported low (and skewed) scores of negative affect. These low and skewed scores caused floor effects and resulted in invalid statistical models in individual participants. To overcome this issue, the data was analysed on the group level as well, which showed a similar (weak) influence of daily stress on tremor symptoms in both patients with FT and OrgT. Given this weak influence and the low levels of negative affect, it seems unlikely that negative affect plays an important role in tremor symptoms in general.

IMPLICATIONS AND FUTURE DIRECTIONS

Conceptual implications

This thesis showed many similarities between patients with FT and OrgT: a similar association between objective and subjective tremor symptoms and a similar association with psychological factors. These similarities argue against the hypothesis of FT being mainly a stress-related (psychiatric) disorder. They do however, fit with other studies finding many similarities on psychological and psychiatric factors and comorbidities in patients with a functional or organic neurological disorder[10–12,26]. Instead of arising from one single psychological factor, FT is likely to be caused by a complex interaction between biological, psychological and social factors[12]. Therefore, it would be better to focus on psychological factors as potential risk factors or maintaining factors[9] instead of as the main cause. This more open-minded approach enables the inclusion of other factors as well, for example, the findings of alexithymia, physical trigger events and abnormal sense of agency[7,27]. Furthermore, this biopsychosocial model fits better with the current emphasis on diagnosing patients with FMD using positive criteria[8,14,27]. Finally, as psychological factors can play a similar role in patients with OrgT (as they do in patients with FT) these psychological factors should also be assessed in patients with OrgT both in clinical care as well as in research.

Research implications and future directions

The use of positive/objective criteria might aid in addressing heterogeneity in FMD, for example, by creating more homogeneous study samples by selecting patients with similar characteristics. Furthermore, this can be combined with the use of vector autoregressive modelling, similar to chapter 6, to identify patients with a relatively strong influence of psychological factors on movement disorder symptoms. It would be interesting to study whether such patients benefit more from psychological therapy than those who have a very weak influence of psychological factors.

The use of positive/objective criteria might also be applied in the study of patients with a mixed presentation: recent literature suggest frequent functional overlay, that is, a recognized

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organic neurological disorder with additional features of FMD[2,3]. For example, up to 30% of patients with Parkinson’s disease have functional neurological symptoms[31] and FMD symptoms can arise after successful deep brain stimulation in Parkinson’s disease patients[32]. The use of positive/objective criteria might aid to diagnose patients with both organic and functional movement disorders, which is necessary to develop focused treatment strategies[31].

Objective tremor assessment in the home-environment might be used in future studies, for example, to monitor treatment effects in drug trials. Before this method will be applied, a number of issues have to be addressed. First, it should be determined which objective tremor characteristics contribute most to subjective symptom level. In the current thesis, the percentage of time with objective tremor was used, however, other parameters should be explored as well, for example tremor amplitude. Second, it should be studied whether tremor burden is similar in different tremor types, for example, a resting tremor might be less bothersome than an action tremor. Third, other patient characteristics might contribute to symptom burden as well, for example, psychological factors, as we showed in the last study of this thesis.

Clinical implications and future directions

The study on wavelet coherence analysis shows the possibility of using objective positive criteria in diagnosing FT. Before this method can find its way into clinical practice, some steps have to be taken. First, a larger cohort of patient is necessary to validate the current findings. Furthermore, this wavelet coherence analysis should be used in addition to other parameters, like other EMG-characteristics and/or clinical items. Future studies should further investigate the possible clinical application of wavelet coherence analysis.

A number of issues have to be addressed before ambulatory movement disorder symptom assessment finds its way into clinical practice. First, symptom assessment in the home environment using long-term recordings may impose a relatively high burden on patients. Therefore, more studies are necessary to investigate the minimum assessment time, like chapter 4 on determining objective tremor characteristics, to limit this study burden. It has to be noted that the minimum assessment time to provide tremor characteristics is different from the minimum number of observations required for reliable statistical models for vector autoregressive modelling. The latter can vary depending on the study design, with studies using T > 90 usually are able to create a stable statistical model[28,29]. Second, vector autoregressive modelling, to study individual patients, can be time-consuming and requires a high level of statistical expertise. New initiatives like automated vector autoregressive modelling, as applied in chapter 6, help in making these methods accessible for clinical purposes. Third, the clinical relevance of these models has to be determined before they can be applied to guide treatment or determine prognosis.

The findings of this thesis are relevant for the attitude of clinicians towards patients with FMD. In accordance with recent literature, a diagnosis of a FMD Is based on the presence of positive criteria, and not merely on the exclusion of other neurological disorders or the presence of psychological distress. This approach circumvents fruitless discussions with patients on whether or not certain potential traumatic events did or did not cause their current symptomatology. The

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explanation of the diagnosis of FMD using positive criteria can help patients understand their own disorder. This understanding is likely to aid acceptance of the diagnosis, which in turn, is regarded as one of the most important prognostic parameters[30]. Also, the presence of a substantial level of objective tremor duration helps to view these patients as having a serious impairment in daily living, which may help to express empathy when treating these patients.

As substantial heterogeneity was detected on the individual level, for example regarding the influence of psychological factors, it is unlikely that a “one size fits all” approach will be sufficient in this patient category. Therefore, a multidisciplinary approach is needed to address this multifaceted disorder and provide patient-specific treatment.

Conclusion

This thesis showed many similarities between patients with FT and OrgT. It demonstrated the possibility to diagnose FT with objective positive criteria. Furthermore, patients with FT have an objectively detectable and persistent tremor during activities of daily living, and they have a similar association between objective and subjective tremor symptoms as patients with an orgT. Finally, psychological factors seemed only to have a weak influence on objective and subjective tremor symptoms in patients with FT, and this was again comparable to patients with OrgT. These findings urge clinicians to treat patients with FT with the same attitude and involvement as patients with OrgT. This thesis also showed some of the complexity underlying FT, thereby stressing the need for a personalized approach and treatment. Concluding, in accordance with other recent literature, this thesis provided evidence against the hypothesis of an exclusive psychological explanation for all FMD symptoms and therefore, this view should be abandoned, both in clinical care as well as in research.

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