Minimal clinically important difference for the quality of life in essential tremor questionnaire

patient at home (36% improvement in stim-on/meds-off at enrollment visit). During the study, the patient continued the home medication regimen and took 1 pill of fast-acting oral levodopa/benserazide 100/25 mg on 2 occasions. Levodopa improved parkinsonian symptoms by 5 points on the MDSUPDRS part III score, without adverse events (i.e., dyskinesias). No adverse events or complaints by the patient were reported. The Ethical Committee approved the study, and all patients gave written informed consent. Our results prove the feasibility of prolonged recordings (up to 24 hours) in freely moving, chronically stimulated patients. They further corroborate the hypothesis that oscillations in the β-frequency range might be used as a levodoparelated biomarker for adaptive DBS paradigms, as they are present during active stimulation and years after surgery. We also provide for the first time preliminary evidence that interhemispheric subthalamic coupling changes between wakefulness and sleep can be monitored and possibly serve as an additional behavior-specific biomarker. These findings pave the way for testing different adaptive stimulation paradigms for STN-DBS and prompt a more accurate definition of symptom-related and behavior-specific biomarkers in PD.

Minimal Clinically Important Difference for the Quality of Life in Essential Tremor Questionnaire Essential tremor (ET) can considerably impair health-related quality of life (HRQoL). Disability and impairment, related to motor and nonmotor symptoms of the disease, can be specifically captured by the Quality of Life in Essential Tremor Questionnaire (QUEST). 1 Although this instrument is increasingly used in clinical practice and research, its minimal clinically important difference (MCID) has not yet been established. We therefore aimed to determine these threshold values that may provide guidance on judging the clinical relevance of changes associated with both disease progression and various treatment options.
A total of 248 consecutive patients with ET attending the Department of Neurology, Pécs, Hungary, between June 2013 and December 2018 were enrolled. In addition to demographic, medication, and disease-related data, the validated Hungarian version of the QUEST 2 was assessed at baseline. Disease severity was determined by the QUEST Summary Index (QUEST-SI) as mild (≤11.25), moderate (11.26-20.35), and severe (>20.35). 2 The major neurocognitive disorder was an exclusion criterion (Montreal Cognitive Assessment score <20.5). At follow-up visits, the QUEST-SI was reassessed, and patients rated the perceived changes in ETrelated difficulties since the last visit on the Patient-rated Global Impression of Improvement (PGI-I) scale. The methods for calculating MCID were previously described in full detail elsewhere. 3 The copyright for this article was changed after original online and print publication.
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Finally, 895 paired examinations were included. The baseline characteristics of the study cohort in the therapy during the follow-up period are presented as Supplementary Tables S1 and S2. The median number of return visits was 3, with a median intervisit interval of 6 months. A statistically significant ordinal logistic regression model could be developed between the PGI-I scale (anchor) and the changes in the QUEST-SI (Nagelkerke pseudo-R 2 , 0.421; P < 0.01). Both anchor-and distribution-based methods were applied for determining the MCID thresholds. 3,4 The mean changes, the effect size, the results of receiver operating characteristic analyses, and the calculated MCID values are shown in Table S3. The threshold values for minimal yet clinically meaningful changes slightly varied across ET severity stages (Table 1).
Previous studies investigating pharmacotherapy 5 and surgical treatments 6,7 for ET evaluated changes in the QUEST-SI only from a statistical point of view (Table S4). However, statistical significance does not necessarily imply clinical relevance, as small but significant improvement may be clinically negligible. Therefore, the simultaneous judging of the statistical significance and MCID thresholds may allow a more reliable interpretation of outcomes in clinical trials. Enrolling a high number of patients representing a wide range of disease severity and using wellestablished methods, 3,4 we found that any improvement greater than 4.47 or any worsening greater than 4.98 in the QUEST-SI indicates a minimal yet clinically relevant change in the HRQoL. Although MCID values may highly depend on the study population, the establishment of distinct MCID thresholds for different disease severity stages may help the wider applicability of our results. Our MCID thresholds may also be a good base for the planning of clinical studies, calculating sample power, and judging the outcomes of clinical trials.

Supporting Data
Additional Supporting Information may be found in the online version of this article at the publisher's web-site. Disease severity was determined by the QUEST score as described by Kovacs et al. 3 Threshold for mild severity is ≤11.25, whereas for moderate and severe 11.26-20.35 and >20.35, respectively. 3 MCID, minimal clinically important difference threshold; PGI-I, Patient-rated Global Impression of Improvement; QUEST-SI, #of the Quality of Life in Essential Tremor Questionnaire.