Trial Design The proposed clinical feasibility pilot study contains two intervention groups. Patients with functional movement disorders (FMD) will be randomized into the two groups. Patients of the intervention group I will receive 10 weeks neuro-physiotherapy (NPT) and patients of the intervention group II a combination of NPT and metacognitive therapy (MCT).
Frequency and Scope of Trial Visits At a screening visit before participation in the clinical trial all patients will be assessed for eligibility by applying the inclusion and exclusion criteria and will be provided with information to obtain informed consent. If eligible, patients are randomized to the two different groups. At baseline examination, social demographic information (age, gender, education, family status etc.) and medical history (age at onset, disease duration, potential triggers, comorbidities, previous therapies etc.) are obtained. At baseline, immediately after completion of the intervention and at three, six and 12 months follow-up visits the investigators will use a standardized video protocol that ensures consistent examination of the movement disorder according to a standardized video-guided instruction protocol. It allows a blinded, objective video rating of patients' symptoms at all five study visits by the investigators that will stay blinded to the treatment status of the patient. Both have extensive experience in design, conduction and analysis of movement disorders video ratings. They will rate the severity of symptoms by applying clinical rating scales and questionnaires for patients with functional movement disorders. The baseline visit will take two hours and the post-interventional as well as follow-up visits will each last one hour.
Medical Problem and Relevance Patients with FMD present with different abnormal movements such as functional tremor, dystonia, myoclonus, or gait disorders and often also other symptoms and signs suggesting the involvement of the nervous system. FMD are incompatible with symptoms and signs of well-defined neurological disorders and are not associated with structural abnormality of the nervous system. Importantly, FMD disorders can reliably be diagnosed clinically on the basis of characteristic signs including incongruency of symptoms regarding anatomy and physiology, variable phenomenology, attention dependency, i.e. increased distractibility, entrainment and other specific signs, for instance, Hoover's sign. Thus, FMD is not a diagnosis of exclusion. Although FMD were referred to as "psychogenic" or "conversion movement disorder" suggesting psychopathology as a pre-requisite, a high percentage of patients in fact do not have psychiatric comorbidities.
The level of distress, disability and chronification of symptoms in patients with FMD is comparable to or even higher than that in patients with defined neurological disorders. FMDs are very common and along with other disorders in the spectrum of functional neurological disorders (FND), account for up to one-third of new referrals seen in neurology clinics. Their prevalence in private neurological practices is about 16% and almost as high as patients with headaches (19%) or epilepsy (14%). FMDs account for up to 20% of patients seen in movement disorders clinics. However, the pattern of care of these patients is highly inconsistent and most patients feel dissatisfied with the treatment they receive.
One reason for this unsatisfactory scenario that is also severely affecting the German healthcare system, is that there are no generally accepted therapeutic guidelines for FND patients. Often, patients are referred from one specialist to the other with neither neurologist nor psychiatrist taking on the long-term care for these patients due to a lack of validated treatment strategies. Patients typically seek advice from different specialists and often receive unnecessary, cost intensive diagnostic procedures that might be associated with complications. This leads to further referrals, unnecessary use of valuable health care system resources and secondary iatrogenic morbidity. The Scottish Neurological Symptom Study showed that patients suffering from FND create direct health care cost of about £11.3 million per year in Scotland. A study from the USA estimated the direct healthcare cost of FND patients in the USA of about $256 billion. In comparison to other neurological disorders, FND patients demand not only significantly more primary, specialty and emergency care visits, but also in- and outpatient clinic administrations.
Therefore, treatment strategies meeting FMD patients' needs are urgently needed. However, finding effective treatment is complicated by the fact that clinical symptoms of FMD are highly heterogeneous. Interestingly, recent neurophysiological studies suggest common underlying disease mechanism across FMD patients. For instance, in a temporal discrimination paradigm, FMD patients had reduced drift rates pointing towards a generalized deficit in information processing. In addition, FMD patients showed a significant reduction of physiological attenuation of self-generated perceptual stimuli reflecting an altered sense of agency, probably as a consequence of aberrant allocation of attentional recourses, which may also explain why voluntary movements are not experienced as such. Conceptually, this calls for therapeutic approaches, in which attention re-focusing is trained. In this respect, MCT and NPT are promising treatment options. MCT, as a form of cognitive behavioral therapy, focusses on patients believes about their own mind and cognition (metacognition). It explains how dysfunctional patterns of thinking and self-awareness can lead to and maintain FMDs and trains patients to consciously (re)-focus their attention away from unpleasant or disturbing mental processes. It has been successfully established in a pilot study conducted at the investigators' study site (University Clinic Schleswig-Holstein = UKSH) for the treatment of patients with Gilles de la Tourette syndrome. NPT is based on physical movement retraining by demonstrating that normal movement is (at least in parts) possible, to facilitate patients' confidence into their own movement capacity.
Importantly, FMD patients have the potential for a full recovery if sufficient treatment is applied. Therefore, the therapeutic approaches of the clinical trial, if successful, are expected to have immediate and strong impact on the care of FMD patients including an improvement in quality of life and to reduce health care system burdens. The latter is particularly relevant in the current coronavirus disease 19 (COVID-19) pandemic given that the incidence of FMD is known to rise with social crises. This is, at least partly, explained by the fact that fear and uncertainty are known to increase the incidence of neuropsychiatric disorders including FMDs.
Justification of Design Aspects Results of the proposed feasibility pilot study will provide important information on NPT and combined NPT/MCT effect size for the power and sample size calculations of a subsequently planned multicenter confirmatory trial. Moreover, patients' acceptance of interventions will be investigated in the proposed feasibility study. According to patients' feedback, adaptation of the interventions for a subsequent confirmatory trial will be possible.
Proposed Sample Size / Power Calculations Sample size was calculated with the aim to ensure that the effect of the interventions can be estimated with sufficient precision. For this purpose, the effect is based on the individual change in motor scores between baseline and after twelve months. Based on data from the only study with published individual patient scores (PMDRS) before and after cognitive behavioral therapy, a decrease of scores after the intervention can be expected with a mean(delta) of -26.87 and SD(delta) of 18.58. From this, it can be estimated that a sample size of 19 patients is sufficient to ensure that the 95% confidence interval of this mean delta is not wider than +/- 50% of the SD of the baseline scores, meaning that a change in pre- to post-interventional scores can be estimated with +/- 0.5 SD accuracy with a probability of 95%. Given that effects are to be estimated in both treatment groups and compared with each other, 19 patients need to be available for analysis in every group. Sample size calculation was performed using nQuery.
Compliance / Rate of Loss to Follow-Up The investigators identified six studies using physiotherapy and seven studies applying psychotherapy that reported exclusion rates during assessment for eligibility and drop-out rates from follow-up visits. Due to this information, the investigators calculated a mean rate of loss to follow-up of about 19% and exclusion rates during assessment for eligibility of 33%. Therefore, the investigators plan to enroll 61 patients and randomize 46 patients over the two groups. According to the drop-out rates, this will leave us with 19 patients per group to be analyzed
Statistical Analysis All analyzes will be performed for descriptive purposes. For primary and secondary endpoints, differences between intervention groups will be estimated with accompanying confidence intervals for every follow-up time. For all remaining variables, location and variation parameters will be estimated depending on their measurement scale. Analyzes of primary and secondary endpoints will be performed both in intention-to-treat as well as per-protocol populations.
In this feasibility study, no missing values will be imputed, and no interim analyzes are planned.
The results of this feasibility study will be used for effect size calculations for a subsequent multicenter confirmatory trial. All statistical analyzes were and will be done at the Institute of Medical Biometry and Statistics, University of Lübeck.
Quality Assurance, Safety, Monitoring and Data Reviewing Measures of quality assurance and safety will be done by a highly qualified clinical research associate at the Center for Clinical Trials Lübeck (ZKS). They will include clinical onsite risk-based monitoring according to ICH-GCP guideline (E6) and written standard operating procedures (SOPs) of the ZKS network to ensure patients' rights, patients' security and reliability of trial results. According to those SOPs, monitoring activities will be defined in a monitoring manual before starting the trial.
To initiate the study, the two trial sites will be visited by a clinical research associate of the ZKS Lübeck. During the ongoing trial, sites will be visited again at least two times to check informed consents and defined key data of all patients. Due to the low risk of the two interventions patient files will be randomly screened for adverse and serious adverse events. Within the frame of source data verification (SVD) during the trial, case report forms, patients' self-questionnaires and clinical ratings will be checked within a defined number of patients during the two onsite visits. At the end of the clinical trial, the two sites will be closed by a close-out visit.
