Date: September 2022
Prepared by SIC Member: Kirsten Zeuner, MD
Authors: Stoyan Popkirov, MD; Petra Schwingenschuh, MD; David L Perez MD, MMSc; Mark Edwards MBBS, BSc, PhD
Editor: Lorraine Kalia, MD, PhD
Functional movement disorders (FMD) are movement disorders where clinical features such as distractibility suggest voluntary movements, but they are experienced by patients as involuntary. Patients may present with functional tremor, dystonia, tics/jerks, gait difficulties, and/or parkinsonism. Functional tremor is the most common clinical presentation. So called “red flags” to suggest functional tremor include sudden onset, spontaneous remissions, and variability over time in the patient’s history or during clinical examination.1 Specific methods for testing distractibility include changes in tremor character with a maneuver such as finger tapping. While the patient is asked to copy a rhythmic movement, the tremor might become variable in frequency, amplitude or direction. Additional maneuvers to test the distractibility of the tremor include performing cognitive tasks (counting months backwards, calculate arithmetic tasks), an externally cued ballistic movement or attaching a vibration fork to fingers, hand or arm.2 Pathophysiologically, there are generally no structural abnormalities in the brain on a macroscopic scale, but alterations in functioning of brain networks.3 Nonetheless, FMD as well as other functional neurological disorders (FND) may reflect BOTH software and hardware problems.4 FMD are considered a multi-network disorder with hypoactivity in the temporoparietal junction and abnormal interaction with the sensorimotor cortex. In addition, a loss of sensory attenuation has been reported that correlated with the loss of sense of agency, and may be a neural correlate of the experience of the abnormal movement as involuntary.5 Other studies have also identified increased cross-talk (connectivity) between motor control and limbic/salience network areas. It is generally accepted that treatment should include specialized physiotherapy6,7 and cognitive behavioral therapy.8 Here we discuss aspects related to diagnosis, pathophysiology, and treatment with four FMD experts.
Which neurophysiological diagnostic criteria for FMD are useful and practical? Are these criteria sufficiently reliable to support the diagnosis, even if the clinician is not 100% certain?
Dr. Stoyan Popkirov and Professor Dr. Petra Schwingenschuh:
Clinical diagnosis of FMD is often possible, but in certain cases neurophysiological measurements are helpful, and a ‘‘laboratory-supported’’ level of certainty can aid early positive diagnosis. Neurophysiology is especially useful for tremor analysis and discrimination of different types of myoclonus or dystonia.9
Professor Dr. Petra Schwingenschuh:
For functional tremor, accelerometry and surface EMG is used to identify variability of tremor frequency and amplitude, tremor entrainment or tremor cessation while applying an externally cued rhythm, and significant coherence between antagonist muscles using standard or wavelet coherence analysis.10, 11 A test battery involving EMG and accelerometer recordings of upper limb tremor in relaxed condition, outstretched with and without weight loading, during tapping tasks and while performing ballistic movements showed high sensitivity (90%) and specificity (96%) for differentiating functional from other tremors.11
So far, the neurophysiological diagnosis of functional jerks was based on polymyographic findings such as variable muscle recruitment, variable burst duration of >100 ms, and distractibility / entrainment and the presence of a Bereitschaftspotential (BP) in the EEG prior to a jerky movement using back-averaging. However, the sensitivity of a positive BP for diagnosing functional jerks is limited and its evaluation is subjective. Combing the event related desynchronisation (ERD) in the broad beta range and quantitative BP analyses improves diagnosing functional jerks and might be useful in patients with a clinical suspicion of functional jerks with a negative classical BP.12
There are a large number of neurophysiological abnormalities in dystonia, most relating to loss of inhibition (e.g. reciprocal inhibition or short-interval intracortical inhibition assessed with transcranial magnetic stimulation). Most of these abnormalities are shared with functional dystonia9. Using the paired associative stimulation technique, non-functional dystonia showed increased plasticity, while functional dystonia did not show this abnormality.13 Eye blink conditioning revealed an disinhibited R2 recovery cycle in patients with blepharospasm, while it was normal in patients with functional blepharospasm.14
Contingent negative variation (CNV) is a potential biomarker for abnormal attention and for treatment response in patients with FMDs. CNV is a negative cortical wave that precedes a pre-cued imperative stimulus requiring a quick motor response. Recently, clinical improvement of FMDs after physiotherapy was associated with faster reaction times and normalization of CNV, which was absent at baseline.15
The value of neurophysiological diagnostic biomarkers for differentiating pure FMDs from FMD co-occurring with another movement disorder is unknown, which is a limitation in clinical practice. Some of the tests are only performed in specialized neurophysiological laboratories and access might therefore be limited.
Dr. David Perez:
Dr. Popkirov and Prof Schwingenschuh have provided an excellent description of many relevant issues. As such, I would like to make only a few complementary reflections. The first is that in a great many clinical cases, a skilled neurological examination can be sufficient to make a "rule in” diagnosis of a FMD. The physical examination signs that can be used to make a bedside clinical diagnosis of a FMD have been recently summarized in a British Medical Journal 2022 publication authored by Selma Aybek and me.16 It is important to emphasize (especially with trainees) that the physical examination signs to confidently make a clinically-established diagnosis of a FMD should be robustly present (in other words, the features of variability/distractibility and/or entrainment are readily apparent on examination).17 In cases where bedside clinical examination findings are only marginally positive, caution should be taken to keep an open mind about the differential diagnosis — as well as consider potential use of laboratory-supported data to provide additional diagnostic confirmation if such tests are available.
Are FMDs a network disease? Which brain areas are involved? What is the evidence from neuroimaging studies?
Dr. Stoyan Popkirov:
There are studies to suggest that (neurodevelopmental) alterations in brain connectivity might contribute to the emergence of FMDs. Certain highly connected hub areas, especially in the medial prefrontal and insular cortex, have repeatedly "lit up" in neuroimaging studies. Considering the variability of symptoms, however, I would not consider FMDs a "network disease" in the strict sense of the term. But thinking in terms of networks, rather than Brodmann Areas, for example, will certainly improve our understanding of FMD.
Professor Dr. Mark Edwards:
I think it is useful to consider the brain networks that appear to be involved in FMDs, as this can give us insights into new targets for treatment and may provide therapeutic biomarkers (for example, a normalization of network activity associated with a novel treatment may encourage us to pursue it further even if clinical effectiveness is initially small). However, there are important pitfalls that we need to be aware of. First, people with FND are remarkably heterogenous in their symptoms, co-morbidities and aetiological risk factors. These aspects can all impact on network function in the brain and may end up confounding the results from functional imaging and electrophysiological studies. By analyzing data at a group level in a very heterogenous cohort, we may miss important inter-individual differences and may also mistake network changes as being part of the mechanism of production of functional symptoms when they instead relate to a common co-morbidity such as depression or post-traumatic stress disorder. There are ways around these confounds, such as doing a within-subject analysis pre- and post-treatment or by having very large cohorts where there is sufficient statistical power to subdivide patients by factors such as symptom type and comorbidities. Second, we must always be careful to remember that the neurobiological level of description of FND through functional magnetic resonance imaging (fMRI), for example, is just one level of description. It is not necessarily the most real or important or fundamental from a treatment perspective. In my opinion, clinicians and academics need to constantly keep in mind the whole range of levels at which one can describe and explain FND (neurobiological, psychological, social and all the shades of grey in between). By doing so, we can develop a truly integrated understanding of FND, giving us the best chance to develop treatments and services that truly meet the needs of patients.
Dr. David Perez:
FMDs are at the intersection of neurology and psychiatry. These are brain-based conditions that appear to be predominantly driven by abnormal functional circuit interactions within and across several brain networks. While a great deal more research is needed to comprehensively elucidate the pathophysiology of FMD (and related FND presentations more broadly), there is emerging data to support functional alterations at the level of sensorimotor, ventral attention (including the temporoparietal junction) and salience/limbic networks amongst other findings.18 To provide a few examples, several papers have identified abnormal functional connectivity between the temporoparietal junction and sensorimotor brain areas19, 20, a finding that has been interpreted to suggest an impairment in self-agency perceptions given the temporoparietal junctions’ role in this higher-order computation. Other studies across task and resting-state fMRI studies have observed increased functional connectivity between motor control brain areas and portions of the salience/limbic networks;21-23 these findings have been suggested to represent heighted “limbic” influence over motor function (akin to high arousal and negative affective states hijacking normal motor function). Another way of summarizing these findings is that the temporoparietal junction and cingulo-insular brain areas perform higher-order integrative brain functions and that abnormalities in the integration of multimodal information may also play a role in the pathophysiology.
I would like to make two additional points. The first is that there is a growing body of structural neuroimaging findings in FMDs (across gray matter and diffuse-weighted imaging).4 This suggests that at the “microscopic” level, structural neuroanatomy may also play a role in the pathophysiology of FND. While there is much work to be, I have wondered if structural findings might relate to the vulnerability for the development of a FMD, and that the functional connectivity profiles may relate more to the “state” characteristics of having a FMD in a given time point. These reflections remain speculative at this time. The second point is that there has been wonderful work in our field highlighting the likely role for predictive processing abnormalities in cognitive models forFMDs.24 My research colleagues and I have discussed how predictive processing and neuroconstruction may also be a perspective through which to propose integrated cognitive-affective models for FMDsand other FND presentations more broadly. Drs. Johannes Jungilligens and Sara Paredes-Echeverri have co-lead an article just published in Brain on this topic that may be of interest to readers.25
What is the evidence for treatment of FMDs? Do the studies more likely support physiotherapy only or in combination with behavioral therapy?
Dr. Stoyan Popkirov:
There are still too few randomized controlled studies to allow for an evidence-based comparison between physiotherapy alone and in combination with behavioral therapy. Considering the wide range of etiology and severity, personalized treatment plans will be more helpful than one-size-fits-all programs. In patients with pronounced psychiatric comorbidity or with dysfunctional relationships that contribute to the course of illness, physiotherapy without psychotherapy is unlikely to lead to sustained recovery. In cases when physiotherapy alone is deemed sufficient, it needs to observe psychological principles at the core of FMDs. Randomized studies have shown, for example, that physiotherapy should guide attention away from the deficit, rather than focus explicitly on the affected limbs or movements, and restore automaticity of movement by harnessing the internal inconsistencies found in functional disorders.6 When chronic pain is a driver of pathophysiology, physiotherapy that counteracts the fear-avoidance-cycle through exposure to painful activities is more effective than pain-contingent treatment.26
Professor Mark Edwards:
Heterogeneity is the key here and, in my experience, clinicians and allied health professionals should really prioritize assessment before making treatment decisions. The process of assessment often takes time, which is often in short supply in modern medical practice. However, it really is essential in people with FND. This assessment process may need to extend over a number of appointments when patients are complex and may involve different members of a multidisciplinary team.
In a randomized feasibility study of specialist physiotherapy, Glenn Nielsen and myself wanted to randomize 60 patients to specialist or standard neurophysiotherapy.6 We ended up screening 210 patients with FMDs for eligibility to get these 60 patients, with people excluded from this intervention due to factors such as overwhelming pain or fatigue, untreated and significant psychiatric disorders. This study was positive and has now been developed into a multi-center trial where we have used the same inclusion and exclusion criteria (www.physio4FMD.co.uk). I am sure that, if we had not used these exclusion criteria, the original study would not have had a positive outcome. Therefore, proper assessment of all the diagnoses and maintaining factors present and triage into the most reasonable treatment (including no active treatment) should form the basis of any service for people with FMD.
Dr. David Perez:
I am pleased to report that there is a growing therapeutic toolkit for the management of FMDs – one that includes potential therapeutic roles for physical rehabilitation and/or psychotherapy.18 A major positive step forward has been the development of consensus recommendations for physical therapy, occupational therapy and speech and language therapy for patients with functional motor symptoms (including speech output difficulties). There is also a growing evidence basis supporting a role for psychotherapy, most notably cognitive behavioral therapy.27 While more large-scale clinical research is needed to further define the most efficacious interventions to treat FMDs, it is becoming increasingly clear that “a-one-size-fits-all” treatment package may not prove to be the optimal end-product. Given the heterogeneity of symptom presentations found in FMDs, as well as the heterogeneity of concurrently present non-motor and neuropsychiatric symptoms, I believe that the field should revisit clinical trial designs in this population to allow for the study of “personalized” treatment packages based on both clinical phenotype and the biopsychosocial formulation. There are many challenges and nuanced issues to work out. Relatedly, while many patients can likely obtain benefit from the new treatment paradigms being developed for FMDs, a subset of treatment-refractory individuals will also be defined. Future research efforts will need to start investigating this specific sub-population of patients with FMDs.
- In general, a skilled neurological examination that reveal clear features of variability/distractibility and/or entrainment allow us to make a clinically-established diagnosis of FMD. Laboratory-supported data may help us to make a timely diagnosis in challenging cases.
- Functional brain network interactions are abnormal in FMD. These abnormalities may provide new circuit-based targets for treatment.
- The main pathophysiological findings to date include impaired self-agency associated with abnormal functional connectivity between the temporoparietal junction and sensorimotor brain areas. However, increased functional connectivity between the salience/limbic network and the sensorimotor area also suggested to potentially negatively impact movements.
- Besides functional alterations, structural neuroanatomy may also be impaired and play a role in the pathophysiology of FND.
- FMDs are very heterogenous. Since not all patients are eligible for some treatment plans, a careful clinical assessment is mandatory to allow a personalized therapeutic intervention.
- Consensus recommendations for physical therapy, occupational therapy and speech and language therapy for patients with FMD have been developed.
- Morgante F, Edwards MJ, Espay AJ. Psychogenic movement disorders. Continuum (Minneap Minn) 2013;19(5 Movement Disorders):1383-1396.
- Thenganatt MA, Jankovic J. Psychogenic tremor: a video guide to its distinguishing features. Tremor Other Hyperkinet Mov (N Y) 2014;4:253.
- Hallett M, Aybek S, Dworetzky BA, McWhirter L, Staab JP, Stone J. Functional neurological disorder: new subtypes and shared mechanisms. Lancet Neurol 2022;21(6):537-550.
- Begue I, Adams C, Stone J, Perez DL. Structural alterations in functional neurological disorder and related conditions: a software and hardware problem? Neuroimage Clin 2019;22:101798.
- Parees I, Brown H, Nuruki A, et al. Loss of sensory attenuation in patients with functional (psychogenic) movement disorders. Brain 2014;137(Pt 11):2916-2921.
- Nielsen G, Buszewicz M, Stevenson F, et al. Randomised feasibility study of physiotherapy for patients with functional motor symptoms. J Neurol Neurosurg Psychiatry 2017;88(6):484-490.
- Nielsen G, Stone J, Matthews A, et al. Physiotherapy for functional motor disorders: a consensus recommendation. J Neurol Neurosurg Psychiatry 2015;86(10):1113-1119.
- Espay AJ, Ries S, Maloney T, et al. Clinical and neural responses to cognitive behavioral therapy for functional tremor. Neurology 2019;93(19):e1787-e1798.
- Hallett M. Neurophysiologic studies of functional neurologic disorders. Handb Clin Neurol 2016;139:61-71.
- Kramer G, Van der Stouwe AMM, Maurits NM, Tijssen MAJ, Elting JWJ. Wavelet coherence analysis: A new approach to distinguish organic and functional tremor types. Clin Neurophysiol 2018;129(1):13-20.
- Schwingenschuh P, Saifee TA, Katschnig-Winter P, et al. Validation of "laboratory-supported" criteria for functional (psychogenic) tremor. Mov Disord 2016;31(4):555-562.
- Beudel M, Zutt R, Meppelink AM, et al. Improving neurophysiological biomarkers for functional myoclonic movements. Parkinsonism Relat Disord 2018;51:3-8.
- Quartarone A, Rizzo V, Terranova C, et al. Abnormal sensorimotor plasticity in organic but not in psychogenic dystonia. Brain 2009;132(Pt 10):2871-2877.
- Schwingenschuh P, Katschnig P, Edwards MJ, et al. The blink reflex recovery cycle differs between essential and presumed psychogenic blepharospasm. Neurology 2011;76(7):610-614.
- Teodoro T, Koreki A, Meppelink AM, et al. Contingent negative variation: a biomarker of abnormal attention in functional movement disorders. Eur J Neurol 2020;27(6):985-994.
- Aybek S, Perez DL. Diagnosis and management of functional neurological disorder. BMJ 2022;376:o64.
- Perez DL, Hunt A, Sharma N, Flaherty A, Caplan D, Schmahmann JD. Cautionary notes on diagnosing functional neurologic disorder as a neurologist-in-training. Neurol Clin Pract 2020;10(6):484-487.
- Perez DL, Edwards MJ, Nielsen G, Kozlowska K, Hallett M, LaFrance WC, Jr. Decade of progress in motor functional neurological disorder: continuing the momentum. J Neurol Neurosurg Psychiatry 2021.
- Voon V, Gallea C, Hattori N, Bruno M, Ekanayake V, Hallett M. The involuntary nature of conversion disorder. Neurology 2010;74(3):223-228.
- Maurer CW, LaFaver K, Ameli R, Epstein SA, Hallett M, Horovitz SG. Impaired self-agency in functional movement disorders: A resting-state fMRI study. Neurology 2016;87(6):564-570.
- Diez I, Ortiz-Teran L, Williams B, et al. Corticolimbic fast-tracking: enhanced multimodal integration in functional neurological disorder. J Neurol Neurosurg Psychiatry 2019;90(8):929-938.
- Aybek S, Nicholson TR, O'Daly O, Zelaya F, Kanaan RA, David AS. Emotion-motion interactions in conversion disorder: an FMRI study. PLoS One 2015;10(4):e0123273.
- Voon V, Brezing C, Gallea C, et al. Emotional stimuli and motor conversion disorder. Brain 2010;133(Pt 5):1526-1536.
- Edwards MJ, Adams RA, Brown H, Parees I, Friston KJ. A Bayesian account of 'hysteria'. Brain 2012;135(Pt 11):3495-3512.
- Jungilligens J, Paredes-Echeverri S, Popkirov S, Barrett LF, Perez DL. A new science of emotion: implications for functional neurological disorder. Brain 2022.
- den Hollander M, Goossens M, de Jong J, et al. Expose or protect? A randomized controlled trial of exposure in vivo vs pain-contingent treatment as usual in patients with complex regional pain syndrome type 1. Pain 2016;157(10):2318-2329.
- Gutkin M, McLean L, Brown R, Kanaan RA. Systematic review of psychotherapy for adults with functional neurological disorder. J Neurol Neurosurg Psychiatry 2020.