Parkinsonism and Related Disorders 20 (2014) 596e599
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Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Psychogenic axial myoclonus: Clinical features and long-term outcome Roberto Erro a, *, Mark J. Edwards a, Kailash P. Bhatia a, Marcello Esposito b, Simon F. Farmer a, c, Carla Cordivari d a
Sobell Department of Motor Neuroscience and Movement Disorders, University College London (UCL) Institute of Neurology, London WC1N 3BG, United Kingdom Department of Neurological Science, University Federico II, Naples, Italy c Department of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London, United Kingdom d Department of Clinical Neurophysiology, National Hospital for Neurology and Neurosurgery, Queen Square, London, United Kingdom b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 28 September 2013 Received in revised form 10 February 2014 Accepted 25 February 2014
Background: It has been increasingly recognized that the majority of patients with a diagnosis of idiopathic propriospinal myoclonus have either a subsequent clinical course or electrophysiological features indicating that the likely etiology is psychogenic. However, the clinical features of psychogenic axial myoclonus and the long-term outcome have not yet well characterized. Patients and methods: Here we describe clinical findings with representative videos and long term outcomes of 76 patients with an electrophysiologically established diagnosis of psychogenic axial myoclonus. Results: Thirty-seven patients were male. Mean age at onset of symptoms was 40.1 15.1 years. Thirtytwo patients (42.1%) presented with isolated axial myoclonus, while 44 patients (57.9%) presented additional features, including involvement of face or limb. In all patients but six (7.9%), the axial myoclonus was in flexion. In more than one-third of patients (42.1%), jerks were multifocal, meaning that there was no clear stereotyped pattern of jerks. Comparison between groups stratified according to the clinical outcome, revealed “delay of diagnosis” as the only predictor of worse outcome. Discussion: We describe here the clinical features and long-term outcome on the largest series of patients with psychogenic axial myoclonus reported in the literature. The description of our series highlights a number of clinical features, which may help neurologists to reach a correct diagnosis on clinical grounds alone. Delay in diagnosis of a psychogenic disorder has a negative effect on long-term outcome. Ó 2014 Elsevier Ltd. All rights reserved.
Keywords: Propriospinal myoclonus PSM Axial jerks Bereitschafts potential Psychogenic movement disorders Functional movement disorders
1. Introduction Myoclonic jerks thought to originate from the spinal cord may be subdivided into two broad types: spinal segmental myoclonus and propriospinal myoclonus (PSM) [1]. While spinal segmental myoclonus is often reported to be secondary to a spinal lesion, most reported cases of PSM are classed as idiopathic without identifiable spinal pathology [1]. Furthermore, it has been increasingly recognized that a number of patients with a diagnosis of idiopathic PSM have either a subsequent clinical course or electrophysiological features indicating that the likely etiology is psychogenic (functional) [2]. In fact, there is considerable uncertainty about the possibility of reaching a firm diagnosis of idiopathic PSM on a clinical basis alone. We have recently reported that all the patients * Corresponding author. E-mail address: [email protected] (R. Erro). http://dx.doi.org/10.1016/j.parkreldis.2014.02.026 1353-8020/Ó 2014 Elsevier Ltd. All rights reserved.
referred over a 9-year period to our center with a clinical diagnosis of idiopathic PSM turned out to have a psychogenic disorder, based on an incongruent EMG pattern for PSM and/or the presence of a Bereitschaftspotential (BP, from German, “readiness potential”, also called the premovement potential) prior the onset of the jerks [3]. Similar data have been reported from another centre where of 35 patients presumed to be affected with idiopathic PSM, 24 patients were diagnosed with psychogenic myoclonus on electrophysiological grounds and a further 10 patients were classed as psychogenic on clinical observation [4]. However, it is important to acknowledge that polymyography and BP recording are not widely available. Therefore, there is the need to accurately define the clinical entity of psychogenic (functional) axial myoclonus (PAM). This is especially important for as discussed above, PAM may be much more prevalent than organic idiopathic PSM and misdiagnosis of the two is a common problem [2e4]. In addition, despite the recognition of PAM, little is known about its clinical
R. Erro et al. / Parkinsonism and Related Disorders 20 (2014) 596e599
features (for instance, whether specific clinical clues are indicative of PAM) and little is known of its long-term outcome. For the purpose of this paper, we have used the term PAM to describe those patients initially presumed to be affected with idiopathic PSM [5], whose axial jerks turned out to be psychogenic. While in our previous work we have only focused on the electrophysiological features, here we wish to highlight the clinical features of PAM. Moreover, we report here the long-term outcome of the 65 patients previously described by the authors [3], and we include 11 additional cases, seen in our center between May 2012 and February 2013. 2. Patients and methods The study was approved by the University College London Hospitals, and written consent forms obtained by the patients (also concerning the publication of their video-recording). Inclusion and exclusion criteria have been extensively described elsewhere [3]. Briefly, the cohort described here includes patients initially referred to us with a diagnosis of idiopathic PSM between 2003 and 2013. They have been first re-assessed by a movement disorder expert, and the diagnosis revised to PAM in a number of them (approximately 50%). Finally, all patients underwent a multichannel video-EEGeEMG, as previously detailed [3]. On the basis of the electrophysiological findings, all patients had a diagnosed revised to PAM [3]. Beyond the electrophysiological recording, all patients had a MRI of the spine, excluding any spinal pathology. Moreover, in a number of them (66 out of 76 patients, 86.8%) a psychiatric assessment was performed within 6 months from the first clinical assessment at our center, using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) [6]. At the end of this diagnostic work-up (Fig. 1), the diagnosis of PAM was communicated to all patients. We retrospectively collected details on the following baseline parameters: age, age at disease onset and disease duration, precipitating factors at onset, prior treatments, concomitant conditions, alleviating/exacerbating factors, clinical examination, and psychiatric assessment, where available. All patients were regularly followed-up and had at least 6 months of follow-up (range: 6e72 months) at the time of this study. Reviewing medical charts with regard of the follow-up period collected the following parameters: presence of fluctuations, treatments, and outcome. The assessment of outcome was based on clinician assessment at last visit. To address whether these patients could be different in basic demographic and clinical parameters to those with other psychogenic movement disorders (PMDs), twenty consecutive patients with clinically established functional limb dystonia were selected as control group. Such control group was not meant to compare the clinical outcome, since we believe it can be strongly influenced by the specific phenotype [7]. Data are shown as mean standard deviation or as percentage. Comparisons between groups were done using t-test or chi2 test, as appropriate. The Kruskal Wallis test was used for more than 2 samples (see text) and P < 0.05 was considered statistically significant. Statistics were performed using STATA software, version 11.0 (StataCorp LP, USA).
3. Results Demographic and clinical data of the patients included in this study are listed in Table 1. For all of the patients, the diagnosis of
597
Table 1 Demographic and clinical characteristics of our patients (ys: years; AM: axial myoclonus; *: after a single injection of botulinum toxin).
Gender Age at onset Disease duration Delay in diagnosis Precipitant Other somatizations Psychiatric co-morbidity
Number of medications Alleviating/exacerbating factors Clinical fluctuations Last follow-up Clinical outcome: Recovery* Better Stable (without medications) Stable (with medications) Worse
Psychogenic AM (n ¼ 76)
Psychogenic dystonia (n ¼ 20)
p Value
37 M; 39 F 40.1 15.1 (range 16e80 ys) 5.9 5.7 (range 1e32 ys) 3.7 5.5 (range 0.5e30 ys) 36.8% 51.3% 28.8% (19 out of 66 for which psychiatric assessment was available) 2.6 1.6 (range: 1e8) 30.3%
2 M; 18 F 27.9 2.7 (range: 22e31 ys) 5.3 5.5 (range 1e13 ys) 0.5 0.7 (range: 0.5e2 ys) 41.3% 39.7% e
0.001 0.0006
ns ns e
e
e
e
e
30.3% 2.2 1.4 (range 0.5e6 ys)
e e
e e
e
e
ns 0.009
22.4% 15.8% 38.1% 6.6% 17.1%
PAM was established on the basis of electrophysiological testing: the presence of a BP associated with the jerks or EMG findings not consistent for PSM (i.e., inconstant pattern of muscle activation, conduction velocity determined from the inter-burst interval between two different muscles >15 m/s, and EMG burst duration > 1000 ms), as previously reported [3]. Of the 76 patients with PAM, 37 were male, while in the functional dystonia group only 2 out of 20 were male (48.7% vs 10%, p < 0.01). Age at onset was higher in the PAM group compared to the functional dystonia group (40.1 15.1 years vs 27.9 2.7 years, respectively, p < 0.01). A precipitating event (most commonly a minor surgical procedure) was identifiable prior to the onset of myoclonus in a 36.8% of patients. Approximately 50% of patients reported other unexplained medical symptoms (mainly gastrointestinal, fatigue and
Fig. 1. Overview of the clinical work-up and data collection.
598
R. Erro et al. / Parkinsonism and Related Disorders 20 (2014) 596e599
pain) in addition to the myoclonus. One third of patients reported the presence of alleviating and/or exacerbating factors. For 66 out of 76 patients, a formal psychiatric assessment was performed. This revealed the presence of psychiatric disorders in 28.8% of patients (anxiety: 36.8%, depression: 36.8%, bipolar disorder: 15.8%, and obsessiveecompulsive disorder: 10.5%). As to the phenomenology of the movement disorder, thirty-two patients (42.1%) presented with isolated axial myoclonus, while 44 patients (57.9%) had additional features, including involvement of face or limbs (see Table 2 and supplemental video). In all patients but 6 (7.9%), the axial myoclonus was in flexion. In more than onethird (42.1%) jerks were multifocal, meaning that there was no clear stereotyped pattern of jerks since they could arise from different muscles at different time. In more than one-half of the patients, there was either a prolonged muscles contraction following the jerks or additional signs, including functional tremor or functional gait disturbance. Supplementary video related to this article can be found at http://dx.doi.org/10.1016/j.parkreldis.2014.02.026 Prior to diagnosis of PAM, all patients were treated with a number of medications (anti-epileptics, benzodiazepines, corticosteroids, neuroleptics), often in combination. Time from symptoms onset to the diagnosis of a functional disorder was significantly longer in the PAM group compared to those with functional dystonia (3.7 5.5 years vs 0.5 0.7 years, p < 0.01). After the diagnosis of PAM was made, patients who received a concomitant psychiatric diagnosis (19 patients, 28.8%) were treated accordingly (antidepressants in 12, benzodiazepines in 4, lithium in 3). Clonazepam was tried in a further 16% of our patients. In another 39 patients (51.3%), botulinum toxin (BoNT) injections were empirically tried in the most affected body segments, according to the clinical judgment. Importantly, almost all of these patients (37 out of 39 patients, i.e., 48.6% of the whole cohort) had an immediate response to low dose of BoNT, strongly suggestive of a placebo response, and therefore also fulfilled the published clinical criteria for definite psychogenic movement disorders [8]. During the follow-up evaluation period, clinical fluctuations were evident in one-third of patients. At the last follow-up evaluation (after 2.2 1.4 years, range: 0.5e6), 17.3% of patients had worsened; 44% were the same; and 38.2% had improved. Regarding the latter, two subgroups could be identified: 17 patients (22.4% of the whole cohort) recovered after a single BoNT injection, whereas 12 patients (15.8% of the whole cohort) improved and were receiving regular injections every 3e4 months. Comparison between groups stratified according to the clinical outcome, revealed “delay of diagnosis” (i.e., delay in determining that this was a functional disorder) as the only predictor of worse outcome (KruskaleWallis test, chi2 ¼ 10.198, p ¼ 0.006). All other demographic and clinical features, including age, age at onset, gender, concomitant psychiatric disorder, and current pharmacological treatment failed to predict the outcome.
Table 2 Overview of the clinical phenotypes associated with psychogenic axial myoclonus. Clinical features
N (%)
Pure axial jerks - In flexion - In extension Atypical phenotypes - Facial involvement - Unilateral limb involvement (arm/hip flexion) - Predominant lower limbs involvement (legs adduction/flexion) Multifocal onset of jerks Prolonged muscle contraction Additional signs (tremor, gait disturbance)
26/76 6/76 44/76 9/44 10/44 25/44 32/76 36/76 7/76
(34.2) (7.9) (57.9) (20.4) (22.7) (56.8) (42.1) (47.3) (9.2)
4. Discussion We describe here the clinical features and long-term outcome on the largest series of patients with PAM reported in the literature. In contrast to other PMDs [8e10], PAM does not appear to be much more common in women than men. On the other hand, there were other features which are in line with published literature on PMDs [8e10]: i) a precipitating factor was indeed identifiable in more than one third of patients; ii) there was either an additional FMD or other unexplained medical symptoms in half of the group; iii) treatment with sub-therapeutic doses of botulinum toxin injections resulted in a dramatic improvement, suggestive of a placebo response [11], even at long-term follow-up; iv) patients reported a number of exacerbating or alleviating factors; and v) symptoms could fluctuate in a variable and inconsistent way over the followup. Concomitant identifiable psychiatric disturbances were seen in less than one third of patients, in line with previously published data in PMDs [10]. There is still a great debate on how neurologists should label these patients [12,13]. The term psychogenic defines the disorder with regard to a proposed etiology (i.e., psychological stress/ trauma), and this was not the case here for the majority of our patients. Moreover, this view seems to be not anymore supported by current evidence [14]. Use of the alternative term functional has been supported by some of late [15,16], and in fact this change in terminology has been included in the current Diagnostic and Statistical Manual of Psychiatry (DSM-V) with regard to Conversion Disorder (Functional Neurological Symptom Disorder), in recognition that relevant psychological factors may not be demonstrable at the time of diagnosis [17]. In our cohort, less than one-third of patients were affected by a discrete major psychiatric disorder as picked up by a formal neuropsychiatric interview. However, such assessments may miss data on social/emotional stressors (i.e., psychodynamic factors), which might be relevant triggers. Possible psychological factors are neither necessary nor sufficient for the diagnosis of PMDs, but there remain arguments on both sides for the terminology used in research and clinical practice. There is clear uncertainty in reaching a firm diagnosis of PAM on a clinical basis alone [2,3], a problem not helped by the lack of formal diagnostic criteria for idiopathic PSM. This difficulty is evidenced here by the fact that a correct diagnosis of PAM was made after a mean interval of almost 4 years (range: 0.5e30 years). This highlights that diagnosis of PMDs can be challenging, particularly when the phenotype is not well characterized in the literature. Also applying published criteria for PMDs, which are focused on clinical features alone, less than half of our cohort could be classified as “definite” PMD [8], while in all of them the electrophysiology strongly supported the diagnosis of PAM [3]. According to the clinical criteria, one of the core features of PMDs is that the movement disorder can be distractible and/or entrainable [8]. This was not the case here, and not surprisingly. Distractibility and entrainability may be reasonably looked for in patients with continuous movement disorders (i.e., tremor), but not in those with intermittent movement disorders (i.e., jerks). However, electrophysiological measures such as the BP can be applied to patients with jerks, reinforcing the relevance of clinical electrophysiology in this patients group and, more in general, strongly supports the previous proposal to include laboratory-supported criteria for diagnosis of PMDs [18]. Clinical diagnostic criteria for idiopathic PSM donot exist and therefore most previously published cases of PSM refer to the original findings reported by Brown et al. [5]. Given the rarity of the disorder (if it really exists), it is impossible to definitively establish its clinical features. However, on the basis of the proposed mechanism for idiopathic PSM, one would expect the jerks to be mainly
R. Erro et al. / Parkinsonism and Related Disorders 20 (2014) 596e599
axial (in flexion or extension), possibly spreading bilaterally to the (upper and/or lower) limbs and worsening upon lying supine. Therefore, analysis of the clinical features of our patients indicate some clinical clues which may help clinicians in making a positive diagnosis of PAM. These include predominant involvement of the lower limbs, facial involvement, and unilateral involvement of the limbs. Of note, all patients with facial involvement showed a stereotyped pattern of facial spasms, with the lower lip going downwards on one or both sides and hyper-contraction of the platysma muscle. This closely resembles the pattern described by Fasano et al. in patients with isolated psychogenic facial spasms [19]. Moreover, a multifocal onset of the jerks and a prolonged muscular contraction during the jerks were seen in some patients and are clearly at odds with the originally proposed mechanism for idiopathic PSM [5]. One would argue that approximately 40% of our cohort would fit the theoretical PSM phenotype, meaning that the remaining 60% would have been improperly diagnosed as PSM. However, we have previously reported that there is often disagreement between different movement disorder experts on whether patients have psychogenic axial jerks from observation of their video assessment [2] and also that the clinical diagnosis of PSM is unreliable, even when made by a movement disorder expert [3]. This reinforces the fact that the polymyography is mandatory for the diagnosis of PSM. However, here we wished to delineate the clinical spectrum of PAM, hoping this may facilitate targeted clinical examination of positive signs for a PMD in patients with a similar phenotype. Misdiagnosis of these patients has crucial implications for their management and their long-term outcome. Patients in this study were given a number of medications with significant potential side effects, including neuroleptics and anti-epileptics. Often, drugs were given in combination. The failure to provide suitable behavioral treatments, along with delay in correct diagnosis, are predictors of poor prognosis in FMDs [20,21]. This was indeed the case here, where delay in the correct diagnosis was the only predictor of worse clinical outcome at last follow-up visit. In other words, remission seemed to be less likely in patients who had symptoms for a longer time, suggesting that a correct diagnosis and a proper management might be more beneficial in the early stage of the disorder. In conclusion, PAM is a clinical entity that accounts for the majority of patients with axial jerks. We acknowledge that the recruitment in a tertiary referring center might have lead to a selection bias. The differential diagnosis of patients with axial jerks remains challenging and this case series highlights a number of clinical clues, which may help doctors to reach a correct diagnosis on clinical grounds. Our data also argue for the increased availability of specialized clinical electrophysiological assessment, which can aid the positive diagnosis of a PMD in patients in whom there is clinical uncertainty. Full financial disclosures KP Bhatia received funding for travel from GlaxoSmithKline, Orion Corporation, Ipsen, and Merz Pharmaceuticals, LLC; serves on the editorial boards of Movement Disorders and Therapeutic Advances in Neurological Disorders; receives royalties from the publication of Oxford Specialist Handbook of Parkinson’s Disease and Other Movement Disorders (Oxford University Press, 2008) and Marsden’s Book of Movement Disorders (Oxford University Press, 2012); received speaker honoraria from GlaxoSmithKline, Ipsen, Merz Pharmaceuticals, LLC, and Sun Pharmaceutical Industries Ltd.; personal compensation for scientific advisory board for GSK and
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Boehringer Ingelheim; received research support from Ipsen and from the Halley Stewart Trust through Dystonia Society UK, and the Wellcome Trust MRC strategic neurodegenerative disease initiative award (Ref. number WT089698), a grant from Parkinson’s UK (Ref. number G-1009) and a grant from the Dystonia Coalition. Dr. Edwards receives royalties from publication of Oxford Specialist Handbook Of Parkinson’s Disease and Other Movement Disorders (Oxford University Press, 2008) and receives research support from a National Institute for Health Research (NIHR) grant where he is the PI as well as Parkinson’s UK, UK Dystonia Society and the Guarantors of Brain. He has received honoraria for speaking from UCB. Dr. Farmer has received support from NIHR via funding for the UCLH CBRC. Dr. Erro, Dr. Esposito, and Dr. Cordivari have no financial disclosures. Financial disclosure related to research covered in this article: none.
References [1] Kojovic M, Cordivari C, Bhatia K. Myoclonic disorders: a practical approach for diagnosis and treatment. Ther Adv Neurol Disord 2011;4:47e62. [2] Esposito M, Edwards MJ, Bhatia KP, Brown P, Cordivari C. Idiopathic spinal myoclonus: a clinical and neurophysiological assessment of a movement disorder of uncertain origin. Mov Disord 2009;24:2344e9. [3] Erro R, Bhatia KP, Edwards MJ, Farmer SF, Cordivari C. Clinical diagnosis of propriospinal myoclonus is unreliable: an electrophysiologic study. Mov Disord 2013;28:1868e73. [4] van der Salm SM, Koelman JH, Henneke S, van Rootselaar AF, Tijssen MA. Axial jerks: a clinical spectrum ranging from propriospinal to psychogenic myoclonus. J Neurol 2010;257:1349e55. [5] Brown P, Thompson PD, Rothwell JC, Day BL, Marsden CD. Axial myoclonus of propriospinal origin. Brain 1991;114:197e214. [6] First MB, Spitzer RL, Gibbon M, Williams JBW. Structured clinical interview for DSM-IV axis I disorders, clinician version (SCID-CV). Washington, D.C.: American Psychiatric Press, Inc.; 1996. [7] Ibrahim NM, Martino D, van de Warrenburg BP, Quinn NP, Bhatia KP, Brown RJ, et al. The prognosis of fixed dystonia: a follow-up study. Park Relat Disord 2009 Sep;15(8):592e7. [8] Fahn S, Williams DT. Psychogenic dystonia. Adv Neurol 1988;50:431e55. [9] Schrag A, Lang AE. Psychogenic movement disorders. Curr Opin Neurol 2005;18:399e404. [10] Kranick S, Ekanayake V, Martinez V, Ameli R, Hallett M, Voon V. Psychopathology and psychogenic movement disorders. Mov Disord 2011;26: 1844e50. [11] Edwards MJ, Bhatia KP, Cordivari C. Immediate response to botulinum toxin injections in patients with fixed dystonia. Mov Disord 2011 Apr;26(5):917e8. [12] Hallett M, Fahn S, Jankovic J, et al., editors. Psychogenic movement disorders: neurology and neuropsychiatry. Philadelphia, PA: AAN Enterprises and Lippincott Williams & Wilkins; 2006. [13] Ellenstein A, Kranick SM, Hallett M. An update on psychogenic movement disorders. Curr Neurol Neurosci Rep 2011 Aug;11(4):396e403. [14] Edwards MJ, Bhatia KP. Functional (psychogenic) movement disorders: merging mind and brain. Lancet Neurol 2012 Mar;11(3):250e60. [15] Edwards MJ, Stone J, Lang AE. From psychogenic movement disorder to functional movement disorder: it’s time to change the name. Mov Disord; 2013 Jul 10. http://dx.doi.org/10.1002/mds.25562. [16] Stone J, LaFrance Jr WC, Levenson JL, Sharpe M. Issues for DSM-5: conversion disorder. Am J Psychiatry 2010 Jun;167(6):626e7. [17] American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Arlington, VA: American Psychiatric Publishing; 2013. [18] Schwingenschuh P, Katschnig P, Seiler S, Saifee TA, Aguirregomozcorta M, Cordivari C, et al. Moving toward “laboratory-supported” criteria for psychogenic tremor. Mov Disord 2011;26:2509e15. [19] Fasano A, Valadas A, Bhatia KP, Prashanth LK, Lang AE, Munhoz RP, et al. Psychogenic facial movement disorders: clinical features and associated conditions. Mov Disord 2012;27:1544e51. [20] Gupta A, Lang AE. Psychogenic movement disorders. Curr Opin Neurol 2009;22:430e6. [21] Stone J, Carson A, Duncan R, Coleman R, Roberts R, Warlow C, et al. Symptoms ’unexplained by organic disease’ in 1144 new neurology out-patients: how often does the diagnosis change at follow-up? Brain 2009;132:2878e88.
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Psychogenic axial myoclonus: Clinical features and long-term outcome Roberto Erro a, *, Mark J. Edwards a, Kailash P. Bhatia a, Marcello Esposito b, Simon F. Farmer a, c, Carla Cordivari d a
Sobell Department of Motor Neuroscience and Movement Disorders, University College London (UCL) Institute of Neurology, London WC1N 3BG, United Kingdom Department of Neurological Science, University Federico II, Naples, Italy c Department of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London, United Kingdom d Department of Clinical Neurophysiology, National Hospital for Neurology and Neurosurgery, Queen Square, London, United Kingdom b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 28 September 2013 Received in revised form 10 February 2014 Accepted 25 February 2014
Background: It has been increasingly recognized that the majority of patients with a diagnosis of idiopathic propriospinal myoclonus have either a subsequent clinical course or electrophysiological features indicating that the likely etiology is psychogenic. However, the clinical features of psychogenic axial myoclonus and the long-term outcome have not yet well characterized. Patients and methods: Here we describe clinical findings with representative videos and long term outcomes of 76 patients with an electrophysiologically established diagnosis of psychogenic axial myoclonus. Results: Thirty-seven patients were male. Mean age at onset of symptoms was 40.1 15.1 years. Thirtytwo patients (42.1%) presented with isolated axial myoclonus, while 44 patients (57.9%) presented additional features, including involvement of face or limb. In all patients but six (7.9%), the axial myoclonus was in flexion. In more than one-third of patients (42.1%), jerks were multifocal, meaning that there was no clear stereotyped pattern of jerks. Comparison between groups stratified according to the clinical outcome, revealed “delay of diagnosis” as the only predictor of worse outcome. Discussion: We describe here the clinical features and long-term outcome on the largest series of patients with psychogenic axial myoclonus reported in the literature. The description of our series highlights a number of clinical features, which may help neurologists to reach a correct diagnosis on clinical grounds alone. Delay in diagnosis of a psychogenic disorder has a negative effect on long-term outcome. Ó 2014 Elsevier Ltd. All rights reserved.
Keywords: Propriospinal myoclonus PSM Axial jerks Bereitschafts potential Psychogenic movement disorders Functional movement disorders
1. Introduction Myoclonic jerks thought to originate from the spinal cord may be subdivided into two broad types: spinal segmental myoclonus and propriospinal myoclonus (PSM) [1]. While spinal segmental myoclonus is often reported to be secondary to a spinal lesion, most reported cases of PSM are classed as idiopathic without identifiable spinal pathology [1]. Furthermore, it has been increasingly recognized that a number of patients with a diagnosis of idiopathic PSM have either a subsequent clinical course or electrophysiological features indicating that the likely etiology is psychogenic (functional) [2]. In fact, there is considerable uncertainty about the possibility of reaching a firm diagnosis of idiopathic PSM on a clinical basis alone. We have recently reported that all the patients * Corresponding author. E-mail address: [email protected] (R. Erro). http://dx.doi.org/10.1016/j.parkreldis.2014.02.026 1353-8020/Ó 2014 Elsevier Ltd. All rights reserved.
referred over a 9-year period to our center with a clinical diagnosis of idiopathic PSM turned out to have a psychogenic disorder, based on an incongruent EMG pattern for PSM and/or the presence of a Bereitschaftspotential (BP, from German, “readiness potential”, also called the premovement potential) prior the onset of the jerks [3]. Similar data have been reported from another centre where of 35 patients presumed to be affected with idiopathic PSM, 24 patients were diagnosed with psychogenic myoclonus on electrophysiological grounds and a further 10 patients were classed as psychogenic on clinical observation [4]. However, it is important to acknowledge that polymyography and BP recording are not widely available. Therefore, there is the need to accurately define the clinical entity of psychogenic (functional) axial myoclonus (PAM). This is especially important for as discussed above, PAM may be much more prevalent than organic idiopathic PSM and misdiagnosis of the two is a common problem [2e4]. In addition, despite the recognition of PAM, little is known about its clinical
R. Erro et al. / Parkinsonism and Related Disorders 20 (2014) 596e599
features (for instance, whether specific clinical clues are indicative of PAM) and little is known of its long-term outcome. For the purpose of this paper, we have used the term PAM to describe those patients initially presumed to be affected with idiopathic PSM [5], whose axial jerks turned out to be psychogenic. While in our previous work we have only focused on the electrophysiological features, here we wish to highlight the clinical features of PAM. Moreover, we report here the long-term outcome of the 65 patients previously described by the authors [3], and we include 11 additional cases, seen in our center between May 2012 and February 2013. 2. Patients and methods The study was approved by the University College London Hospitals, and written consent forms obtained by the patients (also concerning the publication of their video-recording). Inclusion and exclusion criteria have been extensively described elsewhere [3]. Briefly, the cohort described here includes patients initially referred to us with a diagnosis of idiopathic PSM between 2003 and 2013. They have been first re-assessed by a movement disorder expert, and the diagnosis revised to PAM in a number of them (approximately 50%). Finally, all patients underwent a multichannel video-EEGeEMG, as previously detailed [3]. On the basis of the electrophysiological findings, all patients had a diagnosed revised to PAM [3]. Beyond the electrophysiological recording, all patients had a MRI of the spine, excluding any spinal pathology. Moreover, in a number of them (66 out of 76 patients, 86.8%) a psychiatric assessment was performed within 6 months from the first clinical assessment at our center, using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) [6]. At the end of this diagnostic work-up (Fig. 1), the diagnosis of PAM was communicated to all patients. We retrospectively collected details on the following baseline parameters: age, age at disease onset and disease duration, precipitating factors at onset, prior treatments, concomitant conditions, alleviating/exacerbating factors, clinical examination, and psychiatric assessment, where available. All patients were regularly followed-up and had at least 6 months of follow-up (range: 6e72 months) at the time of this study. Reviewing medical charts with regard of the follow-up period collected the following parameters: presence of fluctuations, treatments, and outcome. The assessment of outcome was based on clinician assessment at last visit. To address whether these patients could be different in basic demographic and clinical parameters to those with other psychogenic movement disorders (PMDs), twenty consecutive patients with clinically established functional limb dystonia were selected as control group. Such control group was not meant to compare the clinical outcome, since we believe it can be strongly influenced by the specific phenotype [7]. Data are shown as mean standard deviation or as percentage. Comparisons between groups were done using t-test or chi2 test, as appropriate. The Kruskal Wallis test was used for more than 2 samples (see text) and P < 0.05 was considered statistically significant. Statistics were performed using STATA software, version 11.0 (StataCorp LP, USA).
3. Results Demographic and clinical data of the patients included in this study are listed in Table 1. For all of the patients, the diagnosis of
597
Table 1 Demographic and clinical characteristics of our patients (ys: years; AM: axial myoclonus; *: after a single injection of botulinum toxin).
Gender Age at onset Disease duration Delay in diagnosis Precipitant Other somatizations Psychiatric co-morbidity
Number of medications Alleviating/exacerbating factors Clinical fluctuations Last follow-up Clinical outcome: Recovery* Better Stable (without medications) Stable (with medications) Worse
Psychogenic AM (n ¼ 76)
Psychogenic dystonia (n ¼ 20)
p Value
37 M; 39 F 40.1 15.1 (range 16e80 ys) 5.9 5.7 (range 1e32 ys) 3.7 5.5 (range 0.5e30 ys) 36.8% 51.3% 28.8% (19 out of 66 for which psychiatric assessment was available) 2.6 1.6 (range: 1e8) 30.3%
2 M; 18 F 27.9 2.7 (range: 22e31 ys) 5.3 5.5 (range 1e13 ys) 0.5 0.7 (range: 0.5e2 ys) 41.3% 39.7% e
0.001 0.0006
ns ns e
e
e
e
e
30.3% 2.2 1.4 (range 0.5e6 ys)
e e
e e
e
e
ns 0.009
22.4% 15.8% 38.1% 6.6% 17.1%
PAM was established on the basis of electrophysiological testing: the presence of a BP associated with the jerks or EMG findings not consistent for PSM (i.e., inconstant pattern of muscle activation, conduction velocity determined from the inter-burst interval between two different muscles >15 m/s, and EMG burst duration > 1000 ms), as previously reported [3]. Of the 76 patients with PAM, 37 were male, while in the functional dystonia group only 2 out of 20 were male (48.7% vs 10%, p < 0.01). Age at onset was higher in the PAM group compared to the functional dystonia group (40.1 15.1 years vs 27.9 2.7 years, respectively, p < 0.01). A precipitating event (most commonly a minor surgical procedure) was identifiable prior to the onset of myoclonus in a 36.8% of patients. Approximately 50% of patients reported other unexplained medical symptoms (mainly gastrointestinal, fatigue and
Fig. 1. Overview of the clinical work-up and data collection.
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pain) in addition to the myoclonus. One third of patients reported the presence of alleviating and/or exacerbating factors. For 66 out of 76 patients, a formal psychiatric assessment was performed. This revealed the presence of psychiatric disorders in 28.8% of patients (anxiety: 36.8%, depression: 36.8%, bipolar disorder: 15.8%, and obsessiveecompulsive disorder: 10.5%). As to the phenomenology of the movement disorder, thirty-two patients (42.1%) presented with isolated axial myoclonus, while 44 patients (57.9%) had additional features, including involvement of face or limbs (see Table 2 and supplemental video). In all patients but 6 (7.9%), the axial myoclonus was in flexion. In more than onethird (42.1%) jerks were multifocal, meaning that there was no clear stereotyped pattern of jerks since they could arise from different muscles at different time. In more than one-half of the patients, there was either a prolonged muscles contraction following the jerks or additional signs, including functional tremor or functional gait disturbance. Supplementary video related to this article can be found at http://dx.doi.org/10.1016/j.parkreldis.2014.02.026 Prior to diagnosis of PAM, all patients were treated with a number of medications (anti-epileptics, benzodiazepines, corticosteroids, neuroleptics), often in combination. Time from symptoms onset to the diagnosis of a functional disorder was significantly longer in the PAM group compared to those with functional dystonia (3.7 5.5 years vs 0.5 0.7 years, p < 0.01). After the diagnosis of PAM was made, patients who received a concomitant psychiatric diagnosis (19 patients, 28.8%) were treated accordingly (antidepressants in 12, benzodiazepines in 4, lithium in 3). Clonazepam was tried in a further 16% of our patients. In another 39 patients (51.3%), botulinum toxin (BoNT) injections were empirically tried in the most affected body segments, according to the clinical judgment. Importantly, almost all of these patients (37 out of 39 patients, i.e., 48.6% of the whole cohort) had an immediate response to low dose of BoNT, strongly suggestive of a placebo response, and therefore also fulfilled the published clinical criteria for definite psychogenic movement disorders [8]. During the follow-up evaluation period, clinical fluctuations were evident in one-third of patients. At the last follow-up evaluation (after 2.2 1.4 years, range: 0.5e6), 17.3% of patients had worsened; 44% were the same; and 38.2% had improved. Regarding the latter, two subgroups could be identified: 17 patients (22.4% of the whole cohort) recovered after a single BoNT injection, whereas 12 patients (15.8% of the whole cohort) improved and were receiving regular injections every 3e4 months. Comparison between groups stratified according to the clinical outcome, revealed “delay of diagnosis” (i.e., delay in determining that this was a functional disorder) as the only predictor of worse outcome (KruskaleWallis test, chi2 ¼ 10.198, p ¼ 0.006). All other demographic and clinical features, including age, age at onset, gender, concomitant psychiatric disorder, and current pharmacological treatment failed to predict the outcome.
Table 2 Overview of the clinical phenotypes associated with psychogenic axial myoclonus. Clinical features
N (%)
Pure axial jerks - In flexion - In extension Atypical phenotypes - Facial involvement - Unilateral limb involvement (arm/hip flexion) - Predominant lower limbs involvement (legs adduction/flexion) Multifocal onset of jerks Prolonged muscle contraction Additional signs (tremor, gait disturbance)
26/76 6/76 44/76 9/44 10/44 25/44 32/76 36/76 7/76
(34.2) (7.9) (57.9) (20.4) (22.7) (56.8) (42.1) (47.3) (9.2)
4. Discussion We describe here the clinical features and long-term outcome on the largest series of patients with PAM reported in the literature. In contrast to other PMDs [8e10], PAM does not appear to be much more common in women than men. On the other hand, there were other features which are in line with published literature on PMDs [8e10]: i) a precipitating factor was indeed identifiable in more than one third of patients; ii) there was either an additional FMD or other unexplained medical symptoms in half of the group; iii) treatment with sub-therapeutic doses of botulinum toxin injections resulted in a dramatic improvement, suggestive of a placebo response [11], even at long-term follow-up; iv) patients reported a number of exacerbating or alleviating factors; and v) symptoms could fluctuate in a variable and inconsistent way over the followup. Concomitant identifiable psychiatric disturbances were seen in less than one third of patients, in line with previously published data in PMDs [10]. There is still a great debate on how neurologists should label these patients [12,13]. The term psychogenic defines the disorder with regard to a proposed etiology (i.e., psychological stress/ trauma), and this was not the case here for the majority of our patients. Moreover, this view seems to be not anymore supported by current evidence [14]. Use of the alternative term functional has been supported by some of late [15,16], and in fact this change in terminology has been included in the current Diagnostic and Statistical Manual of Psychiatry (DSM-V) with regard to Conversion Disorder (Functional Neurological Symptom Disorder), in recognition that relevant psychological factors may not be demonstrable at the time of diagnosis [17]. In our cohort, less than one-third of patients were affected by a discrete major psychiatric disorder as picked up by a formal neuropsychiatric interview. However, such assessments may miss data on social/emotional stressors (i.e., psychodynamic factors), which might be relevant triggers. Possible psychological factors are neither necessary nor sufficient for the diagnosis of PMDs, but there remain arguments on both sides for the terminology used in research and clinical practice. There is clear uncertainty in reaching a firm diagnosis of PAM on a clinical basis alone [2,3], a problem not helped by the lack of formal diagnostic criteria for idiopathic PSM. This difficulty is evidenced here by the fact that a correct diagnosis of PAM was made after a mean interval of almost 4 years (range: 0.5e30 years). This highlights that diagnosis of PMDs can be challenging, particularly when the phenotype is not well characterized in the literature. Also applying published criteria for PMDs, which are focused on clinical features alone, less than half of our cohort could be classified as “definite” PMD [8], while in all of them the electrophysiology strongly supported the diagnosis of PAM [3]. According to the clinical criteria, one of the core features of PMDs is that the movement disorder can be distractible and/or entrainable [8]. This was not the case here, and not surprisingly. Distractibility and entrainability may be reasonably looked for in patients with continuous movement disorders (i.e., tremor), but not in those with intermittent movement disorders (i.e., jerks). However, electrophysiological measures such as the BP can be applied to patients with jerks, reinforcing the relevance of clinical electrophysiology in this patients group and, more in general, strongly supports the previous proposal to include laboratory-supported criteria for diagnosis of PMDs [18]. Clinical diagnostic criteria for idiopathic PSM donot exist and therefore most previously published cases of PSM refer to the original findings reported by Brown et al. [5]. Given the rarity of the disorder (if it really exists), it is impossible to definitively establish its clinical features. However, on the basis of the proposed mechanism for idiopathic PSM, one would expect the jerks to be mainly
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axial (in flexion or extension), possibly spreading bilaterally to the (upper and/or lower) limbs and worsening upon lying supine. Therefore, analysis of the clinical features of our patients indicate some clinical clues which may help clinicians in making a positive diagnosis of PAM. These include predominant involvement of the lower limbs, facial involvement, and unilateral involvement of the limbs. Of note, all patients with facial involvement showed a stereotyped pattern of facial spasms, with the lower lip going downwards on one or both sides and hyper-contraction of the platysma muscle. This closely resembles the pattern described by Fasano et al. in patients with isolated psychogenic facial spasms [19]. Moreover, a multifocal onset of the jerks and a prolonged muscular contraction during the jerks were seen in some patients and are clearly at odds with the originally proposed mechanism for idiopathic PSM [5]. One would argue that approximately 40% of our cohort would fit the theoretical PSM phenotype, meaning that the remaining 60% would have been improperly diagnosed as PSM. However, we have previously reported that there is often disagreement between different movement disorder experts on whether patients have psychogenic axial jerks from observation of their video assessment [2] and also that the clinical diagnosis of PSM is unreliable, even when made by a movement disorder expert [3]. This reinforces the fact that the polymyography is mandatory for the diagnosis of PSM. However, here we wished to delineate the clinical spectrum of PAM, hoping this may facilitate targeted clinical examination of positive signs for a PMD in patients with a similar phenotype. Misdiagnosis of these patients has crucial implications for their management and their long-term outcome. Patients in this study were given a number of medications with significant potential side effects, including neuroleptics and anti-epileptics. Often, drugs were given in combination. The failure to provide suitable behavioral treatments, along with delay in correct diagnosis, are predictors of poor prognosis in FMDs [20,21]. This was indeed the case here, where delay in the correct diagnosis was the only predictor of worse clinical outcome at last follow-up visit. In other words, remission seemed to be less likely in patients who had symptoms for a longer time, suggesting that a correct diagnosis and a proper management might be more beneficial in the early stage of the disorder. In conclusion, PAM is a clinical entity that accounts for the majority of patients with axial jerks. We acknowledge that the recruitment in a tertiary referring center might have lead to a selection bias. The differential diagnosis of patients with axial jerks remains challenging and this case series highlights a number of clinical clues, which may help doctors to reach a correct diagnosis on clinical grounds. Our data also argue for the increased availability of specialized clinical electrophysiological assessment, which can aid the positive diagnosis of a PMD in patients in whom there is clinical uncertainty. Full financial disclosures KP Bhatia received funding for travel from GlaxoSmithKline, Orion Corporation, Ipsen, and Merz Pharmaceuticals, LLC; serves on the editorial boards of Movement Disorders and Therapeutic Advances in Neurological Disorders; receives royalties from the publication of Oxford Specialist Handbook of Parkinson’s Disease and Other Movement Disorders (Oxford University Press, 2008) and Marsden’s Book of Movement Disorders (Oxford University Press, 2012); received speaker honoraria from GlaxoSmithKline, Ipsen, Merz Pharmaceuticals, LLC, and Sun Pharmaceutical Industries Ltd.; personal compensation for scientific advisory board for GSK and
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Boehringer Ingelheim; received research support from Ipsen and from the Halley Stewart Trust through Dystonia Society UK, and the Wellcome Trust MRC strategic neurodegenerative disease initiative award (Ref. number WT089698), a grant from Parkinson’s UK (Ref. number G-1009) and a grant from the Dystonia Coalition. Dr. Edwards receives royalties from publication of Oxford Specialist Handbook Of Parkinson’s Disease and Other Movement Disorders (Oxford University Press, 2008) and receives research support from a National Institute for Health Research (NIHR) grant where he is the PI as well as Parkinson’s UK, UK Dystonia Society and the Guarantors of Brain. He has received honoraria for speaking from UCB. Dr. Farmer has received support from NIHR via funding for the UCLH CBRC. Dr. Erro, Dr. Esposito, and Dr. Cordivari have no financial disclosures. Financial disclosure related to research covered in this article: none.
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