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Large-field repetitive transcranial magnetic stimulation with circular coil in the treatment of functional neurological symptoms
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Stimulation magnétique transcrânienne répétitive à large champ avec bobine circulaire dans le traitement des symptômes neurologiques fonctionnels
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D. Parain ∗, N. Chastan
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Physiology Department, Rouen University Hospital, 1, rue de Germont, 76031 Rouen cedex, France
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Received 8 September 2013; accepted 27 April 2014
KEYWORDS
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Psychogenic disorders; Functional neurological symptoms; rTMS; Functional weakness; Functional visual loss; Non-epileptic seizures
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Summary Objective. — Patients with functional neurological symptoms (FNS) are frequently encountered by neurologists and are difficult to treat. Symptoms are multiple and may appear concurrently or successively in the same patient. To date, few studies have been published on focal repetitive transcranial magnetic stimulation (rTMS) in FNS. This type of stimulation induces a focal current, vertically in the cortex. Results are contradictory, probably because it is difficult to identify a limited cortical area that triggers these symptoms. We assessed the efficacy of another type of rTMS: large-field stimulation by means of a circular coil covering a surface area approximately 20 times greater and inducing a circular current tangentially to the cortex. Published studies. — We analysed two studies on the efficacy of large-field rTMS in functional paralysis and in functional movement disorders. The efficacy of large-field rTMS was very marked in these two studies. Personal non-published studies. — We reported several open series, including patients with functional sensory loss, functional visual loss, and non-epileptic seizures. Method. — For all patients, one or several sessions of 60 stimuli with circular coil were carried out with a protocol depending on the symptoms. Results. — The efficacy of large-field rTMS was dramatic in all patient series. Additionally, we discuss the possible involved mechanism: placebo effect, cognitive behavioural effect or neuromodulatory effect.
Corresponding author. Tel.: +33 2 32 88 80 37; fax: +33 2 32 88 83 93. E-mail address: [email protected] (D. Parain).
http://dx.doi.org/10.1016/j.neucli.2014.04.004 0987-7053/© 2014 Published by Elsevier Masson SAS.
Please cite this article in press as: Parain D, Chastan N. Large-field repetitive transcranial magnetic stimulation with NEUCLI 2441 1—7 circular coil in the treatment of functional neurological symptoms. Neurophysiologie Clinique/Clinical Neurophysiology (2014), http://dx.doi.org/10.1016/j.neucli.2014.04.004
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D. Parain, N. Chastan Conclusion. — According to the data from these different studies, large-field rTMS could be a new therapy for patients with FNS. However, controlled studies are mandatory. © 2014 Published by Elsevier Masson SAS.
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MOTS CLÉS Troubles psychogènes ; Symptômes neurologiques fonctionnels ; rTMS ; Paralysies fonctionnelles ; Troubles visuels fonctionnels ; Crises non épileptiques
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Résumé Objectif. — Les symptômes neurologiques fonctionnels (SNF) sont fréquemment rencontrés en pratique neurologique et difficile à traiter. Les symptômes sont multiples et peuvent être associés ou se succéder chez un même patient. Peu d’études ont analysé l’efficacité de la stimulation magnétique transcrânienne répétitive (rTMS) focale dans les SNF. Cette stimulation induit un courant très focal, vertical par rapport au cortex. Les résultats sont contradictoires, probablement parce qu’il est difficile d’identifier une cible corticale limitée qui pourrait être l’origine des ces troubles. Nous avons voulu évaluer l’efficacité d’un autre type de rTMS, la stimulation à large champ à l’aide d’une bobine circulaire qui permet de stimuler une surface de cortex environ 20 fois supérieure et qui induit un courant circulaire tangentiel au cortex. Études déjà publiées. — Nous avons rapporté et analysé deux études concernant l’effet de la rTMS à large champ dans les paralysies fonctionnelles et dans les mouvements anormaux fonctionnels. Dans ces deux études, l’efficacité a été très importante. Études personnelles non publiées. — Nous rapportons plusieurs séries en ouvert concernant des patients avec des déficits sensitifs fonctionnels, des déficits visuels fonctionnels ou des crises non épileptiques. Méthode. — Une ou plusieurs sessions de 60 stimulations sont effectuées avec un protocole différent selon les symptômes. Résultats. — L’efficacité s’est montrée importante dans tous les SNF étudiés. Les hypothèses sur les mécanismes sous-jacents sont discutées: effet placebo; effet cognitivo-comportemental ou effet de neuromodulation. Conclusion. — La rTMS à large champ pourrait être un nouveau type de traitement pour les patients avec des SNF. Cependant, des études contrôlées sont nécessaires. © 2014 Publi´ e par Elsevier Masson SAS.
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Introduction Patients with psychogenic or conversion neurological disorders, now called functional neurological symptoms (FNS), are described as the most difficult to treat. FNS are one of the most common conditions encountered by neurologists [4]. Patients with FNS may present with different symptoms, such as paralysis, primary pain, movement disorders, sensory disturbance or visual loss, and non-epileptic seizures. Patients may have one or several symptoms at the same time or in succession. For more than a decade, numerous studies have been published describing the therapeutic effect of repetitive transcranial magnetic stimulation (rTMS), with depression and neuropathic pain as the main indications. The effect of rTMS has also been studied in epilepsy, movement disorders, tinnitus, auditory hallucinations and stroke, but to a lesser degree. In all these studies, an 8-shaped coil was used to stimulate vertically a 1 to 2-cm2 surface of cortex area with the possibility of modifying the activity of deeper structures (focal rTMS). In this type of rTMS, the location of area to stimulate needs to be well defined. Neuronavigation is mandatory for efficient stimulation of this previously defined area [15]. In a recent review [20], data were reported on the efficiency of rTMS in FNS. Only eight studies have been published in the world literature and only 126 patients were included. The indications were functional weakness or movement disorders. For the first time, the use of large-field
rTMS with circular coil is reported in 2 studies from our team and 76 patients have been reported with dramatic results. The circular coil induces a significant magnetic field over a surface approximately 30 times greater than the 8-shaped coil [10] and this magnetic field triggers a tangential-to-thecortex circular current over the same surface. The rationale for using this type of rTMS is that FNS are probably not triggered by a very restricted cortical area dysfunction but by larger networks or cortical area dysfunction [31]. In other studies [20], focal rTMS was used in FNS with contradictory results. In this article, we first detail the results of several published studies on the efficacy of large-field rTMS in patients with different motor functional symptoms. Secondly, we present the results of other personal non-published studies in patients with non-motor functional symptoms (sensory disturbances, visual loss, non-epileptic seizures). A multicentre controlled study is ongoing, coordinated by one of the authors (NC), with ethical committee agreement, on functional weakness (no RCB: 2010-A006660-39). Focal rTMS is considered safe [16]. Safety of large-field rTMS has not been extensively analysed, but it is routinely used for motorevoked potential (however, in this case, the pulse is usually single). In a published study on large-field rTMS in the prophylactic treatment of migraine [28], the authors carried out sessions of 1000 stimulations per day during 5 consecutive days without significant adverse effects (about 40 times greater than in our protocols with a maximum of 120 stimulations per week).
Please cite this article in press as: Parain D, Chastan N. Large-field repetitive transcranial magnetic stimulation with NEUCLI 2441 1—7 circular coil in the treatment of functional neurological symptoms. Neurophysiologie Clinique/Clinical Neurophysiology (2014), http://dx.doi.org/10.1016/j.neucli.2014.04.004
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Published open studies Functional weakness (FW) FW presents a real treatment challenge. Despite psychotherapy, physiotherapy, antidepressants, acupuncture, or hypnosis, the outcome is often unsatisfactory and 37% to 83% of patients continue to experience symptoms 2 to 16 years after diagnosis with related disability comparable to that of multiple sclerosis [26]. FW was the first disorder in which a trial for large-field rTMS was reported. Our team conducted a retrospective study to assess the efficacy of this alternative treatment [5]. Patients. Seventy patients (44 females and 26 males; mean age: 24.7 years, SD 16.6 years; minimum—maximum: 8—79 years) were selected for FW. Forty-one patients (59%) were adolescents. They experienced paraparesis (57%), monoparesis (37%), tetraparesis (3%), or hemiparesis (3%). A precipitating event was observed in 42 patients, primarily as a psychosocial event or a physical injury. Motor symptoms were isolated (24 cases, 34%) or associated with sensory symptoms (27 cases, 39%), pain (11 cases, 16%), or with both sensory and pain symptoms (8 cases, 11%). Method. An average of 30 stimuli delivered at low frequency (the device allowed stimulation every 4—5 s) and at intensity above the motor threshold (maximal intensity of 2.5 Tesla) was provided with a circular coil (P/N 9784-00) during 2 to 3 min. Another session of 30 stimuli was sometimes delivered a few minutes later in cases of incomplete improvement. The rTMS was applied to the motor cortex opposite to the corresponding paralysis or on the vertex for bilateral paralysis. Efficacy of rTMS was classified in two groups: effective (total recovery or dramatic improvement) or ineffective (mild improvement or failure). Patient follow-up was performed in most cases by the general practitioner, pediatrician, or neurologist. Results. In our study, large-field rTMS applied over the motor cortex was associated with a very good outcome in 89%, with a total recovery in 53 patients [immediately after rTMS (n = 43), quasi-immediately (within a few minutes or hours, n = 8), and a few days later (n = 2)] or a dramatic improvement in 9 patients. As previously described in the literature [27], the factor significantly associated with a favorable outcome was acute onset of symptoms, but not age or sex. In contrast to previous studies, we did not find a significant good outcome for patients with a comorbid psychiatric disorder (depression or anxiety). Despite an improvement in paralysis, a psychological follow-up was sometimes required in certain patients. Symptoms recurred in eight patients, with the same paralysis, after a 160-day average delay for a single recurrence of paralysis (n = 5) and after a 150-day average delay for multiple recurrences (n = 3). Large-field rTMS was applied again in six of the eight patients with recurrence and was effective for all patients.
Functional movement disorders (FMD) Functional movement disorders account for 3% of disorders in movement disorder clinics. Diagnosis and management of FMD remains challenging. Outcome is often poor, since
3 only half of the patients improve after 3 years of followup [1] with a significant related disability, similar to that in neurodegenerative conditions [29]. Two studies on the efficiency of focal rTMS in FMD gave contradictory results [8,23]. Based on these results and the good efficiency of large-field rTMS in FW, another team (Garcin et al.) conducted a prospective pilot study on the effect of this new type of rTMS in FMD [11]. Patients. Twenty-two patients were included with fixed dystonia (11 cases, 46%), myoclonus (5 cases, 21%), tremor (3 cases, 12.5%), jerky dystonia (3 cases, 12.5%), Parkinsonism (1 case, 4%), or stereotypies (1 case, 4%). Median duration of symptoms was 2.8 years (mean duration: 6.8 years, SD: 8.9; range 0.5—30 years). Method. The authors blindly video scored symptoms of consecutive patients with FMD who were recorded before and after rTMS. An average of 20 stimuli (120% of the resting motor threshold) was delivered with a circular coil (9 cm diameter, Magstim device) over the motor cortex either contralaterally to symptoms, or bilaterally, if movement disorders were bilateral. Stimulation intensity was sufficient to induce a motor response. In this study, the authors combined stimulations with suggestion. Results. The overall score of 75% of patients improved by > 50%; furthermore, the clinical benefits were sustained upon protracted follow-up (median 19.8 months). There was no correlation between improvement and duration of symptoms before rTMS. The authors consider that large-field rTMS is a therapeutic option for PMDs, including chronic PMDs.
Functional aphonia (FA) Functional aphonia is a disabling conversion disorder with no standard psychotherapeutic or speech-therapeutic treatment. Our team used large-field rTMS to treat a patient with a long-term evolving psychogenic aphonia [6]. Patient. A left-handed 18-year-old woman developed a sudden total loss of normal speech production, which was preceded by hoarseness. Coughing and syllabic ‘‘trillo’’ phonati were normal, indicating normal articulatory ability. Otolaryngological examination noted a normal larynx with no sign of lesion or vocal cord palsy, and videostroboscopic examination showed no vocal cord adduction, except during coughing. Neurological examination and brain MRI were normal. The patient reported moderate familial conflict and academic problems. Psychological evaluation revealed chronic anxiety. Thirty sessions of speech therapy produced no improvement. The conversion disorder persisted for 20 months. Method and results. As a final treatment, two rTMS sessions of 150 s duration (50 stimuli delivered at 0.33 Hz, and maximal intensity of 2.5 Tesla) were attempted with a circular coil (P/N 9784-00). The first magnetic stimulation was applied to the left prefrontal cortex with no effect. One week later, a second rTMS session was applied to the motor cortex with a dramatic and immediate improvement, leading to normal speech within a few days, and still normal at 6 months follow-up. The authors attributed clinical improvement to the large-field rTMS, and not to a placebo effect (lack of effect with prefrontal cortex rTMS), or the natural course of the illness.
Please cite this article in press as: Parain D, Chastan N. Large-field repetitive transcranial magnetic stimulation with NEUCLI 2441 1—7 circular coil in the treatment of functional neurological symptoms. Neurophysiologie Clinique/Clinical Neurophysiology (2014), http://dx.doi.org/10.1016/j.neucli.2014.04.004
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Others non-published personal open studies Functional sensory loss (FSL) In most studies on patients with FW and sensory disturbance, FSL is less often an initial complaint and may be detected only by the examiner and so, come as a surprise for the patient. In the long-term follow-up of these patients, there is a considerable overlap between motor and sensory symptoms and 58% of those who initially only had sensory symptoms went on to develop weakness [25]. In our study on the efficacy of large-field rTMS on FW, 66% of the patients also had sensory symptoms. All patients who recovered from weakness after rTMS also recovered from sensory disturbance. Consequently, we proposed large-field rTMS for patients with FSL as the main complaint. Patients. Twelve patients were selected for FSL at the beginning of their symptoms and as the main symptom at first attendance. All sensory modalities were decreased. There were seven female and 5 male patients (mean age 31 years, range: 17—48 years). Patients had complete unilateral FSL (n = 3), a unilateral brachio-facial FSL (n = 3), one arm FSL (n = 2) or a FSL of both legs (n = 4). Four patients had associated functional symptoms: slight FW (n = 2), dystonia (n = 1), decreased visual acuity of the ipsilateral eye in a patient with unilateral sensory loss. Method. Diagnosis was explained to each patient, particularly regarding the nature of ‘‘functional’’ sensory loss, i.e., a nervous system dysfunction without lesion or well-defined pathophysiogical process. After informed consent, rTMS was applied to the patient according to the following protocol: a session of 60 stimulations with a circular coil of 9 cm diameter, above the motor threshold, was performed at a low frequency (at about 1 Hz or less). The coil was located over the centro-parietal area (midline or contralaterally to the symptoms). Results. Large-field rTMS was effective in nine patients (75%), with a total recovery in six patients immediately after rTMS and a dramatic improvement in three patients. The rTMS was ineffective in three patients. Three patients with associated symptoms recovered from FSL and from the other symptoms. Functional visual loss (FVL) Visual problems without clear organic cause are present in about 1% of patients in a general ophthalmology practice [3]. FVL is typically bilateral and involves both visual acuity and field. In a series of 140 patients with FVL, follow-up information was available for 24.6% of patients. Normalization of visual acuity occurred in 60.7% of cases vs 27.5% for field defect [17]. We hypothesized that patients with FVL might respond to large-field rTMS in the same manner as patients with FW or FSL. Patients. Ten patients were selected for FVL as main symptom at first attendance. They were six female and four male patients (mean age 18 years). Seven patients had a decrease in visual acuity (5 bilateral and 2 unilateral). Two patients had a decrease in visual field bilaterally. One patient had monocular diplopia. All patients had demonstrated visual symptoms for at least one month and all underwent ophthalmic and neurological investigations, which concluded non-organic visual disturbances.
Method. After informed consent, large-field rTMS was applied to the patient according to the following protocol. A session of 60 stimulations was performed with a 9 cm diameter circular coil, at a low frequency (at about 1 Hz or less) and at an intensity of approximately 50%, the first and the second day after the communication of the diagnosis. The coil was located on the midline and on the occipito-parietal area. Results. Six patients achieved immediate complete recovery and three patients a dramatic improvement. Only one patient with bilateral decreased visual acuity did not respond to rTMS. In two patients, FVL recurred some months later after initial recovery with a good efficacy in a new session of rTMS.
Non-epileptic seizures (NES) NES may be associated with FW in the same patient [27]. We presented a poster with the results of a short study on the efficacy of large-field rTMS on eight patients with NES and FW [19]. The result was dramatic for both symptoms in seven of the patients. We therefore hypothesized that the same therapy might work for both types of FNS. There are some data concerning the possibility of a decrease in network connectivity in dorso-lateral frontal area in NES [13,15]. Large-field rTMS on the fronto-central cortex might improve these alterations and help control NES. Outcome in patients with NES according to the literature is variable, but generally poor and worse than outcome in newly diagnosed epilepsy [2]. In the largest published study, only 28.8% of patients were spell-free at 1 to 10 years after diagnosis [21]. In another, more recent study of short-term (6—12 months) outcome only, the authors found that 38% of patients became attack-free with communication and explanation of diagnosis as sole intervention after EEG video or EEG recording [18]. In this study, the authors have the highest rate of spell-free patients in the literature. In our study, we used large-field rTMS protocol in the clinical management of patients with NES in addition to communication and explanation of the diagnosis after EEG video recording. We then compared the results of the study by McKenzie et al. (REF) without rTMS, and our results with large-field rTMS, in order to evaluate this technique. We therefore carried out a retrospective study of 6 and 12 months outcome in 42 consecutive patients with NES. Patients. From January 2007 to December 2012, 45 consecutive patients admitted to our neurophysiology unit for NES were included in a retrospective outcome study. Mean age was 27.9 years (range 12—52 years, SD 9.3). In total, 71.5% were female. The main differences between the population in the Mackenzie et al. study and ours are the size of the populations (187 vs 42 patients) and the younger age of our patients (< 10 years for the mean age). Method. For all patients, diagnosis of NES was confirmed by inpatient EEG video recording of spells analysed by epilepsy specialists. The first intervention involved communication and explanation of diagnosis. The second intervention involved performance of large-field rTMS protocol. NES frequency was collected at baseline, at 6 and 12 months (± 2 months) follow-up visit or telephone call. The patient was considered spell-free if free of spells for 2 months prior to last visit. The rates of spell-free patients, with > 50%
Please cite this article in press as: Parain D, Chastan N. Large-field repetitive transcranial magnetic stimulation with NEUCLI 2441 1—7 circular coil in the treatment of functional neurological symptoms. Neurophysiologie Clinique/Clinical Neurophysiology (2014), http://dx.doi.org/10.1016/j.neucli.2014.04.004
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reduction in spell frequency and with > 50% increase in spell frequency, were assessed. We compare our results to those in the McKenzie et al. study (REF). We used Fisher’s exact test to compare efficacy in the two studies according to three variables: the rate of spell-free patients, the rate of patients with > 50% reduction or > 50% increase in spell frequency. After informed consent, large-field rTMS was applied to the patient according to the following protocol. Stimulation was performed with a circular coil of 9 cm diameter, over the fronto-central area in the midline. Each session consisted of 60 stimulations above the motor threshold and was performed at a low frequency (at about 1 Hz or less) and with intensity above the motor threshold:
5 worse than epilepsy for NES. In our unit, when diagnosis of FNS is confirmed, we communicate the disease diagnosis to the patient and we explain that it is probably related to a dysfunction in neuronal networks and/or cortical area, triggered or not by emotional stimuli and that this dysfunction could be improved by large-field rTMS. In our experience, large-field rTMS had a dramatic effect on long-term outcome of these patients.
What are the possible therapeutic mechanisms of large-field rTMS in FNS?
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Results. Of the 45 patients included in the study, 42 attended first follow-up visit while 39 patients attended second follow-up visit. At the last follow-up visit (6 or 12 months), 34 patients (80%) had been spell-free for at least 2 months with no significant change in rate between 6-month and 12-month visits. Forty patients (95%) had > 50% reduction and none had > 50% increase in spell frequency at last follow-up visit. For comparison with the McKenzie et al. study, see Table 1. Large-field rTMS after communication and explanation of diagnosis is efficacious (at least P < 0.001 for the 3 variables) in reducing spell frequency. After an initial recovery, four patients had a recurrence, several weeks later, but with a change in the presentation of spells, as if there was a shift in the network dysfunction after rTMS. These four patients were controlled after new sessions.
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Discussion
Placebo effect? The nature of the placebo response is highly complex and is influenced by many factors that relate to the therapeutic setting. One important factor in all areas of medicine, but perhaps particularly in treating FNS, is the expectancy that the therapeutic encounter generates. In our procedure, rTMS was introduced as therapeutic with suggestion of the expected benefice. The placebo effect may vary with complexity and repetition (conditioning) of the procedure. So, it is interesting to compare the efficacy of large-field rTMS and focal rTMS (more complexity in the procedure and often more sessions) in the same type of FNS. FW. In two papers, diagnostic use of single-pulse largefield TMS (for motor-evoked potential) led to recovery in 2 patients [9,14]. In our study [5], 89% of 70 patients improved with 1 or 2 sessions of large-field rTMS (30 or 60 pulses). In only one study, focal rTMS was used on 4 patients [22]. One session of stimulation (4000 pulses) was given by day during 1 to 4 weeks. Three patients improved. FMD. In one study, 75% of 22 patients improved with one session of large-field rTMS (20 pulses). In two studies, focal rTMS was used. A preliminary study suggested its efficiency in psychogenic tremor (one session of 30 pulses) [8]. However, a recent study [22] showed no efficacy of rTMS using stimulation under motor threshold in five patients with chronic PMDs (5 sessions for five consecutive day; no other details). In these studies, for the 2 types of FNS, the efficacy of large-field rTMS tended to be greater than with focal rTMS. Despite the high level of efficacy, controlled studies are mandatory with real sham procedure compared to the different protocols to assess the size of placebo effect.
According to these studies, the efficacy of large-field rTMS in different FNS seems very encouraging, with a better prognosis than the natural evolution as reported in the literature. The natural outcomes of FW, FMD and NES are often poor with significant related disability, similar to multiple sclerosis for FW, to neurodegenerative condition for FMD and
Cognitivo-behavioural effect? Psychotherapy is considered the mainstay of treatment for FNS but the number of appropriately powered studies in this area is small. Recently, a number of randomised controlled studies have provided Class 2—3 evidence of the effectiveness of such interventions for patients with FNS and PNES, at
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• one session the first and the second day after the communication of the diagnosis; • the sequence of the following sessions was dependant on evolution of the frequency of spells: ◦ 1o situation: prolonged disappearance (more than 2 months) of spells. A new session was performed if and when the spells recurred, ◦ 2o situation: there was no initial efficacy of rTMS or the spells recurred at a lower frequency. The sessions were repeated in the same order as frequency of spells with a maximum of eight sessions per month during 3o months.
Table 1 Statistical comparison between McKenzie et al. study and ours to evaluate the efficacy of large-field rTMS in NES (exact Fischer’s test; significant P < 0.05).
No (%) patients spell-free for 2 months at last visit No (%) patients with > 50% reduction in spell at last visit No (%) patients with > 50% increase in spell at last visit
Our study
McKenzie et al. study
P
34/42 (80%) 40/42 (90%) 0/42 (0%)
71/187 (38%) 114/187 (61%) 35/187 (18,7%)
< 10−6 < 10−4 < 0.001
Please cite this article in press as: Parain D, Chastan N. Large-field repetitive transcranial magnetic stimulation with NEUCLI 2441 1—7 circular coil in the treatment of functional neurological symptoms. Neurophysiologie Clinique/Clinical Neurophysiology (2014), http://dx.doi.org/10.1016/j.neucli.2014.04.004
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least in the short-term. Treatments have targeted a range of potentially modifiable factors, including illness perceptions, previous trauma and emotional processing or health utilisation behaviours. A randomized control trial (RCT) of a guided four-session self-help programme based on a cognitive behavioural therapy (CBT) [24] was conducted in 127 patients. The treatment effect was of moderate size with a 13% difference between treatment arms (usual care and usual care + CBT) in participants rating themselves as better or much better (P = 0.016). Another RCT in 66 patients with NES showed that the CBT group tended only to be more likely to have experienced 3 months of seizure freedom (P = 0.086). Large-field rTMS present a greater efficacy in FNS than CBT probably because this may provide a plausible treatment modality, satisfying the individual’s need, expectancy and changing the patient’s belief about their symptoms. In motor FNS, large-field rTMS may have a specific cognitivo-behavioural effect. Motor cortical stimulation produces transient movements that contrast to the deficit that characterises FW. Perception (which may be visual, somatosensory or even proprioceptive), by the patient, that symptom improvement is possible may influence regain of function. In their study, Garcin et al. [11] considered that movements induced by large-field rTMS altered FMD for a few seconds. Thereby, patients were able to discover for themselves the possibility of transiently modifying abnormal movement/posture. During the TMS session, one of the authors discussed this positive motor phenomenon and thereby provided synergistic psychological reinforcement. According to the authors, there might be a cognitive behavioural rather than placebo effect when patients see an unexpected alteration of their movement disorder. However, this analysis does not explain improvement in other FNS, such as FVL, FSL or the prophylactic effect in NES.
Neuromodulatory effect? The effects of focal rTMS are mediated by changes in cortical excitability and/or resultant changes in connectivity between brain areas. Results of functional imaging studies and analysis of network connectivity show that in the different types of FNS, there is, at variable degree, hyperactivity of limbic area, hypoactivity of some specific cortical areas and a decrease in connectivity, above all in the dorsal frontal area, perhaps indicating a decrease in frontal top-down control [31]. One study provides preliminary evidence favouring the hypothesis that normalizing the functional connectivity between the temporo-parietal and frontal brain regions may underlie the therapeutic effect of focal rTMS on auditory hallucinations in schizophrenia [12]. However, we currently have no data on the neuromodulatory effect of large-field rTMS. We consider that the repeated low-frequency large-field rTMS (below 1 Hz) used in these studies could not be responsible for stimulationinduced after effects because stimulation of the motor cortex at 0.1 Hz for 1 h did not change cortical excitability [7]. At 1 Hz, a minimum of 750 TMS pulses was needed to modulate motor-evoked potential amplitude, which is far above the total number of pulses delivered to the studied patients [30].
Conclusion According to the data from these different studies, largefield rTMS could be a new therapy for patients with FNS. This therapy, in our experience, is safe and positively impacted upon clinical management of these difficult-to-treat patients. We consider in the current state of knowledge that the beneficial effect of large-field rTMS might be due to a combination of suggestion/placebo/cognitivo-behavioral effect. Even if large-field rTMS exerts a therapeutic effect through non-neuromodulatory mechanisms, this does not mean that it is an inappropriate treatment for FNS.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
Acknowledgements The authors wish to thank Nikki Sabourin-Gibbs, Rouen University Hospital, for her help in editing the manuscript and Patrick Magnier for his technical assistance.
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7 [22] Schonfeldt-Lecuona C, Connemann BJ, Viviani R, et al. Transcranial magnetic stimulation in motor conversion disorder: a short case series. J Clin Neurophysiol 2006;23:472—5. [23] Shah BB, Zurowski M, Chen R, et al. Failure of motor cortex repetitive transcranial magnetic stimulation (rTMS) combined with suggestion in the treatment of chronic psychogenic movement disorders (PMDs): a pilot study. In: 15th International Congress of Parkinson’s Disease and Movement Disorders. 2011. [24] Sharpe M, Walker J, Williams C, et al. Guided self-help for functional (psychogenic) symptoms: a randomized controlled efficacy trial. Neurology 2011;77:564e72. [25] Stone J, Zeman A, Sharpe M. Functional weakness and sensory disturbance. J Neurol Neurosurg Psychiatry 2002;73:241—5. [26] Stone J, Sharpe M, Rothwell PM, Warlow CP. The 12-year prognosis of unilateral functional weakness and sensory disturbance. J Neurol Neurosurg Psychiatry 2003;74:591—6. [27] Stone J, Warlow C, Sharpe M. The symptom of functional weakness: a controlled study of 107 patients. Brain 2010;133:1537—51. [28] Teepker M, Hötzel J, Timmesfeld N, Reis J, Mylius V, Haag A, et al. Low-frequency rTMS of the vertex in the prophylactic treatment of migraine. Cephalalgia 2010;30:137—44. [29] Thomas M, Vuong KD, Jankovic J. Long-term prognosis of patients with psychogenic movement disorders. Parkinsonism Relat Disord 2006;12:382—7. [30] Touge T, Gerschlager W, Brown P, et al. Are the after-effects of low-frequency rTMS on motor cortex excitability due to changes in the efficacy of cortical synapses? Clin Neurophysiol 2001;112:2138—45. [31] Voon V, Brezing C, Gallea C, Hallett M. Aberrant supplementary motor complex and limbic activity during motor preparation in motor conversion disorder. Mov Disord 2011;13:2396—403.
Please cite this article in press as: Parain D, Chastan N. Large-field repetitive transcranial magnetic stimulation with NEUCLI 2441 1—7 circular coil in the treatment of functional neurological symptoms. Neurophysiologie Clinique/Clinical Neurophysiology (2014), http://dx.doi.org/10.1016/j.neucli.2014.04.004
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ORIGINAL ARTICLE/ARTICLE ORIGINAL
Large-field repetitive transcranial magnetic stimulation with circular coil in the treatment of functional neurological symptoms
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Stimulation magnétique transcrânienne répétitive à large champ avec bobine circulaire dans le traitement des symptômes neurologiques fonctionnels
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D. Parain ∗, N. Chastan
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Physiology Department, Rouen University Hospital, 1, rue de Germont, 76031 Rouen cedex, France
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Received 8 September 2013; accepted 27 April 2014
KEYWORDS
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Psychogenic disorders; Functional neurological symptoms; rTMS; Functional weakness; Functional visual loss; Non-epileptic seizures
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Summary Objective. — Patients with functional neurological symptoms (FNS) are frequently encountered by neurologists and are difficult to treat. Symptoms are multiple and may appear concurrently or successively in the same patient. To date, few studies have been published on focal repetitive transcranial magnetic stimulation (rTMS) in FNS. This type of stimulation induces a focal current, vertically in the cortex. Results are contradictory, probably because it is difficult to identify a limited cortical area that triggers these symptoms. We assessed the efficacy of another type of rTMS: large-field stimulation by means of a circular coil covering a surface area approximately 20 times greater and inducing a circular current tangentially to the cortex. Published studies. — We analysed two studies on the efficacy of large-field rTMS in functional paralysis and in functional movement disorders. The efficacy of large-field rTMS was very marked in these two studies. Personal non-published studies. — We reported several open series, including patients with functional sensory loss, functional visual loss, and non-epileptic seizures. Method. — For all patients, one or several sessions of 60 stimuli with circular coil were carried out with a protocol depending on the symptoms. Results. — The efficacy of large-field rTMS was dramatic in all patient series. Additionally, we discuss the possible involved mechanism: placebo effect, cognitive behavioural effect or neuromodulatory effect.
Corresponding author. Tel.: +33 2 32 88 80 37; fax: +33 2 32 88 83 93. E-mail address: [email protected] (D. Parain).
http://dx.doi.org/10.1016/j.neucli.2014.04.004 0987-7053/© 2014 Published by Elsevier Masson SAS.
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D. Parain, N. Chastan Conclusion. — According to the data from these different studies, large-field rTMS could be a new therapy for patients with FNS. However, controlled studies are mandatory. © 2014 Published by Elsevier Masson SAS.
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MOTS CLÉS Troubles psychogènes ; Symptômes neurologiques fonctionnels ; rTMS ; Paralysies fonctionnelles ; Troubles visuels fonctionnels ; Crises non épileptiques
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Résumé Objectif. — Les symptômes neurologiques fonctionnels (SNF) sont fréquemment rencontrés en pratique neurologique et difficile à traiter. Les symptômes sont multiples et peuvent être associés ou se succéder chez un même patient. Peu d’études ont analysé l’efficacité de la stimulation magnétique transcrânienne répétitive (rTMS) focale dans les SNF. Cette stimulation induit un courant très focal, vertical par rapport au cortex. Les résultats sont contradictoires, probablement parce qu’il est difficile d’identifier une cible corticale limitée qui pourrait être l’origine des ces troubles. Nous avons voulu évaluer l’efficacité d’un autre type de rTMS, la stimulation à large champ à l’aide d’une bobine circulaire qui permet de stimuler une surface de cortex environ 20 fois supérieure et qui induit un courant circulaire tangentiel au cortex. Études déjà publiées. — Nous avons rapporté et analysé deux études concernant l’effet de la rTMS à large champ dans les paralysies fonctionnelles et dans les mouvements anormaux fonctionnels. Dans ces deux études, l’efficacité a été très importante. Études personnelles non publiées. — Nous rapportons plusieurs séries en ouvert concernant des patients avec des déficits sensitifs fonctionnels, des déficits visuels fonctionnels ou des crises non épileptiques. Méthode. — Une ou plusieurs sessions de 60 stimulations sont effectuées avec un protocole différent selon les symptômes. Résultats. — L’efficacité s’est montrée importante dans tous les SNF étudiés. Les hypothèses sur les mécanismes sous-jacents sont discutées: effet placebo; effet cognitivo-comportemental ou effet de neuromodulation. Conclusion. — La rTMS à large champ pourrait être un nouveau type de traitement pour les patients avec des SNF. Cependant, des études contrôlées sont nécessaires. © 2014 Publi´ e par Elsevier Masson SAS.
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Introduction Patients with psychogenic or conversion neurological disorders, now called functional neurological symptoms (FNS), are described as the most difficult to treat. FNS are one of the most common conditions encountered by neurologists [4]. Patients with FNS may present with different symptoms, such as paralysis, primary pain, movement disorders, sensory disturbance or visual loss, and non-epileptic seizures. Patients may have one or several symptoms at the same time or in succession. For more than a decade, numerous studies have been published describing the therapeutic effect of repetitive transcranial magnetic stimulation (rTMS), with depression and neuropathic pain as the main indications. The effect of rTMS has also been studied in epilepsy, movement disorders, tinnitus, auditory hallucinations and stroke, but to a lesser degree. In all these studies, an 8-shaped coil was used to stimulate vertically a 1 to 2-cm2 surface of cortex area with the possibility of modifying the activity of deeper structures (focal rTMS). In this type of rTMS, the location of area to stimulate needs to be well defined. Neuronavigation is mandatory for efficient stimulation of this previously defined area [15]. In a recent review [20], data were reported on the efficiency of rTMS in FNS. Only eight studies have been published in the world literature and only 126 patients were included. The indications were functional weakness or movement disorders. For the first time, the use of large-field
rTMS with circular coil is reported in 2 studies from our team and 76 patients have been reported with dramatic results. The circular coil induces a significant magnetic field over a surface approximately 30 times greater than the 8-shaped coil [10] and this magnetic field triggers a tangential-to-thecortex circular current over the same surface. The rationale for using this type of rTMS is that FNS are probably not triggered by a very restricted cortical area dysfunction but by larger networks or cortical area dysfunction [31]. In other studies [20], focal rTMS was used in FNS with contradictory results. In this article, we first detail the results of several published studies on the efficacy of large-field rTMS in patients with different motor functional symptoms. Secondly, we present the results of other personal non-published studies in patients with non-motor functional symptoms (sensory disturbances, visual loss, non-epileptic seizures). A multicentre controlled study is ongoing, coordinated by one of the authors (NC), with ethical committee agreement, on functional weakness (no RCB: 2010-A006660-39). Focal rTMS is considered safe [16]. Safety of large-field rTMS has not been extensively analysed, but it is routinely used for motorevoked potential (however, in this case, the pulse is usually single). In a published study on large-field rTMS in the prophylactic treatment of migraine [28], the authors carried out sessions of 1000 stimulations per day during 5 consecutive days without significant adverse effects (about 40 times greater than in our protocols with a maximum of 120 stimulations per week).
Please cite this article in press as: Parain D, Chastan N. Large-field repetitive transcranial magnetic stimulation with NEUCLI 2441 1—7 circular coil in the treatment of functional neurological symptoms. Neurophysiologie Clinique/Clinical Neurophysiology (2014), http://dx.doi.org/10.1016/j.neucli.2014.04.004
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Published open studies Functional weakness (FW) FW presents a real treatment challenge. Despite psychotherapy, physiotherapy, antidepressants, acupuncture, or hypnosis, the outcome is often unsatisfactory and 37% to 83% of patients continue to experience symptoms 2 to 16 years after diagnosis with related disability comparable to that of multiple sclerosis [26]. FW was the first disorder in which a trial for large-field rTMS was reported. Our team conducted a retrospective study to assess the efficacy of this alternative treatment [5]. Patients. Seventy patients (44 females and 26 males; mean age: 24.7 years, SD 16.6 years; minimum—maximum: 8—79 years) were selected for FW. Forty-one patients (59%) were adolescents. They experienced paraparesis (57%), monoparesis (37%), tetraparesis (3%), or hemiparesis (3%). A precipitating event was observed in 42 patients, primarily as a psychosocial event or a physical injury. Motor symptoms were isolated (24 cases, 34%) or associated with sensory symptoms (27 cases, 39%), pain (11 cases, 16%), or with both sensory and pain symptoms (8 cases, 11%). Method. An average of 30 stimuli delivered at low frequency (the device allowed stimulation every 4—5 s) and at intensity above the motor threshold (maximal intensity of 2.5 Tesla) was provided with a circular coil (P/N 9784-00) during 2 to 3 min. Another session of 30 stimuli was sometimes delivered a few minutes later in cases of incomplete improvement. The rTMS was applied to the motor cortex opposite to the corresponding paralysis or on the vertex for bilateral paralysis. Efficacy of rTMS was classified in two groups: effective (total recovery or dramatic improvement) or ineffective (mild improvement or failure). Patient follow-up was performed in most cases by the general practitioner, pediatrician, or neurologist. Results. In our study, large-field rTMS applied over the motor cortex was associated with a very good outcome in 89%, with a total recovery in 53 patients [immediately after rTMS (n = 43), quasi-immediately (within a few minutes or hours, n = 8), and a few days later (n = 2)] or a dramatic improvement in 9 patients. As previously described in the literature [27], the factor significantly associated with a favorable outcome was acute onset of symptoms, but not age or sex. In contrast to previous studies, we did not find a significant good outcome for patients with a comorbid psychiatric disorder (depression or anxiety). Despite an improvement in paralysis, a psychological follow-up was sometimes required in certain patients. Symptoms recurred in eight patients, with the same paralysis, after a 160-day average delay for a single recurrence of paralysis (n = 5) and after a 150-day average delay for multiple recurrences (n = 3). Large-field rTMS was applied again in six of the eight patients with recurrence and was effective for all patients.
Functional movement disorders (FMD) Functional movement disorders account for 3% of disorders in movement disorder clinics. Diagnosis and management of FMD remains challenging. Outcome is often poor, since
3 only half of the patients improve after 3 years of followup [1] with a significant related disability, similar to that in neurodegenerative conditions [29]. Two studies on the efficiency of focal rTMS in FMD gave contradictory results [8,23]. Based on these results and the good efficiency of large-field rTMS in FW, another team (Garcin et al.) conducted a prospective pilot study on the effect of this new type of rTMS in FMD [11]. Patients. Twenty-two patients were included with fixed dystonia (11 cases, 46%), myoclonus (5 cases, 21%), tremor (3 cases, 12.5%), jerky dystonia (3 cases, 12.5%), Parkinsonism (1 case, 4%), or stereotypies (1 case, 4%). Median duration of symptoms was 2.8 years (mean duration: 6.8 years, SD: 8.9; range 0.5—30 years). Method. The authors blindly video scored symptoms of consecutive patients with FMD who were recorded before and after rTMS. An average of 20 stimuli (120% of the resting motor threshold) was delivered with a circular coil (9 cm diameter, Magstim device) over the motor cortex either contralaterally to symptoms, or bilaterally, if movement disorders were bilateral. Stimulation intensity was sufficient to induce a motor response. In this study, the authors combined stimulations with suggestion. Results. The overall score of 75% of patients improved by > 50%; furthermore, the clinical benefits were sustained upon protracted follow-up (median 19.8 months). There was no correlation between improvement and duration of symptoms before rTMS. The authors consider that large-field rTMS is a therapeutic option for PMDs, including chronic PMDs.
Functional aphonia (FA) Functional aphonia is a disabling conversion disorder with no standard psychotherapeutic or speech-therapeutic treatment. Our team used large-field rTMS to treat a patient with a long-term evolving psychogenic aphonia [6]. Patient. A left-handed 18-year-old woman developed a sudden total loss of normal speech production, which was preceded by hoarseness. Coughing and syllabic ‘‘trillo’’ phonati were normal, indicating normal articulatory ability. Otolaryngological examination noted a normal larynx with no sign of lesion or vocal cord palsy, and videostroboscopic examination showed no vocal cord adduction, except during coughing. Neurological examination and brain MRI were normal. The patient reported moderate familial conflict and academic problems. Psychological evaluation revealed chronic anxiety. Thirty sessions of speech therapy produced no improvement. The conversion disorder persisted for 20 months. Method and results. As a final treatment, two rTMS sessions of 150 s duration (50 stimuli delivered at 0.33 Hz, and maximal intensity of 2.5 Tesla) were attempted with a circular coil (P/N 9784-00). The first magnetic stimulation was applied to the left prefrontal cortex with no effect. One week later, a second rTMS session was applied to the motor cortex with a dramatic and immediate improvement, leading to normal speech within a few days, and still normal at 6 months follow-up. The authors attributed clinical improvement to the large-field rTMS, and not to a placebo effect (lack of effect with prefrontal cortex rTMS), or the natural course of the illness.
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Others non-published personal open studies Functional sensory loss (FSL) In most studies on patients with FW and sensory disturbance, FSL is less often an initial complaint and may be detected only by the examiner and so, come as a surprise for the patient. In the long-term follow-up of these patients, there is a considerable overlap between motor and sensory symptoms and 58% of those who initially only had sensory symptoms went on to develop weakness [25]. In our study on the efficacy of large-field rTMS on FW, 66% of the patients also had sensory symptoms. All patients who recovered from weakness after rTMS also recovered from sensory disturbance. Consequently, we proposed large-field rTMS for patients with FSL as the main complaint. Patients. Twelve patients were selected for FSL at the beginning of their symptoms and as the main symptom at first attendance. All sensory modalities were decreased. There were seven female and 5 male patients (mean age 31 years, range: 17—48 years). Patients had complete unilateral FSL (n = 3), a unilateral brachio-facial FSL (n = 3), one arm FSL (n = 2) or a FSL of both legs (n = 4). Four patients had associated functional symptoms: slight FW (n = 2), dystonia (n = 1), decreased visual acuity of the ipsilateral eye in a patient with unilateral sensory loss. Method. Diagnosis was explained to each patient, particularly regarding the nature of ‘‘functional’’ sensory loss, i.e., a nervous system dysfunction without lesion or well-defined pathophysiogical process. After informed consent, rTMS was applied to the patient according to the following protocol: a session of 60 stimulations with a circular coil of 9 cm diameter, above the motor threshold, was performed at a low frequency (at about 1 Hz or less). The coil was located over the centro-parietal area (midline or contralaterally to the symptoms). Results. Large-field rTMS was effective in nine patients (75%), with a total recovery in six patients immediately after rTMS and a dramatic improvement in three patients. The rTMS was ineffective in three patients. Three patients with associated symptoms recovered from FSL and from the other symptoms. Functional visual loss (FVL) Visual problems without clear organic cause are present in about 1% of patients in a general ophthalmology practice [3]. FVL is typically bilateral and involves both visual acuity and field. In a series of 140 patients with FVL, follow-up information was available for 24.6% of patients. Normalization of visual acuity occurred in 60.7% of cases vs 27.5% for field defect [17]. We hypothesized that patients with FVL might respond to large-field rTMS in the same manner as patients with FW or FSL. Patients. Ten patients were selected for FVL as main symptom at first attendance. They were six female and four male patients (mean age 18 years). Seven patients had a decrease in visual acuity (5 bilateral and 2 unilateral). Two patients had a decrease in visual field bilaterally. One patient had monocular diplopia. All patients had demonstrated visual symptoms for at least one month and all underwent ophthalmic and neurological investigations, which concluded non-organic visual disturbances.
Method. After informed consent, large-field rTMS was applied to the patient according to the following protocol. A session of 60 stimulations was performed with a 9 cm diameter circular coil, at a low frequency (at about 1 Hz or less) and at an intensity of approximately 50%, the first and the second day after the communication of the diagnosis. The coil was located on the midline and on the occipito-parietal area. Results. Six patients achieved immediate complete recovery and three patients a dramatic improvement. Only one patient with bilateral decreased visual acuity did not respond to rTMS. In two patients, FVL recurred some months later after initial recovery with a good efficacy in a new session of rTMS.
Non-epileptic seizures (NES) NES may be associated with FW in the same patient [27]. We presented a poster with the results of a short study on the efficacy of large-field rTMS on eight patients with NES and FW [19]. The result was dramatic for both symptoms in seven of the patients. We therefore hypothesized that the same therapy might work for both types of FNS. There are some data concerning the possibility of a decrease in network connectivity in dorso-lateral frontal area in NES [13,15]. Large-field rTMS on the fronto-central cortex might improve these alterations and help control NES. Outcome in patients with NES according to the literature is variable, but generally poor and worse than outcome in newly diagnosed epilepsy [2]. In the largest published study, only 28.8% of patients were spell-free at 1 to 10 years after diagnosis [21]. In another, more recent study of short-term (6—12 months) outcome only, the authors found that 38% of patients became attack-free with communication and explanation of diagnosis as sole intervention after EEG video or EEG recording [18]. In this study, the authors have the highest rate of spell-free patients in the literature. In our study, we used large-field rTMS protocol in the clinical management of patients with NES in addition to communication and explanation of the diagnosis after EEG video recording. We then compared the results of the study by McKenzie et al. (REF) without rTMS, and our results with large-field rTMS, in order to evaluate this technique. We therefore carried out a retrospective study of 6 and 12 months outcome in 42 consecutive patients with NES. Patients. From January 2007 to December 2012, 45 consecutive patients admitted to our neurophysiology unit for NES were included in a retrospective outcome study. Mean age was 27.9 years (range 12—52 years, SD 9.3). In total, 71.5% were female. The main differences between the population in the Mackenzie et al. study and ours are the size of the populations (187 vs 42 patients) and the younger age of our patients (< 10 years for the mean age). Method. For all patients, diagnosis of NES was confirmed by inpatient EEG video recording of spells analysed by epilepsy specialists. The first intervention involved communication and explanation of diagnosis. The second intervention involved performance of large-field rTMS protocol. NES frequency was collected at baseline, at 6 and 12 months (± 2 months) follow-up visit or telephone call. The patient was considered spell-free if free of spells for 2 months prior to last visit. The rates of spell-free patients, with > 50%
Please cite this article in press as: Parain D, Chastan N. Large-field repetitive transcranial magnetic stimulation with NEUCLI 2441 1—7 circular coil in the treatment of functional neurological symptoms. Neurophysiologie Clinique/Clinical Neurophysiology (2014), http://dx.doi.org/10.1016/j.neucli.2014.04.004
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reduction in spell frequency and with > 50% increase in spell frequency, were assessed. We compare our results to those in the McKenzie et al. study (REF). We used Fisher’s exact test to compare efficacy in the two studies according to three variables: the rate of spell-free patients, the rate of patients with > 50% reduction or > 50% increase in spell frequency. After informed consent, large-field rTMS was applied to the patient according to the following protocol. Stimulation was performed with a circular coil of 9 cm diameter, over the fronto-central area in the midline. Each session consisted of 60 stimulations above the motor threshold and was performed at a low frequency (at about 1 Hz or less) and with intensity above the motor threshold:
5 worse than epilepsy for NES. In our unit, when diagnosis of FNS is confirmed, we communicate the disease diagnosis to the patient and we explain that it is probably related to a dysfunction in neuronal networks and/or cortical area, triggered or not by emotional stimuli and that this dysfunction could be improved by large-field rTMS. In our experience, large-field rTMS had a dramatic effect on long-term outcome of these patients.
What are the possible therapeutic mechanisms of large-field rTMS in FNS?
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Results. Of the 45 patients included in the study, 42 attended first follow-up visit while 39 patients attended second follow-up visit. At the last follow-up visit (6 or 12 months), 34 patients (80%) had been spell-free for at least 2 months with no significant change in rate between 6-month and 12-month visits. Forty patients (95%) had > 50% reduction and none had > 50% increase in spell frequency at last follow-up visit. For comparison with the McKenzie et al. study, see Table 1. Large-field rTMS after communication and explanation of diagnosis is efficacious (at least P < 0.001 for the 3 variables) in reducing spell frequency. After an initial recovery, four patients had a recurrence, several weeks later, but with a change in the presentation of spells, as if there was a shift in the network dysfunction after rTMS. These four patients were controlled after new sessions.
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Discussion
Placebo effect? The nature of the placebo response is highly complex and is influenced by many factors that relate to the therapeutic setting. One important factor in all areas of medicine, but perhaps particularly in treating FNS, is the expectancy that the therapeutic encounter generates. In our procedure, rTMS was introduced as therapeutic with suggestion of the expected benefice. The placebo effect may vary with complexity and repetition (conditioning) of the procedure. So, it is interesting to compare the efficacy of large-field rTMS and focal rTMS (more complexity in the procedure and often more sessions) in the same type of FNS. FW. In two papers, diagnostic use of single-pulse largefield TMS (for motor-evoked potential) led to recovery in 2 patients [9,14]. In our study [5], 89% of 70 patients improved with 1 or 2 sessions of large-field rTMS (30 or 60 pulses). In only one study, focal rTMS was used on 4 patients [22]. One session of stimulation (4000 pulses) was given by day during 1 to 4 weeks. Three patients improved. FMD. In one study, 75% of 22 patients improved with one session of large-field rTMS (20 pulses). In two studies, focal rTMS was used. A preliminary study suggested its efficiency in psychogenic tremor (one session of 30 pulses) [8]. However, a recent study [22] showed no efficacy of rTMS using stimulation under motor threshold in five patients with chronic PMDs (5 sessions for five consecutive day; no other details). In these studies, for the 2 types of FNS, the efficacy of large-field rTMS tended to be greater than with focal rTMS. Despite the high level of efficacy, controlled studies are mandatory with real sham procedure compared to the different protocols to assess the size of placebo effect.
According to these studies, the efficacy of large-field rTMS in different FNS seems very encouraging, with a better prognosis than the natural evolution as reported in the literature. The natural outcomes of FW, FMD and NES are often poor with significant related disability, similar to multiple sclerosis for FW, to neurodegenerative condition for FMD and
Cognitivo-behavioural effect? Psychotherapy is considered the mainstay of treatment for FNS but the number of appropriately powered studies in this area is small. Recently, a number of randomised controlled studies have provided Class 2—3 evidence of the effectiveness of such interventions for patients with FNS and PNES, at
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• one session the first and the second day after the communication of the diagnosis; • the sequence of the following sessions was dependant on evolution of the frequency of spells: ◦ 1o situation: prolonged disappearance (more than 2 months) of spells. A new session was performed if and when the spells recurred, ◦ 2o situation: there was no initial efficacy of rTMS or the spells recurred at a lower frequency. The sessions were repeated in the same order as frequency of spells with a maximum of eight sessions per month during 3o months.
Table 1 Statistical comparison between McKenzie et al. study and ours to evaluate the efficacy of large-field rTMS in NES (exact Fischer’s test; significant P < 0.05).
No (%) patients spell-free for 2 months at last visit No (%) patients with > 50% reduction in spell at last visit No (%) patients with > 50% increase in spell at last visit
Our study
McKenzie et al. study
P
34/42 (80%) 40/42 (90%) 0/42 (0%)
71/187 (38%) 114/187 (61%) 35/187 (18,7%)
< 10−6 < 10−4 < 0.001
Please cite this article in press as: Parain D, Chastan N. Large-field repetitive transcranial magnetic stimulation with NEUCLI 2441 1—7 circular coil in the treatment of functional neurological symptoms. Neurophysiologie Clinique/Clinical Neurophysiology (2014), http://dx.doi.org/10.1016/j.neucli.2014.04.004
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least in the short-term. Treatments have targeted a range of potentially modifiable factors, including illness perceptions, previous trauma and emotional processing or health utilisation behaviours. A randomized control trial (RCT) of a guided four-session self-help programme based on a cognitive behavioural therapy (CBT) [24] was conducted in 127 patients. The treatment effect was of moderate size with a 13% difference between treatment arms (usual care and usual care + CBT) in participants rating themselves as better or much better (P = 0.016). Another RCT in 66 patients with NES showed that the CBT group tended only to be more likely to have experienced 3 months of seizure freedom (P = 0.086). Large-field rTMS present a greater efficacy in FNS than CBT probably because this may provide a plausible treatment modality, satisfying the individual’s need, expectancy and changing the patient’s belief about their symptoms. In motor FNS, large-field rTMS may have a specific cognitivo-behavioural effect. Motor cortical stimulation produces transient movements that contrast to the deficit that characterises FW. Perception (which may be visual, somatosensory or even proprioceptive), by the patient, that symptom improvement is possible may influence regain of function. In their study, Garcin et al. [11] considered that movements induced by large-field rTMS altered FMD for a few seconds. Thereby, patients were able to discover for themselves the possibility of transiently modifying abnormal movement/posture. During the TMS session, one of the authors discussed this positive motor phenomenon and thereby provided synergistic psychological reinforcement. According to the authors, there might be a cognitive behavioural rather than placebo effect when patients see an unexpected alteration of their movement disorder. However, this analysis does not explain improvement in other FNS, such as FVL, FSL or the prophylactic effect in NES.
Neuromodulatory effect? The effects of focal rTMS are mediated by changes in cortical excitability and/or resultant changes in connectivity between brain areas. Results of functional imaging studies and analysis of network connectivity show that in the different types of FNS, there is, at variable degree, hyperactivity of limbic area, hypoactivity of some specific cortical areas and a decrease in connectivity, above all in the dorsal frontal area, perhaps indicating a decrease in frontal top-down control [31]. One study provides preliminary evidence favouring the hypothesis that normalizing the functional connectivity between the temporo-parietal and frontal brain regions may underlie the therapeutic effect of focal rTMS on auditory hallucinations in schizophrenia [12]. However, we currently have no data on the neuromodulatory effect of large-field rTMS. We consider that the repeated low-frequency large-field rTMS (below 1 Hz) used in these studies could not be responsible for stimulationinduced after effects because stimulation of the motor cortex at 0.1 Hz for 1 h did not change cortical excitability [7]. At 1 Hz, a minimum of 750 TMS pulses was needed to modulate motor-evoked potential amplitude, which is far above the total number of pulses delivered to the studied patients [30].
Conclusion According to the data from these different studies, largefield rTMS could be a new therapy for patients with FNS. This therapy, in our experience, is safe and positively impacted upon clinical management of these difficult-to-treat patients. We consider in the current state of knowledge that the beneficial effect of large-field rTMS might be due to a combination of suggestion/placebo/cognitivo-behavioral effect. Even if large-field rTMS exerts a therapeutic effect through non-neuromodulatory mechanisms, this does not mean that it is an inappropriate treatment for FNS.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
Acknowledgements The authors wish to thank Nikki Sabourin-Gibbs, Rouen University Hospital, for her help in editing the manuscript and Patrick Magnier for his technical assistance.
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Please cite this article in press as: Parain D, Chastan N. Large-field repetitive transcranial magnetic stimulation with NEUCLI 2441 1—7 circular coil in the treatment of functional neurological symptoms. Neurophysiologie Clinique/Clinical Neurophysiology (2014), http://dx.doi.org/10.1016/j.neucli.2014.04.004
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