- Email: [email protected]
Direct Current Motor Cortex Stimulation for Amyotrophic Lateral Sclerosis: A Proof of Principle Study
Brain Stimulation 6 (2013) 969e976
Contents lists available at ScienceDirect
Brain Stimulation journal homepage: www.brainstimjrnl.com
Letters to the Editor
Direct Current Motor Cortex Stimulation for Amyotrophic Lateral Sclerosis: A Proof of Principle Study Cortical hyperexcitability to transcranial magnetic stimulation (TMS) is an early feature of amyotrophic lateral sclerosis (ALS) and it has been suggested that it might trigger motor neuron degeneration [1]. Circuits of human motor cortex can be modulated non-invasively using repetitive transcranial magnetic stimulation (rTMS) and this technique has potential therapeutic effects in several neurological disorders including ALS [2]. The effects of rTMS in ALS patients were evaluated in several small/ proof of principle studies [3e6]. While some of the studies [4e6] reported some benefit, another study [3] reported that there was no significant difference between rTMS-treated and placebo-treated patients. The results of these studies were analyzed in a systematic Cochrane review [7] that concluded that there is currently insufficient evidence to draw conclusions about the efficacy and safety of rTMS in the treatment of ALS and that further studies may be helpful to explore the potential benefit of brain stimulation in ALS. One of the main problems in the therapeutical use of rTMS is that the effects on cortical excitability are short lived making its potential limited [2]. More prolonged effects on cortical excitability can be obtained by transcranial direct current stimulation (tDCS) [8]. Cathodal tDCS can suppress cortical excitability for several hours [9]. In this proof of principle study, we evaluated the effects of cathodal tDCS on disease progression in two ALS patients. The study was approved by the local ethics committee and patients gave their written informed consent before participation. The first patient was a 46 year-old male with clear clinical upper and lower motor neuron signs and a diagnosis of probable ALS according to the El Escorial revised criteria [10], disease duration from first symptom was 12 months. The second patient was a 72 year-old male with clear clinical upper and lower motor neuron signs and a diagnosis of definite ALS, disease duration from first symptom was 22 months. Both patients were observed for 1 month before starting cathodal tDCS, we compared the rate of progression of the disease before and during the period of cortical stimulation using the revised ALS functional rating scale (ALSFRS-R). Patient 1 was treated for 12 months (12 cycles of tDCS), patient 2 was treated with a single cycle of cathodal tDCS, because about 1 month after the end of first cycle he died for an ALS related cause (respiratory failure). TDCS was applied by a battery-driven constant-current stimulator (Eldith - NeuroConn GmbH, Ilmenau, Germany) via
1935-861X/$ e see front matter Ó 2013 Elsevier Inc. All rights reserved.
conductive-rubber electrodes, placed in two saline-soaked sponges (5 7 cm), with cathode positioned over the optimal cortical representation of the first dorsal interosseus muscle (FDI), as revealed by TMS, and the anode electrode above the contralateral orbit. This montage has been shown to be most effective in modulating corticospinal excitability of primary motor cortex [2]. DC polarity refers to the electrode over the primary motor cortex. In all subjects tDCS was given with an intensity of 1 mA for 20 min for each hemisphere. Right and left hemispheres were stimulated consecutively. The current was ramped up or down over the first and last 10 s of stimulation, respectively, in order to avoid retinal phosphenes [8]. During DC stimulation constant-current output was monitored by a built-in ampere-meter. We stimulated first the right and then the left motor cortex. Patients were evaluated one month before starting treatment and then every month. Patient 1 The monthly rate of progression before treatment was 1.0 points/month (initial ALSFRS-R score ¼ 45); after the beginning of treatment the monthly rate of progression remained 1.0 points/ month in the following 12 months. Patient 2 The monthly rate of progression before treatment was 4.0 points/month (initial ALSFRS-R score ¼ 38). Only one cycle of stimulation was performed in this patient because the disease progressed rapidly in the month following the stimulation and the patient died due respiratory failure. Before discussing the significance of present findings we should consider the limitation of our data set: we treated only two patients and the second patient had only one cycle of stimulation, thus no definite conclusion can be drawn from present results. However, because the rate of decline of ALS, as evaluated with ALSFRS-R, is approximately linear it is possible to speculate on the effects of treatment by comparing the rate of progression observed before and after the beginning of motor cortex stimulation. In the first patient we observed no consistent change in disease progression after the beginning of treatment that was performed monthly for one year. The second patient, had a rapid progression of the disease after the first cycle of stimulation and died due to a respiratory failure about one month later. It should be considered that he showed a rapid disease progression even before starting the treatment, thus this might not represent an adverse effect from tDCS.
970
Letters to the Editor / Brain Stimulation 6 (2013) 969e976
In conclusion, even though further studies are needed to evaluate the efficacy and safety of tDCS on ALS progression, present proof of principle study suggests that this treatment might not be effective. This work was supported by the Ministero della Salute (Ricerca finalizzata Bando 2007 e Repetitive transcranial magnetic stimulation as novel therapeutic approach for amyotrophic lateral sclerosis e Regione Abruzzo).
Vincenzo Di Lazzaro*, Federico Ranieri, Fioravante Capone, Gabriella Musumeci Institute of Neurology, Campus Bio-Medico University Rome, Italy Fondazione Alberto Sordi e Research Institute for Ageing Rome, Italy Michele Dileone Institute of Neurology, Campus Bio-Medico University Rome, Italy Neuroscience Department, San Bortolo Hospital Vicenza, Italy * Corresponding
author. Istituto di Neurologia, Università Campus Bio-Medico, Via Alvaro del Portillo 200, 00128 Rome, Italy. Tel.: þ39 06 225411220. E-mail address: [email protected] (V. Di Lazzaro) Received 27 June 2013 Available online 1 August 2013
http://dx.doi.org/10.1016/j.brs.2013.06.005
References [1] Vucic S, Ziemann U, Eisen A, Hallett M, Kiernan MC. Transcranial magnetic stimulation and amyotrophic lateral sclerosis: pathophysiological insights. Journal of Neurology, Neurosurgery, and Psychiatry; 2012 Dec 21. http://dx. doi.org/10.1136/jnnp-2012-304019. [2] Ridding MC, Rothwell JC. Is there a future for therapeutic use of transcranial magnetic stimulation? Nature Reviews Neuroscience 2007;8(7):559e67. PubMed PMID: 17565358. [3] Di Lazzaro V, Pilato F, Profice P, Ranieri F, Musumeci G, Florio L, et al. Motor cortex stimulation for ALS: a double blind placebo-controlled study. Neuroscience Letters 2009;464(1):18e21. PubMed PMID: 19682544. [4] Di Lazzaro V, Dileone M, Pilato F, Profice P, Cioni B, Meglio M, et al. Long-term motor cortex stimulation for amyotrophic lateral sclerosis. Brain Stimulation 2010;3(1):22e7. PubMed PMID: 20633427. [5] Zanette G, Forgione A, Manganotti P, Fiaschi A, Tamburin S. The effect of repetitive transcranial magnetic stimulation on motor performance, fatigue and quality of life in amyotrophic lateral sclerosis. Journal of the Neurological Sciences 2008;270(1e2):18e22. PubMed PMID: 18304580. [6] Di Lazzaro V, Dileone M, Pilato F, Profice P, Ranieri F, Musumeci G, et al. Repetitive transcranial magnetic stimulation for ALS. A preliminary controlled study. Neuroscience Letters 2006;408(2):135e40. PubMed PMID: 16979292. [7] Fang J, Zhou M, Yang M, Zhu C, He L. Repetitive transcranial magnetic stimulation for the treatment of amyotrophic lateral sclerosis or motor neuron disease. Cochrane Database of Systematic Reviews 2013;5:CD008554. PubMed PMID: 23728676. [8] Nitsche MA, Cohen LG, Wassermann EM, Priori A, Lang N, Antal A, et al. Transcranial direct current stimulation: state of the art 2008. Brain Stimulation 2008;1(3):206e23. PubMed PMID: 20633386. [9] Di Lazzaro V, Manganelli F, Dileone M, Notturno F, Esposito M, Capasso M, et al. The effects of prolonged cathodal direct current stimulation on the excitatory and inhibitory circuits of the ipsilateral and contralateral motor cortex. Journal of Neural Transmission 2012;119(12):1499e506. PubMed PMID: 22711234. [10] Brooks BR, Miller RG, Swash M, Munsat TL, World Federation of Neurology Research Group on Motor Neuron D. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders 2000;1(5):293e9. PubMed PMID: 11464847.
A Non-Epileptiform Event in the Course of rTMS: A Case for Close Physician Monitoring Dear Editor: We present the following case to demonstrate the importance of having physician supervision of patients undergoing repetitive transcranial magnetic stimulation (rTMS) treatments. The patient was a married 60-year-old male with a diagnosis of Major Depressive Disorder and Generalized Anxiety Disorder who had continuous symptoms of depression since the early 1980s despite receiving at least 7 adequate antidepressant treatments. The patient had several comorbid medical conditions. The patient did not have any previous history of seizure, stroke, an abnormal EEG, head injury, neurosurgical procedure, implanted devices, frequent headaches, or a neurologic illness. In addition, there was no family history of epilepsy. The patient’s medications included bupropion XL 300 mg, diazepam 10 mg every 8 hours as needed for anxiety, rosuvastatin, lisinopril, rosiglitazone/metformin, finasteride, ranitidine, and vitamins. The patient’s level of depression was moderate with a Quick Inventory of Depressive Symptoms e Self Rated (QIDS-SR) [1] score of 12 and significant impairment in work and social functioning. The patient was treated with the NeuroStar System (Neuronetics, Malvern, PA). After determining the motor threshold (MT) of 1.05 Standard Units, the coil was positioned over the left prefrontal cortex (5.5 cm rule). The treatment parameters were 10 Hz with 4 s on and 26 s off at 120% MT. The patient was not able to tolerate 120% MT or 110% MT, but did tolerate 100% MT. He underwent 4 treatments of 75 trains (3000 pulses) without incident. On the fifth day of treatment, the patient was having considerable difficulty with “worrying,” but no change in medications, sleep, or medical status. After the 19th train, the patient was witnessed to experience a bilateral rhythmic shaking of upper and lower extremities and did not verbally respond to questions. The rTMS treater immediately aborted the treatment by turning off the coil and moving it away from the patient. The covering physician was alerted, and he responded in a matter of seconds. After observing the patient’s movements, the physician was not convinced that it was an epileptic seizure. The physician asked the patient to squeeze his hand. The patient immediately squeezed his hand. This was done 3 times over the approximately 30 s that the event lasted. After the movements subsided, the patient could immediately verbally respond to questions. The patient was alert and oriented to person, place, date, and time. He reported that he had squeezed the physician’s hand three times and could remember the entire event. The patient described it as a panic attack but with a feeling of depression instead of panic. He reported that he sometimes has these events when he is feeling especially depressed. He never lost consciousness, was incontinent, bit his tongue, or had any other sequela. The rTMS treatment was stopped for the day. The physician determined that this episode was a non-epileptiform event based on responsiveness during episode despite bilateral movements, no post-event cognitive changes, and complete memory of events during the episode. The patient was monitored for approximately an hour and then he was allowed to go home without incident. The patient returned the following day and elected to continue rTMS. The patient subsequently underwent 20 additional treatments using the same rTMS parameters without any further incidents. The patient experienced a very robust response and reached remission (QIDS-SR 3) that included a significant improvement in work and social functioning. The patient was followed clinically for 6 months and he maintained his wellness and did not have
Contents lists available at ScienceDirect
Brain Stimulation journal homepage: www.brainstimjrnl.com
Letters to the Editor
Direct Current Motor Cortex Stimulation for Amyotrophic Lateral Sclerosis: A Proof of Principle Study Cortical hyperexcitability to transcranial magnetic stimulation (TMS) is an early feature of amyotrophic lateral sclerosis (ALS) and it has been suggested that it might trigger motor neuron degeneration [1]. Circuits of human motor cortex can be modulated non-invasively using repetitive transcranial magnetic stimulation (rTMS) and this technique has potential therapeutic effects in several neurological disorders including ALS [2]. The effects of rTMS in ALS patients were evaluated in several small/ proof of principle studies [3e6]. While some of the studies [4e6] reported some benefit, another study [3] reported that there was no significant difference between rTMS-treated and placebo-treated patients. The results of these studies were analyzed in a systematic Cochrane review [7] that concluded that there is currently insufficient evidence to draw conclusions about the efficacy and safety of rTMS in the treatment of ALS and that further studies may be helpful to explore the potential benefit of brain stimulation in ALS. One of the main problems in the therapeutical use of rTMS is that the effects on cortical excitability are short lived making its potential limited [2]. More prolonged effects on cortical excitability can be obtained by transcranial direct current stimulation (tDCS) [8]. Cathodal tDCS can suppress cortical excitability for several hours [9]. In this proof of principle study, we evaluated the effects of cathodal tDCS on disease progression in two ALS patients. The study was approved by the local ethics committee and patients gave their written informed consent before participation. The first patient was a 46 year-old male with clear clinical upper and lower motor neuron signs and a diagnosis of probable ALS according to the El Escorial revised criteria [10], disease duration from first symptom was 12 months. The second patient was a 72 year-old male with clear clinical upper and lower motor neuron signs and a diagnosis of definite ALS, disease duration from first symptom was 22 months. Both patients were observed for 1 month before starting cathodal tDCS, we compared the rate of progression of the disease before and during the period of cortical stimulation using the revised ALS functional rating scale (ALSFRS-R). Patient 1 was treated for 12 months (12 cycles of tDCS), patient 2 was treated with a single cycle of cathodal tDCS, because about 1 month after the end of first cycle he died for an ALS related cause (respiratory failure). TDCS was applied by a battery-driven constant-current stimulator (Eldith - NeuroConn GmbH, Ilmenau, Germany) via
1935-861X/$ e see front matter Ó 2013 Elsevier Inc. All rights reserved.
conductive-rubber electrodes, placed in two saline-soaked sponges (5 7 cm), with cathode positioned over the optimal cortical representation of the first dorsal interosseus muscle (FDI), as revealed by TMS, and the anode electrode above the contralateral orbit. This montage has been shown to be most effective in modulating corticospinal excitability of primary motor cortex [2]. DC polarity refers to the electrode over the primary motor cortex. In all subjects tDCS was given with an intensity of 1 mA for 20 min for each hemisphere. Right and left hemispheres were stimulated consecutively. The current was ramped up or down over the first and last 10 s of stimulation, respectively, in order to avoid retinal phosphenes [8]. During DC stimulation constant-current output was monitored by a built-in ampere-meter. We stimulated first the right and then the left motor cortex. Patients were evaluated one month before starting treatment and then every month. Patient 1 The monthly rate of progression before treatment was 1.0 points/month (initial ALSFRS-R score ¼ 45); after the beginning of treatment the monthly rate of progression remained 1.0 points/ month in the following 12 months. Patient 2 The monthly rate of progression before treatment was 4.0 points/month (initial ALSFRS-R score ¼ 38). Only one cycle of stimulation was performed in this patient because the disease progressed rapidly in the month following the stimulation and the patient died due respiratory failure. Before discussing the significance of present findings we should consider the limitation of our data set: we treated only two patients and the second patient had only one cycle of stimulation, thus no definite conclusion can be drawn from present results. However, because the rate of decline of ALS, as evaluated with ALSFRS-R, is approximately linear it is possible to speculate on the effects of treatment by comparing the rate of progression observed before and after the beginning of motor cortex stimulation. In the first patient we observed no consistent change in disease progression after the beginning of treatment that was performed monthly for one year. The second patient, had a rapid progression of the disease after the first cycle of stimulation and died due to a respiratory failure about one month later. It should be considered that he showed a rapid disease progression even before starting the treatment, thus this might not represent an adverse effect from tDCS.
970
Letters to the Editor / Brain Stimulation 6 (2013) 969e976
In conclusion, even though further studies are needed to evaluate the efficacy and safety of tDCS on ALS progression, present proof of principle study suggests that this treatment might not be effective. This work was supported by the Ministero della Salute (Ricerca finalizzata Bando 2007 e Repetitive transcranial magnetic stimulation as novel therapeutic approach for amyotrophic lateral sclerosis e Regione Abruzzo).
Vincenzo Di Lazzaro*, Federico Ranieri, Fioravante Capone, Gabriella Musumeci Institute of Neurology, Campus Bio-Medico University Rome, Italy Fondazione Alberto Sordi e Research Institute for Ageing Rome, Italy Michele Dileone Institute of Neurology, Campus Bio-Medico University Rome, Italy Neuroscience Department, San Bortolo Hospital Vicenza, Italy * Corresponding
author. Istituto di Neurologia, Università Campus Bio-Medico, Via Alvaro del Portillo 200, 00128 Rome, Italy. Tel.: þ39 06 225411220. E-mail address: [email protected] (V. Di Lazzaro) Received 27 June 2013 Available online 1 August 2013
http://dx.doi.org/10.1016/j.brs.2013.06.005
References [1] Vucic S, Ziemann U, Eisen A, Hallett M, Kiernan MC. Transcranial magnetic stimulation and amyotrophic lateral sclerosis: pathophysiological insights. Journal of Neurology, Neurosurgery, and Psychiatry; 2012 Dec 21. http://dx. doi.org/10.1136/jnnp-2012-304019. [2] Ridding MC, Rothwell JC. Is there a future for therapeutic use of transcranial magnetic stimulation? Nature Reviews Neuroscience 2007;8(7):559e67. PubMed PMID: 17565358. [3] Di Lazzaro V, Pilato F, Profice P, Ranieri F, Musumeci G, Florio L, et al. Motor cortex stimulation for ALS: a double blind placebo-controlled study. Neuroscience Letters 2009;464(1):18e21. PubMed PMID: 19682544. [4] Di Lazzaro V, Dileone M, Pilato F, Profice P, Cioni B, Meglio M, et al. Long-term motor cortex stimulation for amyotrophic lateral sclerosis. Brain Stimulation 2010;3(1):22e7. PubMed PMID: 20633427. [5] Zanette G, Forgione A, Manganotti P, Fiaschi A, Tamburin S. The effect of repetitive transcranial magnetic stimulation on motor performance, fatigue and quality of life in amyotrophic lateral sclerosis. Journal of the Neurological Sciences 2008;270(1e2):18e22. PubMed PMID: 18304580. [6] Di Lazzaro V, Dileone M, Pilato F, Profice P, Ranieri F, Musumeci G, et al. Repetitive transcranial magnetic stimulation for ALS. A preliminary controlled study. Neuroscience Letters 2006;408(2):135e40. PubMed PMID: 16979292. [7] Fang J, Zhou M, Yang M, Zhu C, He L. Repetitive transcranial magnetic stimulation for the treatment of amyotrophic lateral sclerosis or motor neuron disease. Cochrane Database of Systematic Reviews 2013;5:CD008554. PubMed PMID: 23728676. [8] Nitsche MA, Cohen LG, Wassermann EM, Priori A, Lang N, Antal A, et al. Transcranial direct current stimulation: state of the art 2008. Brain Stimulation 2008;1(3):206e23. PubMed PMID: 20633386. [9] Di Lazzaro V, Manganelli F, Dileone M, Notturno F, Esposito M, Capasso M, et al. The effects of prolonged cathodal direct current stimulation on the excitatory and inhibitory circuits of the ipsilateral and contralateral motor cortex. Journal of Neural Transmission 2012;119(12):1499e506. PubMed PMID: 22711234. [10] Brooks BR, Miller RG, Swash M, Munsat TL, World Federation of Neurology Research Group on Motor Neuron D. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders 2000;1(5):293e9. PubMed PMID: 11464847.
A Non-Epileptiform Event in the Course of rTMS: A Case for Close Physician Monitoring Dear Editor: We present the following case to demonstrate the importance of having physician supervision of patients undergoing repetitive transcranial magnetic stimulation (rTMS) treatments. The patient was a married 60-year-old male with a diagnosis of Major Depressive Disorder and Generalized Anxiety Disorder who had continuous symptoms of depression since the early 1980s despite receiving at least 7 adequate antidepressant treatments. The patient had several comorbid medical conditions. The patient did not have any previous history of seizure, stroke, an abnormal EEG, head injury, neurosurgical procedure, implanted devices, frequent headaches, or a neurologic illness. In addition, there was no family history of epilepsy. The patient’s medications included bupropion XL 300 mg, diazepam 10 mg every 8 hours as needed for anxiety, rosuvastatin, lisinopril, rosiglitazone/metformin, finasteride, ranitidine, and vitamins. The patient’s level of depression was moderate with a Quick Inventory of Depressive Symptoms e Self Rated (QIDS-SR) [1] score of 12 and significant impairment in work and social functioning. The patient was treated with the NeuroStar System (Neuronetics, Malvern, PA). After determining the motor threshold (MT) of 1.05 Standard Units, the coil was positioned over the left prefrontal cortex (5.5 cm rule). The treatment parameters were 10 Hz with 4 s on and 26 s off at 120% MT. The patient was not able to tolerate 120% MT or 110% MT, but did tolerate 100% MT. He underwent 4 treatments of 75 trains (3000 pulses) without incident. On the fifth day of treatment, the patient was having considerable difficulty with “worrying,” but no change in medications, sleep, or medical status. After the 19th train, the patient was witnessed to experience a bilateral rhythmic shaking of upper and lower extremities and did not verbally respond to questions. The rTMS treater immediately aborted the treatment by turning off the coil and moving it away from the patient. The covering physician was alerted, and he responded in a matter of seconds. After observing the patient’s movements, the physician was not convinced that it was an epileptic seizure. The physician asked the patient to squeeze his hand. The patient immediately squeezed his hand. This was done 3 times over the approximately 30 s that the event lasted. After the movements subsided, the patient could immediately verbally respond to questions. The patient was alert and oriented to person, place, date, and time. He reported that he had squeezed the physician’s hand three times and could remember the entire event. The patient described it as a panic attack but with a feeling of depression instead of panic. He reported that he sometimes has these events when he is feeling especially depressed. He never lost consciousness, was incontinent, bit his tongue, or had any other sequela. The rTMS treatment was stopped for the day. The physician determined that this episode was a non-epileptiform event based on responsiveness during episode despite bilateral movements, no post-event cognitive changes, and complete memory of events during the episode. The patient was monitored for approximately an hour and then he was allowed to go home without incident. The patient returned the following day and elected to continue rTMS. The patient subsequently underwent 20 additional treatments using the same rTMS parameters without any further incidents. The patient experienced a very robust response and reached remission (QIDS-SR 3) that included a significant improvement in work and social functioning. The patient was followed clinically for 6 months and he maintained his wellness and did not have