- Email: [email protected]
Reduction of disease progression in a patient with amyotrophic lateral sclerosis after several years of epidural motor cortex stimulation
Accepted Manuscript Reduction of disease progression in a patient with amyotrophic lateral sclerosis after several years of epidural motor cortex stimulation Vincenzo Di Lazzaro, Giovanni Pellegrino, Fioravante Capone, Lucia Florio, Michele Dileone, Beatrice Cioni, Federico Ranieri PII:
S1935-861X(16)30313-8
DOI:
10.1016/j.brs.2016.11.012
Reference:
BRS 981
To appear in:
Brain Stimulation
Received Date: 2 November 2016 Revised Date:
12 November 2016
Accepted Date: 19 November 2016
Please cite this article as: Di Lazzaro V, Pellegrino G, Capone F, Florio L, Dileone M, Cioni B, Ranieri F, Reduction of disease progression in a patient with amyotrophic lateral sclerosis after several years of epidural motor cortex stimulation, Brain Stimulation (2016), doi: 10.1016/j.brs.2016.11.012. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Reduction of Disease Progression in a Patient with Amyotrophic Lateral Sclerosis after Several Years of
RI PT
Epidural Motor Cortex Stimulation Vincenzo Di Lazzaro,1,2 Giovanni Pellegrino,1,3, Fioravante Capone,1,2 Lucia Florio,1,2
SC
Michele Dileone,4 Beatrice Cioni,5 Federico Ranieri1,2
M AN U
1: Unit of Neurology, Neurophysiology, Neurobiology, Department of Medicine, Università Campus Bio-Medico di Roma, via Álvaro del Portillo 21, 00128 Rome, Italy 2: Fondazione Alberto Sordi - Research Institute for Ageing, Via Álvaro del Portillo 5, 00128 Rome
TE D
3: IRCCS, Fondazione Ospedale San Camillo, Venice, Italy
4: CINAC, HM Puerta del Sur, Hospitales de Madrid and CEU San Pablo University, Madrid, Spain
AC C
Correspondence to:
EP
5: Neurosurgery, Università Cattolica – Fondazione Policlinico Gemelli, Roma, Italy
Prof. Vincenzo Di Lazzaro
Unit of Neurology, Neurophysiology, Neurobiology, Department of Medicine, Università Campus Bio-Medico di Roma, via Álvaro del Portillo 21, 00128 Rome, Italy PHONE +3906225411320 FAX +3906225411936; email [email protected] Key words: Epidural motor cortex stimulation; Amyotrophic lateral sclerosis; Brain stimulation
1
ACCEPTED MANUSCRIPT Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no cure that affects motor neurons of the brain and spinal cord, and leads to death on average within 3 years of symptom onset. Cortical hyperexcitability to transcranial magnetic stimulation, possibly related to glutamate-mediated excitotoxicity, is an early feature of ALS that might
RI PT
trigger motor neuron degeneration [1]. Motor cortex excitability can be modulated using noninvasive (NIBS) brain stimulation techniques. This potential has led to several small studies evaluating NIBS as a non-pharmacological therapeutic approach in ALS, aimed at
SC
antagonizing excitoxicity related to enhanced glutamatergic transmission [2]. Earlier studies reported a slight reduction in disease progression but this was not confirmed by a subsequent
M AN U
study [2]. A main limitation of NIBS is that its after-effects are short-lived. Invasive motor cortex stimulation through implanted electrodes similarly to NIBS activates cortico-cortical circuits producing similar physiologic effects [3], but it offers the opportunity to perform stimulation chronically. The potential therapeutic role of invasive motor cortex stimulation in
TE D
ALS has been evaluated in four patients using subdural electrodes by Sidoti and Agrillo [4] and in a single patient by our group using epidural electrodes [5]. The patient in our study, a male surgeon who was 56 years old at the time of study, first manifested symptoms in
EP
September of 2004. We evaluated him for the first time in June 2006 and electrodes were implanted in August 2006 after a 2-month lead-in phase in order to evaluate disease
AC C
progression before electrode implantation (Figure 1). The epidural electrodes (Resume; Medtronic, Minneapolis, MN, USA) were implanted bilaterally over the motor cortex parallel to the central sulcus (motor hand knob) and connected to a Kinetra (Medtronic) neurostimulator placed in a subcutaneous subclavicular pocket. Disease progression was monitored with the revised ALS functional rating scale (ALSFRS-R). The patient was stimulated for 22 months 24 hours each day. The rate of progression before treatment was 1 point/month, suggesting an aggressive, rapidly progressive, form of ALS. This rate of progression continued over the following months during which several protocols of stimulation 2
ACCEPTED MANUSCRIPT with different frequencies and intensities were evaluated (3Hz/ 5V months 1-4, 30 Hz/5V in the following 8 months, 3 Hz/8V in the 10 months after that) (Figure 1). Twenty-two months after the beginning of stimulation, because of a respiratory crisis, tracheostomy was performed. We concluded that there was no consistent effect of stimulation on disease progression and decided to
RI PT
stop the stimulation and the follow-up publishing the negative result [5].
However, in October 2016 we were told by a patient’s neighbour that he was still alive and we decided to re-evaluate him. We learned that a few days after our last follow-up, the patient had
SC
restarted stimulation, with the same frequency of 3 Hz used in the last 10 months of stimulation but at lower intensity (4V) and only for 12 hours during the day, because he felt a relief from spasticity
M AN U
and, with the help of his relatives, he could turn off and on the stimulator using the patient programmer. Stimulation was maintained for one year and half until December 2009 when subjective benefits of the stimulation were no longer felt by the patient. He had been on tracheotomy ventilation only during sleep until June 2015, when continuous ventilation was
TE D
required, and he did not require insertion of a gastrostomy tube until March 2016, when his clinical condition deteriorated further because of two episodes of urinary tract Aspergillosis. ALSFRS-R score at this time was 3, corresponding to a mean of 0.1 points/month deterioration since the last
EP
evaluation performed in June 2008 (Figure 1). The patient lived at home, did no report depression and he had no cognitive impairment.
AC C
Because this is a single case study, no definite conclusion can be drawn and it should also be considered that tracheostomy with mechanical ventilation might have contributed to the long survival. Another limitation of present case report is that we did not evaluate the patient for eight years thus, we have no clear idea of the rate of progression during the period of self-managed stimulation and in the following period. However, considering that the rate of decline of ALS, as evaluated with ALSFRS-R, is approximately linear [6], that our patient had a rapidly progressive form of ALS, and that median ALS survival after tracheotomy is less than nine months [7], the fact that he is still alive 12 years after the first manifestation of the disease is quite surprising and 3
ACCEPTED MANUSCRIPT indicative of a change in disease progression that might be related to the about four years of chronic motor cortex stimulation. It is also unusual that a patient with a rapidly progressive form of ALS could survive for more than 10 years without continuous ventilatory support and without gastrostomy feeding. We cannot conclude that disease slowing was attributable to the stimulation
RI PT
also because this was performed only for about four years while the patient was still alive seven years after stopping it. Moreover, we cannot determine whether any positive effect was attributable to the low-intensity 12 hours/day stimulation started by the patient after the end of the observation
SC
or if it could be considered a delayed benefit of the whole period of stimulation. It could be speculated that low-intensity chronic epidural motor cortex stimulation could modulate
M AN U
glutamatergic neurotransmission, thus reducing glutamate excitotoxicity. According to the recently proposed hypothesis of prion-like mechanism in ALS [8], it could also be speculated that chronic subthreshold activation of cortical synapses might interfere with the spreading of motor neuronal death. Interestingly, a recent study using bilateral epidural motor cortex stimulation in a murine
TE D
model of ALS reported a significant increase in the survival period in the stimulated animals [9]. Though we cannot be sure whether the reduction in disease progression observed in our patient and the positive effects in two of the four patients reported by Sidoti and Agrillo [4] can be
EP
attributed to invasive chronic motor cortex stimulation, these observations might motivate possible future exploratory studies evaluating the effects of invasive motor cortex stimulation in ALS
AC C
patients. It should also be considered that in 2006 the available stimulators did not give the possibility of using more complex stimulation protocols, such as continuous theta burst stimulation. The latter has strong inhibitory effects on human cerebral cortex and was used in most of previous NIBS studies in ALS [2]. Recently new devices capable of delivering theta burst stimulation through implanted electrodes have been introduced. The use of this form of stimulation in a patient with essential tremor has already been shown to be more effective than previous protocols of high frequency stimulation [10] , thus, this approach might also be more effective in ALS patients.
4
ACCEPTED MANUSCRIPT Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
RI PT
Acknowledgments
AC C
EP
TE D
M AN U
SC
We are extremely grateful to our patient who made this observation possible.
5
ACCEPTED MANUSCRIPT References
[5]
[6]
[7]
[8]
[9]
[10]
RI PT
SC
M AN U
[4]
TE D
[3]
EP
[2]
Vucic S, Ziemann U, Eisen A, Hallett M, Kiernan MC. Transcranial magnetic stimulation and amyotrophic lateral sclerosis: pathophysiological insights. J Neurol Neurosurg Psychiatry 2013;84:1161-70 Lefaucheur JP, André-Obadia N, Antal A, Ayache SS, Baeken C, Benninger DH, Cantello RM, Cincotta M, de Carvalho M, De Ridder D, Devanne H, Di Lazzaro V, Filipović SR, Hummel FC, Jääskeläinen SK, Kimiskidis VK, Koch G, Langguth B, Nyffeler T, Oliviero A, Padberg F, Poulet E, Rossi S, Rossini PM, Rothwell JC, Schönfeldt-Lecuona C, Siebner HR, Slotema CW, Stagg CJ, Valls-Sole J, Ziemann U, Paulus W, Garcia-Larrea L. Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS). Clin Neurophysiol 2014;125:2150-206 Di Lazzaro V, Oliviero A, Pilato F, Saturno E, Dileone M, Meglio M, Cioni B, Papacci F, Tonali PA, Rothwell JC. Comparison of descending volleys evoked by transcranial and epidural motor cortex stimulation in a conscious patient with bulbar pain. Clin Neurophysiol 2004;115:834-8 Sidoti, C. and U. Agrillo. Chronic cortical stimulation for amyotropic lateral sclerosis: a report of four consecutive operated cases after a 2-year follow-up: technical case report. Neurosurgery 2006;58: E384. Di Lazzaro V, Dileone M, Pilato F, Profice P, Cioni B, Meglio M, Papacci F, Sabatelli M, Musumeci G, Ranieri F, Tonali PA. Long-term motor cortex stimulation for amyotrophic lateral sclerosis. Brain Stimul 2010;3:22-7 Traynor BJ, Zhang H, Shefner JM, Schoenfeld D, Cudkowicz ME; NEALS Consortium. Functional outcome measures as clinical trial endpoints in ALS. Neurology 2004; 63:19335 Chiò A, Calvo A, Ghiglione P, Mazzini L, Mutani R, Mora G; PARALS. Tracheostomy in amyotrophic lateral sclerosis: a 10-year population-based study in Italy. J Neurol Neurosurg Psychiatry 2010;81:1141-3 Braak H, Brettschneider J, Ludolph AC, Lee VM, Trojanowski JQ, Del Tredici K. Amyotrophic lateral sclerosis a model of corticofugal axonal spread. Nat Rev Neurol 2013; 9:708-14 Kim H, Kim HI, Kim YH, Kim SY, Shin YI. An animal study to examine the effects of the bilateral, epidural cortical stimulation on the progression of amyotrophic lateral sclerosis. J Neuroeng Rehabil 2014;11:139 Picillo M, Moro E, Edwards M, Di Lazzaro V, Lozano AM, Fasano A. Subdural Continuous Theta Burst Stimulation of the Motor Cortex in Essential Tremor. Brain Stimul 2015;8:840-2
AC C
[1]
6
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
S1935-861X(16)30313-8
DOI:
10.1016/j.brs.2016.11.012
Reference:
BRS 981
To appear in:
Brain Stimulation
Received Date: 2 November 2016 Revised Date:
12 November 2016
Accepted Date: 19 November 2016
Please cite this article as: Di Lazzaro V, Pellegrino G, Capone F, Florio L, Dileone M, Cioni B, Ranieri F, Reduction of disease progression in a patient with amyotrophic lateral sclerosis after several years of epidural motor cortex stimulation, Brain Stimulation (2016), doi: 10.1016/j.brs.2016.11.012. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Reduction of Disease Progression in a Patient with Amyotrophic Lateral Sclerosis after Several Years of
RI PT
Epidural Motor Cortex Stimulation Vincenzo Di Lazzaro,1,2 Giovanni Pellegrino,1,3, Fioravante Capone,1,2 Lucia Florio,1,2
SC
Michele Dileone,4 Beatrice Cioni,5 Federico Ranieri1,2
M AN U
1: Unit of Neurology, Neurophysiology, Neurobiology, Department of Medicine, Università Campus Bio-Medico di Roma, via Álvaro del Portillo 21, 00128 Rome, Italy 2: Fondazione Alberto Sordi - Research Institute for Ageing, Via Álvaro del Portillo 5, 00128 Rome
TE D
3: IRCCS, Fondazione Ospedale San Camillo, Venice, Italy
4: CINAC, HM Puerta del Sur, Hospitales de Madrid and CEU San Pablo University, Madrid, Spain
AC C
Correspondence to:
EP
5: Neurosurgery, Università Cattolica – Fondazione Policlinico Gemelli, Roma, Italy
Prof. Vincenzo Di Lazzaro
Unit of Neurology, Neurophysiology, Neurobiology, Department of Medicine, Università Campus Bio-Medico di Roma, via Álvaro del Portillo 21, 00128 Rome, Italy PHONE +3906225411320 FAX +3906225411936; email [email protected] Key words: Epidural motor cortex stimulation; Amyotrophic lateral sclerosis; Brain stimulation
1
ACCEPTED MANUSCRIPT Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no cure that affects motor neurons of the brain and spinal cord, and leads to death on average within 3 years of symptom onset. Cortical hyperexcitability to transcranial magnetic stimulation, possibly related to glutamate-mediated excitotoxicity, is an early feature of ALS that might
RI PT
trigger motor neuron degeneration [1]. Motor cortex excitability can be modulated using noninvasive (NIBS) brain stimulation techniques. This potential has led to several small studies evaluating NIBS as a non-pharmacological therapeutic approach in ALS, aimed at
SC
antagonizing excitoxicity related to enhanced glutamatergic transmission [2]. Earlier studies reported a slight reduction in disease progression but this was not confirmed by a subsequent
M AN U
study [2]. A main limitation of NIBS is that its after-effects are short-lived. Invasive motor cortex stimulation through implanted electrodes similarly to NIBS activates cortico-cortical circuits producing similar physiologic effects [3], but it offers the opportunity to perform stimulation chronically. The potential therapeutic role of invasive motor cortex stimulation in
TE D
ALS has been evaluated in four patients using subdural electrodes by Sidoti and Agrillo [4] and in a single patient by our group using epidural electrodes [5]. The patient in our study, a male surgeon who was 56 years old at the time of study, first manifested symptoms in
EP
September of 2004. We evaluated him for the first time in June 2006 and electrodes were implanted in August 2006 after a 2-month lead-in phase in order to evaluate disease
AC C
progression before electrode implantation (Figure 1). The epidural electrodes (Resume; Medtronic, Minneapolis, MN, USA) were implanted bilaterally over the motor cortex parallel to the central sulcus (motor hand knob) and connected to a Kinetra (Medtronic) neurostimulator placed in a subcutaneous subclavicular pocket. Disease progression was monitored with the revised ALS functional rating scale (ALSFRS-R). The patient was stimulated for 22 months 24 hours each day. The rate of progression before treatment was 1 point/month, suggesting an aggressive, rapidly progressive, form of ALS. This rate of progression continued over the following months during which several protocols of stimulation 2
ACCEPTED MANUSCRIPT with different frequencies and intensities were evaluated (3Hz/ 5V months 1-4, 30 Hz/5V in the following 8 months, 3 Hz/8V in the 10 months after that) (Figure 1). Twenty-two months after the beginning of stimulation, because of a respiratory crisis, tracheostomy was performed. We concluded that there was no consistent effect of stimulation on disease progression and decided to
RI PT
stop the stimulation and the follow-up publishing the negative result [5].
However, in October 2016 we were told by a patient’s neighbour that he was still alive and we decided to re-evaluate him. We learned that a few days after our last follow-up, the patient had
SC
restarted stimulation, with the same frequency of 3 Hz used in the last 10 months of stimulation but at lower intensity (4V) and only for 12 hours during the day, because he felt a relief from spasticity
M AN U
and, with the help of his relatives, he could turn off and on the stimulator using the patient programmer. Stimulation was maintained for one year and half until December 2009 when subjective benefits of the stimulation were no longer felt by the patient. He had been on tracheotomy ventilation only during sleep until June 2015, when continuous ventilation was
TE D
required, and he did not require insertion of a gastrostomy tube until March 2016, when his clinical condition deteriorated further because of two episodes of urinary tract Aspergillosis. ALSFRS-R score at this time was 3, corresponding to a mean of 0.1 points/month deterioration since the last
EP
evaluation performed in June 2008 (Figure 1). The patient lived at home, did no report depression and he had no cognitive impairment.
AC C
Because this is a single case study, no definite conclusion can be drawn and it should also be considered that tracheostomy with mechanical ventilation might have contributed to the long survival. Another limitation of present case report is that we did not evaluate the patient for eight years thus, we have no clear idea of the rate of progression during the period of self-managed stimulation and in the following period. However, considering that the rate of decline of ALS, as evaluated with ALSFRS-R, is approximately linear [6], that our patient had a rapidly progressive form of ALS, and that median ALS survival after tracheotomy is less than nine months [7], the fact that he is still alive 12 years after the first manifestation of the disease is quite surprising and 3
ACCEPTED MANUSCRIPT indicative of a change in disease progression that might be related to the about four years of chronic motor cortex stimulation. It is also unusual that a patient with a rapidly progressive form of ALS could survive for more than 10 years without continuous ventilatory support and without gastrostomy feeding. We cannot conclude that disease slowing was attributable to the stimulation
RI PT
also because this was performed only for about four years while the patient was still alive seven years after stopping it. Moreover, we cannot determine whether any positive effect was attributable to the low-intensity 12 hours/day stimulation started by the patient after the end of the observation
SC
or if it could be considered a delayed benefit of the whole period of stimulation. It could be speculated that low-intensity chronic epidural motor cortex stimulation could modulate
M AN U
glutamatergic neurotransmission, thus reducing glutamate excitotoxicity. According to the recently proposed hypothesis of prion-like mechanism in ALS [8], it could also be speculated that chronic subthreshold activation of cortical synapses might interfere with the spreading of motor neuronal death. Interestingly, a recent study using bilateral epidural motor cortex stimulation in a murine
TE D
model of ALS reported a significant increase in the survival period in the stimulated animals [9]. Though we cannot be sure whether the reduction in disease progression observed in our patient and the positive effects in two of the four patients reported by Sidoti and Agrillo [4] can be
EP
attributed to invasive chronic motor cortex stimulation, these observations might motivate possible future exploratory studies evaluating the effects of invasive motor cortex stimulation in ALS
AC C
patients. It should also be considered that in 2006 the available stimulators did not give the possibility of using more complex stimulation protocols, such as continuous theta burst stimulation. The latter has strong inhibitory effects on human cerebral cortex and was used in most of previous NIBS studies in ALS [2]. Recently new devices capable of delivering theta burst stimulation through implanted electrodes have been introduced. The use of this form of stimulation in a patient with essential tremor has already been shown to be more effective than previous protocols of high frequency stimulation [10] , thus, this approach might also be more effective in ALS patients.
4
ACCEPTED MANUSCRIPT Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
RI PT
Acknowledgments
AC C
EP
TE D
M AN U
SC
We are extremely grateful to our patient who made this observation possible.
5
ACCEPTED MANUSCRIPT References
[5]
[6]
[7]
[8]
[9]
[10]
RI PT
SC
M AN U
[4]
TE D
[3]
EP
[2]
Vucic S, Ziemann U, Eisen A, Hallett M, Kiernan MC. Transcranial magnetic stimulation and amyotrophic lateral sclerosis: pathophysiological insights. J Neurol Neurosurg Psychiatry 2013;84:1161-70 Lefaucheur JP, André-Obadia N, Antal A, Ayache SS, Baeken C, Benninger DH, Cantello RM, Cincotta M, de Carvalho M, De Ridder D, Devanne H, Di Lazzaro V, Filipović SR, Hummel FC, Jääskeläinen SK, Kimiskidis VK, Koch G, Langguth B, Nyffeler T, Oliviero A, Padberg F, Poulet E, Rossi S, Rossini PM, Rothwell JC, Schönfeldt-Lecuona C, Siebner HR, Slotema CW, Stagg CJ, Valls-Sole J, Ziemann U, Paulus W, Garcia-Larrea L. Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS). Clin Neurophysiol 2014;125:2150-206 Di Lazzaro V, Oliviero A, Pilato F, Saturno E, Dileone M, Meglio M, Cioni B, Papacci F, Tonali PA, Rothwell JC. Comparison of descending volleys evoked by transcranial and epidural motor cortex stimulation in a conscious patient with bulbar pain. Clin Neurophysiol 2004;115:834-8 Sidoti, C. and U. Agrillo. Chronic cortical stimulation for amyotropic lateral sclerosis: a report of four consecutive operated cases after a 2-year follow-up: technical case report. Neurosurgery 2006;58: E384. Di Lazzaro V, Dileone M, Pilato F, Profice P, Cioni B, Meglio M, Papacci F, Sabatelli M, Musumeci G, Ranieri F, Tonali PA. Long-term motor cortex stimulation for amyotrophic lateral sclerosis. Brain Stimul 2010;3:22-7 Traynor BJ, Zhang H, Shefner JM, Schoenfeld D, Cudkowicz ME; NEALS Consortium. Functional outcome measures as clinical trial endpoints in ALS. Neurology 2004; 63:19335 Chiò A, Calvo A, Ghiglione P, Mazzini L, Mutani R, Mora G; PARALS. Tracheostomy in amyotrophic lateral sclerosis: a 10-year population-based study in Italy. J Neurol Neurosurg Psychiatry 2010;81:1141-3 Braak H, Brettschneider J, Ludolph AC, Lee VM, Trojanowski JQ, Del Tredici K. Amyotrophic lateral sclerosis a model of corticofugal axonal spread. Nat Rev Neurol 2013; 9:708-14 Kim H, Kim HI, Kim YH, Kim SY, Shin YI. An animal study to examine the effects of the bilateral, epidural cortical stimulation on the progression of amyotrophic lateral sclerosis. J Neuroeng Rehabil 2014;11:139 Picillo M, Moro E, Edwards M, Di Lazzaro V, Lozano AM, Fasano A. Subdural Continuous Theta Burst Stimulation of the Motor Cortex in Essential Tremor. Brain Stimul 2015;8:840-2
AC C
[1]
6
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT