- Email: [email protected]
Long-term motor cortex stimulation for amyotrophic lateral sclerosis
Brain Stimulation (2010) 3, 22–7
www.brainstimjrnl.com
Long-term motor cortex stimulation for amyotrophic lateral sclerosis Vincenzo Di Lazzaro,a,b Michele Dileone,a,b Fabio Pilato,a Paolo Profice,a Beatrice Cioni,c Mario Meglio,c Fabio Papacci,c Mario Sabatelli,a Gabriella Musumeci,a Federico Ranieri,a Pietro A. Tonalia,b a
Institute of Neurology, Universita` Cattolica, L.go A. Gemelli 8, 00168 Rome, Italy Fondazione Don C. Gnocchi, Roma. Italy c Institute of Neurosurgery, Universita` Cattolica, L.go A. Gemelli 8, 00168 Rome, Italy b
Background Motor cortex stimulation has been proposed for treatment of amyotrophic lateral sclerosis (ALS) and preliminary studies have reported a slight reduction of disease progression using both invasive and noninvasive repetitive stimulation of the motor cortex. Objective The aim of this proof of principle study was to investigate the effects of motor cortex stimulation performed for a prolonged period (about 2 years) on ALS progression. Methods Two patients were included in the study; the first patient was treated with monthly cycles of repetitive transcranial magnetic stimulation (rTMS) and the second one was treated with chronic epidural motor cortex stimulation. The rate of progression of the disease before and during treatment was compared. Results The treatments were well tolerated by the patients. Both patients deteriorated during treatment; however, the patient treated with rTMS showed a slight reduction in deterioration rate. Conclusions Although we cannot be sure whether the effects observed in the patient treated with rTMS can be attributed to this form of stimulation, our study set the groundwork for possible future studies investigating the effects of rTMS, for a prolonged period, on a larger group of ALS patients. Ó 2010 Elsevier Inc. All rights reserved.
This work was supported by the Ministero della Salute (Ricerca finalizzata Bando 2007-Repetitive transcranial magnetic stimulation as novel therapeutic approach for amyotrophic lateral sclerosis-Regione Abruzzo). Correspondence: Dr. Vincenzo Di Lazzaro, Istituto di Neurologia, Universita` Cattolica, L.go A. Gemelli 8, 00168 Rome, Italy.
1935-861X/10/$ -see front matter Ó 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.brs.2009.04.004
E-mail address: [email protected] Submitted November 11, 2008; revised March 27, 2009. Accepted for publication April 22, 2009.
Motor cortex stimulation for ALS Keywords
23
ALS; motor cortex; epidural motor cortex stimulation; transcranial magnetic stimulation
Glutamate-mediated excitotoxicity has been proposed as one of the possible mechanisms involved in selective motor neuron degeneration in amyotrophic lateral sclerosis (ALS).1,2 Glutamatergic circuits of human motor cortex can be activated and modulated noninvasively by using repetitive transcranial magnetic stimulation (rTMS).3 This technique has potential therapeutic effects in several neurologic diseases, including ALS.4 Two preliminary studies showed that rTMS protocols, reducing cortical excitability, cause a slight slowing in ALS progression.5,6 It has been suggested that the beneficial effect of rTMS on disease progression could be related to a diminution of glutamate-driven excitotoxicity.7 The potential therapeutic role of motor cortex stimulation in ALS has been supported by another study that used invasive chronic motor cortex stimulation through subdural electrodes.8 Invasive motor cortex stimulation, usually with epidural electrodes, has been performed with encouraging results in a large number of patients with drug-resistant chronic neurogenic pain9 and, more recently, in patients with Parkinson’s disease.10,11 The physiologic effects of TMS and those of epidural motor cortex stimulation (EMCS) are similar in that both may activate corticospinal cells trans-synaptically,12 and may modulate the excitability of these cells when given repeatedly. However, electrical motor cortex stimulation through implanted electrodes has a substantial advantage because it can be performed chronically, whereas rTMS can be performed only in electrophysiologic laboratories and its effects are short lived.4 The results of the preliminary studies on motor cortex stimulation in ALS warrant further controlled studies in a larger number of patients. However, because it is still undefined whether any benefit of cortical stimulation is maintained over a prolonged period of stimulation, it would be useful to explore first the effects of a prolonged treatment with both rTMS and EMCS. In this proof of principle study, we evaluated the effects of long-term cortical stimulation on disease progression in two patients with ALS. Both patients were treated for approximately 2 years. The first patient was treated with rTMS using a novel paradigm of stimulation termed ‘‘continuous theta burst stimulation’’ (cTBS),13,14 and the second one was treated with EMCS.
Patients The study was approved by the ethics committee of the Medical Faculty of the Catholic University in Rome, and the patients gave their written informed consent before participation. The two patients, not included in previous studies, had
a diagnosis of definite ALS according to the El Escorial revised criteria15 with clear clinical upper and lower motor neuron signs. Both patients were taking riluzole. The first patient, a 72-year-old female owner of a coffee factory, started to present dysphagia and dysarthria in February 2005. At baseline evaluation 12 months after the beginning of symptoms, she presented slight weakness of right proximal upper limb muscles and of left lower limb muscles, tongue atrophy, fasciculations in shoulder girdle muscles and in the tongue, right Babinski sign, and the neurophysiologic testing revealed denervation in the tongue and in the lower limbs. This patient was treated with noninvasive stimulation, she was observed for 2 months before starting treatment and then treated for 26 months (26 cycles of cTBS). The treatment was stopped because of a hip fracture caused by an accidental fall. At this time, the patient still did not require ventilatory support, tracheotomy, and percutaneous endoscopic gastrostomy. The second patient, a 56-year-old male surgeon, started to present lower limb weakness, manifesting as difficulty with walking and lower limb fasciculations in September 2004. At baseline evaluation 22 months after the beginning of symptoms, he presented spastic paraparesis, fasciculations in the tongue and in upper and lower limb muscles, dysarthria, tongue atrophy, bilateral Babinski sign, and the neurophysiologic testing revealed denervation in the tongue and in the upper and lower limb muscles. This patient was treated with invasive stimulation, he was observed for 2 months before starting treatment and then was chronically treated for 22 months, at this time the patient needed ventilatory support and underwent tracheotomy; the stimulation was stopped.
Motor cortex stimulation Transcranial motor cortex stimulation To monitor upper motor neuron function during the treatment, we calculated central motor conduction time using TMS before starting the treatment and after 1 and 2 years of treatment. Motor-evoked potentials (MEPs) were recorded from the biceps, first dorsal interosseous, and tibialis anterior muscles. Central motor conduction time (CMCT) was calculated by subtracting the peripheral conduction time, from spinal cord to muscles, from the latency of responses evoked by cortical stimulation at the maximum stimulator output during voluntary contraction at about 20% of maximum. We also calculated the average change of tibialis anterior CMCT per month, to compare the changes observed in our patient with the reported mean CMCT changes over time.16 This study was performed only in the patient treated with the noninvasive stimulation
24 because magnetic stimulation was contraindicated in the patient with the implanted neurostimulator.
Repetitive motor cortex stimulation Repetitive TMS was applied over the motor cortex using a MagPro (Medtronic A/S, Copenhagen, Denmark) stimulator. Motor cortex of each side was stimulated for 5 consecutive days every month using the cTBS pattern in which three pulses of stimulation are given at 50 Hz, repeated every 200 milliseconds for a total of 600 pulses.13 We used a butterfly coil (MCF-B-65) with the handle pointed posteriorly and approximately perpendicular to the central sulcus. The initial direction of the current induced in the brain was posterior-anterior. The stimulation intensity was 80% of the active motor threshold, defined as the minimum single-pulse intensity required to produce a MEP greater than 200 mV on more than five of 10 trials from the contracted contralateral first interosseous muscle. This protocol leads to pronounced and prolonged suppression of cortical excitability.13,14 Repetitive TMS was performed bilaterally. The order of stimulation of the two hemispheres was changed each month. The stimulation of the two hemispheres was performed sequentially at an interval of 1 minute. The motor cortex of each side was stimulated for 5 consecutive days every month.
EMCS The epidural electrodes were implanted bilaterally over the motor cortex. The electrode strips (Resume; Medtronic, Minneapolis, Minnesota) consisted of four contacts (0-3) of 4 mm in diameter, each separated by 1 cm. The electrodes were implanted parallel to the so-called motor hand knob. The implant of the strip electrode (Resume, Medtronic) was performed under general intravenous anesthesia (propofol and remifentanyl), avoiding muscle relaxant after intubation. Craniometer landmarks and neuronavigation were used for surgical planning: the expected motor cortex was marked on the scalp and the epidural electrode was implanted through a burr hole or a small craniotomy. The neurophysiologic localization of the multicontact electrode included the phase reversal technique to identify the central sulcus, and the MEPs to map the motor cortex. Somatosensory potentials evoked by the stimulation of the contralateral median nerve were recorded directly from the cortex through the strip electrode: the cortical N20 potential was recorded from the sensory cortex, whereas a mirror image (P20) was recorded from the motor cortex. Motor potentials were evoked by direct cortical anodal stimulation through the single contacts of the plate electrode using train of 35 stimuli, 0.5 millisecond, ISI 4 milliseconds, up to 30 mA and the muscle responses were recorded from muscles of upper and lower extremities. The implanted electrodes were connected to a Kinetra (Medtronic) neurostimulator placed in a subcutaneous
Di Lazzaro et al subclavicular pocket. This stimulator does not give the possibility to use protocols in which differing interstimulus interval are used, such as TBS, but can only deliver repetitive stimuli spaced apart by identical interstimulus intervals. Thus, we did not have the possibility to use the same protocol used for transcranial stimulation. Our first study suggests that protocols of stimulation decreasing cortical excitability can produce a slight reduction in disease progression,5 thus we first tried protocols of stimulation aimed at reducing cortical excitability. When using rTMS, it is well known that low-frequency stimulation reduces cortical excitability.17,18 Because EMCS and TMS may activate similarly populations of cortical neurons,12 we decided to stimulate the motor cortex at low frequency (3 Hz). The lowest frequency that can be obtained with the neurostimulator is 2 Hz; however, we used 3 Hz because at this frequency the patient reported a subjective reduction of spasticity during the trial screening period in the first days after the implantation. We planned to use different frequencies of stimulation in case of no change or of an increase in the disease progression after an appropriate period of observation. The minimum period of observation was at least 3 months because our previous study suggests that changes in disease progression may become evident after 3 months of treatment.6 Because the previous study that used invasive motor cortex stimulation in ALS reported beneficial effects with stimulation at a frequency of 30 Hz,8 we planned to evaluate the effects of this frequency of stimulation as alternative treatment. An intensity of stimulation below the active motor threshold (5-8 V), was used. Stimulation was performed with a bipolar montage (0-3) for 1 hour twice daily.
Disease progression We compared the rate of progression of the disease before and during the period of cortical stimulation using the revised ALS functional rating scale-revised (ALSFRSR). Patients were evaluated 2 months before starting treatment and every month until the end of the study. At each visit, patients were evaluated using the ALSFRS-R.
Results The monthly rate of progression before and after the beginning of treatment for both patients is reported in Figure 1.
Patient 1 (noninvasive motor cortex stimulation) The monthly rate of progression before treatment was 1 point/month; after the beginning of treatment the monthly
Motor cortex stimulation for ALS
25
Figure 1 Monthly rate of disease progression as evaluated with the revised ALS functional rating scale-revised (ALSFRS-R) before and after the beginning of motor cortex stimulation treatment (arrows) in the two patients. The rate of progression is slower than that evaluated before treatment in the patient who underwent transcranial motor cortex stimulation, with a more pronounced change in the first 12 months. No consistent change is observed in the patient treated with epidural motor cortex stimulation.
rate of progression was reduced to 0.4 points/month in the next 26 months. In the first year, it was 0.2 points/month, whereas in the next 14 months, it was 0.6 points/month. At baseline, CMCT was prolonged for the right tibialis anterior muscle and within normal limits for the remaining muscles. After 1 year of treatment, CMCT was abnormal also for the right biceps muscle. In the last control, 2 years after the beginning of treatment, CMCT was abnormal for all the studied muscles. The average increase of tibialis anterior CMCT was 0.3% per month for the first year and 1.3% per month for the second year.
Patient 2 (invasive motor cortex stimulation) The monthly rate of progression before treatment was 1 point/month.
Treatment First period of low-frequency EMCS (3Hz/5V) This protocol was used for the first 4 months. During this period the disease progression remained substantially
unchanged with a monthly rate of 1.3 points. Because of this, we decided to change the protocol of stimulation with a frequency of 30 Hz as performed by Sidoti et al.8 30Hz EMCS (5V) This protocol was used for the next 8 months. During this period, the disease progression remained unchanged with a monthly rate of 1.1 points. For this reason we decided to again use low-frequency stimulation at slightly higher intensity. Second period of low-frequency EMCS (3Hz/8V) This protocol was used for 10 months. The disease progression was not modified with a monthly rate of 0.9 points. At this time, because of the absence of any consistent effect of epidural stimulation, we planned to explore the effects of a third protocol of stimulation at 80 Hz. This protocol was specifically developed for epidural stimulation for the treatment of Parkinson’s disease.19,20 However, this was not possible, because after a few weeks the patient required tracheotomy and ventilatory support.
26
Discussion Before discussing the significance of current findings, it would be circumspect to describe the limitations of our dataset. First, we treated only two patients and thus no definite conclusion can be drawn from these results. Second, the main hypothesis of our study is that glutamate-driven excitotoxicity is fundamental in ALS progression. However, this is only one of the putative mechanisms that should be considered in addition to oxidative damage, accumulation of intracellular aggregates, mitochondrial dysfunction, defects in axonal transport, growth factor deficiency, aberrant RNA metabolism, and glial cell disease.2 Third, even though the role of glutamate excitotoxicity seems to be confirmed in human studies by increased levels of glutamate in the cerebrospinal fluid21 and by the evidence of a selective loss of glial glutamate transporter in ALS patients,22 the therapeutic efficacy of strategies aimed at reducing glutamate excitotoxicity is mainly supported by animal studies. It should be considered that many therapeutic approaches targeting the glutamate system, such as the calcium channel blockers verapamil and nimodipine, the voltage-gated calcium channel blocker lamotrigine, the N-methyl-D-aspartate (NMDA) receptor antagonist dextromethorphan, and the AMPA/kainate glutamate receptor antagonist topiramate, failed to slow the disease progression in patients with ALS.23 Also, a large number of trials that were based on different strategies that used neurotrophic and antiapoptotic compounds in an animal model of ALS have failed in ALS.24 The recent lesson from the minocycline trial in ALS confirms the complexity of translational neuroscience.25 This trial, based on a Nature article26 reporting effects of minocycline in an animal model showed an enhanced deterioration in the treated group.25 We treated only two patients, however, because the rate of decline of ALS, as evaluated with ALSFRS-R, is approximately linear.27 It is possible to obtain some information on the effects of treatment by comparing the rate of progression observed before and after the beginning of motor cortex stimulation. The long-term transcranial stimulation that uses the cTBS protocol suggests that this treatment might produce a slight reduction of disease progression. In the first year, after the beginning of treatment the rate of ALSFRS-R decline for the patient treated with noninvasive stimulation was 0.8 units per month slower than before the treatment. In the next 14 months, the rate of ALSFRS-R decline tended to increase. This suggests that the slight tendency to a reduction of disease progression might be more pronounced in the first year. The reduction in the rate of decline for the first year after the beginning of cTBS was clearly greater than the mean change in the rate of decline (0.23 units per month) between the prerandomization and postrandomization phases for the placebo group reported in
Di Lazzaro et al a study evaluating the effects of minocycline in ALS.25 However, the ALSFRS-R might not show a linear decline in all ALS patients,25 and the reduction in disease progression might also be explained by a spontaneous change in the decline rate in our patient. Interestingly, the average increase of tibialis anterior CMCT that was 0.3% per month for the first year and 1.3% per month for the second year was, for the first year, below the average value of 0.9% increase per month reported in a previous study.16 However, this finding should be considered with caution because there is no general agreement on the usefulness of electrophysiologic measures of central motor function for monitoring ALS patients in clinical trial settings.28 Toxicity to glutamate in motor neurons is mediated principally by non-NMDA receptor subtype.29 Because the non-NMDA glutamatergic connections of the motor cortex can be activated by TMS,3 and cTBS produces long-lasting changes in motor cortex excitability, it can be hypothesized that the slight change in disease progression observed in our patient might be related to the long-lasting changes in glutamatergic neurotransmission of the motor cortex induced by cTBS. The suppression of motor cortex excitability in ALS patients could possibly reduce the excessive activation of glutamate receptors of corticospinal cells in ALS patients thus reducing glutamatergic excitotoxicity. It should be considered that both of our patients have been treated with the glutamate-modulating therapeutic agent riluzole and that this drug may affect the excitability of the motor cortex.30-35 Riluzole reduces intracortical facilitation to paired-pulse stimulation in control subjects.32,33 The effects of riluzole on cortical excitability were also evaluated in ALS patients.30,31,34,35 Interestingly, in these patients there is an hyperecitability of the motor cortex at least in part related to an impaired function of inhibitory interneuronal circuits.30,36,37 This cortical hyperexcitability can be reversed by riluzole.31,35 Thus, in our patients, riluzole might have interfered with the effects of cortical stimulation by reducing or inhibiting its effect. Although cTBS treatment was well tolerated by the patient and we observed no side effect, further studies in a larger number of patients are required to evaluate whether prolonged rTMS is safe in ALS. In the patient treated with EMCS, we observed no consistent change even with the use of the protocol of stimulation that has been reported to produce a positive effect in two of four patients treated by Sidoti et al.8 It should be considered that at present the available stimulators do not give the possibility to use complex protocols of stimulation thus the results are not directly comparable with those observed with rTMS. However, in our opinion, before using EMCS for ALS, it could be useful to study more patients with noninvasive stimulation to evaluate whether the benefit of cortical stimulation is confirmed in a larger number of patients and also to define the best protocol of stimulation. It might also be useful to develop new devices for the stimulation through epidural electrodes
Motor cortex stimulation for ALS capable of delivering more complex patterns of stimulation, such as TBS. In conclusion, though we cannot be sure whether the slight reduction in disease progression observed in our patient who underwent rTMS can be attributed to this treatment, this study set the groundwork for possible future studies evaluating the effects of prolonged repetitive motor cortex stimulation on disease progression in ALS patients.
References 1. Rowland LP, Shneider NA. Amyotrophic lateral sclerosis. N Engl J Med 2001;344:1688-1700. 2. Rothstein JD. Current hypotheses for the underlying biology of amyotrophic lateral sclerosis. Ann Neurol 2009;65(Suppl 1):S3-S9. 3. Di Lazzaro V, Oliviero A, Profice P, et al. Ketamine increases human motor cortex excitability to transcranial magnetic stimulation. J Physiol 2003;547:485-496. 4. Ridding MC, Rothwell JC. Is there a future for therapeutic use of transcranial magnetic stimulation? Nature Rev 2007;8:559-567. 5. Di Lazzaro V, Oliviero A, Saturno E, et al. Motor cortex stimulation for amyotrophic lateral sclerosis: time for a therapeutic trial? Clin Neurophysiol 2004;115:1479-1485. 6. Di Lazzaro V, Dileone M, Pilato F, et al. Repetitive transcranial magnetic stimulation for ALS. A preliminary controlled study. Neurosci Lett 2006;408:135-140. 7. Ziemann U, Eisen A. TMS for ALS: why and why not. Clin Neurophysiol 2004;115:1237-1238. 8. Sidoti C, Agrillo U. 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; discussion E384. 9. Drouot X, Nguyen JP, Peschanski M, Lefaucheur JP. The antalgic efficacy of chronic motor cortex stimulation is related to sensory changes in the painful zone. Brain 2002;125:1660-1664. 10. Canavero S, Bonicalzi V, Paolotti R, et al. Therapeutic extradural cortical stimulation for movement disorders: a review. Neurol Res 2003;25:118-122. 11. Lefaucheur JP. Principles of therapeutic use of transcranial and epidural cortical stimulation. Clin Neurophysiol 2008;119:2179-2184. 12. Di Lazzaro V, Oliviero A, Pilato F, et al. Comparison of descending volleys evoked by transcranial and epidural motor cortex stimulation in a conscious patient with bulbar pain. Clin Neurophysiol 2004; 115:834-838. 13. Huang YZ, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC. Theta burst stimulation of the human motor cortex. Neuron 2005;45:201-206. 14. Di Lazzaro V, Pilato F, Saturno E, et al. Theta-burst repetitive transcranial magnetic stimulation suppresses specific excitatory circuits in the human motor cortex. J Physiol 2005;565:945-950. 15. Brooks BR, Miller RG, Swash M, Munsat TL. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 2000;1:293-299. 16. Floyd AG, Yu QP, Piboolnurak P, et al. Transcranial magnetic stimulation in ALS: utility of central motor conduction tests. Neurology 2009;72: 498-504. 17. Chen R, Classen J, Gerloff C, et al. Depression of motor cortex excitability by low-frequency transcranial magnetic stimulation. Neurology 1997;48:1398-1403.
27 18. Di Lazzaro V, Pilato F, Dileone M, et al. Low-frequency repetitive transcranial magnetic stimulation suppresses specific excitatory circuits in the human motor cortex. J Physiol 2008;586:4481-4487. 19. Cioni B. Motor cortex stimulation for Parkinson’s disease. Acta Neurochir Suppl 2007;97:233-238. 20. Cioni B, Meglio M, Perotti V, De Bonis P, Montano N. Neurophysiological aspects of chronic motor cortex stimulation. Neurophysiol Clin 2007;37:441-447. 21. Rothstein JD, Tsai G, Kuncl RW, et al. Abnormal excitatory amino acid metabolism in amyotrophic lateral sclerosis. Ann Neurol 1990; 28:18-25. 22. Rothstein JD, Van Kammen M, Levey AI, Martin LJ, Kuncl RW. Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol 1995;38:73-84. 23. Brooks BR. Managing amyotrophic lateral sclerosis: slowing disease progression and improving patient quality of life. Ann Neurol 2009; 65(Suppl 1):S17-S23. 24. de Carvalho M, Costa J, Swash M. Clinical trials in ALS: a review of the role of clinical and neurophysiological measurements. Amyotroph Lateral Scler Other Motor Neuron Disord 2005;6:202-212. 25. Gordon PH, Moore DH, Miller RG, et al. Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. Lancet Neurol 2007;6:1045-1053. 26. Zhu S, Stavrovskaya IG, Drozda M, et al. Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature 2002;417:74-78. 27. Traynor BJ, Zhang H, Shefner JM, Schoenfeld D, Cudkowicz ME. Functional outcome measures as clinical trial endpoints in ALS. Neurology 2004;63:1933-1935. 28. Mills KR. The natural history of central motor abnormalities in amyotrophic lateral sclerosis. Brain 2003;126:2558-2566. 29. Rothstein JD, Martin LJ, Kuncl RW. Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis. N Engl J Med 1992;326:1464-1468. 30. Caramia MD, Palmieri MG, Desiato MT, et al. Pharmacologic reversal of cortical hyperexcitability in patients with ALS. Neurology 2000;54: 58-64. 31. Desiato MT, Palmieri MG, Giacomini P, Scalise A, Arciprete F, Caramia MD. The effect of riluzole in amyotrophic lateral sclerosis: a study with cortical stimulation. J Neurol Sci 1999;169:98-107. 32. Liepert J, Schwenkreis P, Tegenthoff M, Malin JP. The glutamate antagonist riluzole suppresses intracortical facilitation. J Neural Transm 1997;104:1207-1214. 33. Schwenkreis P, Liepert J, Witscher K, et al. Riluzole suppresses motor cortex facilitation in correlation to its plasma level: a study using transcranial magnetic stimulation. Exp Brain Res 2000;135:293-299. 34. Sommer M, Tergau F, Wischer S, Reimers CD, Beuche W, Paulus W. Riluzole does not have an acute effect on motor thresholds and the intracortical excitability in amyotrophic lateral sclerosis. J Neurol 1999; 246(Suppl 3):III22-III26. 35. Stefan K, Kunesch E, Benecke R, Classen J. Effects of riluzole on cortical excitability in patients with amyotrophic lateral sclerosis. Ann Neurol 2001;49:536-539. 36. Ziemann U, Winter M, Reimers CD, Reimers K, Tergau F, Paulus W. Impaired motor cortex inhibition in patients with amyotrophic lateral sclerosis: evidence from paired transcranial magnetic stimulation. Neurology 1997;49:1292-1298. 37. Vucic S, Kiernan MC. Novel threshold tracking techniques suggest that cortical hyperexcitability is an early feature of motor neuron disease. Brain 2006;129:2436-2446.
www.brainstimjrnl.com
Long-term motor cortex stimulation for amyotrophic lateral sclerosis Vincenzo Di Lazzaro,a,b Michele Dileone,a,b Fabio Pilato,a Paolo Profice,a Beatrice Cioni,c Mario Meglio,c Fabio Papacci,c Mario Sabatelli,a Gabriella Musumeci,a Federico Ranieri,a Pietro A. Tonalia,b a
Institute of Neurology, Universita` Cattolica, L.go A. Gemelli 8, 00168 Rome, Italy Fondazione Don C. Gnocchi, Roma. Italy c Institute of Neurosurgery, Universita` Cattolica, L.go A. Gemelli 8, 00168 Rome, Italy b
Background Motor cortex stimulation has been proposed for treatment of amyotrophic lateral sclerosis (ALS) and preliminary studies have reported a slight reduction of disease progression using both invasive and noninvasive repetitive stimulation of the motor cortex. Objective The aim of this proof of principle study was to investigate the effects of motor cortex stimulation performed for a prolonged period (about 2 years) on ALS progression. Methods Two patients were included in the study; the first patient was treated with monthly cycles of repetitive transcranial magnetic stimulation (rTMS) and the second one was treated with chronic epidural motor cortex stimulation. The rate of progression of the disease before and during treatment was compared. Results The treatments were well tolerated by the patients. Both patients deteriorated during treatment; however, the patient treated with rTMS showed a slight reduction in deterioration rate. Conclusions Although we cannot be sure whether the effects observed in the patient treated with rTMS can be attributed to this form of stimulation, our study set the groundwork for possible future studies investigating the effects of rTMS, for a prolonged period, on a larger group of ALS patients. Ó 2010 Elsevier Inc. All rights reserved.
This work was supported by the Ministero della Salute (Ricerca finalizzata Bando 2007-Repetitive transcranial magnetic stimulation as novel therapeutic approach for amyotrophic lateral sclerosis-Regione Abruzzo). Correspondence: Dr. Vincenzo Di Lazzaro, Istituto di Neurologia, Universita` Cattolica, L.go A. Gemelli 8, 00168 Rome, Italy.
1935-861X/10/$ -see front matter Ó 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.brs.2009.04.004
E-mail address: [email protected] Submitted November 11, 2008; revised March 27, 2009. Accepted for publication April 22, 2009.
Motor cortex stimulation for ALS Keywords
23
ALS; motor cortex; epidural motor cortex stimulation; transcranial magnetic stimulation
Glutamate-mediated excitotoxicity has been proposed as one of the possible mechanisms involved in selective motor neuron degeneration in amyotrophic lateral sclerosis (ALS).1,2 Glutamatergic circuits of human motor cortex can be activated and modulated noninvasively by using repetitive transcranial magnetic stimulation (rTMS).3 This technique has potential therapeutic effects in several neurologic diseases, including ALS.4 Two preliminary studies showed that rTMS protocols, reducing cortical excitability, cause a slight slowing in ALS progression.5,6 It has been suggested that the beneficial effect of rTMS on disease progression could be related to a diminution of glutamate-driven excitotoxicity.7 The potential therapeutic role of motor cortex stimulation in ALS has been supported by another study that used invasive chronic motor cortex stimulation through subdural electrodes.8 Invasive motor cortex stimulation, usually with epidural electrodes, has been performed with encouraging results in a large number of patients with drug-resistant chronic neurogenic pain9 and, more recently, in patients with Parkinson’s disease.10,11 The physiologic effects of TMS and those of epidural motor cortex stimulation (EMCS) are similar in that both may activate corticospinal cells trans-synaptically,12 and may modulate the excitability of these cells when given repeatedly. However, electrical motor cortex stimulation through implanted electrodes has a substantial advantage because it can be performed chronically, whereas rTMS can be performed only in electrophysiologic laboratories and its effects are short lived.4 The results of the preliminary studies on motor cortex stimulation in ALS warrant further controlled studies in a larger number of patients. However, because it is still undefined whether any benefit of cortical stimulation is maintained over a prolonged period of stimulation, it would be useful to explore first the effects of a prolonged treatment with both rTMS and EMCS. In this proof of principle study, we evaluated the effects of long-term cortical stimulation on disease progression in two patients with ALS. Both patients were treated for approximately 2 years. The first patient was treated with rTMS using a novel paradigm of stimulation termed ‘‘continuous theta burst stimulation’’ (cTBS),13,14 and the second one was treated with EMCS.
Patients The study was approved by the ethics committee of the Medical Faculty of the Catholic University in Rome, and the patients gave their written informed consent before participation. The two patients, not included in previous studies, had
a diagnosis of definite ALS according to the El Escorial revised criteria15 with clear clinical upper and lower motor neuron signs. Both patients were taking riluzole. The first patient, a 72-year-old female owner of a coffee factory, started to present dysphagia and dysarthria in February 2005. At baseline evaluation 12 months after the beginning of symptoms, she presented slight weakness of right proximal upper limb muscles and of left lower limb muscles, tongue atrophy, fasciculations in shoulder girdle muscles and in the tongue, right Babinski sign, and the neurophysiologic testing revealed denervation in the tongue and in the lower limbs. This patient was treated with noninvasive stimulation, she was observed for 2 months before starting treatment and then treated for 26 months (26 cycles of cTBS). The treatment was stopped because of a hip fracture caused by an accidental fall. At this time, the patient still did not require ventilatory support, tracheotomy, and percutaneous endoscopic gastrostomy. The second patient, a 56-year-old male surgeon, started to present lower limb weakness, manifesting as difficulty with walking and lower limb fasciculations in September 2004. At baseline evaluation 22 months after the beginning of symptoms, he presented spastic paraparesis, fasciculations in the tongue and in upper and lower limb muscles, dysarthria, tongue atrophy, bilateral Babinski sign, and the neurophysiologic testing revealed denervation in the tongue and in the upper and lower limb muscles. This patient was treated with invasive stimulation, he was observed for 2 months before starting treatment and then was chronically treated for 22 months, at this time the patient needed ventilatory support and underwent tracheotomy; the stimulation was stopped.
Motor cortex stimulation Transcranial motor cortex stimulation To monitor upper motor neuron function during the treatment, we calculated central motor conduction time using TMS before starting the treatment and after 1 and 2 years of treatment. Motor-evoked potentials (MEPs) were recorded from the biceps, first dorsal interosseous, and tibialis anterior muscles. Central motor conduction time (CMCT) was calculated by subtracting the peripheral conduction time, from spinal cord to muscles, from the latency of responses evoked by cortical stimulation at the maximum stimulator output during voluntary contraction at about 20% of maximum. We also calculated the average change of tibialis anterior CMCT per month, to compare the changes observed in our patient with the reported mean CMCT changes over time.16 This study was performed only in the patient treated with the noninvasive stimulation
24 because magnetic stimulation was contraindicated in the patient with the implanted neurostimulator.
Repetitive motor cortex stimulation Repetitive TMS was applied over the motor cortex using a MagPro (Medtronic A/S, Copenhagen, Denmark) stimulator. Motor cortex of each side was stimulated for 5 consecutive days every month using the cTBS pattern in which three pulses of stimulation are given at 50 Hz, repeated every 200 milliseconds for a total of 600 pulses.13 We used a butterfly coil (MCF-B-65) with the handle pointed posteriorly and approximately perpendicular to the central sulcus. The initial direction of the current induced in the brain was posterior-anterior. The stimulation intensity was 80% of the active motor threshold, defined as the minimum single-pulse intensity required to produce a MEP greater than 200 mV on more than five of 10 trials from the contracted contralateral first interosseous muscle. This protocol leads to pronounced and prolonged suppression of cortical excitability.13,14 Repetitive TMS was performed bilaterally. The order of stimulation of the two hemispheres was changed each month. The stimulation of the two hemispheres was performed sequentially at an interval of 1 minute. The motor cortex of each side was stimulated for 5 consecutive days every month.
EMCS The epidural electrodes were implanted bilaterally over the motor cortex. The electrode strips (Resume; Medtronic, Minneapolis, Minnesota) consisted of four contacts (0-3) of 4 mm in diameter, each separated by 1 cm. The electrodes were implanted parallel to the so-called motor hand knob. The implant of the strip electrode (Resume, Medtronic) was performed under general intravenous anesthesia (propofol and remifentanyl), avoiding muscle relaxant after intubation. Craniometer landmarks and neuronavigation were used for surgical planning: the expected motor cortex was marked on the scalp and the epidural electrode was implanted through a burr hole or a small craniotomy. The neurophysiologic localization of the multicontact electrode included the phase reversal technique to identify the central sulcus, and the MEPs to map the motor cortex. Somatosensory potentials evoked by the stimulation of the contralateral median nerve were recorded directly from the cortex through the strip electrode: the cortical N20 potential was recorded from the sensory cortex, whereas a mirror image (P20) was recorded from the motor cortex. Motor potentials were evoked by direct cortical anodal stimulation through the single contacts of the plate electrode using train of 35 stimuli, 0.5 millisecond, ISI 4 milliseconds, up to 30 mA and the muscle responses were recorded from muscles of upper and lower extremities. The implanted electrodes were connected to a Kinetra (Medtronic) neurostimulator placed in a subcutaneous
Di Lazzaro et al subclavicular pocket. This stimulator does not give the possibility to use protocols in which differing interstimulus interval are used, such as TBS, but can only deliver repetitive stimuli spaced apart by identical interstimulus intervals. Thus, we did not have the possibility to use the same protocol used for transcranial stimulation. Our first study suggests that protocols of stimulation decreasing cortical excitability can produce a slight reduction in disease progression,5 thus we first tried protocols of stimulation aimed at reducing cortical excitability. When using rTMS, it is well known that low-frequency stimulation reduces cortical excitability.17,18 Because EMCS and TMS may activate similarly populations of cortical neurons,12 we decided to stimulate the motor cortex at low frequency (3 Hz). The lowest frequency that can be obtained with the neurostimulator is 2 Hz; however, we used 3 Hz because at this frequency the patient reported a subjective reduction of spasticity during the trial screening period in the first days after the implantation. We planned to use different frequencies of stimulation in case of no change or of an increase in the disease progression after an appropriate period of observation. The minimum period of observation was at least 3 months because our previous study suggests that changes in disease progression may become evident after 3 months of treatment.6 Because the previous study that used invasive motor cortex stimulation in ALS reported beneficial effects with stimulation at a frequency of 30 Hz,8 we planned to evaluate the effects of this frequency of stimulation as alternative treatment. An intensity of stimulation below the active motor threshold (5-8 V), was used. Stimulation was performed with a bipolar montage (0-3) for 1 hour twice daily.
Disease progression We compared the rate of progression of the disease before and during the period of cortical stimulation using the revised ALS functional rating scale-revised (ALSFRSR). Patients were evaluated 2 months before starting treatment and every month until the end of the study. At each visit, patients were evaluated using the ALSFRS-R.
Results The monthly rate of progression before and after the beginning of treatment for both patients is reported in Figure 1.
Patient 1 (noninvasive motor cortex stimulation) The monthly rate of progression before treatment was 1 point/month; after the beginning of treatment the monthly
Motor cortex stimulation for ALS
25
Figure 1 Monthly rate of disease progression as evaluated with the revised ALS functional rating scale-revised (ALSFRS-R) before and after the beginning of motor cortex stimulation treatment (arrows) in the two patients. The rate of progression is slower than that evaluated before treatment in the patient who underwent transcranial motor cortex stimulation, with a more pronounced change in the first 12 months. No consistent change is observed in the patient treated with epidural motor cortex stimulation.
rate of progression was reduced to 0.4 points/month in the next 26 months. In the first year, it was 0.2 points/month, whereas in the next 14 months, it was 0.6 points/month. At baseline, CMCT was prolonged for the right tibialis anterior muscle and within normal limits for the remaining muscles. After 1 year of treatment, CMCT was abnormal also for the right biceps muscle. In the last control, 2 years after the beginning of treatment, CMCT was abnormal for all the studied muscles. The average increase of tibialis anterior CMCT was 0.3% per month for the first year and 1.3% per month for the second year.
Patient 2 (invasive motor cortex stimulation) The monthly rate of progression before treatment was 1 point/month.
Treatment First period of low-frequency EMCS (3Hz/5V) This protocol was used for the first 4 months. During this period the disease progression remained substantially
unchanged with a monthly rate of 1.3 points. Because of this, we decided to change the protocol of stimulation with a frequency of 30 Hz as performed by Sidoti et al.8 30Hz EMCS (5V) This protocol was used for the next 8 months. During this period, the disease progression remained unchanged with a monthly rate of 1.1 points. For this reason we decided to again use low-frequency stimulation at slightly higher intensity. Second period of low-frequency EMCS (3Hz/8V) This protocol was used for 10 months. The disease progression was not modified with a monthly rate of 0.9 points. At this time, because of the absence of any consistent effect of epidural stimulation, we planned to explore the effects of a third protocol of stimulation at 80 Hz. This protocol was specifically developed for epidural stimulation for the treatment of Parkinson’s disease.19,20 However, this was not possible, because after a few weeks the patient required tracheotomy and ventilatory support.
26
Discussion Before discussing the significance of current findings, it would be circumspect to describe the limitations of our dataset. First, we treated only two patients and thus no definite conclusion can be drawn from these results. Second, the main hypothesis of our study is that glutamate-driven excitotoxicity is fundamental in ALS progression. However, this is only one of the putative mechanisms that should be considered in addition to oxidative damage, accumulation of intracellular aggregates, mitochondrial dysfunction, defects in axonal transport, growth factor deficiency, aberrant RNA metabolism, and glial cell disease.2 Third, even though the role of glutamate excitotoxicity seems to be confirmed in human studies by increased levels of glutamate in the cerebrospinal fluid21 and by the evidence of a selective loss of glial glutamate transporter in ALS patients,22 the therapeutic efficacy of strategies aimed at reducing glutamate excitotoxicity is mainly supported by animal studies. It should be considered that many therapeutic approaches targeting the glutamate system, such as the calcium channel blockers verapamil and nimodipine, the voltage-gated calcium channel blocker lamotrigine, the N-methyl-D-aspartate (NMDA) receptor antagonist dextromethorphan, and the AMPA/kainate glutamate receptor antagonist topiramate, failed to slow the disease progression in patients with ALS.23 Also, a large number of trials that were based on different strategies that used neurotrophic and antiapoptotic compounds in an animal model of ALS have failed in ALS.24 The recent lesson from the minocycline trial in ALS confirms the complexity of translational neuroscience.25 This trial, based on a Nature article26 reporting effects of minocycline in an animal model showed an enhanced deterioration in the treated group.25 We treated only two patients, however, because the rate of decline of ALS, as evaluated with ALSFRS-R, is approximately linear.27 It is possible to obtain some information on the effects of treatment by comparing the rate of progression observed before and after the beginning of motor cortex stimulation. The long-term transcranial stimulation that uses the cTBS protocol suggests that this treatment might produce a slight reduction of disease progression. In the first year, after the beginning of treatment the rate of ALSFRS-R decline for the patient treated with noninvasive stimulation was 0.8 units per month slower than before the treatment. In the next 14 months, the rate of ALSFRS-R decline tended to increase. This suggests that the slight tendency to a reduction of disease progression might be more pronounced in the first year. The reduction in the rate of decline for the first year after the beginning of cTBS was clearly greater than the mean change in the rate of decline (0.23 units per month) between the prerandomization and postrandomization phases for the placebo group reported in
Di Lazzaro et al a study evaluating the effects of minocycline in ALS.25 However, the ALSFRS-R might not show a linear decline in all ALS patients,25 and the reduction in disease progression might also be explained by a spontaneous change in the decline rate in our patient. Interestingly, the average increase of tibialis anterior CMCT that was 0.3% per month for the first year and 1.3% per month for the second year was, for the first year, below the average value of 0.9% increase per month reported in a previous study.16 However, this finding should be considered with caution because there is no general agreement on the usefulness of electrophysiologic measures of central motor function for monitoring ALS patients in clinical trial settings.28 Toxicity to glutamate in motor neurons is mediated principally by non-NMDA receptor subtype.29 Because the non-NMDA glutamatergic connections of the motor cortex can be activated by TMS,3 and cTBS produces long-lasting changes in motor cortex excitability, it can be hypothesized that the slight change in disease progression observed in our patient might be related to the long-lasting changes in glutamatergic neurotransmission of the motor cortex induced by cTBS. The suppression of motor cortex excitability in ALS patients could possibly reduce the excessive activation of glutamate receptors of corticospinal cells in ALS patients thus reducing glutamatergic excitotoxicity. It should be considered that both of our patients have been treated with the glutamate-modulating therapeutic agent riluzole and that this drug may affect the excitability of the motor cortex.30-35 Riluzole reduces intracortical facilitation to paired-pulse stimulation in control subjects.32,33 The effects of riluzole on cortical excitability were also evaluated in ALS patients.30,31,34,35 Interestingly, in these patients there is an hyperecitability of the motor cortex at least in part related to an impaired function of inhibitory interneuronal circuits.30,36,37 This cortical hyperexcitability can be reversed by riluzole.31,35 Thus, in our patients, riluzole might have interfered with the effects of cortical stimulation by reducing or inhibiting its effect. Although cTBS treatment was well tolerated by the patient and we observed no side effect, further studies in a larger number of patients are required to evaluate whether prolonged rTMS is safe in ALS. In the patient treated with EMCS, we observed no consistent change even with the use of the protocol of stimulation that has been reported to produce a positive effect in two of four patients treated by Sidoti et al.8 It should be considered that at present the available stimulators do not give the possibility to use complex protocols of stimulation thus the results are not directly comparable with those observed with rTMS. However, in our opinion, before using EMCS for ALS, it could be useful to study more patients with noninvasive stimulation to evaluate whether the benefit of cortical stimulation is confirmed in a larger number of patients and also to define the best protocol of stimulation. It might also be useful to develop new devices for the stimulation through epidural electrodes
Motor cortex stimulation for ALS capable of delivering more complex patterns of stimulation, such as TBS. In conclusion, though we cannot be sure whether the slight reduction in disease progression observed in our patient who underwent rTMS can be attributed to this treatment, this study set the groundwork for possible future studies evaluating the effects of prolonged repetitive motor cortex stimulation on disease progression in ALS patients.
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