J Neurol DOI 10.1007/s00415-013-7236-0
ORIGINAL COMMUNICATION
Spinal cord stimulation for gait impairment in spinocerebellar ataxia 7 Christos Sidiropoulos • Kei Masani • Tiago Mestre • Matija Milosevic Yu-Yan Poon • Melanie Fallis • Binit B. Shah • Suneil K. Kalia • Milos R. Popovic • Andres M. Lozano • Elena Moro
•
Received: 26 November 2013 / Revised: 22 December 2013 / Accepted: 23 December 2013 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract The aim of this study is to report on the clinical efficacy of epidural thoracic spinal cord stimulation on gait and balance in a 39-year-old man with genetically confirmed spinocerebellar ataxia 7. A RESUME Medtronic electrode was placed at the epidural T11 level. Spatiotemporal gait assessment using an electronic walkway and static posturography were obtained and analyzed in a blinded manner with and without stimulation. The Tinetti Mobility Test was also performed in the two conditions. At 11 months after surgery, there was a 3-point improvement in the Tinetti Mobility Test in the on stimulation condition, although there was no statistically significant difference in spatiotemporal gait parameters. Static posturography did not demonstrate a significant improvement in stability measures between the two conditions in a stochastic way. Electronic supplementary material The online version of this article (doi:10.1007/s00415-013-7236-0) contains supplementary material, which is available to authorized users. C. Sidiropoulos T. Mestre Y.-Y. Poon M. Fallis B. B. Shah E. Moro Movement Disorders Centre, Toronto Western Hospital, 399 Bathurst Str, Toronto, ON M5T 2S8, Canada C. Sidiropoulos Parkinson’s Disease and Movement Disorders Program, Henry Ford Hospital, 6777 West Maple Road, West Bloomfield, Detroit, MI 48322, USA K. Masani M. Milosevic M. R. Popovic Lyndhurst Centre, Toronto Rehabilitation Institute, University Health Network, 520 Sutherland Drive, Toronto, ON M4G 3V9, Canada
Thoracic epidural spinal cord stimulation had a mild but clinically meaningful beneficial effect in improving gait and balance in a patient with SCA-7. The underlying pathophysiologic mechanisms remain to be elucidated. Further experience with spinal cord stimulation in refractory gait disorders is warranted. Keywords
Ataxia Gait Spinal cord stimulation
Introduction Spinocerebellar ataxia-7 (SCA-7, OMIM# 607640) is one of the rarest forms of autosomal dominant cerebellar ataxias [15], and is caused by an expanded CAG trinucleotide mutation in the ATX7 gene [1]. Typically, more than 35 repeats are associated with a pathologic phenotype including progressive cerebellar ataxia with pigmentary macular degeneration, a variable degree of pyramidal or B. B. Shah Department of Neurology, University of Virginia, Box 800394, Charlottesville, VA, USA S. K. Kalia A. M. Lozano Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto Western Hospital, 399 Bathurst St, Toronto, ON M5T 2S8, Canada E. Moro (&) Movement Disorders Unit, Department of Psychiatry and Neurology, University Hospital Center (CHU) of Grenoble, BP 217, 38043 Grenoble CEDEX 09, France e-mail: [email protected]; [email protected]
K. Masani M. Milosevic M. R. Popovic Institute of Biomaterials and Biomedical Engineering, University of Toronto, 164 College Street, Toronto, ON M5S 3G9, Canada
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extrapyramidal signs, sensory loss and cognitive decline, as well as significant balance disturbance. Epidural spinal cord stimulation (SCS) has long been investigated in gait disorders associated with increased muscle tone and more recently in disorders such as orthostatic tremor [12] and Parkinson’s disease (PD) [16]. Experience in other disorders with prominent imbalance such as cerebellar ataxias is lacking. We here, firstly, report on a patient with SCA-7 who was implanted with thoracic SCS for an ataxic disorder.
Patient Our patient presented to us at age 36 years with a 20-year history of progressive worsening of ataxia and vision, and nearly daily falls. At age 32 years, he had been diagnosed with cone rod dystrophy. There was no clear family history of a similar disorder. On examination, his uncorrected visual acuity was 20/400 bilaterally. There was impaired optokinetic nystagmus in both the horizontal and vertical planes. Speech was mildly dysarthric. Muscle tone was diminished with diffuse hyperreflexia and clonus, and an almost constant feeling of muscle spasms. There were no motor or sensory deficits. Casual gait was unstable and broad-based, and tandem gait was impossible. He normally used a cane for walking. Brain and spine MRI were notable for marked cerebellar and spinal cord atrophy. Nerve conduction studies of the upper and lower extremities were normal. Genetic testing was undertaken for spinocerebellar ataxia types 1, 2, 3, 6, 7, 8, as well as for Friedreich’s ataxia and fragile-X syndrome. A 48-CAG repeat in one of the alleles in the ATX 7 gene was found (normal range 4–35), establishing the diagnosis of SCA-7. In light of his profound instability and lack of conservative treatments, the patient consented to the placement of a SCS on a compassionate basis.
Methods Surgery took place under general anesthesia in April of 2011. A RESUME lead (Medtronic Neurological, Minneapolis, MN, USA) was placed in the epidural space of the thoracic spinal cord dorsal columns at the T11 level and connected to an implantable pulse generator (IPG, Itrel EZ, Medtronic Neurological, Minneapolis, MN, USA) placed subcutaneously in the right abdominal area. Surgery was well-tolerated and without complications. The stimulation programming plan consisted of a first period of 6 months, during which electrical parameters and different contacts of stimulation were clinically tested (a
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variety of pulse frequencies from 65 to 130 Hz and different pulse widths and amplitudes). Six well-tolerated combinations were left for about 1 month, with the goal to improve the patient’s gait based on his reports about fall frequency and stability during his daily activities. At the end of this period the patient underwent gait assessment using an 8-m long electronic walkway (GaitRite, CIR Systems, Sparta, NJ, USA), in a randomized, double-blinded way [with both patient and operator (K.M.) blinded to stimulation condition and settings]. The patient performed six trials of walking with and without stimulation at his preferred speed. He was requested to walk without his gait aid. Spatiotemporal parameters of gait were measured including: (1) step length, (2) stride length, (3) step time, (4) stride time, (5) swing time, (6) stance time, (7) single support time, (8) double support time, (9) stride velocity, (10) step width, and (11) stride width. Data were sampled at 30 Hz. The mean of each obtained spatiotemporal parameter was statistically compared between the conditions using t-tests with the level of significance set at 0.05. Stimulation parameters were 5 V/130 Hz/360 ls, contacts 3? and 0-. During the second period, the best stimulation setting, based on patient’s reports, was left for 5 months before proceeding with posturographic and clinical assessment, with and without stimulation. For posturography testing the patient performed ten trials of static balance assessment with eyes open for each of the three conditions: at baseline (ON stimulation, the patient being aware of the stimulation condition–condition 1) and ON (patient and rater blinded– condition 2) and OFF (patient and rater blinded–condition 3) stimulation, on a force platform (AccuSwayPlus, Advanced Mechanical Technology Inc., Watertown, MA, USA), each condition tested 30 min apart. Both patient and raters (K.M., M.M.) were blinded to the stimulation condition for conditions 2 and 3. It should be noted that, over time, the patient had gradually lost the initial feeling of leg paresthesias that accompanied the initiation of spinal cord stimulation in the first months after implantation. Each trial lasted 30 s. The data were sampled at 100 Hz and low-pass filtered at 5 Hz. The postural sway was measured as the centre of pressure fluctuation. The anterio–posterior and medio-lateral directions as well as the resultant distance were evaluated separately, and the postural sway measures were calculated including: (1) root mean square distance, (2) mean velocity, (3) range, and (4) 95 % confidence ellipse area [14]. The mean of each obtained postural sway measure was statistically compared between the conditions using one-way ANOVA with a post hoc test (Tukey HSD test). For clinical assessment purposes the Tinetti balance assessment tool [11, 17] (items 1–5, 8a, 8b and 9 of the balance section and 1–8 of the gait section) was applied. Three videos were obtained (baseline ON stimulation, ON
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stimulation and OFF stimulation; for testing definitions see above), with two trials of gait and balance testing with both the rater (T.M.) and patient blinded to the testing conditions. The average of the two scores for each of the three conditions was obtained. At this second assessment his stimulation settings both for posturographic and clinical testing were 4.7 V/130 Hz/450 ls, contacts 3? and 0-.
Posturography Table 2 summarizes the results for the postural sway measures. Overall, the postural sway was larger in condition 3 (OFF stimulation) compared to condition 1 (baseline ON stimulation) as measured by root mean square distance for resultant distance (RD), range of medio-lateral sway (ML), and 95 % confidence ellipse area (CE).
Results
Tinetti balance assessment
Gait assessment
The patient scored a 17/25 in condition 1, compared to 19/25 and 16/25 in conditions 2 and 3, respectively. Higher scores denote a lower risk of falling (maximum score is a 28 in the actual Tinetti Scale, corrected here for the items not tested). The patient had more difficulty with turns and rising from a chair in condition 3 (OFF condition) as compared to ON condition (Supplementary Video, segments 1-ONblinded and 2-OFF-blinded).
There was no statistically significant difference for any of the spatiotemporal parameters (Table 1). Table 1 Summary of spatiotemporal parameters obtained through GaitRite assessment ON and OFF stimulation
Step length (cm) Stride length (cm) Step time (s)
Condition 1
Condition 2
t test
51.1 ± 5.8
51.1 ± 4.9
0.999
103 ± 11 0.596 ± 0.040
104 ± 7 0.589 ± 0.036
0.831 0.377
Stride time (s)
1.20 ± 0.05
1.17 ± 0.05
0.146
Swing time (s)
0.418 ± 0.030
0.420 ± 0.027
0.752
Stance time (s)
0.773 ± 0.054
0.756 ± 0.048
0.153
Single support time (s)
0.418 ± 0.030
0.420 ± 0.027
0.752
Double support time (s)
0.344 ± 0.035
0.328 ± 0.031
0.140
Stride velocity (cm/s)
86.6 ± 11.2
88.6 ± 6.6
0.492
Step width (cm)
55.4 ± 4.3
55.5 ± 4.3
0.897
Stride width (cm)
19.3 ± 4.1
20.1 ± 5.2
0.613
Table 2 Summary of static posturography results in regards to center of pressure fluctuation, where the abbreviations have the following meaning: root mean square (RMS) distance, resultant distance (RD), Condition 1
Condition 2
Discussion Postural instability and gait dysfunction are characteristics of a variety of neurodegenerative disorders, including PD and spinocerebellar ataxias. Our SCA-7 patient, to our knowledge, is the first patient to be implanted with a SCS for an ataxic disorder. Despite the lack of improvement in gait metrics, as assessed by the electrical walkway testing, the patient demonstrated a clinically meaningful stabilization of his balance by using the Tinetti Tool. anterior-posterior sway (AP), medio-lateral sway (ML), confidence ellipse area (CE), and (mean ± standard deviation) Condition 3
ANOVA
Tukey HSD
1 and 3
RMS (cm) RD
1.28 ± 0.19
1.50 ± 0.22
1.57 ± 0.24
0.015
AP
0.97 ± 0.17
1.17 ± 0.24
1.13 ± 0.22
0.103
ML
0.80 ± 0.23
0.89 ± 0.29
1.07 ± 0.26
0.082
Mean velocity (cm/s) RD
2.30 ± 0.41
2.67 ± 0.51
2.44 ± 0.27
0.154
AP
1.86 ± 0.25
2.05 ± 0.36
1.71 ± 0.27
0.051
ML
1.01 ± 0.33
1.25 ± 0.50
1.35 ± 0.25
0.134
3.22 ± 0.85
3.65 ± 0.84
3.96 ± 0.84
0.168
Range (cm) RD AP
5.06 ± 0.96
5.99 ± 1.47
5.46 ± 1.02
0.227
ML
3.70 ± 1.18
4.33 ± 1.50
5.42 ± 1.63
0.041
1 and 3
13.2 ± 3.77
19.3 ± 7.31
21.0 ± 6.19
0.017
1 and 3
Area CE (cm2) –
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It is interesting to note that there was an increased tendency to fall, and a relapse in his clonus and muscle cramps when his IPG expired without him being aware. This fact speaks against a serendipitous improvement based on a day to day variation in gait which does seem to exist in many disorders associated with postural instability. Posturographic and blinded video rating demonstrated the difficulties in capturing improvements in gait and balance function. As one can see from Table 2, there was a difference in posturographic parameters in condition 1 versus condition 3 but not in condition 2 versus condition 3, despite both conditions 1 and 2 being ON stimulation. This underscores the significance of repeated testing, as gait is the result of many processes with wide inter-individual, and even intraday, variability. This may have been the reason why the initial gait assessment failed to capture any improvements in gait parameters. Incorporating clinical scales, such as the Tinetti assessment tool, which simulate different aspects of every day gait (like turning, standing, resisting forced displacement), may add on useful diagnostic and therapeutic information that would be missed by conventional clinimetric testing. As far as the mechanisms that mediate balance restoration through SCS, those remain largely unclear, although many theories have emerged over the past two decades. It has been long known that there are neuronal pools in the spinal cord, the so-called locomotor strip, lateral to the dorsal horns, the electrical stimulation of which can initiate step like movements [18]. Because of some evidence that this can be observed in animals such as rats and cats [9, 13], there have lately been ongoing efforts in humans with spinal cord injuries with encouraging results [7]. Recent data from animal models also suggest that SCS may ameliorate instability related to PD [4, 5], and there are a limited number of cases in humans with conflicting results [2, 8, 16]. Putative mechanisms of locomotion restoration may include recruitment and reorganization of spinal locomotor networks, secretion of neurotrophic factors, reduction of spasticity, disruption of antikinetic synchronization through ascending pathway activation, mainly the dorsal columns [4, 16] and modulation of proprioceptive input [3]. The interplay between these variable mechanisms may result in clinically beneficial effects with chronic stimulation which may last for some time in the OFF stimulation condition. This may contribute, in part, to the lack of improvement in gait metrics observed in this study examining acute ON and OFF states. The optimal spinal level for SCS in uncertain, but it may vary among species, and for humans it may lie in the higher lumbar spinal segments [6]. With regards to stimulation parameters, most of the evidence comes from animal models of spinal cord injury. In humans, standing may be mediated by spinal circuits firing at frequencies between 5
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and 15 Hz whereas stepping movements may be promoted by frequencies between 25 and 50 Hz [10]. In our patient we carefully titrated all parameters. The best results, mainly based on patient’s reports and diaries, were seen with the highest pulse width (450 ls) and frequency (130 Hz) as compared to lower ones. It should be noted that frequencies lower than 65 Hz were not tested. It is interesting to note that in their two patients Thevathasan et al. [16] trialed 130 and 300 Hz respectively with negative results as to gait improvement. Our study should be viewed in light of its several limitations the main one being the single subject studied. However, this case provides proof of concept for the tolerability and efficacy of SCS in patients with various causes of gait dysfunction which can severely affect quality of life and be a major source of morbidity. Further studies are needed to better clarify the benefits, optimal stimulation settings, site and mode of stimulation. Acknowledgments The authors would like to thank Brent Geobey and Alex Valencia Mizrachi for their excellent technical support and support of the patient and his family. Patient consent obtained. Data sharing statement Dr. Moro has full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Conflicts of interest Dr. Moro has received honoraria from Medtronic for lecturing. Dr. Lozano is a consultant for Medtonic, St Jude and Boston Scientific. Ethical standard All ethical standards for the conduct of clinical research met.
References 1. David G, Giunti P, Abbas N, Coullin P, Stevanin G, Horta W, Gemmill R, Weissenbach J, Wood N, Cunha S, Drabkin H, Harding AE, Agid Y, Brice A (1996) The gene for autosomal dominant cerebellar ataxia type II is located in a 5-cM region in 3p12–p13: genetic and physical mapping of the SCA7 locus. Am J Hum Genet 59:1328–1336 2. Fenelon G, Goujon C, Gurruchaga JM, Cesaro P, Jarraya B, Palfi S, Lefaucheur JP (2012) Spinal cord stimulation for chronic pain improved motor function in a patient with Parkinson’s disease. Parkinsonism Relat Disord 18:213–214 3. Fong AJ, Roy RR, Ichiyama RM, Lavrov I, Courtine G, Gerasimenko Y, Tai YC, Burdick J, Edgerton VR (2009) Recovery of control of posture and locomotion after a spinal cord injury: solutions staring us in the face. Prog Brain Res 175:393–418 4. Fuentes R, Petersson P, Nicolelis MA (2010) Restoration of locomotive function in Parkinson’s disease by spinal cord stimulation: mechanistic approach. Eur J Neurosci 32:1100–1108 5. Fuentes R, Petersson P, Siesser WB, Caron MG, Nicolelis MA (2009) Spinal cord stimulation restores locomotion in animal models of Parkinson’s disease. Science 323:1578–1582 6. Gerasimenko Y, Roy RR, Edgerton VR (2008) Epidural stimulation: comparison of the spinal circuits that generate and control locomotion in rats, cats and humans. Exp Neurol 209:417–425
J Neurol 7. Harkema S, Gerasimenko Y, Hodes J, Burdick J, Angeli C, Chen Y, Ferreira C, Willhite A, Rejc E, Grossman RG, Edgerton VR (2011) Effect of epidural stimulation of the lumbosacral spinal cord on voluntary movement, standing, and assisted stepping after motor complete paraplegia: a case study. Lancet 377:1938–1947 8. Hassan S, Amer S, Alwaki A, Elborno A (2013) A patient with Parkinson’s disease benefits from spinal cord stimulation. J Clin Neurosci 20:1155–1156 9. Iwahara T, Atsuta Y, Garcia-Rill E, Skinner RD (1992) Spinal cord stimulation-induced locomotion in the adult cat. Brain Res Bull 28:99–105 10. Jilge B, Minassian K, Rattay F, Dimitrijevic MR (2004) Frequency-dependent selection of alternative spinal pathways with common periodic sensory input. Biol Cybern 91:359–376 11. Kegelmeyer DA, Kloos AD, Thomas KM, Kostyk SK (2007) Reliability and validity of the Tinetti mobility test for individuals with Parkinson disease. Phys Ther 87:1369–1378 12. Krauss JK, Weigel R, Blahak C, Bazner H, Capelle HH, Grips E, Rittmann M, Wohrle JC (2006) Chronic spinal cord stimulation in medically intractable orthostatic tremor. J Neurol Neurosurg Psychiatry 77:1013–1016 13. Lavrov I, Dy CJ, Fong AJ, Gerasimenko Y, Courtine G, Zhong H, Roy RR, Edgerton VR (2008) Epidural stimulation induced
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modulation of spinal locomotor networks in adult spinal rats. J Neurosci 28:6022–6029 Prieto TE, Myklebust JB, Hoffmann RG, Lovett EG, Myklebust BM (1996) Measures of postural steadiness: differences between healthy young and elderly adults. IEEE Trans Biomed Eng 43:956–966 Storey E, du Sart D, Shaw JH, Lorentzos P, Kelly L, McKinley Gardner RJ, Forrest SM, Biros I, Nicholson GA (2000) Frequency of spinocerebellar ataxia types 1, 2, 3, 6, and 7 in Australian patients with spinocerebellar ataxia. Am J Med Genet 95:351–357 Thevathasan W, Mazzone P, Jha A, Djamshidian A, Dileone M, Di Lazzaro V, Brown P (2010) Spinal cord stimulation failed to relieve akinesia or restore locomotion in Parkinson disease. Neurology 74:1325–1327 Tinetti ME (1986) Performance-oriented assessment of mobility problems in elderly patients. J Am Geriatr Soc 34:119–126 Yamaguchi T (1986) Descending pathways eliciting forelimb stepping in the lateral funiculus: experimental studies with stimulation and lesion of the cervical cord in decerebrate cats. Brain Res 379:125–136
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ORIGINAL COMMUNICATION
Spinal cord stimulation for gait impairment in spinocerebellar ataxia 7 Christos Sidiropoulos • Kei Masani • Tiago Mestre • Matija Milosevic Yu-Yan Poon • Melanie Fallis • Binit B. Shah • Suneil K. Kalia • Milos R. Popovic • Andres M. Lozano • Elena Moro
•
Received: 26 November 2013 / Revised: 22 December 2013 / Accepted: 23 December 2013 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract The aim of this study is to report on the clinical efficacy of epidural thoracic spinal cord stimulation on gait and balance in a 39-year-old man with genetically confirmed spinocerebellar ataxia 7. A RESUME Medtronic electrode was placed at the epidural T11 level. Spatiotemporal gait assessment using an electronic walkway and static posturography were obtained and analyzed in a blinded manner with and without stimulation. The Tinetti Mobility Test was also performed in the two conditions. At 11 months after surgery, there was a 3-point improvement in the Tinetti Mobility Test in the on stimulation condition, although there was no statistically significant difference in spatiotemporal gait parameters. Static posturography did not demonstrate a significant improvement in stability measures between the two conditions in a stochastic way. Electronic supplementary material The online version of this article (doi:10.1007/s00415-013-7236-0) contains supplementary material, which is available to authorized users. C. Sidiropoulos T. Mestre Y.-Y. Poon M. Fallis B. B. Shah E. Moro Movement Disorders Centre, Toronto Western Hospital, 399 Bathurst Str, Toronto, ON M5T 2S8, Canada C. Sidiropoulos Parkinson’s Disease and Movement Disorders Program, Henry Ford Hospital, 6777 West Maple Road, West Bloomfield, Detroit, MI 48322, USA K. Masani M. Milosevic M. R. Popovic Lyndhurst Centre, Toronto Rehabilitation Institute, University Health Network, 520 Sutherland Drive, Toronto, ON M4G 3V9, Canada
Thoracic epidural spinal cord stimulation had a mild but clinically meaningful beneficial effect in improving gait and balance in a patient with SCA-7. The underlying pathophysiologic mechanisms remain to be elucidated. Further experience with spinal cord stimulation in refractory gait disorders is warranted. Keywords
Ataxia Gait Spinal cord stimulation
Introduction Spinocerebellar ataxia-7 (SCA-7, OMIM# 607640) is one of the rarest forms of autosomal dominant cerebellar ataxias [15], and is caused by an expanded CAG trinucleotide mutation in the ATX7 gene [1]. Typically, more than 35 repeats are associated with a pathologic phenotype including progressive cerebellar ataxia with pigmentary macular degeneration, a variable degree of pyramidal or B. B. Shah Department of Neurology, University of Virginia, Box 800394, Charlottesville, VA, USA S. K. Kalia A. M. Lozano Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto Western Hospital, 399 Bathurst St, Toronto, ON M5T 2S8, Canada E. Moro (&) Movement Disorders Unit, Department of Psychiatry and Neurology, University Hospital Center (CHU) of Grenoble, BP 217, 38043 Grenoble CEDEX 09, France e-mail: [email protected]; [email protected]
K. Masani M. Milosevic M. R. Popovic Institute of Biomaterials and Biomedical Engineering, University of Toronto, 164 College Street, Toronto, ON M5S 3G9, Canada
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extrapyramidal signs, sensory loss and cognitive decline, as well as significant balance disturbance. Epidural spinal cord stimulation (SCS) has long been investigated in gait disorders associated with increased muscle tone and more recently in disorders such as orthostatic tremor [12] and Parkinson’s disease (PD) [16]. Experience in other disorders with prominent imbalance such as cerebellar ataxias is lacking. We here, firstly, report on a patient with SCA-7 who was implanted with thoracic SCS for an ataxic disorder.
Patient Our patient presented to us at age 36 years with a 20-year history of progressive worsening of ataxia and vision, and nearly daily falls. At age 32 years, he had been diagnosed with cone rod dystrophy. There was no clear family history of a similar disorder. On examination, his uncorrected visual acuity was 20/400 bilaterally. There was impaired optokinetic nystagmus in both the horizontal and vertical planes. Speech was mildly dysarthric. Muscle tone was diminished with diffuse hyperreflexia and clonus, and an almost constant feeling of muscle spasms. There were no motor or sensory deficits. Casual gait was unstable and broad-based, and tandem gait was impossible. He normally used a cane for walking. Brain and spine MRI were notable for marked cerebellar and spinal cord atrophy. Nerve conduction studies of the upper and lower extremities were normal. Genetic testing was undertaken for spinocerebellar ataxia types 1, 2, 3, 6, 7, 8, as well as for Friedreich’s ataxia and fragile-X syndrome. A 48-CAG repeat in one of the alleles in the ATX 7 gene was found (normal range 4–35), establishing the diagnosis of SCA-7. In light of his profound instability and lack of conservative treatments, the patient consented to the placement of a SCS on a compassionate basis.
Methods Surgery took place under general anesthesia in April of 2011. A RESUME lead (Medtronic Neurological, Minneapolis, MN, USA) was placed in the epidural space of the thoracic spinal cord dorsal columns at the T11 level and connected to an implantable pulse generator (IPG, Itrel EZ, Medtronic Neurological, Minneapolis, MN, USA) placed subcutaneously in the right abdominal area. Surgery was well-tolerated and without complications. The stimulation programming plan consisted of a first period of 6 months, during which electrical parameters and different contacts of stimulation were clinically tested (a
123
variety of pulse frequencies from 65 to 130 Hz and different pulse widths and amplitudes). Six well-tolerated combinations were left for about 1 month, with the goal to improve the patient’s gait based on his reports about fall frequency and stability during his daily activities. At the end of this period the patient underwent gait assessment using an 8-m long electronic walkway (GaitRite, CIR Systems, Sparta, NJ, USA), in a randomized, double-blinded way [with both patient and operator (K.M.) blinded to stimulation condition and settings]. The patient performed six trials of walking with and without stimulation at his preferred speed. He was requested to walk without his gait aid. Spatiotemporal parameters of gait were measured including: (1) step length, (2) stride length, (3) step time, (4) stride time, (5) swing time, (6) stance time, (7) single support time, (8) double support time, (9) stride velocity, (10) step width, and (11) stride width. Data were sampled at 30 Hz. The mean of each obtained spatiotemporal parameter was statistically compared between the conditions using t-tests with the level of significance set at 0.05. Stimulation parameters were 5 V/130 Hz/360 ls, contacts 3? and 0-. During the second period, the best stimulation setting, based on patient’s reports, was left for 5 months before proceeding with posturographic and clinical assessment, with and without stimulation. For posturography testing the patient performed ten trials of static balance assessment with eyes open for each of the three conditions: at baseline (ON stimulation, the patient being aware of the stimulation condition–condition 1) and ON (patient and rater blinded– condition 2) and OFF (patient and rater blinded–condition 3) stimulation, on a force platform (AccuSwayPlus, Advanced Mechanical Technology Inc., Watertown, MA, USA), each condition tested 30 min apart. Both patient and raters (K.M., M.M.) were blinded to the stimulation condition for conditions 2 and 3. It should be noted that, over time, the patient had gradually lost the initial feeling of leg paresthesias that accompanied the initiation of spinal cord stimulation in the first months after implantation. Each trial lasted 30 s. The data were sampled at 100 Hz and low-pass filtered at 5 Hz. The postural sway was measured as the centre of pressure fluctuation. The anterio–posterior and medio-lateral directions as well as the resultant distance were evaluated separately, and the postural sway measures were calculated including: (1) root mean square distance, (2) mean velocity, (3) range, and (4) 95 % confidence ellipse area [14]. The mean of each obtained postural sway measure was statistically compared between the conditions using one-way ANOVA with a post hoc test (Tukey HSD test). For clinical assessment purposes the Tinetti balance assessment tool [11, 17] (items 1–5, 8a, 8b and 9 of the balance section and 1–8 of the gait section) was applied. Three videos were obtained (baseline ON stimulation, ON
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stimulation and OFF stimulation; for testing definitions see above), with two trials of gait and balance testing with both the rater (T.M.) and patient blinded to the testing conditions. The average of the two scores for each of the three conditions was obtained. At this second assessment his stimulation settings both for posturographic and clinical testing were 4.7 V/130 Hz/450 ls, contacts 3? and 0-.
Posturography Table 2 summarizes the results for the postural sway measures. Overall, the postural sway was larger in condition 3 (OFF stimulation) compared to condition 1 (baseline ON stimulation) as measured by root mean square distance for resultant distance (RD), range of medio-lateral sway (ML), and 95 % confidence ellipse area (CE).
Results
Tinetti balance assessment
Gait assessment
The patient scored a 17/25 in condition 1, compared to 19/25 and 16/25 in conditions 2 and 3, respectively. Higher scores denote a lower risk of falling (maximum score is a 28 in the actual Tinetti Scale, corrected here for the items not tested). The patient had more difficulty with turns and rising from a chair in condition 3 (OFF condition) as compared to ON condition (Supplementary Video, segments 1-ONblinded and 2-OFF-blinded).
There was no statistically significant difference for any of the spatiotemporal parameters (Table 1). Table 1 Summary of spatiotemporal parameters obtained through GaitRite assessment ON and OFF stimulation
Step length (cm) Stride length (cm) Step time (s)
Condition 1
Condition 2
t test
51.1 ± 5.8
51.1 ± 4.9
0.999
103 ± 11 0.596 ± 0.040
104 ± 7 0.589 ± 0.036
0.831 0.377
Stride time (s)
1.20 ± 0.05
1.17 ± 0.05
0.146
Swing time (s)
0.418 ± 0.030
0.420 ± 0.027
0.752
Stance time (s)
0.773 ± 0.054
0.756 ± 0.048
0.153
Single support time (s)
0.418 ± 0.030
0.420 ± 0.027
0.752
Double support time (s)
0.344 ± 0.035
0.328 ± 0.031
0.140
Stride velocity (cm/s)
86.6 ± 11.2
88.6 ± 6.6
0.492
Step width (cm)
55.4 ± 4.3
55.5 ± 4.3
0.897
Stride width (cm)
19.3 ± 4.1
20.1 ± 5.2
0.613
Table 2 Summary of static posturography results in regards to center of pressure fluctuation, where the abbreviations have the following meaning: root mean square (RMS) distance, resultant distance (RD), Condition 1
Condition 2
Discussion Postural instability and gait dysfunction are characteristics of a variety of neurodegenerative disorders, including PD and spinocerebellar ataxias. Our SCA-7 patient, to our knowledge, is the first patient to be implanted with a SCS for an ataxic disorder. Despite the lack of improvement in gait metrics, as assessed by the electrical walkway testing, the patient demonstrated a clinically meaningful stabilization of his balance by using the Tinetti Tool. anterior-posterior sway (AP), medio-lateral sway (ML), confidence ellipse area (CE), and (mean ± standard deviation) Condition 3
ANOVA
Tukey HSD
1 and 3
RMS (cm) RD
1.28 ± 0.19
1.50 ± 0.22
1.57 ± 0.24
0.015
AP
0.97 ± 0.17
1.17 ± 0.24
1.13 ± 0.22
0.103
ML
0.80 ± 0.23
0.89 ± 0.29
1.07 ± 0.26
0.082
Mean velocity (cm/s) RD
2.30 ± 0.41
2.67 ± 0.51
2.44 ± 0.27
0.154
AP
1.86 ± 0.25
2.05 ± 0.36
1.71 ± 0.27
0.051
ML
1.01 ± 0.33
1.25 ± 0.50
1.35 ± 0.25
0.134
3.22 ± 0.85
3.65 ± 0.84
3.96 ± 0.84
0.168
Range (cm) RD AP
5.06 ± 0.96
5.99 ± 1.47
5.46 ± 1.02
0.227
ML
3.70 ± 1.18
4.33 ± 1.50
5.42 ± 1.63
0.041
1 and 3
13.2 ± 3.77
19.3 ± 7.31
21.0 ± 6.19
0.017
1 and 3
Area CE (cm2) –
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It is interesting to note that there was an increased tendency to fall, and a relapse in his clonus and muscle cramps when his IPG expired without him being aware. This fact speaks against a serendipitous improvement based on a day to day variation in gait which does seem to exist in many disorders associated with postural instability. Posturographic and blinded video rating demonstrated the difficulties in capturing improvements in gait and balance function. As one can see from Table 2, there was a difference in posturographic parameters in condition 1 versus condition 3 but not in condition 2 versus condition 3, despite both conditions 1 and 2 being ON stimulation. This underscores the significance of repeated testing, as gait is the result of many processes with wide inter-individual, and even intraday, variability. This may have been the reason why the initial gait assessment failed to capture any improvements in gait parameters. Incorporating clinical scales, such as the Tinetti assessment tool, which simulate different aspects of every day gait (like turning, standing, resisting forced displacement), may add on useful diagnostic and therapeutic information that would be missed by conventional clinimetric testing. As far as the mechanisms that mediate balance restoration through SCS, those remain largely unclear, although many theories have emerged over the past two decades. It has been long known that there are neuronal pools in the spinal cord, the so-called locomotor strip, lateral to the dorsal horns, the electrical stimulation of which can initiate step like movements [18]. Because of some evidence that this can be observed in animals such as rats and cats [9, 13], there have lately been ongoing efforts in humans with spinal cord injuries with encouraging results [7]. Recent data from animal models also suggest that SCS may ameliorate instability related to PD [4, 5], and there are a limited number of cases in humans with conflicting results [2, 8, 16]. Putative mechanisms of locomotion restoration may include recruitment and reorganization of spinal locomotor networks, secretion of neurotrophic factors, reduction of spasticity, disruption of antikinetic synchronization through ascending pathway activation, mainly the dorsal columns [4, 16] and modulation of proprioceptive input [3]. The interplay between these variable mechanisms may result in clinically beneficial effects with chronic stimulation which may last for some time in the OFF stimulation condition. This may contribute, in part, to the lack of improvement in gait metrics observed in this study examining acute ON and OFF states. The optimal spinal level for SCS in uncertain, but it may vary among species, and for humans it may lie in the higher lumbar spinal segments [6]. With regards to stimulation parameters, most of the evidence comes from animal models of spinal cord injury. In humans, standing may be mediated by spinal circuits firing at frequencies between 5
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and 15 Hz whereas stepping movements may be promoted by frequencies between 25 and 50 Hz [10]. In our patient we carefully titrated all parameters. The best results, mainly based on patient’s reports and diaries, were seen with the highest pulse width (450 ls) and frequency (130 Hz) as compared to lower ones. It should be noted that frequencies lower than 65 Hz were not tested. It is interesting to note that in their two patients Thevathasan et al. [16] trialed 130 and 300 Hz respectively with negative results as to gait improvement. Our study should be viewed in light of its several limitations the main one being the single subject studied. However, this case provides proof of concept for the tolerability and efficacy of SCS in patients with various causes of gait dysfunction which can severely affect quality of life and be a major source of morbidity. Further studies are needed to better clarify the benefits, optimal stimulation settings, site and mode of stimulation. Acknowledgments The authors would like to thank Brent Geobey and Alex Valencia Mizrachi for their excellent technical support and support of the patient and his family. Patient consent obtained. Data sharing statement Dr. Moro has full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Conflicts of interest Dr. Moro has received honoraria from Medtronic for lecturing. Dr. Lozano is a consultant for Medtonic, St Jude and Boston Scientific. Ethical standard All ethical standards for the conduct of clinical research met.
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