Spinal Epidural Electrical Stimulation for recovery of motor function in lower limbs after Spinal Cord Injury: A Phase I/II clinical trial

doi:10.21203/rs.3.rs-2487237/v1

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Spinal Epidural Electrical Stimulation for recovery of motor function in lower limbs after Spinal Cord Injury: A Phase I/II clinical trial

https://doi.org/10.21203/rs.3.rs-2487237/v1

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Study design:

Single-arm prospective phase I/II clinical trial

Objective:

Standing and walking are highly desirable goals forpersons with spinal cord injury (SCI). Spinal epidural electrical stimulation (sEES) has been utilized to produce rhythmic activity in animals and more recently, in a few human case reports. Our objective was to assess the safety and efficacy of sEES in the recovery of motor function after severe SCI.

Setting:

Indian Spinal Injuries Center, New Delhi

Methods:

Fiveparticipantssatisfying the eligibility criteria includingsevere and chronic SCIand an absence of useful power in the lower limbswere included in the study. The Institute Ethics Committee and the Research Review Committee approved the study and it was registered with Clinical Trials Registry of India.

Results:

No intraoperative or early postoperative complications were noted in any of the participants. Two participants had wound complicationsat 1 and 3 months respectively and were managed successfully.Improvement in the voluntary power of lower limbs, motor abilities, and functional recoverywas noted in the majority of the participants when the sEESwas turned on. Even with sEES turned off; there was improvement in motor abilities of a participant though there was no demonstrable neurological recovery.

Conclusions:

sEES is a safe intervention and improves the motor and functional abilities of persons with severe and chronic SCI. Neurological recovery could not be demonstrated. However, a larger,prospective,matched controlledstudy with more participants needs to be done to draw a definite conclusion.

Health sciences/Medical research/Outcomes research

Health sciences/Medical research/Clinical trial design/Clinical trials

Electric stimulation

spinal cord injury

spinal cord stimulation

epidural stimulation

clinical trial

Spinal cord injury (SCI) can cause permanent loss of sensation and motor function below the level of injury, thus causing severe physical disability andpsychological distress. Standing and walking are highly desirable goals forpersons with SCI [1]. However, despite an enormous amount of research onSCI, the neurological prognosis for individuals with complete and severe SCI remains dismal. Activity-based locomotor training, the only practice used to enhance recovery at present, does not yield significant outcomesinpersons with severe SCI [2–4].

Spinal Epidural Electrical Stimulation(sEES) has been shown to produce rhythmic motor activity patterns in spinalisedrats[5]as well as humans with complete SCI[6]. Voluntary control of flexion and extension leg movements has been noticed in two persons with complete SCI after sEES[6, 7]. Subsequently, independent stepping was noticed in a persons with SCI after task-based training with sEES[7]. More recently, intentional overground walking has been noticed in two persons with American Spinal Injury Association Impairment Scale B(AIS-B) SCI after sEESwithlocomotor training[8].Unexpected voluntary motor control of lower limbs and independent standing without sEES was also reported in one of these persons [8].

These studies suggest that the spared structural connections at the site of injury which were functionally inactive may be capable of modulating the excitability of the sensorimotor networks below the level of injury[6]. Also, the plasticity in the local spinal circuits and/or the descending pathways with axonal sprouting was proposed as a hypothesis for the voluntary control of leg movements observed without sEES.

The objective of thissingle-armprospective phase I/II clinicaltrialwastoassessthe safety ofsEES and its role in improving the motor as well as functional abilities and neurological recovery of persons with severe and chronic SCI.

We hypothesize that sEESis a safe intervention and can facilitate standing, stepping and over ground walking in persons with severe and chronicSCI who were previously unable to do such activities.

We also hypothesize that sEES can produce voluntary limb movements in persons with severe and chronic SCI who were unable to do such movements previously.

We conducted a single-armprospectivephase I/II clinical trial in five chronic SCIparticipants withan absence of useful power in the lower limbs. The Institute Ethics Committee and the Research Review Committee approved the study. The trial was registered with the Clinical Trials Registry of India(CTRI/2019/08/020905). The study was planned to be a randomized trial but was later converted to a single-armclinical trialafter obtaining required permissions from the Institute Ethics committee.

Inclusion& exclusioncriteria:

Participants with severe and chronic SCIat leastsix months after injury,ASIA impairment scale(AIS) A,B, or C with a vertebral level of injury above T11 who had undergone a comprehensiverehabilitation program and in whom any neurological recovery had plateaued,those not currently on any anti-spasticity medications and those with stable medical condition without cardiopulmonary disease or dysautonomia that would contraindicate standing or stepping with bodyweight support trainingwere included in the study.

Exclusion Criteria included persons with SCI with pregnancy at the time of enrollment, failure to obtain consent, painful musculoskeletal dysfunction, unhealed fracture, contracture, pressure sore, or urinary tract infection that interfered with standing or stepping training, those currentlyon an anti-spasticity medication regimen, and those with implantedcardiac pacemaker or defibrillator.

Implantation procedure

All the participants provided a written as well as video informed consent. They were implanted with a 16 electrode array sEES over the midline of duramater at L1 to S1 spinal cord level (T10 to L1 vertebral level). The optimal positioning of the array was determined intra-operatively by a direct nerve stimulator (Medtronic NIM Eclipse system, USA). A surgical stimulator (Restore Advanced, Medtronics) was placed subcutaneously in the anterior abdominal wall. The wire leads were then tunnelled subcutaneously and connected to the stimulator (Fig. 1).

Mapping:

Three weeks onwards after surgery multiple combinations of amplitude and frequency were tested (mapping) to obtain information on which combination caused rhythmic muscle activation simulating walking, standing, and stepping.

Spatial mapping was initially performed using low frequency(2Hz) bipolar stimulation of electrodes to identify the flexor and extensor muscle response to stimulation and localize the responses. The frequency and voltage were adjusted to achieve adequate responses. Then, the local field configurations(adjacent anode and cathode) and wide-field configurations(non-adjacent anode and cathode) were tried to generate locomotor-like patterns in the lower limbs. The configuration parameters were also adjusted and training was given to strengthen individual muscle groups, specifically the hip flexors, hip abductors, knee extensors, ankle dorsiflexors, and ankle plantar flexors. Next, the configuration parameters were developed to achieve the best locomotor pattern for stepping activity. The configuration parameters were also adjusted in the subsequent sessions to achieve the best motor activity for stepping. Similar configurations were identified for standing weight-bearing as well.

Training:

Training sessions consisting of a structured program of daily physical rehabilitation involving standing weight bearing, walking with/withoutgaiters and treadmill step training. Once the desired setting of sEES is found, the participantswere trained for three hours a dayfor a minimum of 6 months (and continued later on depending on the individual need) involving one or more of

Standing weight bearing,
Walking with/withoutgaiters
Treadmill step training

Step training was initially given using bodyweight suspension and manual facilitation. The body weight support was reduced gradually as the participant was able to maintain the balance. Training for overground walking was given when the participant was able to perform step movements with full-weight bearing. The training sessions were modified every two to three weeks to determine if such adjustments result in better performance. Trials were also conducted to look if the motor achievements were sustained when the sEES was turned off.

Outcome Measures:

The outcome measuresused for the study are enlisted in Table 1.The participants were assessed for these outcome measures every 4 weeks for all scales except urodynamic studies which were performed 6 monthly or if there was a subjective improvement.

Table 1

Outcome measures assessed in the study
Safety outcome measures	Efficacy outcome measures
Intraoperative complications: 1. Blood loss > 400 ml 2. Cord/dural injury 3. Anaesthesia-related complications Early (< 1 month) and late postoperative(1 month-2 year) complications: 1. Wound complications 2. Meningitis 3. Septicaemia 4. Autonomic dysreflexia/dysfunction 5. Neurological worsening 6. Implant migration 7. Equipment site pain 8. Stimulator revision 9. Stimulator removal 10. Other complications	Primary outcome measures: 1. Duration of standing weight-bearing with minimal assistance, 2. Control of full weight-bearing 3. Assessment of ability to coordinate stepping on a treadmill 4. Assessment of ability to walk with minimal assistance Secondary outcome measures: 1. Improvement in the AIS of at least one grade (for example, conversion from AIS A to AIS B or better) or a change from baseline of 6 points in total AIS motor score or a change in AIS sensory examination with the stimulator on & off. 2. Any voluntary movement by additional muscle groups not included in the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI), 3. Walking Index of Spinal Cord Injury (WISCI), 4. Spinal Cord Independence Measure (SCIM), 5. Urodynamic study to assess bladder function.

Statistical analysis:

Data were compared for standing weight-bearing, duration of walking without gaiter, WISCI, SCIM and LEMS values of all participants before and after treatment. Also, data forWISCI,SCIM andLEMS values were compared with and without sEES turned on. Parametric/non-parametric equivalent tests were used after checking for assumptions.A pvalue less than 0.05 was considered as statistical significant. Excel for Windows 10 and SPSS v25.0 (Armonk, NY: IBM Corp.) was used for performing the analysis.

The enrollment of eligible participants was provided as a flow chart(Fig. 2).The demographic details of the participants, level of injury, duration of injury, neurological level as well as the status of the participantsat the time of recruitment and at the time of final assessmenthave been provided in Table 2.

The median follow up of participantswas 37 months with a range from 35 months to 41 months. All participants' desired motor movements were obtained in the frequency range of 40 to 100 Hz and an average voltage of 3V.The details of the sEES settings at which the desired movements were achieved are provided in Table 3.

Safety outcomes:

Intra-operative complications and early postoperative complications were not noted in any of the participants. Discharge from the abdominal pouch site (wound complication)was noticed in two participants(participants2 and 3). In participant 3, serious discharge (not associated with foul smell) wasnoted after 1 month but it responded to dressing and re-suturing. In participant 2, discharge was noted after 3 months and since it persisted after dressing and re-suturing, the site of implantation needed to be changed (stimulator revision). This complication did not hinder participation in the training in participant 3 whereas participant 2 had to withhold rehabilitation for 2 weeks.

Thermal burns were noted in a participant(participant1) during a household activity not related to the study. The burns were first degree,located on the upper thigh, involved 4.5% of body surface area, and responded to conservative management. She could not participate in the training for 2 weeks.Idiopathic facial nerve palsy was also noted in the same participant(participant 1) in the sixth month of her training which recovered completely in six weeks.

Efficacy outcomes: (Table 4)

Table 4: The outcome variables before and after intervention with p values

Variable	Pre treatment	Post treatment with sEES turned on	p value
Standing weight bearing duration (in minutes)	10 [7.5]	30 [10]	0.041*
Duration of walking (in minutes)	0 [0]	10 [10]	0.083
SCIM	54.4 (5.4)	63.2 (5.0)	0.002*
WISCI	2 [1.5]	6 [7]	0.041*
LEMS Right	0 [3]	7 [10.5]	0.066
LEMS Left	0 [1.5]	7 [10.5]	0.068
The values depicted are either mean (Standard deviation) or median [Inter-quartile Range] based on whether parametric or non-parametric tests were used.

Improvement in voluntary power, motor and functional abilities y was noted in fourparticipants only when the sEESwas turned on. These abilities continue to improve. Fourparticipants had gained better control of full weight bearing with sEES. Four of the participants were able to coordinate stepping on a treadmill with sEES(80%) and three of the participants were able to walk without gaiters after sEES(60%). Participants 2 and 3 achieved stepping in 3 months and participants 4 and 5 achieved stepping in 6 months. Participant 1 could not achieve stepping after sEES. Figure 3 depicts a participant who was able to walk without gaiters after sEES.

The SCIM values improved significantly post treatment with SEES on with a mean difference of 8.8 (2.7) 95% Confidence interval- 5.5 to 12.1). Similarly, WISCI scores and duration of standing weight bearing significantly improved (p = 0.041) with sEES turned on (Table 4). Participant 3 showed improvement in the ability to stand up from sitting position, weight bearing standing, stepping and walking ability even with sEES off. Theelectromyography (EMG) assessment of his walking revealed myoelectric activity in hamstrings, gastrocnemius and gluteus medius.There was no change in the urodynamics of the participants. There was also no improvement in the power of voluntary muscle groups not included in ISNCSCI.

This study reports the safety and recovery of independent walking ability in participantswho underwent locomotortraining with sEES. Only a few case reports have been published on the motor recovery after sEES. They have been performed in only three centers with in the western population. Our study on fiveparticipants is the largest sample size on sEESto establish safety and motor recovery till date. We have also utilized urodynamic studies to look for bladder recovery with sEES. Our study found that SEES is a safe procedure in severe chronic spinal cord injured participants and improves motor abilities as well asfunctional outcomes.

Harkema et al in 2011 reported supraspinal control of toe extension and ankle and leg flexion with sEESin their participant[6]. They also noted improvement in the bladder and sexual function and temperature regulation after sEES. Before that, rhythmic activity had been noted in motor complete spinal cord injury participant with sEESwhile lying supine in other studies[9–11].Rejc et al in 2017 reported a participant with chronic motor paraplegiawho showed progressive recovery in voluntary movements and standing without sEESthroughout3.7 years of training[12]. Gill et al in 2018 reported independent stepping on a treadmill, stepping over ground while using a front-wheeled walker and intermittent trainer assistance, and independent standing in a participant after 43 weeks of training[7].Angeli et al in 2018 reported their clinical study on four participants and noted that two of the four participants (both AIS grade B) were able to walk over ground with assistive devices after intensive physical training with electrical stimulation of the lower spinal cord. The other two participants(both AIS grade A) achieved some components of independent stepping on the treadmill with body-weight support but not overgroundwalking[8].

However, most of these studies have been performed on single person with SCIand one with four persons with SCI. The functional outcome measureshave not been utilized in the previous studiesto report patient outcomes. An analysis of changes in such outcome measures would provide reliable data on the effect of such intervention in daily life.

All the participants in our study had undergone comprehensive rehabilitation and recovery had plateaued before recruitmentin this study. However, after the procedure and locomotor training, four participants demonstrated improvement in the weight-bearing standing, stepping, and walking abilitywith the sEES turned on. Since participant 3 showed improvement inthe ability to stand up from sitting position, weight bearing standing, stepping and walking ability even with sEES off but there was no improvement in neurological function with the sEES switched off, we got an EMG assessment done. This revealed myoelectric activitiy in hamstrings, gastrocnemius and gluteus medius while walking. This suggests that there may be an improvement in motor power with sEES off which is however not enough so far to change AIS motor score. The potential may however be there for improvement of motor score over time with sEES off.

The ability to control standing, stepping, and walking with voluntary intent suggeststhatsuprasegmental networks are reactivated by stimulation with sEES. Participant 2was implanted with sEES 11 years after spinal cord injury. Still, the voluntary control of movements was seen in the participant after stimulation with sEES. This suggests that the spinal networks at the site of injury can be reactivated even many years after injury. Even in persons with complete spinal cord injury, there may be structural connections which are spared at the site of injury and get reactivated with sEES to conduct impulses across the site of injury. These findings are in accordance with the observations at Mayo clinic and University of Louisville[8, 12].

Participant 1 had an injury at T10-11 vertebral level(at the level of conusmedullaris) and the electrode array had to be placed on the injured conusmedullaris. This might have hindered the improvement in the participant. The participant had control of full weight bearing prior to the sEES implantation which continued post-intervention. The duration of standing weight bearing had improved post sEES and there was improvement in the ability to walk withgaitersfrom parallel bar to a walker. The WISCI score had improved in the participant with sEES.

Another interesting finding noted in our study was the loss of voluntary control from sitting to standing position. This was probably because of the change in the contact area of the electrode array to the dorsum of spinal cord.

There are limitations of the study. Firstly, the sample size is still small. The novelty of the study, the ethical issues and high cost involved limited the sample size. Secondly, EMG assessment was not done for all the participants during the locomotor training. Also the COVID 19 pandemic may have interrupted the daily exercise schedule of the participants and may have had an impact on the outcome.

To our knowledge, this study to assess safety and motor, functional and neurological recovery with sEEShas the largest sample size till date.Locomotor training with sEESis safe and improves themotor abilitiesand functional recovery of persons with severe and chronic SCI.Neurological recovery could not be demonstrated. A larger prospectivematched controlled study study with more participants needs to be done in order to draw a definite conclusion in this regard.

Data Availability Statement

All raw data is already presented in manuscript.

Data Availability Statement

All raw data is already presented in manuscript.

Acknowledgements

The authors would like to thank Mrs.VandanaPhadke and Mrs. Rajesh Sherawat for their contributions in the preparation of the manuscript.

Author contributions

HSCwas involved in the conception of the idea and the study design. He was involved in data analysis and interpretation, drafting and critical revision of the article and final approval of the version to be submitted. He was also the lead surgeon in performing the surgeries on the study participants.KKVK was involved in the study design, data collection, data analysis and interpretation, and drafting the article. He was also a part of the surgical team in performing the surgeries on the study participants and involved in the postoperative gait training of the study participants. NG, AS, BC and HKwere involved in the data collection, gait training of the study participants, stimulator setting adjustments and deciding the desirable setting for gait training. They also contributed to relevant parts of the article and reviewed the final article.GVwas involved in the study design, data analysis and interpretation.NS and RSwereinvolved in data collection, mapping of the sEES, data analysis, data interpretation and critical revision of the article.MGandMRBwere involved in the data collection.They were also a part of the surgical team in performing the surgeries on the study participants. They also contributed to relevant parts of the article and reviewed the final article.

Corresponding author

Correspondence to H.S. Chhabra.

Funding

There was no funding in support of this study.

Competing Interests

The authors declare no conflict of interest.

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Tables 2 and 3 are available in the Supplementary Files section.

There is no duality of interest

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Version 1

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Spinal Epidural Electrical Stimulation for recovery of motor function in lower limbs after Spinal Cord Injury: A Phase I/II clinical trial

Status:

Version 1

Abstract

Introduction

Methodology

Inclusion& exclusioncriteria:

Implantation procedure

Mapping:

Training:

Outcome Measures:

Statistical analysis:

Results

Safety outcomes:

Efficacy outcomes: (Table 4)

Discussion

Conclusions

Data Availability Statement

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1