Epidural Spinal Cord Stimulation for Lower-limb Impairment in Adrenomyeloneuropathy

Official title

Spinal Cord Stimulation Surgery for Improving Lower Limb Motor Dysfunction in Adrenomyeloneuropathy (AMN): A Prospective, Multicenter, Single-Arm, Self-Controlled Study.

Overview

Adrenal spinal neuropathy (AMN) is a rare X-linked genetic disease caused by mutations in the ABCD1 gene, and belongs to a special type of adrenal leukodystrophy. The patient's lower limb strength is weakened, the range of motion of the ankle joint is reduced, the hip flexors are weak and affect walking, and the peripheral nerves and vibration sensation are damaged. As the condition worsens, the lower limb muscle tone changes from hyperactivity to decrease, ultimately transitioning from spastic paralysis to flaccid paralysis. At present, the treatment plan for AMN is not yet perfect, and effective therapies are urgently needed to alleviate symptoms. Spinal cord electrical stimulation (SCS) is the implantation of a thin electrode into the epidural space of the corresponding spinal segment within the spinal canal. Then connect the electrodes to a nerve stimulator implanted subcutaneously in the iliac region, and use electrical pulses to stimulate the conduction of sensory neurons in the posterior column and posterior horn of the spinal cord for treatment, which can achieve the goal of controlling pain. In addition, SCS has also conducted research on the recovery of lower limb function in paraplegic patients and upper limb function in post-stroke hemiplegic patients, and has improved corresponding motor dysfunction to a certain extent. Spinal cord stimulation may be a potential treatment for motor dysfunction in AMN. Based on the above, this study attempts to evaluate the efficacy of SCS in treating lower limb muscle tone and movement disorders in AMN patients, and explore the potential therapeutic effects and related mechanisms of SCS on AMN. In this study, 10 AMN patients will be recruited. After enrollment, preoperative evaluation will be conducted. After preliminary assessment of motor function, neurological evaluation, and other related examinations, lumbar spinal nerve stimulators and pulse generators were implanted in our hospital. After the implantation surgery is completed, depending on the patient's recovery status, they will be transferred to various centers for subsequent rehabilitation treatment within one to two weeks, and then turned on for treatment. Before starting up, a second corresponding inspection and evaluation will be conducted. The third and fourth corresponding inspections and evaluations will be conducted one week and four weeks after startup, respectively. The patient will be discharged 4 weeks after starting up, and then return to the hospital for the fifth and sixth corresponding examinations and evaluations at 4 weeks and 6 months after discharge. Evaluate the effectiveness and safety of SCS in improving lower limb motor dysfunction in AMN patients through statistical analysis.

Detailed description

Adrenomyeloneuropathy (AMN) is an X-linked inherited metabolic rare disease caused by mutations in the ABCD1 gene, with an incidence rate of only 1 in 50,000. Currently, it is regarded as a special type of adrenoleukodystrophy (ALD), and AMN is the most dominant disease subtype affecting adult patients. Due to the special phenomenon of skewed X-inactivation, female heterozygotes may also have spinal cord neuropathy. Such mutations can lead to the accumulation of very long chain fatty acids (VLCFA) in the blood and organs, mainly resulting in demyelination of the central nervous system and lesions in the adrenal cortex. As the disease progresses, the strength of the lower limbs and the passive range of motion of the ankle joints of patients will gradually decline. The deterioration of hip flexor muscle weakness is closely associated with a slower walking speed and an increased degree of disability. Most patients will also experience peripheral nerve involvement and impairment of vibration sensation. Hypertonia of the lower limbs will gradually develop into a decline in both muscle strength and muscle tone, and finally progress from spastic paralysis to flaccid paralysis. However, the current commonly used treatment regimens for AMN still have deficiencies, and it is necessary to seek effective treatment methods to alleviate patients' symptoms and improve their quality of life.

Spinal Cord Stimulation (SCS) involves implanting a thin electrode (either strip-shaped or needle-shaped) into the epidural space within the spinal canal at the corresponding spinal segments, adjacent to the posterior columns of the spinal cord. The electrode is then connected to a nerve stimulator implanted subcutaneously in the iliac region, and electrical pulses are used to stimulate the conduction of the posterior columns of the spinal cord and the sensory neurons in the posterior horns for treatment purposes. This blocks the transmission of pain signals from the spinal cord to the brain, preventing them from reaching the cerebral cortex, thereby achieving the goal of pain control. Previous studies have demonstrated that, in addition to having significant therapeutic effects in analgesia, SCS has also been investigated in aspects such as the recovery of lower limb function in paraplegia and the recovery of upper limb function in hemiplegia after stroke, and it has improved the corresponding motor dysfunctions to a certain extent. For the problem of motor dysfunction in AMN, there is currently no good treatment method, and spinal cord stimulation may serve as a potential treatment approach. Based on the above, this study attempts to further explore the potential therapeutic effect and related treatment mechanisms of SCS on AMN through evaluating the efficacy of SCS in treating motor disorders of muscle tone and strength in the lower limbs of patients with AMN.

In the study, 10 patients with AMN will be recruited. After patients are enrolled in the group, preoperative evaluations will be conducted. And after the first evaluations of motor function, neurological assessment and other relevant examinations, the implantation of lumbar spinal cord nerve stimulator and pulse generator will be carried out in our hospital. After the completion of the implantation surgery, depending on the patients' recovery status, they will be transferred to each center for subsequent rehabilitation treatment within one to two weeks, and then the electrical stimulation treatment will be initiated by turning on the device. Before turning on the device, the second corresponding examinations and evaluations will be conducted. The third and fourth corresponding examinations and evaluations will be carried out one week and four weeks after turning on the device, respectively. Patients will be discharged four weeks after turning on the device, and then return to the hospital for the fifth and sixth corresponding examinations and evaluations four weeks and six months after discharge, respectively. Through the statistical analysis of self-controlled comparison before and after the trial, the efficacy and safety of SCS in improving lower limb motor dysfunction in patients with AMN will be evaluated.

Interventions

• Procedure Spinal cord stimulation
  Upon completion of the initial assessments, a lumbar spinal cord nerve stimulator and pulse generator will be implanted. Following surgery, based on the patient's recovery status, the patient will be transferred to the respective center for rehabilitation within one to two weeks. Afterward, electrical stimulation therapy will be initiated. Stimulation should be applied at least three days per week. Each day, the total stimulation time should be between 4 and 8 hours. Stimulation Modes: Continuou

Primary outcome measures

• 6-minute walk test (6MWT) [Time frame: Preoperative stage; One week after surgery; One week after device activation; Four weeks after device activation; Four weeks after discharge from hospital; Six months after discharge from hospital]

Secondary outcome measures (12)

• Adverse event [Time frame: One week after surgery; One week after device activation; Four weeks after device activation; Four weeks after discharge from hospital; Six months after discharge from hospital; One year after discharge from hospital.]
• Discomfort and pain. [Time frame: Preoperative stage; One week after surgery; One week after device activation; Four weeks after device activation; Four weeks after discharge from hospital; Six months after discharge from hospital; One year after discharge from hospital.]
• Spinal cord and brain MRI [Time frame: Preoperative stage; One week after surgery; One week after device activation; Four weeks after device activation; Four weeks after discharge from hospital; Six months after discharge from hospital]
• The degree of improvement in electrophysiological indicators of the muscles in the affected limbs [Time frame: Preoperative stage; One week after surgery; One week after device activation; Four weeks after device activation; Four weeks after discharge from hospital; Six months after discharge from hospital]
• Qmax（The maximum flow rate） [Time frame: Preoperative stage; One week after surgery; One week after device activation; Four weeks after device activation; Four weeks after discharge from hospital; Six months after discharge from hospital]
• Filling bladder pressure [Time frame: Preoperative stage; One week after surgery; One week after device activation; Four weeks after device activation; Four weeks after discharge from hospital; Six months after discharge from hospital]
• Urethral pressure [Time frame: Preoperative stage; One week after surgery; One week after device activation; Four weeks after device activation; Four weeks after discharge from hospital; Six months after discharge from hospital]
• Residual urine volume [Time frame: Preoperative stage; One week after surgery; One week after device activation; Four weeks after device activation; Four weeks after discharge from hospital; Six months after discharge from hospital]
• Evaluation of erectile function (International Index of Erectile Function-5 (IIEF-5) score) [Time frame: Preoperative stage; One week after surgery; One week after device activation; Four weeks after device activation; Four weeks after discharge from hospital; Six months after discharge from hospital]
• Stool scoring (Wexner Incontinence Scale, Bristol Stool Scale (BSFS)) [Time frame: Preoperative stage; One week after surgery; One week after device activation; Four weeks after device activation; Four weeks after discharge from hospital; Six months after discharge from hospital]
• Somatosensory evoked potential, visual evoked potential, auditory evoked potential, motor evoked potential. [Time frame: Preoperative stage; One week after surgery; One week after device activation; Four weeks after device activation; Four weeks after discharge from hospital; Six months after discharge from hospital]
• Motion capture (gait test) [Time frame: Preoperative stage; One week after surgery; One week after device activation; Four weeks after device activation; Four weeks after discharge from hospital; Six months after discharge from hospital]

Eligibility criteria

Inclusion criteria

• Conforming to the diagnostic criteria of AMN, with a definite genetic testing report, and complicated by lower limb motor function disorders;
• Capable of normal communication and able to complete scale tests independently (as determined by on-site scale tests);
• Willing to participate in this study after giving informed consent;
• The muscle tone of the patient's bilateral lower extremities was elevated.

Exclusion criteria

• Other inherited diseases;
• Other severe central nervous system diseases;
• History of brain surgery;
• Psychiatric and psychological diseases such as depression and anxiety;
• The presence of metallic foreign bodies or prostheses (such as cardiac pacemakers, insulin pumps) in the body, claustrophobia, and other contraindications for MRI;
• Informed consent was not obtained;
• Unable to tolerate MRI-related examinations;
• Received anticoagulant, antispasmodic or antiepileptic drug therapies throughout the entire study period;
• Postoperative wound infection;
• Other motor disorders, spinal cord pathologies, fractures, osteoarthritis, amputations, scoliosis and other movement-affecting diseases.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 4 centers

• Beijing TianTan Hospital — Beijing
• The 958 Hospital of Chinese People's Liberation Army, The Jiangbei Campus of Southwest Hos — Chongqing
• the Southwest hospital — Chongqing
• Jingmen No.1 People's Hospital — Jingmen

Publications

• Shanthanna H, Eldabe S, Provenzano DA, Bouche B, Buchser E, Chadwick R, Doshi TL, Duarte R, Hunt C, Huygen FJPM, Knight J, Kohan L, North R, Rosenow J, Winfree CJ, Narouze S. Evidence-based consensus guidelines on patient selection and trial stimulation for spinal cord stimulation therapy for chronic non-cancer pain. Reg Anesth Pain Med. 2023 Jun;48(6):273-287. doi: 10.1136/rapm-2022-104097. Epub PMID 37001888
• North R, Shipley J, Prager J, Barolat G, Barulich M, Bedder M, Calodney A, Daniels A, Deer T, DeLeon O, Drees S, Fautdch M, Fehrenbach W, Hernandez J, Kloth D, Krames ES, Lubenow T, North R, Osenbach R, Panchal SJ, Sitzman T, Staats P, Tremmel J, Wetzel T, American Academy of Pain Medicine. Practice parameters for the use of spinal cord stimulation in the treatment of chronic neuropathic pain. Pai PMID 17995571
• Powell MP, Verma N, Sorensen E, Carranza E, Boos A, Fields DP, Roy S, Ensel S, Barra B, Balzer J, Goldsmith J, Friedlander RM, Wittenberg GF, Fisher LE, Krakauer JW, Gerszten PC, Pirondini E, Weber DJ, Capogrosso M. Epidural stimulation of the cervical spinal cord for post-stroke upper-limb paresis. Nat Med. 2023 Mar;29(3):689-699. doi: 10.1038/s41591-022-02202-6. Epub 2023 Feb 20. PMID 36807682
• Kandhari S, Sharma D, Samuel S, Sharma G, Majumdar P, Edgerton VR, Gad P. Epidural Spinal Stimulation Enables Global Sensorimotor and Autonomic Function Recovery After Complete Paralysis: 1st Study From India. IEEE Trans Neural Syst Rehabil Eng. 2022;30:2052-2059. doi: 10.1109/TNSRE.2022.3158393. Epub 2022 Jul 27. PMID 35271446
• Wagner FB, Mignardot JB, Le Goff-Mignardot CG, Demesmaeker R, Komi S, Capogrosso M, Rowald A, Seanez I, Caban M, Pirondini E, Vat M, McCracken LA, Heimgartner R, Fodor I, Watrin A, Seguin P, Paoles E, Van Den Keybus K, Eberle G, Schurch B, Pralong E, Becce F, Prior J, Buse N, Buschman R, Neufeld E, Kuster N, Carda S, von Zitzewitz J, Delattre V, Denison T, Lambert H, Minassian K, Bloch J, Courtine PMID 30382197
• Rowald A, Komi S, Demesmaeker R, Baaklini E, Hernandez-Charpak SD, Paoles E, Montanaro H, Cassara A, Becce F, Lloyd B, Newton T, Ravier J, Kinany N, D'Ercole M, Paley A, Hankov N, Varescon C, McCracken L, Vat M, Caban M, Watrin A, Jacquet C, Bole-Feysot L, Harte C, Lorach H, Galvez A, Tschopp M, Herrmann N, Wacker M, Geernaert L, Fodor I, Radevich V, Van Den Keybus K, Eberle G, Pralong E, Roulet M PMID 35132264
• Luo S, Xu H, Zuo Y, Liu X, All AH. A Review of Functional Electrical Stimulation Treatment in Spinal Cord Injury. Neuromolecular Med. 2020 Dec;22(4):447-463. doi: 10.1007/s12017-019-08589-9. Epub 2020 Jan 8. PMID 31916220
• Moraud EM, Capogrosso M, Formento E, Wenger N, DiGiovanna J, Courtine G, Micera S. Mechanisms Underlying the Neuromodulation of Spinal Circuits for Correcting Gait and Balance Deficits after Spinal Cord Injury. Neuron. 2016 Feb 17;89(4):814-28. doi: 10.1016/j.neuron.2016.01.009. Epub 2016 Feb 4. PMID 26853304

Identifiers

NCT: NCT06796920 · ThirdMMU-TLiang

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗