Phenol and Botulinum Toxin vs Botulinum Toxin Alone for Post-Stroke Upper-Limb Spasticity
Combined Phenol and Botulinum Toxin vs Botulinum Toxin Alone for Upper-Limb Spasticity After Stroke: A Randomized Trial
This study aims to evaluate the efficacy of a combined treatment approach for post-stroke upper limb spasticity using phenol neurolysis and botulinum toxin (BoNT). Spasticity is a common post-stroke complication that leads to muscle stiffness and significantly hinders functional recovery. While botulinum toxin is the standard treatment, its high cost often limits its application, particularly for large proximal muscles.
The researchers will compare two treatment strategies in 60 adult stroke survivors:
Group A (Combined Therapy): Patients will receive ultrasound-guided phenol neurolysis for the proximal nerves (pectoralis and musculocutaneous nerves) and botulinum toxin for the distal forearm flexors.
Group B (Standard Care): Patients will receive botulinum toxin alone for all affected muscles in the upper limb.
All procedures will be performed under ultrasound guidance to ensure anatomical precision. The study will also utilize Transcranial Magnetic Stimulation (TMS) to assess changes in cortical excitability (RMT, MEPs, and cortical silent period). The primary goal is to determine if this combined approach effectively reduces muscle stiffness (measured by the Modified Ashworth Scale) while potentially reducing the total dose of botulinum toxin required per patient.
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Background and Rationale:
Post-stroke spasticity is a manifestation of Upper Motor Neuron Syndrome, characterized by reduced cortical inhibition and maladaptive plastic changes in both the ipsilesional and contralesional hemispheres. While Botulinum Toxin Type A (BoNT-A) provides focal chemodenervation, its effect on central neurophysiology is an area of active research. This study evaluates a hybrid approach-proximal Phenol neurolysis combined with distal BoNT-A-compared to standard BoNT-A alone. By utilizing Transcranial Magnetic Stimulation (TMS), we aim to investigate how reducing peripheral spasticity influences central motor excitability and interhemispheric inhibition.
Methodology and Procedures:
Participants (n=60) will be randomized 1:1 into:
Group A (Hybrid): Ultrasound-guided Phenol neurolysis (5% aqueous) of the pectoralis and musculocutaneous nerves + distal BoNT-A.
Group B (Standard): Ultrasound-guided BoNT-A for all affected upper limb muscles.
Bilateral TMS Assessment & Rationale:
Single-pulse TMS will be performed on both the ipsilesional and contralesional hemispheres to evaluate the entire motor network.
Ipsilesional Assessment: To measure corticospinal integrity via Resting Motor Threshold (RMT) and Motor Evoked Potential (MEP) amplitude.
Contralesional Assessment: To evaluate compensatory over-activity or maladaptive plasticity.
Rationale: the investigators hypothesize that effective reduction of spasticity via the hybrid approach will lead to a reduction in the Cortical Silent Period (CSP) and a shift toward normalized interhemispheric balance, potentially reflecting decreased "noise" from the spastic periphery to the cortex. If the ipsilesional MEP is absent, the contralesional hemisphere's excitability will serve as the primary neurophysiological marker.
Assessment Time Points:
All participants will undergo a comprehensive battery of assessments (Clinical, Functional, and Neurophysiological) at three specific intervals:
T0 (Baseline): prior to injection. T1 (Early Follow-up): 4 weeks post-injection (to capture peak BoNT-A and Phenol effect).
T2 (Late Follow-up): 12 weeks post-injection (to assess the sustainability of the clinical effect and central plastic changes).
Functional & Clinical Outcomes:
Clinical response is measured via the Modified Ashworth Scale (MAS) and Modified Tardieu Scale (MTS). Functional recovery is assessed through the Fugl-Meyer Assessment for Upper Extremity (FMA-UE) and the Goal Attainment Scale (GAS).
Study Type
Enrollment (Estimated)
Phase
- Phase 4
Contacts and Locations
Study Contact
- Name: Mohammad Ahmad Korayem, Master's degree
- Phone Number: +201021478054
- Email: Mohammadkorayem@aun.edu.eg
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Adult
- Older Adult
Accepts Healthy Volunteers
Description
Inclusion criteria :
- Adults aged 18 to 70 years.
- Diagnosis: Documented Ischemic or Hemorrhagic stroke (with a duration of at least 6 months post-stroke to ensure a chronic, stable phase).
- Spasticity Severity: A score of 2 on the Modified Ashworth Scale (MAS) in at least one proximal muscle group (Shoulder adductors or Elbow flexors).
- Functional Status: Evidence of upper limb motor impairment but with enough stability to participate in follow-up.
- Cognitive Ability: Ability to understand and follow instructions (Mini-Mental State Examination score typically 24) to ensure cooperation during TMS and functional testing.
- Consent: Signed informed consent provided by the patient or a legal guardian.
Exclusion Criteria :
- Fixed Contractures: Any permanent joint deformity or fixed contracture in the target limb that would prevent range of motion improvement.
- Prior Treatment: Received Botulinum Toxin or phenol injections in the affected limb within the last 6 months.
- TMS Contraindications: History of seizures.
- Presence of metallic implants in the head or neck (e.g., clips, shunts).
- Cardiac pacemakers or implanted medication pumps.
- Local Factors:Skin infection or inflammation at the planned injection sites.
- Medical Co-morbidities: Significant peripheral nerve disease (other than the stroke-related upper motor neuron lesion) or severe psychiatric disorders.
- Phenol Sensitivity: Known hypersensitivity to phenol or its derivatives.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Single
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
|---|---|
|
Experimental: Hybrid Neuro-Chemodenervation (Phenol + BoNT-A)
Participants in this arm will receive a combined treatment approach.
Phenol neurolysis (5% aqueous solution) will be administered under ultrasound guidance to the proximal nerves (specifically the pectoralis nerves for shoulder spasticity and the musculocutaneous nerve for elbow flexor spasticity).
Concurrently, Botulinum Toxin Type A (BoNT-A) will be injected into the distal forearm flexor muscles (e.g., Flexor Carpi Radialis, Flexor Carpi Ulnaris, and Flexor Digitorum Profundus/Sublimis) to address wrist and finger spasticity.
|
A chemical neurolysis procedure using a 5% aqueous phenol solution. Under real-time ultrasound (US) guidance, the needle is advanced until it is adjacent to the target nerve trunk. The phenol is then injected to induce protein denaturation and axonal degeneration (Wallerian degeneration), effectively interrupting the spastic reflex arc. Targets: The pectoralis nerves (to address shoulder adduction and internal rotation) and the musculocutaneous nerve (to address elbow flexion). Volume: Typically 1-3 mL per nerve site, adjusted based on patient anatomy and US visualization of the spread. A focal chemodenervation procedure using Botulinum Toxin Type A. The toxin is reconstituted with 0.9% sterile saline. Using ultrasound guidance, the medication is injected directly into the motor points of the hypertonic muscles. The toxin acts by inhibiting the release of acetylcholine at the neuromuscular junction, resulting in localized muscle relaxation. Targets (Experimental Group): Distal muscles only (e.g., Flexor Carpi Radialis, Flexor Digitorum Superficialis/Profundus). Targets (Comparator Group): Both proximal (Biceps, Pectoralis) and distal muscles. Dosing: Total dose per muscle is determined based on the Modified Ashworth Scale (MAS) score and muscle volume, following international consensus guidelines. |
|
Active Comparator: Standard Chemodenervation (BoNT-A Alone)
Participants in this arm will receive the standard-of-care treatment consisting of Botulinum Toxin Type A (BoNT-A) injections alone.
The toxin will be administered under ultrasound guidance to all clinically indicated upper limb muscles, including both proximal (e.g., Pectoralis major, Biceps brachii) and distal muscle groups (e.g., forearm flexors), following standard clinical dosing guidelines.
|
A focal chemodenervation procedure using Botulinum Toxin Type A. The toxin is reconstituted with 0.9% sterile saline. Using ultrasound guidance, the medication is injected directly into the motor points of the hypertonic muscles. The toxin acts by inhibiting the release of acetylcholine at the neuromuscular junction, resulting in localized muscle relaxation. Targets (Experimental Group): Distal muscles only (e.g., Flexor Carpi Radialis, Flexor Digitorum Superficialis/Profundus). Targets (Comparator Group): Both proximal (Biceps, Pectoralis) and distal muscles. Dosing: Total dose per muscle is determined based on the Modified Ashworth Scale (MAS) score and muscle volume, following international consensus guidelines. |
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Change from Baseline in the Modified Ashworth Scale (MAS) at 4 and 12 weeks.
Time Frame: Baseline, 4 weeks, and 12 weeks.
|
The MAS is used to assess muscle spasticity on a scale from 0 to 4. We will calculate the mean change in scores from baseline to each follow-up point.
Lower scores indicate a reduction in muscle tone.
|
Baseline, 4 weeks, and 12 weeks.
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Change from Baseline in Fugl-Meyer Assessment for Upper Extremity (FMA-UE).
Time Frame: Baseline, 4 weeks, and 12 weeks.
|
A stroke-specific scale to evaluate motor recovery.
Scores range from 0 to 66, with higher scores indicating better motor function.
|
Baseline, 4 weeks, and 12 weeks.
|
|
Goal Attainment Scale (GAS).
Time Frame: 4 weeks and 12 weeks.
|
Evaluates the achievement of individual functional goals set at baseline.
|
4 weeks and 12 weeks.
|
|
Change from Baseline in Resting Motor Threshold (RMT) of both hemispheres.
Time Frame: Baseline, 4 weeks, and 12 weeks.
|
Change from Baseline in Resting Motor Threshold (RMT) of both hemispheres measured using single-pulse Transcranial Magnetic Stimulation (TMS). Resting Motor Threshold will be assessed using single-pulse transcranial magnetic stimulation delivered over the primary motor cortex (M1) with a figure-of-eight coil. Surface electromyography (EMG) will record motor-evoked potentials (MEPs) from the contralateral first dorsal interosseous (FDI) muscle. RMT is defined as the minimum stimulator intensity (% of maximum stimulator output) required to elicit MEPs ≥50 μV in at least 5 out of 10 consecutive trials. RMT will be measured separately for the ipsilesional and contralesional hemispheres. Values are expressed as a percentage of maximum stimulator output (% MSO). Lower RMT values indicate increased corticospinal excitability. Assessments will occur at baseline, 4 weeks, and 12 weeks. |
Baseline, 4 weeks, and 12 weeks.
|
|
Change from Baseline in Cortical Silent Period (CSP) duration.
Time Frame: Baseline, 4 weeks, and 12 weeks.
|
Change from Baseline in Cortical Silent Period (CSP) duration measured using transcranial magnetic stimulation (TMS). CSP duration will be assessed using single-pulse TMS delivered over the primary motor cortex during voluntary contraction (approximately 20% of maximal voluntary contraction) of the contralateral first dorsal interosseous muscle. CSP is defined as the duration (milliseconds) from the onset of the motor-evoked potential to the return of continuous EMG activity. CSP duration will be recorded for both hemispheres. Values are expressed in milliseconds (ms). Longer CSP duration reflects increased cortical inhibition. |
Baseline, 4 weeks, and 12 weeks.
|
|
Total Dose of Botulinum Toxin Type A (BoNT-A) administered.
Time Frame: Day 0 (at time of injection).
|
Comparison of the total units of BoNT-A used between the Hybrid group and the Standard group.
|
Day 0 (at time of injection).
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Mohammad Korayem, Master's degree, Assiut University
Publications and helpful links
General Publications
- Murase N, Duque J, Mazzocchio R, Cohen LG. Influence of interhemispheric interactions on motor function in chronic stroke. Ann Neurol. 2004 Mar;55(3):400-9. doi: 10.1002/ana.10848.
- Rossini PM, Burke D, Chen R, Cohen LG, Daskalakis Z, Di Iorio R, Di Lazzaro V, Ferreri F, Fitzgerald PB, George MS, Hallett M, Lefaucheur JP, Langguth B, Matsumoto H, Miniussi C, Nitsche MA, Pascual-Leone A, Paulus W, Rossi S, Rothwell JC, Siebner HR, Ugawa Y, Walsh V, Ziemann U. Non-invasive electrical and magnetic stimulation of the brain, spinal cord, roots and peripheral nerves: Basic principles and procedures for routine clinical and research application. An updated report from an I.F.C.N. Committee. Clin Neurophysiol. 2015 Jun;126(6):1071-1107. doi: 10.1016/j.clinph.2015.02.001. Epub 2015 Feb 10.
- Anwar F, Ramanathan S. Combined Botulinum Toxin Injections and Phenol Nerve / Motor Point Blocks to Manage Multifocal Spasticity in Adults. British Journal of Medical Practitioners. March 2017;10(1):a1002.
- Gonnade N, Lokhande V, Ajij M, Gaur A, Shukla K. Phenol Versus Botulinum Toxin A Injection in Ambulatory Cerebral Palsy Spastic Diplegia: A Comparative Study. J Pediatr Neurosci. 2017 Oct-Dec;12(4):338-343. doi: 10.4103/jpn.JPN_123_17.
- Wissel J, Ward AB, Erztgaard P, Bensmail D, Hecht MJ, Lejeune TM, Schnider P, Altavista MC, Cavazza S, Deltombe T, Duarte E, Geurts AC, Gracies JM, Haboubi NH, Juan FJ, Kasch H, Katterer C, Kirazli Y, Manganotti P, Parman Y, Paternostro-Sluga T, Petropoulou K, Prempeh R, Rousseaux M, Slawek J, Tieranta N. European consensus table on the use of botulinum toxin type A in adult spasticity. J Rehabil Med. 2009 Jan;41(1):13-25. doi: 10.2340/16501977-0303.
Study record dates
Study Major Dates
Study Start (Estimated)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Other Study ID Numbers
- NuroRehabSpasticity
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
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