Chemodenervation and Neurolysis

Author(s): Natasha L Romanoski, DO, Kevin Moser, MD, Neyha Cherin, DO

Originally published:09/20/2013

Last updated:11/29/2019

1. OVERVIEW AND DESCRIPTION

Definition

Chemodenervation is the blockade of neuronal signaling at the neuromuscular junction using botulinum neurotoxin (BoNT). Chemical neurolysis is the application of a chemical agent directly to a nerve or motor point to intentionally interfere with nerve conduction through destruction of a portion of the nerve. Neurolysis is performed with either phenol (carbolic acid) or high concentrations of ethyl alcohol. These procedures are typically performed to reduce spasticity or dystonia related to central nervous system disorders with the goal of achieving functional improvements. Effective use of chemodenervation and neurolysis can result in improvements in gait, independence, completion of ADLs, improved personal hygiene, reduction of caregiver burden, reduction of pain related to spasticity, improvement in self-image and mood, and prevention of contractures.

Mechanism of Action

  1. Phenol and ethyl alcohol: Phenol and ethyl alcohol mediate their effect through nonselective denaturing of proteins upon exposure to nerve, thereby causing nerve injury by precipitating and dehydrating the protoplasm. This in turn interferes with nerve conduction and impairs innervation to muscles. Phenol is typically used at concentrations between 5% and 7%, and ethyl alcohol in concentrations between 45% and 100%.
  2. BoNT: Botulinum Neurotoxin is an exotoxin produced by Clostridium botulinum; it has 7 serotypes, A through G. Only serotypes A and B are currently used in clinical practice. There are currently four FDA approved formulations of BoNT. These include onabotulinumtoxinA, abobotulinumtoxinA, incobotulinumtoxinA, and rimabotulinumtoxinB. All BoNT formulations are composed of two subunits, a light chain and a heavy chain, and mediate their effect through blocking of neuromuscular transmission at the pre-synaptic terminal by inhibiting the release of acetylcholine-filled vesicles. BoNT-A formulations achieve this by cleaving SNAP-25, an integral part of the SNARE complex. BoNT-B cleaves synaptobrevin which similarly is a component of the SNARE complex. This results in partial chemical denervation and localized reduction in muscle activity. Transdermal BoNT works by chemically denervating sweat glands, providing local reduction in sweating.

Summary of Food and Drug Administration-Approved BTX Products

Onabotulinum-toxinA Abobotulinum-toxinA Incobotulinum-toxinA Rimabotulinum-toxinB
Cervical Dystonia Yes Yes Yes Yes
Glabellar lines Yes Yes Yes
Blepharospasm Yes* Yes
Strabismus Yes*
Axillary Hyperhidrosis Yes
Upper extremity spasticity Adults Yes Yes Yes
Lower extremity spasticity Adults Yes Yes
Chronic migraine Yes
Overactive bladder Yes
Detrusor overactivity Yes
Upper Limb Spasticity Pediatrics ** Yes Yes***
Lower Limb Spasticity Pediatrics ** Yes
Sialorrhea Yes Yes

Note:

  • *OnabotulinumtoxinA can be used for treatment of blepharospasm and strabismus in patients 12 years and older.
  • **Pediatric indications are for 2 years or older.
  • ***AbobotulinumtoxinA for upper extremity spasticity in pediatrics excludes cerebral palsy
  • All other indications listed are approved for adult use only.
  • Any other use is considered off-label.
  • Phenol is not FDA approved, but is widely used for treatment of focal spasticity

Side Effects or Complications

  1. Phenol/Alcohol
    • Complications include trauma to the injection site, tissue swelling, muscle necrosis and fibrosis, granuloma formation, muscle atrophy, scarring, skin slough, risk of dysesthesias (most common when injection is to mixed motor and sensory nerves) and permanent weakness due to nerve damage. Systemic absorption can result in seizures and cardiovascular or central nervous system effects.
    • Caution should be taken in patients with advanced liver disease, as the liver metabolizes phenol.
    • Chronic phenol exposure may lead to renal toxicity, skin lesions, and gastrointestinal side effects.
  2. BoNT
    • Most common adverse reactions for spasticity management include pain at injection site, flu-like symptoms, neck pain and headache (related to chronic migraine treatment), and dysphagia and upper respiratory infection (most commonly related to cervical dystonia treatment).
    • All botulinum toxin formulations have a black box warning regarding distant spread of the toxin which may result in symptoms of swallowing and breathing difficulty and risk of death. Risk is greater in children and with higher doses, and if medication is injected intravascularly.

Both phenol and BoNT reduce hypertonia temporarily and need to be repeated periodically. Phenol is more technically difficult to perform and the effects typically last longer.

2. RELEVANCE TO CLINICAL PRACTICE

Available or Current Treatment Guidelines

  1. Botulinum Toxin and Chemical Neurolysis (with phenol or alcohol) may be considered isolated treatment options for focal spasticity but may also be considered in combination with one another and possibly with other treatment modalities for severe spasticity.

Phenol

  1. Although no current guidelines exist, chemical neurolysis with phenol or alcohol has historically been used for pure motor nerves when a large number of muscles are being injected with botulinum toxin and another option is needed to allow toxin use elsewhere. More recently, there has been an increase in the use of phenol neurolysis for mixed motor sensory nerves due to the relatively low cost and positive outcomes. These injections attempt to isolate the motor branch of the mixed nerve by utilizing both ultrasound and electrical stimulation guidance.
  2. Phenol must be prepared by a hospital pharmacy due to its unstable pharmacokinetics. It is unstable at room temperature and oxidizes in the presences of light and air. It is colorless and has a strong odor.
  3. Phenol can be prepared in a water, glycerin or lipid solution to the desired concentration, typically 5-7% for the treatment of spasticity.  At low concentrations, phenol can have a local anesthetic effect and concentrations higher than 3% act as a neurolytic.
  4. Alcohol concentrations between 45-100% can be used for chemical neurolysis.  Alcohol has a local anesthetic property at 5-10% concentrations.
  5. Electrical stimulation using a Teflon coated needle is used to localize a motor point to identify the peripheral nerve for neurolysis. The electric stimulation is decreased, and the needle is reoriented until the minimum current required (ideally 1-2mA at 1-2Hz) to obtain a muscle twitch is reached. This technique facilitates a close approximation to the nerve.
  6. Additionally, ultrasound guidance can be used to isolate peripheral nerves and to localize motor branches in mixed motor sensory nerves.
  7. Medication is then injected.
  8. Maximum injected phenol solution for safe outcomes is generally agreed to be 1000mg– 1200mg (6% aqueous phenol solution = 60mg/mL).
  9. Systemic absorption of phenol in adults is thought to occur at dosages and concentrations much higher than what is traditionally used for chemical neurolysis.
  10. Although effects are generally immediate with higher concentrations; due to the local anesthetic effect of phenol, the therapeutic effect from neurolysis with lower concentrations may not be evaluated until after 24-28 hours, and may take up to 3-7 days.
  11. Results can last weeks to months. Procedure can be repeated.
  12. Incidence of dysesthesias is 2% to 32% in adults and less than 5% in children; dysesthesias can last a few weeks.
  13. Systemic analgesic treatment can be used to treat dysesthesias.
  14. Phenol and alcohol neurolysis is inexpensive and widely approved.

BoNT A and B

  1. Dosing and Administration:
    • The various commercial formulations of botulinum toxin products are NOT interchangeable. Based on which serotype is used, the potency and duration of action may vary.
      1. Average onset varies 2-10 day
      2. Average peak varies 2-8 weeks
      3. Average duration varies 12-16 weeks
    • Side-effects secondary to systemic spread are possible when higher doses are used. Molecular size of botulinum toxin prevents it from crossing the blood brain barrier. The side-effect profile for onabotulinumtoxinA and incobotulinumtoxinA are similar; although, abobotulinumtoxinA seems to produce more local side-effects, which could be because of more diffusion or variations in conversion factors. BoNT type B has a lower pH value compared with the BoNT type A formulations, which could cause more injection site pain. BoNT type B also has a relatively stronger autonomic effect, such as dry mouth, corneal irritation, and accommodation difficulties.
    • Safety of use during pregnancy has not been established. Caution should be rendered when using BoNT in patients with neuromuscular conditions or neuromuscular junction disorders. Aminoglycosides may potentiate the efficacy of BoNT and should be avoided.
    • The FDA has approved dosing guidelines based on the botulinum toxin product, treatment type, age of patient, weight of patient and specific muscle targeted.
    • The FDA restricts repeat injections to every 90 days
    • The FDA recommends no more than 400 Units of OnabotulinumtoxinA. Dosing guidelines for FDA indicated muscles are listed below. All reconstitution should be with preservative free 0.9% normal saline.
      • OnabotulinumtoxinA A Dosing for Chronic Migraine Treatment:
        • Approved for adult patients with chronic migraines, which is defined as, 15 or more migraines a month, with each lasting at least 4 hours a day.
        • Recommended dilution: 200 Units/4mL or 100 Units/2mL. Final concentration of 5 Units/0.1mL.
Facial Muscles Recommended Dose/Number of Sites
Frontalis 20 Units divided in 4 sites
Corrugator 10 Units dived in 2 sites
Procerus 5 Units in 1 site
Occipitalis 30 Units divided in 6 sites
Temporalis 40 Units divided in 8 sites
Trapezius 30 Units divided in 6 sites
Cervical Paraspinals 20 Units divided in 4 Sites
Total Dose 155 Units per treatment session at 31 sites
      • Onabotulinumtoxin A Dosing for Spasticity:
        • Approved to treat adult patients with upper and lower limb spasticity, and pediatric patients (2-17 years of age) with upper limb spasticity.
        • Recommended Dilution: 200 Units/4mL or 100 Units/2mL along with 0.9% Sodium Chloride solution.
Upper Limb Muscles Recommended Dose/Number of Sites
Biceps Brachii 100- 200 Units divided in 4 sites
Flexor Carpi Radialis 12.5 – 50 Units in 1 site
Flexor Carpi Ulnaris 12.5 – 50 Units in 1 site
Flexor Digitorum Profundus 30 – 50 Units in 1 site
Flexor Digitorum Sublimus 30 – 50 Units in 1 site
Adductor Pollicis 20 Units in 1 site
Flexor Pollicis Longus 20 Units in 1 site
Lower Limb Muscles Recommended Dose/Number of Sites
Gastrocnemius – Medial Head 75 Units divided in 3 sites
Gastrocnemius – Lateral Head 75 Units divided in 3 sites
Soleus 75 Units divided in 3 sites
Tibialis Posterior 75 Units divided in 3 sites
Flexor Digitorum Longus 50 Units divided in 2 sites
Flexor Hallucis Longus 50 Units divided in 2 sites
      • OnabotulinumtoxinA Dosing for Cervical Dystonia:
        • Approved for adults and children 16 years of age or older.
        • Recommended dilution: 200 Units/2mL, 200 Units/4mL, 100 Units/1mL, or 100 Units/2mL along with 0.9% Sodium Chloride solution.
Type of Dystonia Recommended Contralateral Muscles  Recommended Ipsilateral Muscles
Torticollis Sternocleidomastoid Splenius Capitis
Trapezius Splenius Cervicis
Scalenes Levator Scapulae
Longissimus
Laterocollis Levator Scapulae
Trapezius
Scalenes
Sternocleidomastoid
Splenius Capitis
Splenius Cervicis
Longissimus
Anterocollis Sternocleidomastoid Sternocleidomastoid
Scalenes Scalenes
Retrocollis Levator Scapulae Levator Scapulae
Trapezius Trapezius
Longissimus Capitis Longissimus Cervicis Longissimus Capitis

LongissimusCervicis

Splenius Capitis

Splenius Cervicis

Splenius Capitis

Splenius Cervicis

Semispinalis Capitis Semispinalis Capitis
Muscle Recommended Dose
Splenius Capitis 15 – 100 units
Splenius Cervicis 20 – 60 Units
Sternocleidomastoid 15 – 100 Units
Scalene Complex 15 – 50 Units
Semispinalis Capitis 30 – 100 Units
Trapezius 20 – 100 Units
Longissimus 30 – 100 Units
Levator Scapulae 20 – 100 Units

Note: Other botulinum toxin formulations have dosing guidelines which can be references in package inserts.

  1. Creating a Treatment Plan:
    • Prior to the utilization of botulinum toxin products, a thorough discussion between patient, caregiver and provider regarding goals of treatment should be addressed.
    • Common goals of treatment:
      • Pain reduction, spasticity reduction, improvement in caregiver burden, improvement in activities of daily living and functional mobility, improvement in range of motion, contracture prevention, skin breakdown prevention, improvement in gait mechanics, improvement in positioning and posture, prevention of joint destruction and skin breakdown, improvement in hygiene.
    • When beginning treatment with botulinum toxin products, the FDA recommends initiation with the lowest approved dosing.
    • It is beneficial to have close follow up with the patient to monitor therapeutic effectiveness and determine whether patient and caregiver goals were achieved. Based on these discussions, future treatments may be tailored on an individual patient basis.
    • If treatments are insufficient, consider increasing dose or dilution, changing injection technique, or adding phenol blocks. If these measures are ineffective, then oral treatment or surgical interventions might be considered.
  2. Localization Techniques:
    • BoNT injections are most effective when injected close to muscle motor points.
    • The effects of BoNT can decrease significantly when given as little as 1 cm away from the motor point.
    • To increase the accuracy of localization the following methods are commonly used: anatomic localization using palpation, electromyography (EMG) guidance, electrical stimulation (ES), sonography (US), and computerized tomography/fluoroscopy guidance (uncommonly used).
    • Anatomic Localization:
      1. Based on common anatomic landmarks, palpation is used to localize the target muscle.
      2. Pro: No extra equipment is required. Very user friendly technique. Fast and easy technique for superficial and easily located musculature. Patient can assist by voluntary contracting the specific muscle targeted. Least time consuming.
      3. Con: This technique is the least precise. There is low reliability that the provider is in the correct musculature, especially for deeper muscles. In addition, it may be difficult with this technique to access deeper musculature.
    • EMG guidance:
      1. Motor unit potentials (MUAPs) that are close to the needle tip are identified either by morphology or acoustic properties. Crisp, full-sized MUAPs confirm needle tip near the contracting muscle fibers.
      2. Pro: Studies demonstrate EMG guidance is an effective way to inject closest to the motor end-plate, which is the target goal.
      3. Con: EMG guidance only indicates the needle being in an active muscle and not a specific muscle. In addition, EMG guidance is not appropriate if there is difficulty obtaining active or passive muscle activation.
    • Electrical Stimulation:
      1. When ES is used for guidance, the needle electrode is introduced into the desired muscle, and the muscle is stimulated. BoNT is injected once contraction of only the desired muscle is noted. With ES, proximity of the needle tip to the motor endplate zones is confirmed, and the ability of BoNT to diffuse in the muscle is relied on.
      2. Pro: ES is an effective way to inject closest to the motor end-plate, which is the target goal.
      3. Con: ES is more time consuming and painful due to stimulation of the muscle. In addition, providers require more experience and training to effectively utilize this methodology. You do not want to use this method if contraction of muscle won’t result in obvious joint movement.
    • Sonography or ultrasound (US) guidance:
      1. Real-time visualization of the target muscle makes US a very helpful guide when targeting muscles.
      2. Pro: US guidance allows for painless tracking of the musculature, precision and accuracy of superficial and deep muscles. This technique allows for avoidance of neuro-vasculature. In addition, a fine, thin needle can be utilized to minimize pain.
      3. Con: Highly dependent on operator’s skill and training. The needle, although in the muscle, may not be close to the motor endplates.
    • Computerized tomography/Fluoroscopic Guidance:
      1. Rarely used for identifying muscles because of cost and time limitations.

3. CUTTING EDGE/UNIQUE CONCEPTS/EMERGING ISSUES

Antigenicity to botulinum toxin formulations should be considered with a primary or secondary nonresponse. Botulinum toxin consists of foreign proteins, thus, antibodies can be formed against these proteins. Risk factors for antibody production include the amount of toxin used at each visit and short treatment intervals. Antibodies can be detected serologically or by assessing paralysis after unilateral frontalis or extensor digitorum brevis injections.

Botulinum toxin is increasingly used to treat off label conditions, such as:

  1. Bruxism: Injecting the masseters and/or the temporalis with up to 100 U of BoNT type A helps reduce pain and discomfort.
  2. Spasm of rectal sphincter: BoNT type A injected into both the internal and external sphincters helps reduce rectal sphincter spasms. Doses up to 80 U are safe.
  3. Pain: The ability of botulinum toxin to inhibit neuropeptide release from nociceptors, thereby blocking central and peripheral pain sensitization processes, is utilized to treat several pain conditions such as low back pain, piriformis syndrome and plantar fasciitis,
  4. Neuropathic Pain Conditions: Favorable results have been reported with subcutaneous injection of botulinum toxin into areas associated with post-herpetic neuralgia, post-traumatic neuralgia and trigeminal neuralgia.
  5. Residual Limb hyperhidrosis: The use of intradermal botulinum toxin at 2cm increments has been used in case reports to treat focal areas of increased perspiration in the amputated limb.
  6. Hidradenitis suppurativa: The use of botulinum toxin has been shown in case reports to alleviate pain, slow the progression and resolve abscess formation.
  7. Scoliosis: The use of botulinum toxin for adolescents with idiopathic scoliosis has shown promising results in regards to improving Cobb angle measurements at 6 weeks following injection into the iliopsoas muscle on the concave side of the curve. Similar studies have looked at this in patients with cerebral palsy, however, no radiographic or clinical improvement was noted.

Phenol toxin off-label uses include:

  1. Currently there are no consensus guidelines for phenol neurolytic injections.
  2. Phenol can be used for persistent and intractable pain conditions. A diagnostic local anesthetic block on the desired nerve should be performed prior to neurolysis. If the desired effect is obtained, the patient may benefit from neurolysis.

4. GAPS IN KNOWLEDGE/EVIDENCE BASE

Although BoNT has been widely approved for the above listed diagnoses, more class I studies are needed to determine safety and efficacy for the treatment of spasticity and other off-label uses. There is increasing evidence that dosages above FDA recommendations may provide improvement in spasticity with post stroke spasticity with minimal adverse effects, however, functional outcome data is limiting. These higher dosages are often used off label and are in need of continued evaluation. Additionally, many muscles are injected off label in order to comprehensively treat spasticity. Further studies are needed to optimize dosing, injection guidance, injection distribution, and dilution in order to enhance functional outcome measures.

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Original Version of the Topic

Supreet Deshpande, MD, Mark E. Gormley Jr. Neurolysis. 09/20/2013

Author Disclosures

Natasha L Romanoski, DO
Nothing to Disclose

Kevin Moser, MD
Nothing to Disclose

Neyha Cherin, DO
Nothing to Disclose

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