Botulinum Toxin in Management of Spasticity

Sabahat Wasti, MD Medical Director Neurorehabilitation Cleveland Clinic Abu Dhabi Disclosures

• NONE in respect of this talk • Not sponsored / supported by any of the Botulinum toxin producing pharmaceutical company Learning Objectives

• Understand spasticity and its mechanisms • Understand how to assess and evaluate a patient with spasticity • Learn about accepted and validated technique for measuring spasticity • How to treat spasticity • What is botulinum toxin and its role in treating spasticity • The practice parameters for using Botulinum toxin What is Spasticity?

“Spasticity is a motor disorder characterized by a velocity-dependent increase in tonic stretch with exaggerated tendon jerk, resulting from hyperexcitability of the stretch ”

James Lance (1980) Mechanism of Spasticity

So what causes a muscle to become spastic? •The absence of an upper ’s inhibitory control on the spinal reflex. •Hyperactive stretch reflexes that are mediated by stretch receptors •Decreased threshold of the alpha lower motor neurons Mechanism of Spasticity

• In patients with spasticity when evaluated at rest (completely relaxed), a positive linear correlation between EMG activity of the stretched muscle and stretch velocity was found using a range of displacement velocities similar to that used in the clinical practice to evaluate the muscle tone.

• When the passive stretch is slow, the stretch reflex tends to be small (low amplitude) and the tone may be perceived relatively normal or just increased. When the muscle is stretched faster, stretch reflex increases and the examiner detects an increase in muscle tone. Therefore, spasticity is due to an exaggerated stretch reflex.

A. F. Thilmann, S. J. Fellows, and E. Garms, “The mechanism of spastic muscle hypertonus. Variation in reflex gain over the time course of spasticity,” Brain, vol. 114, no. 1, pp. 233–244, 1991. Mechanism of Spasticity

Although spasticity is velocity-dependent, surface EMG recordings show that in many cases if the stretch is maintained (velocity = 0), the muscle still keeps contracting, at least for a time. So, although spasticity is considered classically dynamic, there is also an isometric tonic muscle contraction after the stretch reflex elicited it in a dynamic condition. Mechanism of Spasticity

• In patients with UMNS, muscle contracture makes a significant contribution to . Hypertonia in patients with UMNS, therefore, can be divided into two components: • Hypertonia mediated by the stretch reflex, which corresponds to spasticity • Hypertonia due to muscle contracture, which is often referred as non-reflex hypertonia or intrinsic hypertonia. • In intrinsic hypertonia resistance to passive displacements is not related to the velocity of the movement. • It can be difficult to distinguish reflex and non-reflex contributions to muscle hypertonia, especially when muscle fibrosis occurs without shortening. • Extensibility due to muscle contracture might cause “any pulling force to be transmitted more readily to the spindles,” thus increasing spasticity. Schematic Major Causes of Spasticity

• Stroke

• Traumatic brain injury

• injury

• cerebral palsy

• Multiple sclerosis Spasticity Assessment

• History • Clinical Examination • Rating Scales • Complicating factor evaluation • Overall review • Management Planning History

• History should focus on pathology • Date of onset • Course of condition since onset • Effects of spasticity • Ask about exacerbating factors such as: • Pain • Itching • Cough, breathing problems etc; • Constipation • Bladder Incontinence • Bowel Incontinence • Fever • Co-Morbidities • Respiratory Problems • Cardiac Problems • Diabetes • Gastrointestinal problems • Arthritis • Osteoporosis Upper Motor Neuron Syndrome

A group of symptoms that may be caused by damage or injury to motor neuron pathways or brain regions that control movement

Positive Symptoms Negative Symptoms Characterization Muscle overactivity Muscle underactivity Examples Spasticity, clonus, Decreased dexterity, flexor/extensor spasm, weakness, paralysis, hyper-reflexia, fatigability, and dystonia, and rigidity slowness of movement

Katz RT, Rymer WZ. Spastic hypertonia: mechanisms and measurement. Arch Phys Med Rehabil 1989; 70:144-55 O'Brien CF, Seeberger LC, Smith DB. Spasticity after stroke. Epidemiology and optimal treatment. Drugs Aging 1996; 9:332-40 Young RR ,Wiegner AW. Spasticity.ClinOrthop Relat Res 1987; 50-62 Classification of Spasticity

Classification of Spasticity According to Distribution of Affected Body Regions

Distribution Definition

Focal Isolated, local motor disturbance affecting a single body part

Regional Motor disturbance involving a large region of the body

Generalized Motor disturbance involving widespread bodily regions

Esquenazi A. Falls and fractures in older post-stroke patients with spasticity: consequences and drug treatment considerations. Clin Geriatr 2004; 12:27-35 Gracies JM, Nance P, Elovic E, McGuire J, Simpson DM. Traditional pharmacological treatments for spasticity. Part II: General and regional treatments. Muscle Nerve Suppl 1997; 6:S92-120 Spasticity can have both desirable and undesirable symptoms

The Good How can spasticity be good for you?

. Can be used to help with functional activities, such as transfers or hand grip, which allows an individual t be more independent.

. Can strengthen muscles and maintain muscle mass.

. Can serve as an early warning system by acting as alerts for health problems such as UTIs or skin breakdown. We don’t have strong evidence yet that it can benefit bone health and circulation. Spasticity can have both desirable and undesirable symptoms The Bad

. Stiffness – resistance to stretch, which can affect many aspects of life and limit independence.

 Can reduce hand/arm range of motion (ROM) and functional abilities.

 Can lead to contractures (tightening of muscles around joints) of shoulders and hips that can make it difficult to walk, transfer, dress or perform personal hygiene and care.

. May be painful

. Can disturb sleep

. Can lead to skin breakdown from friction or pressure.

. Can interfere with safety if spasms are triggered while driving a vehicle or pushing a wheelchair.

. May cause poor seating posture, especially if it is asymmetric or different from side to side.

. Can increase the number of bladder accidents. The bladder is a muscle, and if the muscle is overactive the bladder does not store enough urine and becomes very irritable.

. Indirect effects: if spasticity makes a person less independent, it can affect work ability, social interaction and care needs. Methods of Spasticity Assessment

• Passive activity measures such as Ashworth scale and passive range of motion. • Voluntary activity measure such as the Fugl-Meyer test and the Nine Hole Peg Test. • Functional measures such as the Functional Independence Measure and the Disability Assessment Scale (DAS) and measures of pain. • Quality of life measures that assess patient satisfaction and perceived importance of spasticity treatment

Elovic EP, Simone LK, Zafonte R. Outcome assessment for spasticity management in the patient with traumatic brain injury: the state of the art. J Head Trauma Rehabil 2004; 19:155-77 Ashworth and Modified Ashworth Scale Valid & reliable measure scale for spasticity TARDIEU SCALE

• This scale quantifies muscle spasticity by assessing the response of the muscle to stretch applied at specified velocities

• Grading is always performed at the same time of day, in a constant position of the body for a given limb. For each muscle group, reaction to stretch is rated at a specified stretch velocity TARDIEU SCALE

• Velocity to stretch (V) • V1 As slow as possible • V2 Speed of the limb segment falling • V3 As fast as possible (> natural drop) • V1 is used to measure the passive range of Motion. (PROM). Only V2 and V3 are used followed by release Tardieu Scale

• Quality of muscle reaction (X) • 0 No resistance throughout passive movement • 1 Slight resistance throughout, with no clear catch at a precise angle • 2 Clear catch at a precise angle, • 3 Fatigable clonus (<10secs) occurring at a precise angle • 4 Un-fatigable clonus (>10secs) occurring at a precise angle • 5 Joint Immobile Signs and Symptoms of Spasticity

• Patients with spasticity may experience a range of sensations in Abnormal the affected limbs posture, pain, Stiffness/ • Mild muscle stiffness or inability limited range to sleep of motion • Painful muscle contractures 34.5% 42.0% and spasms

• In a survey most patients rated Limitations stiffness and limited range of in activities motion as having the most of daily living 23.5% substantial negative impact on their quality of life Percentage of 810 patients with spasticity who identified each aspect

O'Brien CF. Treatment of spasticity with botulinum toxin. Clin J Pain 2002; 18:S182-90 of their condition as having the most WE MOVE. Profile of Patients with Spasticity, 2008. Available at: significant impact on quality of life.8 http://www.wemove.org/reports/spasticity_2008.pdf. Accessed March 26, 2009 Characteristics of Spasticity

• Hyperactive stretch reflex • Increased resistance to passive movement • Posturing of extremities • Obligatory synergies • This occurs in spasticity and manifests as abnormal and stereotypical patterns across joints: • Flexion synergy • Extension synergy • Patient is unable to move a limb segment in isolation • It interferes with normal activities of daily living Upper Limb Spasticity Lower Limb Spasticity Management • Optimize medical care • Treat pain • Prevent incontinence • Effective bladder management • Prevent constipation / soiling • Treat wounds or sores • Treat conditions such as ingrowing toe nails • Take good care of skin • Prevent or treat pressure ulcers • Effective control of diabetes / hypertension • Effective management of dysreflexia (autonomic) Spasticity Treatment

• Cost may inhibit decision to treat • Time-consuming and multidisciplinary • Expensive equipment such as seating systems • Effective but expensive pharmacologic agents

• But untreated spasticity • May mask voluntary movement and increase dependence • Result in permanent contractures • Window of opportunity may be small Reduction of Noxious Stimuli Catheter and catheter bags Reduction of Noxious Stimuli Ulcers / Wounds Reduction of Noxious Stimuli Ingrowing Toe Nail Reduction of Noxious Stimuli Skin Rash / Intertrigo / Itchy lesions Moving, handling and Posture • Careful positioning throughout 24-hours both in bed and chair • Maintaining muscle length • Reducing deformity • Regular stretching? • Splinting and orthoses

All act to reduce the tonic stretch reflex Interventions

• Effective Treatments for reducing Spasticity • Therapy Interventions • Physical therapy • Occupational therapy • Electrical and Functional Electrical Stimulation • Casting • Mental Imagery • Mirror therapy • Constraint induced therapy • Pharmacological Interventions • Surgery Pharmacotherapy

• Do not start pharmacotherapy without • Elimination of precipitating factors • Adequate therapy/splinting/orthosis • Appropriate seating and posture management • Adequate education about moving and handling Pharmacotherapy • Generalised • Oral baclofen • Dantrolene • Tizanidine • Diazepam • Regional • Intrathecal baclofen • Phenol • Rhizotomy • Botulinum Toxin • Focal • Botulinum Toxin • Phenol neurolysis Pharmacological Intervention: Generalized Spasticity

• Oral Agents - also administered enterally. • Baclofen • GABA agonist • Diazepam • Brainstem and spinal polysnaptic pathways. GABA receptor inhibitor. • Dantrolene Sodium • Peripherally acting muscle relaxant. • Shown to increase ADL, transfers, hygiene, no LT effects. • Tizanidine Hydrochloride • Inhibits both pre and post synapses. Fewer side effects than diazepam. • Also functional improvements, ambulation distance on flat ground. • General Side Effects • Fatigue, drowsiness, alcohol-like sedation, reduced motor coordination, impaired intellect, attention, addiction, weakness. Pharmacological Intervention: Regional Spasticity

• Intrathecal Drug Therapy • Administered directly into intrathecal space via a programmable pump.

• Intrathecal Baclofen, • Improvement without impairing uninvolved extremity. • Fewer systemic side effects because not circulating in blood stream. • Infection, impaired wound healing, pump malfunction, and catheter dislocation in 20-25% of cases. Pharmacological Intervention Drug Site of Action Adverse Effects Oral Drugs Diazepam Brainstem reticular formation Fatigue; reduced motor coordination, intellect, attention, and spinal polysynaptic memory pathways Dantrolene Sodium calcium stores Hepatotoxicity, generalized muscle weakness

Oral Baclofen GABA-b receptors Drowsiness, confusion, headache, lethargy Tizanidine Hydrochloride a2-adrenergic receptors Dizziness, sedation, dry mouth

Intrathecal Drugs Intrathecal Baclofen Gaba-b receptors Pump malfunction/ dislocation Focal Drugs Phenol Injection Neuromuscular junction Causalgia with sensory nerve injury, pain at injection site, hematoma Botulinum Toxin Nerve Injection site pain, muscle weakness in injected muscle, hematoma, muscle necrosis, phlebitis Surgical Intervention

• Tendon Lengthening - preferred method • Allow full passive range with some residual muscle tension. • Muscle must be immobilized under tension. • Tendon Transfer - used on children (Shriner’s) • Gait analysis with dynamic electromyographic monitoring helps reduce common errors associated with this procedure. • Osteotomy - for skeletal deformity • Restore boney architecture, muscle-length can be improved. • Used along with tendon lengthening. • Arthrodesis - joint fusion • When the above are prohibited. • Stabilize unstable joints (subtalar, thumb, wrist). Surgical Intervention

• Neurosurgery: severe and painful spasticity, irreversible. • Dorsal rhizotomies - Regional spasticity. • Cut dorsal cords and grey mater (gelatinosa area). • Can cause decrease in voluntary mobility, sepsis, decreased leminiscal sensitivity, and death.

• Peripheral neurotomies - Focal spasticity. • Used if botulinum toxin failed. • Done distally only reducing the myotatic reflex.

• Spinal Cord Stimulation - reversible. • E Stim administered directly to spinal area. • Intrathecal Baclofen is more commonly used. Pharmacological Intervention: Focal Spasticity

• Chemical Neurolysis - destruction of a portion of the nerve. • Phenol Injections - causes chemical (Wallerian) denervation. • Dose dependent, • Hit proximal muscles first. • Works at alpha motor neurons directly. • Pain at administered site, causalgia with sensory nerve injury.

• Botulinum Toxin - binds to presynaptic cell and prevents Neurotransmitter release. • Effect begins 3-7 days and last 2-6 months, specific muscles • Now treatment of choice for focal spasticity • Can also be used for regional spasticity • Can also be part of treatment plan for generalized spasticity The History of Botulinum Toxin

• “botulism” from botulus (sausage) from outbreak of consuming improperly cooked sausage • Published 1st case studies on botulinum intoxication (summarizing 76 cases) of botulism in 1820 • Accurately described neurological symptoms Justinius Kerner • 1st to propose therapeutic use of toxin A German physician Molecular Pathogenesis of BoNT

BoNT synthesized as single-chain polypeptide (inactive form)

Polypeptide cleaved by protease to create di-chain structure (active form)

BoNT binds to epithelium, trans-cytosed, reaches general circulation

Receptor-mediated endocytosis at peripheral cholinergic nerve endings

In cytosol, toxin cleaves target, blocking neurotransmitter release = flaccid paralysis Figure taken from: Arnon, et al. 2001. Available Brands

Adverse Effects

• The most common adverse effects of botulinum injection are related to the injection, rather than to the botulinum toxin itself. These include pain, bruising, swelling, and redness at the injection site. • An uncommon side-effect of botulinum toxin is the unintended weakness of the surrounding muscles (occurring in fewer than 10% of treatments). This weakness results from the spread of the toxin from the injection site into adjacent muscle groups. • The weakness can persist for up to 12 weeks. • Swallowing difficulty • Respiratory insufficiency • Hypersensitivity reactions Contraindications / Cautions

• What are the contraindications to receiving botulinum-A injections? • Botulinum-A is contraindicated in individuals with: • Pre-existing medical conditions that cause muscle weakness, including motor neuron disease (amyotrophic lateral sclerosis) and myasthenia gravis • Infection overlying the injection site • Previous allergic or hypersensitive reactions to botulinum-A. • Botulinum-A should also be avoided during pregnancy and while breastfeeding. • Certain medications that enhance the effects botulinum-A should be avoided. These medications include tetracycline antibiotics and aminoglycoside antibiotics. • Blood thinners including aspirin, warfarin and dabigatran increase the risk of significant bruising from injection sites. Summary • Botulinum toxin is effective treatment for focal spasticity • Can be used for regional and generalized spasticity as part of combination therapy • Patient assessment and selection criteria is key • Must be done with in a multidisciplinary setting • Do not inject if spasticity is helping function • Not one off or stand alone treatment • Must have effective follow up protocol • Education of patient and family is essential References

• Ibuki A, Bernhardt J. What is spasticity? The discussion continues. International Journal of Therapy and Rehabilitation. 2007;14:391-395 • Krause, P., Szecsi, J., and Straube, A. Changes in Spastic Muscle Tone Increase in Patients with Spinal Cord Injury Using Functional Electical Stimulation and Passive Leg Movements. Clinical Rehabilitation. 2008; 22: 627-634 • Lazorthes, Y., Sol, J-C., Verdie, S., & J-C. The Surgical Management of Spasticity. European Journal of Neurology. 2002; 9(1): 35-41 • Preissner, K. (2001). The effects of serial casting on spasticity: a literature review. Occupational Therapy in Health Care, 14(2), 99-106. Retrieved from CINAHL Plus with Full Text database. • Mesci, N. , Ozdemir, F. , Demirbag Kabayel, D. , & Tokuc, B. (2009). The effects of neuromuscular electrical stimulation on clinical improvement in hemiplegic lower extremity rehabilitation in chronic stroke: A single-blind, randomised, controlled trial. Disability & Rehabilitation, 31(24), 2047-2054. References

• Richardson, D. Physical Therapy in Spasticity. European Journal of Neurology. 2002; 9(1): 17-22 • Singer, B. J., Dunne, J. W., Singer, K. P., Jegasothy, G. M., and Allison, G. T. Non-surgical Management of Ankle Contracture Following Acquired Brain Injury. Disability and Rehabilitation. 2004; 26(6): 335-345 • Verplancke, D., Snape, S., Salisbury, C., Jones, P., & Ward, A. (2005). A randomized controlled trial of botulinum toxin on lower limb spasticity following acute acquired severe brain injury. Clinical Rehabilitation, 19(2), 117-125. Retrieved from CINAHL Plus with Full Text database. • Ward A. B. A Summary of Spasticity Management - a Treatment Algorithm. European Journal of Neurology. 2002; 9: 48-52 • Woo, R. Spasticity: Orthopedic Perspective. Journal of Child Neurology. 2001; 16(1): 47-53 References

• Barnes, M. Management of Spasticity. Age and Ageing. 1998;27:239-245 • Bohvend’Eerdt, T. JH., Dawes, H., Sackley, C., Izadi, H., and Wade, D. T. Mental Techniques During Manual Stretching in Spasticity - a pilot randomized controlled trial. Clinical Rehabilitation. 2006; 23: 137-145 • Chung, B. , & Cheng, B. (2010). Immediate effect of transcutaneous electrical nerve stimulation on spasticity in patients with spinal cord injury. Clinical Rehabilitation, 24(3), 202-210. • Gallichio, Joann E. Pharmacologic Management of Spasticity Following Stroke. Physical Therapy Journal. 2004; 84: 973-981 THANK YOU