Chemodenervation: Basics and Practical

Considerations

Cynthia L. Comella, MD, FAANProfessor

Rush University Medical CenterDepartment of Neurological Sciences

Barbara I. Karp, MD Combined NeuroScience Institutional Review Boards

National Institute of Neurological Disorders and Stroke

National Institutes of Health

Cynthia L. Comella, MD, FAANProfessor

Rush University Medical CenterDepartment of Neurological Sciences

Barbara I. Karp, MD Combined NeuroScience Institutional Review Boards

National Institute of Neurological Disorders and Stroke

National Institutes of Health

“Sausage Poisoning”

Justinius Kerner 1786-1862

Kerner’s second monograph

on “fatty poison” (1822)Erbguth FJ. Mov Disord. 2004;(19 Suppl) 8:S2-S6.

Erbguth FJ. Mov Disord. 2004;(19 Suppl) 8:S2-S6.

Botulinum Toxin

• Seven distinct serotypes of toxin• A, B, C, D, E, F, G• Serotypes A and B available for human use

• Botulinum toxin complex• Hemagglutinin and non-hemagglutinin

proteins• Neurotoxin

Botulinum Toxin

• Most potent neurotoxin known

• Nanogram amounts are sufficient to be lethal

• Listed among the 6 highest risk threat agents of bioterrorism by the Centers for Disease Control and Prevention (CDC)

Question

• Which of the following is the primary

mechanism of action of botulinum toxin?

A. Blocks acetylcholine receptors on muscles

B. Inhibits calcium channels

C. Cleaves SNAP proteins for vesicle fusion

D. Weakens muscle by cleavage of actin

SNAP = synaptosomal associated protein.

Botulinum Neurotoxin (BoNT)

• Heavy chain• C terminus: acceptor

binding site cholinergic neurons

• N terminus: translocation

• Light chain• Zinc endopeptidase

• Cleaves specific proteins involved in membrane fusion (SNARE proteins)

Department of Bacteriology. University of Wisconsin-Madison. Available at http://www.bact.wisc.edu/index.php. Accessed October 6, 2010.Department of Bacteriology. University of Wisconsin-Madison. Available at http://www.bact.wisc.edu/index.php. Accessed October 6, 2010.

SNARE = soluble N-ethylmaleimide-sensitive factor attachment protein receptors.

Mauricio Montal

Section of Neurobiology, Division of Biological Sciences, University of

California San Diego, La Jolla, California 92093-0366;

Botulinum Neurotoxin:A Marvel of Protein Design

Montal M. Annu Rev Biochem. 2010;79:591-617.

BoNT Mechanism of Action

Presumed to have local effects in muscle.

BoNT Mechanism of Action

Presumed to have local effects in muscle.

BoNT Mechanism of Action

Presumed to have local effects in muscle

Botulinum Toxin:Role of Heavy and Light Chains

Botulinum Toxin Serotypes:Cleavage of SNARE Proteins

Toxin Type

Substrate

BTX A SNAP-25

BTX B VAMP/Synabtobrevin

BTX C Syntaxin SNAP-25

BTX D VAMP/Synaptobrevin

BTX E SNAP-25

BTX F VAMP/Synaptobrevin

BTX G VAMP/Synaptobrevin

Type B

Type A

BTX = botulinum toxin; VAMP = vesicle-associated membrane protein.BTX = botulinum toxin; VAMP = vesicle-associated membrane protein.

Recovery Following Injection

• Clinical benefit wanes in approximately 3 to 6 months

• EMG evidence of denervation persists up to 1 year but completely resolves

• There is restoration of original neuromuscular junction

EMG = electromyography.

Botulinum Toxins: Perspective on Therapeutic Development

• 1977Used in humans (Allen Scott, MD, Smith- Kettlewell Institute)

• 1979 • Edward Shantz produced 150 mg of BoNT-A licensed for all

therapeutic uses from 1989 to 1998

• 1980s Oculinum® used in patients with variety of neurological conditionsDysport® (BoNT-A) used in Europe

• 1989(FDA approved Botox for strabismus, blepharospasm, and

hemifacial spasm (lack class 1 evidence)

• 1990sSNARE complex described Mechanism of action of botulinum toxin described

FDA = US Food and Drug Administration.FDA = US Food and Drug Administration.

Botulinum Toxin: First Clinical Preparation

• 1979: Original batch BoNT-A (Oculinum)

•150 mg was used for more than 250 000 injections in humans

• 2000 to present Availability of new brands and serotypes

Onabotulinum toxin (Botox® [Type A])Rimabotulinumtoxin (Myobloc® [Type B])Abobotulinumtoxin (Dysport® [Type A]) IncobotulinumtoxinA (Xeomin® [Type A])

• Expanding list of possible uses• Close to 100 uses described in all areas of

medicine• Only a few receiving approval of government

agencies

Botulinum Toxins: Perspective on Development

Toxin BrandsBotox®

Onabotulinumtoxin A

Serotype A Allergan

Vacuum dried

Refrigerate

50 Unit vial

100-U vial size

Reconstitute with saline 

CD dose: 50 to 300 U

Myobloc® (NeuroBloc)RimabotulinumtoxinB

Serotype B Solstice

Liquid

Refrigerate

2500 Unit vial

5000 Unit vial

10 000 Unit vial

No reconstitution

CD dose: 2 500 to 15 000 U

Dysport®

AbobotulinumtoxinA

Serotype AIpsen

Freeze dried

Refrigerate

250 Unit vial

500 Unit vial

Reconstitute with saline

CD dose: 250 to 1000 U

Xeomin®

IncobotulinumtoxinA

Serotype AMerz

Powder

Room temp

50 Unit vial

100 Unit vial

Reconstitute with saline

CD dose: 100 to 300

Toxin Brands

Know Your Botulinum Toxin!

Be familiar with the brand of BoNTStorage, vial size, dosing, immunogenicity

LABEL SYRINGE WITH TYPE AND CONCENTRATION

Evidence-Based Review: Focal Dystonia

Disorder Conclusions Recommend Limitations

Cervical dystonia

Established safe and effective

A No effective alternative

Blepharospasm Probably effective

B Lack of controlled studies

Arm/hand dystonia

Probably effective

B No effective alternative

Leg/foot dystonia

Data inadequate None No effective alternative

Spasmodic dysphonia

Adductor

Probably effective

B No effective alternative

Clinical Uses Proposed for BoNTOphthalmologic

StrabismusNystagmusApraxia of eyelid openingProtective ptosis

DystoniaBlepharospasmCervical dystonia (CD)Spasmodic dysphoniaOromandibular dystoniaLimb dystonia

SpasticityArm/handLegPost-strokeMultiple sclerosisCerebral palsy (CP)Spinal cord injuryOther neurological disorders

Hemifacial spasmPalatal myoclonusTremorTicsParkinson’s disease

TremorFreezing gaitClenched fist

PainHeadacheMigraineTension headacheFibromyalgiaLow back painPainful muscle spasmRadiculopathy

Gastrointestinal disordersAchalasiaAnal sphincter spasmConstipation

UrologicalVaginismusUrinary sphincter spasmSpastic bladder

Sialorrhea StutteringCosmetic usesHyperhidrosis

FDA Approved Indications• 1989

• Blepharospasm/disorders of the VII nerve (onabotulinumtoxinA [Botox])

• 2000• Cervical dystonia (onabotulinumtoxinA [Botox], rimabotulinumtoxinB

[Myobloc])

• 2002• Glabellar lines (onabotulinumtoxinA [Botox] cosmetic)

• 2004• Axillary hyperhidrosis (onabotulinumtoxinA [Botox])

• 2009• Cervical dystonia and wrinkles (abobotulinumtoxinA [Dysport])

• 2010• Cervical dystonia and blepharospasm (incobotulinumtoxinA [Xeomin])• Upper limb spasticity (onabotulinumtoxinA [Botox])• Chronic migraine (onabotulinumtoxinA [Botox])

Clinical Issues

• Methods for administration• Safety • Penetration into central nervous

system (CNS)• Brand and serotype equivalency• Immunogenicity

Clinical Issues

• Methods for administration• Safety • Penetration into central nervous

system (CNS)• Brand and serotype equivalency• Immunogenicity

Treatment Principles

• Establish treatment goals• Understand functional neuroanatomy of

area• Select muscles based on observation,

patient report, posture• Adjust dosing for each muscle• Target injection into intended muscles• Follow up for benefit and side effects

Methods of Administration

• Number of injection sites into each muscle

• Use of electromyography• Outcomes

• Clinically important measures• Scales with demonstrated reliability,

validity, and responsiveness

Question

• Should you utilize electromyography for injections of neck or limbs?

• Yes• No

Is Electromyography Useful?

• Significantly increases the magnitude of improvement at the same dose of BoNT

• Used complementary to clinical examination• Blinded evaluations show significance for both patient and

physician assessments Comella, 1992

• Targeting muscle is not accurate without EMG guidance Van Gerpen, 2000

• Sternocleidomastoid “missed” in 20%; splenius capitis and deeper muscles missed up to 60% of the time without EMG guidance

Brans, 1996

• Accuracy in forearm approximately 37% without EMG Molloy, 2002

Methods of Administration

• Appropriate dilutions• Dose into specific muscles• Number of injection sites into each

muscle• Use of electromyography• Outcomes

• Clinically important measures• Scales with demonstrated reliability,

validity, and responsiveness

Methods of Administration

OutcomesResponse assessed by patient• Normalization of posture• Functional improvement• Relief of discomfort

Outcomes

Response Assessed by Patient Visual Analog ScaleNo improvement Complete Improvement0%

100%

0 = No benefit1 = Minimal benefit (1–25%)2 = Mild benefit (26–50%)

3 = Moderate benefit (51–75%)4 = Excellent benefit (76–100%)

Outcomes

Response Assessed by Examiner

Scales with demonstrated reliability, validity, TWSTRs (CD)

Blepharospasm rating scale

Spasticity scales (modified Ashworth)

Clinical Issues

• Methods for administration• Safety • Penetration into CNS• Brand and serotype

equivalency• Immunogenicity

Botulism

• Symmetric Cranial Neuropathies• Diplopia/blurred vision• Ptosis• Dysphagia• Dysarthria• Dry mouth• Mydriasis

• Flaccid paralysis• Respiratory failure

Demonstration of Neuromuscular Junction Blockade by Repetitive

Stimulation

• November 2006– 100 micrograms pure BoNT- A,

research grade (40,000 MU)– 4 people get botulism from cosmetic

injections• 40 to 104 days in hospital

Chertow DS, et al. JAMA. 2006;296:2476-2479.

Safety

Evidence of Spread of Botulinum Toxins Beyond Local Injection Site

• Systemic spread• Increased jitter in distant muscles• Dysphagia following CD injections• Dry mouth following injection of

BoNT-B into limb muscles

• Direct or indirect central effects• Altered plasticity

SafetyReport from FDA’s Adverse Event Reporting System

Figure 1. Serious adverse events and botulinum toxin type A sales figures (used with permission from M Brin, MD; Allergan, Inc), January 1989 to December 2002.

Cote TR et al. J Am Acad Dermatol. 2005;53:407-415.

In 217 serious AEs with therapeutic uses, there were 28 deaths.

AE = adverse event.AE = adverse event.

Serious AEs

• More common with therapeutic than cosmetic use

• Not necessarily related to toxin (eg, MI, seizure)

• Probably related• Weakness, dysphagia, flu-like syndromes, injection

site trauma

• 28 deaths: 26 with underlying diseases• Deaths from: MI, respiratory arrest, CVA, PE,

pneumonia, other/unknown

CVA = cardiovascular accident; MI = myocardial infarction; PE = pulmonary embolism.CVA = cardiovascular accident; MI = myocardial infarction; PE = pulmonary embolism.

Safety FDA safety review in 2008 Deaths reported in children receiving high doses for

CP; risk complicated by underlying disorders and use of anesthesia

• Black box warning required (April 2009)• Risk of adverse events with toxin spread beyond

injected site• Developed generic names to emphasize difference

between marketed products

• Risk Evaluation and Mitigation Strategy• Information of risk for distant spread• Medication guide

Black Box Warning

• The effects of (brand name) and all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects. These symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be life threatening, and there have been reports of death. The risk of symptoms is probably greatest in children treated for spasticity, but symptoms can also occur in adults, particularly in those patients who have underlying conditions that would predispose them to these symptoms.

Safety Issues for CP

• Risk factors for adverse events in CP• Dosing considerations (see review below)• Gross motor function classification-V

• Nonambulatory

• Presence of comorbidities (neurological, physical)

• Presence of pseudobulbar palsy • Method of sedation/anesthesia

Graham K. Toxins. 2008.Heinen et al. Euro J Ped Neurol. 2006.

Clinical Issues

• Methods for administration• Safety • Penetration into CNS• Brand and serotype equivalency• Immunogenicity

Evidence of Central Effects

• Effects on spinal cord circuitry• Reduced presynaptic inhibition between flexor

and extensor forearm muscles following injection for limb dystonia/tremor

• Effects on brainstem• Changes in abducens motoneurons with lateral

rectus muscle injections• No effects on blink reflex recovery, brainstem

auditory evoked potentials

• Cortical effects• Conflicting evidence of altered central plasticity

and excitability following injections

Caleo M et al. J Neurochem. 2009;109:15-24.

Botulinum Toxin: Physiologic Effects: H Reflex

Botulinum Toxin: Physiologic Effects: H Reflex

Before BTX:

Loss of reciprocal inhibition

Before BTX:

Loss of reciprocal inhibition

3 Weeks after BTX: Restoration of reciprocal inhibition

3 Weeks after BTX: Restoration of reciprocal inhibition

Priori et al. Brain. 1995.;118 (Pt 3):801-107

Before

1 mo p-BTX

3 mos p-BTX

Gilio et al. Ann Neurol. 2000;48:20-26.

Botulinum Toxin: Physiologic Effects: H Reflex

Botulinum Toxin: Physiologic Effects: H Reflex

MO = month.MO = month.

Retrograde Effects of BoNT-A• Effects of BoNT-A (cleaved SNAP-25) observed:

• In retinal cells and visual cortex following superior colliculus injection

• In ipsilateral facial nucleus following injection into mouse whisker pad

• In contralateral hippocampus following unilateral injection

Antonucci F, et al. J Neurosci. 2008;28:3689-3696.

(BoNT-A cleaved SNAP-25 shown in red above)

Central Effects: Clinical Implications

• Central effects difficult to interpret clinically• Primary clinical effect is denervation

• Altered central plasticity due to altered sensory input (Effects on gamma neurons?)

• Retrograde axonal transport with central BoNT activity

• “Lack of adverse central effects suggest that physicians can continue to use BoNT safely as therapy.”

Curra A et al. Neurology. 2009;72:1095-1099.

Clinical Issues

• Methods for administration• Safety • Penetration into CNS• Brand and serotype equivalency• Immunogenicity

Question

• All brands and types of botulinum toxin can be used interchangeably.

• Yes• No

• Four brands of BoNT available for clinical use• 3 are BoNT-A (Botox [OnabotulinumtoxinA], Dysport

[AbobotulinumtoxinA], Xeomin [IncobotulinumtoxinA])• 1 is BoNT-B (Myobloc [RimabotulinumtoxinB]/NeuroBloc [Botulinum

Toxin Type B])

• Each brand of BoNT except Xeomin (IncobotulinumtoxinA) is a complex mixture of components with BoNT being the therapeutically active component, but…

• Each of these components influence therapeutic efficacy, adverse effects profile, and antigenicity.

• Comparative studies have not established simple dose equivalency calculations that can be utilized in a clinical setting.

• Clinicians should consider each brand and serotype individually.

Can BoNT Brands and Serotypes Be Used Interchangeably?

Can BoNT Brands and Serotypes Be Used Interchangeably?

No!• When starting a new brand, base dosing on

the package insert and studies of that brand

• Consider changing from one brand to another:• If there is resistance to 1 serotype

• Based on patient need or insurance

• Avoid “rotating” brands and serotypes

Clinical Issues

• Methods for administration• Safety • Penetration into CNS• Brand and serotype equivalency• Immunogenicity

Question

• Which of the following is the most common reason for failure of efficacy following botulinum toxin injection?

A. Immunoresistance

B. Inactivated toxin

C. Wrong muscles selected

D. Previous tetanus inoculation

Failure to Benefit Rarely Due to Antibodies

• Common reasons for lack of efficacy• Injection into the wrong muscles• Inadequate dosing• Unrealistic patient expectations• Stress-induced exacerbation

• Uncommon reasons for lack of efficacy• Change in dystonia• Immunoresistance

Factors Associated With Immunoresistance

• ? Protein content of BoNT • Complexing proteins

• Hemagglutinin and nonhemagglutinin

• More frequent injections • Intervals less than 3 months

• “Booster” injections• Large doses/cumulative doses• Genetic predisposition

Pre-UBI Pre-UBI

Post-UBI Post-UBI

Negative UBI Positive UBI

Unilateral Brow Injection (UBI) for BoNT Resistance

• Injection of small amount of BoNT into corrugator on 1 side• Re-evaluate at 4 weeks• Assess symmetry of corrugator contraction by comparison of brow furrows

UBI = unilateral brow injection.

Key Points

• Botulinum toxin works through reversible chemodenervation.

• Botulinum has a long history of efficacy and safety when used appropriately.

• Botulinum toxin used in practice requires careful explanation to patients of expectations, risks, and reporting of AE.

• The clinical importance of CNS penetration of BoNT requires further evaluation.

• Each BoNT brand and serotype should be considered a unique drug.