chemodenervation: basics and practical considerations cynthia l. comella, md, faan professor rush...
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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.