Botulinum Toxin for Movement Disorders: Physiology, Pharmacology and Evaluation of Patients

Albert C. Clairmont, MD Associate Professor-Clinical

Department of PM & R The Ohio State University

OBJECTIVES

• Review the pharmacology of botulinum toxin • Review mode of action of botulinum toxin • Be aware of diffusion characteristics of various

formulations of botulinum toxin • Know strategies to evaluate the patient that

requires botulinum toxin or other form of spasmolysis/neurolysis.

Urinary Incontinence due to Neurologic Detrusor Overactivity BOTOX

® for injection is indicated for the treatment of urinary incontinence due to detrusor overactivity associated with a neurologic condition [e.g., spinal cord injury (SCI), multiple sclerosis (MS)] in adults who have an inadequate response to or are intolerant of an anticholinergic medication

Cervical Dystonia Upper Limb Spasticity

Chronic Migraine

Blepharospasm and Strabismus

Primary Axillary Hyperhidrosis Urinary Incontinence due to Neurologic Detrusor Overactivity

Therapeutic Indications 1: Tim

eline of FDA Approvals

Upper Limb Spasticity BOTOX

® for injection is indicated for the treatment of upper limb spasticity in

adult patients, to decrease the severity of increased muscle tone in elbow flexors (biceps), wrist flexors (flexor carpi radialis and flexor carpi ulnaris) and finger flexors (flexor digitorum profundus and flexor digitorum sublimis). Im

portant limitations

Safety and effectiveness of BOTOX® have not been established for the treatment

of other upper limb muscle groups, or for the treatment of lower limb spasticity. Safety and effectiveness of BOTOX

® have not been established for the treatment of spasticity in pediatric patients under age 18 years. BOTOX

® has not been shown to improve upper extremity functional abilities, or range of motion at a joint affected by a fixed contracture.

Chronic Migraine BOTOX

® for injection is indicated for the prophylaxis of headaches in adult patients with chronic migraine (≥15 days per month with headache lasting 4 hours a day or longer). Im

portant limitations

Safety and effectiveness have not been established for the prophylaxis of episodic migraine (14 headache days or fewer per month) in seven placebo-controlled studies.

Primary Axillary Hyperhidrosis BOTOX

® is indicated for the treatment of severe axillary hyperhidrosis that is inadequately managed by topical agents

Cervical Dystonia

BOTOX® is indicated for the treatment of adults

with cervical dystonia to reduce the severity of abnormal head position and neck pain associated with cervical dystonia.

Blepharospasm and Strabismus

BOTOX® is indicated for the treatment of

strabismus and blepharospasm associated with dystonia, including benign essential blepharospasm or VII nerve disorders in patients 12 years of age and above.

1. BOTO

X® (onabotulinum

toxinA) Prescribing Information. Irvine, CA: Allergan, Inc.; 2011.

Please see Important Safety Information, including Boxed W

arning, on slides 4-6 and 36-42.

yg

2004 1989

2000 2010

2002

Botulinum N

eurotoxin Serotypes Differ by W

eight and Composition

NTN

H

HA

HA

S S Zn

COO

H

NH

2

NH

2

COO

H

S-S

SS

Heavy Chain

Light Chain

S-SHeavy Chain

Neurotoxin Com

plex N

eurotoxin

300 kD-900 kD

Botulinum N

eurotoxin Serotypes Differ by W

eight and Composition

•Type A

only one to form the 900 KD com

plex •

Types A, B, C1 , HA (hem

agglutinin) positive D, form

500 KD and 300 KD complexes

•Types E, F, and HA–negative D, form

only the 300 KD com

plex •

Type G forms a 500 KD com

plex

Heavy C

hain delivery/binding

Light Chain

(enzyme)

� Heavy Chain (100 kD)

� Light Chain (50 kD)

� BoN

T-A inhibits calcium

- dependent vesicle exocytosis

Botulinum N

eurotoxin Type A (BoNT-A)

Structure & Function

Neurotoxin Structural Hom

ology

Type A

Type B

BOTOX®

Normal process of acetylcholine release No BOTOX

® present

BOTOX®

attached

Acetylcholine vesicle unable to bind

Cleaved SNAP-25

1. O'Brien CF. Clin J Pain. 2002;18(6 suppl):S182-S190. 2. Cui M

et al. Pain. 2004;107:125-133. 3. Simpson DM

et al. Neurology. 1996;46:1306-1310. 4. Row

land LP. N Engl J Med. 2002;347:382-383. 5. Bergfeldt U

et al. J Rehabil Med.

2006;38:166-171. Im

age adapted from Arnon SS et al. JAM

A. 2001;285:1059-1070.

BOTU

LINU

M TOXIN

A

•BO

TOX

® neurotoxin directly acts on motor neurons to reduce m

uscle activity1

•BO

TOX

® cleaves SNAP-25 in m

otor neurons, which inhibits acetylcholine release at

the motor end plate

2

Mechanism

of action of onabotulinumtoxinA allow

s for: �

Targeted reduction of hypertonicity3

�Transient and reversible effect 1,4,5

dePaiva et al, 1999

Comparisons

Similarities &

Differences Among

Serotypes Sim

ilarities: •

Clostridial neurotoxin •

Bi-chain structure •

Inhibition of acetylcholine release

•Production of flaccid paralysis w

hich is reversible

Differences: •

Antigenically distinct •

Distinct binding sites •

Distinct enzymatic actions

•Pharm

acologic differences •

Different species specificity

Simpson LL, et al. J Pharm

acol Exp Ther. 2004;308:857-864.

Characteristics of Approved BoNT

Preparations and N

T 201(IncobotulinumtoxinA)

Onabotulinum

- toxinA

Abobotulinum

- toxinA

R

imabotulinum

- toxinB

N

T 201

Preparation P

owder

Pow

der R

eady-to-use solution

Pow

der

Storage conditions B

elow 8°C

B

elow 8°C

B

elow 8°C

B

elow 25°C

Shelf-life 24 m

onths 15 m

onths 24 m

onths 36 m

onths

Clostridium

botulinum

strain H

all A

Ipsen strain B

ean B

Hall A

SNA

RE target

SN

AP

25 S

NA

P25

VAM

P

SN

AP

25

Purification process P

recipitation and chrom

atog. P

recipitation and chrom

atog. P

recipitation and chrom

atog. P

recipitation and chrom

atog.

Adapted from: Dressler D, Benecke R. Disabil and Rehab 2007;29(3):1761-1768.

Characteristics of Approved BoNT

Preparations and N

T 201 O

nabotulinum-

toxinA A

bobotulinum-

toxinA

Rim

abotulinum-

toxinB

NT 201

pH after

reconstitution 7.4

7.4 5.6

7.4

Stabilization Vacuum

drying Freeze-drying (lyophilisate)

pH-reduction

Vacuum drying

Excipients H

uman serum

album

in 500 ug/vial N

aCl 900

ug/vial

Hum

an serum

albumin

125 ug/vial Lactose 2500

ug/vial

Not reported

Hum

an serum

albumin

1 mg/vial

Sucrose 5 m

g/vial

Biological activity

100MU

-A/vial

500MU

-I/vial 1.0/2.5/10.0kM

U-

E/vial

100MU

-M/vial

Specific biological activity

60MU

-E

V/ngB

NT

100MU

-E

V/ngB

NT

5MU

-EV

/ngBN

T 167M

U-

EV

/ngBN

T

MU

-A=mouse unit in the Allergan m

ouse lethality assay; MU

-E=mouse unit in the Solstice m

ouse lethality assay; MU

-I=mouse until in the Ipsen lethality assay;

MU

-EV=equivalence mouse unit, 1 M

U-EV=1 M

U-A=1 M

U-I=40 M

U-E

Adapted from: Dressler D, Benecke R. Disabil and Rehab 2007;29(3):1761-1768.

Toxin D

ose, U/kg

110

100

Mean Peak DAS Response

0 1 2 3 4B

otox

ED50 (4.4)

LD50 (70)

Diffusion (30)

BoN

T-A

(Allergan)

Local Effect

Diffusion

Systemic Effects)

BoNT

-A (Allergan): Summ

ary of Efficacy, Distal Atrophy and System

ic Safety

Aoki 2003; AAN Poster # P03.088

Toxin D

ose, U/kg

110

100

Mean Peak DAS Response

0 1 2 3 4B

otox

BoN

T-A

(Allergan)

Effect

Diffusion

Systemic Effects)

Aoki, 2003 AAN Poster # P03.088

BoN

T-A (Ipsen) Lost From

Injected Site B

efore Reaching M

aximum

Local Effect

BoN

T-A

(Ipsen) Effect

BoN

T-A

(Ipsen) D

iffusion

BoNT

-A (Allergan) vs. BoNT-A (Ipsen): Com

parison of Efficacy, Diffusion and Safety

Toxin D

ose, U/kg

110

100

Mean Peak DAS Response

0 1 2 3 4B

otox

BoN

T-A

(Allergan)

Local Effect

Diffusion

Systemic Effects)

BoN

T-B

(Elan) Effect

BoNT-B (Elan) Diffusion

BoNT-B (Elan) (Systemic Effects)

BoN

T-B (Elan) Lost From

Injected Site Before R

eaching M

aximum

Local Effect

BoNT-A (Allergan) vs. BoN

T-B (Elan): Comparison of

Efficacy, Diffusion and Safety

Aoki, 2003 AAN Poster # P03.088

BoN

T-A (A

llergan)

Diffusion

BoN

T-A (Ipsen)

Diffusion

Diffusion Response RD

ose B

oNT-B

(Elan)

Diffusion Characteristics of BoNT Form

ulations

Aoki, 2003 AAN Poster # P03.088

Slide 26

Composition of Botulinum

Toxin Components

Adapted from Dressler D. Der N

ervenarzt. 2006;77(8):912-921

150 150

100 100

50 50

Rimabotulinum

toxinB

600 kD

300 300

100 100

50 50

Onabotulinum

toxinA

900 kD

300 300

100 100

50 50

AbobotulinumtoxinA

900 kD

NT 201

100 50

150 kD

FDA BLACK BOX W

ARNIN

G FD

A A

LE

RT [08/2009]: A

s announced on April 30, 2009, based on a safety evaluation of the

botulinum toxin products, FD

A has concluded that the prescribing inform

ation for O

nabotulinumtoxinA

(marketed as B

otox/Botox C

osmetic) and R

imabotulinum

toxinB

(marketed as M

yobloc) must be updated to ensure their continued safe use. O

n July 31, 2009, FD

A, under the authorities granted by the Food and D

rug Adm

inistration A

mendm

ents Act (FD

AA

A) of 2007, approved the follow

ing revisions to the prescribing inform

ation of Botox/B

otox Cosm

etic and Myobloc:

http://ww

w.fda.gov/D

rugs/DrugSafety/Postm

arketDrugS

afetyInformationforPatientsandProviders/D

rugSafetyInform

ationforHeathcareProfessionals/ucm

174949.htm

FDA ALERT

•Boxed w

arning •

Highlight the possibility of life threatening consequences from

distant spread of BTX after local injection

•Risk assessm

ent and mitigation strategy (REM

S) •

Change to the established drug names

•Reinforce individual potencies

•Prevent m

edication errors

Considerations for Health Care Professionals

•U

nexpected loss of strength/ development of

weakness

•Hoarseness or trouble talking (dysphonia)

•Dysarthria

•Loss of bladder control

•Difficulty breathing

•Difficulty sw

allowing

•Double vision, blurred vision, droopy lids

Indication specific dosage and adm

inistration recomm

endations should be follow

ed. In treating adult patients for one or m

ore indications, the maxim

um

cumulative dose should generally not

exceed 360 Units, in a 3 m

onth interval . The safe and effective use of B

OTO

X®

depends upon proper storage of the product, selection of the correct dose, and proper reconstitution and adm

inistration techniques. P

hysicians administering

BO

TOX

® must understand the relevant

neuromuscular and/or orbital anatom

y of the area involved and any alterations to the anatom

y due to prior surgical procedures. An understanding of standard

General Dosing Inform

ation

Spasticity

Definition of Spasticity Adult Spasticity O

verview

“Spasticity is a motor disorder characterized by a velocity-

dependent increase in tonic stretch reflexes (muscle tone) w

ith exaggerated tendon jerks, resulting from

hyperexcitability of the stretch reflex, as one com

ponent of the upper motor

neuron syndrome.”

— Lance, 1980

Upper M

otor Neuron Syndrom

e

Positive Symptom

s •

Spasticity •

Clonus •

Flexor/extensor spasm

•Hyper-reflexia

•Dystonia

•Rigidity

Negative Sym

ptoms

•Decreased dexterity

•W

eakness •

Paralysis •

Fatigability •

Slowness of m

ovement

Adult Spasticity Overview

Etiologies

•Stroke

•Traum

atic brain injury •

Multiple sclerosis

•Spinal cord injury

•Cerebral palsy

•Anoxia

•N

eurodegenerative disease

Adult Spasticity Overview

Evaluation of the Spastic Patient

•Participation of patient/caregiver in

–Assessm

ent of spasticity

–Perform

ance with ADL

–Level of support

–Life-style m

aintenance/improvem

ent

Basic

Quality

of Life

AD

L=activities of daily living

Comm

on Clinical Patterns: Lower

Limbs

Equinovarus Striatal Toe

Extended Knee

Flexed Knee Adducted Thighs

Adult Spasticity Overview

Patient Evaluation (cont’d)

•Physical Exam

ination –

Standard and consistent technique is im

portant to obtain unbiased results –

Use a fixed evaluation sequence •Provide consistency in outcom

e m

easurements

•Valid assessment m

easure •

Therapist Feedback

MAKIN

G DECISION

S: BOTU

LINU

M

TOXIN O

R OTHER M

ODALITY?

TIBIA

L NERV

E BLO

CK

TRAUM

ATIC BRAIN IN

JURY

S.R.

BEFORE LO

CAL ANESTHETIC BLO

CK

TON

E OR CO

NTRACTU

RE?

AFTER LOCAL AN

ESTHETIC BLOCK

RESULT = ↑

TON

E AND CO

NTRACTU

RE

•Line from

greater trochanter to PSIS

•Corresponds w

ith upper border of piriform

is and with the sciatic

notch

•Sciatic nerve is 3 centim

eters below

midpoint of this line

SPINAL CO

RD INJU

RY

•Tw

enty-plus year old ♀

•Spastic paraparesis

•Knee flexion contractures and spastic dystonia

•Hip flexion contractures and spastic dystonia

•Evaluate to determ

ine managem

ent

MED

IAN

NERV

E BLO

CK

: 1%

LIDO

CA

INE

SPASTIC TETRAPARESIS Bulf

S. T.

SCIATIC NERVE BLO

CK

T. L.

BEFO

RE B

OTU

LINU

M TO

XIN

INJEC

TION

S

STROKE

R. C.

EMG N

EEDLE PLACEMEN

T

R. C.

EMG of the TO

NGU

E

E. S.

SAMPLE EM

G N

EEDLE PLACEMEN

T

SPLENIU

S CAPITIS

R. H.

SUM

MARY

•Botulinum

toxins inhibit release of acetylcholine at the neurom

uscular junction •

Botulinum toxin: U

seful tool for Rx of focal spasticity

•Cases m

ust be well selected

•EDX skills helpful in choosing appropriate procedures and m

uscles for injection •

Set clear, attainable treatment goals