Botulinum Toxin for Movement Disorders: … - Section 17.pdf · Botulinum Toxin for Movement...
Transcript of Botulinum Toxin for Movement Disorders: … - Section 17.pdf · Botulinum Toxin for Movement...
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