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An overview of botulinum Toxin type A in the management of

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					An overview of botulinum toxin type A
in the management of focal spasticity
    following traumatic brain injury

                         27th November 2012

                  Dr T L Landham
                  Consultant in Rehabilitation Medicine
Spasticity

l Overactivity of muscles following
  damage to brain or spinal cord
l High tone spasms
l Leads to muscle and soft tissue
  contracture
Features of Spasticity

Positive symptom        Negative symptoms

l   Muscle tone         l   Weakness
l   Tendon jerks        l   Fine control
l   Clonus              l   Dexterity
l   Babinski response   l   Fatiguability
Chronic Spasticity


l Neurogenic   component

l Physical   consequences
Why Treat Spasticity?

l   Disability              Mobility, dexterity

l   Complications           Poor posture
                            Pressure sores
                            Contractures

                 Vicious cycle!
Spasticity Management

Physical               Pharmacological




           Goal Attainment
            Maintenance
Physical Management

              Essential

 All pharmacological interventions
 adjunctive to physical management

         Before, During, After
Spasticity Symptoms

 §   Limb stiffness
 §   Muscle spasms
 §   Limb deformities from stiff joints
 §   Pain from stiff and shortened muscles
 §   Fatigue
 §   Personal activities of daily living
 §   Poor skin integrity
Consequences of Spasticity


l   Loss of mobility and dexterity
l   Pain
l   Inability to stretch limbs
l   Seating and postural problems
l   Hygiene and sexual dysfunction
Consequences of Spasticity


l   Loss of self-esteem
     § Disfigurement
     § Sexuality problems
l   Comfort
l   Mood changes
When To Treat Spasticity


l When it becomes a problem
l Prevention
l Potential for improvement
When Not To Treat


l No potential for improvement
l Spasticity not the underlying feature
l Fixed limb contracture
l Spasticity assisting function
Assessment


l   What’s wrong?
l   Is spasticity causing
    problem?
l   Determine aims of
    treatment
l   ?Specialist help needed
Important points to consider when
managing spasticity

l   Treatment goals can be1
    –   Active functional goals
    –   Passive functional goals
    –   To avoid progression of impairment



l   Muscle selection1
    –   Distinguish between spasticity and weakness
    –   Spasticity usually involves several muscles and
        may occur in common postural patterns
Injection technique

l   EMG can be useful to confirm placement within the
    muscle and
    to confirm the presence of muscle activity (Keenan et
    al. 1990)”1
l   “Nerve or muscle stimulation may be useful to
    confirm placement
    by producing a ‘twitch’ in the target muscle”1
l   “Imaging, such as ultrasound (or occasionally
    CT/MRI scanning)
    may also be used”1
l   Single/multiple injection sites per muscle1
Available Medical Interventions

l Oral agents
l Botulinum toxin
l Phenol - nerve/motor point block
      - intrathecal
l Intrathecal baclofen
l Surgery
Oral Agents



 Baclofen, Dantrolene, Tizanidine
        Benzodiazepines
          Cannabinoids
      Gabapentin, Clonidine
Oral Agents



         40% side-effects

        Narrow margin for
  tolerance, therapeutic effect and
             side-effects
What is botulinum toxin type A?
Botulinum toxin type A

Clostridium botulinum is a gram positive, anaerobic, rod-shaped
bacterium that produces seven serologically distinct neurotoxins (A-G)1,2



                                                Accessory protein2*
                   =   Type A neurotoxin3   +   −Toxin size is determined by content
Botulinum toxin timeline

                 1968                                       1970s–80s
                 Medical use
                 evaluation

                                                       - Strabismus
                               First clinical          - Blepharospasm
                               development
   900kDa Complex
                          2000
    1944                  Allergan
    E. Schantz            BOTOX® (botulinum toxin type A)
                          Current formulation
                                                                   1989
                                                                   Allergan
                                                                   BOTOX®
How does botulinum toxin
     type A work?
BOTOX® mechanism of action
– introduction

l   Hyperactive muscle contraction is characterised by excessive
    nerve stimulation, leading to excessive release of acetylcholine
l   BOTOX® inhibits acetylcholine release at the neuromuscular
    junction, and the injected muscle becomes partially denervated,
    which inhibits muscle activity1
l   BOTOX® blocks neuromuscular transmission through
    a three-step process1,2:
     – Binding
     – Internalisation
     – Blocking
            ®
BOTOX mechanism of action

                                                             Synaptic vesicle
                               BOTOX


 Binding1-3                                                SNARE complex
 BOTOX® binds to specific
 receptors on the external
 membrane of cholinergic
 motor neurons                                 ACh

     The binding site of       Light
                                                     End-plate region
     BOTOX®                    chain

     is located on the heavy           Heav
                                       y
     chain                             chain


                                        Disulphide
                                        bond
                     ®
      BOTOX mechanism of action
                                                   ®

Internalisation
BOTOX® is taken into
   the nerve terminal by                                     Synaptic vesicle

   endocytosis to form a         BOTOX
   toxin-receptor vesicle1                             ACh


    – The light chain is then
       released into the fluid
       centre of the cell
       (cytoplasm)2




                                    UK/0182/2010                                26
                   ®
BOTOX mechanism of action
l   Blocking
l   The light chain cleaves SNAP-25,1,2 one of the intracellular SNARE
    proteins required for acetylcholine release3
     – Acetylcholine remains trapped within the synaptic vesicles,
        its release is blocked and muscle activity decreases2
     – This is known as chemodenervation2

           Light chain
           cleaves specific
           SNARE proteins


           Heavy chain
                                                            SNARE complex
                                                              does not form
           Light chain

                         SNAP-25
                                                      Membranes
                         Syntaxin
                                                      do not fuse
                         VAMP (Synaptobrevin)
                                                Neurotransmitter
                                                 not released
Re-establishing innervation

l   Blocking neuromuscular
    transmission triggers
    expansion of the end-plate
    region and growth
    stimulation of axonal
    sprouts over time1                                Collateral
                                                      axonal sprout
    –   A nerve sprout
        can release acetylcholine
    –   A nerve sprout eventually establishes a
        new neuromuscular junction,
        and muscle activity gradually returns after                   Neuromuscular junction
        a period of
        2–4 months
Botulinum toxin type A products
       available in the UK
Botulinum toxin type A

l   Three botulinum toxin type A products are
    available in the UK:
    –   BOTOX® (Allergan Ltd.)
    –   Dysport (Ipsen Ltd.)
    –   Xeomin (Merz GmBH)


l   Differences in production translate to
    individual characteristics
    and dosing units; they are not
    interchangeable1-3
              DIFFERENT BOTULINUM TOXINS

                                   Allergan toxin         IPSEN toxin              MERZ toxin
              FIRST APPROVAL       1989                   1990                     2005
                                                     4
              PROCESS              Crystallization        Chromatography 5         Chromatography 5


              STABILISATION        Vacuum drying 5        Lyophilisation 5         Vacuum drying 5
DIFFERENCES




              COMPLEX SIZE         ~900kDa6               400kDa 7                 150kDa 3
               UNIFORMITY          Homogeneous8           Heterogeneous 8          Homogeneous 3
              Amounts of           ~2.5ng/50 units        ~4.35ng 10               ~0.6ng11
              neurotoxin           ~5ng/100 units
              protein (ng/vial)    ~10ng/200 units 9
              VIAL SIZES (units)   200/ 100 /50           500/300                  100
              STORAGE              2 - 8°C or < -5°C1     2 - 8°C2                 < 25°C3


              RECONSTITUTED        Up to 24 hours at 2-   Up to 8 hours at 2°C -   Up to 24 hours at
               VIAL STORAGE        8°C1                   8°C2                     2°C - 8°C3
Post Traumatic Brain Injury spasticity in
the UK

l   Early On-set
l   Needs treatment information
l   May need much larger dose
Clinical Effect


l Onset of action            12 hours
l Onset of clinical effect   3-7 days
l Maximal effect             3-4 weeks
l Average duration           3-4 months
Rehabilitation


l Optimises patient functioning
l Decreases complications and need for
  other treatments
l Looks at long term consequences of
  spasticity
Conclusions

l Spasticity – huge impact on people’s
  lives
l Difficult management problem
l Not well-recognised in context of
  underlying condition
l Benefits of treatment and rehabilitation
Post-injection

l   The clinical effect of muscle weakening is
    usually observed 7–14 days post-injection1
l   Essential to ensure appropriate follow up
    for1:
    –   Clinical evaluation against defined goals
    –   Physiotherapy
    –   Splinting/Orthotics
    –   Stretching
    –   Strengthening of opposing muscle groups

				
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