Botulinum Toxin in Post-Stroke Spasticity

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Botulinum Toxin in Post-Stroke Spasticity

• 19/05/03
• Craig Douglas

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Spasticity

• Overactivity in the muscles following damage to
  the brain or spinal cord
• Causes pain and deformity
• Decreases independence
• Increases post stroke complications
• Treatment may involve a combination of physio,
  antispasmodic drugs, BT and surgery

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Botulinum Toxin

• BT neurotoxin binds with H chain to the BT
  receptor at the cholinergic nerve ending
• L chain then transported into the nerve ending,
  where it blocks the transport of molecules
  mediating the transport of Ach to the synapse
• L chains also cleave SNARE proteins, preventing
  membrane formation for Ach transport
• Action is terminated by axonal sprouting of the
  peripheral nerve (takes 12 weeks)

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BT- Mechanism of Action
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Botulinum Toxin

• Objective of therapy is to decrease dystonic
  strength as much as possible
• However, BT has same effects on voluntary
  strength
• Voluntary Strength FS RS
• For BT to be effective, FS must be preserved

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BT Therapeutic Goals

• Patient Care Indications
• -Goals are expected decreases in staffing
  requirements, caring time and resource
  consumption
• Therapeutic Indications
• -Goals are increasing patients independency
  and decreasing pain

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BT Favourable Prognosis

• Focal spasticity
• No connective tissue involvement
• Realistic goals
• Relatively good power (BMRC gt2)
• Voluntary activity
• Absence of psychological or mental impairment
• Good motivation

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BT Available Preparations

• BOTOX and Dysport
• -Neurotoxin per vial
• BOTOX 4.8 ng
• Dysport 12.5 ng
• -Adverse Reactions
• BOTOX 15
• Dysport 26

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BT Clinical Info

• Clinical improvement after 2 weeks
• Peak effects after 4-6 weeks
• Contraindications
• -MG, aminoglycosides, bleeding disorders,
  pregnancy and lactation
• Adverse Reactions
• -Purpura, arm pain, muscle weakness,
  hypertonia
• No known transmission of HIV or Hep.
  

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BT Clinical Info

• BOTOX max. dose 400-500 units
• 1 injection site for strap-like muscles
• Multiple injection sites for flat/pennate muscles
• May use EMG to help locate injection site
• Therapeutic doses too low to produce immune
  response
• Macromolecule, mol wt 150 kDa, blood-brain
  barrier is not crossed

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Other Options!
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Local Treatments

• Local anaesthetics
• Ethyl alcohol
• Phenol

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Local Anaesthetics

• Lidocaine, etidocaine or bupivocaine
• Decrease/prevent the large transient increase in
  membrane permeability to Na ions
• Reversible
• Act within minutes, but effects only last hours!

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Local Anaesthetics Risks!

• If drug enters systemic circulation, it
  interferes with the function of all organs where
  impulse conduction occurs
• CNS effects- tremor, convulsions
• May cause hypotension and inhibit cardiovascular
  reflexes
• Allergic responses
• Never use in hepatic dysfunction!

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Ethyl Alcohol

• At low conc. (5-10), it acts as a local
  anaesthetic by decreasing Na and K conductance
• At higher conc. (30-50), it acts as a hypobaric
  compound that denatures proteins and damages cells

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Ethyl Alcohol Risks!

• Burning pain at site of injections
• Local Hyperaemia (Carpenter et al)
• Phlebitis (OHanlon et al)
• Temporary sensory defecit

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Phenol

• Phenol is a derivative of benzene
• It works by non-selectively denaturing proteins
  and causing tissue necrosis
• May cause occlusion of small blood vessels and
  fibrosis in the injected area

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Phenol Risks!

• Tendency to cause pain
• Chronic dysaesthesiae (2-32)
• Peripheral oedema
• DVT
• Local infection due to bacteriocidal properties
• Tremor and convulsions

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Alcohol and Phenol

• Advantages
• early onset action
• low cost
• better stability

• Disadvantages
• lack of selectivity
• tissue destruction
• propensity to pain
• lots of SEs

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General Treatments

• Baclofen
• Benzodiazepines
• Dantrolene

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Baclofen

• Structural analogue of GABA
• Rapid absorption, and half life of two to six
  hours
• Binds to GABAb receptors pre and post
  synaptically, causing membrane hyperpolarisation
  and a decrease in endogenous transmitter release
• Excreted by kidneys (unchanged)

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Baclofen Side Effects!

• Sedation and fatigue
• Confusion, NV in brain injury!!!
• -Hulme et al, Eur Journal of Clin Pharm, 1985
• Trial stopped due to unacceptable levels of
  the above side effects in elderly stroke patients
• Increase bronchoconstriction
• May cause ataxia and paraesthesiae
• May cause memory loss (animal stu)

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Benzodiazepines

• These drugs work at the GABAa receptor
• Increase presynaptic inhibition
• Duration of action is related to metabolism of
  parent compound
• Side Effects
• -Depression of CNS, synergistic with alcohol
• A decrease in alertness, memory,
  co-ordination
• Deterioration of ability to walk and grip
  strength

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Dantrolene

• Unique
• Acts at muscle fibre rather than at the neural
  level
• Decreases muscle AP induced release of Ca from
  the SR, THEREFORE, partial uncoupling of motor
  nerve excitation and muscle contraction develops

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Dantrolene Sde Effects!

• Sedating
• Nausea and vomiting
• Slurred speech, dizziness, diarrhoea and
  paraesthesiae
• Hepatotoxicity 2 of patients

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