Botulinum Toxin in Post-Stroke Spasticity 19/05/03 Craig Douglas
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
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)
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
BT – Therapeutic Goals • Patient Care Indications -Goals are expected decreases in staffing requirements, caring time and resource consumption • Therapeutic Indications -Goals are increasing patient’s independency and decreasing pain
BT – Favourable Prognosis • Focal spasticity • No connective tissue involvement • Realistic goals • Relatively good power (BMRC >2) • Voluntary activity • Absence of psychological or mental impairment • Good motivation
BT – Available Preparations • BOTOX and Dysport -Neurotoxin per vial: BOTOX = 4.8 ng Dysport = 12.5 ng -Adverse Reactions: BOTOX = 15% Dysport = 26%
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.
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
Local Treatments Local anaesthetics Ethyl alcohol Phenol
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!
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!
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
Ethyl Alcohol – Risks! • Burning pain at site of injections • Local Hyperaemia (Carpenter et al) • Phlebitis (O’Hanlon et al) • Temporary sensory defecit
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
Phenol – Risks! • Tendency to cause pain • Chronic dysaesthesiae (2-32%) • Peripheral oedema • DVT • Local infection due to bacteriocidal properties • Tremor and convulsions
Advantages: early onset action low cost better stability Disadvantages: lack of selectivity tissue destruction propensity to pain lots of SE’s Alcohol and Phenol
General Treatments Baclofen Benzodiazepines Dantrolene
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)
Baclofen – Side Effects! • Sedation and fatigue • Confusion, N&V 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)
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
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
Dantrolene – Sde Effects! • Sedating • Nausea and vomiting • Slurred speech, dizziness, diarrhoea and paraesthesiae • Hepatotoxicity – 2% of patients