Botulinum toxin
EUROPIAN JORNAL OF
NEUROLOGY 2006,13 (suppl. 1)
Pharmacology of botulinum toxin :
difference between type A preparation
Pharmacological difference between botulinum toxin types
at molecular level
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It acts by blocking the docking and fusion of SNARE proteins at neuromuscular junction
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The SNARE proteins targeted by different BoNT vary :
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BoNTA and BoNTE cleave synapsomal –associated protein SNAP-25
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BoNTB , BoNTD , BoNTF , BoNTG cleave synaptobrevin or vesicle associated membrane
protein
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BoNTC1 uniqelly cleave both SANP-25 and syntaxin
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The duration of action is longest for BoNTA
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BoNT has heavy and light chain domains
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Heavy chain is binding domain
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Light chain act as a catalytic domain
Pharmacological difference between botulinum toxin types
at molecular level
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The receptor type that it acts upon are
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Cholinergic endings of neuromuscular junction and the autonomic pre
and post –ganglionic synapses
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Synapse–rich areas of the hippocampus , cerebellum and Renshaw
cells
BoNT is more effective when it is injected in activated muscle
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BONT does not cross BBB rather is transported by retrograde axonal
transport to the spinal cord and cranial motor nuclei
Comparison between Botox and Dysport at the
experimental level
Comparison between Botox and Dysport at the
experimental level
Comparison between Botox and Dysport at the
experimental level
Conclusion
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Pharmacological differences between BoNT preparation are influenced by :
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Properties intrisic to the drug eg. protein load
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Muscle selection eg. Muscle activity pattern ,muscle architecture and fascial planes
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Injection technique eg. Volume , dilutions and doses
Botox to Dysport dose conversion ratio of 1 : 2.5 -3 is workable
At therapeutic doses Dysport seems to produce more adverse effects
Immunological aspect of
Botox ,dysport and
Myobloc/neurobloc
Treatment parameters as risk factor for botulinum toxin
antibody formation
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Short inter injection interval
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High BoNT dosages at each injection series
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Higher cumulative BoNT dosage
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Booster injections (with inter injection interval less than 2 weeks )
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Female gender
Patient characteristics as risk factor for botulinum toxin
antibody formation
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The overall reactivity of the patients immune system
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Priming of BT antibodies by structurally similar environmental agent
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Although formal studies have not been performed in special patient
characteristics , Allergies seem to play minor role in BT antibody formation
Botulinum toxin preparation as risk factor for botulinum
toxin antibody formation
Conclusion
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Corrected specific biological activities are measure of antigenicity
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The lower the corrected specific biological activities the higher the antigenicity and hence
antibody induced therapy failure
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Testing for neutralizing antibody against BTB revealed BT antibodies in
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9.6 % of patients at 1 year
18.2% of patients at 18 months
22.6% of patients after 610 days
It may produce antibody-induced treatment failure in as many as 44% of patients
For BTA preparations the rate of antibody induced therapy failure is in the range of 5%
Treatment of cervical
dystonia with botulinum
toxin
Introduction
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Cervical dystonia
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is due to asymmetric contractions of neck and shoulder muscles
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Anterocollis
Retrocllis
Laterocollis
Rotational
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Pain is present in up to 60% of patients and is the most disabling feature
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A variety of medications have been used to treat CD
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Anticholinergic
Baclofen
Benzodiazepins
BoNT is the treatment of choice providing 85% improvement in CD
Botulinum toxin treatment for CD - efficacy and safety
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Both BoNTA and BoNTB are safe and effective
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Technical aspect of BoNT have not been adequately studied
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Number of muscles to inject
Optimal dosing
Number of injection sites for specific muscles
Best means of muscle selection and injection
Botullinum toxin injection technique
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Anatomy of neck muscles include >26 muscle pairs
CD may be simple with two muscle activation or complex with multidirectional
activation
Selecting muscles for injection requires knowledge of the major neck muscles and their
primary and secondary actions
Botulinum toxin treatment for CD - efficacy and safety
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Botulinum toxin doses for CD
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Dysport starting dose 500 units
Botox dose range from 100 – 300U
Myobloc /Neurobloc doses range from 2500 to 10 000
Publish recommendations for the doses of Botox and Dysport are available for
individual muscles
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SCM 20U of Botox
SCM 100U of Dysport
Target muscle selection for CD
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The role of EMG has not been defined
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Investigators using EMG guidance have reported increased benefit and the
potential to use smaller doses
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The number of injection sites into cervical muscles range from
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one site in smaller muscles
to eight sites in larger muscles
Duration of benefit CD
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The mean duration of benefit assessed to time of retreatment in randomized
double blind study was
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83.9 +/- 13.6 days for Dysport
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80.7+/-14.4 days for Botox
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Duration of benefit tend to last longer in patients with moderate symptoms
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The greatest degree of improvement was after the first injection
Treatment failures in CD
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Primary non–responders
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15-30% of CD patients
Anterocollis is the major head posture
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Secondary failure
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in approximately 10 -15% patients
Due to neutralizing antibody
Common side effects following treatment include
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Dysphagia
Dry mouth
Neck weakness
Botulinum toxin in blepharospsm and
oromandibular dystonia: comparing different
toxin preparations
Oromandibular Dystonia
Oromandibular Dystonia
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OMD
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Cranial dystonia
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FORM OF FOCAL DYSTONIA
INVOLVES MASTICATORY , LOWER FACIAL , LAIBIAL AND LINGUAL
MUSCULATURES
Uncommon representing 5% all forms of dystonia
OMD plus blepharospsm
the second most common form of dystonia
Etiology
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Idiopathic most patients
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Blepharospsm , cervical dystoina , and spasmodic dysphonia are more commonly
associated with idiopathic OMD
Tardive dystonia the most common cause of secondary OMD
Neurodegenerative
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neuroacanthocytosis
Treatment options for OMD
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OMD responds poorly to oral medications
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Muscle afferent block helpful but needs further evaluation
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Anticholinergics
Tetrbenzine
Baclofen
Clonazepam
Lidocaine and alcohol
Pallidial deep brain stimulation
Botullinum toxin the therapy of choice
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Jaw opening
Jaw closing
Jaw deviation
Mean total duration of response 16.4+/-7/1 weeks
The best response obtained with jaw closing
Injection techniques
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Jaw closing
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Masseter the initial muscle to be denervated
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Medial pterygiod
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Botox 50U
Dysport 100U
Approached intra orally or from below
EMG verification needed when approached from below
Botox 20U
Dysport 30U
Temporalis muscle
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Three to four injections should be given
Butox 40U
Dysport 100U
Injection techniques
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Jaw opening dystonia
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Lateral pterygoid
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Digastric muscle
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Injection should be given on the anterior belly
Mylohyoid
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Approached intra orally or laterally
EMG recommended in the lateral approach
Botox 20 -40 U
Dysport 60 U
1 cm from the mandibular tip and lateral to the midline
Botox 20U
Dysport 90U
platysma
Injection techniques
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Lingual OMD
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Exrinsic muscles of the tongue
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Tongue trusting is the most common movement in OMD
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Genioglossus
Hypoglossus
Styloglossus
Palatoglossus
Posterior fibers of Genioglossus
Botox 10U
Dysport 30U
The treatment of lingual dystonia is often difficult and the success rate is
usually low
Injection techniques
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Pharyngeal OMD
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Pharyngeal muscles
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Three constrictor muscles
Stylo-, salpingo- ,and palatopharyngie muscles
Patient often complain of choking and swallowing difficulty
Often occurs with spasmodic dysphonia
Constrictor pharynges invariably involved with dysphagia
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For Dysport 30U
Blepharospasm
Clinical features
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Focal dystonia with involuntary closure of the eyes
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Due to spasm of the orbicularis occuli
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Begins 5th to 6th decade of life
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Females are affected more
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Apraxia of the eye lids
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Due to failure to activate levator palpebra muscle
Does not respond well to botulinum toxin
Blepharospasm and apraxia of eye opening may coexist together
Etiology
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Psychogenic
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Idiopathic
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Secondary in only 10%
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Reflex due to local conditions
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Neurodegenerative disorders PD ,HD , WILSON’S ,CJ ,PSP
TREATMENT OPTIENS
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Conservative treatment
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Sun glasses
Benzodiazpines
Anticholinergic
Botulinum toxin injection
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Superficially over the orbicularis oculli
The corrugator muscle injected intramuscularly
orbicularis oculli is injected at five sites with total dose of 12.5-20 for Botox
Avoiding injection of the medial 2/3 of the eye lid is important
Effect lasts for up to 12 weeks
Botulinum toxin therapy of hemifacial
spasm
Introduction
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Involuntary irregular clonic or tonic movements of the muscles innervated by the
7th nerve on one side
Most often the result of vascular compression of the VII nerve
Typical HFS
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Compress the non-facicular portion of facial nerve
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Atypical HFS
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Anterior aspect
Caudal aspect
Compress the posterior or rostral portion
Initiate at orbicularis oris ,businator
And spread to involve the orbicularis oculli
Prevalent in females and in those 40-79
Facial weakness can develop
Symptoms tend to persist during sleep
Occurs usually unilaterally
Non vascular causesof HFS :neuroma ,cystic tumor
Ddx
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Blepharospsm
Facial myokymia
OMD
Facial tic
Masticatory spasm
Post –Bell’s palsy synkinesis
Focal seizure
Treatment
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Medications
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Microvascular decompression
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Baclofen
Clonazepam
Carbamazepine
Gabapentin
Phenytoin
88-97%sucess rate
Doxorubicin
Botulinum toxin
Botulinum toxin therapy of
laryngeal muscle hyperactivity
syndromes : comparing different
toxin preparations
Introduction
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Spasmodic dysphonia is focal dystonia characterized by task specific , action
induced spasm of the vocal cord
First described in 1871 by Traube
It can occur independently or as part of Meige’s syndrome or in other disorders
like Tardive dyskinesia
There are three types of SD: the adductor type ,the abductor type and the mixed
type
The adductor type is characterized by strain-strangled voice quality and
intermittent voice stoppage or breaks due to over adduction of the vocal folds
Abductor spasmodic dysphonia is characterized by intermittent breathy breaks
,associated with prolonged abduction folds
Patients with mixed type have features of both
It affect patient in their mid forties and is more common in females
Treatment options for ADSD
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Surgery
Botulinum toxin
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Muscles injected
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Thyroarytenoid muscle
Lateral cricoarytenoid muscle
Injection protocols
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97%improvment
35%mild breathiness
Choking in 15%
Unilateral decrease side effects
Bilateral increase side effect/prolonged duration of benefit
Injection technique
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Percutaneous approach
Trans oral approach
Trans nasal approach
Point touch injection
( EMG between cricoid and thyroid cartilage )
indirect laryngoscopy
through thyroid cartilage half way b/n notch and lower border
Botulinum toxin therapy for
writers cramp
Introduction
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First reporeted in the 18th century under the title ‘occupational palsy ‘
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disabling spasm only when they write
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On other tasks requiring the same hand muscles they perform normally
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Incidence 14per 1 000 000in Europe
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Contrary to other dystonias WC is more frequently seen in males
Etiology
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Unknown
Deficient activation of the premotor cortex
Loss of inhibition during generation of muscle command
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Excessive activation of antagonist
Over flow into synergist
Prolongation of muscle activation
Decreased level of GABA
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In the contralateral sensory motor cortex
In the contralateral lentiform nucleus
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There is evidence that dystonia is a sensory disorder as well as a disorder of
movement preparation
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Functional MRI showed impairerd activation of
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Primary sensorimotor cortex
Supplementary motor cortex
Persistent increase of Basal Ganglia activity after cessation of task
Treatment of WC
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Limb immobilization by plastic splint for 4-5 weeks
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Sensory training by Braille reading 30 minutes /day for 1 year
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cooling of the hand and forearm muscles
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Low frequency and low dose transcranial magnetic stimulation
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Botulinum toxin
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Effective in 80%
Benefit starts at 1 week and peaks at the 2nd week
improvement last for 3 months
Other indications of botulinum toxin therapy
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Cranial application other than dystonia
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Others
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Strabismus
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Foot dystonia
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Protective ptosis
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Axial dystonia
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Bruxism
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Tourettet’s disorder
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Hyperhidrosis urologic disorder
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Achalasia
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Anal fissure
Rhinitis
Lacrimation
wrinkles
Thank you !