Botulinum toxin

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Botulinum toxin

• EUROPIAN JORNAL OF NEUROLOGY 2006,13 (suppl. 1)

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Pharmacology of botulinum toxin difference
between type A preparation
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Pharmacological difference between botulinum
toxin types at molecular level

• It acts by blocking the docking and fusion of
  SNARE proteins at neuromuscular junction
• The SNARE proteins targeted by different BoNT
  vary
• BoNTA and BoNTE cleave synapsomal associated
  protein SNAP-25
• BoNTB , BoNTD , BoNTF , BoNTG cleave
  synaptobrevin or vesicle associated membrane
  protein
• BoNTC1 uniqelly cleave both SANP-25 and syntaxin
  
• The duration of action is longest for BoNTA
• BoNT has heavy and light chain domains
• Heavy chain is binding domain
• Light chain act as a catalytic domain

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Pharmacological difference between botulinum
toxin types at molecular level

• The receptor type that it acts upon are
• Cholinergic endings of neuromuscular junction and
  the autonomic pre and post ganglionic synapses
• Synapserich areas of the hippocampus ,
  cerebellum and Renshaw cells
• BoNT is more effective when it is injected in
  activated muscle
• BONT does not cross BBB rather is transported by
  retrograde axonal transport to the spinal cord
  and cranial motor nuclei

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Comparison between Botox and Dysport at the
experimental level
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Comparison between Botox and Dysport at the
experimental level
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Comparison between Botox and Dysport at the
experimental level
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Conclusion

• Pharmacological differences between BoNT
  preparation are influenced by
• Properties intrisic to the drug eg. protein load
  
• Muscle selection eg. Muscle activity pattern
  ,muscle architecture and fascial planes
• 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

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Immunological aspect of Botox ,dysport and
Myobloc/neurobloc
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Treatment parameters as risk factor for botulinum
toxin antibody formation

• Short inter injection interval
• High BoNT dosages at each injection series
• Higher cumulative BoNT dosage
• Booster injections (with inter injection interval
  less than 2 weeks )
• Female gender

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Patient characteristics as risk factor for
botulinum toxin antibody formation

• The overall reactivity of the patients immune
  system
• Priming of BT antibodies by structurally similar
  environmental agent
• Although formal studies have not been performed
  in special patient characteristics , Allergies
  seem to play minor role in BT antibody formation

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Botulinum toxin preparation as risk factor for
botulinum toxin antibody formation
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Conclusion

• Corrected specific biological activities are
  measure of antigenicity
• The lower the corrected specific biological
  activities the higher the antigenicity and hence
  antibody induced therapy failure
• Testing for neutralizing antibody against BTB
  revealed BT antibodies in
• 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

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Treatment of cervical dystonia with botulinum
toxin
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Introduction

• Cervical dystonia
• is due to asymmetric contractions of neck and
  shoulder muscles
• Anterocollis
• Retrocllis
• Laterocollis
• Rotational
• Pain is present in up to 60 of patients and is
  the most disabling feature
• A variety of medications have been used to treat
  CD
• Anticholinergic
• Baclofen
• Benzodiazepins
• BoNT is the treatment of choice providing 85
  improvement in CD

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Botulinum toxin treatment for CD - efficacy and
safety

• Both BoNTA and BoNTB are safe and effective
• Technical aspect of BoNT have not been adequately
  studied
• 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
• Anatomy of neck muscles include gt26 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

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Botulinum toxin treatment for CD - efficacy and
safety

• Botulinum toxin doses for CD
• 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
• SCM 20U of Botox
• SCM 100U of Dysport

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Target muscle selection for CD

• The role of EMG has not been defined
• Investigators using EMG guidance have reported
  increased benefit and the potential to use
  smaller doses
• The number of injection sites into cervical
  muscles range from
• one site in smaller muscles
• to eight sites in larger muscles

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Duration of benefit CD

• The mean duration of benefit assessed to time of
  retreatment in randomized double blind study was
• 83.9 /- 13.6 days for Dysport
• 80.7/-14.4 days for Botox
• Duration of benefit tend to last longer in
  patients with moderate symptoms
• The greatest degree of improvement was after the
  first injection

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Treatment failures in CD

• Primary nonresponders
• 15-30 of CD patients
• Anterocollis is the major head posture
• Secondary failure
• in approximately 10 -15 patients
• Due to neutralizing antibody
• Common side effects following treatment include
• Dysphagia
• Dry mouth
• Neck weakness

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Botulinum toxin in blepharospsm and oromandibular
dystonia comparing different toxin preparations
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Oromandibular Dystonia
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Oromandibular Dystonia

• OMD
• FORM OF FOCAL DYSTONIA
• INVOLVES MASTICATORY , LOWER FACIAL , LAIBIAL
  AND LINGUAL MUSCULATURES
• Uncommon representing 5 all forms of dystonia
• Cranial dystonia
• OMD plus blepharospsm
• the second most common form of dystonia
• Etiology
• Idiopathic most patients
• Blepharospsm , cervical dystoina , and spasmodic
  dysphonia are more commonly associated with
  idiopathic OMD
• Tardive dystonia the most common cause of
  secondary OMD
• Neurodegenerative
• neuroacanthocytosis

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Treatment options for OMD

• OMD responds poorly to oral medications
• Anticholinergics
• Tetrbenzine
• Baclofen
• Clonazepam
• Muscle afferent block helpful but needs further
  evaluation
• Lidocaine and alcohol
• Pallidial deep brain stimulation
• Botullinum toxin the therapy of choice
• Jaw opening
• Jaw closing
• Jaw deviation
• Mean total duration of response 16.4/-7/1 weeks
• The best response obtained with jaw closing

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Injection techniques

• Jaw closing
• Masseter the initial muscle to be denervated
• Botox 50U
• Dysport 100U
• Medial pterygiod
• Approached intra orally or from below
• EMG verification needed when approached from
  below
• Botox 20U
• Dysport 30U
• Temporalis muscle
• Three to four injections should be given
• Butox 40U
• Dysport 100U

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Injection techniques

• Jaw opening dystonia
• Lateral pterygoid
• Approached intra orally or laterally
• EMG recommended in the lateral approach
• Botox 20 -40 U
• Dysport 60 U
• Digastric muscle
• Injection should be given on the anterior belly
• Mylohyoid
• 1 cm from the mandibular tip and lateral to the
  midline
• Botox 20U
• Dysport 90U
• platysma

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Injection techniques

• Lingual OMD
• Exrinsic muscles of the tongue
• Genioglossus
• Hypoglossus
• Styloglossus
• Palatoglossus
• Tongue trusting is the most common movement in
  OMD
• Posterior fibers of Genioglossus
• Botox 10U
• Dysport 30U
• The treatment of lingual dystonia is often
  difficult and the success rate is usually low

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Injection techniques

• Pharyngeal OMD
• Pharyngeal muscles
• 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
• For Dysport 30U
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

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Blepharospasm
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Clinical features

• Focal dystonia with involuntary closure of the
  eyes
• Due to spasm of the orbicularis occuli
• Begins 5th to 6th decade of life
• Females are affected more
• Apraxia of the eye lids
• Due to failure to activate levator palpebra
  muscle
• Does not respond well to botulinum toxin
• Blepharospasm and apraxia of eye opening may
  coexist together

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Etiology

• Psychogenic
• Idiopathic
• Secondary in only 10
• Reflex due to local conditions
• Neurodegenerative disorders PD ,HD , WILSONS ,CJ
  ,PSP

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TREATMENT OPTIENS

• Conservative treatment
• Sun glasses
• Benzodiazpines
• Anticholinergic
• Botulinum toxin injection
• 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

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Botulinum toxin therapy of hemifacial spasm
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Introduction

• 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
• Compress the non-facicular portion of facial
  nerve
• Anterior aspect
• Caudal aspect
• Atypical HFS
• 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

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Ddx

• Blepharospsm
• Facial myokymia
• OMD
• Facial tic
• Masticatory spasm
• Post Bells palsy synkinesis
• Focal seizure

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Treatment

• Medications
• Baclofen
• Clonazepam
• Carbamazepine
• Gabapentin
• Phenytoin
• Microvascular decompression
• 88-97sucess rate
• Doxorubicin
• Botulinum toxin

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Botulinum toxin therapy of laryngeal muscle
hyperactivity syndromes comparing different
toxin preparations
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Introduction

• 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 Meiges
  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

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Treatment options for ADSD

• Surgery
• Botulinum toxin
• 97improvment
• 35mild breathiness
• Choking in 15
• Muscles injected
• Thyroarytenoid muscle
• Lateral cricoarytenoid muscle
• Injection protocols
• Unilateral decrease side effects
• Bilateral increase side effect/prolonged duration
  of benefit
• Injection technique
• Percutaneous approach ( EMG between cricoid
  and thyroid cartilage )
• Trans oral approach indirect
  laryngoscopy
• Trans nasal approach
• Point touch injection through
  thyroid cartilage half way b/n notch and lower
  border

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Botulinum toxin therapy for writers cramp
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Introduction

• First reporeted in the 18th century under the
  title occupational palsy
• disabling spasm only when they write
• On other tasks requiring the same hand muscles
  they perform normally
• Incidence 14per 1 000 000in Europe
• Contrary to other dystonias WC is more frequently
  seen in males

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Etiology

• Unknown
• Deficient activation of the premotor cortex
• Loss of inhibition during generation of muscle
  command
• Excessive activation of antagonist
• Over flow into synergist
• Prolongation of muscle activation
• Decreased level of GABA
• In the contralateral sensory motor cortex
• In the contralateral lentiform nucleus
• There is evidence that dystonia is a sensory
  disorder as well as a disorder of movement
  preparation
• Functional MRI showed impairerd activation of
• Primary sensorimotor cortex
• Supplementary motor cortex
• Persistent increase of Basal Ganglia activity
  after cessation of task

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Treatment of WC

• Limb immobilization by plastic splint for 4-5
  weeks
• Sensory training by Braille reading 30 minutes
  /day for 1 year
• cooling of the hand and forearm muscles
• Low frequency and low dose transcranial magnetic
  stimulation
• Botulinum toxin
• Effective in 80
• Benefit starts at 1 week and peaks at the 2nd
  week
• improvement last for 3 months

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Other indications of botulinum toxin therapy

• Cranial application other than dystonia
• Strabismus
• Protective ptosis
• Bruxism
• Rhinitis
• Lacrimation
• wrinkles

• Others
• Foot dystonia
• Axial dystonia
• Tourettets disorder
• Hyperhidrosis urologic disorder
• Achalasia
• Anal fissure

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• Thank you !