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

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

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

Synapse–rich 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

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

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

Immunological aspect of Botox ,dysport and Myobloc/neurobloc

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

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

Botulinum toxin preparation as risk factor for botulinum toxin antibody formation

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%

Treatment of cervical dystonia with botulinum

toxin

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

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 >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

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

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

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

Treatment failures in CD

Primary non–responders 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

Botulinum toxin in blepharospsm and oromandibular dystonia: comparing different

toxin preparations

Oromandibular Dystonia

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

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

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

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

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

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

Blepharospasm

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

Etiology

Psychogenic

Idiopathic

Secondary in only 10%

Reflex due to local conditions

Neurodegenerative disorders PD ,HD , WILSON’S ,CJ ,PSP

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

Botulinum toxin therapy of hemifacial spasm

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

Ddx Blepharospsm Facial myokymia OMD Facial tic Masticatory spasm Post –Bell’s palsy synkinesis Focal seizure

Treatment

Medications Baclofen Clonazepam Carbamazepine Gabapentin Phenytoin

Microvascular decompression 88-97%sucess rate

Doxorubicin Botulinum toxin

Botulinum toxin therapy of laryngeal muscle hyperactivity

syndromes : comparing different toxin preparations

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 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

Surgery Botulinum toxin

97%improvment 35%mild 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

Botulinum toxin therapy for

writers cramp

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

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

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

Other indications of botulinum toxin therapy

Cranial application other than dystonia

Strabismus

Protective ptosis

Bruxism

Rhinitis

Lacrimation

wrinkles

Others

Foot dystonia

Axial dystonia

Tourettet’s disorder Hyperhidrosis urologic disorder

Achalasia

Anal fissure

Thank you !