2. History
1. The organism C. botulinum(a spore-producing Gram +ve anaerobic
bacillus )was originally isolated by Professor E Van Ermengem in 1895
2. Botoxis a neuroprotective protein produced by Clostridium botulinum
3. 1973, Dr Alan Scott and co-workers demonstrated the effectiveness of
Botoxtype A for the management of strabismus in humans.
3. Types of botulinum toxin
1. C. botulinum elaborates eight antigenically distinguishable
exotoxins (A, B, C1, C2, D, E, F and G)
2. Types A, B and E are commonly associated with systemic
botulism in humans.
3. Type A is the most potent toxin, f/b types B and F toxin.
4. In 1989 BotoxA (botox) FDA approved in 1989 for
blepharospasm and hemifacial spasm.
5. In 2000 BotoxB was approved for cervical dystonia
4. Molecular biochemistry
1. All botulinum neurotoxins are produced as
relatively inactive, single polypeptide chains
2. 150 kDa weight
3. The parent polypeptide chain consists of a
1. heavy (H) chain(100 kDa) – helps in
binding to nerve terminal
2. light (L) chain(50 kDa) – prevent release of
Ach from nerve terminal ,
3. linked by a disulfide bond.
5. Mechanism of action
1. act at four different sites in the body
1. the NMJ,
2. autonomic ganglia,
3. postganglionic parasympathetic nerve endings
4. postganglionic sympathetic nerve endings
2. Intramuscular administration of Botoxacts at the NMJ to cause muscle
paralysis by inhibiting the release of Ach from presynaptic motor
neurons
that release Ach
6. 3.At NMJ
1. binding,
2. internalisation and
3. inhibition of Ach release through
inactivation of SNARE proteins.
7. 4.SNARE (soluble N- ethylmaleimide-sensitive factor attachment receptor )
1. protein involved in vesicle fusion and mediating release of
neurotransmitter acetylcholine, from axon endings.
2. synaptosomal-associated protein (SNAP- 25), a protein forms the
SNARE
8. Botox cleaves SNAP- 25
Formation of SNARE
release of acetylcholine
nerve impulses are blocked
flaccid (sagging) Paralysis of muscles
(characteristic of botulism)
9. 5. The peak of the paralytic effect occurs 4-7 days after injection.
6. Approx 2 months after the administration of botox, the axon begins
to expand, and new nerve terminal sprouts emerge and extend
towards the muscle surface
7. These new nerve sprouts re-establish the motor nerve unit and the
muscle paralysis is reversed within 2-4 months.
8. The Botoxis inactivated by heat 850C or greater in 5 minutes
10.
11. Commercial preparations
Botoxtype A
1. Botox (Allergan Inc, Irvine, CA) ( Worldwide)
2. Dysport (Ipsen Pharmaceuticals, France). (European Union )
Botoxtype B
1. Myobloc (Élan Pharmaceuticals, South SanFrancisco, CA).
(United States)
12. Type A toxin
1. easily producible in culture in a highly purified, stable and
crystalline form
2. has the longest duration of action.
3. stored at -5°C until reconstitution
BotoxÒ
1. purified neurotoxin complex is a sterile vacuum-dried purified
extract, produced from fermentation of the Hall strain of C.
botulinum type A.
2. Each vial contains
1. 100 units (U) of C. botulinum type A neurotoxin complex,
2. 0.5 mg of human albumin, and
3. 0.9 mg of NaCl in a sterile vacuum-dried solid without
preservatives.
3. BotoxÒ is 50-100 times more potent than MyoblocÒ
DysportÒ
13. MyoblocÒ
1. is a sterile liquid formulation of purified neurotoxin type B
2. produced by fermentation of Bean strain of C. botulinum type B.
3. packaged as a liquid formulation at a conc of 5000 U/ml.
4. available in 0.5 ml (2500 U), 1 ml (5000 U) and 2 ml (10 000 U) vials
and does not require reconstitution.
5. vials are stable for 30 months when refrigerated, and for 9 months
at room temperature
6. slightly acidic with a pH of 5.6.
7. has a faster onset of action, and a larger area of diffusion, but the
greater acidity of its storage medium translates to greater
discomfort upon injection.
14. Antibody production:
1. Botoxis capable of inducing formation of humoural antibodies in
humans leading to decreased effect of the toxin over
2. Antibody production is a function of cumulative dose, antigenic
load per dose, and time interval between injections.
3. So smallest therapeutic dose be given with maximum time
interval between two injections.
4. In patients who develop antibodies to type A toxin, successful Rx
with type F toxin has been reported.
15. 5. BotoxÒ, DysportÒ and MyoblocÒ contain human serum albumin
(HSA) to stabilise neurotoxin complex and prevent it from aggregating
onto surfaces
6. HSA is derived from a screened pool of donors
7. Prions are normal (helical) or abnormal (helical) proteins with toxic
effects, and can accompany HSA that is derived from the donors.
8. Concerns have been raised about the potential risk of human-to-
human transmission of prion disease by the HSA used in commercially
available Botoxproducts
9. Although this theoretical risk exists, there have been no reports of
transmission of Hepatitis A, B or C, human immunodeficiency virus or
Creutzfeldt-Jacob disease through HSA.
16. Toxin reconstitution
1. Because the pure neurotoxin protein is unstable and toxic, it is
complexed to a nontoxic protein and other stabilizers, such as
pasteurized albumin.
2. Botox is supplied as a lyophilized powder & reconstituted with sterile
saline Due to its large size, the protein is subject to shearing if handled
too vigorously ,which can diminish the toxin’s biologic activity. So
carefully introduce the saline into the medication vial, directing the
fluid slowly down the side of the vial to avoid directly impacting the
lyophilized protein.
3. The protein will dissolve in the saline solution with minimal
manipulation of the vial, so shaking of the vial is not needed
4. A large-bore needle (e.g., 21 gauge) should be used to draw the
Botoxsolution into the syringe & to minimize patient discomfort, a 30-
guage
needle is suggested for the injection
17. 5.The type A toxin has to
be
reconstituted with sterile,
nonpreserved 0.9% saline
prior to injection
19. 7.The reconstituted solution should be clear, colourless and free of
particulate matter, and should be stored in a refrigerator at 40C until
use.
8.The reconstituted toxin is drawn into a tuberculin syringe via a fine
gauge needle (30G or 32G) for final injection.
9. The Botox reconstituted with non-preserved saline should be used
within 4 hours , reconstituted by preserved saline can be refrigerated
upto 2 wks
20.
21. 10. start Rx with low conc (2.5 units/0.1 mL) and low total doses (12.5–
15.0 units per eyelid) and gradually increase ,administered if
symptomatic spasms persist or if spasms recur before the average
10–12 weeks Rx duration.
11. Higher doses used to treat dystonias like torticollis stimulate
antibodies which affect the toxin’s paralytic potential.
12. Botoxtype B has been used in botulinum A-resistant patients, but the
duration of paralysis is shorter than the paralysis induced by
botulinum A, and the toxin injection is more painful than toxin A
injection
22. contraindications
1. pregnancy, nursing mothers,
2. children
3. patients with a known hypersensitivity to egg Albumin
4. Peripheral motor neuropathic diseases
1. Amyotropic lateral sclerosis
2. Motor neuropathy
5. Neuromuscular junction disorders
1. Myasthenia gravis
2. Eaton-Lambert syndrome
6. Areas of active infection
drug interaction
1. aminoglycosides (e.g. gentamycine, tobramycin, streptomycin)
and
2. drug interfering neuromuscular transmission like curarin, Sch
23. Indications in ophthalmic plastic
surgery
Therapeutic
1. Facial dystonias:
1. Benign Essential
Blepharospasm
2. Hemifacialspasm
3. Orbicularis myokimia
4. Meige syndrome
5. Apraxia of lid opening (ALO)
2. Lower eyelid senile entropion
3. Chemo-tarsorrhaphy
1. For corneal exposure in
temporary VII nerve palsy
2. Indolent corneal ulcers or
epithelial defects
4. Upper eyelid retraction
5. Aberrant regeneration of VII
nerve
1. Crocodile tears (Gustatory
epiphora)
2. Frey's syndrome (Gustatory
sweating)
3. Abnormal facial movements
6. Lacrimal gland hypersecretion
1. Primary
2. Functional epiphora
(irreparable true epiphora)
7. Dry eye syndromes
24. Cosmetic
1. Dynamic facialwrinkles
1. Crow's feet
2. horizontal forehead wrinkles
3. glabellar furrows
2. Chemicalbrow lift
Other indications in Ophthalmology
1. Concomitant strabismus (primary or secondary esotropia or
exotropia)
2. Duane’s syndrome
3. Nonconcomitant strabismus (III, IV, VI nerve palsy, internuclear
ophthalmoplegia)
4. Thyroid eye disease related strabismus
5. Pain relief in acuteangle closure glaucoma?
25. Facial dystonias
1.BEB
1. an involuntary and repetitive bilateral spasmodic contraction of the
orbicularis oculi muscle and is often progressive
2. It usually presents in the fourth to sixth decade with an increase in the
blink rate, which increases in 1 or 2 years to forceful involuntary closure of
eyelids.
3. Symptoms are often exacerbated by environmental conditions like bright
light, dusty air or optokinetic stimulus
4. The aetiology of blepharospasm is considered to be an organic
dysfunction of
the rostral brainstem.
26. Rx:
1. central nervous system depressants (diazepam and clonazepam),
2. orbicularis myectomy
3. selective facial nerve
4. Botox
chemodenervation
27. Reflex blepharospasm:
1. caused by dry eye or ocular surface pathology
2. can mimic BEB
3. Often associated with spastic lower eyelid entropion that in turn
induces ocular surface damage, and the vicious cycle continues
4. It is typically relieved by instillation of topical anaesthetic.
5. Botoxinjection helps to break the vicious cycle, by inducing
temporary paralysis of orbicularis oculi
28. Meige Syndrome
1. first described in 1910 by Henry Meige, as ‘spasm facial median’.
2. It is a form of cranial dystonia characterised by the presence of bilateral
blepharospasm with concurrent dystonia of the lower face, in the form of
lip
pursing, chewing, or jaw opening movements.
3. Dysarthria, and dysphonia may also be seen
4. The most common and disabling manifestation -blepharospasm, which
can render the patient functionally blind.
29. HFS
1. Characterised by repetitive unilateral periodic tonic contractions of
ipsilateral facial muscles
2. begins in middle age ,MC in females
3. causes
1. mechanical-vascular compression of the 7th cranial nerve root in
the cerebello-pontine angle
2. posterior fossa tumours1%
4. In : MRI
5. Rx :
1. neurosurgical microvascular decompression procedure may be
the definitive form of Rx
Botoxinjections are effective in controlling HFS.
30. Orbicularis myokimia
1. generally occurs in younger individuals
2. involuntary twitching of the upper or lower eyelid, resulting from
spasm of individual bundles of muscle fibres.
3. It is related to stress, fatigue, use of alcohol, or excess caffeine.
31. For chemodenervation of facial dystonias
1. Videography of spasms before and after injection may allow
identification
of the involved muscles, and help in planning future Rx.
2. Patients with BEB typically require repeat injections every 3–4 months,
whereas those with HFS have a longer spasm-free interval of 4–6
months. because HFS demonstrates less of nerve and muscle
hyperactivity & the facial nerve progressively degenerates in HFS,
leading to a longer spasm free interval.
3. Patients are evaluated 2– 4 weeks after their initial injections to assess
the efficacy, and side effects or complications
4. Injection into the pretarsal muscle has been shown to produce
a significantly better response compared to preseptal injection
in blepharospasm and HFS patients.
32. Common complications of botoxchemodenervation for facial
spasms
1. upper eyelid ptosis (d/t paresis of LPS)
2. lagophthalmos
3. ectropion or entropion of the eyelid
4. functional epiphora due to lacrimal pump failure
5. diplopia(d/t paereis of IO)
6. eyelid haematoma
7. Motility defects
Sites of injection
1. Spare central upper lid to decrease risk of ptosis
2. Spare medial & central lower lid to decrease risk of
1. Paralytic ectropion
2. Paresis of IO
3. Atrophy of canaliculi or its closure
33.
34. Apraxia of lid opening :
1. nonparalytic motor abnormality characterised by difficulty in initiating
the act of lid elevation.
2. Causes :extrapyramidal disorders like
1. Parkinson’s disease,
2. Huntington’s chorea,
3. Progressive supranuclear palsy, and
4. Shy-Drager syndrome.
3. Abnormal persistence of orbicularis oculi activity detectable
electromyographically but not clinically, has been suggested to be the
main factor contributing to the delay in lid opening in these patients.
4. often associated with blepharospasm
5. Botoxinjection has been shown to improve lid opening delays in ALO
35. Chemo-tarsorrhaphy
1. Traditionally, tarsorrhaphy has been used in cases of corneal
exposure due to facial nerve palsy, persistent epithelial defects, and
indolent corneal ulcers.
2. Botoxchemodenervation of levator muscle is a quick and easy
procedure for induction of temporary ptosis for corneal protection
thereby avoiding surgical tarsorrhaphy and subsequent scarring of
eyelid margin.
3. Transient superior rectus underaction lasting for 6 weeks has been
reported to occur in 68–80% of treated patients.
4. 5 U of Botox -onset of ptosis in an average of 4 days, and lasting for
46 days.
36.
37. Upper eyelid retraction :
1. Botoxinjection into the levator can be an effective
Rx for upper eyelid retraction associated with thyroid eye disease
2. the amount of resultant ptosis is unpredictable, but effective in
reducing
symptoms and improves the cosmetic appearance.
38.
39. Lower eyelid senile entropion :
1. d/t overriding of preseptal orbicularis muscle over pretarsal
orbicularis muscle is Rx with Botox injection into the lower
orbicularis muscle for temporary control
2. Surgical Rx of senile lower eyelid entropion is definitive
3. But Botox chemodenervation is a quick outpatient procedure
patients who are unfit or waiting for surgery.
4. 10– 20 U of Botox – mean duration of action12 to 15 weeks
42. Gustatory epiphora
1. characterised by excessive
lacrimation while eating or
smelling food.
2. usually follows a Bell’s palsy or
stroke, involving the proximal
facial nerve or its nucleus.
3. treated with intraglandular
injection of botulinum toxin
4. Ptosis and superior rectus
underaction are common side
effects.
43. Frey’s syndrome or ‘auriculo-temporal syndrome’ :
1. characterised by ipsilateral excessive facial sweating while eating.
2. Typically follows parotid surgery where subcutaneous dissection
disrupts the sympathetic fibres innervating the sweat glands of the
face and parasympathetic fibres innervating the parotid gland.
3. Aberrant innervation of the sweat glands by the parasympathetic
salivary gland fibres results in Frey’s syndrome.
4. The Minor’s iodine starch test is performed to reveal hypersecreting
areas of the skin, which are treated with intracutaneous/ID injection
of botulinum toxin.
5. Botoxis also used in Rx of idiopathic craniofacial hyperhidrosis, and
diabetic autonomic gustatory sweating.
44. Synkinetic facial movements
1. D/t partially regeneration facial nerve.
2. Synkinesis between orbicularis oculi and lower facial muscles would
lead to narrowing of palpebral aperture on smiling, creating a
cosmetic deformity
45. Lacrimal gland hypersecretion
1. Injection of Botoxinto the lacrimal gland can also be used for
1. primary lacrimal gland hypersecretion, and
2. secondary causes like functional epiphora.
2. Transient mild ptosis and diplopia were the main side effects.
Dry eye
1. Injection of Botoxinto the medial eyelid decreases lacrimal drainage by
paralysing the lacrimal pump mechanism.
2. This can prove to be a useful adjunct in the management of dry eye
patients.
46. Cosmetic oculoplasty
1. Facial wrinkles or rhytides may be categorised as static or dynamic.
2. static wrinkles result from thinning of the dermis due to age, sun
exposure, and smoking.
3. Dynamic wrinkles are the result of activity of underlying muscles.
4. Repeated, prolonged effect of dynamic wrinkles can lead to loss of
subcutaneous fat, hyaluronic acid and collagen leading to static
wrinkles.
5. The dynamic wrinkles are most common over the upper third of
the face (brow and peri-orbital regions), and are amenable to
management with chemodenervation agents.
47. Glabellar frown lines:
1. caused by the actions of corrugator
supercilli, depressor supercilli and
procerus muscles.
2. Injection into these areas has been
shown to cause temporary paralysis
that lasts up to 6 months thereby
eliminating these wrinkles.
3. 2.5–5 U of Botox - injected at five to
seven sites into both corrugators and
into the procerus muscle
48. Horizontal forehead wrinkles:
1. the action of the frontalis muscle may, lead to the development of
horizontal forehead wrinkles.
2. Injection of Botoxtype A (Botox) in four to eight sites spaced evenly
over the forehead may relax the muscle and soften these lines.
3. The injections are typically given 2-3 cm above the orbital rim using
2.5-5 U per injection sites
49. Periocular crow’s feet:
1. the contraction of the lateral orbicularis fibres, zygomaticus and
risorius muscles gives rise to dynamic wrinkles spreading out from
the lateral canthus, known as the crow’s feet
2. Three to four injections of 2.5–5 U of Botox into lateral orbicularis
oculi are required for effective Rx of crow’s feet
3. Injection into the zygomaticus major can cause ipsilateral lip
ptosis, and should thus be avoided
4. Lower eyelid injection with 2 U of botox can widen the eye with
reduction in infraorbital wrinkles
50. Chemical brow lift:
1. Botoxcan be used to create a chemical browlift by selectively
paralysing the depressors of the eyebrow.
2. Botoxinjections are given into the glabellar area and lateral orbital
orbicularis muscle below the eyebrow
51.
52.
53. 1. Other aesthetic facial applications of botulinum toxin
1. ‘bunny lines’,
2. peri-oral Rx,
3. dimpled chin,
4. ‘marionette lines’ and
5. platysmal bands.
2. Botoxhas also been found to be useful in the
management of Migraine and Tension type headache
When injected into the neck or facial muscles(temporalis, frontalis,
corrugator-procerus complex and occipitalis), it is believed to
block the release of nociceptive neuropeptides involved in the
chronic inflammatory pain response, such as substance P and
glutamate.
3. This theoretically inhibits both peripheral and central sensitisation,
thereby down regulating pain
54. Strabismus
1. Botox was first used in ophthalmology by Dr. Alan Scott to treat
strabismus by weakening the contraction force of specific opposing
muscles to straighten the eye.
2. Injection usually requires the use of electromyographic-guided
needle placement to ensure the toxin is delivered to the target
muscle.
3. For infantile esotropia it has been shown that two thirds of children
receiving simultaneous bimedial rectus muscle toxin injection
achieve some degree of stereopsis.
4. One third of patients with comitant exotropia may also show
improvement in their deviation.
55. 5. For larger-angle deviations, increasing the dose of toxin per
injection
may give better results, but higher incidence of complications such
as ptosis.
6. Botoxhas also shown some benefit for traumatic paralytic
strabismus, where it is used to minimize contracture of the
opposing muscle until recovery.
7. Botoxhas a specific role in decompensated heterophoria, allowing
the visual axes a chance to 'lock on' and subsequently maintain
binocular vision.
8. The main reported complications are those of ptosis, induced
vertical deviation and subconjunctival haemorrhage.
56. 9.Stabilize eye with forcep - slide needle
along muscle orbital surface - muscle is
stretched initially - then allow for some
contraction to get EMG signal. Inject
when signal heard
57. Graves’ ophthalmopathy
1. Diplopia following orbital decompression is a common
complication in Graves’ ophthalmopathy.
2. Strabismus surgery is often required to treat the persistent
diplopia.
3. Rx with BotoxA in the management of new-onset diplopia
following orbital decompression has been suggested in a case
that is not amenable to prism Rx and may eliminate strabismus
surgery in some cases
58. Acute traumatic partial thirdnerve palsy
1. Patients with acute traumatic partial thirdnerve palsy treated by
injection of BotoxA in the lateral rectus muscle showed marked
recovery when injection was performed within 2 months of the onset
of palsy.
2. Botoxinjection into the lateral rectus muscle may provide temporary
relief of symptoms in some patients and seems to be a useful Rx
option in cases of acute traumatic third nerve palsy in the short-term
59. Retrobulbarbotox
1. Botox can be injected in the retrobulbar space for
oscillopsia in one eye only - rare indication - treat
one eye only.
2. In most cases, patient will have systemic problem
such as brain stem stroke.
60. THAN Q
Ref:
1. Jakobeic’s Principles and Practice of Ophthalmology 3rd ed
2. Botulinum toxin in ophthalmic plastic surgery IJO Year :
2005 | Volume : 53 | Issue : 4 | Page : 279-288
3. Botulinum Toxin: A Clinical Update on Ophthalmic Uses Shraddha
Panday
Indian Journal of Clinical and Experimental Ophthalmology, July
September 2015;1(3):119-123
