Botulinum toxin in ophthalmology

1. Botulinum Toxin in
Ophthalmology
DR K HARIPRIYA

2. Introduction
• Botulinum toxin is an exotoxin produced
by the bacterium Clostridium botulinum,
an anaerobic Gram-positive sporulating
organism.
• Most potent biological toxin in nature
• causative agent of the deadly food
poisoning, botulism

3. • Past three decades it has been
commercially produced as
preparations .
• Since 1970s, the use of botulinum toxin
has been expanded to Strabismus ,eyelid
spasticity, pain syndromes, and facial
aesthetics.

4. Historical Perspective
• In 1822, Justinius Kerner, a German
physician, collated data on 230 cases of
botulism, a disorder he called ‘‘sausage
poisoning.’’
• The Latin word for sausage is botulus, and
it was long known to be associated with a
form of food poisoning

5. • Kerner identified a fatty acid as the
poisonous agent, and he speculated that
the toxin might have a therapeutic role
in medicine
• 1895- Professor Emile Pierre Marie van
Ermengen, first isolated the bacterium
Clostridium botulinum

6. • In 1928- Botulinum neurotoxin was first
purified as a stable acid precipitate by
Herman Sommer
• In 1949- A.S. Burgen discovered that
botulinum toxin blocks neurotransmitter
release at the neuromuscular junction
• In 1980-Alan Scott collaborating with
Schantz, tested botulinum toxin in
monkeys to determine its effectiveness in
treating strabismus

7. • Shortly Scott formed his own company to
produce botulinum toxin type A under the
name Oculinum,
• He also Initiated FDA sponsored clinical
trials for its use in strabismus and
blepharospasm
• 1989- FDA approved Oculinum to treat
strabismus, blepharospasm, and
hemifacial spasm in patients 12 years of
age and older

8. • IN 1990- Allergan Inc. purchased the right
to market the toxin and changed the
name to Botox
• IN 2000 FDA approval was granted for use
in cervical dystonia and spastic dysphonia .
• IN SAME YEAR, Elan Pharmaceuticals
gained FDA approval to market botulinum
toxin type B under the name Myobloc for
cervical dystonia.

9. • In 2002 - FDA approved this drug for the
treatment of glabellar furrows
• FDA approval is pending for other
aesthetic applications

10. Pharmacology
A.STRUCTURE
• Botulinum toxin exists as 7 distinct serotypes,
A—G
• Each strain of Clostridium produces only one
type of toxin
• Clinical botulism in humans is caused by types A,
B, E, F, and potentially G
• It is composed of a neurotoxin molecule with
one or more associated non-toxin proteins that
surround and protect the toxin.

12. • The neurotoxin molecule is synthesized by the
Clostridium bacterium as a single-chain
polypeptide of 150 kDa.
To become active, the 150-kDa molecule is
endogenously cleaved, or ‘‘nicked,’’ by bacterial
protease-mediated cleavage into two unequal
polypeptide fragments that remain linked by a
disulfide bond
This results in a
1) zinc-dependent 50-kDa light chain fragment
2) 100-kDa heavy chain fragment.
The heavy chain contains two functional domains,
each of 50 kDa.

13. B. MECHANISM OF ACTION
• Botulinum toxin acts on cholinergic nerve
terminals.
• At the neural bouton there are synaptic vesicles
containing acetylcholine (ACh), a
neurotransmitter that crosses the
neuromuscular junction to stimulate the muscle
to contract.
• The Ach vesicles are associated with a protein
aggregate called the SNARE complex (soluble N-
ethylmaleimide- sensitive fusion attachment
protein receptor)

15. • Vesicles of ACh in the pre-synaptic neural bouton
must be released into the synaptic cleft.
• Here the neurotransmitter binds to specific
receptors on the muscle plate that trigger
opening of sodium ion channels, resulting in
depolarization and contraction in the adjacent
striated muscle.
• This ACh release requires the participation of the
SNARE proteins that mediate the fusion of
synaptic vesicles with the neuronal plasma
membrane.

17. • Under influence of an action potential in the
neuron, calcium channels open and calcium
binds to the SNARE proteins.
• This assemble into a soluble ternary complex
where the SNARE complex enables the ACh
vesicle to fuse with the cell membrane.

18. • Mode of action of botulinum toxin is to inhibit
neuromuscular transmission by blocking the
extracellular release of acetylcholine
• After injection of botulinum toxin in the region
of the target muscle, the C-terminal half of
the100-kDa toxin heavy chain binds externally to
gangliosides and protein acceptors on the
bouton of the terminal nerve cell surface
membrane.
• The toxin molecules then become internalized
within vesicles by the process of endocytosis.
• conformational change occur in neurotoxin,
active 50-kDa light chain released into the
cytosol of presynaptic bouton

20. • Light chain in cytosol acts as a zinc-
dependant endopeptidase that cleaves
specific SNARE proteins necessary for the
exocytosis of acetylcholine.
• This Results in local chemodenervation
of the muscle causes a flaccid paralysis.
• Botulinum toxins A and E cleave SNAP-25.
• Botulinum toxins B, D, F, and G cleave
VAMP/synaptobrevin.
• Toxin serotype C cleaves syntaxin.

21. • Inhibition of ACh exocytosis by botulinum
toxin is temporary and neurotransmission
is eventually restored.
• Most important is the noncollateral
sprouting of nerve fibers .
• Restoration of synaptic function to the
parent terminal occur around 90 days after
exposure to botulinum toxin type A
• Then concomitant retraction of these
outgrowths.
• The SNARE proteins can also be
regenerated in the cell body

22. • Extrajunctional acetylcholine receptors
and sodium channels appear.
• The time for recovery of function differs
between the botulinum toxin serotypes.
• Effects of botulinum toxin type A last for
an average of three months, whereas
recovery from botulinum toxin type E
tends to be more rapid, over several weeks

23. C. ACTIVITY AND DOSING
• Biologic effect of botulinum toxin is
expressed in terms of units (U).
• 1 U is defined as the amount of toxin that
is lethal in 50% of female Swiss-Webster
mice following intraperitoneal
injection, defined as the mouse LD50
• LD50 for humans is about 1 ng/kg
• Typical dose used is 50--100 units

24. • Biological effect of 5 U botulinum toxin type A will
give approximately equivalent clinical results as
500 U botulinum toxin type B.
• Botulinum toxin type A(Botox in the USA; Dysport in
the UK) is dried and stored frozen.
• It must be reconstituted with saline prior to
injection, usually in concentrations of 5--10 U per 0.1
ml.
• Botulinum toxin type B (Myobloc) is stable in
solution at acidic pH, and is stored in this form.
• It is provided in a stock concentration of 500U per
0.1 ml,
• But diluting it with preserved saline at 1:1 to 1:2 can
very significantly reduce the pain of the acidic
injection.

25. • onset of clinical effect with either serotype
is generally between 1 and 3 days,
• Full benefit achieved by about 5 days.
• The clinical benefit lasts about 3--4
months in most patients

26. IV. Immunology
• Development of an immune response to an
antigen is influenced by several factors
- molecular size,
- Presence of an adjuvant,
- persistence of the antigen in the tissues,
- antigen quantity, and
- exposure frequency.
• Botulinum toxins, by virtue of their large size
and bacterial origin, are highly immunogenic.

27. • Large doses of botulinum toxin type A
1)250 U of large cumulative doses,
2)injections administered at less than 3-
month intervals
are possible risk factors for the
development of antibodies and increased
risk of secondary treatment failure
• However, smaller doses of less than 100 U
and a dosing interval of not more than
every 3 months carries a very low risk of
developing blocking antibodies

28. • Antibodies may develop against portions
of the toxin protein but most of these will
not attenuate its effect on the
neuromuscular junction.
• These are termed non-neutralizing
antibodies, clinically not important
• Only a very small percentage of
antibodies formed will neutralize the
neurotoxin at the functional site of the
heavy chain thus preventing binding to the
neuronal membrane.

29. • Such antibodies are termed neutralizing
antibodies and block toxin function.
• To date, no cross-reactive neutralizing
antibodies have been recognized between
different serotypes.
• For this reason patients who become
resistant to botulinum toxin type A usually
will respond to type B, and vice versa.

30. Clinical Uses

35. Benign Essential Blepharospasm
• Benign essential blepharospasm is a focal
cranial dystonia involving the eyelid and
forehead muscles.
• It manifests as involuntary orbicularis
muscle contraction resulting in increased
frequency and forcefulness of blinking .
• In severe cases, blinking may be so
repetitive and forceful that the patient will
be unable to open their eyes, resulting in
functional blindness.

36. • Botulinum toxin, has become the
treatment of choice, and is very successful
in controlling eyelid spasms.
• effective in 75--100% of patients .
• Average doses of toxin type A are
12.5-- 25 U per eye for Botox and
50—100 U for Dysport.
• Injected just beneath the skin into the
orbicularis muscle.

38. • The most common injection pattern is into
the medial and lateral portion of the upper
and lower lid pre-septal orbicularis,
• Avoid the central lid region to minimize
the risk of ptosis .
• Cakmur et al reported a better response
and fewer complications when injected
into the pre-tarsal portion of the muscle.
• Treatment benefit lasts an average of 13
weeks

39. • We reserve type B toxin (Myobloc) for
those patients who develop resistance to
type A, from presumed antibody
formation.
• As long as type A remains effective, we will
not immunologically expose patients to
type B until it is necessary for therapeutic
effect.
• The typical dose of type B is 1,200 to 2,500
U per eye.

40. • 50 to 100 times the dose of type A.
• Type B has a shorter duration of effect (8--
10 weeks)
• Shows a greater tendency to diffuse into
adjacent areas.
• More pain and burning on injection due to
the low pH of the preparation

41. STRABISMUS
• MOA is to weaken the force of contraction
of specific opposing muscles to straighten
the eye.
• Injection requires the use of EMG-guided
placement of the needle to ensure the
toxin is accurately delivered to the target
muscle
• open sky technique is often used.

42. • Infantile esotropia- simultaneous bimedial rectus
muscle injection with botulinum toxin
• Reestablish motor and sensory fusion
• 70--75% of treated children can be corrected to
less than 10 prism diopters deviation at distance.
• higher success rate with botulinum toxin in
patients upto 18 months of age, but
disappointing results in younger children.
• good initial results after botulinum toxin, but
significant long-term recurrence of esotropia
ultimately requiring surgery

43. • Acquired esotropia in children
-Botulinum toxin success rates increases
with repeat injections.
-More than 70% of children achieve at least
peripheral fusion.
• Acute onset esotropia in older children
-good results noted in 79%, with 57%
maintaining high-grade stereopsis.
• Other uses-
Small angle esotropia in older children and
adults

44. • For larger angle deviations,
-increasing the dose of toxin per injection
give better results, but this is associated
with a higher incidence of complications
such as ptosis.
• Intermittent exotropia is difficult to
manage, and surgery is associated with a
high recurrence rate.
• 69% success rate , as good as with
surgery.

45. • In sixth nerve palsy
-weaken the medial rectus muscle
• sub- Tenon’s injection without EMG-
controlled intramuscular injection gave
similar results.
• In sensory strabismus,
- used to prevent muscle contracture.

46. CHRONIC DRY EYES
• Botulinum toxin injected into the medial portion
of the orbicularis muscle of the lower lid or
both the upper and lower lids to reduce the
effectiveness of the orbicularis muscle pump
mechanism
• Mean blink tear output decreases up to 62%,
• subjective improvement in dry eye symptoms in
70% patients.
• Alternative treatment choice for patients with
severe dry eyes.

47. ELEVATEDINTRAOCULARPRESSUREFROM
RESTRICTIVEMYOPATHY
• Patients will have increased intraocular pressure (IOP),
particularly in upgaze.
• Reduction in IOP occurs following injection of 10-15 U
botulinum toxin into the inferior rectus muscle.
• The mean decrease was 2 mm Hg in primary gaze and
5 mm Hg in upgaze
• Lasting for 2--4 months.
• Effect results from a decreased tone in the extraocular
muscles and possibly reduced orbital volume.

48. CONGENITALAND ACQUIREDNYSTAGMUS
AND OSCILLOPSIA
• Injecting botulinum toxin directly into multiple
rectus muscles.
• Reduces amplitude of nystagmus and improved
visual acuity in 43% and 50%
• Retrobulbar injection of botulinum toxin also
has been reported to result in improved visual
acuity in up to 66% of patients.
• Ptosis and symtomatic diplopia was the most
common side effect and compliation of
retrobulbar injection.

49. Eyelid myokymia
• Uncontrollable twitching of the orbicularis muscle,
typically involving the lower lids, and less commonly the
upper lid.
• It is sometimes triggered by stress, fatigue, caffeine, or
alcohol.
• The affected muscle shows a slow, undulating fine
movement in the most superficial muscle layers.
• EMG studies show rhythmic bursts of normal-appearing
potentials in group discharges.
• Injection of 5 U botulinum toxin into the superficial
orbicularis muscle temporarily relaxes the muscle until
the condition resolves spontaneously.

50. CORNEAL PROTECTIVE PTOSIS
• Corneal exposure resulting from a poor blink or
lagophthalmos may require a surgical tarsorrhaphy
• A protective ptosis to cover the cornea without
surgically altering the eyelid margin.
• It is performed by injecting 2.5--5 U toxin directly into
the levator muscle through a transcutaneous injection in
the superior sulcus or through a transconjunctival
approach.
• In 75--80% of cases ptosis results that is sufficient to
allow corneal healing.

51. LACRIMAL HYPERSECRETION
SYNDROMES
• Injection of 2.5--5 U botulinum toxin into
the palpebral lobe of the lacrimal gland
results in a clinically significant reduction
in tear production

52. • ENTROPION
-FOR SPASTIC ENTROPION
• COMPRESSIVE OPTIC NEUROPATHY IN GRAVES’
DISEASE
• -botulinum toxin injected into the retrobulbar
space, showed narrowing of the extraocular
muscle bellies due to reduction of contraction.
• This appears to have reduced the mechanical
compression of the optic nerve by the muscle
bellies.
• JUST TO BUY SOME TIME

53. APRAXIA OF EYELID OPENING
• It is non-paralytic inability to raise the upper
eyelid in the absence of discernable orbicularis
muscle contraction or levator muscle injury.
This occurs in
• dystonic Parkinson syndrome,
• progressive superanuclear palsy,
• isolated loss of levator muscle control, --
-blepharospastic apraxia

54. • ETIOLOGY-abnormal co-contraction of the
levator and orbicularis muscles or a failure
at relaxation of the orbicularis during early
levator contraction.
• chemodenervation of the pretarsal portion
of the orbicularis with botulinum toxin
seems to help eyelid opening

55. Oromandibular Dystonia
• Oromandibular dystonia affects the lower
face.
• It is characterized by spasms along the
sides of the nose, the mouth, and chin.
• It have a profound influence on eating
and speaking.
• Treatment is with small doses (1--2 U) into
the affected facial muscles .

56. • Because these muscles are so tiny,
overdosage and facial weakness, with
drooling or cheek biting, are potential
risks.
• Oromadibular dystonia is sometimes
associated with jaw closure dystonia
characterized by strong jaw clenching.
• This can be treated with 50--100 U into
each masseter muscle as needed.

57. FACIAL ASTHETICS

58. COMPLIATIONS