Botulinum Toxin in Ophthalmology

DR K HARIPRIYA

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

• 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.

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

• 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

• 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

• 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

• 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.

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

aesthetic applications

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.

• 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 a1) zinc-dependent 50-kDa light chain fragment 2) 100-kDa heavy chain fragment. The heavy chain contains two functional domains, each of 50 kDa.

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)

• 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.

• 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.

• 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

• 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.

• 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

• 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

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

• 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.

• 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

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.

• 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

• 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.

• 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.

Clinical Uses

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.

• 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.

• 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

•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.

• 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

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.

• 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

• 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

• 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.

• 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.

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.

ELEVATED INTRAOCULAR PRESSURE FROMRESTRICTIVE MYOPATHY

• 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.

CONGENITAL AND ACQUIRED NYSTAGMUSAND 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.

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.

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.

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

• 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

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

• 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

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 .

• 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.

FACIAL ASTHETICS

COMPLIATIONS