Eye ( 1988) 2, 29-32

Antitoxin Reduces Botulinum Side Effects ALAN B. SCOT T San Francisco, USA

Extensive experimental application of bot­ 1. Orbicularis ATX following orbicularis ulinum toxin (BTX) has shown the drug to be BTX without reported systemic toxicity in doses To study the ability of small local doses of used in ophthalmology (Table I). However, ATX to inhibit BTX effect, eleven induced vertical strabismus and/or ptosis blepharospasm patients were injected with occur in 15 to 25% of horizontal extraocular ATX in the right orbicularis immediately after muscle injections due to diffusion from the receiving BTX injections of equal doses to target muscle into adjacent muscles. This is both eyes. ATX doses ranged from 1.0 x 104 especially true of the medial rectus, where to 1.6 x 10-3 IV of ATX per BTX unit. This combined weakness from overflow to the dosage range had been previously worked out supradjacent superior oblique and subjacent in mouse experiments. An additional eleven inferior rectus, both depressor muscles, patients received delayed ATX injections, results in hypertropia. While local side effects with intervals between BTX and ATX injec­ are usually mild and transient, they limit dos­ tions ranging from � hour to 21 hours. Results age, interfere with securing binocularity were assessed by measuring the pre- and post­ during the period of drug-induced palsy, and injection orbicularis force in both eyes. When create vertical strabismus of two prism diop­ direct force measurements were unobtain­ ters or more at six months after injection in able, a subjective assessment of the difference 1.8% of cases. In the eyelid, diffusion of the in spasm duration and intensity between the drug from the injected orbicularis muscle may two eyes was obtained by telephone follow­ involve both the levator, causing ptosis, and up. All responses were then graded on a scale the superior rectus, causing vertical diplopia. of 0 to 3, where 0 no ATX effect (response This paper describes some experiments to to BTX equal in both eyes) and 3 marked limit or avoid these side effects using antitoxin ATX effect (orbicularis force/spasm intensity (ATX). Timely use of antitoxin may be useful much greater in the ATX-treated eye, indicat­ to avoid effects of erroneous BTX usage, too. ing inhibition of BTX effect). After the effect of ATX was assessed, patients who had a reduced BTX effect in the ATX-treated eye Methods and Results We used botulism antitoxin ABE, Connaught were retreated with BTX to that eye to give Laboratories, containing about 750 inter­ them the usual relief from spasm. Results are shown in Table II and sum­ national units (IV) of type A antitoxin of equine origin per milliliter. By convention marised in Figure 1. As expected, increasing each IV neutralises 10,000 mouse LD/50 ATX doses resulted in increasing blockage of doses of type A toxin. Botulinum toxin type A BTX effect. An unexpected result was that is expressed in units, each unit being equal to a delaying the ATX injection for up to 5 hours mouse LD/50 dose and corresponds to about following BTX injection resulted in increased 0.36 nanograms of the crystalline toxin­ blockage of BTX effect. Delays of 16-21 hours showed a reduced ATX effect, but did haemagglutin complex. =

=

Corre$pondence to: Smith-Kettlewell Eye Research Foundation, San Francisco, California, USA. Supported by National Institutes of Health grants #EY06523 and EY06883.

30

ALAN B. SCOTT

Table I

AVERAGE ANTITOXIN EFFECT

Numbers and conditions of patients Number of patients

Condition

Number of treatments

(n)

BTX BLOCKAGE Marked

Strabismus Blepharospasm

3, 787 2,865

Eyelid retraction Myokymia Entropion Bell's palsy VII nerve palsy

34 20 137 12 39

74 6 17

n

Orbicularis ATX injection orbicularis BTX injection

ATX dose (IVIBTX unit)

Delay (hours)

•

No delay

:::J

112-5 16-21

o

hr. he.

1, 281 42 Moderate

(2)

1

following

Effect of ATX (0 none, 3 marked) =

=

(4)

(5) Mild

Table

(3)

6, 685 8, 261

608 26 12 12

Hemifacial spasm Nystagmus

(4)

None

1

-

4

16

8

ATX IU/BTX U xl0-4

1.0 x 1{}-4 2.0 x 1{}-4

0 0

1 2

4 .0 x 1{}-4 4 . 0 x 1{}-4 4 .0 x 1{}-4

0 0 0

0 3 0

III.) Eight of the

8.0 8.0 8.0 8.0

0 0 2 2

1 2 2

these

8.0 x 1{}-4

3. 5

3

1.6 1.6 1.6 1.6

x

10-3 10-3 X 10-3 X 10-3

0 0 0 0

3 1 1 2

1.6 1.6 1.6 1.6

X

10-3 x 10-3 X 10-3 X 10-3

0.5 1 4 5

3 3 3 2

cent protection. Two patients did not get

1 1 1

by ATX diffusing forward into the orbicularis.

1{}-4 1{}-4 x 1{}-4 x 1{}-4

x

x

X

1.6 X 10-3 1.6 x 10-3 1.6 x 10-3 1.6 x 10-3

Fig. 1.

20 per cent to complete lid closure. Of 8 patients, 7 had no ptosis in the ATX­ treated right eye, indicating 100 per cent pro­

from

3

16 18 18 21

10 patients showed ptosis in

the left eye (not treated with ATX), ranging

tection from levator paralysis, including the patient whose ATX injection was delayed by

21

hours. The other patient who had ptosis

showed and

25

50 per cent

lid closure in the left eye

per cent in the right eye, or a

50

per

ptosis in either eye. One patient showed a slight reduction in the duration of spasm relief in the eye which received ATX, presumably

3. Levator or inferior rectus ATX following horizontal rectus BTX injection

2

Five strabismus patients received ATX injec­ not eliminate entirely the effect of ATX on

tions: to the temporal side of the levator or

BTX-induced paralysis.

inferior rectus following BTX injection to the medial rectus, and

2. Levator ATX following orbicularis

BTX

Ten patients were injected in their right leva­ tors with ATX dose.s ranging from to

1.6

X

4.0

X 10-4

10-3 IV of ATX following BTX injec­

tion of equal doses to the orbicularis of both eyes. Nine patients were injected with ATX

vice versa

for the lateral

rectus. (See Table IV). Ptosis of occurred in patient

#815

1

mm

and slight inferior

rectus weakness occurred in patient

#501.

The paralysis of the target muscle was com­ plete in all cases. Reversal of

established

paralysis,

even

immediately following BTX injection; one

using high ATX doses, was not possible in

patient had a delay of

patient

21

hours. (See Table

#801.

31

ANTITOXIN REDUCES BOTULINUM SIDE EFFECTS

Table III Levator ATX orbicularis BTX injection

injection

following

described pertain to the Connaught Botu­ linum Antitoxin, ABE and to the toxin of units per

ATX dose IU/BTX U x 1(}-4

Ptosis: OS BTX

Ptosis: OD BTX+ATX

50

140

nanograms made here. Differ­

ences in potency, protein content and other factors would be very likely to alter these rela­ tionships for any other products. The Lederle

0 SO%

0 2S%

4.0 4.0 8.0 8.0 8.0 8.0 8.0

0 0 0 0 0

100% SO% SO% 20% 0

16.0 16.0

0 0

SO% 2S%

ATX used, and a much lower ATX dose would probably have been quite adequate. Short delays in ATX injection (up to

5 hours

following BTX injection) result in greater blockage of BTX effects than do immediate ATX injections. We suppose that the lighter ATX molecule diffuses away sooner than does the heavy BTX. ATX injections delayed up to

21-hour delay to ATX: 0

8.0

ATX dose was far above the other doses of

21

7S%

hours are not as effective as immediate

injections are, but some blockage of BTX Table IV

Ptosis, inferior rectus weakness after ATX ATX IU x 10-4

BTX

4.0 RIR

S.O LMR

4.0 LIR 4.0 Levator

S.OLMR

16.0 Levator

S.O LLR

16.0 Levator

nerve terminals has not yet occurred or that it is still reversible. ! This has important clinical

Paralytic effect

7.S RMR

effect still occurs, indicating that binding to

implications in that errors of drug dilution or

RMR-4 RIR -1 LMR-4 LIRO No ptosis LMR-4 1 mm ptosis LLR -4 No ptosis

of drug usage may be able to be ameliorated for a number of hours after the occurrence. ATX

cannot,

however,

reverse

existing

paralysis. The small ATX doses injected into the leva­ tor or inferior rectus reduced but did not fully prevent the side effects of ptosis or vertical deviation caused by BTX strabismus injec­ tions. Higher doses should be effective as in

20-day delay after ATX: 2.S LMR 80.0 Levator No effect

the orbicularis. The reverse problem, diffu­ sion of ATX into the BTX-targeted muscles

4. A

ATX to

64 year

right

block incorrect

BTX

which would result in a reduction of the inten­

use

old man was to be injected in the

medial

rectus

for

diplopia. An error was made and

5

ded effects did not seem to occur. Indeed, to

with

the extent observable, we thought the ampli­

units of

tudes of angle change during paralysis of the

esotropia

BTX were given to the right lateral rectus.

injected eyes were greater than usual. To

Thirty minutes later,

IV) of

explain this we suppose BTX in high doses

Lederle ATX was injected into the right lat­

may involve also the antagonist and that ATX

0. 1

ml

(100

eral rectus. This provided full protection, and

protects the antagonist; a beneficial effect of

no

ATX, if so.

change

in

strabismus

patient had been treated

30

occurred.

This

years before for

tetanus exposure with ATX of equine origin.

The

occurrence

of

ptosis·· and

vertical

diplopia following BTX injection at small

No allergic response to the Lederle equine

BTX doses is a limiting factor in the treatment

ATX ensued.

Three weeks later, the left

of a few blepharospasm and hemi-facial spasm

medial rectus was injected with a good paraly­

patients. With ATX injections to the levator,

tic and clinical effect.

however, BTX doses may be able to be

Discussion

cial orbicularis paralysis and to protect the

increased to give a longer duration of benefi­ Local injections of botulism antitoxin are

levator and superior rectus in those patients

effective

who seem especially susceptible.

in

preventing

induced paralysis.

botulinum

toxin­

The dose relationships

Strabismic children are more susceptible to

32

ALAN B. SCOTT

BTX-induced ptosis and vertical strabismus

way but not yet available. A human-derived

than are adults. We hope that prophylactic

ATX and the non-toxic large fragment of the

injection of ATX to the levator and inferior

toxin molecule to block unwanted toxin bind­

rectus following BTX injection. of horizontal

ing3 are additional related techniques to

extraocular muscles may reduce or eliminate

reduce side effects and to increase efficacy

ptosis with its risk to vision, and vertical

which we are pursuing and which avoid the

strabismus with its barrier to binocularity. The highest ATX dose proposed is in the

theoretical risks of immunity or sensitisation to equine-derived proteins.

range of doses proposed for use to test allergic sensitivity and is approximately one

20

mil­

lionth of the amount of the dose ordinarily proposed for use in botulinum intoxication; this latter dose gives allergic sensitivity reac­ tion in about

2

per cent of the patients

treated.2 There has been no systemic allergic reaction in this study, even in the one patient who was known to have had horse serum treatment in the past. Serum assays for anti­ bodies to the Connaught product are under-

References Simpson LL: Kinetic Studies on the Interaction between Botulinum Toxin Type A and the Cho­ linergic Neuromuscular Function. J Pharmacol Exp Therapeut 1980 , 212: 16-2l. 2 Black RE and Gunn RA: Hypersensitivity Reactions Associated with Botulinal Antitoxin. Am J Med 1980 , 69: 567-70. 3 Krysinski EP and Sugiyama H: Purification and Some Properties of the H. Chain Subunit of Type 1

A Botulinum Neurotoxin. 705-10.

Toxicon 1980 , 18: