Usefulness of Botulinum Toxin Type-A in the Treatment of Chronic Sixth Nerve Palsy

doi:10.4236/ojoph.2012.21001

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Open Journal of Ophthalmology, 2012, 2, 1-4

http://dx.doi.org/10.4236/ojoph.2012.21001 Published Online February 2012 (http://www.SciRP.org/journal/ojoph)

Usefulness of Botulinum Toxin Type-A in the Treatment

of Chronic Sixth Nerve Palsy

Lelio Sabetti*, Immacolata Greco, Domenico Di Lodovico, Antonio Berarducci

Eye Clinic, San Salvatore Hospital, University of L’Aquila, L’Aquila, Italy.

Email: *[email protected]

Received November 7th, 2011; revised December 16th, 2011; accepted January 28th, 2012

ABSTRACT

Purpose: The purpose of the study was to evaluate the efficacy of botulinum toxin type A (BTX-A) injection in patients

with acquired VI nerve palsy. Methods: Twenty-eight patients (16 F and 12 M), mean age 36.4 +/− 17.8 DS; range 10 -

69 years with acquired VI nerve palsy, have been treated with BTX-A injection into the ipsilateral medial rectus, at least

6 months after onset. At 6 months follow up, a paresis and a paralysis, were respectively diagnosed if the affected eye

could be actively abducted or not, across the mid-line; a simple horizontal rectus muscle procedure was performed for

the paresis whilst for the paralysis, both a horizontal and vertical muscle transportation procedure were required. Re-

sults: A gradual physiological recovery of the lateral rectus muscle was observed in 9 (32%) patients (GROUP I) and

surgical treatment was therefore unnecessary; the remaining 19 cases (68%), of which 5 paresis (GROUP II) and 14

paralysis (GROUP III) underwent surgery and within 1 year were all restored to orthotropia. Conclusion: Botulinum

toxin type-A (BTX-A) injection is an invaluable tool in the differential diagnosis between paresis versus paralysis of the

VIth nerve, allowing the correct choice of surgical procedure.

Keywords: Chronic Acquired VI Nerve Palsy; Botulinum Toxin Type-A

1. Introduction

Acquired sixth nerve palsy is usually a consequence of

vascular or neurological diseases, diabetes, head trauma

[1,2] or cerebral tumors [3]. Diagnosis and management

of this neurogenic ocular palsy are often difficult largely

due to the fact that the ophthalmologist has insufficient

and/or inaccurate clinical history of the patients. It is

generally necessary, prior to surgical treatment, to wait at

least for 6-8 months, in order for the paralysis to be con-

sidered stable. A spontaneous recovery of this paralysis

is rare [4]. It is important to note, however, that there is a

frequent occurrence of the contraction of the joint an-

tagonist muscle which may mask the functional recovery

of the latter. Patients thus affected manifest large angle

isotropia. Adults experience double vision and are forced

to tilt the head to neutralize diplopia or to use prismatic

lenses. If diplopia is not adequately controlled it may

require surgical treatment, the functional result of which

is often however unpredictable. Botulinum toxin type-A

(BTX-A) injected in the hyperfunctional muscles causes

a flaccid paralysis by preventing the release of acetylcho-

line at the neuromuscular junction and thus results in a

gradual physiological recovery of the hypofunctional

muscles [5]. BTX-A injection can be used either during

the waiting period for the spontaneous recovery or for

surgery; in cases where VI nerve palsy is resolved,

BTX-A help to prevent diplopia, whereas in the case of

unresolved palsy, the toxin is an invaluable tool in the

differential diagnosis between paresis versus palsy,

which in turn allows the correct choice of surgical pro-

cedure.

2. Materials and Methods

Between April 2001 and February 2007, twenty-eight

consecutive patients were referred to our clinic with ac-

quired sixth nerve palsy. The 16 women and the 12 men

were 10 to 69 years of age (mean 36.4 +/− 17.8 SD). All

patients underwent a complete preoperative ophthal-

mological and orthoptic clinical protocol, including ocu-

lar refraction with and withuot cycloplegia, Goldmann’s

tonometry, biomicroscopy of the anterior segment and

funduscopic examination. The orthoptic examination

evaluated the ocular motility in the nine diagnostic gaze

positions; strabismus was measured with the prism and

cover test for near and distance fixation and presence of

anomalous head positions was identified, Worth and mi-

cro-Worth 4-dot test, Lang test (I-II), Titmus, red filter

ladder test, Hess-Lancaster screen test and passive and

*Corresponding author.

Usefulness of Botulinum Toxin Type-A in the Treatment of Chronic Sixth Nerve Palsy

active abduction test were also performed. Mean pre-

injection angle deviation was 22˚ ET (+/− 0.64 SD) near

and 24.9˚ ET (+/− 0.74 SD) distance. Inclusion criteria

were sixth nerve palsy more than 6 months after onset

and an anomalous position of the head. The patients were

divided into 3 class according the time of onset of the

palsy: 9 patients (CLASS I) with more than 24 months

after onset; 11 patients (CLASS II) between 12 and 24

months after onset; 8 patients (CLASS III) between 6 and

12 months after onset. Exclusion criteria were: previous

surgical treatments, congenital abnormalities of ex-

traocular muscles and cases where there had been ad-

ministration of aminoglycosides or other drug causing

interference with the neuromuscular system, in the last 6

months. Appropriate informed consent was obtained in

all cases. Each patient underwent a single injection of

BTX-A (20 IU, Botox, Dysport, Ipsen) under local an-

aesthesia directly in the ipsilateral medial rectus muscle.

3. Results

Follow ups were performed at 1 and 6 months intervals.

At 6 months the differential diagnosis between a paresis

and paralysis was respectively defined if the affected eye

could or could not be actively abducted or not across the

midline. Patients with paresis underwent a single hori-

zontal rectus muscle procedure, whilst patients with pa-

ralysis further underwent horizontal and vertical muscle

transposition procedure [6,7]. The patients were divided

into 3 groups. Nine of them (32%) (group I) manifested a

gradual physiological recovery of the lateral rectus mus-

cle at 1 month follow up (mean 4.57˚ ET +/− 0.90 SD

near and 3.42˚ ET +/− 0.51 SD distance). This group was

composed of 4 patients with head trauma, 3 patients with

vascular diseases, 1 patient with diabetes and 1 patient

with an idiopathic case; six of them belonged to CLASS

I, one of them belonged to CLASS II and two of them

belonged to CLASS III. These patients complained of

diplopia within only two months of the BTX-A injection

but this condition could be neutralized with prismatic

lenses. Consequently these patients did not require a sur-

gical procedure. In contrast, at 1 and 6 months follow up,

five patients (18%) (group II) manifested paresis with an

active abduction across the mid-line, at 1 month (mean

14.28˚ ET +/− 0.90 SD near and 18.28˚ ET +/− 0.90 SD

distance). This group was composed of two patients with

vascular diseases, 1 patient with head trauma, 1 patient

with diabetes and 1 patient with cerebral tumor; two of

them belonged to CLASS I, two of them belonged to

CLASS II and one of them belonged to CLASS III.

These patients underwent horizontal procedure of muscle

recession and/or resection. Finally, 14 cases (50%) (group

III) manifested paralysis without an active abduction

across the mid-line, at 1 month (mean 21.34˚ ET +/−

1.06 SD near and 22.28˚ ET +/− 0.74 SD distance) and at

6 months follow up (mean 23.05˚ ET +/− 0.91 SD near

and 24.48˚ ET +/− 0.86 SD distance) consequently all of

them underwent a horizontal as well as a vertical muscle

transposition procedure. This group was composed of 6

patients with head trauma, 3 patients with vascular dis-

eases, 3 patients with cerebral tumors, 1 patient with di-

abetes and 1 patient with an idiopathic case; one of them

belonged to CLASS III. Within a year of surgery all pa-

tients were either restored to orthotropia or remained

with a small-angle residual isotropy in primary position,

easily corrected with lenses.

4. Discussion

The aim of surgery in paralytic strabismus is to restore

the best equilibrium between muscle forces unbalanced

by ocular palsy. Moreover it is necessary to eliminate the

eventual presence of diplopia and/or of anomalous head

posture. In the VI nerve palsy the choice of the surgical

strategy could depend on the extent of recovery induced

by BTX-A injection, which thus becomes an invaluable

tool in surgical evaluation [8]. During the first 3 months

after the onset of palsy, it is possible to have a spontane-

ous recovery, but in the following period there is often

the occurrence of contraction of the joint antagonist

muscle. Elasticity of the deficient muscle is gradually

reduced due to a constant elongation resulting in a grad-

ual loss of tonus, hyper-extensibility and progressive

degeneration of muscolar fibres [9]. According to avail-

able literature, the degeneration becomes irreversible

after one or two years of the reduction of active muscle

tension, and the high-resolution MRI can directly dem-

onstrate the degeneration of muscolar fibres [10]. How-

ever, as demonstrated in this study, a full recovery (24%)

or a partial recovery of the lateral rectus function (20%)

are possible even in long term VI nerve palsy [11].

BTX-A injection in acquired sixth nerve palsy, avoids a

hyper-contraction of the ipsilateral medial rectus muscle

[12], promotes the recovery of the lateral rectus function

and eliminates the need of surgical intervention in pa-

tients who can benefit from restored orthotropia by a sole

injection. Patients who manifest a persistent large angle

isotropy with diplopia or anomalous head position, allow

for a differential diagnosis between a paresis vs paralysis;

as previously stated, this comparison becomes instru-

mental in establishing the need of surgery. If the affected

eye cannot be abducted beyond the mid-line, the transpo-

sition procedure will be required; if eye abduction is pos-

sible the recession and resection procedure should be

sufficient. Botulinum toxin treatment was originally de-

veloped 25 years ago by Ala B. Scott to produce reversi-

ble weakening of extraocular eye muscle (chemodener-

vation) [2,13] in the treatment of strabismus. Today it is

Usefulness of Botulinum Toxin Type-A in the Treatment of Chronic Sixth Nerve Palsy 3

an important aid in the preoperative evaluation of possi-

ble postoperative diplopia on patients in which this can-

not be done by means of prism or traction test; in acute

paretic loss of ocular muscle function; when surgical

treatment of the ocular muscles is not yet possible but the

patient is obviously affected by diplopia or a forced pos-

ture of the head [2], in situations where strabismus sur-

gery is not suitable (as in elderly patients unfit for gen-

eral anaesthesia; when the clinical condition is evolving

or unstable, or in case of unsuccessful surgery) [13], in

acute Graves’ disease, and especially into VI cranial

nerve paresis [2], or in association with the surgery [14].

Depending on the surgical approach in VI nerve palsies,

Botulinum toxin may be injected in the medial rectus

muscle before muscle transposition surgery to loosen

contracture [2] or, on the basis of our results, BTX-A

injection can be considered an invaluable tool in the

management and diagnosis of VI nerve palsy, and it al-

lows differential diagnosis between paresis vs paralysis,

which is the necessary condition to plan the correct sur-

gical treatment and to obtain a successful functional out-

come. In other strabismus, as congenital esotropia or

horizontal strabismus in adults, Botulinum toxin is defi-

nitely an inferior surgical treatment of the ocular muscles

[2]. Moreover the use of botulinum toxin type A is effi-

cient in the identification of adult patients with constant

strabismus who are at high risk o developing intractable

diplopia after surgery [15]. The majority of studies iden-

tify the Botulinum toxin A injection into extra-ocular

muscles the ideal therapy for the treatment of sixth cra-

nial nerve palsy [1], on 36.8% of the patients with a final

ocular alignment within 10 prism dioptres of orthotropia

and achieved fusion and primary gaze position. There

was no correlation among the number of injection for

patient (the mean number of injection is 1 to 5), the size

of strabismus, the grade of lateral rectus muscle function,

the age, the gender or the time paresis it occurred [1]. In

our study all patients had to undergo a single injection

and only in 32% of cases (9 patients) a gradual physio-

logical recovery of the lateral rectus muscle was obtained

at 6 months like if the surgical treatment could be

avoided and nobody of them was candidate for a second

injection; patients under-corrected at six months from the

onset were been treated with surgery. The most interest-

ing result was to identify in GROUP 1 six patients who

had been suffering with palsy for a period in excess of 24

months before the injection (CLASS I); although it is

known and documented that VI nerve deficit of traumatic

origin tends to normalize without any treatment or after

botulinum toxin injection [7,16,17] this has never been

recorded for cases where patients have been subject to

palsy for such a long time. Moreover it is also possible to

combine the injection with surgery [14] to preserve the

function of the medial rectus muscle, in order to avoid

surgery on more than two rectus muscles to prevent the

risk of anterior segment ischemia (which can occur when

there is surgery of multiple muscles) and to expand the

field of binocular single vision as much as possible. In

our trials, Botulinum toxin type-A (BTX-A) was directly

injected in the hyperfunctional muscle without electro-

myographic assistance, in order to reduce the incidence

of blepharoptosis [18]; a study of 2003 proposed that

subtenon injection of the medial rectus muscle for the

treatment of acute tramatic sixth nerve palsy [19]. The

results on the patients treated with subtenonian injection

of botulinum toxin without electromyography (EMG)

guidance was comparable to that obtained using EMG-

guided intramuscolar injection of botulinum toxin [19,

20], the reason is in fact that the substance injected in the

muscle has the tendency to diffuse into the surrounding

tissues. Finally BTX injection has been used for 11 years

by 292 ophthalmologists in 8854 patients, from the age

of three months to 90 years, in a variety of eye muscle

and eyelid disorders [21]. According to international lit-

erature, no systemic toxin reaction has occurred, local

complications are few and visual loss has not occurred in

any case [21]; ptosis and acquired vertical deviation caused

by diffusion of the substance into the surrounding tissues

are the commonest complications encountered. These are

minor and reversible damages induced by the traumatic

action of the needle and/or the substance into the tissues

(edema and minor subconjunctival hemorrhage), as fur-

ther proof that the repeated use of BTX-A could be con-

sidered safe [13].

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