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Original Article ~~~~

Modern management of sixth nerve palsy John Lee, FRCS, MRCP, FCOphth

Abstract Between November 1982 and September 1991,179 patients with unilateral or bilateral sixth nerve palsy were treated in the Botulinum Toxin Strabismus Clinic at Moorfields Eye Hospital. Indications for treatment included prophylaxis (as part of a prospective treatment trial), maintenance therapy, diagnosis and adjunct to surgical therapy. A management plan for established sixth nerve palsy based on the rational use of toxin and surgery is suggested.

Key words: Botulinum toxin, sixth nerve palsy.

Sixth nerve palsy is the commonest isolated cranial nerve palsy, as shown by several large Common aetiologies are trauma, especially due to road traffic accidents, microvascular disease and raised intracranial pressure from a variety of causes.

The standard management of sixth nerve palsy is well described in major textbook^.^,^ Assuming that there is no causative factor requiring treatment in its own right, the palsy should be hlly documented with appropriate tests and then the patient observed for spontaneous recovery. This may occur in up to 70% of cases3 being naturally more common when the aetiology is microvascular. When the ocular motility status has stabilised, as shown by serial examinations, a further interval of four to six months is allowed to elapse before surgery is undertaken. Complete and partial palsies are distinguished on clinical grounds or by the performance of special tests such as forced duction, force generation or electromyography. Partial palsies are managed by horizontal rectus muscle surgery on one or both eyes. Complete palsy requires a combination of medial rectus recession

and lateral transposition of the vertical recti to restore passive abduction. As such procedures carry a risk of anterior segment ischaemia, the usual procedure advocated in adults is the Jensen muscle union procedure.6 Even this procedure has been reported to cause anterior segment perfusion problems.

Although a few studies of the outcome after the Jensen procedure have been publi~hed,',~ there is little written on the success and outcome of management of sixth nerve palsy in the long term.

It would clearly be of value to both patient and surgeon if a reliable prognosis for treatment could be given, in particular an estimate of the likely number of operations and the time taken to achieve the final result.

Botulinum Neurotoxin A (BTXA) was introduced by Alan Scott in 197gY9 for the management of a variety of types of adult strabismus, and its value in paralytic strabismus was obvious from an early stage. Our group,'O and that of Scott," reported early success with BTXA in paralytic strabismus, and we were later the first to point out the value of BTXA as an adjunct to transposition surgery, using it to paralyse the medial rectus without compromising its blood supply and permitting safer and more effective surgery in unrecovered sixth nerve palsy." Long-term follow-up of our series has enabled us to offer our patients a more accurate prediction of the likely success of surgery and in particular the number of procedures required to achieve the desired result.

In assessing the outcome of treatment of incomitant strabismus, a measure of the deviation in the primary position is of little value. The aim in all cases is the largest possible field of diplopia-free vision without the need to adopt an abnormal head posture. It is generally agreed that the most important areas for normal everyday activities are the primary position

Reprint requests: John Lee, Moorfields Eye Hospital, City Road, London ECIV 2PD, England.

Modern management of sixth nerve palsy 41

and downgaze. Several a ~ t h o r s ' ~ . ' ~ have addressed the idea of quantitative assessment of the field of binocular single vision with the aim of expressing the field as a percentage of normal and thereby measuring the patient's subjective disability. The method of Fitzsimons and White14 has been used consistently in this study.

Materials and methods The Botulinum Toxin Strabismus Clinic at Moorfields Eye Hospital was begun in November 1982 and to date 1290 patients have received treatment for ocular motility problems. A retrospective analysis shows that 179 patients (14%) were treated for unilateral or bilateral sixth nerve palsy without detectable involvement of other cranial nerves. All patients were treated with Botulinum Neurotoxin A in a dose of 62.5 picograms '(2.5 units) in 0.1 mL of sterile preservative-free saline. All injections were given with continuous electromyographic monitoring using monopolar electrodes and a Medelec MS6 amplifier/oscillo- scope to permit visual and audible monitoring of the signal. Adults were treated under topical anaesthesia with G. amethocaine 1% and G . N.adrenaline 0.01%. Children were treated under intravenous ketamine anaesthesia with topical anaesthesia as €or adults. In all cases BTXA was injected into one or both medial rectus muscles.

Complications Ptosis occurred in 3.4% of injections, being rather commoner in children, and spread of toxin to the inferior rectus, causing hypertropia, occurred in less than 1% of injections. No systemic complications were encountered.

Indications These are prophylaxis, maintenance, cure, diagnosis and adjunct to surgery. Each will be considered in turn, with results and discussion combined.

Prophylaxis It has repeatedly been asserted that there is a specific indication for the use of BTXA in acute acquired sixth nerve palsy, to prevent contracture of the ipsilateral medial rectus by temporarily paralysing it while full recovery of lateral rectus function takes place. This is specified as one of the indications for treatment recommended by the American Academy of Ophthalm~logy.'~ The evidence for this suggested line of management is to date completely ane~dotal , '~, ' ' with authors reporting non-

randomised series in which a higher rate of recovery was noted in a treated versus an untreated group. We have recently reported18 the preliminary results of a randomised prospective treatment trial of BTXA in acute sixth nerve palsy. Twenty-three patients had entered the study, 10 treated and 13 controls. The most frequent aetiology was microvascular disease. Seventeen patients (74%) recovered completely within four months. No significant difference could be found between the recovery rate ofthe treated or untreated groups, although the treated group reported subjective benefit from early straightening of the visual axes. At the time of preparing this paper, there were 23 injected patients and 19 controls and there was still no evidence of any difference between the two groups in terms of ultimate outcome. On this evidence, therefore, there seems no indication for the use of BTXA to improve the outcome of acute sixth nerve palsy, although it may represent good symptomatic treatment for such patients by realigning their eyes and improving their abnormal head posture.

Maintenance Some patients with sixth nerve palsy may be unsuitable for normal surgical management by virtue of pre-existing systemic disease which makes general anaesthesia and surgery particularly hazardous. Other patients present with sixth nerve palsy and are found to have inoperable lesions causing the palsy. Both groups will find diplopia bothersome and may require strong prisms, an abnormal head posture or even permanent occlusion with consequent reduction of field and cosmetic deficit.

Such patients may benefit from regular injections of BTXA to the ipsilateral medial rectus. We have treated five such patients. Three had medical contraindications to surgery, a woman of 73 with severe bronchiectasis, a woman of 80 with rheumatic heart disease and a young woman of 19 with an arteriovenous malformation of her brainstem.

Two had inoperable intracranial lesions, a woman of 75 with an intracavernous giant aneurysm and a man of 31 with an osteochondroma of the clinoid process.

The value of toxin therapy as the best alternative is clear in such cases and should be considered as effective palliative therapy.

Cure Despite the apparent lack of effect of BTXA in the prevention of medial rectus contracture, there is no

42 Australian and New Zealand Journal of Ophthalmology 1992; 20(1)

Table 1 Characteristics of the 20 patients for whom BTXA effected a cure

Table 2 Preoperative and postoperative deviations - partial sixth nerve palsy

Sex Male 10 Female 10

Mean 40 years Range 5 to 68 years

Age

Aetiology Trauma 5 CNS infection 4 C.C. Fistula 2 Post-surgical 1 Multiple sclerosis 1 Unknown 3 Tumour 1 Vascular 3

doubt that in certain cases of sixth nerve palsy (and indeed third nerve palsy), the injection of BTXA into the antagonist of a chronically palsied muscle may restore normal ocular motility, presumably by relieving a reversible contracture and lengthening the injected muscle. We reported five cases in a previous paper, four of sixth nerve palsy and one of third nerve palsy.1° A similar mechanism may explain the successful treatment of some cases of dysthyroid ophthalmopathy that we have reported.19

Twenty patients achieved a cure with toxin injection alone. All had their sixth nerve palsy for a minimum of six months and none were showing signs of spontaneous improvement at the time of injection. The patient characteristics are shown in Table 1. Follow-up was from seven to 98 months. The range of deviations was 14 to 65 prism dioptres with a mean of 40.5 pd.

We conclude that all cases of partial sixth nerve palsy which have not spontaneously improved after six months should be offered an injection of BTXA as a successhl result may make surgery unnecessary.

Diagnosis The diagnosis of sixth nerve palsy usually presents little difficulty, and the differential diagnosis of the cause, although important, is not the concern of this paper. However, BTXA may be very valuable in two other diagnostic situations. In chronic sixth nerve palsy, despite partial recovery of lateral rectus function, medial rectus contracture may prevent the eye from abducting beyond the midline. Indirect tests such as saccadic velocity measurement and electromyography may indicate the presence of lateral rectus function, but we have found it simple to paralyse the medial rectus with BTXA and see how far the eye could then abduct, and this has become our standard test to distinguish partial from complete palsies.

Secondly, one sees patients who have sustained major head trauma in traffic accidents or who have

Prism dioptres

Preoperative Postoperative

Unilateral Mean + 28 + 6 Range +10 to +40 - 2 to + I 6

Mean + 41 - 4 Bilateral

Range -20 to +90 -20to +8

had massive cerebrovascular accidents. Such cases ~

are known sometimes to have central disruption of hsion.2O Temporary realignment of the eyes is easily achieved and will allow doctor and patient to judge the likely prognosis for single vision.

We have recently reviewed2',z2 a series of long- term results in sixth nerve palsy managed with surgery with or without BTXA. In all cases BTXA was used to distinguish complete from partial palsy.

Twelve patients had a partial palsy, five unilateral, due to road traffic accidents, microvascular disease or sarcoid, and seven bilateral, due to chronic palsy or road traffic accident. Chronic palsy indicates isolated non-progressive palsy of greater than one year duration with no identified cause despite complete medical and neuroradiological investi- gation. All patients were treated after full recovery from the effect of BTXA. Seven patients had ipsilateral medial rectus recession and lateral rectus resection (two muscles), two had bilateral medial rectus recession and unilateral lateral rectus resection (three muscles), and three had bilateral medial rectus recession and bilateral lateral rectus resection (four muscles). Eight cases had adjustable sutures. The surgical aim was to correct the esotropia for distance and expand the field of single vision. The averages and ranges of preoperative and postoperative deviation are shown in Table two. The average change of deviation with surgery is shown in Table three. No patient required further surgery for the horizontal deviation. Preoperatively no

Table 3 Average change of deviation with surgery Number Number Prism of muscles of patients dioptres

2 3 4

7 27 2 32 3 56

Modern management of sixth nerve palsy 43

patient could achieve single vision in the primary position without an abnormal head posture. Postoperatively 11 of the 12 patients (92%) had a central field of binocular single vision (BSV) with an average score of 53% and one patient is suppressing. We conclude that in identifiable cases of partial sixth nerve palsy appropriate amounts of horizontal rectus surgery are effective.

Adjunct to surgery In 1988l2 we reported our experience of the management of unrecovered sixth nerve palsy with combined BTXA and surgery. The rationale has already been mentioned. In order to achieve effective improvement in unrecovered sixth nerve palsy it is necessary to both relieve the inevitable medial rectus contracture and to provide some abducting force, which can be achieved by laterally shifting the insertions of the vertical recti. To remove three rectus muscles in an adult, especially when the two vertical recti are involved, is to risk anterior segment i~chaemia,~~ and therefore a variety of operations has been devised, of which the most popular seems to be the Jensen muscle union procedure. Combined therapy offers several advantages over conventional therapy. The risk of anterior segment ischaemia is reduced as only two muscles are disinserted. Subse- quent surgical re-exploration is far easier after a full tendon transfer than a Jensen procedure. Finally, the medial rectus remains available for subsequent surgery with the possibility of adjustable sutures.

We have recently reviewedz2 a series of 59 patients who were managed with combined therapy in order to ascertain the necessity for further surgery and the final sensory outcome.

There were 3 1 men and 28 women with an average age of 41 years (range nine to 84 years). Twenty- nine patients had a unilateral palsy. Thirty were bilateral, with 20 having a partial palsy on the other side and 10 with bilateral unrecovered palsies. Final outcome was known in 50 with an average follow-up of 1 I months from the time of final surgery.

Table 4 Previous surgery - unrecovered sixth nerve palsy

Bilateral

Partial Unrecovered Unilateral

No previous surgery 16 14 6 Previous transposition 6 1 3 Previous horizontal recti 7 5 1

Table 5 Unilateral unrecovered sixth palsy treated with combined medial rectus BTXA and vertical muscle transposition

No previous Previous Previous surgery transposition horizontal

TO requiring further 33 33 50

70 obtaining field of 84 67 33

Average 70 BSV score 59 54 33

horizontal surgery Average total operations 1.3 2.8 3.2

BSV

Road traffic accidents were the major aetiology in all groups, accounting for 38% of unilateral palsies and 70% of bilateral unrecovered palsies. Other major aetiologies were microvascular disease in the unilateral group and head injury and intracranial tumours in the bilateral group.

Twenty-three patients (39%) had previously undergone surgery. The surgery undertaken is shown in Table 4. It will be seen that a total of 13 patients (22%) had previously undergone horizontal rectus muscle surgery.

All patients had BTXA injected into the ipsilateral medial rectus, two to 20 days preoperatively in 51 patients, perioperatively in four patients, and two to seven days postoperatively in four patients. Forty eight patients who had not had previous transpo- sition surgery had a full tendon transfer of the vertical recti. One had a Jensen procedure. The 10 patients who had a previous transposition procedure had this revised with conversion of a previous Jensen procedure to a full tendon transfer.

The results are shown graphically in Figure 1. It will be seen that the pattern of response is similar in all three groups with an initial moderate reduction of the esotropia after toxin, a temporary overcor- rection following transposition surgery, an esotropic drift as the effect of toxin wears off and a final status after all subsequent surgery has been performed.

Table 6 Unrecovered sixth nerve palsy treated initially with combined medial rectus BTXA and vertical muscle transposition

Bilateral Unilateral Contralateral Eye

Partial Complete

70 requiring further 33 60 83

Average total operations 1.3 1.6 2.8 '70 obtaining field of BSV 84 60 50

horizontal surgery

Average 70 BSV score 59 48 49

44 Australian and New Zealand Journal of Ophthalmology 1992; 20(1)

KI 40

Ex0

-30 4

-60

y2r I

Ex0 -45 -60

Pre Pre Earlv Late Final BTX Tx Post Tx

(b) Bilateral palsy unrecovered/partial

1201 P

(c) Bilateral palsy bilateral unrecovered 1201

-35 Ex0

-60 Pre Pre Early Late Final BTX Tx Post Tx

Figure 1 Clinical course of unrecovered VIth nerve palsy initially treated with combined medial rectus botulinum toxin

(BTX) and vertical muscle transposition (Tx).

Of the 29 pdtients with unilateral sixth nerve palsy, the proportion requiring further surgery, in all cases bilateral medial rectus surgery with

recessions, faden procedures or both, was 33% in the previously unoperated group and in the group that had previously undergone transposition surgery. However, the proportion requiring further surgery rose to 50% in the group of patients who had previ- ously had horizontal rectus surgery. In addition, this group had a lower percentage of cases who achieved a useful field of BSV, and in those who did achieve a usehl field the percentage score was notably lower. Table 5 summarises this data. We conclude that for patients with unilateral unrecovered palsy who have received no previous surgical intervention that the rate of subsequent surgery is 33% and that previous horizontal rectus muscle surgery adversely affects the outcome, both in terms of number of operations required and the functional result obtained.

In the 10 previously unoperated patients with bilateral palsy with partial recovery in the less affected eye, six have required hrther surgery. This took the form of unilateral or bilateral medial rectus muscle recessions combined where necessary with lateral rectus resection. Again previous horizontal rectus muscle surgery adversely affected the outcome.

In the group of six patients with bilateral unreco- vered palsy who had not previously had surgery, five have had further surgery after the initial toxin plus transposition. In all cases a bilateral transposition or revision of the first transposition has been per- formed. Table 6 summarises the outcome in the 28 patients who received toxin plus transposition as their primary management.

Complications were infrequent. Five cases became exotropic and required further surgery and/or prisms. This occurred in only one patient who had not had previous surgery. Four cases developed a vertical deviation requiring surgery, prisms or both. Six patients showed minimal signs of anterior segment ischaemia. This was detected as part of another ongoing study and probably represents a higher than normal detection rate. Of the patients showing anterior segment hypoperfusion, two had cavernous sinus tumours and one had undergone a previous Hummelsheim procedure with medial rectus recession.

In summary, these results extend those previously reported by Fitzsimons el aL, l2 and show that the combined approach to unrecovered sixth nerve palsy is safe, effective and predictable. It is now possible to make some reliable statements regarding prognosis and outcome.

In patients undergoing combined therapy as initial management of unrecovered unilateral sixth nerve

Modern management of sixth nerve palsy 45

palsy, 33% will require further surgery for the esodeviation, usually bilateral medial rectus procedures. Eighty-four per cent overall will achieve a centrally placed field of BSV with an average score of 59%. Previous horizontal rectus muscle surgery markedly worsens the outcome and should not be undertaken in this situation.

In bilateral palsy with partial unilateral recovery, initial toxin plus transposition will achieve a satis- factory result in 40% with 60% requiring further surgery. Sixty per c e h will achieve a useful field of BSV with an average score of 48%. In bilateral unrecovered palsy, 83% will require hrther surgery for the horizontal deviation, with an average total number of operations of 2.8 per patient. Fifty per cent of patients will achieve a field of BSV with an average score of 49%.

Conclusions Botulinum toxin has a major role in the management of paralytic strabismus, especially sixth nerve palsy. It seems unlikely that there is any true prophylactic effect in acute sixth nerve palsy, but patients receive symptomatic relief from having their eyes straightened. The use of toxin as long- term maintenance therapy in cases unsuitable for surgery is clearly valuable, as the only alternative management is chronic occlusion. It is however in the treatment of established sixth nerve palsy that we feel this agent has its greatest application.

Such patients, who would normally have been offered surgery on reaching a stable esotropic state, can now be given an injection of toxin to the appropriate medial rectus. In some cases, medial rectus contracture will be relieved and normal binocularity achieved without any hrther treatment. In the remainder, a clear distinction can be made between partial and unrecovered palsies and appropriate treatment offered in the form of horizontal rectus muscle surgery in partial cases or combined toxin and transposition in those patients with unrecovered palsy. In addition, an accurate prognosis can now be offered to patients with this common yet difficult motility defect.

Acknowledgements I would like to thank my collaborators, John Elston, Ross Fitzsimons, Caroline MacEwen, Steven Jones, Karen Cooper and Paul Riordan-Eva for much of the data collected for this paper. I would also wish to thank Mr Peter Fells and the surgeons of Moorfields Eye Hospital for referring and allowing me to report their patients. I have also been greatly

supported by the Orthoptists of Moorfields in the running of the Toxin Clinic over many years.

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Australian and New Zealand Journal of Ophthalmology 1992; 20(1)