7.2 Congenital Cranial Dysinnervation Disorders: Perspectives to Understand Ocular Motility Disorders

Some more descriptions of single synkinetic disorders concerning the sixth nerve and its target muscle such as abduction of the globe on mouth opening, upgaze and drinking exist [47].

A typical combination of mostly bilateral sixth nerve and seventh nerve underaction can be observed in Möbius syndrome. Recent publications hint to the total spectrum of Möbius syndrome that is broader and encompasses also combinations of horizontal gaze palsies or bilateral Duane syndrome and facial weakness and presumably lower brainstem disorders such as pharyngeal and tongue anomalies. But also third nerve anomalies reminding of CFEOM are described. Furthermore limb anomalies and problems of motor coordination occur. Thus Möbius syndrome covers features of a more generalized developmental brainstem syndrome [56, 57].

Isolated unior bilateral facial palsy is described as a familial disorder; gene loci are mapped [16, 53].

Summary for the Clinician

■A group of congenital ocular motility disorders are caused by developmental disturbances. These are nonprogressive, incomitant forms of strabismus with certain typical motility patterns and clinical features such as synkinetic movements that help to establish the diagnosis.

■Because of the developmental origin some of these motility disorders occur in syndromatic constellations. A thorough general examination is necessary.

7.2Congenital Cranial Dysinnervation Disorders: Perspectives to Understand Ocular Motility Disorders

While some of the congenital ocular motility disorders with restrictive features are explained, others are not yet understood.

In 1949,H.W.Brown (1898–1978) at the First Strabismus Symposium in Iowa City gave a lecture on congenital structural muscle anomalies. In this talk and in the subsequent publication, he discussed congenital motility disorders with fibrotic features such as retraction syndrome, strabismus fixus, vertical retraction syndrome and general fibrosis syndrome. Furthermore, under the name of superior oblique tendon sheath syndrome, he introduced a special form of congenital elevation deficiency in this context that since then is known as congenital Brown syndrome [9, 58].

We investigate whether there is evidence that more congenital eye motility disorders than currently listed, namely Brown syndrome, Double elevator palsy and vertical retraction syndrome represent congenitial cranial dysinnervation disorders.

7.2.1Congenital Ocular Elevation Deficiencies: A Neurodevelopmental View

7.2.1.1Brown Syndrome

Motility Findings

Brown syndrome is an oculomotor disturbance characterized by an elevation deficiency on adduction, normal or near normal elevation on abduction, mild elevation deficiency in straight upgaze, positive forced duction test and no or only slight superior oblique hyper function as cardinal features. Sometimes a head posture is adopted, hypotropia of the a ected eye in primary position may occur, a relative divergence of the eyes in upgaze may exist and sometimes widening of the lid fissure on adduction can be observed [59, 60] (Fig. 7.7).

In acquired cases, Brown syndrome results from damage that hinders the passage of the superior oblique tendon through the trochlea. The pathogenesis in congenital cases is not completely understood [60–63].

Brown’s initial assumption that a congenital palsy of the inferior oblique leads to secondary changes in the superior oblique tendon sheath was disproven by

c

electromyography, which showed normal innervation in the inferior oblique. Brown subsequently regarded the disorder to be caused by a structural anomaly in a superior oblique tendon sheath [59, 64]. Many studies report

7structural anomalies in the tendon and its surrounding tissue. Current textbooks explain Brown syndrome as a form of restrictive strabismus and suggest varying anomalies in the superior oblique muscle or its tendon and the trochlea complex including the surrounding tissues [60–63].

The notion of Brown syndrome as a misinnervation syndrome was put forward already in 1969 by Papst and Stein who in an electromyographic study demonstrated paradoxical innervation of the superior oblique muscle on intended elevation in adduction of the globe. The authors interpreted this finding in analogy to the paradoxical coinnervation found in Duane retraction syndrome and postulated a neurodevelopmental origin of the syndrome. Other authors confirmed the results by electromyography, so that a total of five cases with electromyographic recording of paradoxical innervation to the superior oblique are reported by three di erent investigators [43, 65, 66, De Decker, personal communication, 2004]. Nevertheless, this explanation currently is not widely accepted. One argument put forward against the hypothesis of a paradoxical innervation refers to an electromyographic study by Catford and Hart [67] who could not find paradoxical innervation in patients with Brown syndrome. But the patients examined by Catford and Hart mostly displayed late onset of Brown syndrome and may represent acquired cases. A second counter-argument points to the common finding of a positive forced duction test under anesthesia in congenital Brown syndrome that hints to a mechanical component rather than to a mere innervational one [62]. Discussing the question whether a passive restriction of the globe under anesthesia on forced duction to elevation in adduction contradicts the hypothesis of a primary misinnervation, one has to consider that a misinnervation could lead to secondary changes in the muscle, tendon, trochlea and surrounding connective tissues. In the publication by Gutowski that defines CCDDs it is summarized that “dysinnervation may be associated with secondary muscle pathology and/or other orbital and bony structural abnormalities” [16].

In the light of the understanding of CCDDs, we think it worthwhile to reconsider the question whether Brown syndrome represents a misinnervation disorder.

The hypothesis is that a primary developmental dysinnervation of the superior oblique muscle as it occurs in congenital fourth nerve palsy is accompanied by a secondary dysinnervation of the superior oblique by fibers of the third nerve.

Up to now CCDDs with secondary dysinnervation of ocular target muscles by nerve fibers intended for other eye muscles are described for defects in the sixth nerve, for the third nerve and for combined defects of the third and fourth nerve but not for isolated defects in the fourth nerve.

Misinnervation by fibers normally intended for the antagonists of the primary dysinnervated muscles occurs in Duane syndrome and often keeps the deviation of the eyes in primary position remarkably small.

A misinnervation of a nonor underinnervated superior oblique muscle by fibers intended for the inferior oblique or the medial rectus would eliminate the elevation on adduction found in congenital fourth nerve palsy. Furthermore, the vertical and torsional angles of deviation in primary position would be kept small by a coinnervation by fibers normally running to the inferior oblique muscle. First, because the antagonist of the primarily paretic superior oblique muscle might receive less nerve fibers and second, because its tone now simultaneously is antagonized by a tone in the superior oblique.

An aberrant innervation in the superior oblique by fibers intended for the inferior oblique would result in blockage of elevation in adduction by cocontraction of the two muscles. This could be the explanation for the elevation deficiency on adduction. Primary dysinnervation in some muscular regions and cocontraction of the muscle against the action of the inferior oblique could lead to structural changes in the superior oblique and thus explain restriction against elevation in adduction in the forced duction test.

A cocontraction of the superior and inferior oblique that both have their functional origin anterior to their insertion could also be claimed to explain widening of the lid fissure on adduction. This would be an e ect reverse to the narrowing of the lid fissure on adduction by retraction of the globe in Duane syndrome.A paradoxical coinnervation in the lid due to compensation of a hypoplasia in the subnucleus of the levator palpebrae could also be possible.

As well passive forces by a secondarily tight superior oblique as active forces by a potential coinnervation of the superior oblique by fibers originally destined for the medial rectus would explain depression of the globe on adduction. Moreover, an overcompensation of the primary defect by misrouting of axons intended for the antagonist of the underinnervated muscle could occur as it is the case in the subset of Duane syndrome with exotropia.

Clarke described three cases with a depression on adduction of the globe that was primarily diagnosed as Brown syndrome but was in this publication presented as an own entity. In these cases, an innervation of the

superior oblique by fibers primarily destined to the medial rectus would be possible [68].

At last even a miswiring of fibers prone to the superior rectus could be discussed. This would explain why many patients show also a minor elevation deficiency in abduction.

Thus, the motility findings of Brown syndrome could be explained by an aberrant innervation of a primarily dysinnervated superior oblique muscle.

We analyzed the literature and our own data of 87 patients examined for congenital Brown syndrome in our clinic in the years 1995–2007 for information supporting or contradicting the hypothesis that the typical features of congenital Brown syndrome result from primary and secondary misinnervation.

a

b

c

Saccadic Eye Movements

Barton [69] in a study on vertical saccades described the eye tracking of vertical saccades in a patient with Brown syndrome. Reproducibly, there occurred a marked and punctuated lateral shift, described as a “horizontal flip,” of the globe in the upward saccades and a medial shift in the downward saccades. Under the proposed hypothesis, this would be explained by an additional abductor acting by cocontraction of the superior oblique when the eye comes into the field of action of the inferior oblique.

The authors compare the flip movement of the eye to that in horizontal saccades in Duane syndrome. With the onset of cocontraction, a flip could occur by the sudden action of the antagonist.

Comorbidity

In the majority of cases Brown syndrome represents an isolated disease. Among the diseases reported to accompany Brown syndrome interestingly CCDDs such as Duane syndrome, congenital Ptosis, crocodile tears and Marcus Gunn phenomenon [70] are prevailing. Contralateral congenital fourth nerve palsy is frequent as well [71–73]. Moreover, colobomata and cardiac malformations are named.

In our 87 patients, three demonstrated additional Duane syndrome, two ptosis, one incomplete lid closure and one Marcus Gunn yaw winking phenomenon. In 13/87 patients, (14.9%) contralateral fourth nerve palsy with superior oblique underaction in downgaze was documented. Figure 7.8 shows a patient with right-sided Duane syndrome and left-sided Brown syndrome.

The coincidence with CCDDs could be caused by common pathogenetic mechanisms interfering with brainstem and cranial nerve development.

The high incidence of contralateral fourth nerve palsies also is of interest with regard to a potential

d

Fig. 7.8 Patient with right-sided Duane and left-sided Brown syndrome. Right upgaze (a) shows abduction deficiency in the right eye and elevation deficiency on adduction on the left side. Right gaze (b) shows abduction deficiency in the right eye and widening of the palpebral fissure in the left eye. Eyes shown in primary gaze

(c). Left gaze (d) shows narrowing of the right lid fissure

misinnervation disorder in Brown syndrome. In these cases a bilateral disturbance of trochlear nerve development could be postulated that in the side with Brown syndrome is answered by a misinnervation or restrictive alteration in the superior oblique and in the other side leads to the symptoms of fourth nerve palsy.

Epidemiologic Features

Under the hypothesis of a similar etiology, we compared epidemiologic data for Brown and Duane syndrome because both the fourth and sixth cranial nerves have developmentally an origin of rhombomeres which is different from the third nerve [52].

Laterality

De Respinis [34] reviewed publications on Duane syndrome and figured out side distribution from pooled data of di erent studies. We pooled the data of ten studies on Brown syndrome [60, 65, 74–81] and of our own series. In a total of 11 studies, including 246 patients with congenital Brown syndrome the right side was a ected in 53%, the left side in 38% and both sides in 9%.

In the series on Duane syndrome [34], a total of 835 cases were analyzed.

In 59% the left eye was a ected, in 23% the right eye and in 18% bilaterality was found.

to have been congenital in this series. Wright summarizes the incidence of inheritance by 2% in Brown syndrome and found 1 of 38 cases, thus 3%, with inheritance in his own series.Wright hints to eight reports of inheritance in the lit-

logic mechanism has a tendency to a ect rather the left eye, these data seem contradictory to a common pathogenesis.

This contradiction resolves because the fibers of the fourth nerve are crossing and the nucleus of the fourth nerve lies contralaterally. The hypothesis stating a primary brainstem related pathophysiologic mechanism of Brown syndrome, the data concerning laterality show an interesting parallel between Duane and Brown syndrome.

Nevertheless a higher bilateral incidence in Brown syndrome has to be noticed.

But if according to the hypothesis congenital Brown syndrome would represent a subgroup of congenital fourth nerve palsy in which paradoxical coinnervation occurs, cases with a contralateral fourth nerve palsy should be understood as bilateral with regard to the underlying pathology, thus the percentage of bilateral cases would increase significantly.

Sex Distribution

Pooled data of ten and our own studies [60, 65, 74–81] encompassing 246 patients showed the a ection of 55% females and 45% males. For Duane syndrome de Respinis [34] found in pooled data of 835 patients, 58% were women and 42% were men. Again, an analogy between the entities of Brown and Duane syndrome under the hypothesis of a similar pathophysiologic mechanism could be drawn.

Incidence

Incidence of Brown syndrome is estimated to be 1 per 430–450 strabismus cases, i.e., 0.22% [60]. Duane syndrome occurs in at least 1% of strabismus cases [34].

Both syndromes are rare but a 4 times greater incidence of Duane syndrome remains to be explained. Stating a failed innervation of the superior oblique muscle by fibers of the fourth nerve and paradoxical innervation of the superior oblique in Brown syndrome one would have to add the cases of unior bilateral congenital fourth nerve palsy to figure out the incidence of the underlying pathophysiologic entity of a developmental fourth nerve disorder.

Heredity

In Brown syndrome, most cases seem to occur spontaneously.Of the 126 cases in the 1973 report of Brown [59] 2 are familial, although it cannot be confirmed whether all 126 cases were congenital ones, but at least 100 can be estimated

ing another one [60]. Lobefalo [82] reported a family with autosomal distal arthrogryposis multiplex congenita and Brown syndrome; thus, we overlook a total of ten descriptions of familial Brown syndrome.

Three of the reports of familial Brown syndrome involve monocygotic twins with mirror images. In Duane syndrome, mirror images in twins are also described.

But, although there are as in Brown syndrome far more sporadic than familial cases, the amount of hereditary cases in Duane syndrome with about 10% is greater than in Brown syndrome. As well in Brown syndrome as in Duane syndrome, the familial cases are presumed to be mostly inherited by an autosomal dominant transmission [34, 83, 84].

A genetic study performed under the assumption that Brown syndrome might be looked upon in the context of the other congenital strabismus syndromes already has been done in a family with familial a ection [85]. ARIX was not found to be mutated. But the case reports of the patients should be read carefully for the late onset of symptoms in the teenage years should also let an acquired pathology maybe on the basis of a familial rheumatic disposition being taken into consideration. Thus, this paper in our opinion does not contradict the hypothesis in question.

Of our 87 patients, 21 patients had a positive family history in regard to strabismus or amblyopia (24.1%).

Three patients (3.4%) had relatives with Brown syndrome: two pairs of brothers, amongst them one pair of twins with “mirror images” and one parent child constellation.

One patient’s grandfather was reported to us to be “unable to move the eyes to the right or left.” We had no opportunity to examine the patient but a video of him showed a condition that might represent bilateral Duane syndrome or horizontal gaze palsy.

Potential Induction of the Syndrome

Among the developmental defects caused by thalidomide there are also cranial miswiring syndromes. We investigated whether in thalidomide embryopathy also Brown syndrome is described. In 21 patients with thalidomide embryopathy and ocular motility disorders, Miller [86] describes nine patients with Duane syndrome and two patients with decreased function of the right-sided inferior oblique; furthermore, patients su ered from gaze paresis, isolated abduction weakness, aberrant lacrimation and facial nerve palsy.