It could be discussed whether the patients described with inferior oblique underaction were patients with a paradoxical coinnervation in fourth nerve hypoor aplasia.

Saito in a neurological work-up of the data of 137 patients with thalidomide embryopathy described three patients with disturbances of the fourth nerve [87].

Radiologic Findings

Imaging studies in Brown syndrome displayed di erent pathologies. Enlargement and irregularities in the trochlear complex were shown by Sener et al. Bhola et al. examined three patients with Brown syndrome, two of whom showed hypoplasia on NMR tomography in the muscular portion of the superior oblique – a remarkable finding with regard to the hypothesis of a primary developmental disorder in the fourth nerve underlying Brown syndrome.

To test the hypothesis of a fourth nerve dysinnervation in Brown syndrome, Kolling and coworkers examined the trochlear nerve with nuclear magnetic resonance imaging and presented their results at the 12th meeting of the Bielschowsky society in 2007 [unpublished data]. In two of four patients, the trochlear nerve was found absent on the side of the motility deficiency a finding in favor of the hypothesis. Muscular anomalies were not found in these patients [80, 88].

Natural Course in Brown Syndrome

As to the natural course of the disease, reports are inconsistent. Whereas Wright states that congenital Brown syndrome yields rather stable findings, many authors report spontaneous improvement or even resolution [89–91]. In most of our patients findings were quite stable but in single cases – for example, at the age of 2 years in one of the twins with mirror image – we saw significant spontaneous improvement.

The finding of spontaneous resolutions challenges the hypothesis of a dysinnervation. But one has to consider that the hypothesis states secondary fibrotic changes. Also under the assumption of a mere mechanical cause of Brown syndrome, spontaneous improvements remain to be explained. Any explanation such as growth changes of the orbital anatomy or changes in fibrotic tissues would serve under both assumptions. In the setting of cocontraction, changes in fibrous strands even may be more probable. Furthermore, the postnatal plasticity of the neuromuscular connections with potential processes of initial polyneuronal innervation and gradual synapse elimination in the eye muscles is not well examined especially under the condition of coinnervation [18].

Intra-and Postoperative Findings

Structural changes in the superior oblique tendon in Brown syndrome have been described by many surgeons [79, 92, 103]. In our series, 28 patients underwent operation, in 20 cases the surgical protocol mentions tightness of the tendon, in one case in which a tucking procedure was performed on the inferior oblique also fibrotic changes in this muscle were reported.

Surgical results are often disappointing as indicated by the multitude of approaches suggested. Surgeons often recognize a disappointing discrepancy between intraoperative findings after interventions on the superior oblique in that passive motility is improved after the procedure but active motility in the postoperative course is still not improved significantly.

Papst and Stein in their thorough early discussion of a potential misinnervation already hinted to this finding as an argument for an innervational abnormality in Brown syndrome [43, 66, 93].

We summarize from our studies that the hypothesis of Brown syndrome as a neurodevelopmental disorder should still be pursued to be verified or falsified.

7.2.1.2Congenital Monocular Elevation Deficiency and Vertical Retraction Syndrome

While in congenital Brown syndrome an elevation deficiency of the eye exists if the globe is adducted, in congenital monocular elevation deficiency or in “double elevator palsy,” elevation of the globe is hindered in adduction as well as in abduction.

An early description of the disorder is given by White in 1942 [94].

Acquired and congenital cases are reported. Congenital cases are characterized by orthotropia or hypotropia in primary position, true ptosis or pseudoptosis in the majority of cases. In a considerable number of cases restriction of the globe to forced duction into elevation is found. Often the lid shows paradoxical movements on yaw movements, i.e., the Marcus Gunn phenomenon. Furthermore dissociated vertical deviation (DVD) is present, sometimes it occurs after operation. Often Bell’s phenomenon is preserved although elevation on following movements, saccades and in compensatory eye movements cannot be elicited [62] (Fig. 7.9).

Olson and Scott report a series of 31 patients with congenital monocular elevation deficiency in which they registered pseudptosis in 90%, true ptosis in 64%, chin-up head position in 77%, hypotropia in primary gaze in 97%

a

7

b

c

d

Fig. 7.9 Patient with congenital monocular elevation deficiency in the right eye. Elevation of the right eye hindered in right upgaze (a), straight upgaze (b) and left upgaze (c). Higher elevation of the right eye on lid closure, Bell’s phenomenon, (d) than on elevation (b)

with a mean of 20 PD, Marcus Gunn jaw winking in 28%, reduced or absent Bell’s phenomenon in 75% and restriction to elevation on forced duction in 42% of those tested [95].

In our own series of 23 patients with double elevator palsy in eight cases Bell’s phenomenon was positive.

The fact that in some cases elevation of the globe is preserved under the conditions of Bell’s phenomenon, DVD or under anesthesia [96] led several authors to conclude that double elevator palsy represents a supranuclear disorder and seemed to exclude an infranuclear disorder. Some authors discuss a fascicular lesion [62, 94, 97].

Further, the finding that elevation is hindered in abduction, which means in the field of action of the superior rectus, and in adduction, which means in the field of action of the inferior oblique, led many observers to exclude a nuclear disorder: for the third nerve, the subnucleus for the innervation of the superior rectus lies contralaterally, and for the inferior oblique, it lies ipsilaterally in the mesencephalon.

Remarkably, as in Brown syndrome, which was initially understood as a paresis of the inferior oblique in a case of so-called double elevator palsy, innervation of the inferior oblique was found normal in an electromyographic examination [98].

It was speculated that a longstanding palsy of the superior rectus alone also would impede elevation on adduction and that an inferior oblique palsy not necessarily is required to produce the typical motility pattern, [62, 94] thus a nuclear origin confined to the subnucleus of the superior rectus was not out of discussion.

In cases with resistance to forced duction, impairment of Bell’s phenomenon also exists, where sometimes a primarily fibrotic origin is presumed.

Thus supranuclear, nuclear, fascicular and muscular etiologies are discussed for the rare disorder of congenital monocular elevation deficiency.

With the Marcus Gunn phenomenon, ptosis and restriction as accompanying signs some features exist that could be compatible with a neurodevelopmental origin of double elevator palsy. A case with the combination of Duane syndrome and double elevator palsy has been reported [99]. In our series of 23 patients, two showed contralateral fourth nerve palsy.

Three of our patients showed retraction of the globe on vertical eye movements.

This leads to similarities with vertical retraction syndrome that also had been included by Brown into the structural anomalies [9].

Descriptions of vertical retraction syndrome are inconsistent in that some authors describe only anomalies in vertical eye movements with retraction of the globe with narrowing of the lid fissure; others describe vertical motility disorders with retraction combined with horizontal abnormalities that resemble Duane syndrome.

Vertical retraction syndrome seems to be even rarer than congenital monocular elevation deficiency.

A secondary misinnervation as cause for the retraction of the globe on vertical movements would be a possible explanation.

The view upon congenital double elevator palsy and vertical retraction syndrome as neurodevelopmental disorders would require a model that solves the question why Bell’s phenomenon remains intact in some cases.

7.2.2A Model of some Congenital Elevation Deficiencies as Neurodevelopmental Diseases

Our inquiries into the field of congenital elevation deficiencies lead us to hypothesize that these disorders might represent rather a continuum of developmental disorders than distinct diseases.

Clinically, it is sometimes hard to di erentiate between a Brown syndrome and a congenital monocular elevation deficiency. Wright in his review hinted to 70% of patients that had been operated and that demonstrated significant elevation deficiency in abduction [60]. In 76 own examinations of patients with congenital Brown syndrome, we found 66% to have remarkable hindrance of elevation in abduction. We remarked that some patients with typical Brown syndrome display a slight ptosis on the a ected side. Patients with congenital monocular elevation deficiency may display retraction on upor downgaze so that clear di erentiation from vertical retraction syndrome may be di cult. At last even di erentiation between a unilateral congenital fibrosis syndrome and these disturbances may be di - cult. Thus one might ask for an explanation taking into account that borders are not clear cut.

In prenatal development segmentation, anterior– posterior and dorso–ventral patterning is achieved by

sequential activation of genes and the building up of gradients of mediators for developmental steps.

The crossing of fibers in certain segments of the brainstem depends on the integrity of the cascade of interactions between substances mediating attraction to and repulsion from the midline and their receptors. The mutations in the ROBO3 gene leading to HGPPS are an example of a locally defined failure of midline crossing of certain neurons.

If such a failure occurred in the lower mesencephalic region, an isolated unior bilateral fourth nerve palsy could result.If fibers of the third nerve e.g.,fibers intended for the superior rectus or the inferior oblique would enter the superior oblique paradoxical innervation could result in the motility pattern of Brown syndrome (Fig. 7.10). If the defect extended higher to the region of the crossing fibers of the third nerve, the subnucleus sending fibers across the midline that lies next to the fourth nerve and innervates the levator palpebrae muscle would be a ected and fourth nerve palsy or Brown syndrome accompanied by ptosis would result. A substitutional innervation, e.g., by fibers of the motor portion of the fifth nerve or of the third nerve would compensate the primary dysinnervation partially but lead to synkinetic movements of the lid on jaw movements as Marcus Gunn phenomenon or on downgaze producing a lid lag or on adduction producing widening of the lid fissure.

Fig. 7.10 Model of congenital Brown syndrome as a neurodevelopmental disorder. A schematic drawing shows the third and fourth nerve nuclei in the brainstem. A unilateral gradual disturbance exists that mostly a ects the fourth nerve nucleus or its crossing neurons. An x indicates disruption of normal fourth nerve innervation. Dashed lines indicate secondary misinnervation of the superior oblique by third nerve fibers. Note that this misinnervation does not run topographically in the way shown. The lines just indicate which muscles might share innervation

N. III- nucleus

N. IV-nucleus

x

N.IV

N.IIIfibers

superior rectus, SIF

levator palpebrae, SIF

superior oblique, SIF

Further extension would encompass the subnucleus for the superior rectus. Brown syndrome and ptosis would be accompanied by an elevation deficiency in abduction, thus completing the image of congenital monocular ele-

7vation deficiency. If the superior rectus is innervated by fibers of its main antagonist, retraction movements as well as depression deficiency result.

Interestingly, recent studies on the functional neuroanatomy of the third nerve nucleus state a dual innervation of the eye muscles. So called single innervated muscle fibers (SIF) and multiple innervated muscle fibers (MIF) receive input each from a special subset of motoneurons that di er in their histologic appearance from neurons innervating SIF fibers. These are located in distinct regions of the third nerve nucleus [100, 101].

Such a dual innervation would make it necessary to reconsider the presumption of a final common path in eye muscle innervation. The principle itself as introduced by Sherrington referred to the motoneuron as the final path [102] and is not in question but it has been adopted in a way that looked upon the eye muscle as a structure with

homogeneous innervation. In consequence of the idea of a dual innervation of the eye muscles, concepts of supranuclear disorders in general have to be reconsidered.

The motoneuron group innervating the MIF of the superior rectus is found in the so-called S-group, which in man lies in the cranial part of the nucleus. The functional role of the MIF fibers is not yet elucidated but they are presumed to play a role in tonic muscle activity [100, 101]. One could speculate that MIF neurons play a role in the mediation of Bell’s phenomenon and further that these neurons either by their special cytologic features or just by their cranial position are not reached by the pathologic process hindering midline crossing. This would explain why Bell’s phenomenon remains intact in some cases of monocular elevation deficiency. Thus the concept of a supranuclear disorder would not be necessary.

This model would explain Brown syndrome, congenital monocular elevation deficiency and vertical retraction syndrome as disorders of mesencephalic disturbance of midline crossing of fourth and third nerve fibers with dysinnervation (Fig. 7.11).

N.V- fibers

N.III