Summary for the Clinician

■ Numerous structural abnormalities of extraocular muscles and associated connective tissues

6may cause strabismus.

■Structural causes of strabismus may mimic neurological causes of strabismus.

■High-quality orbital imaging is generally necessary to diagnose structural abnormalities of extraocular muscles and associated connective tissues that cause strabismus.

syndrome in the absence of high myopia: posterior surgical ligature between the lateral margin of the SR muscle and the superior margin of the LR muscle.

6.6Congenital Peripheral Neuropathy: The Congenital Cranial Dysinnervation Disorders (CCDDs)

Certain congenital forms of strabismus occur despite normal orbital connective tissues and pulleys, as the result of deficiency or misdirection of motor nerves to the EOMs. Genetic causes of many of the CCDDs are described in chapter 7 in this volume byAntje Neugebauer and Julia Fricke, and will not be discussed here in this chapter that emphasizes the pathophysiology of strabismus. It is useful to understand two general principles in the functional anatomy of these CCDDs. First, EOMs with insu cient motor innervation are hypoplastic and hypofunctional. Second, e ectively innervated antagonists of congenitally noninnervated EOMs exhibit contracture and increased sti ness (Table 6.5).

6.6.1Congenital Oculomotor (CN3) Palsy

Congenital oculomotor (CN3) palsy is typically partial. It may appear clinically bilateral or unilateral, although on careful evaluation apparently unilateral cases may be discovered to be bilateral albeit highly asymmetrical [33]. Patients may present with variable deficiencies of adduction, supraduction, and infraduction, along with variable mydriasis and blepharoptosis. A ected EOMs are hypoplastic, corresponding to their functional deficiencies. Intraorbital motor nerves to EOMs innervated by CN3 are hypoplastic, as is the subarachnoid CN3 (Fig. 6.6).

6.6.2Congenital Fibrosis

of the Extraocular Muscles (CFEOM)

In many fundamental respects similar to congenital CN3 palsy, CFEOM is a heritable congenital CN3 hypoplasia with frequent misdirection of remaining fibers, more profoundly a ecting the superior than inferior division of CN3. Three distinct phenotypes, CFEOM1–3, are recognized. The classic form, CFEOM1 (MIM 135700), is

typified by bilateral congenital blepharoptosis and ophthalmoplegia, with the eyes restricted to infraduction below the horizontal midline [34]. Horizontal strabismus may coexist (Tables 6.5, 6.6).

Forced duction testing in CFEOM1 demonstrates restriction to passive supraduction, consistent with surgical observations of increased extraocular muscle (EOM) stiffness. Older pathologic reports of specimens of resected EOMs in CFEOM suggested replacement by fibrous tissue [35–37]. The classic concept of CFEOM as a primary myopathy, however, was challenged by autopsy findings in a subject from a pedigree with the KIF21A mutation [34]. Engle et al. alternatively suggested that CFEOM1 is a primary disorder of EOM motor neuron development, leading to hypoplasia or atrophy of the EOMs they innervate, and secondary contracture of their antagonists [34]. Older reports of “fibrosis” in EOM tendons are likely to have been artifacts of inadvertent biopsy of distal EOM tendons [34].

Orbital MRI in CFEOM1 demonstrates hypoplasia of the motor nerves normally innervated by CN3, most profound for the SR and levator palpebrae superioris corresponding to the clinically prominent hypotropia

and blepharoptosis (Fig. 6.7a, b) [38]. Intraorbital motor branches of CN3 are also hypoplastic (Fig. 6.7c).

MRI in CFEOM1 demonstrates marked hypoplasia of the subarachnoid CN3. Significant but usually subclinical optic nerve (ON) hypoplasia occurs in CFEOM1, as may superior oblique (SO) muscle hypoplasia presumably due to trochlear nerve (CN4) hypoplasia. The posterior parts of multiple EOMs may be dysplastic in CFEOM, although their anterior portions generally appear normal both by MRI and at EOM surgery.

The frequent occurrence of synergistic eye movements and the Marcus Gunn jaw winking phenomenon in CFEOM1 [39, 40] suggests motor axonal misrouting.

More direct evidence of this misrouting is provided by high-resolution MRI showing innervation of the inferior zone of the LR by a branch of CN3 that would normally be fated to innervate the IR. In most cases, when a patient with CFEOM1 attempts deorsumversion, the eyes abduct dye to LR contraction, increasing the exotropia present in central gaze. In CFEOM1, CN6 innervates the superior zone of the LR muscle.

Patients with CFEOM2 (OMIM 602078) have congenitally bilateral exotropic ophthalmoplegia and blepharoptosis. This rare recessive disorder occurs in consan guineous pedigrees. The orbital and cranial nerve phenotype of CFEOM2 have not been studied in detail.

The third CFEOM variant, CFEOM3, encompasses patients with CFEOM not classifiable as either CFEOM1 or CFEOM2. This “atypical” group includes unilateral cases who have orthotropic central gaze, or whose central gaze is hypotropic but who can supraduct above the central position. Subjects with CFEOM3 have asymmetrical blepharoptosis, limited supraduction, variable ophthalmoplegia, and are usually exotropic. MRI demonstrates asymmetrical levator palpebrae superioris and SR atrophy correlating with blepharoptosis and deficient supraduction, and small orbital motor nerves [41]. While at least one subarachnoid CN is hypoplastic, ophthalmoplegia occurs only when subarachoid CN3 width is less than the 2.5th percentile of normal. Multiple EOMs exhibit variable hypoplasia, correlating with duction in individual orbits. A-pattern exotropia is frequent in CFEOM3, correlating with LR misinnervation by CN3. ON crosssections are slightly subnormal, but rectus pulley locations are normal [42]. Some cases of CFEOM3 are associated with brain abnormalities including corpus callosum hypoplasia.

Summary for the Clinician

■CFEOM is not a primary muscle disorder, but rather a cranial nerve disorder.

6.6.3Congenital Trochlear (CN4) Palsy

While SO hypoplasia may coexist with other CCDDs such as CFEOM, SO dysfunction may not be clinically evident in the setting of di use external ophthalmoplegia or anomalous innervation of other EOMs. Isolated congenital CN4 palsy is often suspected in the presence of clinical evidence of ipsilateral hypertropia increasing on contralateral gaze, and with head tilt toward the ipsilateral shoulder. While the congenital nature of the disorder appears clear when there is a history of lifelong spontaneous head tilt to the contralateral shoulder, in many cases present after many years of compensation for what the history suggests has been a progressive condition without identifiable cause. Whether lifelong or insidious, orbital imaging in presumably congenital SO palsy demonstrates reduction in SO muscle size, and reduction in the normal contractile increase in SO cross-section due to infraduction (Fig. 6.8). Since even the normal subarachnoid CN4 cannot be reliably imaged by MRI, correlations with CN4 size have not been made in congenital CN4 palsy.

6.6.4Duane’s Retraction Syndrome (DRS)

Pure congenital abducens (CN6) palsy is exceptionally rare except as secondary to an obvious intrauterine or neonatal pathology such as tumor or hydrocephalus. Rather, in congenital developmental CN6 palsy, the LR is innervated or coinnervated by a branch of CN3, usually a motor branch ordinarily fated to innervate the MR. In this respect, the situation is similar to CFEOM. DRS is characterized by congenital abduction deficit, narrowing of the palpebral fissure on adduction, and globe retraction with occasional upshoot or downshoot in adduction [43]. Early electrophysiological studies suggested absence of normal abducens (CN6) innervation to the LR muscle as the cause of DRS, with paradoxical LR innervation in adduction [44, 45]. Absence of the CN6 nerve and motor neurons has been confirmed in one sporadic unilateral [46] and another bilateral autopsy case of DRS [47]. Parsa et al. first used MRI to demonstrate absence of the subarachnoid portion of CN6 in DRS [48], a finding that has been confirmed in 6 of 11 additional cases [49], and later correlated with the presence of residual abduction in multiple cases [50, 51].

Innervation of the LR by CN6 is deficient in both DRS and CN6 palsy, although unlike CN6 palsy, the eyes in central gaze are frequently aligned in DRS [52]. While most DRS cases are sporadic, a dominant form DURS2 is linked to chromosome 2. MRI demonstrated that DRS linked to the DURS2 locus is associated with bilateral abnormalities of many orbital motor nerves, and structural abnormalities of all EOMs except those innervated by the inferior division of CN3 [53]. Orbital motor nerves are typically small, with CN6 often nondetectable. Lateral rectus (LR) muscles are often structurally abnormal, often with MRI and motility evidence of oculomotor nerve (CN3) innervation from vertical rectus EOMs leading to A or V patterns of strabismus. Cases may include SO, SR, and LPS hypoplasia, sparing only the MR, IR, and IO EOMs. The subarachnoid CN3 may be small. Therefore, DURS2-linked DRS is a di use CCDD involving but not limited to CN6.

Summary for the Clinician

■CCDDs are nonprogressive developmental disorders featuring reduced and aberrant innervation.

■Subnormal innervation of some EOMs in CCDDs leads to secondary EOM hypoplasia, dysplasia, and weakness.