Causes of Sixth Nerve Palsy

There are numerous causes of acquired sixth nerve palsy in childhood.4,182 Robertson et al458 reviewed 133 cases of isolated acquired sixth nerve palsy in children and found the major diagnostic categories to include neoplasm (39%), trauma (20%), inflammation (17%), and idiopathic conditions (9%), which included cases of benign recurrent sixth nerve palsy. Martonyi349 reviewed the cases of 16 children with sixth nerve palsies and found that eight had benign recurrent sixth nerve palsy, four had elevated intracranial pressure, one had meningitis, one had meningomyelocele, one had ependymoma, one had an idiopathic condition, and one also had a transient palsy in infancy. More recently, Lee et al323 reviewed the charts of 75 children with sixth nerve palsies who had undergone modern neuroimaging. Neoplasms or their neurosurgical removal were the most common cause (45%), followed by elevated intracranial pressure without tumor (15%), trauma (12%), congenital (11%), inflammatory (7%), miscellaneous (5%), and idiopathic conditions (5%). These authors and others have recommended neuroimaging due to the high risk of neoplasm in pediatric sixth nerve palsies.191

In general, the relative prevalence of tumor versus benign recurrent sixth nerve palsy probably reflects the proximity of the investigators to a neurosurgical referral center. In one

retrospective review of 64 children with sixth nerve palsy,20 an underlying etiology could be identified in all but three. The most common cause was tumor (335), followed by hydrocephalus (23%) and trauma (19%). These figures undoubtedly reflect the study center’s proximity to a large neurosurgical center.

In our experience, the most readily identifiable causes of nontraumatic sixth nerve palsy in childhood are benign recurrent sixth nerve palsy, elevated intracranial pressure, and pontine glioma. When we examine the child with a nontraumatic acquired sixth nerve palsy, our examination is directed toward obtaining historical information and looking for clinical signs that would suggest one of these conditions. We inquire about recent head trauma, antecedent viral illnesses or immunizations, a history of previous episodes, time of onset, symptoms of increased intracranial pressure, and other neurological symptoms. Our initial neuro-ophthalmo- logic examination is primarily directed toward looking for ipsilateral facial weakness (which would suggest a pontine glioma) and signs of papilledema. We obtain a complete neurological examination and MR imaging in all children with an initial episode of sixth nerve palsy, including cases that are clearly traumatic in origin. The decision whether to perform a lumbar puncture is then predicated on the results of these studies (Fig. 6.14). We classify the major causes of pediatric sixth nerve palsy as follows:

Congenital Sixth Nerve Palsy

Congenital sixth nerve palsy is rare. However, it may also be underdiagnosed due to inherent difficulties in identifying abduction deficits in neonates. Such cases are almost always identified in the neonatal nursery and not in the eye clinic. Congenital esotropia has been reported to occur after 6–8 weeks of life, because occurrence in the neonatal period has not been documented.18,401 Therefore, the observation of an esotropia shortly after birth should lead one to consider the possibility of a congenital sixth nerve palsy. Most congenital sixth nerve palsies without peripheral misdirection are transient, probably arising as sequelae to perinatal cranial trauma.

Two forms of transient congenital sixth nerve palsy can be identified. The first presents as a neonatal esotropia with an obvious unilateral abduction deficit that generally improves or resolves over the first month of life.46,132,450 The incidence has been variously estimated to occur in 1 in 124450 and 1 in 182132 neonates. Such cases may be due to perinatal trauma. The second form presents with neonatal esotropia with no obvious abduction deficit.18 The presence of subtle abduction weakness is, however, very difficult to exclude in such neonates.

Traumatic Sixth Nerve Palsy

Sixth nerve palsies occur frequently in head trauma patients. Blunt trauma is believed to damage the sixth nerve where it is tethered beneath the petroclinoid ligament at its entrance to the dura overlying the clivus.29 Closed head trauma may also elevate intracranial pressure and secondarily produce unilateral or bilateral sixth nerve paresis. Basilar skull fractures may damage the petrous segment of the abducens nerve after the nerve has penetrated the dura and passed beneath the petroclinoid ligament.29,68,133,326,457,560 Posttraumatic carotid cavernous fistulas can also be associated with sixth nerve palsy.

Clinical signs of traumatic sixth nerve injury are more readily recognizable than those of fourth nerve injury because the resultant ocular deviation is usually larger in the primary gaze position. The occurrence of sixth nerve palsy after apparently trivial head trauma should raise suspicion of an underlying intracranial tumor.107 In one retrospective series of all traumatic sixth nerve palsies,393 the spontaneous recovery rate was found to be 27% for traumatic unilateral sixth nerve palsy and 12% for traumatic bilateral sixth nerve palsy.

Benign Recurrent Sixth Nerve Palsy

In 1967, Knox et al286 described 12 children ranging in age from 18 months to 15 years who developed an acute unilateral sixth nerve palsy after an apparently benign viral illness.

Reinecke and Thompson449 reported five recurrent cases of a similar nature. Werner et al591 reported several cases of benign recurrent sixth nerve palsy that followed viral illness or immunization (with measles, mumps, and rubella in one child and diphtheria, pertussis, and tetanus [DPT] in another). Other reports have mentioned the association with DPT vaccination.60,116 Sternberg et al531 described recurrent attacks of sixth nerve palsy after febrile illness. Afifi et al3 reviewed the literature and found that this condition had a female and leftsided preponderance. Benign transient sixth nerve palsy may also follow varicella infection.16,190,231,286,397,458 They speculated that possible etiologies could include viral infection, neurovascular compression by an aberrant artery, and migraine. Isolated reports implicate Epstein–Barr virus infection as the causative agent in some cases105,535 and impetigo in others.57 Other reported antecedent infections include cytomegalovirus,184 Q fever, and Lyme disease.60,116 The pathophysiological mechanism and location of injury to the sixth nerve are unclear. It is not known whether the much less common recurrent form of third nerve palsy in childhood represents a variant of the same disorder.

Unlike sixth nerve palsies associated with compression or elevated intracranial pressure, benign recurrent sixth nerve palsies are usually sudden in onset and associated with a severe abduction deficit in the involved eye (Fig. 6.15). Affected children are normal between attacks and have no other intracranial or metabolic abnormalities.55,60,449,591 Recurrences typically involve the same eye.349 In most cases, complete resolution occurs over 8–12 weeks, however, some children retain a residual esotropia after numerous recurrences and require surgical correction.55,449,565 Because strabismic amblyopia may develop prior to resolution,349 we generally institute part-time occlusion therapy for children in the amblyogenic age range at the initial office visit.

The diagnosis of benign recurrent sixth nerve palsy can be suspected on the initial visit on the basis of the following information: (1) acute onset, (2) complete absence of abduction, (3) antecedent febrile viral illness, (4) absence of other cranial nerve dysfunction, and (5) absence of signs and symptoms of elevated intracranial pressure. Because there are numerous causes of sixth nerve palsy in children (Fig. 6.8), we obtain neuroimaging for all initial episodes of sixth nerve palsy in children, although we rarely repeat these studies for recurrent episodes. However, if an apparently benign sixth nerve palsy in a child with negative neuroimaging studies improves but fails to completely resolve, neuroimaging should be repeated, because this scenario has been noted in children who are ultimately found to have a pontine glioma on repeat neuroimaging.597

When an otherwise normal child presents with idiopathic sixth nerve paresis, clinical features suggestive of later recurrence include female sex, left eye involvement, younger age, and recent vaccination.614 Recurrence is less likely if it has not occurred within 1 year of the initial event.614

Pontine Glioma

Brainstem gliomas are particularly common in children. More than 80% appear to arise from the pons. The peak age of onset is between 5 and 8 years.341 They characteristically present with an insidious onset of symptoms and signs, including disturbances of gait, sixth and seventh nerve palsies, headaches, nausea, and vomiting. Neuroradiologically, they produce a diffuse, relatively symmetrical expansion of the pons.341 Larger tumors may elevate the floor of the fourth ventricle to produce obstructive hydrocephalus. Presenting symptoms include ataxia, gait disturbance, and unilateral or bilateral abducens palsy. Esotropia greater at a distance than near may be the presenting abnormality in some children.81 The presence of intact sensory and motor fusion does not preclude the diagnosis of pontine glioma.81 Facial palsies, trigeminal deficits, and palsies of cranial nerves IX and X can also develop. Headache, nausea, and vomiting in the absence of hydrocephalus may develop from irritation of the posterior fossa structures. Open biopsy is generally avoided, as it commonly worsens the neurological picture and may not result in a positive biopsy due to tissue sampling.341 Stereotactic biopsy guided by CT scanning or MR imaging is generally reserved for cases in which there is a major question as to the clinical diagnosis.

The prognosis for pontine glioma remains poor, although it has improved with radiation therapy. Favorable prognostic features include neurofibromatosis, duration of symptoms of 1 year or more before diagnosis, calcification present on neuroimaging studies, focal (versus diffuse infiltrating) tumors, exophytic growth, and histopathological features of a low-grade tumor.341,369 Chemotherapeutic regimens have not increased survival.

Although the clinical presentation and neuroimaging findings are highly specific for this entity, other conditions rarely produce similar findings. The differential diagnosis of sixth nerve palsies with a thickened pons on MR imaging includes multiple sclerosis, brainstem vascular malformation, Bickerstaff’s brainstem encephalitis, tuberculoma, cysticercosis, and AIDS.341 Because many authors advocate radiotherapy without biopsy, it is important to always consider the possibility of multiple sclerosis (which may improve spontaneously) and to search carefully for other white matter lesions before committing a child with diffuse pontine enlargement to irradiation.188

A compressive etiology should always be ruled out by neuroimaging in the child with unilateral sixth nerve palsy. Skull base tumors (chordoma, meningioma, nasopharyngeal carcinoma, metastasis) predominate in adults, while posterior fossa tumors (pontine glioma, medulloblastoma, ependymoma, cystic cerebellar astrocytoma) can produce unilateral or bilateral sixth nerve palsies in children. The tempo of onset, associated neurological signs, and the pres-

ence or absence of papilledema provide the most important diagnostic clues, but the possibility should be more definitively evaluated with MR imaging. Mechanism of abducens nerve injury include direct infiltration of the pons and elevation of intracranial pressure (with or without hydrocephalus). Sixth nerve palsy is also a common postoperative complication following neurosurgical resection of posterior fossa tumors in children. Schwannomas and, less commonly, malignant peripheral nerve sheath tumors originating from the trigeminal nerve, rarely present with sixth nerve palsy.461 Associated trigeminal dysfunction should suggest a spaceoccupying lesion.461

Medulloblastoma93 and clival tumors compressing the pons, 321,359 are particularly prone to present with unilateral or bilateral sixth nerve palsies in children. Salvin et al480 described a child who had abducens palsy consequent to a large middle cranial fossa arachnoid cyst that required cystoperitoneal shunting. Chemotherapeutic agents can cause sixth nerve palsy.319 Unilateral sixth nerve palsy in children can also be caused by the acute neurotoxic effects of vincristine therapy for leukemia. Although intracranial aneurysms are rare in children, intracavernous aneurysms rarely cause isolated sixth nerve palsies.180,281

Elevated Intracranial Pressure

Elevated intracranial pressure can result in downward displacement of the brainstem, thereby stretching the sixth nerves, which are tethered in Dorello’s canal. In children, an elevation of intracranial pressure may occur in the setting of posterior fossa tumors, neurosurgical trauma, shunt failure, pseudotumor cerebri, venous sinus thrombosis, meningitis, Lyme disease, or hemolytic uremic syndrome. In this context, the sixth nerve palsy may be unilateral or bilateral, and it is almost always partial rather than complete. Sixth nerve palsy due to elevated intracranial pressure summarily resolves when the intracranial pressure is normalized. However, Chiari 1 malformation has been reported to cause bilateral sixth nerve palsy in children367 and adults.434 Because Chiari malformation may be associated with pseudotumor cerebri, it is important to rule out an associated Chiari malformation, especially when the sixth nerve palsy fails to resolve with otherwise successful treatment of the condition.

Infectious Sixth Nerve Palsy

Hanna et al214 found abducens palsy in 16.5% of patients with acute bacterial meningitis, compared with 3% for ocul-