thereby resulting in “cross talk” between adjacent axons that is not dependent on actual synaptic transmission. Lepore and Glaser327 cited a case of ophthalmoplegic migraine in which signs of aberrant regeneration occurred as a transient phenomenon and argued that ephaptic transmission may offer a possible explanation for such cases, because rewiring of the peripheral nerve would not be compatible with the evanescence of synkinetic movements.37 Ephaptic transmission has also been implicated in disorders involving the fifth nerve nucleus.199 However, the potential role of ephaptic transmission in synkinesis is controversial. This phenomenon is seen only as a transient event in the dystrophic mouse model447 and is not considered likely in the clinical situation, where stereotyped and reproducible movements occur over a period of decades following neuronal recovery.

The final potential mechanism for oculomotor synkinesis is that of central reorganization. After motoneuron transection, dendrites acquire the ability to produce autonomous spike potentials.198 The rearrangement of synaptic input to the motoneuron may unmask existing inputs that usually are weak or suppressed. Such changes in the efficacy of normally weak pathways could theoretically participate in the development of synkinetic movements. In this scheme, ipsilateral monosynaptic input to motoneurons is lost and not re-established, and preexisting but normally-suppressed projections become functionally significant with synaptic reorganization after nerve damage. Histologic studies have documented such alterations in synaptic contacts on motoneuron cell bodies.58 However, these changes are present only transiently after injury, and a more normal appearance to the synaptic contacts reappears with time. When Lyle337 sectioned the right oculomotor nerve in eight monkeys, he observed that bilateral pseudo-Graefe’s sign occurred 21 days postoperatively. It is difficult to explain the bilaterality of these synkinetic movements resulting from a peripheral nerve injury without invoking at least one central mechanism.37 Although neuroanatomical studies provide more direct evidence for peripheral misdirection, the potential for the participation of synaptic reorganization in development of synkinesis cannot be dismissed.225,557 Rather than serving a maladaptive role that contributes to synkinesis, central reorganization might well be expected to function in the suppression of abnormal motor movements generated by aberrant axonal regrowth and reinnervation.

A panoply of congenital and traumatic synkinetic eye movements continue to be described.174 Congenital ptosis and congenital ocular fibrosis syndromes may be associated with ocular motor synkinesis as part of the congenital cranial dysinnervation syndromes.73,408,553 Cases of abducens to oculomotor misdirection after trauma have been attributed to peripheral nerve misdirection.84 Khan et al276 described a large family in which two siblings exhibited ptosis with abnormal synkinetic elevation on ipsilateral abduction. One

was bilaterally affected, while the other had unilateral findings. A third demonstrated classic bilateral congenital ptosis, while a fourth demonstrated Duane syndrome. Teratogens such as isoretinoin A can produce disturbed ocular motility with congenital ocular motor synkinesis.388 Because the synkinetic lid elevation with depression that follows injury to the oculomotor nerve (pseudo-Graefe’s sign) is often greater in adduction than in abduction, it has been speculated that it may occasionally arise from the trochlear nerve.163,347,348

Rarely, cascade-like forms of ocular motor synkinesis are present at birth. Pieh et al433 described a 6-month-old boy with lack of innervation to a lateral rectus muscle, causing misrouting from the ipsilateral medial rectus muscle; this possibly induced secondary misrouting of trigeminal motor nerve fibers to the medial rectus muscle (manifesting as convergence during sucking).

Etiology

The clinical algorithm in Fig. 6.3 is useful in facilitating the diagnostic workup of third nerve palsy in childhood.

Congenital Third Nerve Palsy

Congenital third nerve palsies account for a sizable portion of patients in all reported series of childhood ocular motor nerve palsies.390 These children very frequently exhibit aberrant innervation, indicating that the mechanism probably involves an interruption and regrowth of axons (Fig. 6.4). In congenital third nerve palsy with aberrant regeneration, the involved pupil may be miotic compared with the normal pupil.210 In a retrospective review of 41 cases of pediatric oculomotor palsy, Mudgil and Repka390 found the most common causes to be congenital (39%), traumatic (37%), and neoplastic (17%). Oculomotor palsy was associated with a poor sensorimotor outcome in children younger than 8 years of age.

In children who are otherwise normal, birth trauma, either with prolonged labor and molding of the skull or with a difficult forceps delivery, has been considered the most likely etiology.210,243 The presumed mechanism of third nerve damage in this circumstance is compression of the nerve as it crosses the tentorial edge while passing from the posterior to the middle cranial fossa. This compression is probably due to either diffusely increased intracranial pressure or compression of the temporal lobe uncus over the tentorial edge and into the posterior cranial fossa. However, Norman et al403 found nodular enlargement of the cisternal segment of the involved oculomotor nerve on MR imaging, in several cases of third nerve palsy in infancy, suggesting that neurinoma

can be a causative lesion in this age range. Direct injury to the oculomotor nerve during amniocentesis has also been implicated as a cause of third nerve palsy.428 Neonates with congenital third nerve palsy may recover some degree of function over weeks to months. Although congenital third nerve palsy is frequently an isolated event,368,567 it may also be accompanied by neurological deficits.37,210 Some congenital third nerve palsies may be due to a congenital absence of the

nerve and/or nucleus.111 Contralateral hemiplegia accompanies congenital third nerve palsy in some cases, suggesting a ventral mesencephalic injury.37,243 Midbrain hypoplasia of the ventral portion of the midbrain has been associated with bilateral complete third nerve paresis without aberrant regeneration.168,537 MR imaging demonstrates hypoplasia of the involved extraocular muscles (Fig. 6.5) and, in some cases, intracranial absence of the affected oculomotor nerve.262

Congenital third nerve palsy has also been associated with septo-optic dysplasia.318 The syndrome of congenital third nerve palsy, cerebellar hypoplasia, and facial capillary hemangioma592 probably represents the PHACE

syndrome.361,362,592

Fig. 6.5  Congenital left oculomotor nerve palsy. Coronal orbital MR image shows selective hypoplasia of superior, medial, and inferior rectus muscles

Amblyopia is common in congenital third nerve palsy.243,567 Occasionally, preferential fixation with the paretic eye may lead to the development of amblyopia in the nonparetic eye. This finding has been noted in patients with nystagmus and probably relates to preferential dampening of the nystagmus on the side with oculomotor palsy.210,243,268 Although the potential for restoration of binocularity is poor, patients with congenital third nerve palsy often achieve reasonable cosmesis with strabismus and ptosis surgery.322

Congenital Third Nerve Palsy with Cyclic Spasm

A unique form of oculomotor nerve palsy is associated with cyclic spasm of the affected muscles. This condition is usually noticed during the first year of life and consists of partial or complete third nerve palsy, with a dramatic additional feature. Every 1½ to 2 min, the paretic upper lid elevates, the pupil constricts, the eye adducts, and a myopic shift may

occur in the refraction (Fig. 6.6). The spastic phase usually lasts less than a minute, giving way to another paretic phase. The cycles continue throughout life and persist during sleep, although they become slower and less extensive than when the patient is awake.

A review of all published cases41 suggests that the condition is frequently seen in the absence of other neurological abnormalities. A history of birth trauma or a significant intracranial infection may be seen in as many as half of the cases.166,335 Near fixational effort is noted to increase the extent and duration of the spastic phase in many cases. Abduction efforts shorten and reduce the spasms and accentuate or prolong the paretic phase. The condition is usually fully developed when first noted, but progression to cyclic spasm has been reported in a patient with a partial third nerve palsy.177 Cases in which the pupil is the only structure to cycle are probably underrecognized.177

Determining the site of the lesion in this condition is an intriguing neurophysiologic problem. The movements resemble oculomotor synkinesis, which is known to be caused primarily by misdirected regrowth of peripheral axons. However, in oculomotor synkinesis, the abnormal involuntary movements are always associated with attempted voluntary movements, whereas in oculomotor paresis with cyclic spasm, the involuntary movements are not reproducible by a particular voluntary effort, although they are influenced by these efforts. The weight of evidence suggests that the primary injury involves the peripheral nerve. However, indirect evidence suggests that reorganization of the central neurons also occurs subsequent to this damage, causing increased susceptibility to supranuclear influences or recurrent discharges of the neurons themselves due to abnormal supranuclear input. It is known that axotomy leads to changes in central nuclei, predominantly a decrease in synapses on the dendritic tree followed by a hypersensitivity to depolarization when exposed to neurotransmitters from other sources. The observation that the cyclic spasm almost always appears in infancy may reflect a particular sensitivity or predilection of the infant brain to develop the aforementioned central reorganization.37,210

Traumatic Third Nerve Palsy

Head trauma may cause injury to the third cranial nerve anywhere from the nucleus to the orbit. The intra-axial fascicles of the nerve or the nucleus itself may be damaged as part of a diffuse axonal and neuronal injury pattern in severe head trauma or as part of an ischemic syndrome from temporary occlusion of the perforating branches of the basilar artery, as a result of the brainstem movement during rapid acceleration and deceleration of the head. Outside the brainstem, the nerve may be torn at its exit from the midbrain in the interpeduncular fossa, or it may be damaged at the tentorium from

elevated intracranial pressure and uncal herniation. A basilar skull fracture may damage the nerve as it courses along the base of the middle cranial fossa and enters the cavernous sinus. Traumatic cavernous sinus thrombosis can cause third nerve palsy alone or in combination with a palsy of cranial nerves IV and VI. The orbital apex and superior orbital fissures syndromes can be the result of penetrating trauma to the orbit or diffuse orbital fractures. The nature of traumatic injury assures that most, but not all, cases have pupillary involvement.260

Patients with cranial nerve deficits and a history of trauma usually have had neuroimaging by the time they arrive for neuro-ophthalmologic consultation. Neuroimaging is usually warranted in traumatic third nerve palsy to rule out the possibility of a subdural hemorrhage87,598 or an occult intracranial tumor that can compress the oculomotor nerve, predisposing it to injury following relatively minor head trauma.561,586

thies in acute bacterial meningitis are often multiple372 and can sometimes involve all ocular motor nerves bilaterally.40 Oculomotor palsy is much less common than abducens palsy, but both occur with sufficient frequency to warrant vigilance.214 The ocular motor nerve palsies that occur in children with acute bacterial meningitis usually result from encasement of the nerves by purulent exudate in the subarachnoid space.339 Rarely, ocular motor nerve injury in meningitis can result from elevated intracranial pressure or septic cavernous sinus thrombosis.372

Acute bacterial meningitis in young children produces nonspecific symptoms and signs, including fever, irritability, drowsiness, failure to feed, and vomiting. Older children present with fever, severe headache, and nuchal rigidity. Other neuro-ophthalmologic complications include cortical blindness and optic atrophy (from the direct effects of the inflammatory process on the optic nerves and chiasm.)369

Cranial nerve palsies are more likely to develop in forms of purulent meningitis and in forms that involve the skull base. Due to their basilar involvement, tuberculous, sarcoid, carcinomatous, and fungal meningitis are most likely to injure the cranial nerves, but these are uncommon. Due to its common occurrence, acute bacterial meningitis accounts for most cases of postinflammatory ocular motor nerve palsy.

The possibility of acute bacterial meningitis should be considered when the child with one or more acute ocular motor nerve palsies is febrile or lethargic. Cranial neuropa-

The recent revision of the International Headache Classi­ fication has reclassified ophthalmoplegic migraine from a subtype of migraine to the category of neuralgia.223 Oculomotor palsy associated with migraine headache was the least common of the migraine syndromes (0.3% of children attending an outpatient neurology practice).338 The current definition of ophthalmoplegic migraine requires that at least two attacks fulfill the criterion for migraine headache, migraine-like headaches are accompanied or followed within 4 days of onset by paresis of one or more of the third, fourth, or sixth cranial

nerves and parasellar, orbital fissure, and posterior fossa lesions have been ruled out by appropriate investigation.224

Most migraine patients with this finding are in the pediatric age group.176 Unlike other forms of migraine, ophthalmoplegic migraine shows no female predominance (probably because it is primarily a disorder of childhood, and the incidence of migraine is about the same in both sexes prior to puberty).122 Most children with ophthalmoplegic migraine experience their first attack in the first decade of life, and several reports have documented its occurrence in infancy.372 It is rare for ophthalmoplegic migraine to recur after age 30.

A severe ipsilateral hemicranial headache of the crescendo type usually precedes the attack. The headache may abate hours or days before the onset of ophthalmoplegia. The third nerve is the most frequently involved ocular motor nerve, followed in frequency by the sixth nerve and the fourth nerve.240 Ophthalmoplegic migraine usually involves all branches of the oculomotor nerve, although a case with involvement confined to the superior division has recently been documented.266 The pupil is usually involved to some degree.176 The ophthalmoplegia usually lasts 3 or 4 days and resolves without any permanent extraocular muscle paralysis.240 However, repeated or prolonged episodes may last as long as 1 month and, eventually, some degree of permanent ophthalmoplegia and/or pupillary mydriasis may develop.92 Some patients develop transient or permanent oculomotor synkinesis.25,327 Nigerians with hemoglobin AS, seem to have an especially high incidence of ophthalmoplegic migraine, suggesting that a serum hemoglobin electrophoresis should be obtained in black children, who are suspected to have ophthalmoplegic migraine.419

Ophthalmoplegic migraine remains a diagnosis of exclusion. Other life-threatening causes of acute painful third nerve

palsy must be ruled out by neuroimaging, arteriography, or both.585 The differential diagnosis of ophthalmoplegic migraine includes aneurysm, pituitary apoplexy, diabetic ophthalmoplegia, and Tolosa–Hunt syndrome.240 Findings that should call the diagnosis of ophthalmoplegic migraine into question include alteration of consciousness, absence of a history typical for migraine, onset after age 20, signs and symptoms of subarachnoid hemorrhage, and severe or persistent headache with total ophthalmoplegia.240

Older theories regarding etiology of ophthalmoplegic migraine invoked either (1) compression of the oculomotor nerve by a dilated intracavernous portion of the carotid artery585,600 or (2) an ischemic mechanism involving the artery supplying the vasonervosum of the ocular motor nerve. Walsh and O’Doherty585 suggested that the wall of the intracavernous carotid artery becomes thickened and edematous, causing compression of one or more of the adjacent ocular motor nerves. This mechanism is consistent with the finding that intravenous norepinephrine, which has the capacity to constrict large and small arteries and to reduce edema, has produced resolution of the palsy in several patients. When angiography has been performed during an attack of ophthalmoplegic migraine, changes in the caliber of the intracavernous carotid artery have been observed only occasionally.568 Some have argued that the partial pupillary sparing in many children with ophthalmoplegic migraine is more consistent with an ischemic than a compressive mechanism.568

Numerous neuroimaging studies have now demonstrated gadolinium enhancement of the perimesencephalic oculomotor nerve during an attack of ophthalmoplegic migraine support an ischemic mechanism (Fig. 6.7).2,329,345,405,439,532,605 Some investigators believe MRI findings should be required