B.

Diseases of Cranial Nerves

48
Diseases of the Third, Fourth, and Sixth
Cranial Nerves
JACQUELINE A. LEAVITT AND BRIAN R. YOUNGE

Overview Cranial Nerve III Effects of Trauma

Nuclei of the Third, Fourth, and Sixth Cranial Nerve IV Aberrant Regeneration of Cranial
Nerves Cranial Nerve VI Nerve III
Cranial Nerve III (Oculomotor) Cavernous Sinus Neoplasms
Cranial Nerve IV (Trochlear) Blood Supply Vascular Diseases and Aneurysms
Cranial Nerve VI (Abducens) Histologic Features Infections and Toxins
Courses of the Third, Fourth, and Sixth Clinical Features
Nerves Congenital Defects

This chapter updates the previous work of James C. from within the brainstem to the orbit and even remotely,
Trautmann and Charles R. Barnett, describing the nuclear as in the false localizing signs of increased intracranial
anatomy, relationships, and intracranial course of the third, pressure or from the paraneoplastic syndromes. The fre-
fourth, and sixth cranial nerves, their relationships within quency and important clinical findings of vascular diseases
the cavernous sinus, the blood supply to each nerve, and that affect the three ocular motor nerves emphasizes the
their histologic compositions. We describe the clinical fea- localizing value of vascular syndromes within the brain-
tures of a palsy of each nerve, with some special mention stem. It is important to suspect an aneurysm involving the
of partial palsy of the third nerve in its anatomic relation- interpeduncular portion of the third nerve, which almost
ships. A discussion of congenital defects involving the always causes early pupillary dilatation. Diabetes and other
three oculomotor nerves is next, and some of the more less common vascular diseases are also discussed in this
peculiar associated syndromes, such as the Möbius syn- section. The variety of infections that can cause paresis of
drome and Duane’s syndrome, are included, along with one or more of the oculomotor nerves is legion, but the
substitution syndromes. Trauma plays an important role in frequency is not common; similarly, toxins and drugs that
the etiology of many cranial nerve palsies, and we have produce diplopia are many and varied.
devoted some discussion to the mechanisms of injury and
the relationships of bony and ligamentous anatomy to the
nerves as they course by. The recovery rate after surgical OVERVIEW
trauma is usually good, and we refer to a paper showing
surprisingly favorable prognosis for traumatic sixth nerve Cranial nerves III, IV, and VI and their nuclei constitute the
palsies. Theories of aberrant regeneration of the third lower motor neuron pathways for the extraocular and
nerve are included. Tumors can produce isolated palsies, intraocular muscles. Cranial nerve III (the oculomotor
but more often associated signs are present, anywhere nerve) innervates the superior rectus, medial rectus, inferior
1191
1192 Diseases of the Peripheral Nervous System

rectus, and the inferior oblique muscles of the globe as well

as the levator muscle of the upper eyelid. Parasympathetic
neurons to the intraocular muscles of the ciliary body and
iris sphincter also course through the oculomotor nerve.
Cranial nerve IV (the trochlear nerve) innervates the super-
ior oblique muscle. Cranial nerve VI (the abducens nerve)
innervates the lateral rectus muscle. These three cranial
nerves, and their supranuclear connections, provide the
neural pathways subserving the complex mechanisms of
ocular motility.
The literature on acquired ocular palsies has repeatedly
emphasized the existence of a relatively large group of
cases for which no cause is apparent or determined despite
long-term follow-up.92–94,96 Richards et al.92 combined data
from several series of patients at one institution and found
that almost 25% of their 4278 cases had no determinable
cause. These reports emphasize not only the variety of
causal factors for disturbance of function of cranial nerves
III, IV, and VI, but also the limitation of our present
knowledge concerning the pathophysiology of this portion
of the peripheral nervous system. This chapter is not an
all-inclusive treatise on the diseases of cranial nerves III,
IV, and VI, but rather a review of the common disease
processes that affect these nerves and of the importance of
the third, fourth, and sixth cranial nerves as a part of the
peripheral nervous system.

NUCLEI OF THE THIRD, FOURTH,

AND SIXTH NERVES

Cranial Nerve III (Oculomotor)

FIGURE 48–1
The oculomotor nuclei are located in the mesencephalon
Cranial nerve III (oculomotor) nucleus of monkey. Lines (A,
at the level of the superior colliculi. These paired midline B, C, and D) on the right locate sites of sections shown on
structures are located ventrolateral to the aqueduct of the left. AN ⫽ anteromedial nucleus; EW ⫽ Edinger-Westphal
Sylvius and are bordered laterally by the median longitu- nucleus; CCN ⫽ central caudal nucleus; IV ⫽ cranial nerve
dinal fasciculi. Warwick119 compiled studies of the anatomy IV. (From Wolff, E.: Anatomy of the Eye and Orbit: Including
of the oculomotor nuclei and proposed a scheme for the Central Connections, Development, and Comparative
the nuclei in primates. He warned that Wolff’s diagram Anatomy of the Visual Apparatus, 6th ed. [revised by Last,
(Fig. 48–1) appears more precise than is actually the case R. J.]. London, H. K. Lewis & Company, p. 283, 1968, with
and cautioned against its direct application to humans. permission.)
The motor neurons of the oculomotor nucleus extend
over a large area and are arranged in a rostrocaudal and
dorsoventral pattern. Most of the neurons are situated in thirds of the contralateral oculomotor nucleus. These cells
two large lateral nuclei, the dorsal group, representing the in the caudal two thirds of the contralateral nucleus are
neurons of the ipsilateral inferior rectus muscle, and the defined as the “motor pool” of the superior rectus muscle.
ventral group, representing the neurons of the ipsilateral This seems to be the only extraocular muscle supplied by
medial rectus muscle. The inferior oblique muscle is the contralateral oculomotor nucleus.
represented by neurons in the intermediate area of the The motor neurons of the nerves to the levator muscle
ipsilateral lateral nucleus. of the upper eyelid of each eye are located in the central
Warwick118 documented contralateral innervation of the caudate nucleus. This midline dorsal group of neurons is
superior rectus muscles. After unilateral interruption of also the most caudal portion of the oculomotor complex
the oculomotor nerve, chromatolysis is evident in the ipsi- and, being unpaired, is believed to supply the levator
lateral oculomotor nucleus and also in the caudal two muscle of the upper eyelids of both eyes.
 Diseases of the Third, Fourth, and Sixth Cranial Nerves 1193

The Edinger-Westphal nucleus consists of a paired The oculomotor fibers congregate into fascicles within
group of small neurons in the dorsorostral portion of the the midbrain; descend medially; pass through the median
oculomotor complex. The Edinger-Westphal complex, longitudinal fasciculus, the tegmentum, the red nucleus,
together with the anteromedian nucleus, gives rise to ocu- and the medial margin of the substantia nigra; and emerge
lomotor axons, which become the preganglionic parasym- as 10 to 15 rootlets on the medial aspect of the cerebral
pathetic fibers to the ciliary ganglion and continue to the peduncle. The rootlets soon fuse into a single nerve trunk,
eye via the short ciliary nerves. Ciliary ganglionectomy which becomes covered by a well-formed pial sheath. This
interrupts the ocular parasympathetic supply and also nerve trunk passes obliquely forward, downward, and lat-
causes retrograde changes in both the Edinger-Westphal erally at the level of the tentorium. Shortly after leaving
and anteromedian nuclei. Warwick121 estimated that 97% the brainstem, it passes between the posterior cerebral
of the ocular parasympathetic axons supply the ciliary and superior cerebellar arteries. As it approaches the
muscle and mediate accommodation, with only 3% supply- cavernous sinus, it crosses the free edge of the reflected
ing the pupil light reaction. leaf of the tentorium and enters the cavernous sinus lateral
to the posterior clinoid process (Fig. 48–2).
Cranial Nerve IV (Trochlear)
Cranial Nerve IV
The nucleus of cranial nerve IV is located caudal to the
oculomotor nucleus, beneath the periaqueductal gray mat- The trochlear nerve emerges from the dorsal surface of the
ter at the level of the inferior colliculus in the midbrain. brainstem below the inferior colliculus. Cranial nerve IV
This nerve consists of large motor neurons that supply the passes laterally around the superior cerebral peduncle and
contralateral superior oblique muscle; its fibers decussate through the quadrigeminal, ambient, crural, and pon-
around the central gray matter and emerge from the brain- tomesencephalic cisterns. It then passes between the
stem dorsally through the midline medullary velum caudal superior cerebellar artery and the posterior cerebellar
to the inferior colliculus. Wolff125 described the trochlear artery. The fourth nerve pierces the dura mater below the
nerve as the most slender of the cranial nerves and the one entry of the oculomotor nerve into the cavernous sinus.
with the longest intracranial course (75 mm). Although the
overlying tentorium may offer some protection against Cranial Nerve VI
compressive injury to the trochlear nerve in its course
from the dorsal midbrain, its attachment to the anterior The abducens nerve is composed of approximately 6000 to
medullary velum is very delicate, and the nerve may easily 7000 nerve fibers125 that pass forward through the pons and
be detached at this point. emerge on the ventral surface of the brainstem between
the pons and the medulla, just lateral to the pyramidal
prominence. Some of its rootlets pass through the pyram-
Cranial Nerve VI (Abducens) idal tract. Unlike cranial nerves III and IV, the rootlets of
The sixth cranial nerve nucleus is located close to the mid- cranial nerve VI may remain as separate fascicles for
line of the pons, beneath the floor of the fourth ventricle. varying distances before merging as a common nerve trunk.
It is bordered on its medial side by the median longitudinal As the nerve passes upward along the ventral surface of the
fasciculus and capped by the facial colliculus, an inden- pons, the anterior inferior cerebellar and anterior auditory
tation in the floor of the fourth ventricle made by the facial arteries, as well as other small lateral branches of the basilar
nerve (cranial nerve VII) as it travels around cranial nerve artery, cross it. In the posterior fossa, its course is upward
VI and its nucleus on its circuitous route through the pons. and slightly lateral; it pierces the dura of the clivus approxi-
mately 1 cm below the crest of the petrous portion of the
temporal bone and approximately 1.5 cm from its site of
exit from the pons. Beneath the dura, it is in close proxi-
COURSES OF THE THIRD, FOURTH,
mity to the inferior petrosal sinus and ascends to the sharp
AND SIXTH NERVES
border of the petrous portion of the temporal bone, at
which point it bends forward beneath the petrosphenoid
Cranial Nerve III
ligament of Gruber before entering the cavernous sinus. In
The oculomotor nerve is composed of approximately this region, it is often within the inferior petrosal sinus as it
15,000 fibers, most of which are large myelinated motor passes through Dorello’s canal.
fibers that arise from the bulk of the oculomotor nucleus.
Smaller myelinated fibers from the Edinger-Westphal and
Cavernous Sinus
anteromedian nuclei also travel with the ipsilateral oculo-
motor nerve and provide the parasympathetic innervation Cranial nerve III travels horizontally within the superior
to the ciliary muscle and the iris sphincter. lateral wall of the cavernous sinus with cranial nerve IV
1194 Diseases of the Peripheral Nervous System

FIGURE 48–2
Representation of cranial nerves and related basal structures in area of midbrain, middle fossa, cavernous sinus, and
orbital apex. Roof of right orbit, sphenoid wing, floor of middle fossa, and petrous ridge have been sectioned; a section
of the tentorial edge is removed to demonstrate course of trochlear nerve (4). Cerebellum is retracted to show struc-
tures in posterior fossa. Cross-section of midbrain is at level of superior colliculi and red nuclei. 2, Optic nerves and
chiasma. 3, Oculomotor nerves (note relationship to posterior cerebral and posterior communicating arteries). 4,
Trochlear nerve in edge of tentorium. 5, Trigeminal nerve (51, ophthalmic division; 52, maxillary division; 53, mandibu-
lar division). 6, Abducens nerve (note course up clivus and passage under petroclinoid ligament into posterior aspect
of cavernous sinus). 7, Facial nerve. 8, Acoustic nerve. (From Glaser, J. S.: Neuro-ophthalmology. New York, Harper
& Row, p. 251, 1978, with permission.)

and the ophthalmic division of cranial nerve V (trigem- sinus but probably do not become an integral part of the
inal) immediately beneath it. Cranial nerve VI passes nerves.
horizontally among the interstices of the cavernous All of the nerves to the ocular muscles pass into the orbit
sinus, first winding around the lateral aspect of the through the superior orbital fissure: cranial nerves III and
ascending portion of the internal carotid artery (ICA) VI are within the annulus of Zinn and cranial nerve IV is
and then lying beneath and lateral to the horizontal por- outside the annulus of Zinn. The abducens nerve continues
tion of the artery. Within the anterior portion of the cav- a short distance under the lateral rectus muscle before
ernous sinus, Asbury et al.4 demonstrated enlargement it terminates among the muscle fibers. Cranial nerve IV
and septation of cranial nerve III by connective tissue travels forward and medially under the orbital roof, crosses
bands. Sympathetic fibers from the carotid plexus join the superior rectus muscle, and then enters the dorsal bor-
the nerves to the ocular muscles within the cavernous der of the superior oblique muscle. The superior oblique
 Diseases of the Third, Fourth, and Sixth Cranial Nerves 1195

muscle originates at the annulus of Zinn, extending super- HISTOLOGIC FEATURES

omedially within the orbit through the trochlea before
attaching to the globe posterior to the equator. Sunderland and Hughes109 studied myelinated fibers
The third cranial nerve separates into two divisions within the nerves to the ocular muscles in humans.
either within the anterior portion of the cavernous sinus or Myelinated fibers range in size from 3 to 18 ␮m. They
as it enters the orbit. The superior division passes medially classified the fibers into three groups—small, medium,
over the optic nerve, divides, and enters the ventral sur- and large—and stated that fibers of all diameters could be
face of the superior rectus muscle and the levator muscle traced into the muscles from each of the nerves. Fibers
of the upper eyelid. The inferior division immediately passing to the ciliary ganglion were found to be of the
divides into branches to the medial rectus, interior rectus, small variety (3 to 5 ␮m). Within the intracranial portion of
and inferior oblique muscles. The parasympathetic fibers cranial nerve III, these small fibers, presumed to be pupill-
travel a short distance into the orbit within the inferior ary fibers, are concentrated in and around the superior
branch to the inferior oblique muscle; then they exit by surface of the nerve. Kerr and Hollowell68 also found that
one or two short branches to synapse within the ciliary the pupillomotor fibers are located superficially along the
ganglion. The postganglionic parasympathetic fibers travel dorsomedial and medial aspect of cranial nerve III but
from the ciliary ganglion to the globe as the short ciliary have a gradually descending position within the nerve as it
nerves, joined in this course by sympathetic fibers. passes anteriorly. The accommodative fibers appear to be
Warwick120 has shown that iridectomy results in chroma- intimately associated with the pupillomotor fibers.
tolysis of only 3% of the cells in the ciliary ganglion, Figure 48–3 illustrates the number of myelinated fibers
whereas lesions affecting the short ciliary nerves result in and the spectrum of fiber diameters within normal cranial
chromatolysis of approximately 97% of these cells. These nerve VI. The measurements were made on photographic
findings confirm the facts that almost all of the cells of the enlargements of 1.5-␮m transverse sections of each nerve
ciliary ganglion innervate intrinsic ocular musculature (for at its intracranial-dural junction. This method for evaluat-
accommodation) and that only a small fraction of their ing peripheral nerves has been described by Dyck and
axons supply the iris sphincter. co-workers.36 The oculomotor nerve that was examined
was 2.33 mm2 in transverse area and contained 18,542
fibers; the trochlear nerve measured was 0.19 mm2 and
BLOOD SUPPLY contained 2381 fibers; and the abducens nerve measured
was 0.56 mm2 and contained 4016 fibers. Among the
The blood supply of cranial nerves III, IV, and VI in their myelinated fibers, large fibers were predominant. In cra-
peripheral course is derived from small adjacent vessels in nial nerves III and VI, the mean diameter of these large
the subarachnoid space. There is a rich anastomosis of fibers was approximately 14 ␮m; in cranial nerve IV,
ascending and descending branches of these nutrient the mean diameter of the large fibers was slightly less.
arteries within the pial septa. Capillaries penetrate the There is a strong suggestion that the oculomotor nerve
fasciculi and form a complex longitudinal ascending contains a population of intermediate-sized fibers not
and descending network within the nerves. Asbury and evident in cranial nerves IV or VI. Whether these fibers
co-workers4 have traced in detail the entire nutrient circu- represent the parasympathetic fibers of cranial nerve III
lation of cranial nerve III. They found the vascular supply remains to be proved. In the sections examined, essentially
to be from three sources: (1) small arteries from the pos- no unmyelinated fibers were detected.
terior cerebral and the basilar arteries; (2) three or four
branches from the artery to the inferior cavernous sinus,
arising from the base of the carotid siphon; and (3) recur- CLINICAL FEATURES
rent branches from the ophthalmic artery to the orbital
portion of the nerve. Tekemir et al.110 found that the pos- A complete third nerve palsy would present with complete
terior cerebellar artery supplies the proximal segment of ptosis, the eye deviated down and out, and a large, unre-
III, whereas branches from the lateral trunk of the intra- sponsive pupil. If the pupil is not involved, this is called an
cavernous ICA supply the segment within the cavernous external oculomotor palsy. Many cases are incomplete
sinus. third nerve palsies, with each innervated extraocular
Tekemir et al.110 found that the sixth nerve segment muscle being affected partially and equally. Some cases
within Dorello’s canal is supplied by the meningeal branch may affect only the superior or inferior division of cranial
of the ICA, whereas between the petrous apex and the nerve III. In nuclear third nerve involvement, ptosis would
superior orbital fissure it is supplied by branches of the be bilateral, whereas the superior rectus involvement
lateral trunk of the intracavernous ICA. The tentorial cere- would be on the contralateral side.
bellar artery supplies the fourth nerve after it pierces the The primary action of the superior oblique is to intort
cerebellar tentorium. the eye; secondary and tertiary actions are depression and
1196 Diseases of the Peripheral Nervous System

FIGURE 48–3
A, Normal cranial nerve VI (⫻500).
B, Normal cranial nerve III (⫻500).
C, Myelinated fiber spectra of cranial
nerves III and VI (top) and myeli-
nated fiber spectrum of cranial nerve
IV (bottom). Counts were made on
phase-contrast enlargements of intra-
cranial portion of normal nerves at
site of contact with dura. (Courtesy of
Peter J. Dyck, MD.)

abduction. Patients with trochlear nerve palsy report causes the eye to excyclotort; therefore, the two images
binocular vertical diplopia that is worse in adduction and will not be parallel. When the patient looks at a horizon-
downgaze. Hypertropia (elevated eye) occurs on the side tal line, the images will form a tilted V (⬍or⬎). The
of the palsied nerve. The hypertropia will be worse (1) in pointed portion of the V will point in the direction of the
lateral gaze to the side opposite the palsy, (2) with head affected eye.
tilt to the same side, and (3) in downgaze. Often the In bilateral fourth nerve palsy, there is often only a small
patient will unconsciously tilt the head away from the eye vertical deviation in primary gaze. The hypertropia
with the nerve palsy. The inaction of the superior oblique “reverses” in lateral gaze (right hypertropia in left gaze
 Diseases of the Third, Fourth, and Sixth Cranial Nerves 1197

and left hypertropia in right gaze). A vertical deviation is Some congenital superior oblique palsy patients have
present with head tilt (ear to shoulder) and reverses direc- been found on magnetic resonance imaging (MRI) to have
tion with head tilt in the opposite direction (i.e., bilateral an absent superior oblique muscle and /or tendon.25
positive head tilt). The patient may assume a chin-down Congenital absence of the superior oblique tendon may be
position. Excyclotorsion of greater than 10 degrees can associated with craniofacial dysotoses, Down syndrome,
occur. A V-pattern phoria, exophoria in upgaze, and and anencephaly.116 Laxity of the superior oblique tendon
esophoria in downgaze often coexist. on traction testing has been associated with attenuated
The function of the trochlear nerve in the presence of superior oblique muscles on MRI.100 At the time of surgical
third nerve palsy can be determined by asking the patient correction for congenital trochlear nerve palsy, a structural
to look down. If cranial nerve IV is still functioning, the top abnormality in the superior oblique tendon (tendon laxity
of the globe will rotate in toward the nose. The examiner or anomalous insertion) has been found in 87% of cases.47
can watch a blood vessel on the conjunctiva to see the In 1905, Duane34 described patients with congenital
incyclotorsional movement. deficiency of abduction. These patients have limited or
Nuclear cranial nerve IV lesions are very rare. A lesion absent abduction with variable limitation of adduction.
of the trochlear nucleus would result in a contralateral Also, on adduction, the globe retracts, the lid fissure nar-
superior oblique palsy. Associated midbrain findings might rows, and occasionally the globe moves upward. Duane’s
include ipsilateral internuclear ophthalmoplegia113 from syndrome occurs more frequently in females than in males
median longitudinal fascicular damage, ipsilateral Horner’s and may be unilateral or bilateral; the left eye is affected
syndrome from sympathetic damage, or a contralateral more often than the right, and some cases are familial.
afferent pupil defect from damaged pretectal fibers in the Patients are usually asymptomatic and do not have diplopia,
superior colliculus.37 Etiologic mechanisms for a nuclear although they may be aware of their restricted abduction.
lesion could include ischemia, inflammation, trauma, There are three subtypes of Duane’s syndrome.57 Hotchkiss
tumor, or idiopathic causes. et al.54 reported a bilateral Duane’s syndrome with absent
Abducens nerve palsy will cause the affected eye to abducens nerve nuclei but innervation of the lateral rectus
deviate inward (secondary to the unopposed medial rec- by a branch of the oculomotor nerve.
tus), and the deviation will be more apparent in gaze to the Möbius87 described a 50-year-old man who presented
side of the palsy. with hand paralysis secondary to lead poisoning who also
happened to have congenital bilateral sixth and seventh
nerve palsies. The patient could converge and had learned
CONGENITAL DEFECTS to converge to look laterally with one eye at a time. These
congenital cranial nerve palsies are stationary from birth.
Congenital abnormality of ocular movements may be due Carr et al.21 reported on 29 cases of congenital facial
to defects of the nuclei of cranial nerves or of the periph- nerve palsy and 186 cases from the literature. Seventeen
eral nerve. The literature contains several reports of such cases had isolated facial nerve palsy and six had bilateral
defects,56 which include unilateral or bilateral absence of abducens nerve palsy, three of them with hypoglossal palsy,
the sixth cranial nerve, in isolation or associated with one with bilateral trochlear nerve palsy, and one with bilat-
abnormalities of other cranial nerves, as well as hypopla- eral oculomotor palsy. Carr et al.’s literature review
sia or aplasia of the brainstem nuclei. Of interest also are revealed facial nerve palsy associated most frequently with
a few reports of aberrant innervation of extraocular abducens palsy (68%), followed by glossopharyngeal
muscles, such as innervation of the lateral rectus muscle (28%), hypoglossal (26%), and oculomotor (20%) palsy.
by a branch of cranial nerve III in the absence of cranial Other abnormalities associated with Möbius’ syndrome
nerve VI. can include multiple cranial nerve palsies (cranial nerves
Congenital trochlear nerve palsy is often excluded from III, IV, XII, V, IX, and X); limb malformations (syndactyly,
large studies; however, it is the most common cause for polydactyly, brachydactyly, absent digits, talipes); malfor-
trochlear nerve palsy in children.53 Familial congenital mation of the orofacial structures (bifid uvula, micro-
fourth nerve palsy has been reported.5,45 Decompensation gnathia, ear deformities); epicanthal folds; anomalies of
of congenital trochlear nerve palsy can present with symp- the musculoskeletal system (Klippel-Feil anomaly, absent
toms in late childhood or adulthood. In fact, a decom- sternal head of the pectoralis major, rib defects, brachial
pensated congenital etiology should be suspected in all muscle defects); cardiac anomalies; and occasionally men-
adults who present with an apparently new-onset fourth tal retardation.
nerve palsy. Several characteristics distinguish congenital Facial diplegia with ophthalmoplegia, axonal peripheral
trochlear nerve palsy: long-standing head tilt (evident in neuropathy, and hypogonadism has been reported in six
old photos), large vertical fusional amplitudes (⬎4 to 5 cases, four males and two females.9 All of these cases
prism diopters), underaction of the ipsilateral superior had more extensive eye movement abnormalities than
oblique, and possible associated horizontal strabismus. were originally described by Möbius. The peripheral
1198 Diseases of the Peripheral Nervous System

neuropathy onset is late in childhood and is slowly pro- Minor head trauma is the most common (30%92) cause
gressive in half of the cases. Muscle biopsy has shown determined for acquired isolated trochlear nerve
neurogenic atrophy. Low testosterone and a normal palsy.17,20,55,66,69,71,127 The trochlear nerve is vulnerable to
response to gonadotropin-releasing hormone character- trauma because of its long course and its delicate structure,
ized the hypogonadotropic hypogonadism in the males. despite the protection of the overlying tentorium. Both
The etiology of this constellation of findings is unknown. trochlear nerves can be injured by traumatic compression
There does not appear to be any genetic cause. Several by the tentorium. Recent use of the fluid attenuation inver-
papers have proposed a posterior circulation vascular sion recovery (FLAIR) technique in MRI found a traumatic
cause, with subsequent necrosis and calcification in the fourth nerve palsy caused by a small subarachnoid hemor-
brainstem, in Möbius’ syndrome.30,73,91 rhage near the trochlear nerve.44 Another case of traumatic
Henderson48 noted only three reports of pathologic trochlear nerve palsy was caused by compression from an
studies in Möbius’ syndrome. These cases strongly support unsuspected tentorial vascular malformation.61 Transient
the view that the basis for the cranial nerve palsies is trochlear nerve palsy can occur after temporal lobectomy,
nuclear hypoplasia. The nerve roots of the affected cranial which may be because of manipulation above the tento-
nerves were either absent or sparsely developed, depend- rium.62 Other neurosurgical procedures (petroclival or cav-
ing on the degree of ganglion cell loss. The causes for this ernous sinus tumor surgery, aneurysm repair) can also
nuclear loss are obscure; only occasionally can a hereditary produce trochlear nerve palsy.65 Trauma to the trochlea has
factor be traced in Möbius’ syndrome or in other types of been reported after orbital penetrating injury, iatrogenic
congenital palsies except congenital ptosis. surgical trauma (sinus surgery), and blunt nonpenetrating
Congenital horizontal gaze palsy may be seen as an trauma resulting in superior oblique weakness.72 Other
isolated cranial nerve defect. It differs from the ocular orbital trauma can cause damage locally to the superior
palsy of Möbius’ syndrome in that usually no convergent oblique tendon, nerve or muscle.6,97 After cataract surgery
strabismus and no facial paralysis are present. Zweifach or retrobulbar anesthesia, paresis of a vertical muscle (usu-
and colleagues128 described five children with complete ally inferior rectus or superior rectus) can occur, which may
absence of abduction on attempted conjugate gaze to mimic superior oblique palsy.38
either side; four of these five children substituted conver- The frequent paralysis of the abducens nerve (15%) in
gence and cross-fixation for lateral eye movements. This trauma92 is related to several anatomic factors. The long
substitution phenomenon has been reported in both con- course along the basiocciput of the skull beneath the lateral
genital and acquired conjugate gaze paralysis.18 Because branches of the basilar artery, the firm dural attachment over
the sparing of vertical gaze associated with severe impair- the clivus, and arching over the ridge of the petrous bone at
ment of horizontal gaze is similar to that seen with approximately a 90-degree angle beneath the rigid petro-
acquired midline pontine lesions, a congenital defect in sphenoid ligament all predispose the abducens nerve to con-
this region is suggested. tusion and tearing injury. Fractures through the temporal
bone or through the posterior clinoids may injure the nerve
directly or may be associated with hemorrhage sufficient to
EFFECTS OF TRAUMA cause either unilateral or bilateral paralysis. Schneider and
Johnson102 have reported bilateral abducens palsies after
Trauma to the head frequently results in injury to cranial severe hyperextension injury to the head and fractures of the
nerves III, IV, and VI. Among 4278 cases of acquired ocu- cervical spinal column. The mechanism postulated by them
lar paralysis reviewed by Richards et al.,92 686 (16%) were was an upward and posterior displacement of the brain caus-
secondary to head trauma. ing avulsion of the abducens nerves under the rigid petro-
The oculomotor nerve is vulnerable to traumatic injury sphenoid ligaments.
at several sites. The study by Richards et al.92 found a 15% Holmes et al.,52 in a prospective review of 99 patients
incidence of oculomotor nerve palsy with head trauma. with acute traumatic sixth nerve palsy, found a recovery
The nerve is easily compressed between the rigid posterior rate of 71% at 6 months after onset. Complete sixth nerve
cerebral and superior cerebellar arteries and at the free palsy (inability to abduct past the midline) or bilateral palsy
edge of the reflected leaf of the tentorium. Trauma that has a poor prognosis and may require strabismus surgery.51
results in shearing of the dural attachments of the third
cranial nerve as it enters the cavernous sinus, as well as
Aberrant Regeneration of Cranial Nerve III
damage to the nerve in the cavernous sinus itself, is possi-
ble. Head injury associated with oculomotor nerve injury is As early as 1935, Bielschowsky13 described anomalous
usually also associated with loss of consciousness and skull synkinetic ocular and lid movements after injury to the
fracture.7 Hegde et al.46 reported a case after head trauma oculomotor nerve. The clinical findings in aberrant
of internal carotid dissection in the petrous portion with regeneration of the oculomotor nerve may consist of
resultant oculomotor nerve palsy. ptosis in primary gaze with lid retraction in downgaze
 Diseases of the Third, Fourth, and Sixth Cranial Nerves 1199

(pseudo-Graefe’s sign), elevation of the lid on adduction, Neoplasms involving the midbrain affect the nuclei and
limited vertical gaze with globe retraction on attempts at the intramedullary portion of the cranial nerves directly.
vertical gaze, adduction on attempted vertical gaze, and Examples of such tumors are pontine gliomas, medul-
pupil constriction on adduction or depression. Aberrant loblastomas, hemangiomas, and metastatic tumors.
regeneration of the oculomotor nerve occurs in approxi- Specific syndromes of the midbrain are discussed below
mately 50% of cases of congenital oculomotor nerve under Vascular Diseases and Aneurysms.
palsy.8 In 1883, Parinaud89 described lesions of the midbrain
Schatz et al.101 first described aberrant regeneration of that produced paralysis of conjugate upward gaze and con-
the oculomotor nerve without preceding nerve palsy or vergence. Later, Koerber et al.70 completed the clinical
history of trauma. They termed this entity primary aber- picture by describing retraction nystagmus, large pupils
rant regeneration. The entity causing the primary aberrant poorly reactive to light, and papilledema associated with a
regeneration in their patient was an intracavernous menin- tumor in the region of the pineal gland and posterior third
gioma. Since that publication, other intracavernous15 as ventricle. Bilateral superior oblique palsy, although usually
well as extracavernous etiologies have been identified for secondary to trauma, has also been described in dorsal
primary aberrant regeneration, including intracranial inter- midbrain neoplasms.11
nal carotid aneurysm,29 posterior communicating artery Brainstem glioma was the most common neoplasm
aneurysm,22,114 abetalipoproteinemia,26 trigeminal neuroma, found causing an acquired ocular cranial nerve palsy in
extracavernous meningioma, neurilemmoma, and asym- children in the study by Kodsi and Younge.69 Most often
metrical mamillary bodies.63 Rare cases of aberrant regen- the glioma presented with abducens nerve palsy (58.3%).
eration have been reported after midbrain stroke84 or from In a population-based study, Holmes et al.53 found a low
a microvascular etiology.10 incidence (8%) of tumors in pediatric ocular cranial nerve
Several theories have been advanced to explain aberrant palsies. None of their patients with a neoplasm presented
regeneration. The most commonly accepted theory proposes with the cranial nerve palsy in isolation.
that, after damage to the axons of the nerve, regeneration Tumors in the region of the cerebellar pontine angle
may occur with new axons developing from the severed ends may affect the ocular nerves. Acoustic neurinomas com-
of the uninjured axons. Sibony et al.104 used retrograde prise 8% of all primary intracranial tumors and account for
horseradish peroxidase transport through the superior rectus 40% of all tumors of the posterior fossa. Van Meter and
muscle and found that neurons innervating the superior colleagues112 studied 100 patients operated on for patho-
rectus, after oculomotor regeneration, originated from the logically confirmed acoustic neurinoma and found a low
subnuclei of the inferior rectus, medial rectus, inferior incidence (3%) of ocular nerve palsy (cranial nerve VI).
oblique, and superior rectus. Neoplasms in the region of the clivus affect the
Two other theories have been suggested to explain aber- abducens nerves early in their course. An example of such
rant regeneration, especially of the primary type. Ephaptic a neoplasm is the chordoma, a tumor derived from rem-
transmission is thought to occur when action potentials nants of the notochord. More frequently found in the
from demyelinated portions of the injured peripheral sacrococcygeal region, this tumor occasionally manifests as
nerve are transmitted to intact adjacent axons. This might an intracranial neoplasm. Intracranial chordomas account
explain reports of transient or evolving signs of synkinesis. for approximately 1% of all intracranial tumors and occur
Some reports of temporary oculomotor synkinesis, how- predominantly in young men. Cranial nerve VI is most
ever, have theorized that the incorrectly regenerated fibers often affected and is often the site of initial manifestation
are subsequently replaced with correctly regenerating of the tumor. Isolated oculomotor nerve palsy, isolated
fibers.105 Nuclear synaptic reorganization might also trochlear nerve palsy, and multiple cranial nerve palsies
account for aberrant regeneration.40,75,105 have also been reported with clivus chordomas and chon-
drosarcomas.115
Tumors of the pituitary gland can expand laterally into
NEOPLASMS the cavernous sinus and compress the cavernous sinus suf-
ficiently to cause paresis of the cranial nerves within it.
In a series by Richards et al.92 of 4176 cases of acquired Cranial nerve III, which lies within the superolateral wall
ocular palsies, 767 were due to neoplasm (18%). The of the sinus, is particularly likely to be compressed against
abducens nerve was involved in 413 cases, the oculomotor the rigid interclinoid ligament. It is the most frequently
nerve in 141, and the trochlear nerve in 28. The types of affected cranial nerve, although cranial nerves IV and VI as
neoplasm included meningioma, metastases, pituitary well as the ophthalmic branch of cranial nerve V may also
tumors, glioma (pontine and midbrain), chordoma, be involved. In a study by Hollenhorst and Younge50 of
nasopharyngeal tumors, other primary tumors, acoustic 1000 cases of pituitary tumor, 46 cases presented with ocu-
neuroma, multiple myeloma, squamous cell carcinoma, lar cranial nerve palsy: 24 with cranial nerve III palsy, 6
adenoid cystic carcinoma, and others. with cranial nerve VI palsy, 12 with multiple palsies of
1200 Diseases of the Peripheral Nervous System

cranial nerves III and IV or III and VI, and 2 with bilateral are rare. A recent case of presumed neuroma of the fourth
cranial nerve III palsy. nerve is illustrated in Figure 48–4.
A sudden hemorrhage within a pituitary tumor may Perineural spread of malignant tumors is a complication
result in precipitous loss of vision and ophthalmoplegia from cutaneous squamous cell carcinoma and rarely from
unilaterally or bilaterally (usually cranial nerve III, then basal cell carcinoma and melanoma. McNab and col-
VI).19 These symptoms are usually accompanied by severe leagues83 and Wilcsek and colleagues124 described perineural
headache in the classic “pituitary apoplexy.” In such cases, spread of squamous cell carcinoma through the orbit with
the prognosis for recovery of ocular muscle function is 67% of the patients presenting with ophthalmoplegia,
good after immediate surgical evacuation of the hemor- usually partial oculomotor nerve paresis at the onset.
rhagic tumor. Neurologic syndromes associated with carcinoma but
Cavernous sinus tumors usually present with multiple not resulting from metastatic lesions or direct involvement
cranial nerve palsies. The types of tumor involved are of the central nervous system can assume several forms
many: pituitary tumor, craniopharyngioma, meningioma, and involve any level of the nervous system. The Lambert-
metastatic lesions, nasopharyngeal tumors, and lymphoma, Eaton syndrome (LES) may occur and result in weakness
as well as aneurysms and infectious/inflammatory and fatigability of proximal limb muscles associated with
processes. Differentiating cavernous sinus involvement loss of tendon reflexes. Paralysis of the extraocular muscles
from superior orbital fissure involvement is difficult, may be seen as a part of this disorder. LES is associated
because clinically they are indistinguishable. with malignancy in approximately 70% of cases, most com-
The nasopharynx is a common site for neoplasms that monly with small cell lung carcinoma (SCLC). A presyn-
extend intracranially. Nasopharyngeal tumors may extend aptic calcium channel antibody has been identified in
into the cavernous sinus and affect the cranial nerve to the many of these cases and is a marker for paraneoplastic
extraocular muscles. The patients usually present with neurologic immunity.74 Paraneoplastic encephalomyelitis
nasal fullness/stuffiness, and nonspecific findings related can primarily affect the brainstem, leading to ophthalmo-
to the sinuses are found on scanning. plegia. Most of these cases are also associated with SCLC.
Intrinsic tumors of the ocular motor nerves, such as The antibody found in these cases is antineuronal nuclear
neurinoma,1,24 schwannoma,39a,59a,76 cavernous angioma,81,82 autoantibody, type 1 or anti-Hu.79

A B
FIGURE 48–4
Fourth nerve neuroma in a patient with long-standing fourth nerve palsy. No biopsy was obtained, and there were no
other symptoms. A, Magnetic resonance imaging (MRI) with gadolinium enhancement showing lesion along the course
of the fourth nerve. B, Coronal section MRI through the midbrain showing enhancing lesion along the course of the
fourth nerve (arrows).
 Diseases of the Third, Fourth, and Sixth Cranial Nerves 1201

Pseudotumor cerebri (idiopathic intracranial hyper- basilar artery occlusion. Excluding the 26 patients who
tension) is an entity with elevated intracranial pressure were comatose, they found 30 with cranial nerve IV, VI, and
without any intracranial mass lesion. Headache is the VII involvement, 22 with horizontal gaze paresis, 13 with
predominant symptom, with transient visual obscurations, oculomotor palsies, and 4 with vertical gaze palsy. Diplopia
disc edema, and diplopia occurring frequently. There are was the most common visual symptom in 51 episodes of
many cases of nonlocalizing abducens palsy associated with vertebral artery dissection described by Hicks et al.49
pseudotumor cerebri. Trochlear nerve palsy has also been Abducens nerve palsy was the most common abnormality,
reported.90,108 followed by skew deviation, cranial nerve III palsy, and
cranial nerve IV palsy.
The most common cause of sudden paralysis of cranial
VASCULAR DISEASES AND ANEURYSMS nerve III in an adult with headache and a dilated fixed
pupil is an aneurysm at the junction of the posterior com-
Vascular disease of the central or peripheral nervous sys- municating artery and the internal carotid artery. This is
tem is a frequent cause of acquired ocular palsy. Small especially true in women older than 40 years of age. The
arteries arising from the posterior cerebral or basilar artery clinical picture of oculomotor palsy from an aneurysm is
perfuse the brainstem nuclei of cranial nerves III, IV, and similar to that of one associated with diabetes except that
VI. These arteries provide a rich vascular network to the the pupil is only rarely normal when an aneurysm is the
brainstem, but this area lacks the great availability of underlying cause. Rucker94 observed only 4 patients with a
collateral circulation that is predominant in the anterior normal pupil in 114 cases of cranial nerve III palsy result-
circulation. Therefore, a vascular insult, ischemic or ing from aneurysms. An unruptured intracranial aneurysm
hemorrhagic, in this area often results in major clinical may present early in the course with an incomplete oculo-
symptoms of the oculomotor system. Atherosclerosis is an motor paresis.12
important factor in the cause of ophthalmoplegia. Aneurysms of the top of the basilar artery and the junc-
Weber122 stated that 50% of third cranial nerve palsies tion between the basilar artery and the superior cerebellar
occur in patients with hypertension and atherosclerosis. artery can also cause oculomotor nerve palsy.14,80
Vascular lesions may also be responsible for acute ocular Occasionally oculomotor nerve palsy associated with minor
palsy that is related to infectious or toxic disease. head trauma can be the first sign of the intracranial
Several clinical syndromes can pinpoint the exact aneurysm.117
anatomic location of the lesion in the midbrain. Trochlear nerve palsy caused by an intracerebral
Paramedian infarcts of the middle midbrain lead to aneurysm is rare,92 but there have been cases reported
nuclear third nerve palsy of a severe or complete nature.16 with superior cerebellar artery,2,27 posterior communicat-
Weber’s syndrome (ipsilateral oculomotor palsy with ing artery, posterior cerebral artery, basilar artery, and
contralateral hemiparesis) is the most common midbrain internal carotid artery3 aneurysms. Most of these cases
syndrome involving cranial nerve III, localizing laterally to had other associated findings: headache, nausea, or long-
the fascicle of the oculomotor nerve within the cerebral standing trochlear nerve palsy without evidence for a
peduncle. Benedikt’s syndrome (ipsilateral oculomotor congenital palsy.
palsy with contralateral tremor) localizes to the fascicle of Carotid-cavernous sinus fistula presents with engorged
the oculomotor nerve within the red nucleus and sub- arterialized blood vessels on the conjunctiva, retinal
stantia nigra.78 Claude’s syndrome includes ipsilateral venous engorgement, ocular bruit, and ophthalmoplegia
oculomotor palsy with contralateral ataxia, dysmetria, and (frequently abducens paresis).98,103 Posterior drainage of a
dysdiadochokinesia from a lesion of the oculomotor nerve carotid-cavernous fistula or a dural-sinus fistula may cause
fascicle, red nucleus, and brachium conjunctivum.78 oculomotor damage.86
Nothnagel described tumors of the quadrigeminal bodies The association of ocular palsies and diabetes mellitus is
causing unilateral or bilateral oculomotor palsy and ipsilat- well recognized.95 Rucker93,94 found cranial nerves III and
eral ataxia from involvement of the third nerve fascicles, VI to be about equally affected and cranial nerve IV less
the brachium conjunctivum, and the superior and inferior frequently affected. Sudden onset of ptosis and paralysis of
colliculi.78 the extraocular muscles supplied by cranial nerve III char-
Ocular palsies resulting from vertebrobasilar disease are acterize the acute oculomotor palsy associated with dia-
associated with other signs and symptoms of brainstem and betes. Initially there may be severe pain within or behind
cerebellar involvement; rarely a partial or complete oph- the orbit in the distribution of the ophthalmic division of
thalmoplegia may be the only evidence of vertebrobasilar cranial nerve V. The pupillomotor fibers within cranial
disease. Minor and associates85 reviewed 183 cases of ver- nerve III are frequently spared, although partial pupil
tebrobasilar disease and noted varying degrees of paralysis involvement can occur in up to one third of cases.58,59
of cranial nerves III, IV, and VI in 27% of patients. Ferbert Usually, recovery begins in a few weeks and is complete
et al.39 described 85 cases of angiographically proven within 6 to 8 weeks. In a study by Keane and Ahmadi,67
1202 Diseases of the Peripheral Nervous System

among 49 patients with diabetes with isolated third nerve INFECTIONS AND TOXINS
palsies, only 2% had brainstem localization.
In oculomotor nerves of diabetics who had not had a The literature contains many case reports of various
previous palsy, Smith and Dyck107 found microfascicula- infections, toxins, and inflammatory conditions that can
tions and a change in size distribution of myelinated fibers. produce oculomotor palsies, and the list includes
Demyelination with some loss of axons within the central mucormycosis, sarcoidosis, cysticercosis, botulism, tetany,
portion of the peripheral part of cranial nerve III has been and diphtheria. Paranasal sinus infections with spread to
the essential finding in three reports describing the the orbit or cavernous sinus may produce oculomotor
clinicopathologic features of oculomotor palsy in diabetes palsies, and though uncommon, are often associated with
mellitus. Dreyfus and co-workers33 noted a focal zone of an immunocompromised state, diabetes, or even chronic
destruction of myelin sheaths and axons within the intra- drug abuse, as in cocaine sniffing.42 Though less common
cavernous portion of the nerve. They were unable to find since the advent of effective antibiotics, Gradenigo’s syn-
any occluded vessels in the many sections they studied, but drome of a petrous abscess from chronic mastoid infection
concluded that the lesion was ischemic in origin and with spread to the posterior fossa can cause a sixth nerve
postulated that a nutrient vessel remote from the site of palsy. The occurrence of isolated trochlear nerve palsy can
fiber degeneration was occluded. The exact pathogenesis occur after cutaneous ophthalmic herpes zoster infection43
of the pain often associated with this disorder has yet to be or herpes zoster oticus.64
documented; ischemia within a sensory nerve in the area Meningitic processes, including bacterial, tuberculous,
of the cavernous sinus or dura may be a contributing herpes zoster, syphilis, lymphoma, cryptococcosis,99 neuro-
factor. Asbury and associates found a circumscribed patch borreliosis,88 Ehrlichia,23 and carcinomatous meningitis,
of demyelination within the intracavernous portion of the have all been associated with trochlear nerve palsies.
third cranial nerve.4 Its borders were sharply demarcated Meningismus, headache, other cranial nerve palsies, and
on the proximal edge and less distinct on the distal edge. A abnormal findings on examination of the cerebrospinal
paucity of wallerian degeneration distally and an absence fluid should help determine these entities.
of central chromatolysis in the cell bodies of the oculo- Drug therapy, particularly for neoplasms, can induce
motor nerve nucleus were notable histologic features. ophthalmoparesis, and the list of such drugs includes
Both findings are consistent with a demyelinating process vincristine, phenytoin, pancuronium,106 nemaline,126 and
and compatible with the rapid and complete recovery that doxepin overdosage.77 Botulinum poisoning can produce
ensues in most oculomotor palsies with diabetes. Weber ophthalmoplegia, particularly internal, with loss of accom-
and colleagues123 reported a similar demyelination with modation and mydriasis. Years ago diphtheria was noted to
some loss of central axons within the subarachnoid portion produce a selective internal ophthalmoplegia.
of cranial nerve III. Hyalinization of the intraneural arteri- Ocular palsies are more frequent with bacterial infec-
oles was evident, but again no occluded vessels were tions, particularly when the meninges are involved.
found. Impaired ocular movement was reported to be the most
All three studies of the pathologic changes in cranial frequent sign of cranial nerve dysfunction in 147 cases of
nerve III noted a relative sparing of the peripheral acute bacterial meningitis.31,32 Among that group were 36
fibers.4,33,123 Dreyfus and co-workers33 hypothesized that cases of ocular palsy, equally divided between cranial
the superficial position of the fine “parasympathetic” fibers nerves III and VI. The ocular palsies tended to be tran-
protected them from the effects of ischemia. The same sient and to disappear shortly after recovery from the
argument is used for their susceptibility to injury from meningitis. This result contrasts with the damage often
external pressure. sustained by cranial nerve VIII; permanent hearing loss is
Also relevant to the ischemic theory for diabetic an important sequela of acute bacterial meningitis.
neuropathy is the study by Dyck and collaborators35 of the Whether the conditions discussed next belong in this
peripheral nerves of patients with necrotizing angiopathy section on Infections and Toxins remains to be seen. The
and neuropathy. Similar central fascicular fiber degener- Tolosa-Hunt syndrome, in which a granulomatous inflam-
ation was noted, with only an occasional occluded vessel in matory infiltration of the cavernous sinus region can produce
the vicinity of the fiber degeneration. They postulated a painful ophthalmoplegia, is really very rare. There are
that areas within the peripheral nerves examined (the literally over 100 causes of painful ophthalmoplegia, and the
mid-upper arm and midthigh levels) represented water- Tolosa-Hunt syndrome needs to be a diagnosis of exclusion
shed zones of poor perfusion. Under these conditions, the for that reason.111
ischemic effects would be greatest within the most remote The Miller Fisher syndrome, characterized by progres-
portion of a region supplied by a specific epineurial vessel sive ophthalmoplegia, ataxia, and areflexia, usually follows
or vessels, and the typical picture of an infarct with soften- an upper respiratory syndrome, and has a benign course
ing and necrosis would not be seen even though the under- with complete recovery in 3 to 6 weeks.41 In some variants
lying mechanism may be occlusive vascular disease. of Guillain-Barré syndrome, diplopia may ensue as a result
 Diseases of the Third, Fourth, and Sixth Cranial Nerves 1203

of an ocular palsy, but more often the facial nerve is 16. Bogousslavsky, J., Maeder, P., Regli, F., and Meuli, R.: Pure
involved. Multiple sclerosis patients frequently have midbrain infarction: clinical syndromes, MRI, and etiologic
diplopia, more often as a result of internuclear ophthalmo- patterns. Neurology 44:2032, 1994.
plegia, but approximately 5% have ocular palsies.60 17. Burgerman, R. S., Wolf, A. L., Kelman, S. E., et al.:
Traumatic trochlear nerve palsy diagnosed by magnetic res-
Sarcoidosis affects the facial nerve much more commonly
onance imaging: case report and review of the literature.
than other cranial nerves. In 118 cases reviewed by
Neurosurgery 25:978, 1989.
Colover,28 the facial nerve was involved in 59 cases; there 18. Burian, H. M., VanAllen, M. W., Sexton, R. R., and Baller,
were only 6 with ptosis, 3 with oculomotor paralysis, and 1 R. S.: Substitution phenomena in congenital and acquired
with trochlear involvement. Recovery is usually complete. supranuclear disorders of eye movement. Trans. Am. Acad.
Ophthalmol. 69:1105, 1965.
19. Cardoso, E. R., and Peterson, E. W.: Pituitary apoplexy:
a review. Neurosurgery 14:363, 1984.
REFERENCES 20. Carlow, T. J.: Paresis of cranial nerves III, IV, and VI: clin-
ical manifestations and differential diagnosis. Bull. Soc.
1. Abe, T., Iwata, T., Shimazu, M., and Matsumoto, K.: Belge Ophtalmol. 237:285, 1989.
Trochlear nerve neurinoma associated with a giant throm- 21. Carr, M., Ross, D., and Zuker, R.: Cranial nerve defects in
bosed dissecting aneurysm of the contralateral vertebral congenital facial palsy. J. Otolaryngol. 26:80, 1997.
artery. Surg. Neurol. 42:438, 1994. 22. Carrasco, J. R., Savino, P. J., and Bilyk, J. R.: Primary aberrant
2. Agostinis, C., Caverni, L., Moschini, L., et al.: Paralysis of oculomotor nerve regeneration from a posterior communi-
fourth cranial nerve due to superior cerebellar artery cating artery aneurysm. Arch. Ophthalmol. 120:663, 2002.
aneurysm. Neurology 42:457, 1992. 23. Carter, N., and Miller, N. R.: Fourth nerve palsy caused by
3. Arruga, J., DeRivas, P., Espinet, H. L., and Conesa, G.: Ehrlichia chaffeensis. J. Neuroophthalmol. 17:47, 1997.
Chronic isolated trochlear nerve palsy produced by intra- 24. Celli, P., Ferrante, L., Acqui, M., et al.: Neurinoma of the
cavernous internal carotid artery aneurysm. J. Clin. third, fourth and sixth cranial nerves: a survey and report of
Neuroophthalmol. 11:104, 1991. a new fourth nerve case. Surg. Neurol. 38:216, 1992.
4. Asbury, A. K., Aldredge, H., Hershberg, R., and Fisher, C. M.: 25. Chan, T. K., and Demer, J. L.: Clinical features of congenital
Oculomotor palsy in diabetes mellitus. Brain 93:555, absence of the superior oblique muscle as demonstrated by
1970. orbital imaging. J. AAPOS 3:143, 1999.
5. Astle, W. F., and Rosenbaum, A. L.: Familial congenital 26. Cohen, D. A., Bosley, T. M., Savino, P. J., et al.: Primary
fourth cranial nerve palsy. Arch. Ophthalmol. 103:532, 1985. aberrant regeneration of the oculomotor nerve: occurrence
6. Bachynski, B. N., and Flynn, J. T.: Direct trauma to the in a patient with abetalipoproteinemia. Arch. Neurol.
superior oblique tendon following penetrating injuries of 42:821, 1985.
the upper eyelid. Arch. Ophthalmol. 103:1510, 1985. 27. Collins, T. E., Mehalic, T. F., White, T. K., and Pezzuti, R. T.:
7. Balcer, L. J., Galetta, S. L., Bagley, L. J., et al.: Localization Trochlear nerve palsy as the sole initial sign of an aneurysm
of traumatic oculomotor nerve palsy to the midbrain exit of the superior cerebellar artery. Neurosurgery 30:258, 1992.
site by MRI. Am. J. Ophthalmol. 22:437, 1996. 28. Colover, J.: Sarcoidosis with involvement of nervous system.
8. Balkan, R., and Hoyt, C. S.: Associated neurologic abnor- Brain 71:451, 1948.
malities in congenital third nerve palsies. Am. J. Ophthalmol. 29. Cox, T. A., Wurster, J. B., and Godfrey, W. A.: Primary aber-
97:315, 1984. rant oculomotor regeneration due to intracranial aneurysm.
9. Baraitser, M., and Rudge, P.: Moebius syndrome, an axonal Arch. Neurol. 36:570, 1979.
neuropathy and hypogonadism. Clin. Dysmorphol. 5:351, 30. D’Cruz, O. F., Swisher, C. N., Jaradeh, S., et al.: Möbius
1996. syndrome: evidence for a vascular etiology. J. Child Neurol.
10. Barr, D., Kupersmith, M., Turbin, R., et al.: Synkinesis 8:260, 1993.
following diabetic third nerve palsy. Arch. Ophthalmol. 31. Dodge, P. R., and Swartz, M. N.: Bacterial meningitis: a
118:132, 2000. review of selected aspects. I. General clinical features, spe-
11. Barr, D. B., McFadzean, R. M., Hadley, D., et al.: Acquired cial problems and unusual meningeal reactions mimicking
bilateral superior oblique palsy: a localizing sign in the bacterial meningitis. N. Engl. J. Med. 272:898, 1965.
dorsal midbrain. Eur. J. Ophthalmol. 7:271, 1997. 32. Dodge, P. R., and Swartz, M. N.: Bacterial meningitis: a
12. Bartleson, J. D., Trautmann, J. C., and Sundt, T. M. Jr.: review of selected aspects. II. Special neurologic problems,
Minimal oculomotor nerve paresis secondary to unrup- postmeningitis complication and clinicopathological corre-
tured intracranial aneurysm. Arch. Neurol. 43:1015, 1986. lations. N. Engl. J. Med. 272:954, 1003, 1965.
13. Bielschowsky, A.: Lectures on motor anomalies of the eyes. 33. Dreyfus, P. M., Hakim, S., and Adams, R. D.: Diabetic oph-
II. Paralysis of individual eye muscles. Arch. Ophthalmol. thalmoplegia: report of case, with postmortem study and
13:33, 1935. comments on vascular supply of human oculomotor nerve.
14. Boccardo, M., Ruelle, A., and Banchero, M. A.: Isolated Arch. Neurol. Psychiatry 77:337, 1957.
oculomotor palsy caused by aneurysm of the basilar artery 34. Duane, A.: Congenital deficiency of abduction, associated
bifurcation. J. Neurol. 233:61, 1986. with impairment of adduction, retraction movements, con-
15. Boghen, D., Chartrand, J.-P., Laflamme, P., et al.: Primary traction of the palpebral fissure and oblique movements of
aberrant third nerve regeneration. Ann. Neurol. 6:415, 1979. the eye. Arch. Ophthalmol. 34:133, 1905.
1204 Diseases of the Peripheral Nervous System

35. Dyck, P. J., Conn, D. L., and Okazaki, H.: Necrotizing Transsphenoidal Microsurgery. New York, Appleton-
angiopathic neuropathy: three-dimensional morphology of Century-Crofts, p. 111, 1982.
fiber degeneration related to sites of occluded vessels. 51. Holmes, J. M., Beck, R. W., Kip, K. E., et al.: Predictors of
Mayo Clin. Proc. 47:461, 1972. nonrecovery in acute traumatic sixth nerve palsy and par-
36. Dyck, P. J., Gutrecht, J. A., Bastron, J. A., et al.: Histologic esis. Ophthalmology 108:1457, 2001.
and teased-fiber measurements of sural nerve in disorders 52. Holmes, J. M., Droste, P. J., and Beck, R. W.: The natural
of lower motor and primary sensory neurons. Mayo Clin. history of acute traumatic sixth nerve palsy or paresis.
Proc. 43:81, 1968. J. AAPOS 2:265, 1998.
37. Eliot, D., Cunningham, E. T. Jr., and Miller, N. R.: Fourth 53. Holmes, J. M., Mutyala, S., Maus, T., et al.: Pediatric third,
nerve paresis and ipsilateral relative afferent pupillary defect fourth and sixth nerve palsies: a population-based study.
without visual sensory disturbance: a sign of contralateral dor- Am. J. Ophthalmol. 127:388, 1999.
sal midbrain disease. J. Clin. Neuroophthalmol. 11:169, 1991. 54. Hotchkiss, M. G., Miller, N. R., Clark, A. W., and Green, W. R.:
38. Esswein, M. B., and von Noorden, G. K.: Paresis of a vertical Bilateral Duane’s retraction syndrome. a clinical-pathologic
rectus muscle after cataract extraction. Am. J. Ophthalmol. case report. Arch. Ophthalmol. 98:870, 1980.
116:424, 1993 55. Hoya, K., and Kirino, T.: Traumatic trochlear nerve palsy
39. Ferbert, A., Bruckmann, H., and Drummen, R.: Clinical following minor occipital impact. Neurol. Med. Chir.
features of proven basilar artery occlusion. Stroke 21:1135, 40:358, 2000.
1990. 56. Hoyt, W. F., and Nachtigäller, H.: Anomalies of ocular
39a. Feinberg, A. S., and Newman, N. J.: Schwannoma in patients motor nerves: neuroanatomic correlates of paradoxical
with isolated trochlear nerve palsy. Am. J. Ophthalmol. innervation of Duane’s syndrome and related congenital
127:183, 1999. ocular motor disorders. Am. J. Ophthalmol. 60:443, 1965.
40. Fernandez, E., Pallini, R., Lauretti, L., et al.: Motonuclear 57. Huber, A.: Electrophysiology of the retraction syndromes.
changes after cranial nerve injury and regeneration. Arch. Br. J. Ophthalmol. 58:293,1974.
Ital. Biol. 135:343, 1997. 58. Ing, E. B., Leavitt, J. A., and Younge, B. R.: Incidence of
41. Fisher, M.: An unusual variant of acute idiopathic polyneur- pupillary involvement in ischemic oculomotor nerve
itis (syndrome of ophthalmoplegia, ataxia, and areflexia). palsies. Ann. Ophthalmol. 32:90, 2000.
N. Engl. J. Med. 255:57, 1956. 59. Jacobson, D. M.: Pupil involvement in patents with dia-
42. Goldberg, R. A., Weisman, J. S., McFarland, J. E., et al.: betes-associated oculomotor nerve palsy. Arch.
Orbital inflammation and optic neuropathies associated Ophthalmol. 116:723, 1998.
with chronic sinusitis from intranasal cocaine abuse: possi- 59a. Jackowski, A., Weiner, G., and O’Reilly, G.: Trochlear nerve
ble role of contiguous inflammation. Arch. Ophthalmol. schwannomas: a case report and literature review. Br. J.
107:831, 1989. Neurosurg. 8:219, 1994.
43. Grimson, B. G., and Glaser, J. S.: Isolated trochlear nerve 60. Jacobson, D. M., Moster, M. L., Eggenberger, E. R., et al.:
palsies in herpes zoster ophthalmicus. Arch. Ophthalmol. Isolated trochlear nerve palsy in patients with multiple scle-
96:1233, 1978. rosis. Neurology 53:877, 1999.
44. Hara, N., Kan, S., and Simiziu, K.: Localization of post- 61. Jacobson, D. M., Warner, J. J., Choucair, A. K., and Ptacek, L.
traumatic trochlear nerve palsy associated with hemorrhage J.: Trochlear nerve palsy following minor head trauma: a sign
at the subarachnoid space by magnetic resonance imaging. of structural disorder. J. Clin. Neuroophthalmol. 8:263, 1988.
Am. J. Ophthalmol. 132:443, 2001. 62. Jacobson, D. M., Warner, J. J., and Ruggles, K. H.:
45. Harris, D. J., Memmen, J. E., Katz, N. N. K., and Parks, M. M.: Transient trochlear nerve palsy following anterior temporal
Familial congenital superior oblique palsy. Ophthalmology lobectomy for epilepsy. Neurology 45:1465, 1995.
93:88, 1986. 63. Johnson, L. N., Kamper, C. A., Hepler, R. S., et al.: Primary
46. Hegde V., Coutinho, C. M. A., and Mitchell, J. D.: aberrant regeneration of the oculomotor nerve from pre-
Dissection of the intracranial internal carotid artery pro- sumed extracavernous neurilemoma, meningioma, and asym-
ducing isolated oculomotor nerve palsy with sparing of metric mammillary body. Neuroophthalmology 9:227, 1989.
pupil. Acta Neurol. Scand. 105:330, 2002. 64. Keane, J. R.: Delayed trochlear nerve palsy in a case of
47. Helveston, E. M., Krach, D., Plager, D. A., and Ellis, F. D.: zoster oticus. Arch. Ophthalmol. 93:382, 1975.
A new classification of superior oblique palsy based on con- 65. Keane, J. R.: Trochlear nerve pareses with brainstem
genital variations in the tendon. Ophthalmology 99:1609, 1992. lesions. J. Clin. Neuroophthalmol. 6:242, 1986.
48. Henderson, J. L.: The congenital facial diplegia syndrome: 66. Keane, J. R.: Fourth nerve palsy: historical review and study
clinical features, pathology and aetiology; a review of sixty- of 215 patients. Neurology 43:2439, 1993.
one cases. Brain 62:381, 1939. 67. Keane, J. R., and Ahmadi, J.: Most diabetic third nerve
49. Hicks, P. A., Leavitt, J. A., and Mokri, B.: Ophthalmic mani- palsies are peripheral. Neurology 51:1510, 1998.
festations of vertebral artery dissection. Ophthalmology 68. Kerr, F. W. L., and Hollowell, O. W.: Location of pupillo-
101:1786–92, 1994. motor and accommodation fibres in the oculomotor nerve:
50. Hollenhorst, R. W., and Younge, B. R.: Ocular manifest- experimental observations of paralytic mydriasis. J. Neurol.
ations produced by adenomas of the pituitary gland: analysis Neurosurg. Psychiatry 27:473, 1964.
of 1000 cases. In Laws, E. R. Jr., Randall, R. V., Kern, E. B., 69. Kodsi, S. R., and Younge, B. R.: Acquired oculomotor,
and Abboud, C. F. (eds.): Management of Pituitary trochlear and abducent cranial nerve palsies in pediatric
Adenomas and Related Lesions with Emphasis on patients. Am. J. Ophthalmol. 114:568, 1992.
 Diseases of the Third, Fourth, and Sixth Cranial Nerves 1205

70. Koerber, H., Salus, R., and Elschnig (Cited in Wold, J. K.: 92. Richards, B. W., Jones, F. R. Jr., and Younge, B. R.: Causes
The Classical Brain Stem Syndromes. Springfield, IL, and prognosis in 4,278 cases of paralysis of the oculomotor,
Charles C Thomas, p. 157, 1971.) trochlear, and abducens cranial nerves. Am. J. Ophthalmol.
71. Lavin, P. J. M., and Troost, B. T.: Traumatic fourth nerve 113:489, 1992.
palsy. Arch. Neurol. 41:679, 1984. 93. Rucker, C. W.: Paralysis of the third, fourth and sixth cranial
72. Legge, R. H., Hedges, T. R. III, Anderson, M., and Reese, P. D.: nerves. Am. J. Ophthalmol. 46:787, 1958.
Hypertropia following trochlear trauma. J. Pediatr. 94. Rucker, C. W.: The causes of paralysis of the third, fourth
Ophthalmol. Strabismus 29:163, 1992. and sixth cranial nerves. Am. J. Ophthalmol. 61:1293, 1966.
73. Lengyel, D., Zaunbauer, W., Keller, E., and Gottlob, I.: 95. Rush, J. A.: Extraocular muscle palsies in diabetes mellitus.
Möbius syndrome: MRI findings in three cases. J. Pediatr. Int. Ophthalmol. Clin. 24:155, 1984.
Ophthalmol. Strabismus 37:305, 2000. 96. Rush, J. A., and Younge, B. R.: Paralysis of cranial nerves
74. Lennon, V. A., Kryzer, T. J., Griesmann, G. E., et al.: III, IV, and VI: cause and prognosis in 1,000 cases. Arch.
Calcium-channel antibodies in the Lambert-Eaton syn- Ophthalmol. 99:76, 1981.
drome and other paraneoplastic syndromes. N. Engl. J. Med. 97. Ruttum, M. S., and Harris, G. J.: Orbital blowout fracture
332:1467, 1995. with ipsilateral fourth nerve palsy. Am. J. Ophthalmol.
75. Lepore, F. E., and Glaser, J. S.: Misdirection revisited: a 100:343, 1985.
critical appraisal of acquired oculomotor nerve synkinesis. 98. Sabates, F. N. Jr., Tsai, F., Sabates, N. R., and Blitsein, B.:
Arch. Ophthalmol. 98:2206, 1980. Transient cranial nerve palsies after cavernous sinus fistula
76. Leunda, G., Vaquero, J., Cabezudo, J., et al.: Schwannoma embolization. Am. J. Ophthalmol. 111:771, 1991.
of the oculomotor nerves. J. Neurosurg. 57:563, 1982. 99. Sadun, F., DeNegri, A. M., Santopadre, P., and Pezzi, P. P.:
77. LeWitt, P. A.: Transient ophthalmoparesis with doxepin Bilateral trochlear nerve palsy associated with cryptococcal
overdosage. Ann. Neurol. 9:618, 1981. meningitis in human immunodeficiency virus infection.
78. Liu, G. T., Crenner, C. W., Logigian, E. L., et al.: Midbrain J. Neuroophthalmol. 19:118, 1999.
syndromes of Benedikt, Claude and Nothnagel. Neurology 100. Sato, M.: Magnetic resonance imaging and tendon anomaly
42:1820, 1992. associated with congenital superior oblique palsy. Am.
79. Lucchinetti, C. F., Kimmel, D. W., and Lennon, V. A.: Clinical, J. Ophthalmol. 127:379, 1999.
oncological and serological profiles of patients seropositive for 101. Schatz, N. J., Savino, P. J., and Corbett, J. C.: Primary aber-
type 1 anti-neuronal nuclear antibody (ANNA-1, a.k.a. “anti- rant oculomotor regeneration: a sign of intracavernous
Hu”). Neurology 44(Suppl. 2):A156, 1994. meningioma. Arch. Neurol. 34:29, 1977.
80. Lustbader, J. M., and Miller, N. R.: Painless, pupil-sparing 102. Schneider, R. C., and Johnson, F. D.: Bilateral traumatic
but otherwise complete oculomotor nerve paresis caused by abducens palsy. J. Neurosurg. 34:33, 1971.
basilar artery aneurysm. Arch. Ophthalmol. 106:583, 1988. 103. Selky, A. K., and Purvin, V. A.: Isolated trochlear nerve
81. Matias-Guiu, X., Alejo, M., Sole, T., et al.: Cavernous palsy secondary to dural carotid-cavernous sinus fistula.
angiomas of the cranial nerves. J. Neurosurg. 73:620, 1990. J. Neuroophthalmol. 14:52, 1994.
82. Maruoka, N., Yamakawa, Y., and Shimauchi, M.: Cavernous 104. Sibony, P. A., Evinger, C., and Lessell, S.: Retrograde
hemangioma of the optic nerve. J. Neurosurg. 69:92, 1988. horseradish peroxidase transport after oculomotor nerve
83. McNab, A. A., Francis, I. C., Benger, R., and Crompton, J. L.: injury. Invest. Ophthalmol. Vis. Sci. 27:975, 1986.
Perineural spread of cutaneous squamous cell carcinoma 105. Sibony, P. A., and Lessell, S.: Transient oculomotor syn-
via the orbit. Ophthalmology 104:1457, 1997. kinesis in temporal arteritis. Arch. Neurol. 41:87, 1984.
84. Messé, S. R., Shin, R. K., Liu, G. T., et al.: Oculomotor syn- 106. Sitwell, L. D., Weinshenker, B. G., Monpetit, V., and Reid, D.:
kinesis following a midbrain stroke. Neurology 57:1106, 2001. Complete ophthalmoplegia as a complication of acute
85. Minor, R. H., Kearns, T. P., Millikan, C. H., et al.: Ocular corticosteroid- and pancuronium-associated myopathy.
manifestations of occlusive disease of the vertebral-basilar Neurology 42:939, 1992.
arterial system. Arch. Ophthalmol. 62:84, 1959. 107. Smith, B. E., and Dyck, P. J.: Subclinical histopathological
86. Miyachi, S., Negoro, M., Handa, T., et al.: Dural carotid changes in the oculomotor nerve in diabetes mellitus. Ann.
cavernous sinus fistula presenting as isolated oculomotor Neurol. 32:376, 1992.
nerve palsy. Surg. Neurol. 39:105, 1993. 108. Speer, C., Pearlman, J., Phillips, P. H., et al.: Fourth cranial
87. Möbius, P. J.: Ueber angeborene doppelseitige Abducens- nerve palsy in pediatric patients with pseudotumor cerebri.
Facialis-Lähmung. Munch. Med. Wochenschr. 35:91, 1888. Am. J. Ophthalmol. 127:236, 1999.
88. Müller, D., Neubauer, B. A., Waltz, S., and Stephani, U.: 109. Sunderland, S., and Hughes, E. S. R.: The pupilloconstrictor
Neuroborreliosis and isolated trochlear palsy. Eur. J. Paediatr. pathway and the nerves to the ocular muscles in man. Brain
Neurol. 2:275, 1998. 69:301, 1946.
89. Parinaud, M. H.: Paralysie des mouvements associes des 110. Tekdemir, I., Tuccar, E., Cubuk, H. E., et al.: Branches of the
yeux. Arch. Neurol. (Paris) 5:145, 1883. intracavernous internal carotid artery and the blood supply of
90. Patton, N., Beatty, S., and Lloyd, I. C.: Bilateral sixth and the intracavernous cranial nerves. Anat. Anz. 180:343, 1998.
fourth cranial nerve palsies in idiopathic intracranial hyper- 111. Thomas, J. E., and Yoss, R. E.: The parasellar syndrome: prob-
tension. J. R. Soc. Med. 93:80, 2000. lems in determining etiology. Mayo Clin. Proc. 45:617, 1970.
91. Pedraza, S., Gamez, J., Rovira, A., et al.: MRI findings in 112. Van Meter, W. S., Younge, B. R., and Harner, S. G.:
Möbius syndrome: correlation with clinical features. Ophthalmic manifestations of acoustic neurinoma.
Neurology 55:1058, 2000. Ophthalmology 90:917, 1983.
1206 Diseases of the Peripheral Nervous System

113. Vanooteghem, P., Dehaene, I., Van Zandycke, M., and 121. Warwick, R.: Oculomotor organisation. Ann. R. Coll. Surg.
Casselman, J.: Combined trochlear nerve palsy and inter- Engl. 19:36, 1956.
nuclear ophthalmoplegia. Arch. Neurol. 49:108, 1992. 122. Weber, R. B.: Cranial neuropathies and diabetes [letter].
114. Varma, R., and Miller, N. R.: Primary oculomotor nerve Lancet 1:645, 1971.
synkinesis caused by an extracavernous intradural 123. Weber, R. B., Daroff, R. B., and Mackey, E. A.: Pathology of
aneurysm. Am. J. Ophthalmol. 118:83, 1994. oculomotor nerve palsy in diabetics. Neurology 20:835, 1970.
115. Volpe, N. J., Liebsch, N. J., Munzenrider, J. E., and Lessell, S.: 124. Wilcsek, G. A., Francis, I. C., Egan, C. A., et al.: Superior
Neuro-ophthalmologic findings in chordoma and chon- oblique palsy in a patient with a history of perineural
drosarcoma of the skull base. Am. J. Ophthalmol. 115:97, spread from a periorbital squamous cell carcinoma.
1993. J. Neuroophthalmol. 20:240, 2000.
116. Wallace, D. K., and von Noorden, G. K.: Clinical character- 125. Wolff, E.: Anatomy of the Eye and Orbit: Including the
istics and surgical management of congenital absence of the Central Connections, Development, and Comparative
superior oblique tendon. Am. J. Ophthalmol. 118:63, 1994. Anatomy of the Visual Apparatus, 6th ed. (revised by Last,
117. Walter, K. A., Newman, N. J., and Lessell, S.: Oculomotor R. J.). London, H. K. Lewis & Company, pp. 283, 286, 1968.
palsy from minor head trauma: initial sign of intracranial 126. Wright, R. A., Plant, G. T., Landon, D. N., Morgan-
aneurysm. Neurology 44:148, 1994. Hughes, J. A.: Nemaline myopathy: an unusual cause of
118. Warwick, R.: A study of retrograde degeneration in the ophthalmoparesis. J. Neuroophthalmol. 17:39, 1997.
oculomotor nucleus of the rhesus monkey, with a note on a 127. Younge, B. R., and Sutula, F.: Analysis of trochlear nerve
method of recording its distribution. Brain 73:532, 1950. palsies: diagnosis, etiology and treatment. Mayo Clin. Proc.
119. Warwick, R.: Representation of the extra-ocular muscles in 52:11, 1977.
the oculomotor nuclei on the monkey. J. Comp. Neurol. 128. Zweifach, P. H., Walton, D. S., and Brown, R. H.: Isolated
98:449, 1953. congenital horizontal gaze paralysis: occurrence of the near
120. Warwick, R.: The ocular parasympathetic nerve supply and reflex and ocular retraction on attempted lateral gaze. Arch.
its mesencephalic sources. J. Anat. 88:71, 1954. Ophthalmol. 81:345, 1969.