13 Ocular motor disorders

A detailed description of the neural control of eye movements and their disorders can be found in the excellent monograph by Leigh and Zee (2006).

Each eye is rotated by six muscles: four recti and two obliques. It should be noted that the actions of the muscles are dependent on the starting position of the eye. For example, the superior rectus, because of the anatomy of its insertion into the sclera, acts as a pure elevator only when the globe is abducted by 23 deg. With increasing adduction of the eye from this position, the superior rectus acts more as an intorter and less as an elevator. Similarly, the superior oblique acts purely as a depressor only when the eye is adducted, and more as an intorter with increasing abduction of the eye. The primary and secondary actions of the different extraocular muscles are shown in Table 13.1.

The other important feature is that the yoke pair of muscles from each eye, for instance right medial rectus and left lateral rectus, or left superior rectus and right inferior oblique, receive equal innervation so that eye movements are conjugate: Hering’s law of motor correspondence. It should be noted that the fixating eye determines the innervational input to both eyes. This is of importance in the assessment of the cover test, and in the interpretation of investigations such as the Hess screen test.

It is first essential to decide whether the patient is complaining of diplopia due to a disparity in retinal stimulation between the two eyes, that is binocular diplopia, or more rarely when it is present in one eye only, monocular diplopia (Shaunak et al. 1997). Monocular diplopia occurs, with few exceptions, when there are abnormalities of the ocular refractive surfaces and media, producing multiple overlapping images on the retina. The commonest cause is myopic astigmatism, but monocular diplopia may occur in early cataracts, especially under conditions of dim illumination. Other causes include abnormalities of the cornea and iris, foreign bodies in the aqueous or vitreous humour, retinal disease, occipital cortex pathology, and psychogenic causes.

If the diplopia is alleviated by covering one eye a systematic approach to evaluation is required. As well as determining the nature of the separation of the two images and the direction of maximal separation, enquiries as to the presence of a family history of strabismus, or a childhood history of orthoptic treatment should be made. If the eyes are misaligned, it should be ascertained at an early stage if one is dealing with a non-comitant or comitant strabismus; the degree of misalignment varies with gaze position in the first, but does not vary with gaze position in the second. Non-comitance suggests a recent paretic or restrictive aetiology. Comitance is characteristic of childhood strabismus, and diplopia in such circumstances is usually due to decompensation of a long-standing phoria, a deviation of the visual axes when only one eye is viewing. Normally this is kept in check by fusional mechanisms, a latent deviation. The term tropia as used later refers to a manifest deviation of the visual axes when both eyes are viewing, which is not kept in check by fusion.

Patients with diplopia may adopt a compensatory head posture, and the position of the chin, head, and face should therefore be carefully observed. The purpose of the abnormal head posture is to turn the eyes as far as possible from the field of action of the weak muscle. Hence, if one of the muscles that mediates conjugate gaze to the right is underacting, the face will be turned to the right. Underaction of the superior and inferior recti, which act primarily to move the eyes in the vertical plane, is compensated by head flexion and extension respectively. Torsional diplopia usually arises from underaction of the superior and inferior oblique muscles, and patients with this symptom often tilt their head towards the shoulder opposite to that of the weak muscle.

In the cover/uncover test the patient, wearing appropriate refractive correction, is asked to fixate a distant target such as a letter on the Snellen chart, with the eyes in the primary position, repeating the test in the nine cardinal positions of gaze and with near fixation (Fig. 13.1). For each position in turn each eye is covered and then uncovered and initially the movements of the uncovered eye are observed. Cover tests rely on the fact that foveation occurs in an eye that is forced to fixate. If the retinal image was not directed on to the fovea before the eye took up fixation, a movement of redress will be noted as the eye fixates, which gives an indication of the degree of misalignment of the visual axes. If the uncovered eye moves to take up fixation, it can be assumed that under binocular viewing conditions the eye was not aligned with fixation, and a manifest deviation was present: a tropia. Inward movement of the uncovered eye indicates an exotropia, and an outward movement an esotropia. A vertical deviation may be either a hypotropia or a hypertropia, depending on whether the eye moves up or down respectively. The examiner should determine whether the tropia is comitant or non-comitant by seeing if the magnitude of the deviation varies with the position of the eye. If no tropia is present, and the uncovered eye is observed to

assume fixation just after it is uncovered, a latent deviation or heterophoria is present. Depending on the direction of the deviation this may be classified as an exophoria, esophoria, hypophoria, or a hyperphoria. The test is then repeated, and the same observations made while covering the other eye. It should be noted that the convention is that if there is a vertical deviation of the eyes, the higher of the two is referred to as hypertropic/hyperphoric, regardless of which eye is at fault.

The alternate cover test is more dissociating than the cover/uncover test, and is used to fully dissociate the eyes and show the maximal deviation. While the patient fixates a target the occluder is quickly switched from eye to eye to prevent binocular viewing, allowing sufficient time for the eyes to settle in their new position after each transfer. The test should be performed in the nine cardinal positions of gaze to determine the direction of gaze that elicits the maximal direction, the eye in which fixation in that field of gaze causes the maximal deviation. Whilst ensuring that the patient is never allowed to regain fixation during transfer of the occluder, the examiner notes the movement of the uncovered eye as the occluder is transferred from one eye to the other. Movement of the uncovered eye may indicate either a heterotropia or a heterophoria, and the alternate cover test will not differentiate between the two. The cover/uncover test should therefore be performed first to determine if a tropia is present.

When there is a vertical deviation of the visual axes the hypertropic ‘higher’ eye always gives rise to the lower image. This may be due either to a paresis of the depressor muscles of the hypertropic eye or the elevators of the other eye. There are now four possible defective muscles, which can be further reduced to two by asking the patient to look to the left and the right and state in which direction the deviation is maximal. Finally, determining which of these two muscles is paretic is decided by finding whether the deviation is maximal in up or down gaze.

In some instances there may be no differential vertical deviation; this situation occurs with chronic palsies due to an adaptive phenomenon, termed ‘spread of comitance’. To work out which vertical muscle is paretic the Bielschowsky head tilt test is performed. In this test the vertical deviation is compared with the alternate cover test in right and left head tilt positions. The degree of misalignment will increase when the head is tilted to the side of the paretic muscle if the ipsilateral intorters, superior oblique and superior rectus, are weak, and to the opposite side if the extorting muscles, inferior oblique and inferior rectus, are weak. In practice an increased misalignment on head tilt is usually indicative of an ipsilateral superior oblique palsy. The test is less often positive with palsies of the vertical recti or inferior oblique muscles.

The explanation for the effect lies in the fact that a head tilt to either shoulder induces an ocular counter-rolling, which is mediated by the ipsilateral intorters, superior rectus and superior oblique, and by the contralateral extorters, inferior rectus and inferior oblique. If, for example, the ipsilateral superior oblique is paretic, the superior rectus on the same side receives excessive innervation to intort the eye, and by virtue of its relatively unopposed primary action elevates the eye.

The oculomotor, or third cranial nerve, in addition to innervating the superior, medial, and inferior rectus, and inferior oblique eye

muscles also supplies the levator palpebrae superioris muscle, and carries the parasympathetic nerve fibres to the sphincter muscle of the pupil and the ciliary body. A complete oculomotor palsy is easily recognized by ptosis, a fixed dilated pupil and an eye which is deviated ‘down and out’ due to the unopposed action of the lateral rectus and superior oblique. Partial palsies are more common (Fig. 13.2). The nerve may be damaged anywhere along its course from nuclear complex to the muscles, and the combination of an oculomotor palsy with other cranial nerve deficits (II, IV, V, VI) and the long tract signs usually enables accurate localization of the site of the lesion.

Numerous causes of oculomotor nerve palsies have been described (Table 13.2). In adults, the commonest are either an aneurysm or presumed peripheral nerve vascular microinfarction, although evidence is growing that fascicular damage in the brainstem may be a more frequent cause than previously thought (Rush and Younge 1981). These infarcts are commonly associated with arteriosclerosis, hypertension, and diabetes mellitus. Infarcts and aneurysms each account for approximately 20 per cent of the total number of oculomotor palsies. The next commonest are tumours or trauma, which each account for 10–15 per cent of cases (Richards et al. 1992).

Brainstem lesions The oculomotor nuclear complex is a paired structure lying beneath the aqueductal grey matter of the rostral mid-brain at the level of the superior colliculus. The nuclear complex is divided into distinct motor pools subserving individual extraocular muscles. From the clinical point of view the following features should be noted: the caudal nucleus is a single midline structure supplying the levator palpebrae superioris muscles; the nuclei for each superior rectus muscle lie dorsally, close to the midline, and the axons cross the midline to innervate the contralateral muscle. Two patterns of ocular motility are characteristic of lesions of the oculomotor complex, either an isolated complete bilateral ptosis or a unilateral palsy of the medial rectus, inferior rectus, and inferior oblique together with a contralateral superior rectus palsy. Daroff (1970) has suggested clinical rules to decide whether or not a disorder of the oculomotor nerve is due to a nuclear lesion (Table 13.3).

Infarction of this region of the mid-brain often involves more rostral structures resulting in supranuclear vertical gaze disorders. Isolated nuclear oculomotor nerve palsies of vascular origin usually occur as a result of selective embolic or thrombotic occlusion of small dorsal perforating branches of the mesencephalic portion of the basilar artery, or less often, from occlusion of the distal portion of the basilar artery itself, the top of the basilar syndrome. Other aetiologies include haemorrhage, infiltration by tumour, inflammation, and brainstem compression (Bogousslevsky et al. 1994).

It has been proposed that both medial rectii subnuclei may be damaged in patients who show bilateral adduction failure with exotropia and loss of convergence. This has been called ‘WEBINO’: Wall-Eyed Bilateral InterNuclear Ophthalmoplegia (Daroff and Hoyt 1971).

The fascicles of the oculomotor nerve pass ventrally through the medial longitudinal fasiculus, red nucleus, substantia nigra, and the medial cerebral peduncle. Lesions of the nerve in this location are normally either due to infarction or tumours, and their precise anatomical location determines the associated neurological signs (Section 2.4). Thus, a lesion in the red nucleus results in a contralateral cerebellar tremor Nothnagel’s syndrome, or is associated with contralateral involuntary movements Benedikt’s syndrome. If the lesion is in the cerebral peduncle the oculomotor palsy is associated with a contralateral hemiparesis Weber’s syndrome. When the lesion is more extensive, involving the red nucleus and cerebral peduncle, all these signs are present as a result of Claude’s syndrome. Palsies of one extraocular muscle may occur due to a mid-brain lesion within the oculomotor nerve fascicles are a result of their topographic organization. It is suggested that the most medial fibres are for the pupil, followed by fibres for the inferior rectus, levator, medial rectus, superior rectus, and most laterally the inferior oblique (Castro et al. 1990).

Intradural, extramedullary lesions The fascicles emerge from the mid-brain as several rootlets in the interpeduncular space where basal tumours as well as the rare basilar artery aneurysm may compress the nerve as well as the cerebral peduncle in an extrinsically produced Weber’s syndrome. The nerve then passes below the uncus of the temporal lobe lying lateral to the posterior communicating artery. During cerebral herniation due to a unilateral mass lesion the nerve is compressed against the tentorial edge, petroclinoid ligament, or clivus by the uncus. Since the pupillary fibres travel superficially and superonasally in the nerve they are normally affected first during compression leading to mydriasis, to be followed by ptosis and then extraocular muscle weakness. Aneurysms of the posterior communicating artery damage the oculomotor nerve by haemorrhage into the nerve itself or into the aneurysm sac, which causes enlargement and stretching of the nerve to which it is adherent. These aneurysms are often associated with orbital or facial pain, which may precede the oculomotor paresis by up to 2 weeks. It is very unusual for an aneurysm to present with an oculomotor nerve with complete sparing of the pupil i.e. normal pupillary function, and in such cases the pupil usually becomes involved within 7 days (Nadeau and Trobe 1983; Trobe 1988; Cullom et al. 1995).

Trauma An important cause for an oculomotor palsy is trauma which usually has to be severe enough to lead to skull fractures and loss of consciousness. The nerve may be damaged at three different locations: rootlet avulsion as it emerges from the mid-brain, in the subarachnoid space where the nerve is fixed as it penetrates the dura, and finally in relation to fractures of the superior orbital fissure. Mild head injury resulting in an oculomotor palsy should always raise the possibility of a tumour in the skull base (Eyster et al. 1972). As the nerve lies in the subarachnoid space it is vulnerable to damage from inflammatory processes, particularly infection such as tuberculosis, meningococcus, and syphilis.

Peripheral lesions Shortly after piercing the dura lateral to the posterior clinoid process the oculomotor nerve enters the cavernous sinus where it lies above the trochlear nerve. In this location it is usual for the nerve to be involved with the other ocular motor nerves, and the first and second divisions of the trigeminal nerve. A partial involvement of the nerve, often with sparing of the pupilloconstrictor fibres, is common. Involvement of the nerve in this location may be due to local infection or inflammation, compression by aneurysms of the intracavernous portion of the internal carotid artery, in which case there is often accompanying orbital or facial pain, or by meningiomas or lateral extensions of pituitary tumours.

In the rostral part of the cavernous sinus or in the superior orbital fissure the oculomotor nerve divides into a superior division, which supplies the superior rectus and levator palpebrae superioris muscles, and an inferior division, which supplies the medial and inferior rectii and the inferior oblique muscles, as well as the parasympathetic pupilloconstrictor fibres. Isolated palsy of the superior branch has been described due to intracavernous internal carotid artery aneurysm or mucocoele from the frontal or ethmoid sinuses, and of the inferior branch to trauma and tumour. Presumed post-infectious isolated branch palsies have also been reported. However, since the oculomotor nerve has a divisional topographic arrangement beginning in the brainstem, a divisional oculomotor nerve palsy can also arise from a lesion anywhere along its course, including the brainstem.

Infarction One of the commonest causes for an isolated oculomotor nerve palsy is micro-vascular infarction, which may be associated with diabetes mellitus, hypertension, smoking, hypercholesterolaemia, and collagen vascular disease a ‘medical third’. Under these circumstances, there is usually minimal involvement or complete sparing of the pupil (Goldstein and Cogan 1960). Pathological studies have shown focal demyelination without axonal degeneration due to occlusion of intraneural arteries in the intracavernous or subarachnoid segments, with relative sparing of the peripherally located parasympathetic fibres which are supplied by the vasa nervorum (Asbury et al. 1970). Occasionally the nerve may be damaged by a mesencephalic infarct. Rarely, the pupil may be involved with vascular oculomotor nerve lesions. Clinically the palsy may be preceded by orbital or facial pain, which may disappear with the onset of the paresis or continue over several days as may the paresis. In diabetes mellitus the palsy may be the presenting symptom, sometimes with involvement of the abducens and trochlear nerve, and ophthalmic division of the trigeminal nerve due to occlusion of branches of the inferolateral trunk arising from the intracavernous carotid artery. However, in an established diabetic, when associated with other ocular motor palsies, a paranasal sinus or orbital infection by mucormycosis must be considered. The normal course is for spontaneous recovery within 8–12 weeks.

Aberrant regeneration Injury of the oculomotor nerve often results in subsequent aberrant regeneration. The commonest clinical findings are lid elevation, when the globe is adducted or depressed, the pseudo-von Graefe phenomenon, with absence of or only partial vertical eye movement. In addition, lid depression on abduction and pupil constriction on adduction or depression despite absent pupillary reflexes may occur (Forster et al. 1969). These various combined movements are due to co-contraction of muscles innervated by the oculomotor nerve. Aberrant regeneration may occur after trauma, aneurysm, congenital third nerve palsy, and migraine, but not after micro-infarction due to hypertension or diabetes mellitus, presumably due to preservation of axonal continuity. In addition, it may occur without a history of preceding oculomotor palsy, primary aberrant regeneration. In this case an intracavernous meningioma or carotid aneurysm should be sought (Cox et al. 1979). The hypothesis which has traditionally been used to explain this oculomotor synkinesis is that at the site of nerve injury axons become misdirected and eventually innervate muscles for which they were not originally intended. Although there is good support for this hypothesis both experimentally and clinically, other explanations have had to be considered to explain both primary aberrant regeneration, in which there is no acute nerve injury, and the transient nature of the phenomenon in some patients (Lepore and Glaser 1980). These have included ephaptic transmission, in which synkinetic movements may arise from interaxonal cross activation (ephaptic) at the site of the injury, or as a result of peripheral axonolysis there may be reorganization of neuronal central connections which unmask previously encoded synkinetic movements. Currently there is no single explanation which adequately explains all the clinical features of oculomotor synkinesis.

Childhood lesions Isolated oculomotor palsy in infancy and childhood is rare and most often congenital (Victor 1976; Kodshi and Younge 1992). They probably result from ischaemic or hypoxic insults to the brainstem in utero, which may lead to hypoplasia of the nucleus. Some probably result from traction to the subarachnoid portion of the nerve during labour. These palsies are often incomplete and show evidence of aberrant regeneration. The acquired causes include trauma, inflammatory disease, tumour, aneurysms, and ophthalmoplegic migraine (Miller 1977). Slowly progressive isolated palsies should undergo imaging every 2 years with the expectation of eventually detecting a small tumour somewhere along the course of the nerve. An unusual phenomenon is cyclic oculomotor paresis which usually occurs in early childhood, but may be noted at birth. In this condition oculomotor paresis alternates every 2 min with the shorter spasms of oculomotor ‘overactivity’ lasting 10–30 s when the ptotic lid elevates, the globe begins to adduct, the pupil constricts, and accommodation increases. The condition usually persists unchanged throughout life (Loewenfeld and Thompson 1975).

Ophthalmoplegic migraine Ophthalmoplegic migraine has its onset in childhood and occurs in the setting of headache, photophobia, cyclical vomiting, or other migrainous symptoms. A family history of migraine is usually absent. The oculomotor palsy may persist for some time after the headache has resolved, and the palsy may in fact develop as the headache phase abates. The cause of the palsy is considered to be due either to compression of the oculomotor nerve by a swollen dilated carotid or basilar artery, or a delayed ischaemic neuropathy (Walsh and O’Doherty 1960). When such a condition occurs in a young child there is obviously concern about the possibility of an aneurysm. However, presentation of a Berry aneurysm under the age of 10 years is exceptionally rare, and if the palsy recovers along with the other symptoms angiography is not indicated. In a teenager MR angiography is advisable.

Ocular neuromyotonia Patients with ocular neuromyotonia experience paroxysmal diplopia due to involuntary contraction of muscles supplied by the oculomotor nerve, although the abducens and trochlear nerves may also be involved. This condition usually but not always occurs in the context of a patient who has previously received radiotherapy for skull-base or thalamic tumours. The presumed cause is a radiation-induced cranial neuropathy manifesting as a spontaneous discharge from axons with unstable cell membranes. This produces a tonic contraction of one or more muscles, and the paroxysms occur 20–30 times daily. The paroxysms, which last several minutes, may be induced by sudden shifts of gaze into the field of action of the involved muscles. Most patients respond satisfactorily to carbamazepine (Ezra et al. 1996).

The crucial issues regarding the diagnostic procedures, which should be undertaken in adult patients with acute acquired oculomotor nerve palsies, are the patient’s age and the presence or absence of pupil involvement. A patient with an acute complete or partial oculomotor nerve palsy with pupil involvement should be urgently investigated for a possible posterior communicating artery aneurysm. On the other hand patients over 50 with an isolated complete pupil sparing oculomotor nerve palsy and vascular risk factors such as diabetes mellitus or hypertension can be observed without resorting immediately to MR scanning. They should be frequently followed up and any worsening in the oculomotor palsy or failure to improve after 8 weeks should lead to MR scanning. In a case of pupil sparing partial oculomotor nerve palsy it has been proposed that scanning is only required if over the next week the pupil becomes involved (Trobe 1988). After this a vasculopathic cause is most likely. However, other causes of pupil sparing oculomotor nerve palsy, such as myasthenia gravis and thyroid eye disease should be considered and the appropriate investigations undertaken.

Isolated oculomotor nerve palsies or in combination should raise the possibility of meningeal processes such as Lyme disease, tuberculous, fungal, carcinomatous, or lymphomatous meningitis, and a CSF examination should be performed along with an MRI with gadolinium enhancement.

The management of patients with oculomotor nerve palsies is complex because of the varied pattern of paresis of the four involved muscles. Initially monocular occlusion or prisms can be used but only after the paresis has been shown to be stable for at least 6 months are ophthalmologists prepared to propose surgery to attempt to produce alignment of the eyes in at least the primary position.

The trochlear nerve, or fourth cranial nerve, passes from its nucleus to decussate with the contralateral nerve in the anterior medullary velum, which forms the anterior roof of the fourth ventricle just caudal to the inferior olive. It is unique amongst motor nerves not only for its decussation but for the fact that it emerges from the dorsal surface of the brain, and then passes round the mid-brain tectum, crossing the inferior cerebellar artery to reach the free edge of the tentorium, where it enters the dura to run forward into the cavernous sinus. It finally enters the orbit through the superior orbital fissure to innervate the superior oblique muscle. It is the most slender of all the cranial nerves and has the longest intracranial course.

Clinically the patient with a trochlear nerve paresis usually complains of vertical diplopia with a torsional component, accentuated by looking down. There is usually a compensatory head tilt to the side opposite the affected eye with the chin down. In the majority of cases there is a hypertropia of the affected eye with an increased vertical deviation of the two images, when the head tilted to the side of the paretic muscle, the Bielschowsky manoeuvre. A simple way to identify the side of a suspected trochlear nerve palsy is to ask the patient to view a straight object such as a pen as if is moved horizontally from the primary position downwards. The patient will observe two images, one horizontal and the other tilted, coming together laterally on one side which is the side of the abnormal eye,

‘the arrow points to the affected fourth nerve’. Torsion greater than 10 deg is usually indicative of a bilateral weakness of the superior obliques, as does a V pattern esotropia.

A trochlear nerve palsy is the commonest cause for vertical extraocular muscle weakness, but is less common than palsies of the other ocular motor nerves (Richards et al. 1992; Tiffin et al. 1996). The aetiological causes of trochlear nerve palsies are listed in Table 13.4. However, as with an isolated lateral rectus muscle paresis, other orbital causes for an isolated paresis of the superior oblique muscle must be sought before it can be attributed to a trochlear nerve lesion. These include skew deviation, myasthenia gravis, dysthyroid myopathy, and other restrictive ocular myopathies, childhood strabismus syndromes. In Brown’s superior oblique tendon sheath syndrome there is restricted elevation of the adducted eye, which may be congenital due to a shortened superior oblique tendon, or acquired when it is caused by a tenosynovitis or neoplastic infiltration of the tendon as it passes through the trochlear pulley (Brown 1973).

It is impossible to clinically differentiate a lesion of the nucleus from a nerve lesion. The nucleus may be congenitally hypoplastic or damaged by haemorrhage or tumour. The only clue to a lesion of the nucleus or fascicle is the association of a trochlear nerve paresis with a contralateral Horner’s syndrome or a contralateral internuclear ophthalmoplegia which localizes the pontomesencephalic junction (Mansour and Reinecke 1986). More commonly the nerve is affected in its long subarachnoid course, especially from head trauma, both severe and minor. The nerve is particularly prone to damage at its posterior decussation, the anterior medullary velum, due to its relationship to the edge of the tentorium. Blunt injury to the forehead or skull leads to a contrecoup contusion of the mid-brain tectum by the free tentorial edge. The resulting trochlear nerve palsy is often bilateral (Lepore 1995). Skull base fractures can also lead to trochlear nerve palsies.

Ischaemic lesions The second commonest cause of an isolated trochlear nerve paresis is microinfarction, particularly in an individual over 50 associated with vasculopathic risk factors such as smoking, hypertension, hypercholesterolaemia, and diabetes mellitus (Keane 1993). This has a better prognosis than a traumatic nerve lesion although unlike oculomotor nerve palsies there has been no clinicopathological correlation. The nerve may be affected in the cavernous sinus and the superior orbital fissure by other diseases such as tumours and aneurysms, but it is usual for the other ocular motor and trigeminal nerves to also be involved.

Muscle underactivity The gradual or occasionally sudden onset of vertical diplopia, without any predisposing cause, should always be considered clinically to be due to an underacting superior oblique muscle, which when occurring from late childhood up to 50 years of age may be due to a decompensated congenital trochlear nerve palsy. The torsional component of the diplopia is less frequent than in the acquired trochlear nerve palsies. Old photographs of the patient may show a head tilt in infancy. These patients tend to have large vertical fusional amplitudes.

In many patients with isolated trochlear nerve pareses no cause can be found even after tensilon testing, MR scanning and a glucose tolerance test. In this situation recovery usually occurs spontaneously. Some patients can be treated by occlusion of the lower half of the spectacle lens over the affected eye with opaque tape. This provides occlusion in the field of action of the impaired superior oblique muscle. Alternatively a base-down prism such as a Fresnel lens may be worn over the affected eye.

Myokymia A rare disorder is superior oblique myokymia in which there are bursts of small amplitude, high frequency torsional oscillations of one eye (Hoyt and Keane 1970, Miller 1996). This results in symptoms of recurring monocular blurring of vision and oscillopsia, vertical or torsional diplopia, and tremulous sensations in the eye. These episodes last less than 10 s and occur many times per day. The attacks may be induced by looking downward, tilting the head toward the side of the affected eye, or by blinking. The oscillations may be difficult to observe on gross examination but can be readily observed with the ophthalmoscope or slit lamp by asking the patient to move the eyes in the direction known to induce the oscillations. Electromyographic studies have suggested that this condition is due to neuronal damage with subsequent regeneration leading to desynchronized contraction of muscle fibres (Komerell and Schaubele 1980). The condition is usually benign, although rare cases have been reported following trochlear nerve palsy, after mild head trauma, associated with multiple sclerosis and after brainstem infarction. Superior oblique myokymia spontaneously resolves in some patients, but may relapse. Whereas in some patients the symptoms are not troublesome, in those in whom their symptoms are distressing a range of medical treatments are available. These include membrane stabilizing drugs such as carbamazepine and phenytoin, baclofen, and systemically administered β-adrenergic-blocking agents. Gabapentin has also been of benefit in some patients. If drug therapy fails surgical procedures such as superior oblique tenotomy sometimes combined with ipsilateral inferior oblique tenectomy are available.

An abducens, or sixth cranial nerve palsy, which results in a lateral rectus muscle paresis, is the commonest type of ocular nerve palsy (Fig. 13.3) (Richards et al. 1992). Clinically it results in horizontal double vision with the separation of the images increasing with gaze towards the affected side. It is important to differentiate an abducens nerve palsy from disorders of the neuromuscular junction such as myasthenia gravis, or extraocular muscles, such as dysthyroid eye disease and orbital inflammation or pseudotumour. Other conditions which need to be excluded include orbital trauma ‘ethmoid blowout’, convergence spasm, and the congenital innervation abnormalities of Duane’s and Mobius syndromes. The various causes of abducens nerve paresis at different locations along its course are listed in Table 13. 5.

The abducens nucleus lies in the floor of the fourth ventricle and contains, in addition to motor neurons that supply the ipsilateral lateral rectus muscle, interneurons whose axons cross the midline to ascend in the medial longitudinal fasciculus to the contralateral oculomotor nucleus or medial rectus subnucleus. Lesions of the nucleus, therefore never produce ipsilateral abduction weakness, but always result in an ipsilateral conjugate gaze palsy often associated with an ipsilateral lower motor neuron palsy of the facial nerve, the fascicles of which course around the abducens nucleus (Henn and Büttner 1982). The abducens nucleus is susceptible to abnormalities of development, such as Duane’s syndrome, and acquired lesions mainly due to metastatic tumours and vascular infarction. Patients with Wernicke–Korsakoff syndrome (Section 34.5), often develop horizontal paralysis of conjugate gaze, presumably from a metabolic insult to the abducens nuclei.

Brainstem lesions Involvement of the abducens nerve fascicles in the lateral tegmentum due to infarction in the territory of the anterior inferior cerebellar artery produces abduction paresis, ipsilateral lower motor neuron facial palsy, loss of taste from the anterior two-thirds of the tongue, ipsilateral Horner’s syndrome, ipsilateral analgesia of the face, and ipsilateral peripheral deafness: Foville’s syndrome. As the abducens nerve fascicles pass ventrally through the pontine tegmentum they pass lateral to the pyramidal tract. An infarction at this site, due to thrombotic or embolic occlusion of paramedian penetrating branches of the basilar artery, results in an ipsilateral abducens paresis, ipsilateral facial palsy, and contralateral hemiplegia: Millard–Gubler syndrome. Other causes for a fascicular abducens nerve palsy are brainstem glioma or metatasis, and demyelination, which commonly result in bilateral palsies (Silverman et al. 1995).

Intradural, extraaxial lesions The abducens nerve may leave the caudal border of the pons as a single or double trunk, the latter possibility explaining the partial palsies which may occur due to trauma or raised intracranial pressure. The nerve passes almost vertically in front of the clivus where it may be damaged by an enlarged ectatic basilar artery or by tumours such as a chordoma, meningioma, or nasopharyngeal carcinoma (Volpe and Lessell 1993). Minor head trauma resulting in an abducens paresis should raise the suspicion of a clivus or parasellar tumour. In the subarachnoid space the nerve is liable to damage from meningeal inflammation, especially due to secondary carcinoma and any infective organism, particularly tuberculosis. The nerve then enters the dura, medial to the trigeminal nerve, and passes under the petroclinoid ligament in Dorello’s canal. It is fixed at this point and hence downward displacement of the brainstem due to a supratentorial lesion may result in unilateral or bilateral abducens palsies a ‘false localizing sign’. Partial palsies have been reported after lumbar punctures or myelography, not necessarily associated with raised intracranial pressure (Bell et al. 1994). They usually resolve after a few days to weeks after the pressure has been normalized.

Petrons bone lesions Before the nerve passes into the cavernous sinus it lies on the medial tip of the petrous temporal bone where it is susceptible to damage from trauma, particularly as a result of a longitudinal fracture of the temporal bone. The commonest cause for abducens nerve involvement at this site is infection, usually in the middle ear or mastoid, leading to a petrositis with or without thrombosis of the inferior petrosal sinus. The trigeminal ganglion and facial nerve lie nearby, often resulting in associated pain in the face or eye, and a facial paresis may occur in addition to the abducens palsy Gradinigo’s syndrome.

Cavernous sinus lesions On entering the cavernous sinus the nerve lies lateral to the internal carotid artery and medial to the ophthalmic division of the trigeminal nerve, in close proximity to the oculomotor and trochlear nerves. Despite this, lesions in the sinus often lead to an isolated abducens nerve palsy, probably because it is not tethered to the dural wall. For a short distance the pupillosympathetic fibres run with the abducens nerve as they pass from the internal carotid artery to the first division of the trigeminal nerve. Tumour, inflammation, dural arteriovenous malformation, or intracavernous aneurysm of the internal carotid artery may affect the abducens nerve in this location. An isolated palsy may also be the first indication of the contralateral spread of a cavernous sinus thrombosis. When the nerve passes through the superior orbital fissure to innervate the lateral rectus muscle it may be compressed by tumours of the skull base, such as nasopharyngeal carcinoma, often with involvement of the other ocular motor nerves, when facial pain and proptosis may also be a feature. Although isolated chronic abducens nerve palsies require investigation, many have benign causes (Savino et al. 1982). Bilateral abducens nerve palsies, in contrast to unilateral palsies, are most commonly due to demyelination, subarachnoid haemorrhage, meningitis, tumours, Wernicke’s encephalopathy, and raised intracranial pressure. These palsies need to be carefully differentiated from convergence spasm and divergence paresis.

Management Initial management of a patient with an isolated abducens nerve palsy should be with either monocular occlusion or press-on Fresnel prisms (base-out). Botulinum toxin injection to the ipsilateral medial rectus muscle may also help restore single binocular vision and may prevent the development of medial rectus contracture (Lee 1992). Surgery is usually offered only after 6–12 months with no sign of recovery.

Childhood palsies A transient abducens palsy is occasionally present in the newborn which resolves within approximately 6 weeks (Knox et al. 1967). It is important to differentiate this from congenital abnormalities such as Duane’s syndrome or congenital esotropia with cross-fixation. Full abduction can be achieved in the latter by the doll’s head manoeuvre or by patching one eye for a week. Several diseases in children lead to isolated abducens palsies, which may be the first sign of a posterior fossa tumour (Robertson et al. 1970). When it is associated with a gaze palsy a brainstem glioma is suggested, and if associated with cerebellar dysfunction, an astrocyoma, ependymoma, or medulloblastoma. An abducens nerve palsy sometimes follows an upper respiratory tract infection or measles immunization, or develops during a chickenpox infection usually with full recovery. It should, however, always be remembered when a child develops a sudden ocular deviation that this may be due to a unilateral loss of vision resulting from a tumour of the retina or anterior visual pathways, or the battered child syndrome.

It is important to distinguish multiple ocular motor palsies from orbital disease due to dysthyroid eye disease, myasthenia gravis, and progressive myopathy or chronic progressive external ophthalmoplegia. This can usually be achieved by careful consideration of the tempo of progression and associated signs such as pupil involvement, response to edrophonium, and the forced duction test. Unilateral multiple ocular motor nerve palsies are usually associated with lesions involving the cavernous sinus or superior orbital fissure. If bilateral, a wide range of possible diagnoses must be considered (Table 13.6). An isolated or multiple ocular motor nerve palsy associated with pain in or around the eye constitutes the syndrome of painful ophthalmoplegia which again has a wide differential diagnosis (Table 13.7).

Brainstem lesions In the brainstem several conditions can involve the three ocular motor nerves. In particular, Wernicke’s

encephalopathy in which ophthalmoplegia is usually associated with nystagmus, altered mental status, and ataxia, should always be considered, since administration of thiamine can rapidly reverse the ophthalmoplegia. Other conditions are Bickerstaff’s brainstem encephalitis (see below) and rarely in motor neurone disease, usually when the patient’s course has been artificially prolonged with long-term ventilatory support.

Meningeal causes Various combinations of involvement of the ocular motor nerves, sometimes with other cranial nerves, in the subarachnoid space may occur with acute and chronic bacterial, fungal, tuberculous, syphilitic or borrelial meningitis, and sarcoid, carcinomatous or lymphomatous meningitis.

Trauma When multiple ocular nerve palsies occur as a result of trauma the head injury is usually severe and associated with fractures of the sphenoid, petrous temporal, or orbital bones (Lepore 1995). They can be confused with blowout fractures of the orbit which lead to restricted eye movements, particularly of upward gaze, due to prolapse of the inferior rectus muscle through the bony defect in the orbital floor.

Skull base lesions Lesions of the skull base can lead to a combination of ocular motor palsies. These include metastatic tumours typically from breast, lung, or prostate primary tumours. Other primary tumours in this region include sphenoid wing or clival meningiomas, chordomas, and chondrosarcomas.

Cavernous sinus lesions Many different disease processes may affect the ocular motor nerves in the cavernous sinus; differentiation between lesions at this site or at the orbital apex is suggested by sensory disturbance in the trigeminal distribution in the former, and by proptosis and visual loss in the latter. The commonest causes for multiple ocular motor palsies in the cavernous sinus areaneurysms and tumours. In a large series of cases of cavernous sinus syndrome Thomas and Yoss (1970) found the differentiation was not possible clinically by analysis of the mode of onset, presence or absence of pain, the pattern of neurologic deficit, or the response to steroids. However, in a series of patients with meningiomas and aneurysms of the cavernous sinus Trobe et al. (1978) found that patients with meningiomas tended to be aged over 70 years, systemically healthy and pain free, with a subtle onset of symptoms and insidious progress. Aneurysms presented in patients, who were usually women over 70 years with hypertension or cardiovascular disease, acute severe orbital pain or trigeminal, first and second divisions, dysaesthesiae at onset, early abduction defect due to early involvement of the abducens nerve, and with negligible or an explosive progression. Visual loss secondary to compression of the anterior visual pathway is a late consequence of large aneuryismal expansion. Intracavernous aneurysms, which account for only 2 per cent of intracranial aneurysms, may expand rapidly but rarely rupture, in which case the dural envelope of the cavernous sinus usually contains the haemorrhage and a carotid-cavernous fistula is formed with obvious physical signs. The aneurysm or fistula may be treated electively if symptomatic by endovascular coiling or carotid occlusion.

In the cavernous sinus syndrome it is commonly found that when the oculomotor nerve is compressed there appears to be relative pupil sparing. It has been suggested that this is due to coincident sympathetic and parasympathetic paresis. It is often difficult to clinically differentiate between meningioma, intracavernous aneurysm, and nasopharyngeal carcinoma or other metastatic tumours, which are the commonest cause of a cavernous sinus syndrome, occurring in 20 per cent. In the case of multiple ocular motor nerve palsies, with or without pain, in which CT and MR scanning has failed to localize a lesion, a ‘blind’ nasopharyngeal biopsy may be positive even in the absence of visible nasopharyngeal tumour. Metastases from other sites may infiltrate the cavernous sinus and progressive involvement of the ocular motor and other cranial nerves may be the presenting signs of carcinomatous meningitis.

Pituitary tumours may suddenly expand laterally into the cavernous sinus. This is usually due to infarction of the tumour leading to pituitary apoplexy. Patients with this condition usually present with a sudden onset of severe headache, multiple ocular motor palsies, which are often bilateral, variable degrees of visual loss, and signs of endocrine insufficiency.

Cavernous sinus thrombosis may occur as a complication of infectious and non-infectious processes, and may be life-threatening demanding prompt recognition. Septic thrombosis of the cavernous sinuses is most commonly due to staphylococcal and streptococcal organisms. These organisms gain entry to the cavernous sinus via the valveless veins from the middle third of the face, paranasal and usually sphenoid sinusitis, dental abscess, and less often otitis media. They may also spread from the maxillary and sphenoid sinuses. Fever is a nearly constant feature, but headache may not be prominent. Periorbital oedema, chemosis, proptosis, and limitation of extraocular movements, especially lateral gaze due to abducens nerve involvement, develop in almost all recognized cases. Involvement of the opposite eye frequently appears within 2 days following the onset of unilateral signs when the infection spreads across to the contralateral cavernous sinus. Most patients have elevated peripheral white cell count and positive blood cultures. MRI is the diagnostic procedure of choice. Treatment includes immediate intravenous antibiotics, which should include therapy against penicillinase-resistant staphylococci and anaerobes, and often surgical drainage of the primary site of infection. The use of anticoagulation in this condition is still controversial but early use of heparin may lead to an improved outcome (Levine et al. 1988). Less than half the patients recover completely, and the mortality is approximately 30 per cent.

The development of an acute or subacute painful ophthalmoplegia demands extensive investigation of the patient to exclude an aneurysm, tumour, or one of the rarer causes. In particular, fungal infections should be considered in diabetics and immunocompromised individuals. Mucormycosis and more rarely aspergillosis may rapidly spread from the sinuses to the cavernous sinus and orbit. MRI will delineate the extent of invasion of the fungus. Patients at risk of this infection may require its urgent exclusion by sinus mucosal biopsies, since a favourable outcome with intravenous amphotericin B and surgical debridement, is only possible if treatment is instituted early.

Tolosa–Hunt syndrome Once these other causes have been excluded then the diagnosis of a non-specific granulomatous inflammation in the region of the cavernous sinus resulting in the Tolosa–Hunt syndrome should be considered (Lakke 1962; Kline 1982). The criteria for the diagnosis of the syndrome (Hunt et al. 1961) are as follows:

It is clear that the so-called Tolosa–Hunt syndrome may be caused by a spectrum of inflammatory processes, both granulomatous and non-granulomatous inflammation. This condition cannot be clearly distinguished pathologically from the lesions causing the painful superior orbital fissure syndrome and orbital pseudotumour.

MR venography is a useful investigation in these cases often showing obstruction of the cavernous sinus or superior ophthalmic vein. In addition, irregularities of the intracavernous portion of the internal ophthalmic artery may be found. MR imaging often shows an abnormal soft tissue area in the cavernous sinus, with intermediate to high signal on T1-weighted images and enhancement of the abnormal area with gadolinium. These abnormalities reflect the low-grade inflammatory response in the cavernous sinus which has been found pathologically, and which have been shown to disappear with corticosteroids.

It is important to note that a similar systemic steroid responsiveness may be observed with other lesions in the superior orbital fissure and cavernous sinus, which include tumours and aneurysms. It is therefore important that complete neuroradiological investigations are carried out in patients with the syndrome of painful ophthalmoplegia.

The aetiology of the Tolosa–Hunt syndrome is poorly understood. Mathew and Chandy (1970) identified a high prevalence of parasitic infections and tuberculosis in their patients, which suggested that the syndrome may be the result of an unusual immune reaction to endemic infections. Most cases of the condition have no evidence of systemic disease, although some cases have positive serology for systemic lupus erythematosus and a raised ESR. The evidence for a generalized connective tissue disease or endemic infection as being the underlying cause is poorly substantiated. An excellent review of the painful ophthalmoplegia syndrome and Tolosa–Hunt syndrome in particular, has been written by Kline (1982).

Involvement of the third, fourth, and sixth cranial nerves may occur in typical Guillain–Barré syndrome (Section 21.10.1). In the variant of this condition, the Miller Fisher syndrome, an external, and often internal, ophthalmoplegia develops in association with ataxia and areflexia (Section 21.10.5). Because the ophthalmoplegia is often incomplete and the resulting paresis symmetrical, suggesting a horizontal or vertical gaze palsy, some authors have suggested that some cases of the syndrome may be due to a central lesion which has been called Bickerstaff’s brainstem encephalitis, a monophasic illness. In this condition, typically preceded by an infection or immunization, the patient is stuporosed, and has an ophthalmoparesis associated with ataxia, brisk reflexes, and occasionally a CSF pleocytosis. However, the majority of cases are probably associated with a peripheral demyelinating neuropathy (Berlit and Rakicky 1992). As in Guillain–Barré syndrome, many of these cases have been found to have evidence of Campylobacter jejuni infection, and to have autoantibodies against certain gangliosides in their serum, particularly anti-GQ₁b IgG antibody (Chiba et al. 1992). These antibodies may be found in some patients with chronic ophthalmoplegia of unknown cause (Reddel et al. 2000). There is a growing consensus that Miller Fisher syndrome and Bickerstaff’s brainstem encephalitis may represent a spectrum of a similar disease process (Al-Din 1987) since both are self -limited and share the anti-GQ₁b antibodies. Most patients with the Miller Fisher syndrome improve completely in 8–12 weeks without treatment.

A number of different diseases affecting transmission at the neuromuscular junction may produce ocular motor disorders.

Botulism Contaminated food or infected wounds may lead to an elaboration of the toxin of Clostridium botulinum (Miller and Moses 1977). This neurotoxin blocks the release of acetycholine from the presynaptic nerve terminals and may lead to varying degrees of internal and external ophthalmoplegia, ptosis, and bilateral facial weakness (Section 24.10.5).

Myasthenia gravis. The commonest disorder affecting the neuromuscular junction is myasthenia gravis, an autoimmune disorder affecting the postsynaptic acetylcholine receptor (Weinberg et al. 1994) (Section 24.10.1). The presenting symptoms are ocular with ptosis or motility disorders, due to weakness of levator palpebrae superioris or extraocular muscles respectively, in about 50 per cent of cases. During its course ocular involvement occurs in 90 per cent (Oosterhuis 1982). Half remain as ‘ocular myasthenics’ and the other 50 per cent develop generalized features usually within 2 years. The risk of developing generalized involvement after presentation with ocular myasthenia reduces to about 15 per cent after 2 years (Bever et al. 1983). Since the disorder is one of muscle fatiguability and spontaneous remissions, it is not surprising that the ocular signs and symptoms fluctuate over hours or weeks. The commonest sign is lid ptosis, which is usually asymmetrical and may be especially pronounced on sustained upgaze. The contralateral lid may be elevated due to the increased innervation required by the ptotic lid, which when covered results in the normal lid returning to normal. Rapid shifts of ptosis from one eye to the other are considered pathognomonic of the disorder (Osserman 1957), as is the lid ‘twitch’ sign described by Cogan (1965). In this, rapid refixations from downgaze to the primary position result in transient lid retraction followed by a slow droop to the ptotic position or else it twitches several times before settling into a stable position. Forced eyelid closure may lead to fatigue of the orbicularis oculi muscle resulting in the eye ‘peeking’ at the examiner. Patients with myasthenia gravis have an increased prevalence of thyroid eye disease, which may result in bilateral or unilateral eyelid retraction, the latter without contralateral ptosis.

Myasthenia gravis is the ‘great mimicker’ of ocular motor disorders and may produce pseudostrabismus, any muscle may be involved to give the appearance of pupil sparing oculomotor, trochlear and/or abducens palsies, and mimic supranuclear conditions which normally are associated with central lesions such as internuclear ophthalmoplegia with abducting nystagmus, one-and-a-half syndrome and conjugate gaze palsies. The medial rectus is the most commonly affected muscle, but muscle fatigue may be seen on sustained upward and lateral gaze. Apart from these ophthalmoplegias, myasthenia can result in a number of saccadic abnormalities including; slow saccades, slowing after repeated refixations, and saccadic dysmetria, as well as increasing nystagmus on sustained lateral gaze. It is still not clear why there is a predilection for the levator and extraocular muscles in myasthenia gravis although several hypotheses have been proposed:

It is generally agreed that pupillary reflexes in patients with myasthenia gravis appear clinically normal.

Prolonged ocular involvement in myasthenia gravis may lead to a chronic or ‘fixed’ ophthalmoplegia which fails to improve with anticholinesterase medication. The resulting symmetrical external ophthalmoplegia, ptosis, and facial weakness may make separation from chronic progressive external ophthalmoplegia difficult, but a slow symmetric progressive course without fluctuations or remissions favours the latter.

When there is a moderate or marked deficit of lid elevation or ocular motility the diagnosis of myasthenia gravis is best confirmed by the edrophonium or Tensilon test. To increase the objective sensitivity of the test the response of the ophthalmoplegia can be assessed by the Hess chart, prisms, or the Lancaster red-green test performed before and 1–2 min after the injection of edrophonium. Ocular deviations may actually get worse if the muscles are differentially responsive to edrophonium, in which case the test is still considered positive. About 50–75 per cent of patients with pure ocular myasthenia were found to have anti-acetylcholine receptor antibody, and abnormal jitter on single fibre electromyographic examination of skeletal muscle was found in 50 per cent of such cases (Kelly et al. 1982). Another simple test, the ice pack test (Ertas et al. 1994), which has a high degree of sensitivity and specificity and is useful in patients with a cardiac condition in whom the edrophonium test is contraindicated, may be used. Local cooling, using a bag containing ice is placed over the ptotic lid for 2 min and following removal the size of the palpebral fissure is measured and compared with the size before cooling. Patients with myasthenia gravis usually show a difference of greater than 2 mm indicating an improvement in the levator strength. Because a thymic tumour is found in about 10 per cent of patients with myasthenia gravis, part of the evaluation of a patient suspected of having the disease should include a CT scan of the mediastinum.

It is commonly found that the paresis of the extraocular muscles responds poorly to anticholinesterase drugs, although the ptosis may respond more favourably. For this reason steroid therapy has been used in ocular myasthenia and often results in considerable and sometimes complete resolution of ocular symptoms (Oosterhuis 1982). Patients with ocular myasthenia can be commenced on low doses of daily or alternate day steroids (equivalent to 10 mg per day). The dose is gradually increased until the desired effect is achieved. A year later a gradual reduction should be attempted to see if the symptoms reappear (Weinberg et al. 1994).

When diplopia becomes troublesome occlusion of one eye is the best initial measure since prisms are unhelpful because of the fluctuations in the angle of the optical axes. The ptosis may be relieved with a ptosis hook attached to spectacles but, if chronic, the patient may be helped by ptosis surgery.

Lambert–Eaton syndrome In contrast to myasthenia gravis, ocular symptoms are rare in Lambert–Eaton syndrome, but mild ptosis and both clinical and subclinical ocular motor involvement does occur in some patients. Autonomic involvement may lead to dry eyes and sluggish pupillary responses (Section 24.10.2).

Ocular myopathies. A progressive limitation of ocular motility, accompanied by ptosis but usually without diplopia or pupillary abnormalities occurs in many diseases (Table 13.8). There are several subgroups of myopathies predominantly affecting the extraocular muscle, chronic progressive external ophthalmoplegia, and these are often accompanied by a variety of other findings and have been called ‘ophthalmoplegia plus’ (Drachman 1968; Petty et al. 1986).

Oculopharyngeal dystrophy. This is inherited as an autosomal dominant trait mapped to chromosome 14q11.2-013 in the region of the gene for myosin where a guanine–cytosine–guanine repeat has been demonstrated (Blumen et al. 1999) (Section 24.2.6). The marked ptosis with some restriction of ocular motility is associated with wasting of the temporalis muscle and weakness of the bulbar

muscles. The onset is usually in the fifth and sixth decades and mild ptosis usually precedes the dysphagia by years (Murphy and Drachman 1968). Sporadic isolated cases have been reported but may represent poor case ascertainment or reduced penetrance. Myotonic dystrophy may give rise to slowed eye movements due to involvement of the extraocular muscles (Ter Bruggen et al. 1990) (Section 24.3).

Kearns–Sayre syndrome. Although chronic progressive external ophthalmoplegia may occur in association with a number of other defects those found in the Kearns–Sayre syndrome are the most varied (Kearns and Sayre 1958) (Section 24.6.3). The onset of this condition, in which bilateral ophthalmoparesis is associated with symmetric ptosis, is within the first or second decades, without any family history, is associated with retinal pigmentary degeneration, and at least one of cardiac conduction abnormalities, raised CSF protein to <100 mg/dl, and ataxia. Excessive ragged red fibres are found in peripheral muscle with trichrome staining methods. Other neurological features may be observed (Table 13.9). The sequence of manifestations varies and the cardiomyopathy may be delayed for years. Pathologically there is a spongy degeneration of the brain. The disease is now characterized as a mitochondrial cytopathy in which a deletion from the circular strand of mitochondrial DNA may result in defects of the intracellular respiratory chain. These are large deletions of 1.3–9.1 kb, the commonest of which are from positions 8470 and 13460. Approximately 50 per cent of patients with chronic progressive external ophthalmoplegia and 90 per cent of patients with Kearns–Sayre syndrome have demonstrable mitochondrial deletions (Newman 1992).

Familial varieties of chronic progressive external ophthalmoplegia have been described which are inherited either autosomal dominantly or recessively where multiple mitochondrial deletions have been observed.

Chronic progressive external ophthalmoplegia must be differentiated from a number of conditions. In progressive supranuclear palsy full ocular rotations to oculocephalic manoeuvres are maintained. Chronic ocular myasthenia may be confused with chronic progressive external ophthalmoplegia, especially since there may be a lack of response to edrophonium; but a progressive course lacking fluctuations or remissions favours chronic progressive external ophthalmoplegia. Dysthyroid restrictive myopathy usually has associated lid retraction, proptosis, or congestive conjunctival signs which are absent in chronic progressive external ophthalmoplegia.

A number of different congenital abnormalities have been described in which there is ocular motor paresis, often associated with synkinesis of movement of other eye and lid muscles. It is important that these congenital conditions should be distinguished from acquired ocular motor disorders so that unnecessary investigations are not undertaken.

Möbius syndrome. In this condition there is a variable degree of facial diplegia associated with a disturbance of horizontal eye movements, most commonly a failure of abduction. In about 25 per cent of cases there is a total external ophthalmoplegia. Other abnormalities include tongue atrophy, cleft palate, and various musculoskeletal dysplasias involving the head and neck, chest, and upper extremities. The diversity of pathological findings in patients with Möbius syndrome suggests that the syndrome is actually a heterogeneous group of congenital disorders which in some cases are due to developmental defects, and in others due to acquired hypoxic or other insults (Towfighti et al. 1979).

Duane’s retraction syndrome. This syndrome is due to abnormal development of the abducens nucleus, and is so named because of co-contraction of the medial and lateral rectus muscles leading to retraction of the globe with narrowing of the palpebral fissure, which occurs on attempted adduction in association with limited or absent abduction. Duane’s syndrome is usually unilateral, the left eye being more frequently affected than the right, and is bilateral in 15–20 per cent of cases. The condition may be familial and sometimes associated with other congenital abnormalities such as Klippel–Fiel anomaly, deafness, urinary tract abnormalities, and cardiac defects.

The condition occurs in three forms (Huber 1974): type I, which is the most common, consists of limited or absent abduction with relatively normal adduction; in type II there is impaired adduction and full abduction, and in type III there is impairment of both adduction and abduction. A number of electromyographic and oculographic studies have indicated abnormal innervation patterns, compatible with the clinicopathological studies which have shown hypoplastic abducens nuclei, and partial or complete innervation of the lateral rectus from branches of the inferior division of the oculomotor nerve (Miller et al. 1982). Patients with Duane’s syndrome usually have excellent visual adaptation resulting in absence of diplopia, good stereopsis, and fusion in directions of gaze where the visual axes are aligned.

Although Duane’s syndrome is usually sporadic it may be familial and one large family showed linkage to the condition at chromosome 2q31 (Appukuttan et al. 1999).

Congenital elevator palsies. In the congenital ‘double elevator palsy’ there is paresis of both the superior rectus and inferior oblique muscles in one eye. Since the eyes are straight in the primary position and the Bell’s phenomenon is preserved, it is considered to be a supranuclear paresis of monocular elevation. This condition may develop in later life when it is usually due to a small discrete vascular lesion in the pretectum. Such a lesion would disrupt the efferent fibres from the rostral interstitial nucleus of the medial longitudinal fasciculus to the inferior oblique subnucleus and the contralateral superior sub-nucleus, which innervates the superior rectus muscle contralateral to it.

Marcus Gunn jaw-winking phenomenon. This is an example of anomalous innervation in which a unilateral ptosis of variable extent is noted shortly after birth. When the baby suckles the ptotic lid rhythmically jerks and is intermittently retracted, as it does later with chewing and jaw movements. Two major groups are described: the commonest is external pterygoid-levator synkinesis with lid elevation when the jaw is moved to the opposite side, and internal pterygoid-levator synkinesis with lid elevation on clenching the jaw closed (Sano 1959).

Assessment of a patient complaining of diplopia, which includes taking a history and examining the static eye movements (Section 13.1.1), aims to determine which muscles are involved, whether the cause of the diplopia is due to an ophthalmological, neurological, or old congenital strabismus, and finally the cause. However, it is important to include a neurological examination, including all the cranial nerves and evidence for abnormal long tract signs, to help localize the site of the lesion. Several characteristic ophthalmoparetic or ocular motility patterns may be identified. For example, observing that an eye is in an abducted and slightly depressed position at rest, and that it fails to move in adduction, elevation, and depression, associated with a dilated pupil and ptosis, clearly indicates a complete oculomotor nerve palsy. Similarly the findings of horizontal diplopia at distance, worse on gaze to one side, or of vertical diplopia with a torsional component worse on down gaze and associated with an ipsilateral head tilt are typical of an abducens and trochlear nerve palsy, respectively. Some brainstem lesions leading to diplopia can also give typical pattern of eye movements, for example, an internuclear ophthalmoplegia in which there is slowed or absent ipsilateral adduction with nystagmus in the abducting eye. Disorders of ocular muscle can also lead to diplopia and diplopia worse on up gaze associated with impaired elevation and adduction with conjuctival injection, chemosis, proptosis, and lid retraction is a typical presentation of thyroid eye disease.

If a characteristic ocular paretic picture is not observed it is then necessary to determine which muscles/ocular motor nerves are affected, plus any associated neurological signs, and by applying knowledge of the neuroanatomy of the course of the various nerves, from muscle to brainstem nucleus, it should be possible to determine where the lesion may be located. The history relating to the tempo of onset of the diplopia will also contribute to developing a differential diagnosis. As examples, the combination of oculomotor, trochlear, and abducens nerve palsies locates the lesion to the cavernous sinus which if acute suggests a pituitary apoplexy or cavernous sinus thrombosis or if slowly progressive a mass lesion such as a giant internal carotid aneurysm.

It is important to emphasize the two great mimickers of a wide variety of both central and peripheral oculomotor abnormalities giving rise to diplopia without any accompanying abnormal brainstem signs, myasthenia gravis, and Wernicke’s encephalopathy due to thiamine deficiency usually in the context of alcoholism or malnutrition (Section 34.5).

Many different disease processes affecting the central nervous system, from the brainstem to the cortex, can give rise to supranuclear disorders of eye movements. Examination of eye movements offers a number of advantages to the neurologist over skeletal movements. These include: eye movements are directly related to the activity of brainstem neurons since the extraocular muscles lack a stretch reflex; eye movements have limited degrees of freedom so that disordered movements lend themselves to analysis (clinical or quantitative) in three planes, horizontal, vertical, and torsional; finally there are several functional classes of eye movements, each with special physiologic properties that suit a particular purpose and which have a separate and well-segregated neural substrate. This enables the clinician to examine each of these various types of eye movements and identify abnormalities which can then provide information regarding anatomical, physiological, and pharmacological lesions (Leigh and Zee 2006).

The various types of functional classes of eye movements all subserve the same goal, the acquisition or maintenance of the projection of an image of the object of interest onto the most sensitive part of the retina, the fovea. Rapid conjugate eye movements, saccades, enable the line of gaze to be redirected to bring the image of a new object of interest onto the fovea, and the dysjunctive or vergence eye movements ensure that these images are simultaneously placed on both foveae regardless of their distance from the observer. There is also a need to stabilize the image of the object of interest on the fovea when the object itself moves, performed by the smooth pursuit system, or when the subject’s head or body moves as occurs during locomotion when the vestibular and optokinetic ocular motor reflexes are activated. These different functional types of eye movements can each be rapidly tested at the bedside (Shaunak et al. 1997)

Saccades. Voluntary saccade initiation should be assessed by instructing the patient to look from side to side and up and down. The patient is then asked to fixate two targets alternately—for example, a pen in one hand and a raised finger of the other—so that for each saccade the location of one or other of the targets has been briefly moved and their distance from each other varied. This generates reflexive saccades towards a novel target, which are tested in the horizontal and vertical planes, and the examiner should observe saccadic variables such as speed of initiation orlatency, accuracy, and velocity. Any slowing of saccades can be accentuated by using an optokinetic striped drum or tape, when the repositioning saccades will appear clearly slowed. This is of particular help when showing slowed adducting saccades in a partial internuclear ophthalmoplegia. Another method to accentuate this abnormality is to use oblique targets. Because the velocity is slowed in the horizontal and not the vertical plane, the resulting saccade is L-shaped. Predictive saccades are tested by alternately raising a finger of one hand and then the other in a predictable and regular pattern. The patient is asked to make saccades back and forth to the moving finger. Normally after a few saccades they anticipate the appearance of the stimulus and make a saccade in advance. Finally, the patient should be observed for any head movements or head thrusts or blinks before making a saccade, as occurs in Huntington’s disease and ocular motor apraxia.

Smooth pursuit. Smooth pursuit can be tested by asking the patient to track a small target, such as the head of a hat pin, at a distance of about 1 m, whilst keeping their head stationary. Both horizontal and vertical smooth pursuit should be assessed. The target should be moved initially at a slow uniform speed and the pursuit eye movements observed to determine whether they are smooth, or broken up by catch-up saccades. This is a non-specific sign when present in both directions—for example, it may be due to ageing or cerebellar disease—or it may indicate a focal posterior cortical lesion if only present in one direction, in which case the abnormal pursuit is in the direction of the lesion. The speed should be gradually increased, but at high velocities of >50 deg per second of all smooth pursuit eye movements will be broken up by saccades even in normal subjects. The optokinetic nystagmus drum and tape is a useful method to elicit a series of pursuit movements, and does not in fact elicit true optokinetic eye movements.

Optokinetic nystagmus, The optokinetic system cannot be tested as part of the clinical examination, because the optokinetic nystagmus drum and tape commonly used tests smooth pursuit and not the optokinetic system. A full field revolving striped drum is required to elicit true optokinetic nystagmus.

Vestibular system. If the vestibulo-ocular system is functioning normally passive rotation of the patient’s head should result in a slow eye movement so that the eyes move in the opposite direction to that of the head movement. This is known as the doll’s head or oculocephalic manoeuvre and should be performed both horizontally and vertically. This technique is not only valuable for assessing vestibular function, but also for differentiating infranuclear and nuclear gaze palsies, when the response is absent, from supranuclear gaze palsies in which a normal doll’s head response is present. It is also useful in the evaluation of brainstem function in comatose patients. It should be noted that the eye movements elicited in unconscious patients by this procedure largely reflect the integrity of the semicircular canals and their central connections, whereas in conscious patients the effects of visual input on eye movements may influence the response to head rotation.

A rough estimate of any deterioration of vestibular gain, that is head velocity divided by eye velocity, can be obtained by asking the patient to read a Snellen chart while their head is being passively rotated. If there is an abnormality the visual acuity will show a deterioration compared with the acuity obtained when the head is stationary. Another bedside test of the horizontal vestibulo-ocular reflex is for the examiner to observe the patient’s optic disc with an ophthalmoscope while the patient tries to fixate a distant object and shake their head from side to side. If the gain of the vestibulo-ocular reflex is normal the optic disc will appear stationary to the examiner, but if abnormal the disc will repeatedly slip from view.

The vestibulo-ocular reflex can be suppressed by activating the smooth pursuit system. This may be tested by asking the patient to fixate their thumbnails with their arms outstretched while rotating their head and trunk in harmony. Impaired cancellation of the vestibulo-ocular reflex and hence abnormal smooth pursuit are shown by observing the eye repeatedly moving off fixation due to the vestibulo-ocular reflex, followed by refixation saccades. This is a particularly useful technique for testing pursuit in patients with gaze-evoked nystagmus.

Further details of tests used to assess the vestibular system are to be found in Section 15.5.

There are two main features of the brainstem neural control of horizontal and vertical gaze: an anatomic separation so that the neural substrate for horizontal gaze is located in the pons and for vertical gaze in the mid-brain, and the requirement to overcome viscous drag and resist elastic restoring forces in the orbit when making dynamic eye movements. An understanding of the neural mechanisms which generate a horizontal saccade will serve as an illustration of the principles involved. A rapid phasic contraction of the extraocular muscle is required to overcome the orbital viscosity, and a rapid, high frequency burst of nerve impulses, the pulse, is transmitted to the muscle via the ocular motor nerve. The premotor inputs to the motor neurons in the abducens nucleus arise from neurons in a region of the reticular formation which lies ventral and anterior to the nucleus, the paramedian pontine reticular formation. The equivalent premotor region for vertical gaze is the rostral interstitial nucleus of the medial longitudinal fasciculus in the mid-brain, rostral to the oculomotor nucleus at the level of the red nucleus. The pulse, a velocity signal, is generated by cells called burst neurons, and must be of an appropriate size to ensure that the fovea of the eye is aligned to the target. Once the saccade has been completed it is necessary to maintain the new position of the eye against orbital viscoelastic restoring forces. The muscle must, therefore, now maintain a sustained tonic contraction to counter these forces and this is achieved by the tonic innervation, the step, which is a position signal the motor neuron receives from so-called integrator neurons, which integrate the step in a mathematical sense, lying in the nucleus prepositus hypoglossi and the medial vestibular nucleus. The pulse and step must be perfectly matched to prevent drift of the eye back to the primary position at the end of the saccade. Faulty neural integration leads to an inadequately maintained step, and after a saccade the eye drifts back in an exponential manner due to the unopposed orbital elastic restoring forces, followed by a saccade to refixate the target. This pattern leads to gaze-evoked nystagmus and is observed in cerebellar disease and anticonvulsant or sedative intoxication. An abnormal pulse may either be of reduced duration or of reduced firing frequency. If the step is appropriately matched to the abnormal pulse a reduced duration will result in a reduced amplitude or hypometric saccade, whereas if the firing frequency is reduced a saccade of reduced velocity but of normal amplitude will be generated.

The final neuron in the brainstem involved in saccade generation is the omnipause neuron, located in the raphe interpositus nucleus. These neurons are tonically active and pause before saccades in any direction. They are presumed to inhibit the burst neurons from firing except when a saccade is required.

The abducens nucleus contains two populations of neurons, motor neurons innervating the ipsilateral lateral rectus muscle and interneurons. The abducens nucleus is, therefore, the final common pathway for horizontal gaze. The axons from the interneurons cross the midline and ascend in the medial longitudinal fasciculus to the medial rectus subdivision of the oculomotor nerve nucleus (Fig. 13.4a). The final instructions for horizontal conjugate eye movements, therefore, lie within the abducens nucleus itself, so that its activation results in an ipsilaterally directed horizontal conjugate gaze movement.

Unilateral horizontal gaze palsy. A lesion of the abducens nucleus will result in a horizontal gaze palsy for all types of ipsilateral conjugate eye movements: saccades, pursuit, and vestibular. Vergence movements of the eyes are spared, however, so that adduction is possible with a near stimulus (Müri et al. 1996). The palsy is usually associated with an ipsilateral lower motor neuron facial nerve palsy, due to involvement of the genu of the facial nerve, which passes around the abducens nerve (Fig. 13.5). A selective horizontal gaze palsy involving all saccades, including the quick phases of vestibular and optokinetic nystagmus, occurs when the lesion involves the paramedian pontine reticular formation in isolation, since the vestibular and pursuit inputs pass directly to the abducens nucleus and are therefore spared. The commonest causes for horizontal gaze palsies in adults are either vascular infarction or haemorrhage in the distribution of the pontine paramedian penetrating arteries arising from the basilar artery, demyelination, cavernous angiomas, or trauma. In children medulloblastomas or pontine gliomas are the commonest aetiologies.

Bilateral horizontal gaze palsy. A bilateral pontine lesion involving the paramedian pontine reticular formation can cause a bilateral selective saccadic palsy with preservation of vestibular and optokinetic eye movements (Hanson et al. 1986). Such a lesion may impair vertical eye movements since signals for vertical vestibular and smooth pursuit eye movements ascend in the medial longitudinal fasciculus and other pathways through the pons. The commonest causes of a bilateral horizontal gaze palsy, with sparing of vertical gaze, are neurodegenerative diseases such as Huntington’s disease or Gaucher’s disease. In a patient presenting solely with a gaze palsy other possible causes including the Miller Fisher variant of Guillian–Barré syndrome, myasthenia gravis, Wernicke’s encephalopathy, and thyroid disease.

Internuclear ophthalmoplegia. A lesion of the medial longitudinal fasciculus produces an internuclear ophthalmoplegia, in which there is weakness of adduction ipsilateral to the side of the lesion (Zee 1992) (Fig. 13.6). In a partial internuclear ophthalmoplegia adduction will be slowed, but will be completely absent in a complete lesion. Since the fibres of the medial longitudinal fasciculus carry the horizontal gaze commands subserving all types of conjugate eye movements, this adduction paresis involves not only saccades but pursuit and vestibular eye movements. The presence of intact convergence in the absence of voluntary adduction implies that the medial rectus subdivision of the oculomotor nerve is intact, and that the internuclear ophthalmoplegia is due to a caudal lesion. Cogan (1970) called this a ‘posterior’ internuclear ophthalmoplegia in contrast to patients with absent convergence which he called ‘anterior’. However, such patients do not necessarily have a lesion involving the medial rectus subdivision of the oculomotor nucleus.

The second major feature of an internuclear ophthalmoplegia is the nystagmus on abduction in the contralateral eye. This consists of a centripetal or inward drift, followed by a corrective saccade. Several different mechanisms have been proposed to explain the abducting nystagmus (Zee 1992). These include, (a) a gaze-evoked nystagmus, (b) impaired inhibition of the medial rectus contralateral to the lesion, (c) an increase in convergence tone, and (d) in response to the adduction weakness an adaptive increase in innervation to the adducting eye, which because of Hering’s law of equal innervation results in a commensurate change in the innervation to the abducting eye, which leads to overshooting and postsaccadic drift giving the appearance of abducting nystagmus. The latter is generally considered the most appropriate explanation.

A skew deviation consists of a vertical misalignment of the visual axes due to a disturbance of prenuclear inputs. It is often observed in patients with a unilateral internuclear ophthalmoplegia, with the higher eye usually on the side of the lesion. Patients with bilateral internuclear ophthalmoplegias have bilateral adduction weakness and abducting nystagmus. In addition, they also have impaired vertical pursuit and vestibular eye movements, and impaired vertical gaze holding with gaze-evoked nystagmus on looking up or down (Ranalli and Sharpe 1988).

Patients with an internuclear ophthalmoplegia are usually asymptomatic, although if there is a complete adduction failure they may complain of diplopia especially during shifts of horizontal gaze. Occasionally they may complain of oscillopsia. A number of different aetiologies lead to an internuclear ophthalmoplegia (Table 13.10), but if unilateral the commonest is ischemia, and if bilateral, demyelination is associated with multiple sclerosis.

A rarer so-called posterior internuclear ophthalmoplegia of Lutz has been described in which there is an impairment of abduction (not adduction) of saccades and pursuit, but not vestibular eye movements. This is different to the posterior internuclear ophthalmoplegia described by Cogan in which convergence is intact. The pathogenesis of the posterior internuclear ophthalmoplegia of Lutz is unclear (Thömke et al. 1992).

One-and-a-half syndrome. A combined lesion of the abducens nucleus or paramedian pontine reticular formation and the adjacent medial longitudinal fasciculus on one side of the brainstem results in an ipsilateral horizontal gaze palsy and internuclear ophthalmoplegia (Wall and Wray 1983). The only preserved horizontal eye movement is abduction of the contralateral eye, and the condition is therefore termed the ‘one and a half’ syndrome. Although the majority of patients have no deviation or an esotropia in the primary position of gaze, some patients may habitually fixate with the horizontally immobile ipsilesional eye, which results in exotropia of the contralesional eye that has intact abduction. This condition is called paralytic pontine exotropia (Sharpe et al. 1974). Convergence is often preserved. Some lesions of the medial longitudinal fasciculus cause an adduction palsy due to internuclear ophthalmoplegia that is bilateral and result in exotropia in the primary position, termed a ‘wall-eyed’ bilateral internuclear ophthalmoplegia.

The main causes of a one-and-a-half syndrome are brainstem ischemia, haemorrhage, and tumour. The syndrome can be mimicked by a bilateral internuclear ophthalmoplegia with an ipsilateral abducens nerve palsy.

Lateropulsion. This is a feature of lateral medullary infarction, the Wallenberg syndrome, in which there is a compelling sensation of being pulled toward the side of the lesion, accompanied by appropriate eye movement signs. During voluntary eye closure and sometimes even during blinks, the eyes deviate toward the side of the lesion, and have to make corrective saccades on eye opening to refixate the target. All ipsilaterally directed saccades overshoot the target hypermetrically, and saccades directed away from the side of the lesion undershoot the target hypometrically (Baloh et al. 1981). Vertical saccades have a parabolic ipsiversive trajectory. This ipsipulsion is in contrast to the overshooting of contralateral saccades, termed saccadic contrapulsion, observed in patients with infarction in the territory of the superior cerebellar artery. The eye signs of lateropulsion are considered to be due to damage to olivo-cerebellar projections in the inferior cerebellar peduncle (Solomon et al. 1995).

Disturbances of vertical gaze are usually associated with damage to one or more of three structures in the mesencephalon, the posterior commissure, the rostral nucleus of the medial longitudinal fasciculus, and the interstitial nucleus of Cajal (Fig. 13.4b). The only exceptions are an apparent vertical gaze palsy due to mechanical restriction of extraocular muscles in orbital disorders such as thyroid eye disease; large acute pontine lesions involving the paramedial pontine reticular formation bilaterally producing a temporary vertical saccadic palsy, in addition to the permanent horizontal saccadic palsy; and certain degenerative disorders of the nervous system such as progressive supranuclear palsy or adult Niemann–Pick disease.

Dorsal midbrain syndrome also called pretectal syndrome or Parinaud’s syndrome. This is due to a lesion which involves the posterior commissure and is associated with a variety of aetiologies (Table 13.11) and clinical features, some of which may not be present in an individual patient (Baloh et al. 1985). The essential sign is a loss of upward gaze involving all types of eye movement, although the vestibulo-ocular reflex and Bell’s phenomenon may sometimes be spared. When acute, the eyes may be deviated downwards (thesetting-sun sign), and may be observed in premature infants following intraventricular haemorrhage, and when a ventricular shunt becomes acutely blocked. Downward saccades and smooth pursuit may be impaired and downbeat nystagmus may be present.

The dorsal mid-brain syndrome may also be associated with disturbances of vergence eye movements including an impairment of convergence, which is usually paralysed but may rarely be excessive and cause convergence spasm, convergence-retraction nystagmus (asynchronous convergent saccades—see Section 8.12.5), eyelid retraction (Collier’s sign), and a pupillary light-near dissociation.

Selective vertical gaze palsy due to a rostral nucleus of the medial longitudinal fasciculus lesion. A unilateral or bilateral lesion of the rostral nucleus of the medial longitudinal fasciculus produces a downgaze palsy, mainly affecting saccades, or more rarely a complete vertical gaze palsy (Büttner-Ennever et al. 1982). Patients with unilateral midbrain lesions can develop combined upgaze and downgaze palsies, isolated upgaze palsies, an uniocular upward ophthalmoplegia with no primary position hypotropia (monocular double elevator palsy), and a vertical one-and-a-half syndrome which describes the combination of a vertical gaze palsy in one direction and a monocular vertical ophthalmoplegia in the other direction, with no primary position heterotropia (Hommel and Bogousslavsky 1991).

The ocular tilt reaction and lesions of the interstitial nucleus of Cajal. A lesion of the interstitial nucleus of Cajal, which lies immediately caudal to the rostral interstitial nucleus of the medial longitudinal fasciculus and rostral to the oculomotor nucleus, produces two distinct deficits: an ocular tilt reaction, and a deficit in vertical pursuit and vertical gaze holding (Halmagyi et al. 1990). The ocular tilt reaction is a head-eye postural synkinesis that consists of a skew deviation with a head tilt towards the side of the hypometric eye, and torsion of the eyes as incyclotropia of the hypermetric eye and excyclotropia of the hypometric eye. Such patients also show a deviation of their subjective vertical. Although the ocular tilt reaction is produced by a lesion of the interstitial nucleus of Cajal it can be found whenever peripheral or central lesions cause an imbalance of otolithic inputs (Brandt and Dieterich 1993).

Lesions of the thalamus can give rise to disorders of both horizontal and vertical eye movements (Clark and Albert 1995). Conjugate deviation of the eyes contralateral to the lesion, so-called wrong-way deviation is associated with haemorrhage in the medial thalamus. Thalamic haemorrhage may also lead to forced downward deviation of the eyes, associated with convergence and miosis. Caudal lesions in the thalamus have been associated with esotropia, which although usually associated with a downward gaze deviation may be present as an isolated finding. A paralysis of downgaze is associated with a caudal thalamic infarction, due to occlusion of the proximal portion of the posterior cerebral artery or its perforator branch, the thalamosubthalamic paramedian artery. However, the ocular motor deficit may well be due to damage to the rostral interstitial nucleus of the medial longitudinal fasciculus or its immediate premotor inputs.

Although it is generally accepted that the cerebellum plays an important role in the control of eye movements in man, pure lesions of the cerebellum without some brainstem involvement are unusual (Lewis and Zee 1993). This creates some difficulty in determining eye movement abnormalities specific for cerebellar dysfunction. It is appropriate to segregate lesions to three main regions of the cerebellum, each of which has a particular ocular motor syndrome: the dorsal vermis and underlying fastigial nucleus, the nodulus and ventral uvula, and the flocculus and paraflocculus. The dorsal vermis and underlying fastigial nucleus are involved in controlling saccadic accuracy and smooth pursuit. Lesions in this region lead to saccadic dysmetria, usually hypermetria, and mild deficits of smooth pursuit. The nodulus and ventral uvula are involved in the control of the low frequency response of the vestibulo-ocular reflex, and disorders in this region give rise to periodic alternating nystagmus, positional nystagmus, and impaired habituation of the vestibulo-ocular reflex, with increased duration of the vestibular responses. The flocculus and parafloculus are concerned with retinal image stabilization during smooth tracking with the head still, gaze-holding, control of the vestibulo-ocular reflex and its suppression, and pulse-step matching. Lesions of this region, therefore, lead to impaired pursuit and vestibulo-ocular reflex cancellation with gaze-evoked, rebound, centripetal, and downbeat nystagmus; and inappropriate amplitude of the reflex. Other signs which have been associated with cerebellar lesions, although precise localization is not available, include torsional nystagmus during vertical pursuit which occurs with a lesion in the middle cerebellar peduncle, square wave jerks, esotropia with alternating skew deviation, divergent nystagmus, primary position upbeating nystagmus, and centripetal nystagmus.

The cerebellum is also important in generating long-term adaptive responses which enable eye movements to be maintained appropriate to the visual stimulus. For example, when wearing lens corrections there is a magnifying or minifying effect which requires adaptive changes in the gain of the vestibulo-ocular reflex. These changes due to cerebellar adaptation take a few hours to days to occur and explain why some individuals experience difficulties when prescribed new lens.

The cerebral hemispheres are extremely important for the programming and co-ordination of both saccadic and pursuit conjugate eye movements (Fig. 13.4c). Since different areas are involved in these two types of eye movements they will be dealt with separately, always realizing that for fully effective ocular motor control, co-ordination between these subtypes of eye movement is essential.

There appear to be four main cortical areas in the cerebral hemispheres involved in the generation of saccades (review Leigh and Kennard 2004). In the frontal lobe in man there is the frontal eye field which lies laterally at the caudal end of the second frontal gyrus in the premotor cortex, Brodmann’s area 8, and the supplementary eye field which lies mesially at the anterior region of the supplementary motor area in the first frontal gyrus, Brodmann’s area 6. The third area is in the dorsolateral prefrontal cortex, which lies anterior to the frontal eye field in the second frontal gyrus, Brodmann’s area 46. Finally, a posterior eye field lies in the parietal lobe, possibly in the superior part of the angular gyrus, Brodmann’s area 39, and the adjacent lateral intraparietal sulcus. Studies in monkeys reveal that these areas are all interconnected with each other, and they all appear to send projections to the superior colliculus and the premotor areas in the brainstem-controlling saccades.

It appears that there are two parallel pathways involved in the cortical generation of saccades. An anterior system originating in the frontal eye field projecting both directly, and via the superior colliculus, to the brainstem saccadic generators. This pathway also passes indirectly via the basal ganglia to the colliculus. The second or posterior pathway originates in the posterior eye field passing to the brainstem saccadic generators via the superior colliculus. Only after bilateral lesions to both the frontal eye field and superior colliculus in monkeys is there a failure to trigger saccades.

Although the precise functions of these various cortical areas in saccade generation have not been determined, a number of general statements can be made. The frontal eye field is involved in triggering volitional saccades which, for example, may be predictive in anticipation of the appearance of a target, memory-guided to a previously seen target, or scanning so as to search for a particular target of interest. The posterior eye field could be involved in triggering reflexive saccades to the sudden appearance of novel visual or auditory stimuli, and appears to be involved in visuo-spatial integration and shifting visual attention. The dorsolateral prefrontal cortex may be responsible for maintaining a spatial map of the environment in short-term memory providing spatial information for memory-guided saccades and other volitional saccades as well as playing an important role in antisaccades, when a saccade is made to the mirror image location of a novel visual target, by inhibiting unwanted misdirected reflexive saccades to the target. The supplementary eye field appears to be involved in the generation of sequences of memory-guided saccades and complex ocular motor behaviours.

A subsidiary neural circuit related to saccade generation is from the frontal lobe to the superior colliculus via the basal ganglia. Projections from the frontal cortex pass to the substantia nigra pars reticulata, via a relay in the caudate nucleus. An inhibitory pathway from this nigral nucleus projects directly to the superior colliculus. This appears to be a gating circuit related to volitional saccades, especially of the memory-guided type.

To maintain foveation of a moving target the smooth pursuit system has developed relatively independently of the saccadic oculomotor system, although there are interconnections between the two. To visually track a target it is first necessary to identify and code its velocity and direction. This is carried out in the extrastriate visual area known as the middle temporal visual area, also called visual area V5, which contains neurons sensitive to visual target motion. In man, this lies immediately posterior to the ascending limb of the inferior temporal sulcus at the occipito-temporal border, Brodmann areas 19/37 junction. The middle temporal area sends this motion signal to the medial superior temporal visual area, which in monkeys is located on the anterior bank of the superior temporal sulcus, but in man is considered to lie superior and a little anterior to middle temporal area within the inferior parietal lobe (Petit and Haxby 1999). Damage to this area results in an impairment of smooth pursuit of targets moving towards the damaged hemisphere. Evidence of a possible contribution of the frontal eye field to the generation of smooth pursuit has recently been obtained in the monkey.

Both areas, medial superior temporal and the frontal eye field, send direct projections to a group of nuclei, which lie in the basis pontis of the pons. In the monkey, the dorsolateral and lateral groups of pontine nuclei receive direct cortical inputs related to smooth pursuit. Lesions of similarly located nuclei in man result in abnormal pursuit. These nuclei transfer the pursuit signal bilaterally to the posterior vermis, contralateral flocculus, and fastigial nuclei of the cerebellum. Finally, the pursuit signal passes from the cerebellum to the brainstem, specifically the medial vestibular nucleus and nucleus prepositus hypoglossi, and thence to the paramedial pontine reticular formation and possibly directly to the ocular motor nuclei. This circuitry, therefore, involves a double decussation, first at the level of the midpons, the pontocerebellar neuron, and second in the lower pons, the vestibulo-abducens neuron.

Disorders of saccades can be considered in terms of abnormalities of the saccadic pulse-step innervation pattern. A change in the amplitude of the pulse, either too big or too small, leads to saccadic hypermetria or overshoot, or to hypometric undershoot, respectively. Such a saccadic pulse dysmetria is associated with a lesion of the dorsal vermis in the cerebellum. A decrease in the height of the pulse, which implies disturbed function of the burst neurons in the paramedial pontine reticular formation or medial longitudinal fasciculus, leads to slow saccades. Many causes of slow saccades, several of which involve these areas, have been described (Table 13.12). A mismatch between the size of the pulse and the step (pulse-step mismatch) results in post-saccadic drifts and glissades. They are observed in diseases involving the vestibulo-cerebellum. If the pulse is not followed by a step, called a saccadic pulse, the eye drifts back to its previous position in a decreasing velocity exponential smooth eye movement. Both conjugate and monocular saccadic pulses may occur in patients with multiple sclerosis.

Disturbances in the initiation of saccades may lead to a prolonged latency, or the addition of a head movement or blink to initiate the saccade. This may be seen in congenital or acquired oculomotor apraxia, and various degenerative conditions including Parkinson’s disease (O’Sullivan and Kennard 1998), Huntington’s disease (Lasker and Zee 1997), and Alzheimer’s disease (Fletcher and Sharpe 1986).

Saccades may also occur inappropriately, particularly during attempted fixation. Square wave jerks are small amplitude saccades of up to 5 deg that take the eyes off fixation, followed some 200 ms later by a corrective saccade. Many normal subjects have these jerks at a low frequency of < 15/min, but elderly subjects often have a higher frequency. They are most prominent in cerebellar disease, progressive supranuclear palsy, multiple system atrophy, and schizophrenia. Macrosquare wave jerks (5–40 deg) are encountered in multiple sclerosis and olivopontocerebellar degeneration. Patients with diffuse cerebral cortex damage often exhibit large amplitude saccades away from the object of regard. After an interval of several hundred milliseconds the patient makes a saccade back to the target. These anticipatory saccades are particularly observed in Alzheimer’s disease.

Ocular motor apraxia is a term used for failure to generate saccades to commands, and may be of a congenital (Cogan 1952) or acquired type (Pierrot-Deseilligny et al. 1988). Congenital types may be recognized shortly after birth when the child does not appear to be fixating upon objects normally. At around 4–6 months the child develops the characteristic thrusting horizontal head movements, sometimes with blinking, when the child wants to change fixation. This manoeuvre serves to use the intact vestibulo-ocular reflex to drive the eyes into an extreme eccentric position in the orbit. As the head moves past the target, the eyes are dragged along in space until they align with the target. The head then rotates back and the vestibulo-ocular reflex ensure that fixation is maintained until the eye is in the primary position (Harris et al. 1996). Although the cause of congenital ocular motor apraxia is usually unknown some children are found to have a nonprogressive, noninheritable structural abnormality of the brain either a developmental anomaly or prenatal or perinatal insult, for example cerebellar hypoplasia, Dandy–Walker syndrome, or dysgenesis of the cerebellar vermis or corpus callosum. A variety of genetic disorders with multisystem involvement may present in infancy with congenital ocular motor apraxia including Joubet’s syndrome. Patients with congenital ocular motor apraxia usually improve with age. In certain diseases affecting the brainstem an acquired form of ocular motor apraxia similar to congenital types may occur. These include ataxia-telangectasia, cerebral Whipple’s disease, Gaucher’s disease, Niemann–Pick type C, some of the spinocerebellar ataxias, vitamin E deficiency and many other storage diseases and aminoacidureas.

A number of different disturbances of smooth pursuit are found (Morrow and Sharpe 1993). The commonest abnormality is a low gain, when gain = eye velocity/target velocity. This appears as deficient pursuit in which pursuit is broken by small catch-up saccades. Low gain pursuit can occur as a result of tiredness and inattention, as a side-effect of medications such as sedatives and anticonvulsants, or due to lesions in the vestibulo-cerebellum. Generally bilateral low gain pursuit has no localizing value. This is not the case with asymmetrical low gain pursuit, which usually occurs as a result of a lesion in the ipsilateral parietal lobe, thalamus, mid-brain tegmentum, dorsolateral nucleus of the pons, and vestibulo-cerebellum (Heide et al. 1996). Occasionally a disturbance of pursuit ‘tone’ or balance occurs due to cerebral hemisphere lesions, when the eyes drift towards the side of the lesion. Disturbances of direction can occur, for example, in congenital nystagmus in which there is an apparent ‘inversion’ of pursuit when the eyes move in an opposite direction to the motion of the target.

The commonest causes of disturbed vergence are congenital abnormalities. Various forms of convergence or divergence excess or insufficiency are usually accompanied by a concomitant strabismus associated with abnormalities of the accommodation-convergence synkinesis. Although this may not give rise to diplopia in childhood it can present as intermittent diplopia later in life. In particular convergence insufficiency is a common disorder in teenagers and university students, the elderly, and after relatively minor head trauma. Such individuals may show impaired phoria adaptation to prisms. It is usually treated by orthoptic exercises or prism therapy. Acquired forms of vergence disorders commonly occur in association with disturbances of vertical gaze as in the dorsal mid-brain syndrome, and in idiopathic Parkinson’s disease and particularly in progressive supranuclear palsy. Occasionally acquired cerebral lesions may give rise to impaired stereopsis and poor fusional vergence.

Convergence spasm, or spasm of the near triad, is only rarely due to an organic lesion and is usually a voluntary convergence in patients with a conversion syndrome (Sarkies and Sanders 1985). The organic form occurs most commonly with lesions at the diencephalic-mesencephalic junction, so called thalamic esotropia. This may be due to thalamic haemorrhage, pineal tumours, and mid-brain stroke. It may also rarely occur with lower brainstem and cerebellar disorders. However, the majority of patients presenting with convergence spasm have a psychological disorder. They often complain of discomfort and the convergence, which only lasts for a brief period on each occasion, may be associated with visual blurring, diplopia, and ‘eye strain’. It is often misdiagnosed as bilateral sixth nerve palsy, but an important clue to the correct diagnosis is the strong pupillary miosis which accompanies the convergence, and the observation of a full range of eye movements and less pupillary constriction with only one eye viewing. Treatment is best directed toward the underlying psychological factors, although cyclopegic eye drops and refractive measures may be effective.

These are covered in Sections 15.4 and 15.5.

There is an important distinction between saccadic oscillations, which are sustained oscillations that are initiated by fast saccadic eye movements, and nystagmus where the oscillations are initiated by smooth eye movements, thus the fast phase in jerk nystagmus is corrective and not primary.

Saccadic oscillations are bursts of saccades, which may be intermittent or continuous, causing a disruption of fixation. Two main types can be identified, those with intersaccadic intervals and those composed of back-to-back saccades.

The oscillations with intersaccadic intervals include square wave oscillations consisting of sequences of square wave jerks which can occur in Parkinson’s disease and progressive supranuclear palsy. Macrosaccadic oscillations straddle the intended fixation position and do not occur in the dark. The amplitudes, up to 40 deg, of sequential saccades increase in amplitude and then decrease in a crescendo-decrescendo pattern (Selhorst et al. 1976). This type of oscillation is usually observed in acute damage to the fastigial nucleus and its output in the superior cerebellar peduncles as in demyelination, tumour, or haematoma. It can also occur in some forms of spinocerebellar ataxia.

Oscillations without any intersaccadic interval, that is back-to-back, include opsoclonus, ocular flutter, and convergence-retraction saccadic pulses. Opsoclonus consists of multidirectional, including oblique and torsional, back-to-back saccades of varying amplitude (Averbuch-Heller and Remler, 1996) (Section 38.4.5). It is often associated with eye blinking, facial twitching, myoclonus, and ataxia. It has been suggested that the disorder arises due to disordered pause cell glycinergic function in the paramedial pontine reticular formation. It can occur in neonates associated with myoclonus producing ‘dancing eye and dancing feet’. This appears to be a maturational deficit, which resolves over approximately 6 weeks. In the teens and young adults it is often post-infectious. Other causes of opsoclonus are stroke, trauma, tumours, hyperosmolar nonketotic coma or drug induced by amitriptyline, lithium, phenytoin, cocaine. Opsoclonus is particularly associated with a paraneoplastic (non-metastatic) disorder, which in children is associated with occult neuroblastoma. Fifty per cent of children with opsoclonus have neuroblastoma and thus it is essential to exclude this tumour in all children with the condition. On the other hand only 2 per cent of children with neuroblastoma have opsoclonus. In adults it occurs in association with carcinoma of the lung (small cell), breast, and uterus. A number of anti-neuronal antibodies have been associated with opsoclonus, including anti-Hu, anti-Ri, anti-Yo, anti-Ma1, and anti-amphyphisin antibodies. Treatment may be offered with propranolol, verapamil, clonazepam, verapamil, and thiamine. Intravenous immunoglobulin may benefit those with postinfectious or idiopathic opsoclonus. The condition may disappear following tumour removal in the paraneoplastic variety.

Ocular flutter consists of bursts of back-to-back saccades in the horizontal plane only. It can therefore be observed in patients recovering from opsoclonus. Isolated ocular flutter is most often observed in patients with multiple sclerosis and signs of cerebellar disease. A voluntary form of flutter (voluntary flutter) can be induced by about 8 per cent of the population, usually by convergence. It consists of salvoes of horizontal back-to-back saccades. Lesions of the dorsal mid-brain are often associated with upward gaze palsies and convergence-retraction nystagmus (Ochs et al. 1979). This is incorrectly termed a nystagmus since it actually consists of adducting saccades and should be redesignated convergence-retraction saccadic pulses. Finally, a further type of saccadic oscillation is ocular bobbing (Susac et al. 1970). This consists of rhythmic, sudden, downward jerks of the eyes followed by slow return to the midposition, either immediately or after a short delay. The typical type, associated with pontine haemorrhage or infarction, is associated with paralysis of horizontal eye movements. Atypical bobbing is similar except that horizontal eye movements are intact, and occurs in metabolic encephalopathy, obstructive hydrocephalus, or cerebellar haematoma. When the fast movement is upward followed by a delayed slow return the condition is known as reverse bobbing.

Nystagmus is an oscillation which is initiated by a slow eye movement. When this slow movement is accompanied by a fast, saccadic, eye movement it is called jerk nystagmus. Although the direction of the nystagmus is conventionally determined by the direction of the quick phases it is important to remember that it is the smooth eye movement imbalance which is responsible for the nystagmus. If both phases are smooth eye movements pendular nystagmus is observed.

Vestibular nystagmus is the commonest form of jerk nystagmus and most frequently results from labyrinthine or vestibular nerve dysfunction. Several different types of central vestibular nystagmus are described, all of which show no change in intensity with the removal of fixation by using Frenzel goggles. This is in contrast to peripheral vestibular nystagmus in which removal of fixation leads to an increased intensity of the nystagmus.

Downbeat nystagmus may or may not be present in the primary position; it beats directly downwards and is often accentuated in downward and lateral gaze (Halmagyi et al. 1983). When it is present in the primary position a disturbance of the cerebellar flocculus is found, commonly due to a disturbance at the craniocervical junction such as an Arnold Chiari malformation, type 1 and foramen magnum mass lesions. Other causes include spinocerebellar degenerations, anticonvulsant drugs, lithium toxicity, and intra-axial brainstem lesions. In about one quarter of cases no cause can be found. The pathophysiology of downbeat nystagmus is thought to be an imbalance of the vertical semicircular canal pathways favouring the anterior canal.

Upbeat nystagmus when present in the primary position, is less well localized than downbeat nystagmus but is usually associated with focal brain stem lesions in the tegmental gray matter, either at the pontomesencephalic junction or at the pontomedullary junction, involving the nucleus prepositus hypoglossi or the ventral tegmental pathway of the upward vestibulo-ocular reflex (Fisher et al. 1983). It does not usually increase in lateral gaze as does downbeat nystagmus, but follows Alexander’s law becoming accentuated on increasing upgaze. Upbeat nystagmus may be influenced by head posture and downbeat nystagmus may convert to upbeat nystagmus in the supine position. Multiple sclerosis, tumour, infarction, Wernicke’s encephalopathy, and cerebellar degeneration are the commonest causes.

Torsional nystagmus is a jerk nystagmus around the anteroposterior axis. It is commonly associated with other types of nystagmus. However, when it is pure it indicates a lesion of the lateral medulla involving the vestibular nuclei such as syringobulbia and Wallenberg’s syndrome of lateral medullary infarction. Occasionally it may be due to a mid-brain or thalamic lesion, involving the interstitial nucleus of Cajal and medial longitudinal fascuculus.

Periodic alternating nystagmus is a primary position horizontal nystagmus that changes direction in a crescendo-decrescendo manner, characteristically approximately every 90–120 s (Fletcher 1993). Between each directional change there is a null period of 0 to 10 s. There is a congenital form which shows a less regular pattern, and acquired forms are due to Chiari malformations, multiple sclerosis, fourth ventricle tumours, spinocerebellar degenerations, and anticonvulsant intoxication. Ablation of the cerebellar nodulus and uvula which have a velocity-storage role mediated by the neurotransmitter GABA, in monkeys, causes periodic alternating nystagmus. Thus the GABA_b agonist baclofen has been shown to be an effective treatment (Halmagyi et al. 1980).

Gaze-evoked nystagmus is a common clinical observation with limited localizing value. It is a jerk nystagmus of amplitude > 4 deg, which is absent in the primary position and is only present and often asymmetric on eccentric gaze. It is due to a disturbance in the gaze-holding neural network, integrator neurons in the paramedian pontine reticular formation or inputs to them. Gaze-evoked nystagmus usually signifies cerebellar parenchymal disease, particularly involving the flocculus or its projections to the brainstem in the region of the medial vestibular nucleus and the nucleus prepositus hypoglossi. Bilateral horizontal, together with vertical, gaze-evoked nystagmus commonly occurs with structural brainstem and cerebellar lesions, diffuse metabolic disorders, and drug intoxication. A variant of gaze-evoked nystagmus is rebound nystagmus in which there is a jerk nystagmus that beats away from the previous direction present in eccentric gaze, which appears after the eyes return to the primary position. It usually lasts for 3–25 s, and is associated with parenchymal cerebellar disease.

Pendular nystagmus is either congenital or acquired and is usually due to cerebellar and brainstem disease, most frequently multiple sclerosis and brainstem infarction (Fletcher 1993). Acquired pendular nystagmus may have torsional and both horizontal and vertical components, with the amplitude and phase relationships of the two sine-waves for the horizontal and vertical components determining the final trajectory of the eyes as oblique, circular, or elliptical. This form of nystagmus only has slow phases without any fast phases. It can affect one eye or both, equally or unequally, and is often symptomatic resulting in oscillopsia. It may be associated with oscillations of other structures such as the palate, head, or limbs. When it is present in association with palatal myoclonus at 1–3 Hz, oculopalatal myoclonus, the lesion usually occurs several months after an infarction in the region of Mollaret’s triangle which consists of the red nucleus, dentate nucleus, and inferior olivary nucleus (Nakada and Kwee 1986). The latter nucleus usually shows pseudohypertrophic degeneration. However, the red nucleus is not known to be involved in eye movements and more recent explanations have proposed an interruption of a pathway from the deep cerebellar nuclei through the superior cerebellar peduncle, which then loops caudally through the central tegmental tract to the inferior olive. A combination of a convergence-induced slow pendular nystagmus 1 Hz and synchronous jaw contractions, called oculomasticatory myorhythmia, is characteristic of Whipple’s disease (Schwartz et al. 1986). However, it may also be observed in brainstem stroke and multiple sclerosis. In see-saw nystagmus one eye intorts and rises while the other eye extorts and falls in a rapidly alternating sequence. In this pendular form a bitemporal hemianopia is often present, and the condition is associated with large parasellar masses which have expanded up into the third ventricle and are distorting structures in the mesencephalic-diencephalic region (Daroff 1965).

Congenital nystagmus is almost invariably a horizontal conjugate nystagmus which is unaltered by vertical position. It is generally of jerk type with accelerating slow phases, and has an eccentric null position. Fixation effort enhances congenital nystagmus. Less commonly the nystagmus is of a pendular type. Reversed optokinetic nystagmus, beating in the direction of the target motion, is a feature of congenital nystagmus. Patients may show a head turn or occasionally a head oscillation (Dell’Osso and Daroff 1975).

Latent nystagmus is a type of congenital nystagmus that is only present on monocular viewing and which then beats toward the viewing eye (Gresty et al. 1992). It is absent on binocular viewing. If the patient has amblyopia in one eye latent nystagmus is present with both eyes viewing, then it is called manifest latent nystagmus.

The size of the pupil depends on the relative contraction of the iris sphincter and dilator muscles, supplied by the parasympathetic and sympathetic input, respectively. Disruption of the parasympathetic input results in a fixed dilated pupil ‘mydriasis’, whereas if the sympathetic input is damaged a small pupil ‘miosis’ ensues. Anisocoria is a difference in the size of the two pupils and may be physiological or due to under- or over-activity of the parasympathetic or sympathetic inputs.

The afferent pupillary light reflex pathway is a three-neurone reflex arc originating in the retinal ganglion cells, which project to the pretectal nucleus in the mid-brain (Loewenfeld 1993) (Fig. 13.7). Interneurons from this area project to the Edinger–Westphal subnucleus of the oculomotor nucleus at its rostral end. Passing from the Edinger–Westphal nucleus preganglionic, parasympathetic efferent pupillary fibres lie in the periphery of the oculomotor nerve, where they are particularly susceptible to compression by aneurysms of the posterior communicating artery. They then pass via its inferior division to the ciliary ganglion lying in the floor of the orbit, and reach the iris sphincter muscle via the short ciliary nerves. Interruption of this pathway from the mesencephalon to the sphincter muscle causes pupillary dilatation and decreased speed and amplitude of constriction in response to light.

At the optic chiasm a slightly higher proportion of afferent fibres cross into the contralateral optic tract with a ratio of crossed:uncrossed fibres which has been estimated at 53:47 (Kupfer et al. 1967). This may explain the afferent pupillary defect which is sometimes observed in patients with isolated retrochiasmal lesions. In the Edinger–Westphal nucleus there is a functional dissociation with the rostral portion containing mainly efferent neurones relating to accommodation and the caudal neurones involved in pupil constriction.

The pupillary near response results from accommodative effort induced by retinal image blur or conscious near fixation. It is part of the ‘near triad’ which consists of pupillary constriction, lens accommodation, and convergence of the visual axes. It is possible for a number of neural lesions to give rise to a dissociation of components of the near triad in which there is absent pupillary constriction with the other components remaining intact, but preservation of pupillary constriction with absence of convergence and lens accommodation does not occur.

The size of the pupil is in a constant state of flux adjusting to a variety of external stimuli, such as ambient illumination and fixation distance, as well as psychosensory stimuli. Pupillary diameter tends to be smaller in infants and older adults compared to young adults. A subtle anisocoria is often observed, and a difference in pupillary size of 0.4 mm or more is easily identified clinically in 20 per cent of the normal population. This so-called simple or physiologic anisocoria is associated with a pupil inequality which is the same under all lighting conditions, and the pupillary light reactions are equally brisk.

A unilateral lesion of the afferent pupillary pathway results in an impaired direct light reflex of the affected eye, sparing the consensual response elicited by stimulating the contralateral eye. If there is a complete lesion either in the retina or optic nerve there will be a complete failure of the direct light reflex. However, in most instances there is an impaired response which is best identified clinically by using the swinging light test. It is performed by using a hand-held torch with a bright light beam which is moved back and forth from one eye to the other, the light being held on each eye for approximately 1 s. When the light is shining in the normal eye the pupil is constricted and the contralateral consensual response is maximal. When the light is then shifted to the eye with impaired vision the direct light reflex is now reduced in comparison with the former consensual response resulting in further dilatation of the pupil (Thompson 1966). It is best to perform the test in a dimly lit room. The magnitude of the relative afferent pupillary defect may be estimated by placing neutral density filters over the normal eye until the responses from the two eyes are balanced (Thompson et al. 1981). A relative afferent pupillary defect does not occur when the visual loss is a result of refractive errors, opaque optic media, amblyopia, or functional visual loss.

The degree to which a relative afferent pupillary defect is identified due to retinal disease depends on the degree and location of the lesion. A small retinal detachment involving the macula may not result in an afferent pupillary defect, whereas a complete detachment will certainly do so. A useful clinical guide is that if ophthalmoscopy reveals a normal macula the presence of an afferent pupillary defect is unlikely to be due to retinal disease. Suppression amblyopia does not result in a relative afferent pupillary defect.

Optic nerve disease is commonly associated with a relative afferent pupillary defect, the magnitude of which correlates closely with the extent of the visual field defect and the visual acuity, particularly when due to optic neuritis (Ellis 1979). The absence of an afferent pupillary defect in a patient with unilateral visual loss and an otherwise normal eye should raise the possibility of bilateral optic nerve disease or non-organic visual loss. Bilateral optic nerve disease is suggested by a dissociation between the direct light reflex and the amplitude of the pupillary near response. Recovery of optic neuritis leads to a reduced degree of relative afferent pupillary defect but not usually to its absence.

A relative afferent pupillary defect may be observed in some patients with optic tract disease in association with a homonymous hemianopia (Bell and Thompson 1978). The defect is in the eye with the temporal field loss, and is thought to be due to the asymmetric decussation of optic nerve fibres at the chiasm as described above.

The pupillary fibres coming from the ipsilateral optic tract to the pretectal nucleus, via the brachium of the superior colliculus, may be involved by a unilateral lesion such as an arteriovenous malformation, infarction, or tumour (Wilhelm et al. 1996). This may produce a contralateral relative afferent pupillary defect without any loss of visual acuity or colour vision and without any visual field defect, although the afferent pupillary defect may occasionally be associated with an ipsilateral or contralateral trochlear nerve paresis.

The essential features of classic Argyll Robertson pupils, which are usually bilateral and symmetric, are miosis with poor dilation in darkness, absence or marked impairment of the light reflex, and relative preservation of the near response ‘light-near dissociation’. In addition the pupil may be irregular due to iris damage, and shows impaired dilatation to mydriatic drugs. For over a century, since the original description by Douglas Argyll Robertson in 1869 of the pupillary abnormalities subsequently shown to be associated with neurosyphilis (Section 42.5.1), there has been controversy regarding the site of the lesion. The most widely held current view (Loewenfeld 1993) is that the Argyll Robertson pupil is the result of neuronal damage in the region of the Sylvian aqueduct in the rostral mid-brain. Diffuse damage around the sylvian aqueduct and the posterior portion of the third ventricle is a prominent finding in patients with Argyll Robertson pupils who have died from tabes or general paralysis. In this location the damage interferes with the light reflex fibres and the supranuclear inhibitory fibres as they approach the visceral oculomotor nuclei.

As the incidence of tertiary syphilis has declined since the introduction of penicillin, the percentage of nonsyphilitic patients with Argyll Robertson pupils has increased. Typically they are observed in patients with diabetes mellitus (Smith and Smith 1983), chronic alcoholism, encephalitis, multiple sclerosis, age-related and degenerative diseases of the central nervous system, some rare mid-brain tumours, and rarely in systemic inflammatory diseases, including sarcoidosis and neuroborreliosis. However, the main differential diagnosis is with bilateral tonic pupils, which after many years become small, unreactive to light, and show light-near dissociation. The major distinguishing feature is the presence of tonicity of the near response in tonic pupils.

Pressure on the dorsal mesencephalon may produce Parinaud’s syndrome, also known as the dorsal mid-brain syndrome or the Sylvian aqueduct syndrome. This syndrome, due to damage in the region of the posterior commissure, includes a supranuclear vertical gaze palsy, disturbances of pupillary function, accommodation difficulties, and frequently convergence–retraction nystagmus. The pupils are usually midposition to large, fail to constrict to light or do so very poorly, and show relative preservation of the reaction to near vision ‘light-near dissociation’. It is considered that it is due to disruption of the ganglion cell axons entering the pretectal region. Dilated pupils due to an impaired light reflex may be the first sign of a pineal or other tumour that compresses or infiltrates the dorsal mid-brain, or from hydrocephalus, particularly if caused by aqueductal stenosis or a blocked shunt.

Mesencephalic lesions in the region of the oculomotor nerve nucleus nearly always damage both the sympathetic and parasympathetic pathways to the eye, resulting in slightly unequal and irregular pupils. Rarely in mid-brain lesions a phenomenon called correctopia occurs in which there is an upward, inward displacement of the pupil (Selhorst et al. 1976).

Involvement of the preganglionic parasympathetic fibres located in the periphery of the oculomotor nerve results in a dilated pupil which has an impaired or absent direct, consensual, and near response. Although such a finding suggests significant intracranial pathology, for example, an unruptured posterior communicating artery aneurysm, there is usually in addition some degree of ptosis and ophthalmoplegia. A dilated pupil exposes spherical aberrations of the lens and cornea which may give rise to blurred vision in patients with pupil involving third nerve palsies.

However, a dilated pupil which fails to respond either to light or to the near reflex raises the possibility of accidental or deliberate instillation of a pharmacologically active agent such as scopolamine, atropine, or some plant juices containing belladonna alkaloids. This can be reversed by instilling 1 per cent pilocarpine in contrast to the pupillary dilatation which occurs due to an oculomotor nerve palsy or a tonic pupil. The possibility of acute angle closure glaucoma must be considered in any patient presenting with pupillary inequality with reduced visual acuity or pain.

A rare condition of episodic unilateral transient pupillary dilatation with headache has been described in young women (Edelson and Levy 1974).

The commonest cause of abnormal unilateral pupillary light reactions and a dilated pupil is the tonic pupil, due to a lesion involving the preganglionic parasympathetic neuron. The essential feature of a tonic pupil is light-near dissociation, a slow steady near pupil response followed by the pupil holding its contraction for a few seconds and then redilating slowly when the patient is asked to look back into the distance. The tonic pupil is the result of damage to the ciliary ganglion or the short ciliary nerves resulting in denervation and subsequent reinnervation of the iris sphincter and the ciliary muscle. Several different causes have been found which have been classified by Thompson (1979):

Holmes–Adie syndrome. This is a relatively uncommon syndrome which usually occurs between 20 and 50 years of age. It has a clear predilection for women who constitute 70 per cent of cases. It is unilateral in 80 per cent of cases. The onset is usually acute with the patient often complaining of photophobia, particularly when going outdoors into bright sunlight, blurred near vision when reading, an enlarged pupil and headaches. The essential features of the pupil abnormality are a delayed and reduced amplitude light reaction. When the iris is viewed via a slit lamp in about 90 per cent of cases it can be seen that there is segmental contraction of the sphincter muscle ‘vermiform movements’ with other segments appearing paralysed ‘sectoral paralysis’. This is in contradistinction to a tonic pupil due to pharmacologic anticholinergic blockade in which the entire sphincter is paralysed. The near response which is tonic, however, results in contraction of all the sphincter muscle. The pupillary dilatation is also tonic. As a result of denervation hypersensitivity the tonic pupil constricts with a low concentration of pilocarpine 0.125 per cent, but a normal pupil will not. However, the value of this pharmacologic test has recently been questioned because of the false positive results due to the variable corneal penetration of pilocarpine. Deep-tendon hyporeflexia or areflexia, particularly of the ankle and triceps jerks, can be demonstrated in a substantial number of patients with Holmes–Adie syndrome (Thompson et al. 1979b).

The pathology of the Holmes–Adie syndrome is considered to be damage to neurons in the ciliary ganglion or the postganglionic short ciliary nerves, as has been observed in two post-mortem studies. The hyporeflexia or areflexia is probably due to a central lesion within the spinal cord. In one case degeneration was observed in the gracile and cuneate fascicles resulting from a reduction in the neuronal population in the dorsal root ganglia (Selhorst et al. 1984).

Two pathophysiological explanations have been proposed for the pupillary abnormalities. In the first Loewenfeld and Thompson (1967) proposed that some of the fibres originally destined for the ciliary muscle resprouted randomly, with some of the fibres reaching the iris sphincter and causing miosis every time the ciliary muscle was innervated. There is also a marked predominance of fibres arising from the ciliary ganglion passing to the ciliary muscle compared to those passing to the iris sphincter in a ratio of 97:3 per cent, making such aberrant reinnervation a likely outcome of damage to the ganglion. This explanation was challenged by Wirtschafter and colleagues (1978), who proposed that the iris sphincter remains permanently dennervated, and that the pupillary near-vision constriction results from acetylcholine released by the accommodative nerve endings in the ciliary muscle. This then diffuses to the pupillary sphincter via the aqueous fluid. On the basis of several clinical observations this hypothesis is not widely supported (Loewenfeld and Thompson 1981).

Follow-up of patients with the Holmes–Adie syndrome have shown the following changes over time (Thompson et al. 1979a):

An acute internal ophthalmoplegia followed by the development of a tonic pupil has been reported following a variety of infections, inflammations, and infiltrative processes which involve the ciliary ganglion. These include infections by herpes zoster, chickenpox, measles, diphtheria, neurosyphilis, rheumatoid arthritis, sarcoidosis, primary and metastatic choroidal and orbital tumours, blunt injury to the orbit and penetrating injuries, as well as following various ocular and orbital surgical procedures (Lowenstein and Loewenfeld, 1965).

This category consists of tonic pupils which are a result of involvement of the ciliary ganglion or short ciliary nerves as part of a generalized peripheral or autonomic neuropathy. These include those with chronic alcoholism, advanced diabetes mellitus, Guillain Barré syndrome, and the Miller Fisher variant and some hereditary neuropathies such as Charcot–Marie–Tooth disease. Those autonomic neuropathies, which can result in a tonic pupil, include acute pandysautonomia, Shy–Drager and Riley–Day syndromes, and Sjögren’s syndrome, in which the pupil abnormality may be the presenting sign.

A lesion anywhere along the long sympathetic pathway results in a typical Horner’s syndrome with miosis and ptosis. The central, first-order, neuron lies in the ipsilateral hypothalamus, and its axon passes to the ciliospinal centre in the intermediolateral gray column via the dorsolateral medulla. Here it synapses with the preganglionic second-order neuron in the upper three dorsal segments of the spinal cord. The axon from the preganglionic neuron exits the spinal cord at this level, passes across the pulmonary apex to ascend to the superior cervical ganglion via the inferior and middle cervical ganglia. The postganglionic, third-order, neuron passes from the superior cervical ganglion up along the internal carotid artery, where it is termed the carotid plexus. It leaves the internal carotid artery in the cavernous sinus, to briefly join the abducens nerve before leaving it to join the ophthalmic division of the trigeminal nerve, entering the orbit with its nasociliary branch.

The ptosis in Horner’s syndrome is usually mild, <2 mm, and is due to paralysis of the sympathetically innervated smooth muscle ‘Müller’s muscle’ in the upper eyelid. Similar smooth muscle fibres in the lower eyelid are denervated leading to a slight elevation of the lower lid, producing an ‘upside-down’ ptosis (Fig. 2.5). Combined these result in a narrowed palpebral fissure and an apparent enophthalmos. The ptosis is suggestive but not diagnostic of Horner’s sydrome since there are other causes for a mild ptosis such as senescent levator aponeurosis dehiscence, congenital dystrophy, myasthenia gravis, trauma or long-term contact lens wear. The miosis is due to complete or partial sympathetic denervation of the iris dilator muscle leading to constriction of the iris sphincter producing a small pupil. The weakness of the dilator muscle is greatest in the dark when the anisocoria is most apparent, and may be almost absent in the light. The extent of the anisocoria varies in extent depending on a number of factors which include completeness of the lesion and the extent of reinnervation, the alertness of the patient, the degree of denervation supersensitivity, and the level of circulating adrenergic substances in the blood. The pupil reacts normally to light and to near stimuli.

The paresis of the dilator muscle can be detected by observing a dilation lag of the affected pupil compared to the normal pupil when the lights are turned out. This is best performed observing both pupils by directing a dim torchlight on the eyes from below and turning the room lights out (Loewenfeld 1993). A simultaneous sudden noise accentuates the lag, due to enhanced sympathetic activation of the intact pupil.

Depigmentation of the affected iris is rarely observed in acquired Horner’s disease, although hypochromia of the iris is a common finding in the congenital form ‘iris heerochromia’.

Horner’s syndrome is also associated with characteristic vasomotor and sudomotor changes on the affected side of the face, such as loss of sweating (anhidrosis) and occasionally facial flushing. These changes are most frequently observed following preganglionic lesions, since the fibres for sweating pass onto the external carotid artery from the superior cervical ganglion.

On some occasions the presence or absence of a Horner’s syndrome may be in doubt, particularly if ptosis is absent. In this situation pharmacological pupillary testing is advisable. The cocaine test is used to diagnose an oculosympathopareis anywhere along the sympathetic pathway, and the hyroxyamphetamine test is used to determine whether the lesion lies in the central/preganglionic or the postganglionic segments. Cocaine blocks the reuptake of noradrenaline produced tonically by the postganglionic synaptic endings, but only if the entire three-neuron chain is intact. When applied to the eye it leads to a dilatation of the pupil (Thompson 1977). The test is performed by measuring the pupil size in the dark, and then instilling two drops of a 10 per cent solution of cocaine in each eye in turn. After 30 min the pupil size is remeasured in the dark and the affected pupil is found to have dilated less than the normal pupil. This occurs because the sympathetic denervation leads to a reduced release of noradrenaline and a reduced amount accumulates at the receptors of effector cells. A post-cocaine anisocoria of >1 mm or more signifies Horner’s syndrome. It is important to observe the diameter of the pupils in a dimmed room since the background ambient illumination may lead to pupillary constriction thereby obscuring the pharmacologically induced anisocoria. If mydriasis has not occurred in either eye an additional drop of cocaine should be instilled and the pupil size reassessed after 30 min.

Localization of the site of damage giving rise to a Horner’s syndrome usually depends on the associated clinical findings (Fig. 13.8). Lesions affecting the first-order and second-order neurones may be accompanied by signs of dysfunction of the brainstem and cervicothoracic spinal cord, respectively. Lesions involving the third-order,

post-ganglionic neuron are accompanied by signs of lesions affecting structures around the common and internal carotid arteries. The various aetiologies of Horner’s syndrome at these different levels are listed in Table 13.13. When trying to determine the location of the sympathetic lesion further pharmacological testing can be of assistance. Hydroxyamphetamine (1 per cent) causes the release of noradrenaline from sympathetic nerve endings and if applied to the normal eye results in pupil dilation (Van der Wiel and van Gijn 1983). It can, therefore, be used to differentiate between a post-ganglionic and a preganglionic or central Horner’s syndrome, since in the former the nerve endings are destroyed and there are no noradrenaline stores to release, and there is therefore no mydriatic effect. If the lesion involves the preganglionic or central neuron the pupil will dilate fully since the third-order neuron is intact. The hydroxyamphetamine test is performed in the same way as the cocaine test but at least 24 h should elapse after a cocaine test before it is instilled.

Using some straightforward principles Thompson and Pilley (1976) have described a straightforward approach to determine the cause for anisocoria. If the anisocoria is more apparent in light compared with darkness this suggests that there is a defect in the parasympathetic system or the sphincter muscles, since this implies that both pupils dilate in the dark but one pupil does not respond to light stimulation. If the opposite is observed, that is the anisocoria is more evident in darkness than in light, this suggests that the parasympathetic pathway and the iris sphincter are intact, since both pupils constrict in the light yet one pupil dilates more in darkness than the other.

A flow chart (Fig. 13.9) indicates the various steps required to differentiate between the different causes of anisocoria. The first step is to check the light reaction. A normal light reaction in both eyes suggests that the anisocoria is due either to simple anisocoria or a Horner’s syndrome. These two conditions can be differentiated using the cocaine test. A positive cocaine test may call for a hydroxyamphetamine test on another occasion to differentiate a post-ganglionic from a preganglionic and central sympathetic lesion.

If the light reaction in one or both eyes is impaired the patient has a parasympathetic lesion or a damaged iris sphincter. The iris is then viewed with a slit lamp to identify any iris damage. At this point it is necessary to differentiate a pharmacologically blockaded pupil from a neurogenic cause. Here, 0.1 per cent pilocarpine can be used to detect denervation supersensitivity of the parasympathetic system as occurs in a tonic pupil syndrome. If neither pupil constricts then a 1 per cent solution of pilocarpine will identify a dilated pupil due to pharmacological blockade, since the pupil will fail to constrict.

The orbit has a pear-like shape with the optic canal as the stem. The orbital walls, which are made up of seven bones (maxillary, frontal, zygomatic, ethmoid, sphenoid, palatine, and lacrimal), are of variable thickness and pierced by several fissures and foramina. The optic canal contains the optic nerve, oculosympathetic nerves, and the ophthalmic artery. The superior orbital fissure, formed by the greater and lesser wings of the sphenoid bone, admits to the orbit the three ocular motor cranial nerves III, IV, and VI, the ophthalmic division of the trigeminal nerve, and some sympathetic fibres. In addition the superior ophthalmic vein, which drains most of the orbit, passes through this fissure. The remainder of the venous drainage passes through the inferior orbital fissure, in the floor of the orbit, to join the pterygoid plexus. This fissure also contains branches of the sphenopalaitine ganglion. Since there are no valves in the orbital venous drainage system a carotico-cavernous fistula will lead to reversed flow in the venous system accounting for the marked venous congestion and orbital oedema.

The apex of the orbit is very crowded with the optic nerve emerging through the canal of Zinn, to which are attached the rectus muscles (intraconal portion of the orbit). This explains why enlargement of the extraocular muscles, as in dysthyroid ophthalmopathy, may lead to optic nerve compression. The ethmoid, sphenoid, maxillary, and frontal sinuses surround the orbit which allows spread of disease, especially infection and tumour, from these spaces to the orbit. The contents within the 25–30 cc of the bony orbit can be divided into the intraconal portion and an extraconal space.

Patients with orbital disease may present with a variety of symptoms including periorbital pain, double vision, blurred vision, swelling, proptosis, and ptosis.

Although several imaging modalities including ultrasound, CT, and MR scanning are available to aid the localization and diagnosis of orbital disease a systematic clinical examination enables one to use them appropriately. However, it is important to first carry out the standard assessment of visual function including visual acuity, colour vision, and visual fields.

The initial external examination focuses on the assessment of the appearance of the eye looking for any asymmetry, the position of the globe, swelling, and abnormal eyelid position. The eyelids may show ptosis or retraction, abnormalities of movement, in particular lid lag or lid ‘hang-up’ on asking the patient to look downwards and fatiguability on sustained upward gaze, and the presence of swelling or a mass. The conjunctivae are next examined for evidence of oedema or chemosis, dilated vessels, or neoplastic infiltration. The globe may show axial or non-axial proptosis. This is best judged by inspection alone and may be difficult to determine because of significant inter-individual and racial variation. Viewing the position of each corneal surface relative to each other from a vantage point above and behind or from below the patient referencing to a boney prominence, the brow or anterior orbital rim, respectively, can be helpful. Up to 2 mm of asymmetry is within normal limits, as measured by the Hertel exophthalmometer. Looking at old photographs can assist in estimating the time of onset of protrusion of the eye. The degree of retrocessability of the globe can be estimated by gentle backward pressure through the closed lid. Retrobulbar mass lesions will reduce the ability to push the globe back into the orbit, whereas blood-filled spaces, such as varices, allow compression and repositioning of the exophthalmic globe. Pain to palpation may accompany orbital infection and inflammation, while being uncommon in dysthyroidism and orbital tumours. Auscultation over the globe with the lids closed may reveal vascular bruits suggestive of arteriovenous malformations. Finally, ophthalmoscopy may reveal disc oedema (only if the first half of the optic nerve is compressed) or optic atrophy with optociliary shunts opening up to allow blood to flow between the retinal and choroidal circulation which occurs if there is obstruction of the central retinal vein and is suggestive of an optic nerve sheath meningioma. Choroidal or choroidoretinal folds and acquired hyperopia usually imply a retrobulbar mass lesion deforming the globe from behind, but can also occur in thyroid-associated ophthalmopathy, inflammatory diseases of the orbits, and mucocoeles.

A wide range of disorders can give rise to orbital involvement and are listed in Table 13.14 (Wright 1988).

Dysthyroid eye disease is also known as Grave’s orbitopathy, Grave’s ophthalmopathy, dysthyroid ophthalmopathy, thyroid orbitopathy, endocrine ophthalmopathy/exophthalmos. It is a self-limiting autoimmune disease usually associated with hyperthyroidism (Char 1997). It is the commonest orbital disorder in adults accounting for 32–47 per cent of cases and is associated with diplopia, ophthalmoparesis, and infiltration of extraocular muscles (Sergott and Glaser, 1981). It is usually accompanied by biochemical and immunological evidence of thyroid dysfunction, although this may not be apparent for months or even years. Pathologic examination of extraocular muscles in patients with dysthyroid eye disease shows infiltration by lymphocytes and plasma cells. The relationship between Grave’s disease and dysthroid eye disease is still controversial although it may result from antigenic similarity between the thyroid tissue and orbital tissue. It is thought that Grave’s disease results from clonally restricted B lymphocytes in the thyroid gland producing autoantibodies which act on the TSH receptor on thyroid follicles; these autoantibodies may lead to cytokine release resulting in the proliferation of orbital fibroblasts and increase in the synthesis of intracellular matrix proteins, glycosoaminoglycans, in orbital fat and eye muscles. As the disease progresses the infiltration and oedema of the extraocular muscles produce loss of muscle tissue, and the muscles become fibrotic (van der Gaag et al. 1996).

The early symptoms of this condition may take the form of discomfort, ocular irritation, scratchiness, or ‘burning’, which is typically worse when the patient first awakes. This may be associated with a feeling of orbital fullness and intermittent vertical diplopia. Photophobia and tearing are usual and blurred vision may be due to corneal exposure due to the proptosis or a central scotoma associated with a compressive optic neuropathy. Significant pain is relatively unusual, the onset is usually gradual with the symptoms developing over weeks, and usually there is evidence of bilateral involvement.

In the acute phase there is usually unilateral or bilateral lid retraction, in which the upper eyelid rests above the superior corneal limbus, accompanied by lid lag on downgaze and lid puffiness

(Fig. 13.10). Conjunctival chemosis and injection overlying the insertions of the horizontal rectus muscles are routine. Periorbital oedema varies in degree and may be extreme. Proptosis is present in approximately two-thirds of patients. These signs usually precede the disturbed ocular motility which is frequently observed in this disease, and is usually due to a restrictive myopathy which has a predeliction for the inferior rectus and the medial rectus muscles leading to impaired ocular elevation and abduction, respectively (Fells et al. 1994). In more advanced cases the affected eye becomes hypotropic, and if the medial rectus is similarly affected esotropia may result. If these ocular motility disturbances are found in the context of other typical signs of dysthyroid eye disease the diagnosis is assured. However, in other cases the florid stage is limited and subclinical, and the patient presents with an ophthalmoparesis which has to be differentiated from an ocular motor nerve palsy. To differentiate this from the restrictive myopathy of thyroid eye disease the forced duction test is used. In this test an attempt is made to move the globe with a forceps under topical anaesthesia, into its appropriate field of gaze. CT or MRI of the orbit reveals characteristic enlargement of the rectus muscles, the most frequently affected being the medial and inferior rectii. Although the diagnosis is supported by the demonstration of thyroid-associated autoantibodies and abnormal thyroid function, it is important to remember that these may be absent, and this should not dissuade the clinician from a diagnosis of dysthyroid eye disease if the clinical signs are compatible. Finally it should be remembered that these patients can also develop another autoimmune disease, myasthenia gravis, which can lead to a worsening of the oculomotor abnormalities. There is evidence that cigarette smoking exacerbates dysthyroid eye disease so patients should be advised to quit tobacco (Pfeilschifter and Ziegler 1996).

Management Approximately 2–9 per cent of all patients with dysthyroid eye disease develop visual loss which requires urgent treatment (Neigel et al. 1988) However, since it is impossible to predict which patients will develop an orbitopathy, initial management of the condition is based on rendering the patient euthyroid and using symptomatic therapy such as topical drops and ointments for ocular lubrication, and elevation of the head of the bed at night for oedema. The disorder is self-limiting, usually lasting between 18 and 36 months, before spontaneous improvement in two-thirds of patients.

Worsening of the symptoms, with evidence of infiltrative disease causing myopathy and increased orbital congestion can usually be managed by immunosuppression with corticosteroids or radiotherapy. Systemic corticosteroids in doses up to 120 mg daily, or 1 mg to 1.5 mg/kg (Wiersinga 1996), are used. Benefit is usually apparent within 3 weeks. It may be necessary to add steroid sparing drugs such as cyclosporine. There is some evidence that dysthyroid eye disease can be made worse in patients treated with radioactive iodine for hyperthyroidism. If this is contemplated the patient should be treated with steroids.

Lens sparing, low dose orbital radiotherapy at 1500–2000 cGy in divided fractions over 10 days, should be used if there is a failure to adequately respond to steroids. Usually this produces good results in 7 per cent of patients, although the response may take several weeks. There is now evidence that this therapy should be discussed earlier in the course of the disorder than previously was the case (Kazim et al. 1991).

Failure to respond to either therapy, particularly if a compressive optic neuropathy or severe proptosis with corneal exposure keratitis are present, requires surgical orbital decompression. The surgical treatment of choice is transantral orbital decompression into the ethmoid and maxillary sinuses, although other approaches have been proposed. It should not be used in the acute management of proptosis unless there is sight-threatening disease. In the fibrotic phase of the disease restrictive myopathy may require extraocular muscle surgery to restore binocular single vision, and retracted lids may require plastic surgery.

Idiopathic orbital inflammatory inflammation or orbital pseudotumour are the terms used for an acute syndrome consisting of painful proptosis, orbital congestion, periorbital oedema, conjunctival swelling or chemosis, and injection, diplopia, and sometimes visual loss, for which a specific cause cannot be found after systematic inflammatory conditions such as syphilis, tuberculosis, sarcoidosis, Wegener’s granulomatosis, or collagen vascular disease, polyarteritis nodosa, and systemic lupus erythematosis have been excluded (Lakke 1962; Kline 1982). It may be diffuse or selectively affect any orbital structure resulting in one or more specific symptoms or signs. Histopathologically orbital pseudotumour consists of a mixed cellular infiltrate including lymphocytes, neutrophils, and eosinophils. Some accounts of this condition divide it into different entities depending on the structure involved e.g. sclera (posterior scleritis), lacrimal gland (dacryoadenitis), cavernous sinus/superior orbital fissure (Tolosa–Hunt syndrome), extraocular muscle (myositis), and diffuse orbital (idiopathic orbital inflammation), but they are probably all due to the same pathological process. Orbital lymphoma may be particularly difficult to exclude, even with biopsy material.

The condition is usually unilateral, although occasionally it may be bilateral, and it affects both children and adults. Involvement of one or more extraocular muscles may lead to a painful ophthalmoplegia. Many patients experience a general malaise. The condition may run a chronic remitting course with gradual worsening, or spontaneous remissions may occur.

The CT appearance of orbital pseudotumour varies depending on the orbital structures which are preferentially affected, include contrast enhancement, retrobulbar fatty infiltration, proptosis, extraocular muscle enlargement, optic nerve thickening, and uveoscleral thickening. It may also show muscle tendon sheath involvement, which is spared in dysthyroid eye disease. MRI studies show that on T1-weighted images the lesions are hypointense to fat and isointense to muscle. T2-weighted images show lesions which are isointense or only minimally hyperintense to fat, in contradistinction to the markedly hyperintense signal obtained from orbital metastasis, a not infrequent differential diagnosis.

Patients with this constellation of signs, in whom no other cause can be found, should be given a course of systemic corticosteroid treatment consisting of 80–100mg prednisolone. Corticosteroids usually produce a dramatic response within 48 h of commencement and failure to do so requires revaluation of the diagnosis. When the expected initial response occurs the steroid dose is tapered and may be titrated against the symptoms and signs. If the patient has chronic recurrences after tailing off the corticosteroids, azothiaprine and cyclosporine may be alternatives. In patients who have contraindications to systemic corticosteroids orbital radiotherapy at 1000–2000 cGY can be of value.

A variety of tumours may involve structures within the orbit (Shields et al. 1984). These include neurogenic tumours (meningiomas, gliomas, and schwannomas), vascular lesions (cavernous haemangioma), cystic lesions (dermoids), lymphoproliferative lesions (lymphomas), and secondary tumours (metastatic and contiguous spread). The location of the mass in the orbit is often a clue to their nature. They may be intraconal (within the cone of the extraocular muscles), extraconal, and periorbital (outside the orbit, but impinging on its structures).

Intraconal tumours cause forward displacement of the globe. These include tumours which may be primary, such as optic nerve sheath meningiomas and optic nerve gliomas (Section 12.5.4), or secondary due to metastases. One of the commonest orbital tumours in adults which has an affinity for the intraconal space, is the cavernous haemangioma. They usually present as a painless proptosis and slowly enlarge over a period of many years. Their CT or MRI appearance is of a well-circumscribed homogeneous mass which shows marked enhancement with contrast. Complete surgical excision is the treatment of choice.

Proptosis may be due to venous anomalies or varices. These may exhibit increased proptosis on Valsava manoeuvre or on bending forward. Their CT appearance is characteristic, and non-intervention is appropriate.

Orbital lymphoma is one of the commoner orbital tumours either in its primary form or as a manifestation of a systemic lymphoma. It may be difficult to differentiate from idiopathic orbital inflammation.

The commonest metastatic tumours to the orbit come from breast in 42 per cent, lung in 11 per cent, and prostate in 8.3 per cent. Although patients may present with proptosis, scirrhous breast carcinoma may cause enophthalmos. Any proptotic patient who has a history of treatment of cancer must be suspected of having an orbital metastasis. Histologic verification is mandatory before treatment.

Orbital tumours in the extraconal space cause downward or upward displacement of the globe, when located in the superior and inferior orbital spaces respectively. They may arise in the extraconal space, extend into it from surrounding structures, or be metastatic from distant sources. A rapidly developing unilateral proptosis in a child is likely to be an orbital rhabdomyosarcoma. Tumours frequently located in the superior orbital space are dermoid tumours and mucocoeles, and less frequently lesions of the lacrimal gland and fibrous dysplasia.

The main types of neuro-ophthalmic vascular disorders are the high-flow carotid-cavernous sinus fistulas and the low-flow spontaneous dural-cavernous sinus shunts which produce overlapping clinical syndromes (Keltner et al. 1987). The communication between the arterial and venous systems leads to a rise in the venous pressure in the globe resulting in a fall in the arterial perfusion pressure, and a major drop in perfusion pressure.

Fistulas may be classified (Barrow et al. 1985), according to the velocity of blood flow through the shunt, into low- and high-flow fistulas; the anatomic origin of the arteries supplying the fistula, and their aetiology which may be spontaneous or traumatic:

Direct fistulas may occur at any location along the length of the intracavernous portion of the internal carotid artery and commonly occur as a result of both penetrating or non-penetrating head trauma and from aneurysmal rupture. There may be a delay of days or even weeks for symptoms to develop following injury. The common signs are proptosis associated with chronic conjunctival

injection and oedema, and an audible bruit. The conjunctival veins may be arterialized and appear as corkscrew vessels that go to the limbus. Because of connections between the two cavernous sinus’s a unilateral fistula may give rise to bilateral ocular signs. Damage to cranial nerves and sympathetic and parasympathetic fibres in the cavernous sinus may lead to diplopia and pupillary abnormalities. The commonest cause for diplopia is an abducens nerve palsy. The definitive diagnosis of carotid cavernous fistula is made by selective intra-arterial angiography.

There are several potential causes for the visual loss commonly seen in cavernous sinus fistulas, which include: corneal damage due to exposure; retinal artery occlusion; glaucoma due to raised episcleral venous pressure or rarely to iris neovascularization; macula involvement due to ischaemia, haemorrhage or cystoid oedema; anterior segment ischaemia; retinal artery occlusion; optic nerve ischaemia, and corneal decompensartion due to exposure. Ophthalmoscopy reveals features of a slow flow retinopathy, which include blot haemorrhages, microaneurysms, mild disc swelling, and venous congestion and tortuosity. Occasionally a picture similar to a complete central vein occlusion may occur (Brosnaham et al. 1992).

Without treatment the ocular abnormalities will progress, leading to blindness. A variety of endovascular procedures have been developed for cavernous sinus fistulas with the aim of closing the fistula and maintaining the patency of the distal internal carotid artery. These include electrometallic thrombosis using coils and detachable balloon occlusion.

These slow flow indirect cavernous fistulas are thought to be due to rupture of congenital arteriovenous anomalies, which usually occur in middle-aged women. The clinical manifestations depend on the direction of venous outflow from the fistula. If anterior then the signs are similar, but less dramatic, to those which occur with direct carotid cavernous fistula, including conjunctival venous arterialization, orbital congestion, and proptosis. Posterior drainage may cause cranial nerve palsies, most commonly of the abducens nerve. A bruit may not be present. Less commonly, choroidal detachment and angle closure glaucoma develop as a result of altered venous outflow.

Treatment should be conservative, as between 20 and 50 per cent of spontaneous dural carotid cavernous fistulas close spontaneously, not infrequently after carotid angiography. If vision is threatened then endovascular therapy is indicated (Kupersmith et al. 1988).

Orbital infections are potentially sight- and life-threatening, so require urgent evaluation and treatment. The presentation may be acute as occurs with bacteria or more insidious when due to fungal infection. Patients with orbital cellulitis present with proptosis, periorbital swelling, and ophthalmoplegia associated with pyrexia and a peripheral leucocytosis. Most patients will have contiguous sinus disease commonly of the ethmoid sinus, with the frontal and maxillary sinuses being involved less frequently. Organisms can spread into the orbit through valveless veins from the face, teeth, and neck. If the cellulitis occurs in the context of trauma, scanning must be performed to locate any foreign body, which must then be removed.

The causative agent must be sought by culture of both the blood and any purulent wound drainage. The most likely organisms are Haemophilus influenzae in children, Staphylococcus aureus, and Streptococcus pneumoniae. As soon as blood cultures have been obtained the patient should be treated with intravenous broad-spectrum antibiotics to cover the possible causative organisms, until the specific organism has been identified. Surgical drainage may be necessary if despite antibiotics there is worsening proptosis or visual loss suggestive of an orbital abscess.

Patients presenting with an orbital cellulites who either have diabetes mellitus or are immunocompromised, should be considered to have mucormycosis until proven otherwise (Section 42.3.7). Early symptoms include sinusitis, orbital pain, and sudden visual loss (Gass 1961). The organism causes an obliterative arteritis which results in necrotic lesions appearing in the skin, orbit, nasal mucosa, or palate, although this is infrequently present at the onset of symptoms. If mucormycosis infection is suspected, a complete nasal examination should be undertaken to identify the typical black eschars of mucor. Prompt treatment with amphotericin B and surgical debridement ensuring adequate sinus and orbital drainage is essential.

The clinical approach to diagnosing a patient presenting with proptosis depends on aspects of the history as well as a careful examination (Section 13.4.1). The patients’ past medical history may provide evidence of previous thyroid disease suggesting thyroid eye disease, diabetes mellitus raising the possibility of a mucormycosis infection, or of previous tumour surgery suggesting possible metastatic infiltration. The family history may also provide clues; for example, if members of the family have a history of skin lesions, epilepsy, or brain tumours this raises the possibility of an optic nerve glioma being the cause of the proptosis due to neurofibromatosis.

The tempo of development of the proptosis and the presence or absence of pain are also important features to ascertain. A rapidly developing proptosis in a child would immediately raise the suspicion of a malignant tumour such as a rhabdomyosarcoma or metastatic neuroblastoma. Such a rapid painless onset in adults suggests a metastatic tumour, but if associated with pain the diagnosis includes orbital cellulitis and inflammatory orbital pseudotumour, all of which may be associated with diplopia. If there is a history of intermittent painful proptosis the most likely aetiologies are venous varices or lymphangiomas.

When the tempo of development of the proptosis is unclear evidence for earlier proptosis than is often recognized by the patient can be derived from viewing antecedent photographs. If the history or photographs suggest a more slowly progressive painless course then thyroid eye disease or an orbital tumour should be considered. If the tumour is associated with visual impairment due to associated involvement of the optic nerve, which occurs some time after the onset of the proptosis, the mass is probably within the anterior or mid-third of the orbit. If, however, the visual loss precedes the proptosis the mass is more likely to lie in the posterior third of the orbit. More anterior lesions tend to cause horizontal diplopia, whereas apical or posterior masses cause vertical diplopia due to impaired vertical gaze.

Other symptoms should be sought, such as swishing noises in the head suggestive of a carotid cavernous fistula, a history of chemosis and lid swelling upon rising in the morning associated with photophobia, lacrimation, and burning suggestive of thyroid eye disease, and increasing proptosis with raised intra-abdominal pressure during the Valsalva manoeuvre or change in position suggestive of an orbital varix or mucocele.

Painful proptosis is relatively uncommon and the differential diagnosis includes acute orbital inflammation, metastases, acute thrombosis of orbital varices and of the enlarged veins associated with an AV fistula. It should be remembered that there are other causes for orbital pain including the superior orbital fissure/cavernous sinus syndrome or referral from the dura.

Once a satisfactory history has been obtained an examination of the orbit and its contents, as described above, should be undertaken. This should help to refute or substantiate clues to the diagnosis which have been obtained from the history and so enable the clinician to order the appropriate investigations necessary to confirm the diagnosis.