Clinical Disorders of the Eyelid and Its Interaction with Saccades

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Disorders of Blink Frequency

The spontaneous blink frequency shows a high interindividual variability (10-30/min; on average, 24 blinks/min) [89]. The mean amplitude and peak velocity of spontaneous blinks decrease with age. This is also true of voluntary blinks, but to a less extent [90, 91]. Here, the narrowing of the palpebral fissure width probably plays a role. Alternatively, the reduction in the blink main sequence could reflect a reduction in OO motoneuron activity, which compensates for age-related increases in blink reflex excitability. In contrast, blink frequency and blink conjugacy do not change with age [90, 92]. Blink frequency is strongly modulated by attentional mechanisms under normal and pathological conditions, e.g., in schizophrenic patients [93]. In contrast to reflexive blinks, voluntary blinks may crucially depend on internal vs. external commands, e.g. in parkinsonian syndromes.

Special forms of increased blink frequency are lid nystagmus and eyelid tremor. Lid nystagmus is usually associated with eye movements, is gaze dependent, and modulated by vergence eye movements [94, 95]. It reflects a slow downward drift of the lids with correcting upward jerks of the upper eyelid. Due to the tight lid-eye coupling, vertical nystagmus may be associated with lid nystagmus. While it may be benign [96], it is usually associated with lateral medullary infarction [97] or cerebellar or midbrain disease, e.g. low-grade astrocytoma compressing the CCN [98]. Lid nystagmus may outlast vertical nystagmus [99]. Lid nystagmus may also occur without eye nystagmus due to midbrain lesions [25, 98, 100]. Vestibular stimulation in midbrain-lesioned monkeys causes an upward lid nystagmus, although upbeating nystagmus was abolished [101]. Lid nystagmus with a horizontal nystagmus is found in lateral medullary lesion (Wallenberg's syndrome), which may be inhibited by convergence [97]. In contrast, eyelid nystagmus may also be elicited by convergence in medullary and cerebellar lesions (Pick's sign) [94, 102, 103].

Eyelid tremor is defined as regular eyelid twitches of 7 Hz and is usually not gaze dependent. In contrast, blepharoclonus consists of repetitive eyelid jerks at a slower frequency (2-4 Hz) and may be induced by eye closure [104]. Eyelid tremor may be associated with parkinsonian syndromes [105], but also paramedian thalamic lesions [106]. It is still not known whether the presumed disinhibition of LPM and OO muscle activity is related to the thalamus, the extension of the lesion into the midbrain, or disconnecting cortical areas involved in voluntary lid control. Pathophysiologically, inappropriate contractions of LPM and OO with disturbed reciprocal inhibition have been proposed [19].

In animal experiments, blink rates significantly and positively correlated with the concentration of dopamine in the caudate nucleus, and the severity of experimentally induced parkinsonism was inversely correlated with the blink rate [107]. Accordingly, since spontaneous blink frequency probably reflects central dopamine activity, it is characteristically decreased in parkinsonian syndromes (17 blinks per minute) [108], although it may vary in the 'off' and 'on' periods of patients with fluctuating Parkinson's disease (PD) [109]. Blink rate decreases as PD advances [110], but also de novo PD patients who have not been exposed to dopaminergic therapy show decreased blink rates [108]. The blink rate in patients with levodopa-induced dyskinesias has been shown to be higher than that in optimally treated PD patients and normal individuals [111]. It is consistently found to be decreased in progressive supranuclear palsy (PSP) [112], patients with PD [89], and those patients who receive dopaminergic medication [113], whereas it is not changed in Huntington's disease and dystonia. The strongest decrease is found in PSP patients (4 blinks per minute) [89]. In addition, dopaminergic basal ganglia circuits play a role in the inhibition of LPM during blinks and eye closure [19]. As a major adverse effect, decreased blink rate in PD leads to ocular surface irritation (blepharitis), the most common ocular complaint of PD patients [108].

Apart from recording changes in blink rate, the blink reflex has been established to be a reliable diagnostic tool for assessing the site of brainstem lesions, in particular lesions in the dopaminergic circuit, which controls eyelid blink. The blink reflex is known to be hyperexcitable in PD [92, 114-116]. Pathophysiologically, the loss of dopamine in the substantia nigra pars compacta may lead to increased reflex blink excitability. Descending inhibitory pathways from the basal ganglia modulate the excitability via tectoreticular projections. Decreasing the basal ganglia inhibitory output to the SC and electrical stimulation of the SC reduce blink hyperexcitability and blink amplitude [114]. According to the latter model, the substantia nigra pars reticulata inhibits SC neurons, which excite tonically active neurons of the raphe magnus nucleus. The latter inhibits spinal trigeminal neurons involved in reflex blink circuits [115]. Thus, changes in reflex blink excitability and blink amplitude may help to detect early or preclinical signs in PD. Since a reflex blink inhibits subsequent blinks, the magnitude of a blink reflects a balance between inhibitory and facilitatory processes [117].

Disorders of Tonic Eyelid Position

The eyelid position is greatly influenced by cortical and brainstem mechanisms. Thus, ptosis may result from midbrain and cortical lesions. Midbrain lesions involving the caudal third nerve nucleus (CCN) elicit complete bilateral ptosis since the LPMs are deficient [118-123]. Nuclear third nerve lesions with CCN involvement may elicit bilateral ptosis with contralateral superior rectus paresis [124]. Isolated CCN lesions are rare but may preserve ocular motility [125, 126]. In contrast to the complete ptosis in lesions of the LPM, sympathetic lesions elicit a slight upper lid depression, e.g. in Horner's syndrome, which may be caused by carotid artery occlusion or dissection (peripheral) or lateral medullary infarctions (central Horner's syndrome) [120]. Unilateral ptosis may result from fascicular or peripheral third nerve palsy [127] or large hemispheric lesions, probably related to descending corticonuclear pathways of eyelid control [120]. Weber's syndrome and Claude's syndrome reflect unilateral fascicular third nerve lesion with contralateral hemiataxia or hemiparesis. Cortical bifrontal or unilateral, predominantly right-hemispheric, lesions may elicit bilateral ptosis [31, 32, 128, 129]. Controversial data exist as to which side is more strongly affected: the contralateral [120] or ipsilateral eye [32]. Fourteen of 24 patients with hemispheric strokes had predominantly ipsilateral ptosis, which is probably related to an associated facial weakness superimposed on the asymmetry of the palpebral fissures of bilateral partial ptosis [32]. Otherwise, the common concept of a single motor nucleus innervating both levators would have to be challenged.

Two additional conditions with involuntary eyelid closure or the inability to open the eyelids are blepharospasm and blepharocolysis. Pathological involuntary eyelid closure may result from a deficient excitation, a prolonged inhibition of the LPM (blepharocolysis), or involuntary excitation of the OO muscles, e.g. focal dystonia (blepharospasm).

Blepharospasm is an excessive involuntary focal dystonic unilateral or bilateral contraction of the OO muscles with LP muscle cocontraction. It is characterized by frequent and prolonged blinks, clonic bursts, and prolonged tonic OO contraction [130]. Clinically, the brows are lowered below the superior orbital rim (Charcot's sign). Accordingly, EMG recordings of the LPM and OO muscles simultaneously show impaired timing of the reciprocal inhibition, which may lead clinically to dystonic blinks [48] and electrophysiologically facilitate the R2 component of the blink reflex [131]. Cases of unilateral lid spasm may occur in conjunction with unilateral or hemifacial spasm.

The most common cause of hemifacial spasm is irritation of the seventh nerve roots by a dilated or tortuous vascular structure. Blepharospasm has also been reported to occur with thalamic [132, 133], subthalamic [132, 134], and brainstem [135, 136] lesions, but it is often associated with PD or PSP [137]. Benign essential blepharospasm may be caused by an overexcitatory drive of the basal ganglia. As initial treatment, artificial tear drops are recommended, since ocular surface irritation (due to decreased blink rate) may also contribute to increased OO tone [108]. Blepharospasm may also be secondary to Bell's palsy and may be relieved by passive eyelid lowering [138]. Otherwise, injections of botulinum toxin to weaken the affected muscles, in particular the pre-tarsal portion of the upper eyelid, are the appropriate treatment [139-141]. Blepharospasm may be restricted to dystonic contraction of only the pretarsal portion of the OO without concomitant contraction of the OO (pretarsal LP inhibition, pretarsal blepharospasm) [142]. In contrast to the typical ble-pharospasm, the eyes appear to be nearly closed, and there is a concomitant contraction of the frontal muscles and elevation of the brows. Moreover, the blink frequency is reduced. Patients usually suffer from PD or PSP. Tactile sensory stimulation (eyelash touching or glabellar tapping) may help to release the dystonic position.

Blepharocolysis is a similar - possibly identical - condition characterized by an excessive involuntary closure of the eyelids due to involuntary LPM inhibition. The inappropriate, synonymous term 'apraxia of eyelid opening,' previously widely used, describes the inability of voluntary eyelid opening [143] and of sustained lid elevation [139] caused by an involuntary LPM inhibition. In contrast to blepharospasm, blepharocolysis is due to an involuntary overinhibition of the levator palpebrae superioris muscles with no evidence of ongoing OO activity; it coexists with a coinhibition of these muscles [130], as confirmed by simultaneous EMG recordings of the LP and OO muscles [139]. EMG recordings help to separate pretarsal blepharospasm from blepharocoly-sis and to make adequate therapeutic decisions. Since reflectory blinks remain largely unaffected, it is likely to be a disorder of the supranuclear LP control. However, the mechanism is only partly understood. Blepharocolysis is associated with PD, PSP, motor neuron disease, and putaminal [144] and subthalamic lesions [134]. Its prevalence is about 10% in patients with dystonia, and about 2% in patients with parkinsonian syndromes (PD, 0.7%; PSP, 33.3%) [145].

Finally, under certain circumstances, the activity in the OO may only persist on voluntary eyelid opening but not when the eyes are open. This form of pretarsal motor persistence [139] does not reveal any lid depression and is therefore distinctly different from blepharocolysis. It also responds positively to botulinum toxin.

Although lid retraction also reflects a tonic eyelid disorder, it leads to impaired eyelid-eye coordination and will be discussed below.

Disorders of Eyelid-Eye Coordination

Lid-eye coordination is preserved in most pathological eye movements. For example, in vertical nystagmus the lid usually accompanies the eye movement [146]. Disorders of eyelid-eye coordination occur when lid saccades are impaired but eye saccades preserved. Involuntary lid movement without accompanying vertical eye movement, e.g. in lid nystagmus, is less frequent. Lid nystagmus without vertical nystagmus may be elicited on horizontal gaze, e.g. reported in a case of midbrain astrocytoma [98]. In midbrain lesions in the monkey, vestibular stimulation caused an upward lid nystagmus, although the upbeat nystagmus was abolished [101].

In accordance with the anatomical connections outlined above, lid nystagmus may imply lesions of the M group, the nPC, or their reciprocal connections.

Lid lag and lid retraction are the most common disorders of impaired eyelid-eye coordination [147]. Whereas lid lag is a dynamic sign, which can be observed on downgaze, lid retraction is a static phenomenon.

Lid retraction is diagnosed when the sclera is seen above the corneal limbus during steady fixation. It indicates inappropriate LP muscle activity, presumably related to neurogenic disinhibition of LP [19], but EMG evidence is still missing. The basal tonic LPM activity is likely to be under the inhibitory control of the nPC [12]. Deficient inhibition would result in lid retraction on gaze straight ahead or lid lag with downgaze [147]. A clinicopathological retrospective correlation study based on animal [18, 148] and human [149] case studies delineated the nPC as the most likely lesion site for lid retraction [19]. This is consistent with very few eyelid-and vertical saccade-related burst neurons that have been recorded in nPC [150].

Although lid lag and lid retraction may occur together [151], a feasible pathomechanism has to account for lesions that cause only either lid lag or lid retraction. A single case report showing a patient with slow vertical saccades and lid lag but no lid retraction [152] suggests separate pathways for both clinical signs. This lesion spared the nPC but probably affected the M group. It remains open whether dynamic and static lid-eye coordination is controlled by separate pathways. Lid retraction is seen in ischemic midbrain lesions, e.g. Parinaud's syndrome, and extrapyramidal syndromes, e.g. PD and PSP [153, 154]. The prevalence of lid retraction/lid lag in PD patients is not exactly known, but preliminary data indicate up to 37% of patients [147].

In incomplete vertical gaze palsy caused by midbrain lesions, the lid appears to follow the eye, but it may also cause a lid saccade [19, 155]. In the case of upward gaze palsy, the lids may retain the ability to elevate during attempted vertical upgaze, i.e. so-called 'pseudoretraction'. In turn, the lid may lower during attempted downgaze in downgaze saccade palsy, leading to 'pseudoptosis' [19]. Eye-lid coordination in mesencephalic lesions has not yet been systematically examined in detail.

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