Neurophysiologie clinique 34 (2004) 315

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ORIGINAL ARTICLE

Eyelid movements in health and disease. The supranuclear impairment of the palpebral motility
ngel Esteban *, Alfredo Traba, Julio Prieto
Service of Clinical Neurophysiology, Hospital General Universitario Gregorio Maran, c/ Dr. Esquerdo, 46, 28007 Madrid, Spain
Received 12 September 2003; in revised form accepted 13 January 2004

KEYWORDS Eyelid movements; Blinking; Blink reflex; Lid retraction; Blepharospasm; Blepharocolysis; Eyelid opening disorders; Dystonia; Bells phenomenon; Cerebral ptosis

Abstract The eyelid movements are mediated mainly by the orbicularis oculi (OO) and the levator palpebrae superioris (LPS) muscles. Dissociated upper lid functions exhibit different counterbalanced action of these muscles, and in blinking they show a strictly reciprocal innervation. The disturbance of this close LPSOO relationship likely leads to many of the central lid movement disorders. Three groups of supranuclear motor impairment of lid movements are considered: the disorders of the lid-eye movements coordination, the disturbances of blinking and lid postural maintenance, and the alteration of voluntary lid movements. Nuclei of the posterior commissure control the inhibitory modulation of LPS motor-neuronal activity and they are involved in the lid-eye coordination disorders such as lid retraction, which is observed in the Parinauds syndrome and also in parkinsonism and progressive supranuclear palsy. Spontaneous (SB) and reflex blinking consist of two components: the inhibition of the basal tonic LPS activity, which keeps the eyes open, and the concurrent activation of the OO muscles. LPS inhibition precedes and outlasts the OO activation. This normal configuration is impaired in parkinsonism and blepharospasm (BSP). SB shows a highly interindividual rate variation (among 1020 per minute in adults) and abnormal blink rates occur in neurological diseases related to dopaminergic transmission impairments. Lid postural abnormalities include involuntary eyelid closure, which is usually associated with inability to open the eyes. Two major disorders share these two aspects: BSP and blepharocolysis (BCO). BSP consists of an involuntary overactivity of the OO, with LPS co-contraction activity, and is expressed as frequent and prolonged blinks, clonic bursts, prolonged tonic contraction or a blend of all of them. BCO (commonly named so-called lid opening apraxia) is an overinhibition of the LPS with no evidence of ongoing OO activity. BSP and BCO occur in many instances of idiopathic dystonias and basal ganglia diseases and, less frequently, in rostral brainstem lesions. Both may coincide in the same patient. Voluntary lid movement disorders comprise the impairment of Bells phenomenon, the voluntary eyelid closure palsy and the so-called cerebral ptosis, all related to lesions of frontal cortical areas and/or the corticospinal system. 2004 Elsevier SAS. All rights reserved.

* Corresponding author. Tel.: +34-91-5868338; fax: +34-91-5868018. E-mail address: aesteban.hgugm@salud.madrid.org 2004 Elsevier SAS. All rights reserved. doi: 10.1016/S0987-7053(04)00003-6

Esteban et al.

MOTS CLS Mouvements des paupires ; Clignements ; Rtractation des paupires ; Blepharospasme ; Blepharocolysis ; Troubles de louverture des paupires ; Dystonie ; Phnomne de Bell ; Ptose crbrale

Rsum Les mouvements des paupires sont commands essentiellement par les muscles orbicularis oculi (OO) et levator palpebrae superioris (LPS). Les fonctions dissocies des paupires suprieures ncessitent une action contre-balance de ces muscles qui, dans leur fonction de clignement, montrent une innervation rciproque stricte. Le dysfonctionnement de cette relation LPSOO entraine lapparition des principaux troubles des mouvements des paupires. Il existe trois groupes de troubles supra-nuclaires du mouvement des paupires: les troubles de coordination des mouvements palpbraux, les troubles du clignement et du maintien de la posture des paupires, et enfin laltration des mouvements palpbraux volontaires. Les noyaux de la comissure postrieure contrlent la modulation inhibitrice de lactivit du motoneurone du LPS et sont impliqus dans les troubles de la coordination des mouvements des paupires tels que la rtractation des paupires qui est observe dans le syndrome de Parinaud, la maladie de Parkinson ou la paralysie supranuclaire progressive. Les clignements spontans et rflexes sont ds deux phnomnes diffrents: linhibition de lactivit tonique de base du LPS qui permet de maintenir les yeux ouverts et lactivation concomittante du muscle OO. Linhibition du LPS prcde et dpasse lactivation du OO. Cette configuration normale est dtriore dans la maladie de Parkinson et le blepharospasme (BSP). Il existe une trs grande variation interindividuelle dans la frquence des clignements spontans (de 10 20 par minute chez les adultes) et des frquences anormales des clignements apparaissent dans les cas de troubles neurologiques lis au dysfonctionnement de la transmission dopaminergique. Les anomalies de la posture des paupires comprennent la fermeture involontaire des paupires, gnralement associe lincapacit douvrir les yeux. Deux troubles montrent ces deux aspects, le BSP et le blepharocolysis (BCO). Dans le BSP il existe une suractivit involontaire du muscle OO avec co-contraction du LPS; ce trouble se caractrise par des clignements frquents et prolongs, des salves dactivit cloniques, une contraction tonique prolonge ou un mlange de tous ces symptomes. Dans le BCO, appel galement apraxie de louverture des paupires, il apparat une surinhibition de lactivit du muscle LPS sans vidence dactivit concomitante du muscle OO. Le BSP et le BCO apparaissent dans les dystonies idiopathiques et les troubles des ganglions de la base et, moins frquemment, dans les lsions du tronc crbral rostral. Les deux peuvent coexister chez le mme patient. Parmi les troubles des mouvements volontaires des paupires on trouve le phnomne de Bell, la paralysie de la fermeture volontaire des paupires et anomalie dnomme ptosis crbral , tous ces troubles tant lis des lsions des aires corticales frontales et/ou des lsions du systme corticospinal. 2004 Elsevier SAS. All rights reserved.

Introduction
Their eyelids participate in blinking and, in the coordinated displacement with the conjugate vertical eyes movements, in maintaining the upper palpebral margin near the upper edge of the corneo-scleral junction at all positions of the eyeball [1]. Eyelids also move in the voluntary action of the eyes opening and closing. The eyelid movements are mediated mainly by the orbicularis oculi (OO) and the levator palpebrae superioris (LPS) muscles; the sympathetic dependent tarsal muscle of Muller is also implicated in maintaining an open lid position. The first two muscles exhibit a strictly balanced reciprocal innervation, whose derangement probably leads to many of the lid movement disorders. In the downward lid motion, some passive forces perform an important function, interacting with the relaxation of the LPS; these passive forces are mainly represented by the

tendon-aponeurotic apparatus of the upper eyelid, that is the levator aponeurosis, the palpebral canthal tendons and the superior transverse ligament [2]. Other physical factors involving the upper eyelid, such as stiffness and viscosity, may provide an elastic energy which should contribute to the passive downward tension leading to eyelid closure as the tonic activity of the LPS decreases [1,3]. Dissociated upper lid functions exhibit different counterbalanced actions of the LPS and OO muscles: variable LPS tonic activation with the OO inactive occur in the maintaining of the ocular opening, the gentle closing and opening of the eyes, and the lid adjustment to the vertical globe positions, whereas LPS inhibition with the OO activation are the case for all types of blinking and the firm closure of the eyes [47]. Apart from the OO and LPS muscles, and especially in subprimates species, the extraocular muscles in the coordinated lid/eye movements, as

Eyelid movements in health and disease. The supranuclear impairment of the palpebral motility well as in blinking and voluntary lid movements, except the obliquus superior, play a concomitant notable role [1,8,9]. Neuromuscular and peripheral nerve lesions may cause an impairment of the eyelid motility. Wellknown conditions of this kind, among many others, are fluctuating palpebral ptosis in myasthenia, ptosis in oculomotor nerve palsy or progressive ptosis in mitochondrial myopathy, congenital blepharoptosis, Graves upper eyelid retraction or III nerve synkinesis by aberrant reinnervation. On this occasion, however, we will focus attention exclusively on the motor lid impairments of supranuclear origin. In attempting a general grouping of the supranuclear motor eyelid abnormalities, three main groups will be considered: (1) the disorders of the lid-eye coordination movements, (2) the disturbances of blinking and lid postural maintenance, and (3) the alteration of voluntary lid movements.

Disorders of lid-eye coordination movements. Lid retraction and lid lag

It is generally assumed that lid retraction of neurogenic origin might be the consequence of the LPS muscle overactivity; it is known as the Colliers sign and is typically found in rostral brainstem lesions. In the dorsal midbrain syndrome (Parinauds syndrome), where the pretectal region is involved, conjugate gaze deficits in the vertical plane (predominantly in the up gaze) are usually associated. In this syndrome, however, the inhibition of the LPS-emg activity within spontaneous blinking, voluntary eye closure, and sleep is preserved [10]. On rare occasions lid retraction may exhibit an associated lid-lag phenomenon. A detailed clinicoTable 1 Authors Weinstein and Bender [76] Van Buren [52] Nashold et al. [12]

pathological correlation study of a few cases of lid retraction reported in the literature [10], showed that the lesional areas were concentrated around the nuclei of the posterior commissure. These structures are involved in the inhibitory modulation of levator motor neuronal activity in the lid-eye coordination movements. Conversely, in a few other cases with vertical gaze paralysis without lid retraction, the nuclei and fibres of the posterior commissure were preserved and lesions were found more rostrally, involving the interstitial nucleus of Cajal, the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF) and the periaqueductal grey matter. The authors stress the crucial role of the implication of the nuclei and fibres of posterior commissure in provoking lid retraction. In the same way, experimental lesions in monkeys involving these structures have provoked variable degrees of lid retraction [11], and in humans lid closure has been obtained with the electrical stimulation of a region made up of the periaqueductal grey matter close to the superior colliculus and the posterior commissure [12] (Table 1 and Fig. 1). Lid lag without lid retraction has been described in some rare cases of the pretectal syndrome [13]. In human pathology, aside from the Parinauds syndrome, lid retraction has also been described as a relatively frequent sign in parkinsonism, and a variable degree of lid retraction is commonly observed in the progressive supranuclear palsy (PSP), which contributes to patients characteristic staring face expression from the disease [14]. Lid nystagmus consists of a jerky movement of the eyelids associated or not to ocular nystagmus. It is usually evoked by lateral gaze and ocular convergence and has been ascribed to different levels of brainstem lesions and of the cerebellar system.

Anatomical data for eyelid movement (brainstem and diencephalic levels). Animal Monkey Human Human Experimental/clinical setting Lesion Stimulation Stimulation Anatomical sites (movements characteristics) Eyelids opening Eyelids closing Tegmental pons (OO contralateral) Caudate n. (rapid burst Dorsolateral midbrain tegmentum, below superior colliculi of blinking) Periaqueductal grey matter, superior colliculus, posterior commissure Prerubral fields of Forel and red nucleus (loss of volitional eyelid opening)

Nashold and Gills [77]

Human

Lesion

Pasik et al. [11]

Monkey

Lesion

Nashold et al. [50], Nashold [51]

Human

Stimulation

Pretectal-posterior commissure (upper lid retraction)

Midbrain, ventral to the superior colliculus and central grey matter (...and rhythmic lid flutter)

Esteban et al.

Figure 1 Schematic depiction of brainstem loci regarding movements of the eyelids based on data described in Table 1. PC, posterior commissure; MLF, medial longitudinal fascicle; SC, superior colliculus; PGM, periaqueductal grey matter; RN, red nucleus; SN, substantia nigra; PT, pyramidal tract.

Disturbances of blinking and lid postural maintenance

Blinking and blink abnormalities
Spontaneous blinking (SB) is a continuous, almost periodic and symmetrical brief movement of closing and opening of the eyelids which occurs in the absence of an obvious external stimulus or internal effort. The SB is part of an intrinsic system whose central generator may be composed of different premotor structures in the brainstem [9], highly influenced by dopaminergic activity. Reflex blinks are rapid responses to different external stimuli; their afferent pathways are mainly trigeminal, visual and acoustic, and the premotor areas involve pontine and medullary tegmental levels of the brainstem [15,16]. Voluntary blinks depend on the individual will under internal or external commands. Cortical areas close to those of the frontal eye fields probably mediate these movements [17]. Blinking has a fundamental function in corneal wetting and eye protection (especially spontaneous and reflex blinks) but also is involved in the visual information processing. Other lid movements participate in motor synchronization with eye saccades and with compensation of the eye position in the orbit, and in the motor expression of behavioural states [8]. All eyelid movements are precisely conjugated between both eyes. Spontaneous and reflex blinking normally consists of two different components. One is the inhibition of the sustained activity of the LPS muscles that keep the eyes open and the other is the brief,

concurrent activation of the OO muscles. Once a blink stops, normal tonic activity of LPS is immediately resumed, while the OO returns to a resting position [4,5,7]. The kinematics of the superior lid during blinks, explored by means of the electromagnetic search coil technique, consist of a first rapid down phase, followed by a slower up-phase with a variable total duration; reflex blinks show a duration of around 200 ms [9] which is shorter than the voluntary or spontaneous ones [2]. The lowering of the eyelid occurs during the down-phase, and is directly related to a brief contraction of the OO; their respective durations show a linear relationship [2]. The closing tendon-aponeurotic forces, already mentioned, released by the immediately prior LPS inhibition, help promote ultimate closure. The following up-phase depends entirely on the resumption of LPS activity, which may exhibit an initial reinforcement over the level previous to the blink, a facilitation postinhibition [5,18], or it may simply resume the same basal level of its tonic activity with the eyes open; the former pattern results in a shorter up-phase [2]. In normal SB, as well in voluntary or reflex blinking, the total duration of the OO activation is less than the inhibition period in LPS; that is, LPS inhibition precedes and outlasts the total span of the OO activation (Fig. 2). In spontaneous and voluntary blinking, the OO-EMG activity is gradually built-up and has a longer duration and smaller peak amplitude than that of the reflex blink. The pretarsal portion of this muscle is the one principally or uniquely involved in the phasic OO contraction during the SB, whereas the activation of the pars orbitaria is predominant in the mechanically elic-

Eyelid movements in health and disease. The supranuclear impairment of the palpebral motility

Figure 2 EMG recording of the LPS and different portions of the OO muscle. (A) Normal spontaneous blinking. LPS inhibition period precedes and outlasts the total span of the OO activation. (B) Dystonic spontaneous blinking in blepharospasm. Co-contraction of the LPS and OO muscles activities. A longer duration of the OO activity related to the inhibition of the LPS is shown. LPS, levator palpebrae superioris muscle; OO, orbicularis oculi muscle; UE, upper eyelid; LE, lower eyelid; PP, pars palpebralis; PO, pars orbitaria.

ited reflex blink [19]. In humans, the duration of this EMG phenomenology has been estimated at about 70130 ms [4,5,7,18,19]. In the different types of blinks and in all animal species studied including humans, eye movements accompany the eyelid movements [1,79]. Eyeball shows a retraction and rotation in different planes, which are probably due mainly to the co-contraction of the superior and inferior rectus muscles [1]. A brief upward movement of the eyeballs in SB was first observed by Bell [20] and later corroborated by Bender [21]. A phasic reinforcement of the rectus superior EMG activity has been described during SB and the glabellar tapping [7,22]. More recently, however, a predominant eye movement of downward and nasalward direction has been reported [9]. In blink reflex induced by the electrical stimulation of the supraorbital nerve, two related pauses of inhibition appears within the tonic activity of the LPS muscles [7], besides the known R1 and R2 components of the OO reflex response [23]. Unlike the unilateral R1 and bilateral R2 components of the OO reflex response configuration, the two LPS

inhibitory components, I1 and I2, are bilaterally obtained with unilateral stimulation from each side [16]. The duration of the I2 LPS inhibitory component is greater than the duration of the R2 OO activation, preceding and outlasting respectively the onset and the end of the orbicular component. Furthermore, the inhibitory pauses of the LPS activity appear that the active responses of the OO muscles [7,16]. The spontaneous blinking has an interindividual variable rate and is highly influenced by multiple factors, especially of the emotional and attentive type. In adults, rates show a wide variation between 10 and 20 blinks per minute [2426], although it is remarkably constant in a given individual [27]. In a personal observation on nonneurologic adults patients in a hospital environment, a mean blinking rate of 16 (range 922) was found. Rates are low in infancy, increase in childhood years, and stabilize in adulthood [24]. In elderly people, blink rate exhibits no substantial changes, while blink kinematic shows a decrease in amplitude and velocity [28]. A close relationship between blink rate and dopaminergic level trans-

Esteban et al.

Figure 3 Blepharoclonus. Repetitive clonic bursts of the OO muscles during the near fixed look in a patient with right trigeminal lesion after surgery treatment for trigeminal neuralgia. No other neurological signs were present. Fr, frontalis; OO, orbicularis oculi; OOr, orbicularis oris muscles; R, right; L, left.

mission is supported, based on the variations observed in a series of diseases with impairment of this neurotransmitter. SB rate has been proposed as a marker for the central dopaminergic activity [29] but a serotonergic implication has also been suggested [30]. Variation of blinking rate has been observed in a number of neurological diseases, many, but not all, related to alteration of the dopaminergic transmission. In Parkinsons disease, rate of blinking is decreased [29,31] and prolonged blinks are observed due to the delay of levator in resuming the activity after the end of the orbicularis twitch [6]. In PSP, blink rate is extremely reduced, around three per minute, and slow blinks have also been described [32] Patients with either schizophrenia or Huntingtons disease show higher blink rates than normal subjects [31,33]. Blink frequency in BSP is increased, especially during the onset phase of the disease [26,34,35]. Configuration of spontaneous blink is also abnormal in this focal dystonia; in a series of 13 cases, the mean blinking rates were increased and many instances of blinking showed a longer duration of the OO activity related to the inhibitory period of the LPS, resulting in a partial co-contraction of these antagonistic muscles (Fig. 2). Mean duration of the OO activation (pars pretarsalis) in BSP (123 10 ms) was significantly longer than in patients without central motor eyelids disturbances (89 14.7 ms) while the duration of the LPS inhibition remained almost identical in the both groups (102 8.5 ms and 104 14.5 ms, respectively) [36]. This is what we have termed

dystonic blinks. Loss of SB, with preservation of reflex and voluntary blinks, has been reported in a patient with Ballints syndrome, suggesting that the parietal cortex should act in the generation/ modulation of this kind of blink [37]. Blepharoclonus consists of an abnormal rhythmic eyelid closure by the involuntary contraction of the orbicularis oculi muscles (Fig. 3). The eccentric or vertical gaze [38,39] and the gentle voluntary closure of the eyes [4042] are common contributing factors of blepharoclonus, and these conditions are where it has its maximal clinical relevance. Blepharoclonus has been observed in multiple sclerosis (MS) [38,43], on recovery from severe head trauma [40,41], and in Parkinsons disease and syndromes [6,42,44]. It has also been described as associated with a heterogeneous group of neurological signs or diseases, such as headaches, Arnold-Chiari malformation, tremor, cranial synkinesis or myoclonus [4548]. Abnormal eyelids movements similar to that of the blepharoclonus may occur as part of the BSP [14], but sometimes they has been differentially considered [49]. No common defined CNS topographical lesion can be associated with blepharoclonus; scattered periventricular and brainstem lesions have been found in patients with MS [43] and a dysfunction of the cerebellar system has been postulated in a post-traumatic case [40]. On the other hand, the stimulation of the midbrain, ventral to the superior colliculus and in the central grey matter [50,51], and in the head of the caudate nucleus [52] have provoked rhythmic lid fluttering and rapid bursts of blinking in humans (Table 1).

Eyelid movements in health and disease. The supranuclear impairment of the palpebral motility
Table 2 Clinical settings where involuntary eyelid closure with inability to open the eyes have been described. Idiopathic forms Isolated Secondary to Focal CNS lesions (rostral brainstem and diencephalic regions) In other extrapyramidal disorders Pks disease Postencephalitic Pk PSP Neuroleptic and L-dopa treatments Lithium intoxication Pks disease Postencephalitic Pk PSP Lithium intoxication

Type of disorder Blepharospasm

With other cranial dystonias Familial cases Isolated With blepharospasm In familial cranial dystonias

Blepharocolysis

Bilateral subthalamotomy

The paroxysmal blinking episodes, frequently observed as an epileptic phenomenon, have no pathophysiological relationship with the blepharoclonus; their close clinical resemblance, however, could make convenient a differential diagnosis in some cases.

Involuntary eyelid closure with inability to open the eyes

In the normal awake state, eyes are kept open. Brief closingopening lid movements periodically appear corresponding to the normal SB and some intermingled reflex blinks may also occasionally occur. The more sustained closing and opening of the eyes depends of the subjects will. The lids drop involuntarily when the level of alertness decreases, and they completely close during sleep. There are patients suffering from involuntary eyelid closure in the waking state, which is usually associated with difficulty in opening them. The failure to keep the eyelids open and the inability to initiate lid elevation should be, therefore, parts of the same motor eyelid disturbance [53]. The same opinion has been recently stressed by Defazio et al. [54]. Two major disorders sharing these characteristics are recognized: blepharospasm and blepharocolysis. Blepharospasm is an excessive involuntary closure of the eyelids characterized by spasms of contraction of the orbicularis oculi muscles [34]; blepharocolysis is an excessive involuntary closure of the eyelids characterized by a prolonged inhibition of the LPS muscles in the absence of a demonstrated OO contraction [5557]. In both, the difficulty or inability to open the eyes is systematically associated. Blepharospasm is a chronic and progressive disease which may adopt different clinical aspects, ranging from frequent and strong blinking to clonic spasm to tonic spasm of the eyelids, or a blend of all them [34,58]. They are usually related to the time it takes for the disease to evolve and its intensity.

When it reaches a well-developed clinical state, orbicularis oculi muscles can be observed in a more or less permanent fluctuating contraction with the eyebrows located beneath the superior rim of the orbit (Charcots sign). Not infrequently it causes a functional blindness. Blepharospasm is considered a form of progressive focal dystonia. Idiopathic BSP frequently occurs in isolation or along with contraction spasms of other cranial muscles (Meiges syndrome); many cases with familial generalized or focal dystonias show BSP; it also can be associated with other neurological diseases, such as Parkinsons disease, post-encephalitic parkinsonism and PSP, or may be induced by neuroleptics and L-dopa treatments (Table 2) [59]. Secondary BSP has been described in patients with lesions at different loci of the CNS, predominantly the rostral brainstem region [26,6064]. Simultaneous electromyographic recording of LPS and OO muscles shows variable patterns, ranging from frequent and prolonged blinks that show an impairment in the timing and reciprocity of the two OO and LPS activities (dystonic blinks) [36], to clonic bursts of the OO to prolonged tonic activity of these muscles. Commonly these patterns coincide, and a precise co-contraction between both LPS and OO muscles is observed (Fig. 4). A characteristic finding in the neurophysiological evaluation of the BSP is the facilitation of the R2 recovery curve of the blink reflex [65,66]. A minor form of BSP is called pretarsal BSP [67] which consists of a localized contraction of this OO muscular portion, only demonstrated with complete accuracy by a EMG study which carefully evaluates the different portions of the OO muscle [68]. This type of BSP does not show Charcots sign and clinically may resemble BCO. Blepharocolysis (from the Greek blepharon, eyelid; and colysis, inhibition) was first described by Goldstein and Cogan [55] in four patients with a nonparalytic motor abnormality characterized by the patients difficulty in initiating the act of lid elevation. They coined the term apraxia of lid

10

Esteban et al.

Figure 4 Different EMG patterns in blepharospasm. (A) Increased frequency of spontaneous blinking, many of which showing a prolonged duration and dystonic configuration. (B) Burst of clonic discharges in the OO muscle, with variable duration and coinciding in this case with a tonic activity within its pars orbitaria. (C). Fluctuant tonic activity of OO, predominant in its pars palpebralis, with a complete disruption of the reciprocal innervation between this muscle and the LPS. Legends, as in Fig. 2.

opening for the disorder, which has since been so widely used and widely criticized as inappropriate [59]. In 1973 and later in 1988, a prolonged intermittent or sustained over-inhibition of the LPS activity with no evidence of consistent OO discharges was electrophysiologically demonstrated as the physiopathological basis of this eyelid motor impairment [53,56] (Fig. 5). From a clinical point of view Lepore and Duvoisin [57] suggested an involuntary levator inhibition as the underlying mechanism, and defined some of its diagnostic criteria: (1) inability to initiate lid opening; (2) no evidence of ongoing OO contraction; (3) marked frontalis muscle contraction during a period of inability to raise eyelids; and (4) no ocular motor or ocular sympathetic nerve dysfunction and no ocular myopathy. These criteria were first critically discussed by Fueyo et al. [69] who proposed that the second statement should read no evidence of ongoing OO contraction recorded by EMG and more recently an amendment has also been proposed by Aramideh et al. [70] by introducing two important points: the inability to sustain lid elevation, that is the involuntary closure of the eyelids, in the first criterion, and the necessity of an EMG recording to exclude at least the presence of an abnormal OO activity, as

had already been proposed by Fueyo et al. [69], in the second. The episodes of involuntary drooping of the eyelids may last for long period of time and like BSP, in its maximal intensity may render the patients functionally blind. Similar to BSP and other focal dystonias some patients exhibit a geste antagonistique [71] (Fig. 6). Reflex blinks are normal but sometimes their occurrence in a repetitive manner (i.e., by means of eyelash touching or glabellar tapping) precipitate prolonged episodes of BCO, which also occurs in many cases of BSP. Blepharocolysis is found in various clinical settings (Table 2). It can occur in isolation [54,7173] and more commonly associated with idiopathic blepharospasm (Fig. 5). It is a frequent disturbance in post-encephalitic parkinsonism and PSP, and has also been described in Parkinsons disease [56,57,71]. Some cases have a familial history of cranial dystonias [54,71] and a few of these have improved with levodopa treatment [74] and less frequently with anticholinergic drugs [64]. A combined BSPBCO picture has been described in lithium intoxication [75]. The anatomical basis of BCO is unclear; the impairment of some pons and rostral midbrain areas may be relevant [76,77] (Table 1 and Fig. 1) and a bilateral subthalamotomy

Eyelid movements in health and disease. The supranuclear impairment of the palpebral motility

11

Figure 5 EMG recording in two patients showing blepharocolysis. In (A) after a gradual decrease, an almost complete cessation of the LPS activity occurs. It is followed by an intermittent irregular inhibition until the total return of the basal tonic LPS activity with the final opening of the eyes. Only an unmodified scarce OO activity is seen. In (B) different degrees of inhibition of LPS coexist with clonic and tonic phases of blepharospasm. In both cases, the eyelids dropped despite the continuous effort of patients to keep the eyes opened.

Figure 6 Blepharocolysis. Involuntary closure of the eyes; the patient is attempting to open them and a marked folding of the forehead is evident. On the right, geste antagonistique (sensory trick) trying to facilitate the opening of the eyes.

for treatment of an idiopathic torsion dystonia has been blamed [64] for provoking a combined BCOBSP disorder. The medial frontal and basal ganglia hypometabolism found in PET studies in some lid opening apraxia cases [78] are uncertain because it is likely these cases actually correspond to pretarsal BSP disorders. Progressive supranuclear palsy is considered the most common aetiology for BCO [79] and some cases of palpebral ptosis reported in this disease [8082] would actu-

ally pertain to this disorder. Conversely, some cases with ptosis secondary to cerebral hemispheric infarctions or motor neuron disease have been erroneously referred to as suffering from BCO [83,84]. Detailed electrophysiological studies by means of simultaneous EMG recordings of the LPS and OO muscles, have drawn precise descriptions of the different components comprised in cases of involuntary eyelid closure [53,73] which may be of great importance in establishing the proper treatment

12 with botulinum toxin. In some cases, the presence of EMG activity in the pretarsal portion of the OO, positively precludes a BCO condition, with which sometimes the pretarsal BSP is confused [78,85]. Recovery of the R2 response of the blink reflex has been found normal in three patients with BCO and basal ganglia disease [86]. Many others different terminologies have been used to designate this motor eyelid disturbance: focal eyelid dystonia, pretarsal BSP, atypical BSP, eyelid freezing, akinesia of lid function, akinesia of lid opening, apractic type of essential BSP, involuntary levator palpebrae inhibition, etc. Until now, however, none has achieved a general consensus. From the very beginning, the most common used term apraxia of eyelid openingfrequently referred to as so-called apraxia...has been repeatedly criticized based on the essential argument of the presence of severe motor system impairment in the great majority of patients who suffer the complaint. Blepharocolysis is a concise descriptive term that defines the physiopathological mechanism of this motor disturbancewhich is always comprised of a double component of involuntary closing and difficulty in raising the eyelidsinstead of the partial description of the symptom (disturbance of eyelid opening) or, even worst, the misleading interpretation of its nature. This term also defines a movement disorder which is frequently found closely related with BSP, stressing on the one hand their clinical similarity as a dystonic motor disturbance and, on the other, their differences in the underlying mechanism of production (See Esteban and Gimnez-Roldn, [53] for further discussion). BSP and BCO could be considered as different expressions of a focal dystonic disturbance of eyelid motility, likely related to the different component of the blinking mechanism affected: the increase of the OO activation should be the base in BSP and the increase of the levator inhibition in the BCO. The releasing of the inhibitory components of a motor pattern could be hypothesized as a pathophysiological mechanism likely to induce a motor disorder. In the case of palpebral motility, the isolated predominance of the LPS inhibition should give way to the postural abnormality found in BCO. The motor persistence of orbicularis oculi muscle has been described as a third variant of eyelid-opening disorders [70]. It should be clinically differentiated from BSP and BCO because there is no involuntary drooping of the eyelids and the difficulty in opening the eyes only occurs after voluntary closure of the eyelids. Simultaneous LPS and OO-EMG revealed persistent activity of the pretarsal portion of the OO despite the command to

Esteban et al. open the eyes, although clinical examination did not give evidence of ongoing OO contraction. Of the three patients mentioned, one occurred in isolation, and in the other two it was an additional EMG abnormality to their respective BSP and BCO problems.

Voluntary eyelid movements and disorders

In other voluntary movements of the eyelids, apart from voluntary blinks, reciprocal innervation between LPS and OO also plays a predominant role. Voluntary sustained closure of the eyes can be achieved either by inhibition of the steady tonic activity of LPS without OO activation, leading to soft eyelid closure, or by LPS inhibition plus sustained OO contraction, causing forced closing of the eyes. In both cases, LPS inhibition is a relevant feature for being the unique factor in the gentle closing and for preceding the appearance of the OO activity in the forceful closing [5]. During voluntary occlusion of the eyes, a conjugate upward movement of the eyeball normally occurs, which corresponds to the facio-ocular synkinesia clinically known as Bells phenomenon. Some 10% of the normal healthy population may have no Bells phenomenon [21], although in our experience it was constantly present [87]. Rectus superior muscle, contrary to LPS, shows a sudden intensification of its tonic basal activity, which begins soon after the closure of the eyelids and continues until after their opening [7,22,87]. Ocular saccade and pursuit movements in the vertical plane exhibit a precise coordinated movement of the lids. In these coordinated lid/eye movements, LPS muscles, which act with perfect synchronization on both sides, is activated during upward displacements of the eyes and inactivated during downward displacements, whereas the orbicularis oculi is not involved [1,88]. The steady LPS basal activity in the primary gaze position increases in amplitude and density when a slow upper movement is carried out and progressively diminishes with the downward movement until ceasing completely in the extreme downgaze [5]. Activity in rectus superioris parallels that of the LPS [7]. Gentle closing of the eyes and, to an even greater extent, the full down gaze are the positions where the maximal relaxation of the LPS occurs and present the opportunity to establish an eventual presence of abnormal spontaneous activities in the EMG studies of this muscle. For voluntary eyelid opening, the LPS alone is the responsible.

Eyelid movements in health and disease. The supranuclear impairment of the palpebral motility Supranuclear palsy of voluntary eyelid closure is a motor dysfunction that reflects the inability to close the eyes either wilfully or on command, with preservation of reflex blinking. It has been described in different processes as cerebral infarction, biopercular syndrome, CreutzfeldtJakob disease and amyotrophic lateral sclerosis, which involve pathology of cortical frontal areas or corticospinal system [87,8993]. Although a bilateral process is the common pathological substrate of this dysfunction, a unilateral frontal lesion on the non-dominant side [94] or right brain damage [95] has also been described as provoking a complete failure to voluntarily close the eyes. More infrequently, similar motor eyelid impairment has been observed in PSP [14]. In this case, a simultaneous EMG recording of LPS and OO showed preservation of spontaneous and reflex blinks. A mild lid closure was obtained only after a series of rapid repetitive stimulation of the eyelashes. This gave way to modest OO activity, coinciding with partial inhibition of LPS activity, which was rapidly followed by an impersistence of closure in which OO activity subsided and LPS recovered the basal contraction. A possible predominant deficit of LPS inhibition rather than insufficient OO activation was proposed as the physiopathological mechanism. In both acute unilateral and bilateral hemisphere lesions, motor impersistence keeping the eyes voluntarily closed is not uncommonly found; it predominantly occurs within lesions on the non-dominant side and progressively subsides in several weeks [9597]. Bells phenomenon impairment has been noted in cases of amyotrophic lateral sclerosis [87] and CreutzfeldtJakobs disease [92]. Several degrees may exist and the bilateral decreasing of the supranuclear motor driving caused by loss of the facial cortical motor neurons or the corticogeniculate tract lesions should constitute the pathophysiological basis [87,92]. Some previous cases with bilateral supraspinal pyramidal pathway damage had been described showing an absence of Bells phenomenon and vertical gaze palsy [87,92,98]. Corticogeniculate lesions of a mild degree can produce an isolated disturbance of Bells phenomenon, and its presence should draw attention to a probable cranial level of involvement in some otherwise diffuse pyramidal syndromes restricted to the limbs (personal observation). The so-called cerebral ptosis is a supranuclear motor eyelid disorder associated with hemispheric lesions [99] consisting in a sustained drooping of the eyelids with a more or less pronounced inability to raise them. Although commonly bilateral, with some degree of asymmetry, it may also be unilat-

13

eral. It usually follows a cerebral stroke with bilateral frontal lesions or extensive infarcts of the right, non-dominant, hemisphere [100,101]. In some few cases, cerebral ptosis has been described to be associated with BSP [102]; this association should probably not be so surprising if a minute clinical observation is made, and likely depends on an eventual involvement of the basal ganglia. Nevertheless, cerebral ptosis is a transient situation that progressively subsides, generally reaching normality in some weeks. The clinical background easily leads to its differentiation from other supranuclear eyelid opening impairments, namely BCO, with which, however, it has been occasionally confused [83,103,104].

References
[1] Evinger C, Shaw MD, Peck CK, Manning KA, Baker R. Blinking and associated eye movements in humans, guinea pigs, and rabbits. J Neurophysiol 1984;52:32339. Evinger C, Manning KA, Sibony PA. Eyelid movements. Mechanisms and normal data. Invest Ophthalmol Vis Sci 1991;32:387400. Kennard DW, Smyth GL. The causes of downward eyelid movements with changes of gaze, and a study of the physical factors concerned. J Physiol 1963;166:17890. Gordon G. Observations upon the movements of the eyelids. Br J Ophthalmol 1951;35:33951. Bjrk A, Kugelberg E. The electrical activity of the muscles of the eye and eyelids in various positions and during movements. EEG Clin Neurophysiol 1953;5:595602. Loeffler J, Slatt B, Hoyt W. Motor abnormalities of the eyelids in Parkinsons disease. Arch Ophthalmol 1966;76: 17885. Esteban A, Salinero E. Reciprocal reflex activity in ocular muscles: implications in spontaneous blinking and Bells phenomenon. Eur Neurol 1979;18:15765. Gruart A, Blazquez P, Delgado-Garcia JM. Kinematics of spontaneous, reflex, and conditioned eyelid movements in the alert cat. J Neurophysiol 1995;74:22648. Bour LJ, Aramideh M, de Visser BW. Neurophysiological aspects of eye and eyelid movements during blinking in humans. J Neurophysiol 2000;83:16676. Schmidtke K, Buttner-Ennever JA. Nervous control of eyelid function. A review of clinical, experimental and pathological data. Brain 1992;115:22747. Pasik P, Pasik T, Bender MB. The pretectal syndrome in monkeys. I. Disturbances of gaze and body posture. Brain 1969;92:52134. Nashold Jr BS, Gills JP, Wilson WP. Ocular signs of brain stimulation in the human. Confin Neurol 1967;29:16974. Galetta SL, Raps EC, Liu GT, Saito NG, Kline LB. Eyelid lag without eyelid retraction in pretectal disease. J Neuroophthalmol 1996;16:968. Grandas F, Esteban A. Eyelid motor abnormalities in progressive supranuclear palsy. J Neural Transm Suppl 1994; 42:3341. Holstege G, Blok BFM, Horst GJ. Brain stem systems involved in the blink reflex, feeding mechanisms, and micturation. In: Paxinos G, editor. The rat nervous system. San Diego: Academic Press; 1995. p. 25775.

[2]

[3]

[4] [5]

[6]

[7]

[8]

[9]

[10]

[11]

[12] [13]

[14]

[15]

14
[16] Esteban A. A neurophysiological approach to brainstem reflexes. Blink reflex. Neurophysiol Clin 1999;29:738. [17] Bruce CJ, Goldberg ME, Bushnell MC, Stanton GB. Primate frontal eye fields. II. Physiological and anatomical correlates of electrically evoked eye movements. J Neurophysiol 1985;54:71434. [18] Holder DS, Scott A, Hannaford B, Stark L. High resolution electromyogram of the human eyeblink. Electromyogr Clin Neurophysiol 1987;27:4818. [19] Esteban A. Blinking and eyelids motor central disorders. EMG study. EEG Clin Neurophysiol 1997;103:62. [20] Wilkins RH, Brody IA. Bells palsy and Bells phenomenon. Arch Neurol 1969;21:6612. [21] Bender MB. Comments on the physiology and pathology of eye movements in the vertical plane. J Nerv Mental Dis 1960;130:45666. [22] Bjrk A. Electromyographic studies on the coordination of antagonistic muscles in cases of abducens and facial palsy. Br J Ophthalmol 1954;38:60515. [23] Kugelberg E. Facial reflexes. Brain 1952;75:38596. [24] Zametkin AJ, Stevens JR, Pittman R. Ontogeny of spontaneous blinking and of habituation of the blink reflex. Ann Neurol 1979;5:4537. [25] Karson CN, Berman KF, Donnelly EF, Mendelson WB, Kleinman JE, Wyatt RJ. Speaking, thinking, and blinking. Psychiatry Res 1981;5:2436. [26] Jankovic J, Havins WE, Wilkins RB. Blinking and blepharospasm. Mechanism, diagnosis, and management. JAMA 1982;248:31604. [27] Ponder E, Kennedy WP. On the act of blinking. Quart J Exp Physiol 1928;18:89110 [taken from Stevens, 1978]. [28] Sun WS, Baker RS, Chuke JC, et al. Age-related changes in human blinks. Passive and active changes in eyelid kinematics. Invest Ophthalmol Vis Sci 1997;38:929. [29] Karson CN, LeWitt PA, Calne DB, Wyatt RJ. Blink rates in parkinsonism. Ann Neurol 1982;12:5803. [30] LeDoux MS, Lorden JF, Smith JM, Mays LE. Serotonergic modulation of eye blinks in cat and monkey. Neurosci Lett 1998;253:614. [31] Karson CN. Spontaneous eye-blink rates and dopaminergic systems. Brain 1983;106:64353. [32] Golbe LI, Davis PH, Lepore FE. Eyelid movement abnormalities in progressive supranuclear palsy. Mov Disord 1989;4:297302. [33] Stevens JR. Disturbances of ocular movements and blinking in schizophrenia. J Neurol Neurosurg Psychiatry 1978;41: 102430. [34] Grandas F, Elston J, Quinn N, Marsden CD. Blepharospasm: a review of 264 patients. J Neurol Neurosurg Psychiatry 1988;51:76772. [35] Elston JS, Granje FC, Lees AJ. The relationship between eye-winking tics, frequent eye-blinking and blepharospasm. J Neurol Neurosurg Psychiatry 1989;52: 47780. [36] Esteban A, Traba A, Grandas F. Blinking and blepharospasm. A neurophysiological study. EEG Clin Neurophysiol 1997;103:90. [37] Watson RT, Rapcsak SZ. Loss of spontaneous blinking in a patient with Balints syndrome. Arch Neurol 1989;46: 56770. [38] Keane JR. Gaze-evoked blepharoclonus. Ann Neurol 1978; 3:2435. [39] Sethi KD, Hess DC, Harbour RC, Holmes GL. Gaze-evoked involuntary movements. Mov Disord 1990;5:13942. [40] Safran AB, Moody JF, Gauthier G. Sustained blepharoclonus upon eye closure. J Clin Neuroophthalmol 1983;3: 1336.

Esteban et al.
[41] Behrman S, Scott DF. Blepharoclonus provoked by voluntary eye closure. Mov Disord 1988;3:3268. [42] Gatto M, Micheli F, Pardal MF. Blepharoclonus and parkinsonism associated with aqueductal stenosis. Mov Disord 1990;5:3103. [43] Jacome DE. Blepharoclonus in multiple sclerosis. Acta Neurol Scand 2001;104:3804. [44] Hsieh BH, Deng JF, Ger J, Tsai WJ. Acetylcholinesterase inhibition and the extrapyramidal syndrome: a review of the neurotoxicity of organophosphate. Neurotoxicology 2001;22:4237. [45] Jacome DE. Headache in Ehlers-Danlos syndrome. Cephalalgia 1999;19:7916. [46] Jacome DE. Synkinetic blepharoclonus. J Neuroophthalmol 2000;20:27684. [47] Jacome DE. Blepharoclonus and Arnold-Chiari malformation. Acta Neurol Scand 2001;104:1137. [48] Jacome DE. Blepharoclonus, pseudoasterixis, and restless feet. Am J Med Sci 2001;322:13740. [49] Obeso JA, Artieda J, Marsden CD. Stretch reflex blepharospasm. Neurology 1985;35:137880. [50] Nashold Jr BS, Wilson WP, Slaughter DG. Sensations evoked by stimulation in the midbrain of man. J Neurosurg 1969; 30:1424. [51] Nashold BS. Ocular reactions from brain stimulation in conscious man. Neuroophthalmology 1970;5:92103. [52] Van Buren JM. Confusion and disturbance in speech from stimulation in vicinity of the head of the caudate nucleus. J Neurosurg 1963;20:14857. [53] Esteban A, Gimenez-Roldan S. Involuntary closure of eyelids in parkinsonism. Electrophysiological evidence for prolonged inhibition of the levator palpebrae muscles. J Neurol Sci 1988;85:33345. [54] Defazio G, Livrea P, Lamberti P, et al. Isolated so-called apraxia of eyelid opening: report of 10 cases and a review of the literature. Eur Neurol 1998;39:20410. [55] Goldstein JE, Cogan DG. Apraxia of lid opening. Arch Ophthalmol 1965;73:1559. [56] Esteban A, Gimenez-Roldan S. Intermittent blepharocolysis; a study of its mechanism in striatal disorders. X International Congress of Neurology. Excerpta Medica ICS, 296. 1973. p. 130. [57] Lepore FE, Duvoisin RC. Apraxia of eyelid opening: an involuntary levator inhibition. Neurology 1985;35:4237. [58] Tolosa E, Marti MJ. Blepharospasm-oromandibular dystonia syndrome (Meiges syndrome): clinical aspects. Adv Neurol 1988;49:7384. [59] Hallett M, Daroff RB. Blepharospasm: report of a workshop. Neurology 1996;46:12138. [60] Jankovic J, Patel SC. Blepharospasm associated with brainstem lesions. Neurology 1983;33:123740. [61] Lee MS, Marsden CD. Movement disorders following lesions of the thalamus or subthalamic region. Mov Disord 1994;9: 493507. [62] Kostic VS, Stojanovic-Svetel M, Kacar A. Symptomatic dystonias associated with structural brain lesions: report of 16 cases. Can J Neurol Sci 1996;23:536. [63] Aramideh M, Ongerboer de Visser B, Holstege G, Majoie CB, Speelman JD. Blepharospasm in association with a lower pontine lesion. Neurology 1996;46:4768. [64] Klostermann W, Vieregge P, Kompf D. Apraxia of eyelid opening after bilateral stereotaxic subthalamotomy. J Neuroophthalmol 1997;17:1223. [65] Berardelli A, Rothwell JC, Day BL, Marsden CD. Pathophysiology of blepharospasm and oromandibular dystonia. Brain 1985;108:593608.

Eyelid movements in health and disease. The supranuclear impairment of the palpebral motility
[66] Tolosa E, Montserrat L, Bayes A. Blink reflex studies in focal dystonias: enhanced excitability of brainstem interneurons in cranial dystonia and spasmodic torticollis. Mov Disord 1988;3:619. [67] Elston JS. A new variant of blepharospasm. J Neurol Neurosurg Psychiatry 1992;55:36971. [68] Aramideh M, Koelman JH, Speelman JD, Ongerboer de Visser B. Eyelid movement disorders and electromyography. Lancet 2001;357(9258):8056. [69] Fueyo J, Oliveras C, Pou A, Espadaler JM. Proposal for a clinical definition of blepharokolysis. Mov Disord 1991;6: 1856. [70] Aramideh M, Ongerboer de Visser B, Koelman JH, Speelman JD. Motor persistence of orbicularis oculi muscle in eyelid-opening disorders. Neurology 1995;45:897902. [71] Krack P, Marion MH. Apraxia of lid opening, a focal eyelid dystonia: clinical study of 32 patients. Mov Disord 1994;9:6105. [72] Aramideh M, Ongerboer de Visser B, Devriese PP, Bour LJ, Speelman JD. Electromyographic features of levator palpebrae superioris and orbicularis oculi muscles in blepharospasm. Brain 1994;117:2738. [73] Aramideh M, Ongerboer de Visser B, Koelman JH, Bour LJ, Devriese PP, Speelman JD. Clinical and electromyographic features of levator palpebrae superioris muscle dysfunction in involuntary eyelid closure. Mov Disord 1994;9: 395402. [74] Dewey Jr RB, Maraganore DM. Isolated eyelid-opening apraxia: report of a new levodopa-responsive syndrome. Neurology 1994;44:17524. [75] Micheli F, Cersosimo G, Scorticati MC, Ledesma D, Molinos J. Blepharospasm and apraxia of eyelid opening in lithium intoxication. Clin Neuropharmacol 1999;22:1769. [76] Weinstein EA, Bender MB. Integrated facial patterns elicited by stimulation of the brainstem. Arch Neurol Psychiat 1943;50:3442. [77] Nashold Jr BS, Gills Jr JP. Ocular signs from brain stimulation and lesions. Arch Ophthalmol 1967;77:60918. [78] Smith D, Ishikawa T, Dhawan V, Winterkorn JS, Eidelberg D. Lid opening apraxia is associated with medial frontal hypometabolism. Mov Disord 1995;10:3414. [79] Lepore FE. So-called apraxias of lid movement. Adv Neurol 1988;49:8590. [80] Dix MR, Harrison MJ, Lewis PD. Progressive supranuclear palsy (the Steele-Richardson-Olszewski syndrome). A report of 9 cases with particular reference to the mechanism of the oculomotor disorder. J Neurol Sci 1971;13: 23756. [81] Steele JC. Progressive supranuclear palsy. In: Vinken PJ, Bruyn GW, editors. System disorders and atrophies, Handbook of clinical neurology, 22, part 2. Amsterdam: NorthHolland Publishing Company; 1975. p. 21729. [82] Kristensen MO. Progressive supranuclear palsy20 years later. Acta Neurol Scand 1985;71:17789. [83] Johnston JC, Rosenbaum DM, Picone CM, Grotta JC. Apraxia of eyelid opening secondary to right hemisphere infarction. Ann Neurol 1989;25:6224. [84] Abe K, Fujimura H, Tatsumi C, Toyooka K, Yorifuji S, Yanagihara T. Eyelid apraxia in patients with motor neuron disease. J Neurol Neurosurg Psychiatry 1995;59: 62932. [85] Piccione F, Mancini E, Tonin P, Bizzarini M. Botulinum toxin treatment of apraxia of eyelid opening in progressive supranuclear palsy: report of two cases. Arch Phys Med Rehabil 1997;78:5259.

15

[86] Aramideh M, Eekhof JL, Bour LJ, Koelman JH, Speelman JD, Ongerboer de Visser B. Electromyography and recovery of the blink reflex in involuntary eyelid closure: a comparative study. J Neurol Neurosurg Psychiatry 1995;58: 6928. [87] Esteban A, De Andres C, Gimnez-Roldn S. Abnormalities of Bells phenomenon in amyotrophic lateral sclerosis: a clinical and electrophysiological evaluation. J Neurol Neurosurg Psychiatry 1978;41:6908. [88] Becker W, Fuchs AF. Lid-eye coordination during vertical gaze changes in man and monkey. J Neurophysiol 1988;60: 122752. [89] Alajouanine Th, Thurel R. La diplgie facial crbrale. Forme corticale de la paralysie pseudobulbaire. Rev Neurol (Paris) 1933;2:44158 (Contribution ltude de la disociation des activits volontaires et rflexes). [90] Lessel S. Supranuclear paralysis of voluntary lid closure. Arch Ophthalmol 1972;88:2414. [91] Lapresle J, Salisachs P. Loss of voluntary control and retention of automatic reflex in certain muscles innervated by cranial nerves in 2 cases of amyotrophic lateral sclerosis. Rev Neurol (Paris) 1976;132:15761. [92] Russell RW. Supranuclear palsy of eyelid closure. Brain 1980;103:7182. [93] Nishimura M, Tojima M, Suga M, Hirose K, Tanabe H. Chronic progressive spinobulbar spasticity with disturbance of voluntary eyelid closure. J Neurol Sci 1990;96: 18390 Report of a case with special reference to MRI and electrophysiological findings. [94] Berlin L. Compulsive eye opening and associated phenomena. Arch Neurol Psychiat 1955;73:597601. [95] De Renzi E, Gentilini M, Bazolli C. Eyelid movement disorders and motor impersistence in acute hemisphere disease. Neurology 1986;36:4148. [96] Fisher CM. Left hemiplegia and motor impersistence. J Nerv Mental Dis 1956;123:20118. [97] Joynt RJ, Benton AL, Fogel ML. Behavioral and pathological correlates of motor impersistence. Neurology 1962;12: 87681. [98] Alajouanine Th, Thurel R. Rvision des paralysies des mouvements associs des globes oculaires. Rev Neurol (Paris) 1931;1:12569 (Contribution ltude de la dissociation des activits voluntaire et rflexe). [99] Mrquez M. La hendidura palpebral normal y patolgica. Medicina Ibera (Madrid) 1936;1:20922 [taken from Caplan, 1974]. [100] Caplan LR. Ptosis. J Neurol Neurosurg Psychiatry 1974;37: 17. [101] Averbuch-Heller L, Stahl JS, Remler BF, Leigh RJ. Bilateral ptosis and upgaze palsy with right hemispheric lesions. Ann Neurol 1996;40:4658. [102] Hijosa M, Esteban A, Snchez Migalln MJ, Grandas F. Palpebral ptosis and blepharospasm secondary to hemispheric cerebral infarction. Neurologa 1998;13:4953. [103] Sakajiri K, Matsubara N, Nakajima T, Fukuhara N, Bandoh M. A case of apraxia of eyelid opening secondary to right hemisphere infarction. Assessment of various symptoms of the eye and eyelid. Rinsho Shinkeigaku 1995;35: 1648. [104] Waragai M, Shinotoh H, Kaneko M, Hattori T. Difficulty in eye opening following left hemispheric infarction. Causative lesion and pathophysiology of abnormalities of the eye and eyelids movements. Rinsho Shinkeigaku 1996;36: 57783.