Download Blepharospasm

Neurology
Volume 59 • Number 9 • November 12, 2002
Copyright © 2002 American Academy of Neurology
Views & Reviews
Blepharospasm
Recent advances
Mark Hallett, MD
From the Human Motor Control Section, NINDS, NIH, Bethesda, MD.
From a workshop sponsored by The Benign Essential Blepharospasm Research Foundation and National
Institute of Neurological Disorders and Stroke, November 16–17, 2000, following up a previous
workshop (see reference [22] ). A listing of workshop participants is available at the online version of this
article (access www.neurology.org).
Received December 31, 2001.
Accepted in final form June 11, 2002.
Address correspondence and reprint requests to Dr. Mark Hallett, Human Motor Control Section, NINDS,
NIH, Building 10, Room 5N226, 10 Center Dr, MSC 1428, Bethesda, MD 20892-1428; e-mail:
[email protected]
Abstract
Benign essential blepharospasm is a common focal dystonia characterized by
involuntary eyelid closure. Its etiology, supported by animal models, appears to be
multifactorial, representing the influence of a genetic background and an environmental
trigger. The genetic background could be responsible for the reduced brain inhibition,
identified with physiologic studies that would set up a permissive condition for
increased brain plasticity. Reduced D2 receptors identified with PET might be an
indicator of this reduced inhibition. The trigger could be repetitive use or local ocular
disease. Although symptomatic therapy is available, better approaches are needed and
will likely become available as the genetics and pathophysiology become well
understood.
Introduction
Blepharospasm is a focal dystonia characterized by excessive involuntary closure of
the eyelids. Typically, this is due to spasm of the orbicularis oculi (OO) muscles.
Involuntary closure of the eyelids can also be caused by failure of levator contraction, a
condition known as apraxia of lid opening or motor persistence of the OO muscles. [1] [2]
These two conditions may coexist. It is important to determine the contribution of
apraxia of lid opening because this condition does not respond well to botulinum toxin
injections. [3] Primary, essential, or idiopathic blepharospasm, often called benign
essential blepharospasm (BEB), is not associated with any known etiology, whereas
secondary blepharospasm is due to an identifiable neurologic or ophthalmologic
disorder or documented pathologic lesion. Lesions associated with blepharospasm
have been documented in the basal ganglia, brainstem, and thalamus, and more recent
case reports confirm this. [4] [5] [6] Most of the relevant research relates to BEB.
BEB is present spontaneously, but can be aggravated by bright lights or irritants to the
eyes such as wind or smoke. Eye closure can be so severe as to make vision difficult.
BEB is often accompanied by dystonia of the lower face and jaw, called Meige
syndrome, or other focal dystonias such as cervical dystonia.
Photophobia is a symptom complex in which patients avoid light because of pain or
discomfort in the eyes, and appears to be the reason for light aggravating eyelid closure.
Although photophobia is often seen in disorders of the iris and anterior segment of the
eye, photophobia is also reported in conditions with a normal appearing anterior
segment, including migraine, meningitis, subarachnoid hemorrhage, head injury, and
neurasthenia, as well as BEB. The mechanism of photophobia is not completely
understood but is thought to involve the trigeminal pathway with possible input from
the occipital lobe and thalamus. The term photo-oculodynia—pain in the eye out of
proportion to the stimulus of the light—may be more applicable.
BEB is typically a chronic disorder, but up to about 10% of patients may have a
spontaneous remission, most within the first 5 years. [7] BEB reduces the quality of life
of those affected [8] and appears to be associated with a reactive depression. [9]
Epidemiology and genetics.
The prevalence of BEB has been determined as 12 per million in Japan, [10] 17 per
million in Rochester, MN, [11] 30 per million in North England, [12] 36 per million in the
Epidemiologic Study of Dystonia in Europe, [13] and 133 per million in a region in
Southern Italy. [14] It is not clear whether these geographic differences are real; the
discrepancies may simply reflect acquisition bias. Women are 2.3 times more likely to
be affected than men, and are on average 4.7 years older. [13] [15] There is an increased risk
with a family history of dystonia or postural tremor, a history of head trauma with loss
of consciousness, and prior eye disease such as blepharitis or keratoconjunctivitis. [16] [17]
Trauma of or near the eye often seems relevant and even dental procedures appear to
predispose. [18] Conversely, there may be a decreased risk of developing BEB with
cigarette smoking. [16] BEB does not predispose to developing PD, [16] [19] but patients with
PD may have blepharospasm and apraxia of eyelid opening. Older age at onset, female
sex, and prior head/face trauma increase the possibility of spread of dystonia to adjacent
body regions, which usually occurs during the initial 5 years. [20] Whereas both genetics
and environment appear to play a role in the genesis of BEB, the genetic factor appears
stronger. [16] [20]
Given that local eye disorders seem to be related to BEB and that older women seem
predisposed, it is of interest that dry eye is particularly common in postmenopausal
women. Dry eye may be a potent trigger as suggested from model studies (see below).
Recent evidence suggests that dry eye might be more common in postmenopausal
women taking estrogen replacement therapy. [21]
Most epidemiologic studies suggest that BEB is an autosomal dominant disorder with
reduced penetrance of about 5%. [22] It does not seem to be a forme fruste of the
generalized dystonia resulting from a gene defect at the DYT1 site. Given the low
prevalence, reduced penetrance, and the likely genetic heterogeneity, it will be very
difficult to find genetic linkage unless some families are found with three to five
affected members or a biological marker is identified. An alternative strategy is to study
a large number of sibpairs, and it was estimated that 200 to 400 such pairs might be
needed.
Anatomy of eyelid innervation.
The OO muscle is innervated unilaterally from the facial nucleus and the levator
palpebrae (LP) muscle is innervated bilaterally from the central caudal subdivision of
the oculomotor nucleus. The synaptic circuitry of the input to these brainstem nuclei is
being worked out. [23] [24] Primary sensory afferents from the cornea and eyelid terminate
most densely in the medullary spinal trigeminal nucleus. The pars caudalis of the spinal
trigeminal nucleus sends excitatory projections to the OO motoneurons, ipsilaterally.
The principal trigeminal nucleus sends excitatory projections to the OO motoneurons
and inhibitory projections to the LP motoneurons, bilaterally. This is the appropriate
circuitry for the trigeminal blink reflex, which should occur with OO contraction and
levator inhibition.
There has been a new breakthrough in understanding the cortical innervation of the
eyelids. Whereas there has been the clinical notion that there is bilateral innervation
from the primary motor cortex, anatomic studies have failed to show either contralateral
or ipsilateral innervation. [25] In a study of rhesus monkeys, the musculotopic
organization of the facial nucleus was defined by injecting fluorescent retrograde tracers
into individual muscles of the upper and lower face. [26] Then, anterograde tracers were
placed in different motor regions of the cortex to see the innervation of these defined
regions of the facial nucleus. The OO region was innervated mostly by the rostral
cingulate motor region (called M3). Such a pattern explains the upper face sparing in
typical middle cerebral artery stroke because the descending axons from the rostral
cingulate motor cortex would likely be spared.
Physiology of blinking.
The physiology of spontaneous blinking and voluntary blinking is not well known.
There have been detailed investigations, however, of the blink reflex. Most commonly,
the reflex is elicited with electrical stimulation of the supraorbital nerve. The OO blink
reflex consists of two components: an early, first response (R1) and a late, second
response (R2) (figure 1). R1 is a brief unilateral response, ipsilateral to the stimulated
side, with a latency of about 10 msec. R2 has a latency of about 30 msec, is longer in
duration, and appears bilaterally. The common afferent limb of OO R1 and R2 is the
ophthalmic (first) trigeminal division, whereas the common efferent limb is the facial
(seventh) nerve and its intermediate subnucleus of the facial nucleus.
Figure 1. Silent periods, SP1 and SP2 , of the right levator palpebrae muscle (upper traces) and the
responses in the right orbicularis oculi (OO) muscle (lower traces) after stimulation of the right (R *
) or left (L* ) supraorbital nerve. Stimulation of the supraorbital nerve causes a bilateral SP 1 regardless of
the stimulation side, whereas the R1 response appears only in the OO ipsilateral to the side of stimulation.
Figure from Majid Arahmideh, MD.
In close connection with the excitatory OO responses the LP acts antagonistically with
an inhibitory response. To record from LP, a bipolar needle electrode can be inserted
through the skin in the middle portion of the upper eyelid and directed toward the LP
while the subject looks downward and keeps the eyelids gently closed. The subject is
then asked to open the eye. This maneuver results in tonic EMG activity of LP. The
inhibitory LP response can be examined together with OO responses and consists of two
silent periods (SP): an early, brief, bilateral first SP (SP1) and a late, longer, bilateral
second SP (SP2) (see figure 1). Ipsilateral to the stimulation, R1 of the OO response
occurs during SP1, whereas the contralateral SP1 has no R1 counterpart. SP2 appears
bilaterally and concurrently with the bilateral R2.
Based on analysis of human lesions, the central pathways through which OO responses
are mediated are relatively well known, whereas the pathways for the LP responses are
not (figure 2). Impulses for R1 and R2 enter through the first trigeminal division into
the pons. For R1 they are conducted through the pons and are relayed via an
oligosynaptic arc consisting of one or two interneurons located in the vicinity of the
main sensory trigeminal nucleus. From there, fibers impinge upon motoneurons within
the intermediate subnucleus of the motor facial nucleus. For R2, afferent impulses are
conducted through the descending trigeminal spinal tract in the pons and dorsolateral
medulla oblongata before they reach the caudal spinal nucleus. From there, impulses are
relayed via a medullary-ascending pathway ipsilateral to the stimulated side and an
ascending route that crosses the midline before it ascends contralaterally. Both routes
connect with the facial nerve nucleus in the pons on the two sides. The trigemino-facial
connections are thought to pass through the lateral tegmental field medial to the spinal
trigeminal nucleus. The ascending pathways originate at the level of the lower medulla
oblongata and the crossing of the contralateral path takes place at the level of the lower
third of the medulla oblongata. The OO reflex can be influenced by suprasegmental
structures, including the cortex and basal ganglia.
Figure 2. Schematic drawing of the possible central pathways involved in the generation of
inhibitory responses of the levator palpebrae and excitatory responses of the orbicularis oculi (OO)
muscle during electrically induced blink reflex (Aramideh et al., unpublished, 2000). CCN = central
caudal nucleus; LRF = lateral reticular formation; MRF = medial reticular formation; VII = facial
nucleus. Figure from Majid Arahmideh, MD.
For the inhibitory LP reflex, preliminary data derived from patients with vascular
brainstem lesions suggest that impulses mediating SP1 travel through the midpons and
those for SP2 through the medullary spinal trigeminal tract (Ongerboer de Visser and
Aramideh, unpublished, 2000). A midbrain lesion may impair impulses ascending to the
LP motoneuron nucleus. With such a lesion, antagonistic actions between LP inhibition
and OO excitation are disturbed. Cerebral infarction may reduce or even remove SP2
inhibition similar to the effects on R2.
Dystonia and brain plasticity.
Whereas the etiology of dystonia is unknown, one concept of considerable interest is
that dystonia arises from aberrant brain plasticity. [27] [28] [29] The brain is capable of
changing by processes such as altering synaptic strength and rewiring synaptic
connections. Changes ordinarily occur for a number of reasons; for example, the
learning of a new motor skill or repetitive use of a body part. It would then be possible
for some plastic changes to be aberrant. For example, writing for 5 hours per day might
lead to deranged organization of the motor system and dystonic hand movements.
Plastic changes are facilitated by reduction in the amount of inhibition in brain circuits,
so that if inhibition were for any reason diminished, there might be a propensity for
increased change and possibly aberrant change.
Animal models.
A possible animal model of dystonia was created in nonhuman primates with
synchronous, widespread sensory stimulation to the hand during a repetitive motor task.
[30] [31] Over a period of months, the animals’ motor performance deteriorated. After
development of the movement disorder, the primary somatosensory cortex was mapped,
and each cell was analyzed for the region of the body that activated the cell—its
“receptive field.” Receptive fields in area 3b were increased 10- to 20-fold, often
extending across the surface of two or more digits. The investigators suggested that
synchronous sensory input over a large area of the hand can lead to remapping of the
receptive fields and subsequently to a movement disorder. However, these tasks also
involve repetitive movements, which can lead to remapping of the motor system
directly.
Some trigger appears to initiate BEB in individuals genetically or environmentally
predisposed to dystonia. Animal models of blepharospasm mimic this pattern by
artificially creating a “predisposing neuronal environment” and then testing various
triggers. The predisposing condition in a rat model of blepharospasm [32] is an
approximately 30% unilateral loss of dopamine-containing neurons in the substantia
nigra pars compacta. In the presence of the reduced inhibition within the trigeminal
blink circuits created by this dopamine loss, [33] weakening the OO muscle triggers
spasms of lid closure and other symptoms characteristic of blepharospasm in humans.
Recent studies have examined how OO weakening might be a trigger for
blepharospasm.
Weakening the OO creates two difficulties that initiate compensatory motor learning by
blink neural circuits. First, the difference between the planned and the actual eyelid
movement caused by OO weakness increases the drive on reflex blink circuits to
compensate for muscle weakness. In other words, the nervous system learns a new
relationship between blink-evoking stimulus magnitude and the motor drive required to
generate the correct size blink. Second, muscle weakness decreases tear film
distribution across the cornea, which leads to corneal irritation. Corneal irritation and
dry eye profoundly alter trigeminal reflex blink circuits. Normally, a single trigeminal
stimulus elicits a single reflex blink. With dry eye, however, this same trigeminal
stimulus elicits a reflex blink and a series of additional blinks that occur with a constant
interblink interval—blink oscillations (Evinger, unpublished, 2000). Dry eye might be a
model for the eye irritation that appears to trigger blepharospasm. The blink
oscillations created by the trigeminal complex in response to eye irritation may be a
slower version of the repetitive OO contractions that characterize spasms of lid closure
in some patients with blepharospasm (figure 3). Eye irritation may also be responsible
for photophobic responses.
Figure 3. Reflex blinks and blink oscillations evoked by a single stimulus to the supraorbital branch
of the trigeminal nerve (SO) in a subject with benign essential blepharospasm (top traces) and a
subject with dry eye (bottom traces). Each trace is a single trial showing the position of the upper eyelid.
Calibration bars are 5 degrees for blepharospasm records and 15 degrees for dry eye records. In both
patients, there is an initial reflex blink followed by blink oscillations (Evinger, unpublished, 2000).
Pathophysiology.
A human correlate to the rat model [32] is the observation of patients with facial palsy
who developed blepharospasm. [34] [35] If this is a good model, then facial weakness
should cause an increase in the excitability of reflex blinking. The size of the R2
response on the normal side in 30 normal volunteers and 68 patients with idiopathic or
herpetic peripheral facial palsy was investigated. [36] In patients, the reflex R2 responses
were larger when the stimuli were applied to the contralateral trigeminal nerve than
when the stimuli were applied to the ipsilateral trigeminal nerve. This was significantly
different from what was observed in control subjects, who showed larger responses to
ipsilateral than to contralateral nerve stimulation. A second study reported the blink
reflex recovery curve in normal subjects and patients with Bell palsy who either
recovered facial strength or had persistent weakness. [37] Blink reflex recovery was
enhanced in patients with residual weakness but not in patients who recovered facial
strength. Facial muscles on both the weak and unaffected sides showed enhancement. In
patients with residual weakness, earlier blink reflex recovery occurred when stimulating
the supraorbital nerve on the weak side. Sensory thresholds were symmetric. The
authors concluded that enhancement of blink reflex recovery is dependent on ongoing
facial weakness. Faster recovery when stimulating the supraorbital nerve on the paretic
side, similar to the results of the other study, [36] suggests that sensitization may be
lateralized, and suggests a role for abnormal afferent input in maintaining sensitization.
Interneurons in the blink reflex pathway are the best candidates for the locus of this
plasticity.
The observations in animals and humans that OO weakness may predispose to BEB
raises a point of concern about the use of botulinum toxin for therapy. Might not
induced weakness of the eyelids make the situation worse? From clinical experience,
however, botulinum toxin certainly improves most patients and the improvement can
be sustained for as long as the drug is given, in many patients more than a decade. The
current conclusion is that although weakness might help trigger the development of
BEB, further weakening does not appear to aggravate the condition.
Patients with BEB may have a sensory trick, such as, touching the face, that improves
their eyelid spasms. The physiology of these tricks is unknown. The R2 of the blink
reflex is reduced, but the blink reflex recovery curve is not affected, during a sensory
trick. [38] Patients who have a sensory trick are more likely to have a significant effect of
prepulse inhibition with sensory stimulation of the hand. [39] This appears to indicate a
greater influence of sensory input on eyelid control.
Neuroimaging studies support the general concept that there is pathology in the basal
ganglia and its circuitry. PET studies have identified movement-free patterns of
covariance in fluoro-deoxyglucose (FDG) uptake in the brains of people who are
nonmanifesting carriers of an autosomal dominant childhood onset torsion dystonia
with defects in the DYT1 gene, as well as in manifesting carriers of DYT1. [40] A similar
covariance pattern, involving basal ganglia, was also seen in patients with essential
blepharospasm. [41] Both of these studies identified the abnormal covariance pattern in
sleeping subjects, thereby eliminating the confound of the afferent effects of the
movement on local brain metabolism. When blepharospasm is active during the
scanning, then there are increases in glucose metabolism in pons and cerebellum,
suggesting that these regions either are important in generating the movements or are
involved in afferent activity produced by the movements. [41] In another study of BEB,
increased glucose metabolism was found in the striatum and thalamus. [42] An MRI study
found approximately 10% enlargement of putamen in people with either hand or facial
dystonia, [43] and a magnetic resonance spectroscopy study showed a loss of Nacetylaspartate in basal ganglia. [44]
Several clues from neuroimaging studies implicate striatal dopamine dysfunction or
changes in striatal-cortical pathways in dystonia. Relevant findings come from animal
studies as well as from neuroimaging studies in humans. Nonhuman primates treated
with intracarotid MPTP developed transient hemidystonia prior to chronic
hemiparkinsonism. [45] This transient dystonic phase corresponds temporally with a
decreased striatal dopamine content and a transient decrease in D2 -like receptor
number. [46] The reduction in striatal dopamine receptors matches closely the reductions
of in vivo striatal dopamine receptor binding found in humans with primary focal
cranial or hand dystonia [47] and subsequently confirmed in cervical dystonia. [48] These
changes suggest dysfunction of the D2 -like receptor mediated indirect pathway in the
basal ganglia with a loss of ability to inhibit unwanted motor activity “surrounding” an
intended movement. [49]
PET can be used to measure the brain responses to specific dopamine agonists. Early
studies have demonstrated appropriate dose response and specificity of such techniques
for specific D2 and D1 dopamine agonists. [50] [51] [52] These pharmacologic activation
methods may provide additional insights into the function of selected dopaminergic
pathways in dystonia, as they have already in PD. [53]
There have been few functional neuroimaging studies of sensorimotor processing in
patients with focal dystonias, including blepharospasm. In these studies, several
different groups of patients with dystonia have reduced vibration-induced blood flow
responses in sensorimotor cortex and supplementary motor area. [54] [55] Motor activation
paradigms in focal or generalized dystonia also show abnormal activation in cortical
regions, [56] [57] but there have not been studies in patients with BEB. These studies do not
yet tell a clear story.
Treatment.
The mainstay of treatment remains the use of botulinum toxin. [58] Its efficacy is high
and it can be used for many years without side effect or loss of efficacy. The pretarsal
region may be the best part of the OO to inject, [59] and a recent suggestion, that needs
confirmation, is that injection into Riolan muscle, part of the pretarsal OO, is
particularly effective. [60] Doxorubicin chemomyectomy has provided 10 or more years
of relief but has skin side effects that have limited its acceptance. [61] A liposome
encapsulated form of the drug that limits skin side effects is in clinical trial. Oral agents
work only weakly and cannot be depended on. [22]
Most cases that are refractory to botulinum toxin have eyelid deformities associated
with blepharospasm or associated apraxia of lid opening. These cases as well as the
true nonresponders to botulinum toxin may be successfully treated with the full
myectomy operation. [62] In this operation the OO and corrugator superciliaris muscles
are removed to relieve spasms. The levator aponeurosis is tightened to help elevate the
eyelids, and in rare cases of severe apraxia of lid opening a frontalis suspension may be
required. Dermatochalasis as well as other eyelid deformities can be corrected at the
time of surgery. The limited myectomy operation is used as an adjunct to botulinum
toxin, and the greatest relief is frequently afforded patients by both forms of therapy.
Therapy should be tailored to the patient’s needs, and many patients benefit from
combining all available treatments available to provide maximum benefit.
A method to reduce the light sensitivity (photophobia) associated with BEB has been
the use of tinted lenses; in particular, FL-41 tinted lenses. FL-41 tint was originally
described in Birmingham, England, for use in children with migraine headaches. [63] The
FL-41 rose-tint (as opposed to a blue-tinted lens) reduced migraines by one-half in these
children after 4 months of wear. One optical shop (in Salt Lake City, UT) has dispensed
FL-41 tinted glasses over the last 3 years. In a completely unscientific poll—only
asking patients to “let us know” the effect of the lens—about 70% of patients have
reported an improvement in blepharospasm (Digre, personal communication, 2000).
More work needs to be done in this area.
Physiologic findings in dystonia reveal a decrease in intracortical inhibition measured
with transcranial magnetic stimulation. [64] Because rTMS delivered over the primary
motor cortex at 1 Hz can induce an increase in inhibition, [65] it was proposed that it
might ameliorate the deficit. A study showed a normalization of the intracortical
inhibition and some modest improvement in performance in patients with focal hand
dystonia. [66] Perhaps a similar therapeutic approach would be useful in BEB.
The photophobia of BEB may be caused by sympathetically maintained pain. [67] This
has led to the idea that sympathetic block might be therapeutic. Nineteen patients with
photophobia and BEB were enrolled in an unblinded prospective treatment trial. Ocular
surface disease was present in 18 of 19 patients, adding evidence to the idea that local
eye disease is relevant in the pathogenesis. The intervention was blockade of the
superior sympathetic ganglion with local anesthetic. Outcome measures included
patients’ subjective report of ocular surface dryness, foreign body sensation, and eyelid
spasm, as well as video recordings of eyelid movements. Of the 19 patients, 13 reported
subjective improvement in BEB symptoms after cervical sympathetic blockade.
Thirteen of 19 patients also had objective evidence of decreased light-induced eyelid
spasm. These data are consistent with the hypothesis that in many patients with BEB
there is a sympathetically maintained pain syndrome associated with external ocular
disease, but the study needs to be repeated with appropriate controls. The concept of
sympathetically maintained pain has not proven to be robust as an etiology for complex
regional pain syndrome (reflex sympathetic dystrophy). [68] [69] [70] [71]
Figure 1:
Figure2:
Figure 3:
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