Benign Essential Blepharospasm is a Disorder of Neuroplasticity: Lessons From Animal Models

Bench to Bedside Section Editors: Lynn K. Gordon, MD, PhD Jonathan Horton, MD, PhD Benign Essential Blepharospasm is a Disorder of Neuroplasticity: Lessons From Animal Models Craig Evinger, PhD Journal of Neuro-Ophthalmology 2015;35:374-379 doi: 10.1097/WNO.0000000000000317 © 2015 by North American Neuro-Ophthalmology Society E ffectively modeling benign essential blepharospasm (BEB) requires mimicking its root causes. Current evidence points to BEB arising from the confluence of a genetic predisposing condition and an environmental trigger (1). In this "2 hit" hypothesis, the appropriate environmental trigger engenders dystonic behavior because the predisposing condition creates inappropriate brain functioning. Epidemiological studies demonstrate that eye irritation from dry eye, blepharitis, or keratoconjunctivitis is the environmental trigger (1-6). The strength of the association between dry eye and BEB increases in the fifth and sixth decades of life (6) when BEB typically arises (7). Available data strongly support that the predisposing condition is genetic (1,8-12). There is evidence for an autosomal-dominant gene with reduced penetrance contributing to BEB (9,13), but current studies fail to identify any specific genes (8,14). Thus, creating a useful animal model of BEB must involve combining an environmental trigger with a predisposing condition. Another goal of an animal model is to reproduce the typical symptoms of BEB. The hallmark of BEB is excessive involuntary bilateral lid closure primarily involving the orbicularis oculi muscles (1,15-18). In addition to lid spasms, patients with BEB exhibit trigeminal hyperexcitability (1,15,19-22), an elevated spontaneous blink rate (23), and photophobia (1,24-26). These characteristics are consistent with eye irritation serving as the environmental trigger for BEB because they all appear in patients with dry eye (21,27,28). This relationship between eye irritation and BEB Department Neurobiology and Behavior and Ophthalmology, SUNY Stony Brook, Stony Brook, New York. Supported by grants from NIH (EY07391) and the Thomas Hartman Parkinson Research Center. The author reports no conflicts of interest. Address correspondence to Craig Evinger, PhD, Department Neurobiology and Behavior and Ophthalmology, SUNY Stony Brook, Stony Brook, NY 11790-5230; E-mail: [e-mail] 374 characteristics indicates that eye irritation should be 1 component of an animal model and that the predisposing condition should cause the adaptive changes in eyelid control in response to dry eye to develop into BEB-like characteristics. Current evidence demonstrates that trigeminal blink circuits undergo plastic, adaptive modifications to compensate for the rapid breakup of the corneal tear film in dry eye (29-32). Dry eye or eye irritation elevates trigeminal blink amplitude and duration to increase meibomian gland secretion and enhance restoration of the tear film (20,32-37). Blink frequency increases to reform the tear film more regularly (20,36-40). The trigeminal reflex blink circuit becomes hyperexcitable to allow tear film breakup to evoke a reflex blink more readily (20,21,32). Finally, the trigeminal reflex blink circuit responds to a single reflex evoking stimulus with multiple blinks to help restore the tear film (20,21,32). A simple experiment demonstrates that these modifications are part of a compensatory plastic change occurring in the trigeminal complex (32). Within 30 minutes of restraining 1 eyelid to make blinking more difficult, stimulating the supraorbital nerve ipsilateral to the restrained eyelid evokes hyperexcitable reflex blinks and additional blinks in both eyelids. Stimulating the supraorbital nerve contralateral to the restrained eyelid, however, elicits normal blinks in both eyelids. This pattern would occur only if the trigeminal complex receiving signals of corneal irritation from eyelid restraint expressed the plastic changes. Thus, eye irritation initiates plastic compensatory changes in blinking that could be exaggerated in BEB to produce the eyelid abnormalities of this focal dystonia. We hypothesize that the predisposing condition exaggerates neuroplasticity so that modifications in response to eye irritation become maladaptive and amplify into the characteristics of BEB. There is significant evidence for exaggerated plasticity in dystonia (41,42). With generalized dystonia, homeostatic synaptic plasticity in the striatum is abnormal (43,44). Exaggerated associative plasticity accompanies focal hand dystonia (45-48). Important for our hypothesis, exaggerated plasticity of the trigeminal blink reflex accompanies BEB (49). Evinger: J Neuro-Ophthalmol 2015; 35: 374-381 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Bench to Bedside Our initial rodent model of BEB (50) used a small reduction of substantia nigra dopamine neurons to create the predisposing condition and crushing 1 branch of the facial nerve innervating the orbicularis oculi to generate the environmental trigger. The choice of dopamine depletion as a predisposing condition came from observations showing that baboons undergoing poisoning with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) of dopamine neurons exhibited dystonia before developing Parkinsonian movement abnormalities (51) and that there was a disruption of D2 receptors in patients with BEB (52,53). Thus, changes in dopamine levels or the functioning of specific dopamine receptor subtypes could create the "predisposing condition" for BEB. For an environmental trigger, we created a transient eye irritation by crushing a branch of the facial nerve that provides approximately 30% of the orbicularis oculi innervation. This procedure produced a transient dry eye condition because the weakened eyelid became less effective at restoring the tear film with each blink. The condition was only temporary, however, because regeneration of the crushed nerve branch restored complete lid function within 3 weeks. In the Schicatano model (50), the BEB-like spasms of lid closure only occurred with the combination of the environmental trigger and the dopaminergic predisposing condition. In the absence of the predisposing condition, the environmental trigger of transient eye irritation slightly increased trigeminal reflex blink excitability and resulted in the development of additional blinks similar to those seen in human dry eye (20,21). Without the environmental trigger, the predisposing condition of a small dopamine neuron loss slightly increased trigeminal reflex blink excitability but did not generate spasms of lid closure. Combining the predisposing condition and the environmental trigger, however, caused long-lasting spasms of lid closure, dramatically elevated trigeminal reflex blink excitability, and increased spontaneous blinking similar to the pattern of blink abnormalities of patients with BEB. These BEB-like characteristics continued after the facial nerve regained full function and eliminated the dry eye. Thus, the BEB-like characteristics of this animal model seemed to result from an exaggeration of the normally compensatory process evoked by eye irritation. The Schicatano BEB model also was consistent with the important interactions between the cerebellum and basal ganglia that underlie dystonia (54-63). Previous studies demonstrated that the cerebellum was essential for adaptive responses to the eye irritation created by eyelid restraint. Lesions of the cerebellum (30,31) blocked the increases in blink amplitude and duration initiated by eye irritation (20,32-37). Recordings from blink-related neurons in the cerebellar interpositus nucleus revealed the changes in cerebellar activity that accounted for the changes in blink amplitude and duration associated with lid restraint (29). Although the Schicatano model supported the 2 hit hypothesis as the basis of BEB and identified the basal ganglia and cerebellum as key players in this focal dystonia, the model did not explain how the predisposing condition created the Evinger: J Neuro-Ophthalmol 2015; 35: 374-381 exaggerated plasticity that allowed normally adaptive modification to eye irritation to swell into spasms of lid closure. We hypothesize that the key to the exaggerated plasticity of dystonia is hypersynchronized low-frequency oscillations of basal ganglia activity. Basal ganglia neurons in patients with Parkinson disease and animal models of Parkinson disease exhibit hypersynchronized oscillations in the broad beta band, 10-30 Hz (64-71). In contrast, basal ganglia neurons in dystonic patients exhibit hypersynchronized oscillations in the theta band, 3-10 Hz (71-74). Although the role of these oscillations in modifying voluntary movement is unclear (66,73,75-81), our study in rodents demonstrate that these basal ganglia oscillations modify trigeminal reflex blink plasticity (82). We directly tested the role of basal ganglia oscillations in blink plasticity by delivering deep brain stimulation to the basal ganglia subthalamic nucleus of normal rats undergoing a blink plasticity paradigm (82). The procedure was a cerebellar-dependent plasticity paradigm that we developed for humans (83) and modified for rodents (84). Other investigators used this paradigm to demonstrate impaired blink plasticity with Parkinson disease (85), but exaggerated blink plasticity with BEB (49). If the frequency of basal ganglia oscillations modulates brainstem plasticity, then beta frequency deep brain stimulation in normal rats should impair trigeminal reflex blink plasticity, whereas theta frequency deep brain stimulation should exaggerate blink plasticity. The Kaminer et al study (82) demonstrated the validity of this postulation. Beta frequency, 16 Hz, deep brain stimulation impaired blink plasticity, whereas theta frequency, 7 Hz, deep brain stimulation exaggerated trigeminal reflex blink plasticity in normal rats. Deep brain stimulation at 130 Hz, a therapeutic frequency for deep brain stimulation in humans (86), however, did not affect blink plasticity in normal rats. Thus, hypersynchronized theta frequency basal ganglia oscillations could create a predisposing condition in which adaptive plasticity initiated by eye irritation exaggerated into spasms of lid closure typical of BEB. In a preliminary study on 1 rat, we monitored blinking and spasms of lid closure in a normal rat receiving 7 Hz deep brain stimulation of the subthalamic nucleus 4 hours a day combined with mild dry eye produced by exorbital lacrimal gland removal (36). We tested 3 conditions: 1) 7 Hz subthalamic nucleus deep brain stimulation alone (Fig. 1B, gray bars); 2) 7 Hz subthalamic nucleus deep brain stimulation combined with dry eye (Fig. 1B, black bars); and 3) dry eye alone (Fig. 1B, white bars). In Condition 1, the rat received 5 days of 7 Hz subthalamic nucleus deep brain stimulation alone. In Condition 2, combining the predisposing condition and the environmental trigger, we removed the exorbital gland and the rat received 5 days of 7 Hz subthalamic nucleus deep brain stimulation for 4 hours each day. In Condition 3, we discontinued the 7 Hz subthalamic nucleus deep brain stimulation. For all conditions, we monitored blinking (lid closures ,100 milliseconds) and lid spasms (lid closures .100 milliseconds) continuously over a 30-minute period on the last 2 days of each 375 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Bench to Bedside FIG. 1. An animal model of benign essential blepharospasm using 7 Hz deep brain stimulation (DBS) as the predisposing condition. A. A recording of spasms of lid closure and excessive blinking by a rat with dry eye receiving 7 Hz subthalamic nucleus (STN) DBS. B. Average number of blinks (# Blinks), blink amplitude (Blink amp), blink duration (Blink Dur), number of spasms (# Spasms), amplitude of spasms (Spasm Amp), and duration of spasms (Spasm Dur) relative to 7 Hz STN DBS alone condition. Spasms were lid closures lasting .100 milliseconds. Error bars are SEM. *P , 0.05; ***P , 0.001. condition and normalized all data to the 7 Hz subthalamic nucleus deep brain stimulation alone condition. In the combined 7 Hz subthalamic nucleus deep brain stimulation and dry eye condition, the rat made more blinks than either the 7 Hz subthalamic nucleus deep brain stimulation alone or dry eye alone conditions (Fig. 1B, # Blinks). In the combined 7 Hz subthalamic nucleus deep brain stimulation and dry eye condition, the rat also exhibited more spasms of lid closure than in the other conditions (Fig. 1B, # Spasms). Moreover, the spasm duration was longer in the combined 7 Hz subthalamic nucleus deep brain stimulation and dry eye condition than in the 7 Hz subthalamic nucleus deep brain stimulation alone or dry eye alone condition (Fig. 1A, B, Spasm Dur). Finally, the rat made significantly larger blinks in the combined 7 Hz subthalamic nucleus deep brain stimulation and dry eye condition than in 7 Hz subthalamic nucleus deep brain stimulation alone condition (P , 0.05; Fig. 1B, Blink Amp). Although preliminary, these data indicate that the next rodent model of BEB should be developed by combining theta frequency deep brain stimulation of the subthalamic nucleus and dry eye. Thus far, animal models of BEB have not been tested for the abnormal sensitivity to light associated with BEB (1,24,87). The neural bases of photophobia in patients with BEB are unknown. Physiological and behavioral studies of photophobia implicate changes in blood flow (88), melanopsin ganglion cell inputs to somatosensory thalamic regions (89), intraocular no376 ciceptors (90), and calcitonin gene-related peptide trigeminal sensitization (91,92). Because all of these mechanisms involve elevated trigeminal excitability, we anticipate that rodent models of BEB will also exhibit exaggerated light sensitivity. The evidence from animal models indicates that spasms of lid closure and trigeminal hyperexcitability of BEB result from exaggerated neuroplasticity, an amplification of the normally adaptive modifications of blinking initiated by eye irritation. The adaptive plasticity initiated by eye irritation seems to involve the cerebellum (29-31), and the exaggeration of plasticity ensues from abnormal basal ganglia modulation of cerebellar activity (82). 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Dystonia as a network disorder: what is the role of the cerebellum? Neuroscience. 2013;260C:23-35. Sadnicka A, Hoffland BS, Bhatia KP, van de Warrenburg BP, Edwards MJ. The cerebellum in dystonia-help or hindrance? Clin Neurophysiol. 2012;123:65-70. Benign Essential Blepharospasm-There Is More to It Than Just Blinking Kathleen B. Digre, MD Journal of Neuro-Ophthalmology 2015;35:379-381 doi: 10.1097/WNO.0000000000000316 © 2015 by North American Neuro-Ophthalmology Society B enign essential blepharospasm (BEB) is recognized today as a primary dystonia causing excessive blinking, squeezing, and involuntary contractions of the orbicularis oculi muscles. This involuntary lid closure leads to functional blindness and decreased quality of life. Besides the blinking and squeezing, patients with BEB are known to have trigeminal hyperexcitability as demonstrated by blink reflex testing and photophobia. Patients with BEB frequently use sensory tricks, like touching the side of the eye, humming, or singing that will temporarily improve the spasms. For decades, this led clinicians to consider blepharospasm to be a nonphysiological disorder. However, many studies in the last 60 years have dispelled that belief. The condition occurs more frequently in women by a ration of almost 3 to 1. Most are white. Although the median age is approximately 53 years, blepharospasm occasionally has been reported in children. Many individDepartment of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah, Salt Lake City, Utah. Supported by a grant to the Department of Ophthalmology and Visual Sciences from Research to Prevent Blindness, Inc, New York, NY. K. B. Digre is listed as an inventor on a patent pending for thin-film coatings designed for the treatment of photophobia; she could receive royalties on any commercial sales of these coatings. Address correspondence to Kathleen B. Digre, MD, Department of Ophthalmology and Visual Sciences, John Moran Eye Center, 65 N Mario Capecchi Drive, Salt Lake City, UT 84132; E-mail: Kathleen. [e-mail] Digre: J Neuro-Ophthalmol 2015; 35: 374-381 uals go years before they are appropriately diagnosed. The most valid findings to make the diagnosis are involuntary eyelid narrowing or closure due to spasms of the orbicularis oculi muscle, bilateral spasms that are synchronous and stereotyped, a sensory trick, and inability to suppress the spasms and blink count voluntarily (1). Many individuals report that there is a family history of dystonia or benign tremor or Parkinson disease. Some predisposing factors are believed to be recent stressful events, a history of dry eye or keratitis, and head trauma (2). BEB has profound effects on visual quality of life and overall quality of life, and there is a tendency to more depression (3). For such a disabling condition, we have limited treatment options. There is a real need for greater understanding of this disorder and better treatments to help our patients. In the accompanying article, Evinger (4) reviews what animal models teach us about this vexing condition. These models provide hope that if we can model a condition in an animal, we are more likely to be able to understand factors that cause it and create more effective treatments for our patients. Initially, Evinger reminds us that the etiology of BEB may occur due to a predisposition (e.g., genetic) and an environmental trigger-the so called "2 hit" hypothesis. Although there is no known gene for the condition, frequency of a positive family history suggests that there is a genetic component. But there must also be an environmental trigger. Epidemiological data strongly point to the association of dry eyes and blepharitis as potential environmental triggers. What dry eye and dry eye symptoms do in predisposed individuals is to exaggerate neuroplasticity by increasing blink frequency and amplitude in an attempt to restore tears. Modifying the trigeminal blink reflex becomes 379 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.