Benign Essential Blepharospasm--There Is More to It Than Just Blinking

High-grade (World Health Organization [WHO] Grade II and III) meningiomas constitute a minority of all meningioma cases but are associated with significant morbidity and mortality, due to more aggressive tumor behavior and a tendency to recur despite standard therapy with resection and radiotherapy. They display a higher degree of vascularity than WHO Grade I meningiomas and produce angiogenic and growth factors, including vascular endothelial growth factor (VEGF). Bevacizumab, a humanized monoclonal antibody against VEGF-A, has been used in the treatment of recurrent or progressive meningiomas resistant to standard therapy. We report a patient with a recurrent left frontotemporal meningioma and associated-vision loss who experienced substantial visual field recovery after 3 cycles of bevacizumab. In addition, we provide a review of the literature regarding the efficacy of bevacizumab in the treatment of recurrent meningiomas.

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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. Bench to Bedside maladaptive response. The site of the integration is of this response is believed to be the basal ganglia. Exaggerated neuroplasticity along with decreased inhibition is at the heart of all focal dystonias (5). Evinger demonstrated in initial animal models of blepharospasm how predisposing factors and environmental stimuli complement each other. In the rodent model, he created a predisposition to blepharospasm by depleting the dopamine neurotransmitter and produced an environmental trigger by crushing the facial nerve to damage the orbicularis oculi innervation. This model produced a phenotype of blepharospasm. His group found that neither the lower dopamine nor the eye irritation alone produced the blepharospasm, but having both did (6). Animal modeling also informed us that the cerebellum played a role in modifying the basal ganglia because strategically placed lesions of the cerebellum blocked blink amplitude and duration. The cerebellum is essential for motor learning and plays a role in continuing the blinking in BEB (7). Evinger also demonstrated with animal models that there are important spontaneous brain wave oscillations within the basal ganglia, which probably participate in neuroplasticity. Whereas Parkinson disease shows hypersynchronized oscillations in the beta band (10-30 Hz), dystonias show hypersynchronized oscillations in the theta band (3-10 Hz). These lower oscillations affect trigeminal reflex neuroplasticity and create a predisposing condition that along with an environmental trigger like eye irritation could lead to BEB. To prove this hypothesis, he recorded blinking and spasms of lid closure in 1 normal rat which received 7 Hz (theta band) deep brain stimulation in the subthalamic nucleus. He then recorded lid blinking and eye lid closure in the rat creating dry eye by removing a lacrimal gland and administering brain theta stimulation. Finally, he recorded blink movements after creating only dry eye without brain stimulation. Not surprisingly, the theta band 7 Hz stimulation (predisposing condition) along with the dry eye (environmental factor) produced the most blinks, spasms, and longer duration of spasms than the 7 Hz stimulations or dry eye alone. This model again recreated blepharospasm (4). How can we translate what we learned from these animal models to better care for our patients? First, we will need to look for predisposing factors in patients with BEB. Understanding the genetic background of an individual may help us gain insights into underlying predisposing pathways for BEB. There may be a variety of predisposing factors that are important. And the environmental insult such as dry eyes needs to be carefully considered and prevented in our patients to avoid sending them into trigeminal hypersensitivity. The role of the cerebellum and motor learning and BEB has not been investigated thoroughly, and the role of the cerebellum may be modified 380 to improve symptoms. Other modifiable predisposing and environmental conditions may be found. Second, findings in animal models may help us understand why treatments we use are working in BEB. We can treat dry eye symptoms, but we know that the trigeminal hyperexcitability and motor learning may already be established, and we will need to go further in reducing these resultant responses. Treatment of photophobia, a symptom of trigeminal hyperexcitability, reduces symptoms and may decrease trigeminal hypersensitivity by reducing the light-induced response. Tinted lenses that block certain wavelengths have been found to be helpful in BEB (8). Botulinum toxin, a mainstay in BEB therapy, which is believed to weaken the forceful muscle spasms that disrupt tear film and improve tear film surface, may affect other mechanisms that play a role in changing neuroplasticity or affecting motor memory (9). Ablative procedures such as myectomy and chemodenervation also reduce spasms and improve tear film surface and possibly affect motor memory (10). Third, animal models may identify new targets for treatment, for example, reduce trigeminal hyperexcitability, change motor learning, and affect neuroplasticity. There are reports of certain anticonvulsants such as levetiracetam (11), carbamazepine (12), and trihexyphenidyl (13) demonstrating some improvement in blepharospasm. Can we suppress blinks by stimulation of nerves or brain or both and thereby reduce trigeminal hyperexcitability and affect neuroplasticity? Investigators have suppressed blinks in normal individuals by delivering impulses to the supraorbital nerve at a specific time in the blink reflex (14,15). Can we change the theta low-frequency oscillations in the basal ganglia? Can we use neuromodulation including transcranial stimulators to alter neuroplasticity, which has been used in blepharospasm (16,17)? Finally, having animal models help us test hypotheses for further understanding and possible treatments. Blepharospasm has gone from a psychological disorder 60 years ago to an organic-based disorder that can be modeled in animals. The hope is that these models will help us achieve a better understanding of BEB and lead to better treatments for our patients. REFERENCES 1. Defazio G, Hallett M, Jinnah HA, Berardelli A. Development and validation of a clinical guideline for diagnosing blepharospasm. Neurology. 2013;81:236-240. 2. 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