Role of GABAergic System in Blepharospasm: Response

Letters to the Editor thalamus of both patients with drug-induced blepharospasm and patients with BEB. Notably, glucose hypermetabolism in the thalamus also was found in drug healthy subjects compared to healthy controls, although drug healthy individual had no symptoms of blepharospasm. In the 21 patients with drug-induced blepharospasm, eleven patients successfully lowered the dosage or completely discontinued using the medication, and blepharospasm improved in six of these patients. From these observations, we concluded that benzodiazepines are one of the environmental triggers leading to blepharospasm. We suspect that blepharospasm did not occur in drug healthy subjects because they were not genetically predisposed. Furthermore, we hypothesize that the symptoms of blepharospasm improved in patients with drug-related blepharospasm after benzodiazepines withdrawal because this medication was the environmental trigger. Based on our observations, the drug-induced alteration of the GABAergic inhibition system may be one of the major environmental trigger factors inducing blepharospasm. Currently, the injection of botulinum toxin A is the most effective treatment for blepharospasm. However, besides dry eyes, blepharitis, and medications, there may exist other environmental triggers, and simply removing of these triggers may be an effective treatment for blepharospasm. PET is a powerful and effective tool to understand blepharospasm pathophysiology; thus, we will continue using PET to research the causes of blepharospasm and identify possible treatment options. Yukihisa Suzuki, MD, PhD Department of Ophthalmology, Japan Community Health Care Organization, Mishima General Hospital, Mishima, Japan Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University, Graduate School, Tokyo, Japan Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan Role of GABAergic System in Blepharospasm: Response W e thank Dr. Suzuki et al for their response to our articles (1,2) discussing the origins of benign essential blepharospasm. In their response, the investigators agree with the widely accepted "2 hit" hypothesis for the development of focal dystonia in which a genetic predisposing condition creates a neural milieu in which an adaptation to an environmental trigger exaggerates into the development of the focal dystonia (3-6). For blepharospasm, we argue 350 Kenji Ishii, MD Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan Motohiro Kiyosawa, MD, PhD Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University, Graduate School, Tokyo, Japan Kiyosawa Eye Clinic, Tokyo, Japan Dr. Y. Suzuki was supported by a Grants-in-Aid for Scientific Research by Japan Society for the Promotion of Science (#21791725). Dr. K. Ishii was supported by a Grants-in-Aid for Scientific Research by Japan Society for the Promotion of Science (#20591038). The remaining author report no conflict of interest. REFERENCES 1. Evinger C. Benign essential blepharospasm is a disorder of neuroplasticity: Lessons from animal models. J Neuroophthalmol. 2015;35:374-379. 2. Digre KB. Benign essential blepharospasm-There is more to it than just blinking. J Neuroophthalmol. 2015;35:379-381. 3. Suzuki Y, Mizoguchi S, Kiyosawa M, Mochizuki M, Ishiwata K, Wakakura M, Ishii K. Glucose hypermetabolism in the thalamus of patients with essential blepharospasm. J Neurol. 2007;254:890-896. 4. Tempel LW, Perlmutter JS. Abnormal cortical responses in patients with writer's cramp. Neurology. 1993;43:2252-2257. 5. Poston KL, Eidelberg D. Functional brain networks and abnormal connectivity in the movement disorders. Neuroimage. 2012;62:2261-2270. 6. Wakakura M, Tsubouchi T, Inouye J. Etizolam and benzodiazepine induced blepharospasm. J Neurol Neurosurg Psychiatry. 2004;75:506-509. 7. Emoto Y, Emoto H, Oishi E, Hikita S, Wakakura M. Twelve cases of drug-induced blepharospasm improved within 2 months of psychotropic cessation. Drug Healthc Patient Saf. 2011;3:9-14. 8. Suzuki Y, Kiyosawa M, Wakakura M, Mochizuki M, Ishiwata K, Oda K, Ishii K. Glucose hypermetabolism in the thalamus of patients with drug-induced blepharospasm. Neuroscience. 2014;263:240-249. that the effect of this genetic predisposing condition is modification of basal ganglia-thalamo-cortical activity to create a "hyper-motor adaptation" state (7) in which the compensatory adaptations initiated by an environmental trigger such as dry eye or eye irritation (8) exaggerate into benign essential blepharospasm. Based on their data, Dr. Suzuki et al argue that abnormal GABAergic function is an environmental trigger for the development of blepharospasm. This proposal rests on 3 arguments. First, following withdrawal from benzodiazepine treatment, 6 of 11 patients with drug-induced blepharospasm experienced relief from their spasms of lid closure. Letters to the Editor: J Neuro-Ophthalmol 2016; 36: 343-352 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Letters to the Editor Second, the investigators report that some individuals with long-term drug treatment exhibited hypermetabolism of the thalamus, but did not exhibit drug-induced blepharospasm. Third, the studies by Suzuki et al and others showed that thalamic hypermetabolism occurs in patients with benign essential blepharospasm and in patients exhibiting drug-induced blepharospasm associated with long-term benzodiazepine and thienodiazepine treatment (9-11). The investigators concluded that the individuals on long-term drug treatment who do not exhibit lid spasms lack the genetic predisposing condition to allow blepharospasm to develop. In essence, the authors postulate that thalamic hypermetabolism is the trigger for blepharospasm. We would argue, however, that the authors' data are equally consistent with the hypothesis that thalamic hypermetabolism and reduced GABAergic function are expressions of the genetic predisposing condition rather than the trigger for blepharospasm. Accepting the argument that focal dystonias require both a predisposing neural milieu and an environmental trigger, removing either the predisposing condition or the trigger should resolve blepharospasm. Thus, the data demonstrating that removing benzodiazepine treatment resolves lid spasms in approximately half of the patients with drug-induced blepharospasm do not distinguish between the GABAergic alterations being a trigger or a predisposing condition. Likewise, the argument that many drug-treated individuals do not develop blepharospasm although they exhibit thalamic hypermetabolism is equally consistent with the proposal that the thalamic hypermetabolism is part of a predisposing condition but that these individuals did not experience a significant environmental trigger of eye irritation to cause blepharospasm. Furthermore, treatment with benzodiazepam, a GABAergic agent, reportedly treats blepharospasm (12). The reduction in GABAergic function that the investigators' studies indicate blepharospasm is also consistent with the "hyper-motor adaptation" identified in focal dystonia (7,13-16). For example, an increase in long-term potentiation accompanies the reduction in GABAergic function in the regions around a cortical lesion (17). Based on these data, we argue that the correlated thalamic hypermetabolism and downregulation of GABA function described by Dr. Suzuki et al are components of the "hyper-motor adaptation" state that allows the development of blepharospasm and other focal dystonias (18). Our understanding of the genetics of benign essential blepharospasm is in its earliest stages. What we can identify, however, are the modifications of brain function that the genetic predisposing condition creates. We view the investigations reported by Dr. Suzuki et al as adding to the data showing that disrupting GABA function plays a role in creating the "hyper-motor adaptation" that enables brain plasticity to develop unchecked in dystonia. Letters to the Editor: J Neuro-Ophthalmol 2016; 36: 343-352 Craig Evinger, PhD Departments of Neurobiology and Behavior and Ophthalmology, Stony Brook University, Stony Brook, New York Kathleen Digre, MD Department of Ophthalmology and Visual Science, Moran Eye Center, University of Utah, Salt Lake City, Utah Supported by Grants from the Department of Defense W81XWH-15-1-0345 and The Thomas Hartman Parkinson Research Center. Also supported in part by an Unrestricted Grant from Research to Prevent Blindness, Inc, NY, to the Department of Ophthalmology & Visual Sciences, University of Utah. The authors report no conflicts of interest REFERENCES 1. Evinger C. Benign essential blepharospasm is a disorder of neuroplasticity: lessons from animal models. J Neuroophthalmol. 2015;35:374-379. 2. Digre KB. Benign essential blepharospasm-there is more to it than just blinking. J Neuroophthalmol. 2015;35:379-381. 3. Defazio G, Berardelli A, Hallett M. Do primary adult-onset focal dystonias share aetiological factors? Brain. 2007;130(pt 5):1183-1193. 4. Hallett M, Evinger C, Janovic J, Starg M, BEBRF International Workshop. Update on blepharospasm: report from the BEBRF International Workshop. Neurology. 2008;71:1275-1282. 5. Hallett M. Pathophysiology of dystonia. J Neural Transm Suppl. 2006;113:485-488. 6. Hallett M. Pathophysiology of writer's cramp. Hum Mov Sci. 2006;25:454-463. 7. Quartarone A, Sant'Angelo A, Battaglia F, Bagnato S, Rizzo V, Morgante F, Rothwell JC, Siebner HR, Girlanda P. Enhanced long-term potentiation-like plasticity of the trigeminal blink reflex circuit in blepharospasm. J Neurosci. 2006;26:716- 721. 8. Evinger C, Mao JB, Powers AS, Kassem IS, Schicatano EJ, Henriquez VM, Peshori KR. Dry eye, blinking, and blepharospasm. Mov Disord. 2002;17(suppl 2):S75-S78. 9. Emoto Y, Emoto H, Oishi E, Hikita S, Wakakura M. Twelve cases of drug-induced blepharospasm improved within 2 months of psychotropic cessation. Drug Healthc Patient Saf. 2011;3:9-14. 10. Suzuki Y, Mizoguchi S, Kiyosawa M, Mochizuki M, Ishiwata K, Wakakura M, Ishii K. Glucose hypermetabolism in the thalamus of patients with essential blepharospasm. J Neurol. 2007;254:890-896. 11. Wakakura M, Tsubouchi T, Inouye J. Etizolam and benzodiazepine induced blepharospasm. J Neurol Neurosurg Psychiatry. 2004;75:506-507. 12. Anderson RL, Patel BC, Holds JB, Jordan DR. Blepharospasm: past, present, and future. Ophthal Plast Reconstr Surg. 1998;14:305-317. 13. Quartarone A, Bagnato S, Rizzo V, Siebner HR, Dattola V, Scalfari A, Morgante F, Battaglia F, Romano M, Girlanda P. Abnormal associative plasticity of the human motor cortex in writer's cramp. Brain. 2003;126(pt 12):2586-2596. 14. Quartarone A, Morgante F, Sant'angelo A, Rizzo V, Bagnato S, Terranova C, Siebner HR, Berardelli A, Girlanda P. Abnormal plasticity of sensorimotor circuits extends beyond the affected body part in focal dystonia. J Neurol Neurosurg Psychiatry. 2008;79:985-990. 351 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Letters to the Editor 15. Quartarone A, Pisani A. Abnormal plasticity in dystonia: disruption of synaptic homeostasis. Neurobiol Dis. 2011;42:162-170. 16. Quartarone A, Rizzo V, Bagnato S, Morgante F, Sant'Angelo A, Romano M, Crupi D, Girlanda P, Rothwell JC, Siebner HR. Homeostatic-like plasticity of the primary motor hand area is impaired in focal hand dystonia. Brain. 2005;128(pt 8):1943-1950. 17. Hagemann G, Redecker C, Neumann-Haefelin T, Freund HJ, Witte OW. Increased long-term potentiation in the surround of experimentally induced focal cortical infarction. Ann Neurol. 1998;44:255-258. 18. Levy LM, Hallett M. Impaired brain GABA in focal dystonia. Ann Neurol. 2002;51:93-101. An Evaluation of Educational Neurological Eye Movement Disorder Videos Posted on Internet Video Sharing Sites: Comment agree with the author's call for further regulation of educational videos. In his article, Hickman (1) pointed out that videos from educational institutions and medical journals generally contained better content with fewer errors. The peer-review process is an established route to ensuring videos of high educational quality are produced and uploaded. If these videos were incorporated into modern medical curricula, this would direct students to reliable and trustworthy sources of learning. Moreover, medical students could be encouraged to produce their own content, which may be guided and verified by their teachers. Ultimately, we believe that these 2 proposals would help raise the standard of online educational videos and develop safer practitioners and well-rounded graduates. W e read with great interest the article by Hickman (1) who examined the educational value of eye movement videos on the internet. As medical students with personal experience, we agree with the author that video sharing web sites can be a powerful tool for learning. With regard to ophthalmology-based teaching, modern undergraduate curricula provide little opportunity for such learning, despite the presence of established international guidelines on core concepts that graduating doctors need to practice safety (2). Coupled with the ever-growing body of knowledge and competencies confronting medical students, one may make the case that ophthalmology teaching will be increasingly reduced. Fan et al (3) found that the mean amount of time spent on ophthalmology lectures across medical schools in Asia and Australia was just one day, whereas in the United Kingdom, 21% of universities have no mandatory clinical training in ophthalmology required in their respective curricula (4). Collectively, these examples demonstrate the paucity of education in both preclinical and clinical pedagogy. As a consequence, it is not surprising that there are shortfalls in the diagnosis and management of eye disease, referral accuracy, and confidence in facing ophthalmic problems (5). Thus, alternative methods of teaching, such as internet videos, will become increasingly relied upon for education. Azer (6) compared the content of textbooks, eMedicine articles, and YouTube videos and found that YouTube excelled not only on the user interface front but also in terms of content and integration of information across a molecular and clinical level. Videos provide up-to-date, digestible educational resources that also are interactive, while providing the opportunity to ask questions in the comments section. With the increase of mobile technology and smartphone usage, we suggest that this platform should be investigated as a feasible method for formal teaching. However, unsolicited video sharing with a lack of regulation may cause problems and develop misconceptions in knowledge, and we 352 Ibtesham T. Hossain, BSc (Hons) Hammad H. Malik, BSc (Hons) Sheeraz S. Iqbal, BSc (Hons) School of Medicine, Imperial College London, London, United Kingdom The authors report no conflicts of interest. REFERENCES 1. Hickman SJ. An evaluation of educational neurological eye movement disorder videos posted on internet video sharing sites. J Neuroophthalmol. 2016;36:33-36. 2. International Task Force on Ophthalmic Education of Medical Students on behalf of the International Council of Ophthalmology (ICO). International Curriculum Guidelines on Medical Student Education in Ophthalmology. San Francisco, CA: ICO, 2006. 3. Fan JC, Sherwin T, McGhee CN. Teaching of ophthalmology in undergraduate curricula: a survey of Australasian and Asian medical schools. Clin Experiment Ophthalmol. 2007;35:310- 317. 4. Baylis O, Murray PI, Dayan M. Undergraduate ophthalmology education-a survey of UK medical schools. Med Teach. 2011;33:468-471. 5. Harrison RJ, Wild JM, Hobley AJ. Referral patterns to an ophthalmic outpatient clinic by general practitioners and ophthalmic opticians and the role of these professionals in screening for ocular disease. BMJ. 1988;297:1162-1167. 6. Azer S. Mechanisms in cardiovascular diseases: how useful are medical textbooks, eMedicine, and YouTube? Adv Physiol Educ. 2014;38:124-134. Letters to the Editor: J Neuro-Ophthalmol 2016; 36: 343-352 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.