Role of GABAergic System in Blepharospasm

Letters to the Editor To date there are 4 reported cases of patients developing NAION when on Sildenafil for pulmonary hypertension. The first was a 6-year-old girl who underwent surgical repair of coarctation of the aorta at age 2 years and mitral valve replacement with pacemaker insertion at age 4 years. She presented with a several month history of monocular vision loss and was found to only have light perception in her left eye. She was treated with sildenafil for 15 months before her presentation for pulmonary hypertension (2). The second report was that of a 63-year-old woman with a history of chronic renal failure on hemodialysis after cadaveric kidney transplant, aortic valve replacement, atrial fibrillation, peripheral vascular disease, arterial hypertension, and pulmonary hypertension managed with sildenafil 50 mg 3 times daily. She subsequently developed bilateral NAION. (3) The third case was a 7-month-old girl who was treated with sildenafil for recurrent chylothorax and presumed increased pulmonary vascular resistance on a background of a complex congenital cyanotic heart defect with cavopulmonary anastomosis surgery at age 4 months. Four weeks later, she went on to develop NAION, which resulted in bilateral visual loss despite sildenafil cessation and treatment with corticosteroids (4). It seems that patients with pulmonary hypertension treated with sildenafil may be at risk of developing NAION. We alert clinicians to this possible association. Linda Zheng, MBBS (Hons), MMed Katherine M. Miller, MBBS (Hons) Department of General Medicine, Sydney Eye Hospital, Sydney Hospital, Sydney, Australia Role of GABAergic System in Blepharospasm T wo articles "Benign essential blepharospasm is a disorder of neuroplasticity: Lessons from animal models" (1) and "Benign essential blepharospasm- There is more to it than just blinking" (2) clearly summarized the findings of recent animal and clinical studies about the potential candidate factors that may contribute to blepharospasm according to the so-called "2-hit" hypothesis. We propose the GABAergic system as an additional trigger factor that may be clinically relevant. Many hypotheses have been suggested about what may cause benign essential blepharospasm (BEB); however, the cause of this disorder is still unclear. To answer this question, we have been investigating cerebral functional alterations in patients with blepharospasm using positron emission tomography (PET). Letters to the Editor: J Neuro-Ophthalmol 2016; 36: 343-352 Eugene Kotlyar, MBBS, MD, MPVD, FRACP, FCSANZ, FPHSANZ Department of General Medicine, Sydney Eye Hospital, Sydney Hospital, Sydney, Australia Department of Cardiology, St Vincent's Hospital, Darlinghurst, Australia Raymond Garrick, MBBS (Hons), FRACP, FFPM, ANZCA Department of General Medicine, Sydney Eye Hospital, Sydney Hospital, Sydney, Australia Department of Neurology, St Vincent's Hospital, Darlinghurst, Australia The authors report no conflicts of interest. REFERENCES 1. Pomeranz HD. The relationship between phosphodediesterase-5 inhibitors and nonarteritic anterior ischemic optic neuropathy. J Neuroophthalmol. 2016;36:193-196. 2. Sivaswamy L, Van Stavern GP. Ischemic optic neuropathy in a child. Pediatr Neurol. 2007;37:371-372. 3. Prat NM, Sanchez-Dalmau BF, Foroozan R. Not just for men. Surv Ophthalmol. 2011;56:173-177. 4. Gaffuri M, Cristofaletti A, Mansoldo C, Biban P. Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease. BMJ Case Rep. 2014;3:2014. In one of our first studies, we analyzed cerebral glucose metabolism in 25 patients with BEB using PET and 18Ffluorodeoxyglucose and observed cerebral glucose hypermetabolism in the thalamus in patients with BEB compared with healthy subjects (3). Our findings suggested that hyperactivity of the thalamus and the basal ganglia-thalamocortical motor circuit may be contributing causes of BEB (4,5). Digre (2) discussed the 2-hit hypothesis with regard to BEB. This hypothesis includes both a predisposition (e.g., genetic) and an environmental trigger (e.g., dry eyes, blepharitis) to develop BEB. Blepharospasm also has been reported in individuals on long-term regimens of neuropsychiatric drugs, such as benzodiazepines and thienodiazepines (drug-induced blepharospasm) (6,7). We studied cerebral glucose metabolism in 21 patients with drug-induced blepharospasm, 24 healthy subjects with a long-term history of benzodiazepines use ("drug healthy" group), 21 patients with BEB, and 63 healthy control subjects (8). We observed glucose hypermetabolism in the 349 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. 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.