1. Introduction Case Presentation Results Discussion Conclusions Central Adrenal Insufficiency post Botox Injection Pratima Nayak, MDBenjamin O’Donnell, MD OSU Wexner Medical Center – Department of Internal Medicine References Warning Label on Botox 1.Nishioka, Hiroshi, and Jo Haraoka. "Significance of Immunohistochemical Expression of Rab3B and SNAP-25 in Growth Hormone-producing Pituitary Adenomas." Acta Neuropathologica Acta Neuropathol 109.6 (2005): 598-602. Web: Springer Link. 2.Jacobsson G, Meister B. Molecular components of the exocytotic machinery in the rat pituitary gland. Endocrinology. 1996;137:5344–5356. Web: Google Scholar. 3.Quintanar, J. L., and E. Salinas. "Effect of Hypothyroidism on Synaptosomal-associated Protein of 25 KDa and Syntaxin-1 Expression in Adenohypophyses of Rat." Journal of Endocrinological Investigation J Endocrinol Invest 25.9 (2002): 754-58. Web: Springer Link 4.Meng, Jianghui, and Jiafu Wang. "Role of SNARE Proteins in Tumourigenesis and Their Potential as Targets for Novel Anti-cancer Therapeutics."Biochimica Et Biophysica Acta (BBA) - Reviews on Cancer 1856.1 (2015): 1-12. Web: Elsevier. 5.Ipsen Biopharm Ltd. (2009). DYSPORT ® Highlights of Prescribing Information. Basking Ridge, NJ. 6.Allergan Pharmaceuticals Ireland (1989). BOTOX ®. Highlights of Prescribing Information. Irvine, CA. Botulinum toxin inhibits neurotransmitter release by cleaving SNAP-25 and preventing fusion of the SNARE protein complex. These proteins and their fusion complex are necessary for vesicular exocytosis of hormones and neurotransmitters alike by allowing vesicle fusion to the cell membrane. The protein complex plays a role in the release of hormones from the anterior pituitary such as growth hormone, thyroid hormone, ACTH and prolactin and have been implicated in pathological diseases of the pituitary gland (prolactinoma, acromegaly). 1-3 The mechanism of action of Botox has made it a potential targeted secretion inhibitor to treat prolactinomas and acromegaly. 4 Dysport 5 and Botox 6 have reported adverse effects in areas away from the injection site hours to weeks after treatment but do not specifically endorse endocrine abnormalities. Since SNAP-25 and the SNARE complex proteins are implicated in ACTH release from the pituitary gland, a distant adverse effect of our patient’s Botox in her right upper extremity could potentially have provoked central adrenal insufficiency. Asthenia and generalized muscle weakness are common symptoms seen with adrenal insufficiency. Images “Distant Spread of Toxin Effect. 1 Postmarketing reports indicate that the effects of BOTOX Cosmetic and all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects. These may include asthenia, generalized muscle weakness, diplopia, ptosis, dysphonia, dysarthria, urinary incontinence and breathing difficulties. These symptoms have been reported hours to weeks after injection.” A 70-year-old female presented with dysarthria and right hemiparesis and was found to have suffered a left lenitform nucleus and corona radiata stroke. She was managed medically and completed several weeks of rehabilitation, during which she made tremendous progress in regard to ambulation and nearly resolved dysarthria and facial droop. However, she experienced persistent weakness of her right arm and hand with progressive contractures, and spastic dystonia. Botox injections were recommended as treatment. 300 units of Botox were administered to multiple muscle groups over her right upper extremity. Four days post injection, she was seen for acute onset of bilateral lower extremity myalgias and weakness with inability to participate in her physical therapy sessions. She was assured that these side effects were not unexpected and supportive care was recommended. One week later, myalgias improved but she had persistent fatigue, her blood pressure was found to be lower (90/60), and she was orthostatic. Outside labs revealed an undetectable cortisol level with normal TSH, electrolytes, kidney function and hemoglobin. Endocrinology exam elicited further history including poor appetite with 10-12 lbs. unintentional weight loss, without nausea or dizziness. Based on history and lab testing, she was started on hydrocortisone (HC) 10/5mg daily and her symptoms improved quickly over a few weeks. Imaging from stroke ruled out pituitary masses or infarction, albeit not done with pituitary protocol. Ongoing testing continues to show suppression of the pituitary adrenal axis on 5mg of HC twice a day. Botulinum toxin temporarily weakens muscles by inhibiting neurotransmission between nerve and muscle. There are several medical uses for Onobotulinum A Toxin (Botox) injections including cervical dystonia, overactive bladder, chronic migraines, axillary hyperhidrosis and limb spasticity. Cosmetic uses are more common to remove glabellar and canthal lines and to smooth fine lines and wrinkles. The side effects are usually limited to its known mechanisms of action on unintended organs. Adrenal insufficiency is a severe but treatable condition. From our literature review, this is the first reported case of central adrenal insufficiency occurring acutely after Botox administration. Further research into this serious complication and mechanisms implicated in vesicular exocytosis can help diagnose and treat affected patients more promptly and identify methods to prevent this adverse effect. Figure 1. Mechanism of action of Botulinum Toxin. The SNARE complex formation is prevented due to cleavage of SNAP-25 protein. This results in the lack of vesicle fusion to cell membrane and inhibits exocytosis of neurotransmitters. Figure 2. SNARE complex induced vesicle and cell fusion on a molecular level. The proteins that make up the SNARE complex help bind the synaptic vesicle to the cell’s plasma membrane in preparation for fusion and exocytosis of neurotransmitters or hormones. Figure 3. Hypothalamic-Pituitary Axis. The feedback loop that controls ACTH secretion.