Minocycline-Induced Vasculitis Presenting as a Third Nerve Palsy

A 17-year-old man was evaluated in the emergency department with a 1-day history of binocular oblique diplopia present only at distance. He denied head trauma, as well as blurry vision, ocular pain, numbness, weakness, paresthesias, dysphagia, or difficulty breathing. He had no recent illness, denied drug, or alcohol use and had no history of strabismus. He did report right-sided ptosis, presumably due to traumatic levator dehiscence from participating in multiple contact sports. The ptosis developed 18 months previously and was surgically repaired 6 months before the onset of diplopia. His medical history included inflammatory acne for which he was taking benzaclin 5% gel daily, minocycline 100 mg twice daily, sulfacetamide sodium-sulfur 10-5% cleanser daily and tretinoin 0.1% cream daily.

Clinical Correspondence Minocycline-Induced Vasculitis Presenting as a Third Nerve Palsy Matthew R. Starr, MD, Jan-Mendelt Tillema, MD, Steven R. Ytterberg, MD, M. Tariq Bhatti, MD, John J. Chen, MD, PhD A 17-year-old man was evaluated in the emergency department with a 1-day history of binocular oblique diplopia present only at distance. He denied head trauma, as well as blurry vision, ocular pain, numbness, weakness, paresthesias, dysphagia, or difficulty breathing. He had no recent illness, denied drug, or alcohol use and had no history of strabismus. He did report right-sided ptosis, presumably due to traumatic levator dehiscence from participating in multiple contact sports. The ptosis developed 18 months previously and was surgically repaired 6 months before the onset of diplopia. His medical history included inflammatory acne for which he was taking benzaclin 5% gel daily, minocycline 100 mg twice daily, sulfacetamide sodium-sulfur 10-5% cleanser daily and tretinoin 0.1% cream daily. On examination, his visual acuity was 20/20 in each eye with limited adduction, supraduction, and infraduction of the left eye. Ocular motility of the right eye was normal. His color vision was intact in both eyes. His pupils in the dark were 6 and 7 mm in the right and left eyes, respectively, and the degree of anisocoria did not change in the light. On lid evaluation, his mean pupillary reflex distance was +3 mm in both eyes, and the appearance of the anterior and posterior segments of each eye was unremarkable. A diagnosis of a possible pupil-involving third nerve palsy was made, and the patient underwent computed tomography angiography of his head and neck. These studies were unremarkable. Brain MRI revealed a 5- to 6mm left midbrain lesion, most consistent with an ischemic etiology (Fig. 1). Complete blood count, sedimentation rate, and C-reactive protein were normal. Transaminases were elevated: aspartate aminotransferase 74 U/L (normal: 8-48 U/L) and alanine aminotransferase 110 U/L (normal: 7-55 U/L). Antineutrophil cytoplasmic antibody (ANCA) testing was positive with a perinuclear pattern (p-ANCA) Departments of Ophthalmology (MRS, MTB, JJC), Neurology (J-MT, MTB, JJC), and Rheumatology (SRY), Mayo Clinic, Rochester, Minnesota. This work was supported by Research to Prevent Blindness, New York, NY. All authors have no financial conflicts of interest. The authors report no conflicts of interest. Address correspondence to John J. Chen, MD, PhD, Department of Ophthalmology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905; E-mail: [e-mail] 240 with antimyeloperoxidase (MPO) antibodies at 1.2 U (normal ,1/0 U). Lupus antibodies including anti-Smith and antiphospholipid antibodies were negative. Lumbar puncture revealed an opening pressure of 170 mm H2O, and cerebrospinal fluid (CSF) testing was negative for syphilis, tuberculosis, cytomegalovirus, Epstein-Barr virus, herpes simplex 1 and 2, and varicella zoster virus. There was a mildly elevated protein level of 40 mg/dL (0-35 mg/dL), normal glucose, 11 cells/mL, with a lymphocytic predominance and no oligoclonal bands. NMO-IgG4 and a complete CSF paraneoplastic panel, including GAD65 antibodies, were negative. The laboratory and imaging findings were consistent with minocycline-induced p-ANCA- positive vasculitis resulting in midbrain ischemia and a third nerve palsy. Minocycline was discontinued, and the patient was treated with aspirin 325 mg daily and a 2-month taper of oral prednisone beginning at 60 mg daily. Six weeks after initial presentation, the patient's diplopia had resolved, and follow-up MRI was normal. One year later, the p-ANCA levels returned to the normal range, and the patient was maintained on 81 mg of aspirin daily. Minocycline is known to cause autoimmune conditions such as drug-induced systemic lupus erythematosus and autoimmune hepatitis, whereas vasculitis is less common (1,2). There are several reports of a minocycline-associated cutaneous vasculitis resulting in livedo reticularis and hyperpigmented subcutaneous nodules, but few reports of systemic vasculitis (3). The vasculitis associated with minocycline is typically characterized as similar to polyarteritis nodosa (PAN), being both p-ANCA- and ANApositive. It is believed that, in this PAN-like vasculitis, minocycline induces an autoimmune response directed against neutrophil enzymes resulting in anti-MPO antibodies. However, anti-MPO antibodies may be negative, suggesting the presence of other antigens such as elastase or other enzymes that are not often tested clinically (4). Antibody-antigen complexes can then lead to a thrombotic microangiopathy resulting in a systemic vasculitis and vascular occlusions or, as in our patient, an ischemic brainstem infarction leading to a third nerve palsy (1). There have been reports of a minocycline-induced PANlike vasculitis resulting in ischemic strokes within the posterior circulation (1,4). One of these publications Starr et al: J Neuro-Ophthalmol 2019; 39: 240-241 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. Axial diffusion-weighted imaging shows a hyperintensity within the left midbrain (arrow) (A), which is consistent with restricted diffusion (arrow) on the apparent diffusion coefficient map (B). included a patient with lymphocytic-predominant mild pleocytosis in the CSF, possibly an indicator of CNS vasculitis. The median time of minocycline use in a case series of 9 patients with minocycline-induced vasculitis was 2 years with a minimum of 1 year (3), although there has been a case report of PAN-like vasculitis occurring 8 months after initiation of minocycline (5). Our patient was taking minocycline for 2.5 years before presentation. The treatment of minocycline PAN-like vasculitis includes cessation of the drug coupled with the use of either oral or intravenous steroids. In some instances, there may be the need for a steroid-sparing agent (3). Patients tend to respond well to the cessation of minocycline, but symptoms and signs will recur with rechallenge of the drug (5). STATEMENT OF AUTHORSHIP Category 1: a. conception and design: M. R. Starr, J.-M. Tillema, S. R. Ytterberg, M. T. Bhatti, and J. J. Chen; b. acquisition of data: M. R. Starr; c. analysis and interpretation of data: M. R. Starr, J.-M. Tillema, S. R. Ytterberg, M. T. Bhatti, and J. J. Chen. Category 2: a. drafting the Starr et al: J Neuro-Ophthalmol 2019; 39: 240-241 manuscript: M. R. Starr; b. revising it for intellectual content: M. R. Starr, J.-M. Tillema, S. R. Ytterberg, M. T. Bhatti, and J. J. Chen. Category 3: a. final approval of the completed manuscript: M. R. Starr, J.-M. Tillema, S. R. Ytterberg, M. T. Bhatti, and J. J. Chen. REFERENCES 1. Klaas JP, Matzke T, Makol A, Fulgham JR. Minocycline-induced polyarteritis nodosa-like vasculitis presenting as brainstem stroke. J Clin Neurosci. 2015;22:904-907. 2. Elkayam O, Yaron M, Caspi D. Minocycline-induced autoimmune syndromes: an overview. Semin Arthritis Rheum. 1999;28:392- 397. 3. Kermani TA, Ham EK, Camilleri MJ, Warrington KJ. Polyarteritis nodosa-like vasculitis in association with minocycline use: a single-center case series. Semin Arthritis Rheum. 2012;42:213-221. 4. Baratta JM, Dyck PJ, Brand P, et al. Vasculitic neuropathy following exposure to minocycline. Neurol Neuroimmunol Neuroinflamm. 2016;3:e180. 5. Lenert P, Icardi M, Dahmoush L. ANA (+) ANCA (+) systemic vasculitis associated with the use of minocycline: case-based review. Clin Rheumatol. 2013;32:1099-1106. 241 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.