Granuloma Annulare, Scalp Necrosis, and Ischemic Optic Neuropathy From Giant Cell Arteritis After Varicella-Zoster Virus Vaccination

Giant cell arteritis (GCA) is a systemic vasculitis that begins with activation of dendritic cells in the arterial wall (1). This initiates a cascade that results in the recruitment of macrophages and T cells resulting in the classic histopathological features of GCA including disruption of the internal elastic lamina and luminal obstruction (2). The initial trigger for dendritic activation is not yet known; several infectious agents have been explored including varicella-zoster virus (VZV), but none have been proven (3). Epidemiological studies have not found a relationship between VZV or VZV vaccination and GCA (4,5). In this report, we describe the development of GCA complicated by unintentional weight loss, scalp necrosis, and ischemic optic neuropathy following a live-attenuated VZV vaccine. CASE REPORT An 88-year-old Italian man with hypertension, type 2 diabetes, dyslipidemia, coronary artery disease, and early dementia received a live-attenuated shingles vaccine, Zostavax. A few days later, he developed generalized pink-colored patches on his back and trunks diagnosed as generalized granuloma annulare (GA; Fig. 1). Skin biopsy showed palisading granulomatous inflammation around necrobiotic collagen fibers. He was treated with multiple topical steroid creams and a 1-week oral course of prednisone resulting in temporary improvement.FIG. 1.: A few days after the Zostavax vaccine, he developed pink- to purple-colored coalesced papules on the back due to generalized granuloma annulare.Three weeks after vaccination, he developed progressively worsening fatigue and decreasing appetite with unintentional weight loss of 50 pounds over the next 3 months. Two months after vaccination, he developed new-onset scalp pain and worsening GA. Five months after vaccination, he underwent investigations that included a hemoglobin of 91g/L, platelet count of 311 × 109/L, erythrocyte sedimentation rate (ESR) of 80 mm/hour, and C-reactive protein (CRP) of 44 mg/L (normal < 11 mg/L). He was treated with oral valacyclovir without improvement. His scalp pain significantly worsened, and 6 months after vaccination, he started to have progressive breakdown of the skin in the center of his forehead (Fig. 2A–D). Eight months after vaccination, he developed sudden bilateral vision loss and was referred to neuro-ophthalmology. He had a visual acuity of hand motions in the right eye and no light perception in the left eye. Dilated fundus examination revealed right optic disc edema secondary to anterior ischemic optic neuropathy and signs of a left central retinal artery occlusion (Fig. 3). He also had very firm and nodular temporal arteries (Fig. 2D). Repeat ESR was 108 mm/hour, and CRP was 110 mg/L. He was treated with 5 days of intravenous methylprednisolone followed by oral prednisone. Subsequent biopsy of the left temporal artery confirmed the diagnosis of GCA; viral polymerase chain reaction (PCR) was performed on the temporal artery biopsy, and VZV was not detected (Fig. 4).FIG. 2.: External images demonstrating progressive scalp necrosis that began 6 months after vaccination. Images (A–D) are before treatment with steroids and images (E, F) are 1 and 6 months after steroid treatment, respectively.FIG. 3.: Fundus photographs demonstrating right optic disc edema in the right eye (OD) from an anterior ischemic optic neuropathy. There was limited filling of the retinal arterioles in the left eye (OS) due to a central retinal artery occlusion.FIG. 4.: Hematoxylin and eosin (A) and Gomori trichrome (B) stain of the temporal artery biopsy specimen demonstrating an influx of mononuclear inflammatory cells with associated breakdown of the internal elastic lamina (red arrows) and influx of mononuclear cells in the adventitia (black arrows). The yellow star indicates significant cellular intimal thickening as well as disruption of the internal elastic lamina and inflammatory cells.The patient was continued on oral prednisone under the care of rheumatology, and his inflammatory markers continued to decline. His scalp significantly improved, and he had no necrotic visible areas 4 months after steroid treatment (Fig. 2E–F). His visual acuity mildly improved to 20/400 in both eyes 6 months after vision loss. DISCUSSION It has long been hypothesized that an infectious agent such as VZV may be the cause for a granulomatous arteritis such as GCA (3). Large population-based studies have not found a relationship between VZV reactivation and GCA incidence (4,5). However, some studies have detected VZV in a high proportion of positive and negative temporal artery biopsies (6,7), but this has not been replicated other studies on this topic (8,9). As recent reviews have highlighted (10,11), it is possible that 1) VZV is an innocent bystander in GCA cases because more people carry the virus, 2) VZV may trigger GCA, or 3) VZV actually causes GCA. This case supports the second hypothesis given the clear temporal relationship to the live-attenuated VZV vaccine and less likely the third hypothesis since his symptoms, in particular the scalp necrosis, improved considerably on high-dose corticosteroids alone, and he did not have any clear clinical manifestations of VZV. VZV was also not detectable in the temporal artery biopsy specimen by PCR. Previous studies have reported the development of GCA after vaccination. Soriano et al (12) reported 10 cases of previously healthy individuals that developed GCA or polymyalgia rheumatica (PMR) within 3 months of influenza vaccination. Additional 10 cases of GCA/PMR after vaccination have also been reported in the literature spanning over 30 years, indicating that this phenomenon is not a result of antigen specificity of the vaccine (13–21). A potential explanation is the interaction between vaccine antigens and specific HLA molecules such as HLA-DRB1*04 as a class II molecule on the antigen presenting cells results in an autoimmune reaction directed against the temporal artery and clinical manifestations of GCA (17). Vaccine adjuvants may also play a role in the induction of postvaccine adverse events including vasculitis (22). This also seems to mainly occur in genetically susceptible individuals carrying specific HLA-DRB1 genes (22). Another unique aspect of this case is the relationship between GA and GCA. We were able to retrieve 4 previous cases in the literature where this relationship existed (23–26). The average age of these patients was 76.5 and 3 patients developed GA first, between 1 month and 1 year before developing symptoms of GCA. Only one case was complicated by loss of vision (23) and both conditions responded well to steroids (24). GA and GCA share several common features including a common histopathological pattern of granulomatous inflammation, giant cells, and loss of elastic fibers and response to corticosteroids. However, GA is benign condition that is much more common than GCA and has been reported to be incited by trauma, infections, malignancy, and drugs. Vasculitis is also not believed to play a major role as evidenced by dermatopathology specimens (27). Nonetheless, the close temporal association in our case and those in the literature warrant consideration of GCA in patients presenting with new GA, especially if there are constitutional symptoms. In conclusion, GCA may occur in close temporal relationship to vaccines, including the live-attenuated VZV vaccine. Given the complicated relationship between VZV and GCA, symptoms that develop after the VZV vaccine may be misattributed to the virus itself. Understanding the potential for developing vasculitis after vaccines, such as that directed against VZV, would allow for earlier detection and the prevention of serious complications such as scalp necrosis and permanent vision loss.

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