Acute Posterior Multifocal Placoid Pigment Epitheliopathy Complicated by Fatal Cerebral Vasculitis: Response

At least some cases, however, have been reported in which it was specifically mentioned that there was no history of cigarette smoking, recreational drug use, or alcohol use.

Letters to the Editor The author reports no conflicts of interest. REFERENCES 1. Maamari RN, Stunkel L, Kung NH, Ferguson CJ, Tanabe J, Schmidt RE, Dahiya S, Dhand A, Van Stavern GP, Rajagopal R, Harocopos GJ. Acute posterior multifocal placoid pigment Epitheliopathy complicated by fatal cerebral vasculitis. J Neuroophthalmol. 2019;39:260–268. 2. Von Winiwarter F. Über eine eigentümliche form von endarteritis und endophlebitis mit gangrän des fusses. Arch Kiln Chir. 1878;23:202–226. 3. Buerger L. The Circulatory Disturbances of the Extremities. Philadelphia, PA: W.B. Saunders Company, 1924. 4. Spatz H. Über die beteiligung des gehirns bei der v. WiniwarterBuergerschen krankheit (Thrombo-endangiitis obliterans). Deutsche Zeitschr F Nervenheilk. 1935;136:86–132. 5. Lindenberg R, Spatz H. Über die thrombo arteritis obliterans der Hirngefasse-Buergerschen krankheit. Virchow Arch Path Anat. 1939:531–557. 6. McKusick VA, Harris WS, Ottesen OE. Buerger's disease: a distinct clinical and pathologic entity. JAMA. 1962;181:93–100. 7. Miller Fisher C. Cerebral thromboangiitis obliterans. Medicine. 1957;36:169–234. 8. Friedman DG, Miller Fisher C. Case records of the Massachusetts General Hospital, weekly clinicopathological exercises. Case 51-1964. NEJM. 1964;271:837–845. Acute Posterior Multifocal Placoid Pigment Epitheliopathy Complicated by Fatal Cerebral Vasculitis: Response W e sincerely thank Dr. Knox for his thoughtful and insightful comments regarding a possible relationship between cigarette (and/or marijuana) smoking and acute posterior multifocal placoid pigment epitheliopathy (APMPPE)-associated cerebral vasculitis and between Buerger disease and APMPPE, including a thorough historical account and informative case summaries to illustrate his assertion. We agree with Dr. Knox regarding a possible association between smoking and APMPPE, particularly in cases of APMPPE that are complicated by cerebral vasculitis. In our case report of APMPPE associated with fatal cerebral vasculitis, we made sure to mention the positive history of cigarette smoking for that very reason. However, we did not touch on this point in the discussion, and accordingly, we are grateful to Dr. Knox for raising this issue. In previous reports of APMPPE, even with cerebral vasculitis/neurologic manifestations present, the clinical history has typically focused on the presence or absence of antecedent viral illness but often does not mention a positive vs negative history of smoking (1), perhaps because many authors may have assumed that this was not clinically relevant. At least some cases (2), however, have been reported in which it was specifically mentioned that there was no history of cigarette smoking, recreational drug use, or alcohol use. On the other hand, it is of interest that Dr. Knox unearthed retroactively from de Vries et al a positive Letters to the Editor: J Neuro-Ophthalmol 2021; 41: e817-825 9. Miller Fisher C. A career in cerebrovascular disease: a personal account. Stroke. 2001:2719–2724. 10. van Zyl T, Papakostis TD, Sobrin L. Vision loss and paraesthesias in a young man. JAMA Ophthalmol. 2015:1207– 1208. 11. de Vries JJ, den Dunnen WFA, Timmerman EA, Kruithof IG, De Keyser J. Acute posterior multifocal placoid pigment epitheliopathy with cerebral vasculitis: a multisystem granulomatous disease. Arch Ophthalmol. 2006;124:910– 913. 12. Fazeli B, Moghadam MD, Niroumand S. How to treat a patient with thromboangiitis obliterans: a systemic review. Ann Vasc Surg. 2018;49:219–228. 13. Knox DL, Kerrison JB, Green WR. Histopathologic studies of ischemic optic neuropathy. Trans Am Ophthalmol Soc. 2000;98:203–220, discussion 221–222. 14. Gresser EB. Partial occlusion of retinal vessels in a case of thromboangiitis obliterans. Am J Ophthalmol. 1932;15:235– 237. 15. Birnbaum W, Prinzmetal M, Connor CL. Generalized thromboangiitis obliterans: report of a case with involvement of retinal vessels and suprarenal infarction. Arch Intern Med. 1934;53:410–422. 16. Böke W, Duncker G. Bilateral relapsing ueitis, retinitis and papillitis: a complication of thromboangiitis obliterans? [in German]. Klin Monbl Augenheilkd. 1983;182:294–297. history of smoking in the case they had reported in 2006 (previously referenced). As Dr. Knox also noted, the case report by Van Zyl et al (3) also mentioned a history of cigarette smoking in their patient. We fully agree with Dr. Knox that any patient with APMPPE should be questioned regarding smoking history, and if answering in the affirmative, should of course be counseled as to the importance of cessation. Likewise, it is prudent for authors reporting any future cases of APMPPE to include specific mention of smoking history in their publications. This consistency in reporting is obviously crucial for determining whether a genuine association between smoking and APMPPE exists, and if so, how strong this association may be. Buerger disease (thromboangiitis obliterans) is a nonatherosclerotic inflammatory, vaso-occlusive/obliterative disease most commonly affecting small-sized and mediumsized vessels of the distal extremities (4). However, cerebrovascular involvement is also seen in a minority of patients (up to 18% in some series (5), but only 0.5% in one series of 1700 patients (6)); likewise, involvement of visceral organs, potentially including multiorgan involvement, may be present in a minority of cases (7,8). The cerebrovascular component of Buerger disease that is sometimes seen (also known as cerebrovascular thromboangiitis obliterans) is the subject of Dr. Knox's letter. As to Dr. Knox's assertion that cerebrovascular Buerger disease and APMPPE-associated cerebral vasculitis are one and the same disease entity, we hesitate to agree with this point both from a clinical perspective and especially from a histopathologic perspective. From a clinical perspective, we concede that both entities are most commonly seen in relatively young adults (younger than 45–50 years), and also, both Buerger disease and APMPPE-associated cerebral vasculitis have a gender e819 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Letters to the Editor predilection for men (whereas APMPPE without neurologic manifestations has no gender predilection). On the other hand, although a current or past history of smoking is regarded by most authors as being a requirement for the diagnosis of Buerger disease, there have been at least some cases of APMPPE-associated cerebral vasculitis reported in nonsmokers, as already noted above. Second, regarding infectious triggers, APMPPE is commonly associated with an antecedent viral illness (adenovirus), and associations with rubeola (measles) and mycobacterial infection have also been reported, whereas the infectious triggers reported to be possibly associated with Buerger disease are gramnegative bacteria (Rickettsia and Porphyromonas gingivalis) (9). Third, the clinical ocular manifestations of APMPPE have been reported in association with various other autoimmune diseases (e.g., Wegener granulomatosis, systemic lupus erythematosus, erythema nodosum (3), sarcoidosis, psoriatic arthritis, etc.), whereas there has been no analogous association reported between Buerger disease and other autoimmune diseases. In fact, the presence of any identifiable autoimmune disease is generally regarded as an exclusion criterion for the diagnosis of Buerger disease (8). Moreover, the histopathology of these 2 disease entities does differ, based on reports to date. As we described in our report, vasculitis associated with APMPPE is characterized by granulomatous and lymphocytic infiltration of the vessel wall but not acute inflammation. By contrast, Buerger disease (in the acute phase) exhibits as its hallmark feature an inflammatory infiltrate within the thrombus itself, especially with polymorphonuclear leukocytes, possibly with microabscess formation. Giant cells may also be present, but again classically within the thrombus itself, whereas there is typically relatively less inflammation within the vessel wall (4). With the one entity being bereft of the acute inflammatory features that are classic in the other and with the inflammation being predominantly situated within the vessel wall in the one entity but within the thrombus in the other, one would be hard-pressed on histologic grounds to prove that these are one and the same entity. That said, even if these 2 entities are not identical, might they be variants along the same pathophysiologic spectrum, with cigarette smoking involved in the pathophysiology of both (or in the case of APMPPE-associated cerebral vasculitis, at least serving as a risk factor)? Alternatively, might smoking predispose to different forms of vasculitis in different patients (just as asthma might predispose different patients to different forms of orbital inflammatory disease, e.g., Kimura disease in one patient but xanthogranuloma in another)? Ultimately, one's stance on such questions may to some extent rest on one's tendency toward being a “lumper” vs a “splitter,” as is the case with many disease entities. However, as “lumping” tends to be most appropriate the more the treatments for the entities of interest overlap vs “splitting” being more reasonable the more the treatments differ. In this case, Dr. Knox raises a provocative point that e820 smoking cessation may have been an under used therapy for cases of APMPPE-associated cerebral vasculitis to date, considering that this is the cornerstone therapeutic strategy for preventing progression of Buerger disease and avoiding amputation in that disorder. That aside, however, neurologic complications of APMPPE are generally treated with intravenous/oral corticosteroids, not uncommonly supplemented by an immunosuppressant agent (1–3). By contrast, other therapies for Buerger disease (although generally paling in comparison to the proven benefit of smoking cessation) typically focus on vascular perfusion, for example, iloprost (intravenously) or other prostanoids, bosentan (endothelin receptor antagonist), anticoagulants/antiplatelet agents/thrombolytics, antihypertensive agents, in some cases vascular bypass surgery (usually not possible due to the distal nature of the disease), sympathectomy, spinal cord stimulator, intramuscular vascular endothelial growth factor gene therapy, etc. (4,10) Even in cases of Buerger disease with cerebrovascular involvement, smoking cessation seems to be the only therapeutic strategy with highquality evidence for efficacy, whereas some authors report some benefit from vasodilators and anticoagulants (6,7). (Corticosteroids have been used in some cases of Buerger disease (10) but in general with no convincing demonstration of efficacy, with the exception perhaps of rare cases that are associated with peripheral eosinophilia (11).) In short, the essential target of the therapeutic thrust in APMPPE-related neurologic complications is the immune-mediated vasculitic aspect, whereas in Buerger disease, it is the thrombotic aspect. Furthermore, the existence of shared vs nonoverlapping genetic associations, for example, immune system–related haplotypes or the like, may shed light on whether the entities should most properly be regarded as representing a continuum along a pathophysiologic spectrum vs as being entirely distinct. With respect to the particular entities at hand, APMPPE has been reported (in a series of 30 cases) to be associated with the HLA haplotypes HLA-DR2 (57% of cases) and HLA-B7 (40% of cases) (12), whereas Buerger disease has been reported in association with HLA-A9 and HLA-B5 (13), as well as (in the Iranian population) HLAA3, HLA-A24, HLA-A31, HLA-A11, HLA-B27, HLA-B15, HLA-B7, HLA-B51, HLA-B44, HLA-DRB1*16, HLADRB1*04, HLA-DRB1*14, HLA-DRB1*03, and HLADRB1*15 (14), among others. Thus, HLA-B7 is the only haplotype association reported to date that is shared by both diseases. The differing HLA associations between these entities may account for why APMPPE has been reported in association with other autoimmune diseases, whereas Buerger disease has not and may also account for the differences in infectious disease triggers reported for these 2 entities. Overall, considering the histopathologic differences, as well as the largely differing HLA associations, in addition to the differing treatments, we contend that it is reasonable to regard APMPPE-related cerebral vasculitis and cerebrovascular Buerger disease as being distinct entities. Letters to the Editor: J Neuro-Ophthalmol 2021; 41: e817-825 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Letters to the Editor In any case, we acknowledge that the importance of smoking in the pathophysiology of APMPPE-associated vasculitis may have been underrecognized and underreported to date, and we encourage all readers of our report, and of the subsequent discussion associated therewith, to take note of this. We again thank Dr. Knox for astutely raising awareness of this topic. George Harocopos, MD Gregory Van Stavern, MD Departments of Ophthalmology and Visual Sciences, Washington University in St. Louis, St. Louis, Missouri Sonika Dahiya, MD Department of Pathology, Washington University in St. Louis, St. Louis, Missouri Leanne Stunkel, MD Robi Maamari, MD Departments of Ophthalmology and Visual Sciences, Washington University in St. Louis, St. Louis, Missouri 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. The authors report no conflicts of interest. REFERENCES 1. O'Halloran HS, Berger JR, Lee WB, Robertson DM, Giovannini JA, Krohel GB, Meckler RJ, Selhorst JB, Lee AG, Nicolle DA, O'Day J. Acute multifocal placoid pigment epitheliopathy and Neuro-Ophthalmologic Monitoring of Leaking Arachnoid Cysts R egarding the excellent JNO publication entitled “Neuro-Ophthalmologic Monitoring in the Management of Increased Intracranial Pressure from Leaking Arachnoid Cysts,” (1) we wish to add 2 similar cases that recently came under our care at the same institution. 13. 14. central nervous system involvement: nine new cases and a review of the literature. Ophthalmology. 2001;108:861–868. Algahtani H, Alkhotani A, Shirah B. Neurological manifestations of acute posterior multifocal placoid pigment epitheliopathy. J Clin Neurol. 2016;12:460–467. Van Zyl T, Papakostas TD, Sobrin L. Vision loss and paresthesias in a young man. JAMA Ophthalmol. 2015;133:1207–1208. Olin JW. Thromboangiitis obliterans (Buerger's disease). N Engl J Med. 2000;343:864–869. No YJ, Lee EM, Lee DH, Kim JS. Cerebral angiographic findings in thromboangiitis obliterans. Neuroradiology. 2005;47:912– 915. Lippmann HI. Cerebrovascular thrombosis in patients with Buerger's disease. Circulation. 1952;5:680–692. Fakour F, Fazeli B. Visceral bed involvement in thromboangiitis obliterans: a systematic review. Vasc Health Risk Manag. 2019;15:317–353. Puechal X, Fiessinger JN. Thromboangiitis obliterans or Buerger's disease: challenges for the rheumatologist. Rheumatology. 2007;46:192–199. Mohareri M, Mirhosseini A, Mehraban S, Fazeli B. Thromboangiitis obliterans episode: autoimmune flare-up or reinfection? Vasc Health Risk Manag. 2018;14:247– 251. Olin JW, Young JR, Graor RA, Ruschhaupt WF, Bartholomew JR. The changing clinical spectrum of thromboangiitis obliterans (Buerger's disease). Circulation. 1990;82(suppl IV):3–8. Ul haq Keen M, Dass S, Aslam A. Buerger's disease with severe eosinophilia and acute critical ischemia. Rheumatol Adv Pract. 2019;3(suppl 1)40; poster presentation #44. Wolf MD, Folk JC, Panknen CA, Goeken NE. HLA-B7 and HLADR2 antigens and acute posterior multifocal placoid pigment epitheliopathy. Arch Ophthalmol. 1990;108:698–700. McLoughlin GA, Helsby CR, Evans CC, Chapman DM. Association of HLA-A9 and HLA-B5 with Buerger's disease. Br Med J. 1976;2:1165–1166. Shapouri-Moghaddam A, Mohammadi M, Rahimi HR, Esmaeili H, Mahmoudi M, Saeed Modaghegh MH, Tavakol Afshari J. The association of HLA-A, B, and DRB1 with Buerger's disease. Rep Biochem Mol Biol. 2019;8:153–160. somnolent. Repeat MRI 5 months after diagnosis revealed increased thickness of the subdural collection and an organizing membrane within the fluid collection (Fig. 1B). Accordingly, he underwent cystoperitoneal shunting. Within days, he became alert and cheerful. Repeat brain MRI performed 2 days (Fig. 1C) and 1 month (Fig. 1D) after shunt placement showed progressive resolution of the hygroma. Our examination, conducted almost 2 months after shunt placement, showed nearly complete resolution of papilledema and normal visual function. CASE 1 A 14-year-old boy reported new headache and vomiting immediately after a day of ocean bodysurfing. Our examination disclosed normal visual function but bilateral papilledema. Brain MRI revealed a left temporal fossa arachnoid cyst that seemed to be connected to a crescentshaped extra-axial fluid collection diagnosed as a traumatic subdural hygroma (Fig. 1A). Acetazolamide 500 mg twice a day was prescribed to lower intracranial pressure, but over 5 months, the papilledema worsened, and he became more Letters to the Editor: J Neuro-Ophthalmol 2021; 41: e817-825 CASE 2 A 12-year-old boy playing football without a helmet was tackled and slammed into the ground, striking his head. Within hours, he developed a persistent headache. He sought no medical consultation until 2 weeks later, when the headache worsened and vomiting began. Brain computed tomography showed a left temporal fossa arachnoid cyst connected to a prominent subdural fluid collection that was better delineated on a subsequent brain MRI (Fig. 2A, B). Our e821 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.