Acute Posterior Multifocal Placoid Pigment Epitheliopathy Complicated by Fatal Cerebral Vasculitis

Multifocal granulomatous inflammations have been documented throughout human bodies, mostly in arteries and veins and by optical coherence tomography and histopathology of human ocular choroid.

Letters to the Editor Acute Posterior Multifocal Placoid Pigment Epitheliopathy Complicated by Fatal Cerebral Vasculitis T his is a letter regarding the article, “Acute Posterior Multifocal Placoid Pigment Epitheliopathy Complicated by Fatal Cerebral Vasculitis” (1). This is a superbly crafted report with excellent illustrations of both ocular and cerebral vascular abnormalities. My concept is that this report and pathologies are evidence of the 146-year known Winiwarter-Buerger, or thromboangitis obliterans, disease (TAO) induced and continued by cigarette smoking and possibly aggravated by smoking marijuana. Many of these patients are strongly addicted to cigarettes. Multifocal granulomatous inflammations have been documented throughout human bodies, mostly in arteries and veins and by optical coherence tomography and histopathology of human ocular choroid. Stopping smoking is slowly followed by stabilization of symptoms and signs, decreased inflammation, and recanalization of thrombosed vessels. Most current reports come from Europe, Iran, Iraq, India, China, and Japan, where heavy smoking is common. I encourage the authors of this report and other physicians, to consider TAO as the most likely pathophysiology. Our responsibilities as physicians are to diagnose this disease and encourage patients to stop smoking cigarettes, marijuana, or anything else. Thromboarteritis obliterans was first described by von Winiwarter in Germany in 1878 (2) and reborn in 1908 by Buerger in New York City (3). German neuropathologists H. Spatz in 1935 (4) and R. Lindenberg and Spatz in 1939 (5) revived interest. In the latter article is a microphotograph of an abnormal retinal artery. World War II interfered with many academic interests, except development of Penicillin by combined efforts of Fleurry, a British academician, and 7 American chemical companies. The TAO literature of the late 1940s and 1950s was meager until the 1960s when interest was revived. Richard Lindenberg, a neuropathologist for Germany's Luftwaffe, was brought by Werner von Braun to San Antonio, Texas. He then came to Baltimore and became a neuropathologist for the Medical Examiners Laboratory and Office. He and Frank B. Walsh became good friends and professional colleagues. Lindenberg was given an academic appointment at Johns Hopkins Hospital and School of Medicine. At this time, in the late 1950s and early 1960s, on Monday evenings at 6:00 PM, many of us interested in neurology would convene at the Medical Examiners Laboratory where Lindenberg displayed interesting cases from the past week. These were labeled “Brain Cuttings,” thick slices of brains demonstrating normal and pathologic abnorLetters to the Editor: J Neuro-Ophthalmol 2021; 41: e817-825 malities. Lindenberg, knowing us by first names, would ask one in the audience to look at a specific set of slices, describe what was abnormal, and then try to guess cause or causes. At those times, Lindenberg's emphasis was that for him, the classic lesions of TAO were depressions in cerebral cortexes, their surfaces filled with tangled white threads, and remnants of occluded arteries and veins. We saw many cases and remembered them. The next events in this story began in the early 1960s, at a Saturday morning, Internal Medicine Department “Grand Rounds” at Johns Hopkins Hospital, where a case of a young man with an unclear vasculopathic diagnosis, “arteriosclerosis,” was presented. Fortunately, for the advancement of knowledge, in the audience was Paul S. Crane, MD, 1944 Hopkins Medical School Graduate and a friend of mine. He reported that at his small missionary hospital in Chungju, Korea, none of his patients had arteriosclerosis, but many, often farmers, smoked cigarettes, often two packs per day. At autopsy or amputation, he had found the classic pathology of TAO, thromboses and inflammation of both arteries and veins with giant cells in vessel walls. Hopkins listened, paid for, and sent Victor A. McKusick, MD, a connective tissue expert, to Korea where he studied Crane's patients and their pathology. He confirmed Crane's observations and conclusions, and gave him recognition. McKusick's published articles in several journals are classics, bringing TAO into the thinking of modern American medicine (6). For those of us who have worked in Boston, the confirmation of any idea requires a “Boston Blessing.” In years past, when C. Miller Fisher addressed an issue, he always did a thorough job. Fisher was challenged by the unusual nature of TAO lesions, the relative rarity of the disorder, and the difficulties of patient management. He realized that he had seen and studied 5 patients of his own. He first authored one of his long (40 pages) detailed reports in 1957, in which he proposed that arterial stenosis proximal to areas of thrombo obliterans were responsible. He described the histopathology of the tangled white threads that he saw in atrophic areas of cerebral cortex (7). In an effort to learn about Miller Fisher's, enduring and likely final attitudes about TAO, I searched PubMed listings. After his 1957 report, I could not find any new report by Fisher with TAO in the title. Deference to his 1957 report was included in a 1964 CPC at the Mass General (8) and his 2001 autobiographical article (9). Miller Fisher would have supported the current histopathology of TAO in rapidly dying young men, thrombi and granulomatous inflammation in vessel walls. I have only been involved with 2 patients with TAO and made the diagnosis on a third patient of another doctor. The first 2 were seen as outpatients, consulting at Montebello Rehabilitation Hospital in Baltimore in the 1960s. One was a young woman who had stopped smoking. The other was a young man, still smoking. Both had been documented as having depressed lesions of their e817 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Letters to the Editor cerebral cortexes. The third patient was being explored in one of our neurosurgery operating rooms, next to a patient of mine in another operating room. I wandered into the room, and introduced myself to the surgeon whom I knew. When he knew who I was, he said “Dave, look at this, I am exploring this man because we do not know what this is and why it is happening.” I looked at the exposed area of cerebral cortex and instantly saw depressed cortex, no blood vessels, and tangled white threads. My comment was “that looks just like what Lindenberg used to show us at his brain cutting sessions, Winiwarter-Buerger disease; thromboarteritis obliterans.” The anesthesiologist, hearing this conversation, commented “He smokes 2 packs a day.” I never learned what happened to the patient and the neurosurgeon died an early cancer death. Concurrence of retinal maculopathy and TAO is making itself known. A 2015 report (11) described a young man with sudden onset of vision loss in his left eye; headaches; paresthesias of left thumb, index, and middle fingers; and a 20/100 scotoma of his left eye. He smoked 2–4 packs of cigarettes and drank 1 to 3 alcoholic drinks per day. There was left-side reduction of somatic sensation to light touch, vibration, and temperature. Edematous macular lesions of both eyes were stained with fluorescein. MRI revealed multiple hypointense and hyperintense foci of his cerebral cortex “consistent with acute stroke.” Intravenous methylprednisolone and then oral prednisolone were followed by symptoms and signs of new strokes. Oral cyclophosphamide was continued for 7 months when steroids were tapered. Final acuities were right eye 20/20 and left eye 20/25. Chronologically, for me, the next case report had been published in 2006 (11). I learned about it from reading the bibliography of Maamari (1) report. A 23-year-old Dutch man had the rapid onset of severe loss of vision in his right eye (arm waving at one meter) and 20/40 in left eye. Ophthalmoscopy revealed “multiple creamy white lesions just below pigment epithelium in both eyes.” Fluorescein angiography was interpreted as classic acute posterior multifocal placoid pigment epitheliopathy (APMPPE) in both eyes. The patient then developed bilateral anterior uveitis and 3 days later, acute pain behind right eye, severe headache, left hemiparesis and hypesthesia, and tonic-clonic status epilepticus, which did not respond to intravenous clonazepam and phenytoin sodium. Angiographic studies revealed artery occlusions and infarctions. Brain swelling caused herniation and death. Histopathologic studies of his eyes revealed inflammation and giant cells of only choroid. Retina and pigment epithelium were not affected. Left medial cerebral artery was centrally thrombosed with inflammatory thickening of vessel wall, including adjacent giant cells. At the Spring 2018 Meeting of the VerhoefZimmerman Society, I showed a photocopy of this patient's brain vascular pathology to Hans Grosniklaus, e818 who took a 3-second look and proclaimed “WiniwarterBuerger disease.” After these events, I e-mailed J. J. de Vries, MD, first author of the 2006 report (11), asking about his patient's smoking history. On March 18, 2019, he replied, apologizing for his delay in being able to answer my query, because he had to extract data from their medical record and contact the patient's family who reported that he smoked only “10 cigarettes per day” and only smoked marijuana in his teens. de Vries acknowledged that TAO should remain on the differential diagnosis list. Reviewing both the reports by de Vries and colleagues (11) and Maamari and colleagues (1) has led to my awareness that present-day photo microscopically created images, electronically transmitted by pathologists to clinicians and other pathologists and then to editors and publishers, are of high quality, informative, and permanent. This is a high-quality academic harvest. As a result of the request I received, I began searching pertinent literature in the summer of 2019. I recalled a patient of mine, a 60 year old woman and heavy cigarette smoker whose blind, painful right eye I had enucleated in 1969. At that time, Dick Green and I did not suggest TAO. We did, however, include a photomicrograph of her eye in our 2000 report (12) of our article describing different examples of ischemic optic neuropathic histopathology. Included in that text was the suggestion that this was an instance of TAO, supported by three references in the bibliography of that report (13–15). Preparing this critique led me to our histopathology slide storage area, where I retrieved slides of the eye, enucleated in 1969. Microscopy reveals mild choroidal inflammation and cellular inflammation around small arteries in both the center and sub sheath areas of the optic nerve. A recent review article, “How to treat a patient with thromboarteritis obliterans,” (16) is a long and thorough abstraction of 46 quoted articles published from 1992 to 2015. This report's primary authors are Iranian peripheral vascular surgeons. A major feature of this article is their analyses of cigarette smoking as reported in different articles. Stopping cigarette smoking ranged from only 17%–50% in some articles. The authors stated that managing nonsmokers was easier than those who continued to smoke. Bibliography titles did not include any article featuring cerebral vascular involvement. In summary, recognition and diagnosis of choroiditis with or without optic neuropathy in a young male or female smoker (cigarettes or marijuana) should license clinicians to immediately and forcefully demand that patient to stop smoking anything. If cerebrovascular events develop, systemic corticosteroids and anticoagulants should help the clinical situation. The rarity of these patients reduces development of controlled clinical trials. David L. Knox, MD Johns Hopkins Wilmer Eye Institute, Baltimore, Maryland 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 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.