Vision Loss, Rash, and Abnormal Brain Magnetic Resonance Imaging in a 17 Year Old

Clinical-Pathological Case Study Section Editors: Neil R. Miller, MD Janet Rucker, MD Vision Loss, Rash, and Abnormal Brain Magnetic Resonance Imaging in a 17 Year Old Andrea A. Tooley, MD, Laurence J. Eckel, MD, Diva R. Salomão, MD, John J. Chen, MD, PhD, Jacqueline A. Leavitt, MD Dr. Tooley: A 17-year-old man developed intermittent, progressive left-sided numbness and slurred speech while exercising. Episodes of numbness usually lasted 5-10 minutes, progressed from his left face to his upper and lower extremities, and occurred only when exercising. These episodes increased in frequency and began to occur daily. He identified no other triggers or aggravating factors. His history was positive for a rash along his abdomen and back for the past 2 years. The rash consisted of small pink papules with a central white clearing (Fig. 1). He had recently been placed on minocycline as the rash was presumed to be acne. One week after starting minocycline, he woke up with painless blurred vision in his left eye. Vision was 20/15, right eye and 10/400, left eye. A relative afferent pupillary defect in the left eye was noted with what appeared to be mild optic disc edema in the left eye. Brain MRI was performed. Dr. Eckel: The MRI, performed without and with contrast within a week of presentation, shows no evidence of acute infarction, FIG. 1. Abdominal rash is composed of small pink papules with central white clearing. Departments of Ophthalmology (AAT, JJC, JAL), Radiology (LJE), and Pathology (DRS), Mayo Clinic, Rochester, Minnesota. Supported by Research to Prevent Blindness (New York, NY). The funding organization had no role in the design or conduct of this research. The authors report no conflicts of interest. Address correspondence to Jacqueline A. Leavitt, MD, Department of Ophthalmology, Mayo Clinic, 200 First Street South West, Rochester, MN 55901; E-mail: [e-mail] Tooley et al: J Neuro-Ophthalmol 2017; 37: 303-308 but there is a small right subdural fluid collection, and subtle leptomeningeal enhancement along the lateral aspect of the right cerebral hemisphere (Fig. 2). In addition, there is asymmetric enhancement surrounding the left optic nerve (Fig. 3). All of these findings are radiographically nonspecific but suggest an inflammatory, granulomatous, or infectious disorder. Dr. Tooley: The patient was diagnosed with left optic neuritis and treated with intravenous methylprednisolone, 1 gm/day for 2 days, followed by intravenous immunoglobulin for 2 days, and then a brief course of oral prednisone 1 mg/kg/day. There was no improvement in vision in the left eye. Lumbar puncture demonstrated a white blood cell count of 12 cells/mL, protein of 41 mg/dL (normal , 45 mg/dL), glucose of 86 mg/dL and was negative for an infectious agent and oligoclonal bands. Hematological testing included antinuclear antibody, anticardiolipin screen, beta-2 GP1, immunoglobulin G and immunoglobulin M, rubeola, Lyme, anti-neutrophil cytoplasmic antibodies (c-ANCA and p-ANCA), ds-DNA, anti-Smith, ribonucleoprotein (RNP), anti-Sjogren syndrome A and B (SS-A and SS-B), Scl-70, Jo-1, ribosomal, serum, and CSF testing for adenovirus, cyclomegalovirus, HHV-6, herpes simplex virus, varicella zoster virus, cryptococcus, fungal and mycobacterial cultures, HIV, histoplasma, Epstein-Barr virus, Borrelia titers, cell-based assay for aquaporin antibodies, and paraneoplastic panel. These tests were all negative. Over the next 1-2 months, the patient experienced worsening vision in the left eye, progressive left-sided weakness, problems with dexterity, facial asymmetry, headache, dizziness, slurred speech, cognitive decline, decreased appetite, with a 5-pound weight loss. Two months after his initial vision loss, the patient's acuity was 20/15, right eye, and no light perception (NLP), left eye. The right visual field was normal. Ophthalmoscopy showed moderate right optic disc swelling, whereas the left optic disc was pale. Given the patient's worsening symptoms and right optic disc swelling, he was readmitted for another course of intravenous methylprednisolone. During this admission, he underwent multiple lumbar punctures that showed a progressively increasing white blood cell count from 15 cells/mL to 190 cells/mL with lymphocyte predominance and an elevated opening pressure 303 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study FIG. 2. Initial MRI of the brain. A. Axial diffusion-weighted image is unremarkable. B. Axial T2 image shows a small right subdural fluid collection (arrows). C. Postcontrast axial T1 scan demonstrates mild leptomeningeal enhancement (arrows). ranging from 35 to 42 mm H2O. The patient was started on 500 mg of acetazolamide twice daily. Laboratory evaluation for autoimmune processes, infection, and hypercoagulability were negative with the exception of a positive lupus anticoagulant. Four months after presentation, the patient underwent another brain MRI, positron emission tomography (PET) scan and cerebral angiography. Dr. Eckel: MRI of the brain shows acute infarctions in the right cerebral hemisphere, enlargement of the previously identified right subdural fluid collection, and marked increase in the leptomeningeal enhancement of the right hemisphere (Fig. 4). The enhancement of the left optic nerve was unchanged (not shown). PET shows markedly reduced metabolism throughout the right cerebral hemisphere, although no corresponding decrease in vascular flow is present on the cerebral angiogram (Fig. 5). Dr. Leavitt: Throughout the course of the patient's illness, the differential diagnosis included demyelinating disease, infectious etiologies, vasculitis, and other inflammatory states, With the subdural fluid collection continuing to worsen, the decision was made to drain the fluid and obtain a brain biopsy. The biopsy specimen showed evidence of vasculitis, raising the differential diagnoses of primary angiitis of the central nervous system, autoimmune disease such as systemic lupus erythematosus (SLE), or a systemic vasculitic disorder such Behçet disease or microscopic polyangiitis. The patient's skin rash also was progressing, so a skin biopsy was obtained from the lower back. This also showed evidence of a chronic lymphocytic vasculitis, as might be seen in SLE, rheumatoid arthritis, dermatomyositis, or a drug reaction. At this point the patient was transferred to our institution. Dr. Tooley: Examination revealed vision of 20/25, right eye, and NLP, left eye, normal slit-lamp examination and intraocular pressures that were within normal limits. Ophthalmoscopy revealed a combined central retinal artery and central retinal vein occlusion in the left eye, whereas the right fundus was normal except for one small choroidal lesion (Fig. 6). Fluorescein and indocyanine FIG. 3. Axial (A) and coronal (B) contrast-enhanced T1 images with fat suppression reveal enhancement of the left optic nerve (arrows). 304 Tooley et al: J Neuro-Ophthalmol 2017; 37: 303-308 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study FIG. 4. MRI 4 months after initial presentation. A. Axial diffusion-weighted imaging shows acute infarction in the right cerebral hemisphere. B. Axial T2 image shows enlargement of the right subdural fluid collection (arrows). C. Postcontrast axial T1 scan demonstrates diffuse leptomeningeal enhancement of the right hemisphere (arrows). green angiography showed markedly delayed and decreased perfusion in the left eye (Fig. 7). The outside brain and skin biopsies were reviewed by our pathology department. (Fig. 8). Based on these histopathologic findings in conjunction with the cutaneous lesions and his systemic illness, the patient was diagnosed with Degos disease, or malignant atrophic papulosis (MAP). Dr. Salomão: Dr. Tooley: The brain biopsy shows focal vasculitis, predominantly lymphocytic, with transmural involvement of cortical and leptomeningeal vessels. Subacute cortical microinfarcts also are present. The skin biopsy of a lower back lesion reveals lymphocytic vasculitis, focal dermal and epidermal necrosis The patient was started on cyclophosphamide to treat the vasculitic component of MAP while awaiting approval for the use of eculizumab, a monoclonal antibody directed against complement C5, to treat the sequelae of endothelial damage including vascular occlusion and tissue destruction. FIG. 5. A. Axial fluorodeoxyglucose positron emission tomography shows reduced uptake in the right cerebral hemisphere compared with the left. Anteroposterior view of right (B) and left (C) cerebral angiograms shows no difference in vascular flow between the right and left hemispheres. Tooley et al: J Neuro-Ophthalmol 2017; 37: 303-308 305 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study FIG. 6. A. Right fundus shows a small choroidal lesion (arrow) inferotemporal to the optic disc. B. The left fundus reveals extensive hemorrhage of the disc, dilated tortuous veins, boxcarring, and complete occlusion of retinal arterioles. This drug was eventually prescribed, as was treprostinil to treat the vasculopathy component of MAP and aspirin and pentoxifylline for their antiplatelet effects. Shortly after starting this treatment regimen, the patient's condition stabilized. His neurologic examination showed mild left hemiparesis affecting his hand but significant weakness of his left leg. One week later, he was discharged home to have infusions as an outpatient. After his fourth weekly infusion, he developed new findings: inability to stand and walk on his own, a neurogenic bladder, right-sided ptosis, left-sided facial droop, deviation of the tongue to the left, and many more skin lesions. Repeat brain MRI was performed. Dr. Eckel: On this contrast-enhanced MRI, the leptomeningeal enhancement has progressed and now extends along the basilar cisterns and minimally to the left. Leptomeningeal enhancement along the right cerebral hemisphere is also more prominent (Fig. 9). Dr. Tooley: The patient was transferred back to our hospital and stared on dipyridamole in addition to his previous medications. Repeat eye examination revealed a pupilinvolving right third nerve palsy and a new left homonymous hemianopia. Several days later, he developed vision loss in the right eye. Examination showed visual acuity of NLP bilaterally, but funduscopy did not show any optic disc swelling or vascular occlusions in the right eye. Over the next week, the patient remained stable, with no new findings on brain MRI. Eculizumab and cyclophosphamide were discontinued and tocilizumab was added to treat the vasculitic component of the disorder, with eculizumab being reserved for salvage therapy if he developed worsening symptoms or gastrointestinal (GI) tract involvement. His treatment regimen at this time thus consisted of treprostinil, dipyridamole, aspirin, pentoxifylline, tocilizumab, and oral corticosteroids. Unfortunately, several weeks later, the patient's condition worsened, and he died 10 months after his FIG. 7. Fluorescein (A) and indocyanine green (B) angiography of the left eye at 4 minutes, 13 seconds reveals markedly decreased vascular perfusion. 306 Tooley et al: J Neuro-Ophthalmol 2017; 37: 303-308 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study Dr. Leavitt: MAP, also known as Degos disease, is a rare vasculopathy most commonly seen in white people, with an average age of onset between 20 and 40 years (1,2). However, it has been reported in a patient as young as 8 months (3). The condition typically is sporadic but hereditary forms have been described (4,5) There are 2 forms of the disease, a purely cutaneous form and a systemic form involving multiple organ systems. Although the cutaneous form is benign, and long-term survival can be upward of 20 years, patients with systemic involvement have a 5-year survival rate of less than 50% (6). In the systemic variant of MAP, the GI tract is affected in about half of all cases. Other systemic complications include pericarditis, pleuritis, and thrombosis of the cerebral arteries, cerebral hemorrhage, meningitis, encephalitis, and myelitis. Bowel ischemia with intestinal perforation is the most common cause of death in systemic MAP. FIG. 8. Skin biopsy. There is focal epidermal ulceration with wedge-shaped dermal necrosis characterized by effacement and eosinophilia of the collagen (hematoxylin & eosin, · 40). Inset. Lymphocytic vasculitis is present deeper in the dermis (hematoxylin & eosin, · 400). initial "spells" began and 5 months after his first episode of vision loss. Final Diagnosis Malignant atrophic papulosis (Degos disease). Dr. Salomão: The pathognomonic skin lesions of MAP are usually 0.5- 1.0 cm papules with an atrophic umbilicated white center and an erythematous, telangiectatic rim. Lesions occur on the trunk and the upper extremities and tend to spare the palms, soles, scalp, and face (7). Histology of skin lesions shows a central zone of epidermal thinning and dermal ischemic necrosis that is wedge-shaped, with vascular dropout and lymphocytic vasculitis located deep within the dermis. Extensive occlusive thrombotic microangiopathy with endothelial cell degeneration and sloughing also has been reported (8). Dr. Chen: FIG. 9. Postcontrast axial T1 MRI demonstrates leptomeningeal enhancement involving the basal cisterns (arrows) and left temporal lobe (arrowhead). Tooley et al: J Neuro-Ophthalmol 2017; 37: 303-308 Ocular involvement in MAP is not common but has been documented in several case reports. Findings include ischemic lesions of the eyelid, conjunctiva, sclera, choroid, vascular occlusions, and diplopia and papilledema secondary to CNS involvement (9). Henkind and Clark (10) reported the histopathological changes occurring from MAP in episcleral, retinal, and optic nerve head vessels. Histology showed subendothelial fibrosis, endothelial proliferation, narrowing of the lumen, and thrombosis. The muscular and adventitial layers were relatively normal and fibrinoid necrosis was limited to the intima only (11). The rarity of ocular involvement associated with MAP makes it a difficult disorder to study. The pathophysiology affecting the eyes is presumably the same as that which affects systemic organs and, therefore, neurologic deterioration can include to vision loss, as occurred in our patient. The combined central retinal artery and central retinal vein occlusion in the left eye of our patient demonstrate the occlusive thrombotic nature of MAP, whereas his complete loss of vision in the right eye in the setting of a normal examination is suggestive of a posterior ischemic optic neuropathy. 307 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study Dr. Leavitt: Dr. Tooley: The pathogenesis of MAP is unknown, although theories include viral, genetic, or autoimmune causes. Investigations into the etiology have shown MAP to involve a vasculitic component, a coagulopathy, and endothelial dysfunction leading to vascular thrombosis and tissue infarction (6,12). No therapy is known to successfully treat the systemic condition. Multiple patients with MAP have shown signs of increased platelet aggregation; therefore, aspirin and dipyridamole have become mainstays of treatment (13). Immunosuppressive agents including cyclophosphamide, azathioprine, and corticosteroids are often initiated alongside anticoagulants. Magro et al (8) reported prominent membranolytic attack complex deposits (C5b-9) in the skin, GI tract, and brain vessels of 4 patients with MAP. These findings have led to new therapies aimed at inhibiting C5. Eculizumab, a humanized monoclonal antibody that prevents the cleavage of complement C5 into its proinflammatory components has been used to treat patients with vascular thrombosis including hemolytic uremic syndrome, renal allograft rejection, and thrombotic complications related to paroxysmal nocturnal hemoglobinuria. It is now being used as a therapeutic option for MAP (14). Treprostinil, a prostacyclin analog, has also been used successfully in a case of eculizumab resistant MAP with intestinal and CNS manifestations, although its mechanism of action in treating MAP is unknown (15). Our patient had cutaneous manifestations of MAP 2 years before he developed systemic symptoms. Once he developed with CNS and ocular involvement, however, the disease was rapidly progressive and ultimately fatal despite all treatment attempts. Dr. Chen: Our patient was treated using multiple medications including cyclophosphamide and high-dose corticosteroid therapy to treat the vasculitic component of MAP, treprostinil to treat the vasculopathy, aspirin and pentoxifylline for the antiplatelet effect, and eculizumab to treat the endothelial damage and vascular occlusions. Tocilizumab, a humanized monoclonal antibody against the interleukin-6 receptor was eventually added to treat the vasculitic component of MAP. 308 REFERENCES 1. Köhlmeier W. Multiple Hautnekrosen bei Thrombangitis obliterans. Arch Dermatol Syph (Wien). 1941;181:783-792. 2. Degos R, Delort J, Tricot R. Dermatite papulosqameuse atrophiante. Bull Soc. Fr Derm Syph. 1942;49:148-150. 3. González JA, Noguer S, Cabré J. Degos' malignant atrophic papulosis (observation of a case in an infant) [in Spanish]. Actas Drmosifiliogr. 1975;66:317-319. 4. Newton JA, Black MM. Familial malignant atrophic papulosis. Clin Exp Dermatol. 1984;9:298-299. 5. 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Report of a case with multiple ophthalmic findings. Indian J Ophthalmol. 2003;51:260-263. 12. Ball E, Newburger A, Ackerman AB. Degros' disease: a distinctive pattern of disease, chiefly of lupus erythematosus, and not a specific disease per se. Am J Dermatopathol. 2003;35:308-320. 13. Drucker CR. Malignant atrophic papulosis: response to antiplatelet therapy. Dermatologica. 1990;180:90-92. 14. Magro CM, Wang X, Garrett-Bakelman F, Laurence J, Shapiro LS, DeSancho MT. The effects of eculizumab on the pathology of malignant atrophic papulosis. Orphanet J Rare Dis. 2013;8:185. 15. Shapiro LS, Toledo-Garcia AE, Farrell JF. Effective treatment of malignant atrophic papulosis (Kohlmeier-Degros disease) with treprostinil: early experience. Orphanet J Rare Dis. 2013;8:52. Tooley et al: J Neuro-Ophthalmol 2017; 37: 303-308 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.