A 44-Year-Old Man With Bilateral Optic Neuropathy, Optic Nerve Sheath Enhancement, and Cardiac Dysfunction

In this issue of the Journal of Neuro-Ophthalmology, M. Tariq Bhatti, MD and Mark Moster, MD discuss the following 6 articles.

Clinical-Pathological Case Study Section Editors: Neil R. Miller, MD Janet Rucker, MD A 44-Year-Old Man With Bilateral Optic Neuropathy, Optic Nerve Sheath Enhancement, and Cardiac Dysfunction Angela M. Herro, MD, Norman J. Schatz, MD, Linda L. Sternau, MD, John R. Guy, MD, Sander R. Dubovy, MD, Evelyn M. Sklar, MD, Byron L. Lam, MD Dr. Herro: A 44-year-old man presented to the emergency department with progressive painless vision loss in the right eye for 3 months. Visual acuity was 4/200, right eye and 20/ 20, left eye with a right relative afferent pupillary defect. Automated perimetry revealed a central scotoma in the right eye and was normal in the left eye. The remainder of the examination was normal with the exception of slight elevation of the right optic disc (Fig. 1). Brain and orbital magnetic resonance imaging (MRI) was performed. Dr. Sklar: Coronal T1 fat-saturated orbital images with contrast show peripheral enhancement of the sheaths of the orbital segments of both optic nerves (Fig. 2A). T2 imaging shows no increased signal in the orbital optic nerves and no enlargement of the sheaths (Fig. 2B). Postcontrast axial T1 fat-saturated image demonstrates enhancement of the intracanalicular and intracranial segments of the right optic nerve (Fig. 2C). The lacrimal glands are normal and symmetric, and the pituitary gland and suprasellar cistern are normal in appearance (Fig. 2C, D). Dr. Herro and Dr. Guy: The patient was thought to have idiopathic or demyelinating optic neuritis and was treated with intravenous methylprednisolone 1 g daily for 3 days, followed by oral prednisone with taper starting at 80 mg/d. Complete blood count, basic metabolic profile, quantiferon gold, serum vitamin B12 concentration, rapid plasma reagin, and angiotensinconverting enzyme, genetic testing for the 3 common Leber hereditary optic neuropathy mutations, aquaporin-4 antibodies, antioptic nerve antibodies (a and g enolase, glyceraldehyde, 3-phosphate dehydrogenase, myelin basic proteins, aquaporin-4, and collapsing response mediator protein-5), Bascom Palmer Eye Institute (AMH, NJS, JRG, SRD, BLL), University of Miami Miller School of Medicine, Miami, Florida; Division of Neurosurgery (LLS), Memorial Healthcare System, Hollywood, Florida; and Department of Radiology (EMS), University of Miami Miller School of Medicine, Miami, Florida. The authors report no conflicts of interest. Address correspondence to Angela M. Herro, MD, 18325 N Allied Way, Suite 100, Phoenix, AZ 85054; E-mail: [e-mail] 324 and chest radiograph were all negative or normal. Despite treatment, the patient had experienced no improvement 1 week later. He was treated with IVIg (1 g/kg/d) for 2 days with no visual improvement 1 month later. The patient was lost to follow-up but returned 3 years later because of worsening vision in both eyes. Examination at this time revealed counting fingers vision in the inferonasal quadrant of the right eye and 20/40, left eye, with 10 of 12 Ishihara plates correctly identified with the left eye. Automated perimetry now revealed a temporal defect in the left eye. Repeat brain and orbital MRI was performed. Dr. Sklar: Postcontrast T1 images through the orbit show persistent enhancement of the sheaths of the orbital segments of both optic nerves, right more than left (Fig. 3A). There is now intense dural enhancement at the right orbital apex with extension through the optic canal and along the base of the frontal lobes (Fig. 3B, C). Abnormal enhancing tissue also abuts the canalicular segment of the left optic nerve. In addition, there is thick dural enhancement of the planum sphenoidale extending to the tuberculum sellae and along the medial aspect of the right middle cranial fossa (Fig. 3B, D). All the findings have worsened significantly since the previous study. Dr. Sternau: The patient underwent a right frontal skull-base craniotomy with microscopic removal of abnormal tissue in the suprasellar, right sphenoid wing, and skull base regions. Intraoperatively, the abnormal tissue was found to be molded to and coating the entire skull base, including the arteries. As the mass was wrapped around the optic nerves and chiasm, dissection was not feasible. Accordingly, the abnormal tissue was debulked as much as thought safe, and the roof of the right optic canal was removed to facilitate decompression. Dr. Dubovy: Microscopic examination of the excised material discloses granulomatous inflammation with multinucleated giant cells and no evidence of necrosis (Fig. 4). No organisms were noted on acid-fast bacillus and Gomori methenamine Herro et al: J Neuro-Ophthalmol 2016; 36: 324-328 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study FIG. 1. There is mild elevation of the right optic disc and a normal fundus appearance of the left eye. silver stains. These findings were thought to be consistent with meningeal sarcoidosis and the patient was referred to rheumatology for further management. Dr. Herro: Oral steroids were initiated, along with methotrexate. Three months postoperatively, the patient became short of breath and experienced a cardiac arrest, requiring defibrillation. Evaluation revealed popliteal deep vein thrombosis (DVT) and bilateral pulmonary emboli (PE), as well as radiographic evidence of intraseptal sarcoidosis. An automated implantable cardioverter defibrillator (AICD) was placed, the patient was anticoagulated, and amiodarone was started for nonsustained ventricular tachycardia. On follow-up, visual acuity was counting fingers in the inferonasal FIG. 2. Initial magnetic resonance imaging. A. Postcontrast coronal T1 scan shows bilateral optic nerve sheath enhancement. B. Coronal T2 image demonstrates no increased signal in the optic nerves and no enlargement of the sheaths. C. Postcontrast axial T1 scan reveals enhancement of the intracanalicular and intracranial segments (arrow) of the right optic nerve. D. Sagittal T1 image shows a normal pituitary gland and suprasellar cistern. Herro et al: J Neuro-Ophthalmol 2016; 36: 324-328 325 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study FIG. 3. Magnetic resonance imaging 3 years after presentation. Coronal T1 scan with contrast shows (A) enhancement of the optic nerve sheaths bilaterally and (B) thick dural enhancement along the planum sphenoidale and the medial aspect of the right middle cranial fossa. C. Axial T1 scan with contrast shows extensive enhancement of the right orbital apex involving the optic nerve as it courses through the optic canal. The abnormal enhancement abuts the canalicular segment of the left optic nerve. Thick dural enhancement is noted along the medial aspect of the right middle cranial fossa, the tuberculum sellae, and the anterior aspect of the temporal lobe. D. Postcontrasts sagittal T1 image reveals enhancements along the planum sphenoidale (arrows) that extends to the tuberculum sellae. quadrant in the right eye and improved to 20/20, left eye, with near-complete resolution of the temporal visual field defect in the left eye. Final Diagnosis Meningeal sarcoidosis with intraseptal cardiac involvement. Dr. Herro: Sarcoidosis is a multi-system inflammatory disease of unknown origin that can affect many organ systems and can involve the central or peripheral nervous system in 5%- 10% of cases (1). Often, neurologic involvement can manifest as nonspecific symptoms such as headache, peripheral neuropathy and myopathy (2), or endocrine abnormalities because of pituitary stalk involvement. The most common neurologic manifestations are isolated cranial nerve palsies, particularly facial nerve involvement (3). The absence of associated positive laboratory results or other signs and 326 symptoms can delay the diagnosis. In a review of 35 cases of neurosarcoidosis by Chapelon et al (2), the correct diagnosis was delayed an average of 8 months in patients with isolated cranial polyneuropathies, 12 months in patients with mononeuritis multiplex, and 42 months in patients with polyneuropathy. Our patient experienced monocular painless progressive vision loss. The differential diagnosis includes the following etiologies: inflammatory and autoimmune (sarcoidosis, granulomatosis with polyangitis [Wegener], multiple sclerosis, and neuromyelitis optica spectrum disorder); infectious (tuberculosis, mucormycosis, syphyilis, and Lyme disease); and neoplastic (meningioma, lymphoma, leukemia, multiple myeloma, and metastasis). Our patient's visual loss was initially steroid-resistant, suggesting a noninflammatory etiology and his laboratory workup was unrevealing for an infectious cause. Imaging was not consistent with a neoplasm. His diagnosis was delayed 3 years, in large part because he was lost to follow-up, Herro et al: J Neuro-Ophthalmol 2016; 36: 324-328 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study FIG. 4. Biopsy demonstrates granulomatous inflammation with multinucleated giant cells and no evidence of necrosis (hematoxylin and eosin; A, ·20; B, ·40). but this case also highlights the importance of repeating laboratory tests and imaging studies when the initial evaluation is unrevealing. Dr. Schatz: It is important to maintain a high index of suspicion for subclinical inflammatory disease in patients with progressive vision loss despite the absence of other signs or symptoms, particularly in African Americans. Our patient had no inflammatory symptoms or signs at the time of presentation or at subsequent visits and his initial diagnostic testing was unremarkable. He was resistant to steroid treatment, which also argued against inflammatory conditions. Finally, neuroimaging showed extensive meningeal enhancement of the skull base associated with a tuberculum sellae lesion that seemed consistent with en plaque meningioma rather than inflammatory pachymeningitis. Unfortunately, there are no universally accepted diagnostic criteria for sarcoidosis aside from tissue biopsy. Screening guidelines include an angiotensin-converting enzyme (ACE) level and/or lysozyme level and a chest radiograph. The sensitivity of ACE alone is 60% with a 70% specificity, whereas lysozyme has a sensitivity of 80% with a specificity of less than 60%. Decreased ACE levels can be seen in patients with chronic obstructive pulmonary disease, emphysema, and ACE-inhibitor medications, whereas increased levels can be seen in HIV, tuberculosis, and lymphoma and are also generally higher in children. It is important to understand this relationship when ordering these screening modalities (4). Chest radiography is an important screening and diagnostic test because up to 90% of patients with sarcoidosis have characteristic findings. Hilar lymphadenopathy is found in approximately 50% of patients at the time of diagnosis. A chest radiograph can be normal in biopsyproven sarcoidosis as can false positives in other grandulomatous diseases. This is why the combination of laboratory studies increases the sensitivity and specificity. The decision to proceed to Gallium-67 scanning also is Herro et al: J Neuro-Ophthalmol 2016; 36: 324-328 difficult because it is limited by nonspecificity and is expensive and time-consuming (5). In neurosarcoidosis, the diagnosis can be even more challenging because of the relative inaccessibility of tissue for biopsy. The characteristic inflammatory cerebrospinal fluid profile may be absent when disease is dural-based and focal, as opposed to diffuse leptomeningeal disease. The standard of care is corticosteroids in all cases of suspected neurosarcoidosis but steroid-resistance may occur. Current treatment frequently combines systemic steroids with immunosuppressive drugs with good central nervous system penetration. A monoclonal antibody may also be required (6). Dr. Dubovy: Our case highlights the need for obtaining tissue for diagnosis, particularly when clinical, laboratory, and neuroimaging findings are inconclusive. Over the 3 years that the patient was lost to follow-up, the size of his lesion had grown substantially from a slight optic perineuritis with mild optic nerve sheath enhancement to marked bilateral nerve sheath enhancement and encasement of most of the skull base. The atypical presentation and declining vision led to the eventual tissue diagnosis of meningeal sarcoidosis. Dr. Schatz and Dr. Sternau: This patient also had cardiac septal involvement, resulting in ventricular tachycardia that ultimately required placement of an AICD. He also developed a popliteal DVT and bilateral PE. Cardiac involvement is seen in at least 25% of sarcoidosis patients and imparts a poor prognosis (7). Granulomatous disease can involve any part of the heart, with the myocardium being the most common and often leading to heart block. Myocardial involvement accounts for up to 25% of deaths from sarcoidosis in the US and up to 85% in Japan (7). It is important to ask patients suspected of or known to have sarcoidosis, targeted questions regarding cardiac involvement. 327 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study Dr. Herro and Dr. Lam: Patients with sarcoidosis are at increased risk of pulmonary embolism, a potentially fatal condition. In a large epidemiologic study over 20 years, an examination of death records of all US decedents revealed that patients with sarcoidosis had more than twice the likelihood of having PE mentioned in their death certificate compared with the general population (8). This association remained regardless of gender, race, or other known lung disease such as chronic obstructive pulmonary disease. These findings were consistent with those of a similar study performed in the United Kingdom over a 35-year period (9). The etiology of PE in patients with sarcoidosis is not clear and is likely multifactorial. Patients with sarcoidosis often maintain a proinflammatory state. As such, they have an inherently higher procoagulant activity with alveolar macrophages exhibiting greater tissue activity than in control subjects. The role of medication use including corticosteroids has also been evaluated as a potential cause of increased risk of thrombosis (8). Other potential causes include decreased mobility, oral contraceptive use, and pulmonary hypertension; however, the association seems to persist even when controlling for these factors (9). Patient with sarcoidosis also are more likely to have antiphospholipid antibodies (38%) than the general population (2%-5%) also increasing the risk of developing a PE (7). Finally, it has been suggested that local compression by hilar lymphadenopathy or formation of a vascular granuloma can lead to formation of a venous thrombus in patients with sarcoidosis (10). Regardless of 328 the etiology, the increased incidence of PE in patients with sarcoidosis may prompt the treating physician to prophylactically anticoagulate patients (aspirin 81 mg/d at the minimum). REFERENCES 1. Delaney P. Neurologic manifestations of sarcoidosis: review of the literature with a report of 23 cases. Ann Intern Med. 1977;87:336-344. 2. Chapelon C, Ziza JM, Piette JC, Levy Y, Raguin G, Wechsler B, Bitker MO, Bletry O, LaPlane D, Bousser MG, Godeau P. Neurosarcoidosis: signs, course and treatment in 35 confirmed cases. Medicine (Baltimore). 1990;69:261-276. 3. Pawate S, Moses H, Sriram S. Presentations and outcomes of neurosarcoidosis: a study of 54 cases. QJM. 2009;102: 449-460. 4. Sakuta M, Kunamoto T, Iizuka T, Nishiyama K, Oritsu N. Diagnostic criteria of neurosarcoidosis [in Japanese]. Rinsho Shinkeigaku. 2006;45:837-840. 5. Nawaz Khan A, Lin EC. Thoracic sarcoidosis imaging. Available at: emedicine.medscape.com/article/361490-overview. Accessed April 11, 2016. 6. Segal BM. Neurosarcoidosis: diagnostic approaches and therapeutic strategies. Curr Opin Neurol. 2013;26:307-313. 7. Dougan AR, Williams BR. Cardiac sarcoidosis. Heart. 2006;92:282-288. 8. Swigris JJ, Olson AL, Huie TJ, Fernandez-Perez ER, Solomon JJ, Sprunger D, Brown KK. Increased risk of pulmonary embolism among US decedents with sarcoidosis from 1988 to 2007. Chest. 2011;150:1261-1266. 9. Crawshaw AP, Wotton CJ, Yeates DGR, Goldacre MJ, Ho LP. Evidence for association between sarcoidosis and pulmonary embolism from 35-year record linkage study. Thorax. 2010;66:447-448. 10. Westcott JL, DeGraff AC. Sarcoidosis, hilar adenopathy, and pulmonary artery narrowing. Radiology. 1973;108: 585-586. Herro et al: J Neuro-Ophthalmol 2016; 36: 324-328 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.