OBSERVATION The Pathogenesis and Treatment of Swelling in Neurosarcoidosis A Unique Therapeutic Response to

Jeffrey M. Katz, MD; Michiko Kimura Bruno, MD; Jacqueline M. S. Winterkorn, MD, PhD; Nancy Nealon, MD

Objective: To review the pathogenesis and treatment eye. A 57-year-old woman presented with bilateral, sub- of optic disc swelling in neurosarcoidosis, including a acute, painful visual loss and unilateral papillitis consis- novel therapeutic response to infliximab. tent with . Her visual loss responded rap- idly to intravenous corticosteroids. The funduscopic Design and Setting: Case reports from an inpatient examination findings in both patients prompted further service. clinical investigation, culminating in the diagnosis of neu- rosarcoidosis. Patients: A 35-year-old woman presented with head- ache, chronic visual loss, , and optic atro- Conclusion: Understanding the multiple etiologic mecha- phy, characteristic of chronic intracranial hypertension. nisms that produce optic disc swelling in can Magnetic resonance imaging showed bifrontal cerebral help neurologists tailor treatment for patients with neu- edema with en plaque frontal pachymeningeal enhance- rosarcoidosis who present with this symptom. ment. Her visual loss progressed despite conventional therapies. The use of the tumor necrosis factor ␣ antago- nist infliximab maintained functional vision in her right Arch Neurol. 2003;60:426-430

OSS OF VISION associated with 20/25 OD with a constricted visual field (VF) optic disc swelling (ODS) is and an inferonasal step. The left eye had no a rare initial presentation of light perception and an amaurotic pupil. neurosarcoidosis. Optic disc Funduscopic examination findings re- swelling is an important vealed right optic disc swelling (Figure 1A) clinicalL sign because it can herald central and left optic disc pallor and resolving swell- nervous system disease in an otherwise ing (Figure 1B). General and neurologic ex- neurologically intact patient. We report 2 amination results were unremarkable. cases of neurosarcoidosis in patients who A gadolinium-enhanced magnetic presented with ODS and bilateral visual resonance image of the brain (Figure 2) loss with otherwise normal neurologic ex- revealed bifrontal edema and en plaque amination results. Optic disc swelling can parafalcian and frontal lobe pachymenin- represent papilledema from increased in- geal enhancement. Serum angiotensin- tracranial pressure (ICP), papillitis from converting enzyme (ACE) level was el- optic neuropathy, or infiltration of the evated (61.1 U/L) as was her erythrocyte disc.1 We discuss the various pathophysi- sedimentation rate (33 mm/h). Lumbar ologic features of ODS in sarcoidosis. puncture showed a markedly elevated op- ening pressure of 40 cm H2O and a nega- REPORT OF CASES tive (CSF) ACE level (Ͻ4 U/L) but was otherwise unremark- PATIENT 1 able. Computed tomography of the chest revealed bilateral hilar and mediastinal A 35-year-old black woman presented with lymphadenopathy with clear fields. visual loss in the left eye progressing to no A hilar lymph node specimen con- From the Department of Neurology and Neuroscience, light perception. In the previous 5 months, firmed discrete epithelioid, noncaseating New York Presbyterian she had experienced bifrontal , granulomata consistent with sarcoidosis. Hospital–Weill Medical transient visual obscurations of both eyes, The patient was treated with acet- Center of Cornell University, occasional , tinnitus, and blurred vi- azolamide and intravenous methylpred- New York, NY. sion in the left eye. Visual acuity (VA) was nisolone, without recovery of vision in her

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Figure 1. A, Fundus photograph of the right eye in patient 1 shows optic disc swelling. B, Fundus photograph of the left eye in patient 1 shows resolving optic disc swelling and atrophy.

A B

Figure 2. A, T2-weighted, fluid attenuated inversion recovery, noncontrast axial magnetic resonance image (MRI) of patient 1 shows bifrontal cerebral edema. B, T1-weighted, gadolinium-enhanced axial MRI of patient 1 shows en plaque pachymeningeal enhancement in the anterior cranial fossa and both sides of the anterior falx.

left eye. The vision in her right eye deteriorated. She re- quence of . After 3 months of monthly fused sheath fenestration. In conjunction with infusions, her VA improved to 20/40 OD. an oral prednisone taper, therapy was initiated at a dose of 200 mg orally once daily and rapidly PATIENT 2 increased to 200 mg twice daily, effecting a white blood cell response ranging from 2200 to 5000/µL. This re- A 57-year-old black woman with a history of sulted in stabilization of her VA at 20/200 OD. However, mellitus complained of ocular tenderness and progres- 2 months later her VA declined to 20/800 OD. One dose sive visual loss in both eyes over 7 weeks. Her VA was of the tumor necrosis factor ␣ (TNF-␣) antagonist inflix- light perception in the right eye and 20/200 OS. Ameri- imab (3-mg/kg intravenous infusion) was administered can Optical Hardy Rand Rittler (AOHRR) color plates were without adverse effects. The cyclophosphamide and pred- not seen with either eye, and a red object was seen as dark. nisone taper was continued. Her VA improved to 20/200 The VF testing revealed a nasal island in the right eye OD during the next 3 weeks and remained stable for 6 and a superior altitudinal defect in the left eye. Pupils months. Then the patient’s VA fluctuated between 20/200 showed a right relative afferent pupillary defect. The right OD and 20/400 OD. A second dose of infliximab (3- disc appeared normal (Figure 3A), and the left disc mg/kg intravenous infusion) was given 10 months after the showed chronic swelling (Figure 3B). There was no sign first, with monthly infusions thereafter. Of note, the pa- of diabetic retinopathy. Her general and neurologic ex- tient developed an uncomplicated herpes zoster dermati- amination results were normal except for erythema no- tis 3 weeks after the second treatment, a likely conse- dosum on the anterior aspect of her legs.

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Figure 3. A, Fundus photograph of the right eye of patient 2 shows a pink and sharp optic disc. B, Fundus photograph of the left eye of patient 2 shows optic disc swelling.

COMMENT Pathogenesis of Optic Disc Swelling in Neurosarcoidosis

Papilledema Granulomatous mass Intra-axial mass Optic disc swelling represents obstruction of axoplas- lesion Extra-axial mass mic flow at the lamina cribrosa, resulting in accumula- Obstructive or tion of axoplasm at the disc.2 The patients described herein communicating both presented with predominantly unilateral ODS but Meningoencephalitis Acute, subacute, or chronic bilateral visual loss, and both were proven to have sar- Venous sinus thrombosis coidosis. The pathophysiologic features of the ODS and Macroinfiltrative Optic disc Optic nerve and visual loss differed in the 2 patients and prompted us to optic chiasm infiltration* review the differential diagnosis of ODS in sarcoidosis neuropathy Orbital apex mass Microscopic infiltration (Table). Patient 1 reminded us that although papill- Retro-orbital infiltration Perineural vasculitis edema may manifest more in one eye, owing to ana- Papillitis Optic neuritis Retinal periphlebitis tomic asymmetry of the nerve sheaths, resolution of ODS Severe posterior in a patient with chronic papilledema may also reflect op- tic atrophy. Patient 2 reminded us that optic neuropa- *A form of optic neuropathy that may clinically mimic idiopathic thy can present with or without ODS. Although visual intracranial hypertension. loss was bilateral, the optic neuropathy in the right eye was retrobulbar and only the left disc was swollen. Cor- The findings from gadolinium-enhanced magnetic rect interpretation of disc findings may reveal the de- resonance images of brain and orbits were normal. Op- gree of involvement and have con- ening pressure was 25 cm H2O, and CSF analysis was con- sequences for therapy. sistent with aseptic (white blood cell count, 69/µL; 87% ; high protein level, 0.11 g/dL; PAPILLEDEMA normal glucose level; and negative findings on serologic tests, microbial stains, and cultures). Oligoclonal bands Papilledema is ODS caused by elevated ICP. In neuro- were negative in CSF and serum. The CSF ACE was nor- sarcoidosis, elevated ICP can have several origins. Intra- mal, but serum ACE level was elevated (64.1 U/L). Chest cranial, noncaseating granulomata of sufficient size or at computed tomography disclosed bilateral hilar lymph- significant locations may mimic intracranial tumors on adenopathy and pulmonary nodules. A hilar lymph node neuroimaging3 and can raise ICP, causing papilledema.4 biopsy specimen demonstrated granulomatous lymph- Granulomatous meningoencephalitis can elevate ICP adenitis, and a needle biopsy specimen showed non- sufficiently to cause papilledema and may have an acute, caseating, epithelioid granulomatous hepatitis, consis- subacute, or chronic course. Patients with acute sarcoid tent with a diagnosis of sarcoidosis. meningoencephalitis may develop and changes The patient was treated with methylprednisolone in mental status, ranging from confusion to coma and (500 mg intravenously 3 times daily for 4 days) fol- death.5 Postmortem microscopic analysis in one such pa- lowed by a slow oral prednisone taper. No other immune- tient revealed noncaseating, epithelioid granulomata dis- modulating drugs were administered. She had rapid vi- persed throughout the brain and meninges.5 sual improvement. One week after treatment, her VA was A syndrome mimicking idiopathic intracranial hy- 20/25 OU. AOHRR color plates remained 0/6 OD but im- pertension has been reported in the literature as a rare proved to 4.5/6 OS. Her VF showed cecocentral loss in presentation of neurosarcoidosis, but improved neuro- the right eye and inferonasal constriction bilaterally. The imaging suggests that such presentations may actually right optic disc still appeared normal, and the left showed result from dural venous sinus thrombosis6 or chronic resolving papillitis. The patient has had no further epi- granulomatous meningoencephalitis.7 Hydrocephalus, sodes of visual loss. which occurs in approximately 10% of neurosarcoid-

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 osis patients,8 may cause papilledema. Granulomata that cyclosporine, and antimetabolites, including cyclophos- block ventricular CSF flow produce obstructive hydro- phamide, chlorambucil, and .20 cephalus. Chronic sarcoid meningitis that blocks absorp- Recently, the TNF-␣ antagonist infliximab has been tion of CSF by arachnoid granulations may precipitate tried with some success in the treatment of systemic sar- communicating hydrocephalus, a late complication of coidosis.21,22 Blocking the activity of TNF-␣ is a rational neurosarcoidosis.8,9 approach because this macrophage-derived inflamma- tory mediator is suspected to play a role in the patho- MACROINFILTRATIVE OPTIC NEUROPATHY genesis of sarcoidosis,21 in part by inducing and main- taining the formation of granulomata.23 Antagonizing Macroscopic granulomatous infiltration of the optic nerve TNF-␣ as a therapeutic target in sarcoidosis is not lim- is a cause of apparent ODS with optic neuropathy in neu- ited to infliximab, since some success has been reported rosarcoidosis. Visual loss is typically subacute and uni- with other antagonists, including for ac- lateral. Enlargement of the optic nerve on neuroimag- tive pulmonary sarcoidosis23 and for cuta- ing can result from distension of the nerve sheath10,11 or neous sarcoidosis.24 presence of a granulomatous mass.11 Sarcoidosis can pre- In patient 1, when vision continued to deteriorate sent with granulomatous lesions anywhere in the ante- despite conventional therapies, doses of infliximab were rior visual pathway.12 Presence of the granulomatous mass infused followed by an improvement in vision that was at the nerve head produces the appearance of a “cauli- maintained during approximately 18 months of follow- flower” optic disc.13 A granuloma further back in the nerve up. With the degree of visual loss experienced by pa- may produce ODS from obstipation of axoplasmic flow tient 1, VA is often variable, making it difficult to quan- by mass effect. A posteriorly located sarcoid granuloma tify precisely the magnitude of visual improvement that may present with an orbital apex syndrome,11 including resulted from our treatment. The patient sustained sub- proptosis, diplopia, ODS, and visual loss. Patients with jective visual improvement, and objectively improved VA bilateral optic nerve infiltration or chiasmal involve- to 20/40 OD. Administration of cyclophosphamide and ment may present with bilateral papillitis mimicking pap- a prednisone taper was continued during and following illedema, but whereas VA loss from papilledema is a late infliximab infusion. However, this should not con- occurrence, it is the early hallmark of infiltrative optic found our results, since infliximab was the only new treat- neuropathy. Infiltration of the optic chiasm by sarcoid ment added to an unsuccessful regimen. Furthermore, may cause chiasmal pattern bitemporal VF loss.10 infliximab infusion was temporally related to visual im- provement, and a more rapid steroid withdrawal was suc- PAPILLITIS cessful following treatment. To our knowledge, this is the first report of a therapeutic benefit of infliximab in a Optic neuritis with optic disc swelling, or papillitis, has patient with neurosarcoidosis. been reported as the presenting symptom of sarcoid- The use of infliximab is not without risk. Our pa- osis10,13,14 and is the likely mechanism of vision loss in tient experienced an uncomplicated herpes zoster der- patient 2. In contrast to macroinfiltrative optic neuropa- matitis following her second treatment. Adverse effects thy, sarcoid optic neuritis, whether retrobulbar or at the of infliximab include chest pain, hypertension, fatigue, disc, has a more acute onset and often presents with eye dizziness, and in less than 5% of patients. Other pain, especially on eye movement.13 It mimics demyelin- complications include hypersensitivity reactions, fever ating optic neuritis (DON), but unlike typical DON, sar- and chills during infusion, a lupuslike syndrome, and in- coid optic neuritis may respond rapidly to corticoste- creased risk for invasive bacterial, fungal, mycobacte- roids, as it did in patient 2. Sarcoid optic neuritis may rial, and other opportunistic infections, especially with be subtly differentiated from DON with a more sub- the use of concomitant immunosuppressive therapy.25 It acute loss of vision, progressing from 2 to 6 weeks in one is recommended that patients receive a tuberculin skin study,13 and a lower propensity to cause a central sco- test before the initiation of infliximab therapy.25 toma. The pathogeneses of papillitis in sarcoidosis in- For neurosarcoidosis patients who present with pap- clude perineural vasculitis,15 microscopic granuloma- illedema, additional interventions directed at intracra- tous infiltration of the anterior optic nerve, severe posterior nial hypertension are indicated, usually acetazolamide or uveitis, and retinal periphlebitis characterized by peri- furosemide.26 Successive lumbar punctures are consid- vascular “candle-wax drippings.”16 The latter 2 mecha- ered ineffective in maintaining a decrease in ICP.27 In pa- nisms involve local vascular leakage at the optic disc and tients with progressive VF loss despite medical treat- may be the only manifestations of sarcoidosis, without ment, surgical options include lumboperitoneal shunt,28 central nervous system involvement. ventriculoperitoneal shunt, and optic nerve sheath fen- estration.29 Shunt failure secondary to granulomatous in- TREATMENT filtration of the ventricular catheter has been reported.30 Ventriculoperitoneal shunting is indicated for patients Corticosteroids are the cardinal treatment for sarcoid. with uncompensated, acute, or significantly symptom- However, in patients who present with papilledema, cor- atic hydrocephalus or patients who are both symptom- ticosteroids rarely increase ICP, especially as the atic and refractory to standard treatment.8 The success steroids are tapered.17-19 In cases refractory to corticoste- of optic nerve sheath fenestration has not been evalu- roids, other medical options include T-– ated in sarcoidosis patients but might be low, owing to directed immunosuppressors, including azathioprine and closure of the window by granulomatous scarring.

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 Surgical debulking of large intracranial granulo- 6. Akova YA, Kansu T, Duman S. Pseudotumor cerebri secondary to dural mata is usually performed at the time of biopsy, espe- sinus thrombosis in neurosarcoidosis. J Clin Neuroophthalmol. 1993;13:188- 189. cially if significant mass effect is present. However, re- 7. Pelton RW, Lee AG, Orengo-Nania SD, Patrinely JR. Bilateral optic disk edema currence is common. for sarcoid mass caused by sarcoidosis mimicking pseudotumor cerebri. Am J Ophthalmol. 1999; lesions has been reported with mixed results.20,31,32 Symp- 127:229-230. tomatic benefits, with the lowest risk for long-term ad- 8. Foley KT, Howell JD, Junck L. Progression of hydrocephalus during corticoste- roid therapy for neurosarcoidosis. Postgrad Med J. 1989;65:481-484. verse effects, may be derived from low-dose whole brain 9. Bielska J, Bazowski P, Broda R. Hydrocephalus as a late complication of irradiation, although this remains controversial. sarcoidosis. Neurol Neurochir Pol. 1977;11:379-381. In conclusion, neurosarcoidosis is a heterogeneous 10. Galetta S, Schatz NJ, Glaser JS. Acute sarcoid optic neuropathy with spontane- disease that should be considered in the differential di- ous recovery. J Clin Neuroophthalmol. 1989;9:27-32. agnosis for patients who present with vision loss and ODS. 11. Segal EI, Tang RA, Lee AG, et al. Orbital apex lesion as the presenting manifes- tation of sarcoidosis. J Neuroophthalmol. 2000;20:156-158. By considering the specific pathophysiologic features re- 12. Achiron L, Strominger M, Witkin N, Primo S. Sarcoid optic neuropathy: a case sponsible for the patient’s symptoms, more focused thera- report. J Am Optom Assoc. 1995;66:646-651. peutic decisions can be made. Infliximab and other TNF-␣ 13. Graham EM, Ellis CJK, Sanders MD, McDonald WI. Optic neuropathy in sarcoid- antagonists provide rational therapies directed at the osis. J Neurol Neurosurg . 1986;49:756-763. 14. Fahy S, Houlihan M, O’Keefe M, Nicholson AJ. Unilateral papilloedema in a 12 pathogenesis of sarcoidosis. Further clinical investiga- year old girl: a surprising diagnosis. Ir Med J. 1997;90:230. tions of such agents, including large placebo-controlled 15. Gass JDM, Olson CL. Sarcoidosis with optic nerve and retinal involvement: a clini- trials, are needed. copathologic case report. Trans Am Acad Ophthalmol Otolaryngol. 1973;77: OP739-OP750. Accepted for publication September 23, 2002. 16. Spalton DJ, Sanders MD. Fundus changes in histologically confirmed sarcoid- osis. Br J Ophthalmol. 1981;65:348-358. Author contributions: Study concept and design (Drs 17. Wall M. Idiopathic intracranial hypertension. Semin Ophthalmol. 1995;10:251- Katz, Bruno, Winterkorn, and Nealon); acquisition of data 259. (Drs Katz, Bruno, and Winterkorn); analysis and inter- 18. Liu GT, Kay MD, Bienfang DC, Schatz NJ. Pseudotumor cerebri associated with pretation of data (Drs Katz, Bruno, Winterkorn, and Nea- corticosteroid withdrawal in inflammatory bowel disease. Am J Ophthalmol. 1994; 117:352-357. lon); drafting of the manuscript (Drs Katz, Bruno, Win- 19. Johnston I, Gilday DL, Hendrick EB. Experimental effects of steroids and ste- terkorn, and Nealon); critical revision of the manuscript roid withdrawal on cerebrospinal fluid absorption. J Neurosurg. 1975;42:690- for important intellectual content (Drs Katz, Bruno, and 695. Winterkorn); administrative, technical, and material sup- 20. Agbogu BN, Stern BJ, Sewell C, Yang G. Therapeutic considerations in patients port (Drs Katz and Bruno); study supervision (Drs Win- with refractory neurosarcoidosis. Arch Neurol. 1995;52:875-879. 21. Baughman RP, Lower EE. Infliximab for refractory sarcoidosis. Sarcoidosis Vasc terkorn and Nealon). Diffuse Lung Dis. 2001;18:70-74. 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