Copyright 2003 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.2003
To review the pathogenesis and treatment of optic disc swelling in neurosarcoidosis, including a novel therapeutic response to infliximab.
Design and Setting
Case reports from an inpatient neurology service.
A 35-year-old woman presented with headache, chronic visual loss, papilledema, and optic atrophy, characteristic of chronic intracranial hypertension. Magnetic resonance imaging showed bifrontal cerebral edema with en plaque frontal pachymeningeal enhancement. Her visual loss progressed despite conventional therapies. The use of the tumor necrosis factor α antagonist infliximab maintained functional vision in her right eye. A 57-year-old woman presented with bilateral, subacute, painful visual loss and unilateral papillitis consistent with optic neuritis. Her visual loss responded rapidly to intravenous corticosteroids. The funduscopic examination findings in both patients prompted further clinical investigation, culminating in the diagnosis of neurosarcoidosis.
Understanding the multiple etiologic mechanisms that produce optic disc swelling in sarcoidosis can help neurologists tailor treatment for patients with neurosarcoidosis who present with this symptom.
LOSS OF VISION associated with optic disc swelling (ODS) is a rare initial presentation of neurosarcoidosis. Optic disc swelling is an important clinical sign because it can herald central nervous system disease in an otherwise neurologically intact patient. We report 2 cases of neurosarcoidosis in patients who presented with ODS and bilateral visual loss with otherwise normal neurologic examination results. Optic disc swelling can represent papilledema from increased intracranial pressure (ICP), papillitis from optic neuropathy, or infiltration of the disc.1 We discuss the various pathophysiologic features of ODS in sarcoidosis.
A 35-year-old black woman presented with visual loss in the left eye progressing to no light perception. In the previous 5 months, she had experienced bifrontal headaches, transient visual obscurations of both eyes, occasional diplopia, tinnitus, and blurred vision in the left eye. Visual acuity (VA) was 20/25 OD with a constricted visual field (VF) and an inferonasal step. The left eye had no light perception and an amaurotic pupil. Funduscopic examination findings revealed right optic disc swelling (Figure 1A) and left optic disc pallor and resolving swelling (Figure 1B). General and neurologic examination results were unremarkable.
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 gadolinium-enhanced magnetic resonance image of the brain (Figure 2) revealed bifrontal edema and en plaque parafalcian and frontal lobe pachymeningeal enhancement. Serum angiotensin-converting enzyme (ACE) level was elevated (61.1 U/L) as was her erythrocyte sedimentation rate (33 mm/h). Lumbar puncture showed a markedly elevated opening pressure of 40 cm H2O and a negative cerebrospinal fluid (CSF) ACE level (<4 U/L) but was otherwise unremarkable. Computed tomography of the chest revealed bilateral hilar and mediastinal lymphadenopathy with clear lung fields. A hilar lymph node biopsy specimen confirmed discrete epithelioid, noncaseating granulomata consistent with sarcoidosis.
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.
The patient was treated with acetazolamide and intravenous methylprednisolone, without recovery of vision in her left eye. The vision in her right eye deteriorated. She refused optic nerve sheath fenestration. In conjunction with an oral prednisone taper, cyclophosphamide therapy was initiated at a dose of 200 mg orally once daily and rapidly increased to 200 mg twice daily, effecting a white blood cell response ranging from 2200 to 5000/µL. This resulted in stabilization of her VA at 20/200 OD. However, 2 months later her VA declined to 20/800 OD. One dose of the tumor necrosis factor α (TNF-α) antagonist infliximab (3-mg/kg intravenous infusion) was administered without adverse effects. The cyclophosphamide and prednisone taper was continued. Her VA improved to 20/200 OD during the next 3 weeks and remained stable for 6 months. Then the patient's VA fluctuated between 20/200 OD and 20/400 OD. A second dose of infliximab (3-mg/kg intravenous infusion) was given 10 months after the first, with monthly infusions thereafter. Of note, the patient developed an uncomplicated herpes zoster dermatitis 3 weeks after the second treatment, a likely consequence of immunosuppression. After 3 months of monthly infusions, her VA improved to 20/40 OD.
A 57-year-old black woman with a history of diabetes mellitus complained of ocular tenderness and progressive visual loss in both eyes over 7 weeks. Her VA was light perception in the right eye and 20/200 OS. American Optical Hardy Rand Rittler (AOHRR) color plates were not seen with either eye, and a red object was seen as dark. The VF testing revealed a nasal island in the right eye and a superior altitudinal defect in the left eye. Pupils showed a right relative afferent pupillary defect. The right disc appeared normal (Figure 3A), and the left disc showed chronic swelling (Figure 3B). There was no sign of diabetic retinopathy. Her general and neurologic examination results were normal except for erythema nodosum on the anterior aspect of her legs.
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.
The findings from gadolinium-enhanced magnetic resonance images of brain and orbits were normal. Opening pressure was 25 cm H2O, and CSF analysis was consistent with aseptic meningitis (white blood cell count, 69/µL; 87% lymphocytes; high protein level, 0.11 g/dL; normal glucose level; and negative findings on serologic tests, microbial stains, and cultures). Oligoclonal bands were negative in CSF and serum. The CSF ACE was normal, but serum ACE level was elevated (64.1 U/L). Chest computed tomography disclosed bilateral hilar lymphadenopathy and pulmonary nodules. A hilar lymph node biopsy specimen demonstrated granulomatous lymphadenitis, and a liver needle biopsy specimen showed noncaseating, epithelioid granulomatous hepatitis, consistent with a diagnosis of sarcoidosis.
The patient was treated with methylprednisolone (500 mg intravenously 3 times daily for 4 days) followed by a slow oral prednisone taper. No other immune-modulating drugs were administered. She had rapid visual improvement. One week after treatment, her VA was 20/25 OU. AOHRR color plates remained 0/6 OD but improved to 4.5/6 OS. Her VF showed cecocentral loss in the right eye and inferonasal constriction bilaterally. The right optic disc still appeared normal, and the left showed resolving papillitis. The patient has had no further episodes of visual loss.
Optic disc swelling represents obstruction of axoplasmic flow at the lamina cribrosa, resulting in accumulation of axoplasm at the disc.2 The patients described herein both presented with predominantly unilateral ODS but bilateral visual loss, and both were proven to have sarcoidosis. The pathophysiologic features of the ODS and visual loss differed in the 2 patients and prompted us to review the differential diagnosis of ODS in sarcoidosis (Table 1). Patient 1 reminded us that although papilledema may manifest more in one eye, owing to anatomic asymmetry of the nerve sheaths, resolution of ODS in a patient with chronic papilledema may also reflect optic atrophy. Patient 2 reminded us that optic neuropathy can present with or without ODS. Although visual loss was bilateral, the optic neuropathy in the right eye was retrobulbar and only the left disc was swollen. Correct interpretation of disc findings may reveal the degree of central nervous system involvement and have consequences for therapy.
Papilledema is ODS caused by elevated ICP. In neurosarcoidosis, elevated ICP can have several origins. Intracranial, noncaseating granulomata of sufficient size or at significant locations may mimic intracranial tumors on neuroimaging3 and can raise ICP, causing papilledema.4
Granulomatous meningoencephalitis can elevate ICP sufficiently to cause papilledema and may have an acute, subacute, or chronic course. Patients with acute sarcoid meningoencephalitis may develop seizures and changes in mental status, ranging from confusion to coma and death.5 Postmortem microscopic analysis in one such patient revealed noncaseating, epithelioid granulomata dispersed throughout the brain and meninges.5
A syndrome mimicking idiopathic intracranial hypertension has been reported in the literature as a rare presentation of neurosarcoidosis, but improved neuroimaging suggests that such presentations may actually result from dural venous sinus thrombosis6 or chronic granulomatous meningoencephalitis.7 Hydrocephalus, which occurs in approximately 10% of neurosarcoidosis patients,8 may cause papilledema. Granulomata that block ventricular CSF flow produce obstructive hydrocephalus. Chronic sarcoid meningitis that blocks absorption of CSF by arachnoid granulations may precipitate communicating hydrocephalus, a late complication of neurosarcoidosis.8,9
Macroscopic granulomatous infiltration of the optic nerve is a cause of apparent ODS with optic neuropathy in neurosarcoidosis. Visual loss is typically subacute and unilateral. Enlargement of the optic nerve on neuroimaging can result from distension of the nerve sheath10,11 or presence of a granulomatous mass.11 Sarcoidosis can present with granulomatous lesions anywhere in the anterior visual pathway.12 Presence of the granulomatous mass at the nerve head produces the appearance of a "cauliflower" optic disc.13 A granuloma further back in the nerve may produce ODS from obstipation of axoplasmic flow by mass effect. A posteriorly located sarcoid granuloma may present with an orbital apex syndrome,11 including proptosis, diplopia, ODS, and visual loss. Patients with bilateral optic nerve infiltration or chiasmal involvement may present with bilateral papillitis mimicking papilledema, but whereas VA loss from papilledema is a late occurrence, it is the early hallmark of infiltrative optic neuropathy. Infiltration of the optic chiasm by sarcoid may cause chiasmal pattern bitemporal VF loss.10
Optic neuritis with optic disc swelling, or papillitis, has been reported as the presenting symptom of sarcoidosis10,13,14 and is the likely mechanism of vision loss in patient 2. In contrast to macroinfiltrative optic neuropathy, sarcoid optic neuritis, whether retrobulbar or at the disc, has a more acute onset and often presents with eye pain, especially on eye movement.13 It mimics demyelinating optic neuritis (DON), but unlike typical DON, sarcoid optic neuritis may respond rapidly to corticosteroids, as it did in patient 2. Sarcoid optic neuritis may be subtly differentiated from DON with a more subacute loss of vision, progressing from 2 to 6 weeks in one study,13 and a lower propensity to cause a central scotoma. The pathogeneses of papillitis in sarcoidosis include perineural vasculitis,15 microscopic granulomatous infiltration of the anterior optic nerve, severe posterior uveitis, and retinal periphlebitis characterized by perivascular "candle-wax drippings."16 The latter 2 mechanisms involve local vascular leakage at the optic disc and may be the only manifestations of sarcoidosis, without central nervous system involvement.
Corticosteroids are the cardinal treatment for sarcoid. However, in patients who present with papilledema, corticosteroids rarely increase ICP, especially as the steroids are tapered.17- 19 In cases refractory to corticosteroids, other medical options include T-lymphocyte–directed immunosuppressors, including azathioprine and cyclosporine, and antimetabolites, including cyclophosphamide, chlorambucil, and methotrexate.20
Recently, the TNF-α antagonist infliximab has been tried with some success in the treatment of systemic sarcoidosis.21,22 Blocking the activity of TNF-α is a rational approach because this macrophage-derived inflammatory mediator is suspected to play a role in the pathogenesis of sarcoidosis,21 in part by inducing and maintaining the formation of granulomata.23 Antagonizing TNF-α as a therapeutic target in sarcoidosis is not limited to infliximab, since some success has been reported with other antagonists, including pentoxifylline for active pulmonary sarcoidosis23 and thalidomide for cutaneous sarcoidosis.24
In patient 1, when vision continued to deteriorate despite conventional therapies, doses of infliximab were infused followed by an improvement in vision that was maintained during approximately 18 months of follow-up. With the degree of visual loss experienced by patient 1, VA is often variable, making it difficult to quantify precisely the magnitude of visual improvement that resulted from our treatment. The patient sustained subjective visual improvement, and objectively improved VA to 20/40 OD. Administration of cyclophosphamide and a prednisone taper was continued during and following infliximab infusion. However, this should not confound our results, since infliximab was the only new treatment added to an unsuccessful regimen. Furthermore, infliximab infusion was temporally related to visual improvement, and a more rapid steroid withdrawal was successful following treatment. To our knowledge, this is the first report of a therapeutic benefit of infliximab in a patient with neurosarcoidosis.
The use of infliximab is not without risk. Our patient experienced an uncomplicated herpes zoster dermatitis following her second treatment. Adverse effects of infliximab include chest pain, hypertension, fatigue, dizziness, and headache in less than 5% of patients. Other complications include hypersensitivity reactions, fever and chills during infusion, a lupuslike syndrome, and increased risk for invasive bacterial, fungal, mycobacterial, and other opportunistic infections, especially with the use of concomitant immunosuppressive therapy.25 It is recommended that patients receive a tuberculin skin test before the initiation of infliximab therapy.25
For neurosarcoidosis patients who present with papilledema, additional interventions directed at intracranial hypertension are indicated, usually acetazolamide or furosemide.26 Successive lumbar punctures are considered ineffective in maintaining a decrease in ICP.27 In patients with progressive VF loss despite medical treatment, surgical options include lumboperitoneal shunt,28 ventriculoperitoneal shunt, and optic nerve sheath fenestration.29 Shunt failure secondary to granulomatous infiltration of the ventricular catheter has been reported.30 Ventriculoperitoneal shunting is indicated for patients with uncompensated, acute, or significantly symptomatic hydrocephalus or patients who are both symptomatic and refractory to standard treatment.8 The success of optic nerve sheath fenestration has not been evaluated in sarcoidosis patients but might be low, owing to closure of the window by granulomatous scarring.
Surgical debulking of large intracranial granulomata is usually performed at the time of biopsy, especially if significant mass effect is present. However, recurrence is common. Radiation therapy for sarcoid mass lesions has been reported with mixed results.20,31,32 Symptomatic benefits, with the lowest risk for long-term adverse effects, may be derived from low-dose whole brain irradiation, although this remains controversial.
In conclusion, neurosarcoidosis is a heterogeneous disease that should be considered in the differential diagnosis for patients who present with vision loss and ODS. By considering the specific pathophysiologic features responsible for the patient's symptoms, more focused therapeutic decisions can be made. Infliximab and other TNF-α antagonists provide rational therapies directed at the pathogenesis of sarcoidosis. Further clinical investigations of such agents, including large placebo-controlled trials, are needed.
Corresponding author and reprints: Jeffrey M. Katz, MD, Department of Neurology and Neuroscience, New York Presbyterian Hospital–Weill Medical Center of Cornell University, 520 E 68th St, F-610, New York, NY 10021 (e-mail: firstname.lastname@example.org).
Accepted for publication September 23, 2002.
Author contributions: Study concept and design (Drs Katz, Bruno, Winterkorn, and Nealon); acquisition of data (Drs Katz, Bruno, and Winterkorn); analysis and interpretation of data (Drs Katz, Bruno, Winterkorn, and Nealon); drafting of the manuscript (Drs Katz, Bruno, Winterkorn, and Nealon); critical revision of the manuscript for important intellectual content (Drs Katz, Bruno, and Winterkorn); administrative, technical, and material support (Drs Katz and Bruno); study supervision (Drs Winterkorn and Nealon).
Katz JM, Bruno MK, Winterkorn JMS, Nealon N. The Pathogenesis and Treatment of Optic Disc Swelling in NeurosarcoidosisA Unique Therapeutic Response to Infliximab. Arch Neurol. 2003;60(3):426-430. doi:10.1001/archneur.60.3.426