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Sarcoidosis of the Anterior Visual Pathway: 24 New Cases

Frohman, Larry P. MD; Guirgis, Medhat MD; Turbin, Roger E. MD; Bielory, Leonard MD

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Journal of Neuro-Ophthalmology: September 2003 - Volume 23 - Issue 3 - p 190-197
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Abstract

Sarcoidosis is a multisystem disease that most frequently targets the respiratory system. Ocular involvement has been said to occur in 22% of cases (1). Neurologic involvement occurs in about 5–16% of cases (2). Involvement of the optic nerve, chiasm, and tract (anterior visual pathway, or AVP) in neurosarcoidosis is said to be uncommon, involving 1–5% of cases of sarcoidosis (3), although single case reports of sarcoid optic neuropathy are often published in major journals. However, we believe AVP sarcoidosis is frequently and erroneously labeled idiopathic optic neuropathy when supporting clinical signs go unrecognized and a directed diagnostic strategy is not used. When the AVP is involved in a patient with known sarcoidosis, the diagnosis is relatively straightforward. However, if AVP disease is seen in the absence of known sarcoidosis, it is imperative to establish the systemic diagnosis. In prior series, irreversible visual loss has often occurred as a result of delayed diagnosis or even iatrogenic trauma when biopsies were taken of the optic nerves or when they were resected for presumed meningioma or other suspected disease processes (3–6). Although optic nerve or nerve sheath biopsy may ultimately be indicated in selected cases to preserve the vision in the fellow eye, the astute clinician may often arrive at the diagnosis by more uniformly applying a tailored diagnostic strategy.

MATERIALS AND METHODS

We reviewed the database of all cases seen in neuro-ophthalmic consultation by 1 of us (LPF) from 1989 to 1998 and identified 69 patients with sarcoidosis. This study focused on the clinical features and diagnostic testing of the 24 cases with AVP disease from sarcoidosis whose records were recoverable. The results of the assessment of the non-AVP cases have been previously published in this Journal (7). Examination included Snellen visual acuity, color vision (typically using Ishihara plates), presence of a relative afferent pupillary defect (RAPD), ocular motility, assessment of the adnexa, visual field (usually automated testing of central 24° or 30°), stereo biomicroscopy, and indirect ophthalmoscopy.

Diagnostic studies included serum angiotensin converting enzyme (ACE), purified tuberculin protein derivative skin testing (PPD, 5 TU), cutaneous anergy panel (mumps, candida, trichophyton), pulmonary function tests, 24-hour urinary calcium excretion, chest radiograph, neuroimaging studies (MRI of brain and orbit with fat suppression and gadolinium contrast or CT scan when MRI was not available), gallium-67 citrate body scan, and lumbar puncture. Biopsy site and histologic results were reviewed. As this was a retrospective study, not all tests were performed on all patients, and unless otherwise specified, percentages are reported as the percent positive of those undergoing the procedure in question.

RESULTS

Clinical Features

The clinical features of the 24 cases of sarcoidosis of the AVP are shown in Table 1. Patients 1–17 did not have known sarcoidosis at the time of presentation. The mean age at the time of presentation to our service was 40 years (range 25–75 years). Seventeen patients (71%) were women. Six (25%) patients had unilateral and 18 (75%) had bilateral visual loss at presentation (total of 42 affected eyes). Despite bilateral disease, 16 (67%) had a RAPD detected at the initial examination.

TABLE 1
TABLE 1:
Clinical features
TABLE 1
TABLE 1:
Clinical features

The median visual acuity in the 42 involved eyes was between 20/30 and 20/40 (Fig 1). Four eyes (9.5%) had no light perception; four (9.5%) had counting fingers, hand motion, or light perception; five (12%) had 20/100–20/400; 12 (29%) had 20/30–20/70; and 17 involved eyes (40%) had 20/25 acuity or better. In the 21 involved eyes with acuity of 20/30 or better that underwent color vision testing, 9 (43%) had abnormalities.

FIGURE 1.
FIGURE 1.:
Visual acuity in patients with anterior visual pathway sarcoidosis.

The visual field defects seen in the 34 of 42 eyes tested are summarized in Table 2. Fundus findings are presented in Table 3.

TABLE 2
TABLE 2:
Visual field defects in 34 eyes
TABLE 3
TABLE 3:
Fundus manifestations in 42 eyes

Optic disc pallor was the most common sign, seen in 55% of involved eyes. Optic disc edema was seen in 29% of eyes. Periphlebitis or other vascular sheathing was seen in only 14% of involved eyes (Fig. 2). Optic disc granulomas were seen in 10% of involved eyes (Fig. 3). Less frequently seen funduscopic findings included disc hemorrhage, optic disc telangiectasia, macular exudate, optic disc shunt vessels, and vitreous “snowballs.” No fundus abnormalities were detected in 12% of involved eyes. Phosphenes/photopsias were reported by 8%.

FIGURE 2.
FIGURE 2.:
Right fundus shows multiple shunt vessels on disc and obvious periphlebitis of most veins, most noticeable in superotemporal branch vein (Patient 6).
FIGURE 3.
FIGURE 3.:
Left fundus shows large optic disc granuloma (Patient 14).

In addition to the involvement of the AVP, other ophthalmic signs at presentation included diplopia (13%) and ocular pain (13%). Evidence of past or active anterior uveitis was present in 42%, including 1 patient with Busacca nodules. Among 70% of the patients with anterior uveitis, 7 (70%) did not have known sarcoidosis at the time of presentation. Of these 7, only 3 (43%) had evidence of active uveitis at the time of presentation; the others demonstrated old mutton-fat keratic precipitates. In the 3 cases of uveitis in patients with previously diagnosed sarcoidosis, 2 (67%) had active uveitis at presentation. Six patients (25%) had clinical evidence of lacrimal gland enlargement, 3 (13%) had proptosis, and 3 (13%) had ptosis.

Other neurologic deficits included hearing loss in 2 patients (8%), facial nerve palsy in 2 patients (8%), sixth cranial nerve palsy in 1 patient (4%), unilateral hypesthesia in the territory of all branches of the trigeminal nerve in 1 patient (4%), third cranial nerve palsy in 1 patient (4%), and hemiparesis in 1 patient (4%).

Three patients (13%) had diabetes insipidus; each had previously been diagnosed with sarcoidosis, and had visual field defects that corresponded to chiasmal or optic tract involvement.

Diagnostic Evaluation

Of 21 patients who had a serum ACE performed, 16 (76%) were abnormal. Chest radiography showed radiographic evidence of sarcoidosis in 13 (72%) of 18 patients who underwent this study. Of the 17 patients who underwent both chest radiograph and ACE testing, both were normal in 4 (24%). Of the 14 patients who underwent gallium scintigraphy either before or at time of visual presentation, 13 (93%) demonstrated abnormalities consistent with sarcoidosis. These included abnormal uptake in the glandular tissue (lacrimal, parotid, and submandibular glands) in 7 (50%) or lung parenchyma in 11 (79%). Because 58% of patients with positive gallium scans will either improve or normalize after 4–12 months of corticosteroid therapy (8), we excluded 1 negative gallium scan that was performed after 1 full year of corticosteroid treatment (Patient 13). Ten patients without known sarcoidosis who underwent gallium scanning at the time of acute visual loss demonstrated abnormalities consistent with sarcoidosis (Table 4).

TABLE 4
TABLE 4:
Diagnostic evaluation

Twelve (80%) of the 15 patients who underwent pulmonary function testing had abnormal results, and 4 (57%) of 7 patients tested were anergic. Twenty-four-hour urinary calcium excretion was abnormal in 4 (67%) of 6 patients tested.

Of 23 patients who underwent neuroimaging (20 MRI, 3 CT), 16 (70%) demonstrated involvement of the AVP (Figs. 4 and 5). Eight (35%) had bilateral optic nerve involvement, 6 (26%) had unilateral optic nerve involvement, 9 (39%) had involvement of the sella/chiasm/pituitary/suprasellar area, 2 (9%) had optic tract involvement, and 2 (9%) had an orbital component. Two of the 7 patients with normal neuroimaging only had CT scans; both had optic nerve head granulomas.

FIGURE 4.
FIGURE 4.:
Fat-suppressed axial T1 MRI shows enlargement of the right optic nerve extending from the chiasm nearly to the globe (Patient 6).
FIGURE 5.
FIGURE 5.:
Enhanced coronal T-1 MRI shows enhancement and enlargement of the right cavernous sinus and both optic nerves at their junction with the optic chiasm (Patient 6).

Of 16 patients who underwent lumbar puncture, 14 (88%) had either lymphocytic pleocytosis or elevated protein. Lymphocytic pleocytosis was identified in 11 (69%) and elevated cerebrospinal fluid (CSF) protein in 10 (63%). Both values were elevated in 7 (44%).

Sixteen patients (Table 5) underwent a total of 19 biopsies (including a mediastinoscopy in Patient 2 that was abandoned due to hemorrhage before tissue was obtained). Overall, 13 patients (81%) had histopathology consistent with sarcoidosis (noncaseating granulomas). All biopsies were positive in the seven patients with a previous clinical diagnosis of sarcoidosis who developed AVP involvement. Six (67%) of 9 patients without known sarcoidosis who permitted biopsy had histologic confirmation and the other 3 with negative biopsies had overwhelming clinical evidence supporting the diagnosis of sarcoidosis. For example, Patient 2 had an abnormal ACE, chest radiograph, gallium scan, pulmonary function testing, 24-hour urine calcium excretion, and MRI scan; Patient 16 had an abnormal chest radiograph, gallium scan, anergy panel, MRI scan, and lumbar puncture, as well as lacrimal gland enlargement; Patient 17 had an abnormal ACE, chest radiograph, gallium scan, pulmonary function testing, 24-hour urine calcium, and lumbar puncture. All eight patients (Patients 3, 6, 7, 10, 11, 12, 14, and 15) who refused biopsy had overwhelming clinical and laboratory or radiologic evidence to support the diagnosis of sarcoidosis (Tables 1, 4, and 5).

TABLE 5
TABLE 5:
Biopsy results in 9 cases without preexisting diagnosis*

DISCUSSION

Involvement of the AVP in sarcoidosis may be secondary to extrinsic granuloma compressing the nerve, intrinsic infiltration with or without visible optic nerve granuloma, compression or infiltration of the chiasm, or raised intracranial pressure without ventriculomegaly. Elevated intracranial pressure without ventriculomegaly may occur if meningeal inflammation interferes with cerebrospinal fluid egress (9). AVP sarcoidosis may be encountered in the face of known pulmonary sarcoidosis or its other protean systemic manifestations. It may, however, be the presenting sign of the disease (10). Lower found that 71 (13%) of 554 patients with sarcoidosis at a single institution had neurologic manifestations. Although facial nerve palsy was the most common neurologic manifestation (7%), optic neuropathy was seen in 7 cases (1%). In the series of 520 cases of sarcoidosis reported by Recio et al. (11), 42 (8%) had neurologic disease; only 7 (1%) had visual loss. In that series, 59% of cases with neurologic disease did not present with any other systemic manifestations of sarcoidosis.

Many cases of occult sarcoidosis presenting with isolated optic neuropathy have reportedly required optic nerve biopsy to establish the diagnosis, obviating any chance of visual recovery (12–14). In other cases, diagnosis was established only at autopsy. In a series of 4 cases of AVP sarcoidosis, Beck et al.(15) reported only 1 case that had systemic involvement at the time of the presentation; 2 of the remaining 3 required optic nerve biopsy to establish the diagnosis. Ng et al. (4) described chiasmal involvement as the initial manifestation of sarcoidosis in a 14-year-old girl. Although MRI showed leptomeningeal enhancement, an optic nerve biopsy was used to demonstrate sarcoidosis. Pelton et al. (16) described a patient with increased intracranial pressure without ventriculomegaly who required optic nerve histopathology to disclose sarcoidosis as the cause.

In a 1997 review of 18 cases of biopsy-proven sarcoid optic neuropathy compiled from the English literature, Ing et al. (3) found that sarcoidosis often was confused with optic nerve meningioma in patients who demonstrated no other systemic signs, necessitating biopsy to establish the diagnosis.

Our review suggests that when patients with undiagnosed sarcoidosis first present with visual loss, other systemic signs may act as clues to a diagnosis. In many cases, a careful history and ophthalmic examination and subsequent directed laboratory/radiologic investigation will allow diagnosis of “occult” sarcoidosis without resorting to optic nerve biopsy.

The diagnostic strategy typically begins with an ACE level and a chest radiograph. Serum levels of ACE are said to be elevated in 70–80% of patients with “active disease” (17) referring to active pulmonary disease. The current series finds that ACE was elevated in 76% of cases of sarcoidosis of the AVP. This contrasts with our earlier finding that ACE was elevated in only 27% of cases with neuro-ophthalmic sarcoidosis other than AVP involvement (7).

In this series, 72% of cases had an abnormal chest radiograph. This is similar to our experience with other forms of neuro-ophthalmic sarcoidosis (7). Three of the five patients who had a normal chest radiograph also had a normal ACE. The 2 patients without an antecedent diagnosis of sarcoidosis who had both a negative chest radiograph and a negative ACE were detected by gallium scan. In our series, this was the most effective screening test, being abnormal in 93% of cases. Unlike Kosmorsky et al.(18), we do not routinely use CT of the chest. Our preference for the gallium scan is based on its ability to identify potential sites of active disease in the chest and elsewhere from which one can obtain histologic diagnosis.

High-resolution MRI of the brain, including contrast and fat-suppressed views of the optic nerves, is the neuroradiologic procedure of choice in evaluation of sarcoidosis of the AVP. In previous reports, the most common imaging finding has been diffuse enlargement of the optic nerve, as well as thickening and enhancement of the optic nerve dura (“tram-tracking”) (3). Ng et al.(4) have suggested that sarcoidosis may radiologically resemble the peripheral leptomeningeal enhancement of an optic nerve or chiasmal glioma. Mafee has suggested that abnormal dural enhancement of the optic nerve or enlargement of the intracranial segment of the optic nerve is suggestive of sarcoidosis (19). We have previously reported that we suspect sarcoidosis if the optic nerve enhances from globe to chiasm (20) (Fig. 4) or if there is noncontiguous involvement of the contralateral nerve, especially if the involvement is “nodular” (Fig. 5). Such “stem-to-stern” involvement of the optic nerve, particularly in the presence of enhancement of the frontal-basilar meninges, is very suggestive of sarcoidosis. In our experience, the latter finding may be overlooked, and is best seen in the coronal images anterior to the sella turcica. Enhancement of other cranial nerves may be seen. An enlarged and enhancing lacrimal gland in conjunction with such optic nerve involvement is also a sign that mandates a careful evaluation for occult sarcoidosis. Contrast MRI findings less specific for sarcoidosis include periventricular white matter lesions and intraaxial or extraaxial masses (21).

The characteristic spinal fluid findings described in neurosarcoidosis are lymphocytic pleocytosis and elevated cerebrospinal fluid protein (6). In our series, 88% of cases had 1 of these findings, and 44% had both, but they are nonspecific. We have stopped obtaining cerebrospinal fluid ACE levels because of low sensitivity, even in cases with known histologic confirmation of sarcoidosis.

We generally perform pulmonary function testing, anergy panels (with a PPD), and 24-hour urine calcium excretion. These noninvasive tests were abnormal in 80%, 57%, and 67%, respectively, of our patients tested. Although offering supportive evidence, they are not specific tests.

We encourage histologic confirmation of the diagnosis of sarcoidosis, given the toxicity of corticosteroid and more aggressive immunomodulatory treatment. If there is no obvious superficial lesion to biopsy (conjunctival or cutaneous nodule, enlarged lacrimal gland), we use the gallium scan as a guide to a deeper biopsy site, trying the most accessible “hot spot” first. Using this approach in patients without a prior diagnosis of sarcoidosis, we took biopsy specimens of pulmonary tissue 4 times, the lacrimal gland 3 times, a cutaneous lesion twice, and a paratracheal node, the orbit, and nasal tissue once each. If no clinically visible lesion is present, and nothing is demonstrated by gallium scan (or chest CT if that technique is used), options include biopsy of the liver, especially if abnormalities in liver function testing are present, multiple conjunctival biopsies, or bronchoscopy. In some cases, rather than performing an “undirected biopsy,” if multiple laboratory/radiologic evaluations indicate likely sarcoidosis, we may treat without histologic confirmation.

In the work-up of suspected AVP sarcoidosis, we recommend obtaining, in addition to the MRI, ACE, and chest radiograph, a 24-hour urine collection, PPD and anergy panel, pulmonary function tests, a lumbar puncture, and a gallium scan. It is preferable to obtain these tests before therapy with corticosteroid agents is begun, as this medication may rapidly “normalize” these tests. Even with such a diagnostic strategy, there may be cases where obtaining an optic nerve biopsy is the only way to be sure of the diagnosis (21).

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