Rare presentation of sarcoidosis with optic neuropathy and third nerve palsy

Abstract

Sarcoidosis is a systemic, idiopathic and granulomatous disease, which most commonly affects the skin, lungs and lymph nodes but can affect virtually any organ. Neurosarcoidosis can be the presenting or the only clinical manifestation accounting for 5%–15% of sarcoid diagnoses. In contrast to uveitis which is the most common ophthalmic manifestation, neuro-ophthalmic signs are uncommon in sarcoidosis. Optic neuropathy is the most common neuro-ophthalmic sign (70% in one series). Sarcoid-related optic neuropathy commonly presents with a picture similar to optic neuritis. Less commonly, optic nerve involvement occurs secondary to compressive lesions, or from direct granulomatous infiltration. Neuroimaging is crucial to identify the location of the lesion. We describe a case of sarcoid-related compressive optic neuropathy and third nerve palsy and highlight the challenging nature of neurosarcoidosis in a patient without a prior diagnosis of the disease.

Background

Sarcoidosis is a relatively common idiopathic multisystem disorder, of which the presenting clinical variations are being increasingly well described in literature. This granulomatous inflammatory disease can affect all organs of the body, with the most commonly reported ocular manifestation being uveitis. Despite well-known criteria that allow a high index of suspicion for the clinician, diagnosis is rarely straightforward, especially when the gold standard investigation is histopathological confirmation.

Sarcoidosis can affect any type of ocular tissue, and no clinical sign is diagnostic. While intraocular inflammation is common, it is more rarely found in the orbit and neurological tissues— namely locations where tissue biopsy acquisition is additionally difficult. Large retrospective case series have found that up to 30% of patients with neurosarcoidosis, which represents a 5%–15% proportion of sarcoid diagnoses, demonstrated neuro-ophthalmic signs.¹

In a case series of 20 biopsy proven sarcoidosis, optic neuropathy was the predominant neuro-ophthalmic manifestation accounting for 14/20 patients (70%).¹ Other neuro-ophthalmic manifestations included cranial neuropathy, Horner syndrome, tonic pupil and optic tract involvement.¹ MRI is the imaging modality of choice with pathological contrast enhancement in 84% of patients in one case series.¹ Two clinical entities of sarcoid-related optic neuropathy have been described in a recent cohort study, a subacute variant resembling optic neuritis in presentation, as well as a slower, more progressive variant of neuropathy.² These are shown to produce a variety of visual field defects, most commonly central scotomas.

Further, known variants have been cases of isolated perineuritis and compressive optic neuropathies caused by mass lesions. Retrobulbar non-caseating granulomatous lesions can produce a range of further manifestations, such as severe disc oedema, retinal artery and retinal vein occlusions. Similarly, cranial nerve and optic chiasm involvement can also occur secondary to compressive lesions, or from direct granulomatous infiltration. The disease course of all of these presentations has been found to range from either self-resolving, relapsing and remitting or chronic.

We describe a case of sarcoid-related compressive optic neuropathy associated with third nerve palsy and highlight the challenging nature of neurosarcoidosis in a patient without a prior diagnosis of sarcoidosis.

Case presentation

A 56-year-old man presented to the emergency eye clinic in early September 2020 with left-sided severe headache associated with blurry vision. The headache started 3 months before but increased in severity and became localised to the left side 10 days before presentation. He describes the pain as coming from behind his left eye. The patient is black British with origins from South America. He reported that he was evaluated in 2018 for the asymmetric optic disc in another hospital. At that time, he had left inferior altitudinal field defect. A diagnosis of left Non-arteritic Anterior Ischemic Optic Neuropathy (NAION) was made. After that, he lost follow-up at this hospital. He denied any history of high blood pressure, diabetes or any chronic systemic illness. He is an ex-smoker and drinks alcohol occasionally.

On examination, best spectacle corrected visual acuity (BSCVA) in the left eye was 6/12 while the right eye was 6/5. Anterior segment examination was unremarkable. Pupils didn’t show any signs of a relative afferent pupillary defect in either eye. Colour vision was tested using Ishihara plates with a score of 16/17 in both eyes with a slower response in the left eye. Dilated fundus examination revealed a pale left optic disc sparing the inferior quadrant (figure 1). The right optic disc was healthy looking. Otherwise, the retina, the retinal blood vessels and the macula were normal in both eyes. No limitation of extraocular motility was detected and the examination of third, fourth, fifth, sixth and seventh cranial nerves revealed normal findings. Optical Coherence Tomography (OCT) scan of the right optic disc revealed normal thickness of the nerve fibre layers (NFL) apart from the borderline thickness of the temporal quadrant whereas there was thinning of the superior, nasal and temporal quadrants of the NFL of the left optic nerve (figure 2). The Humphrey Visual Field (HVF) 24–2 showed left eye inferior altitudinal field defect with an unremarkable right eye visual field (figure 3).

Figure 1.

Healthy looking right optic disc (right side) and left optic disc pallor (left side).

Figure 2.

OCT optic disc showed borderline thickness of the retinal nerve fiber layer (RNFL) of the temporal quadrant of the right optic disc (right side) and thinning of the RNFL of superior, nasal and temporal quadrants of the left optic disc (left side).

Figure 3.

Humphrey Visual Field (HVF) 24–2 showed unremarkable right eye visual field (right side) and left eye inferior altitudinal field defect (left side).

Erythrocyte sedimentation rate (ESR), C reactive protein (CRP) and full blood count showed normal findings apart from slightly high mean corpuscular volume (MCV) of 100.5 (77–95 fL). Renal and liver functions test showed normal results apart from elevated GGT at 124 IU/L (1–55 IU/L). Thyroid function tests, HbA1c, B12 and folate levels were within normal limits but methylmalonic acid was elevated at 353 (0–280 nmol/L). Coagulation screen and homocysteine level were both normal. ANA and anti-dsDNA, anti-MPO and anti-PR3 antibodies were negative. HIV and Treponema antibody tests were negative. ACE level was within normal limits at 42 (8–52 IU/L). An urgent MR scan of the brain and orbit was reported as normal. Our neurology colleagues prescribed Gabapentin 300 mg once/day for headaches.

Two weeks later, he started to have drooping of the left upper lid followed by double vision. On examination, he had left-sided upper lid ptosis (margin reflex distance 1 (MRD1) was measured at 2 mm and palpebral fissure (PF) height was 7 mm), mid-dilated left pupil with sluggish reaction to light and limitation of extraocular motility except abduction. A diagnosis of left pupil-involving third nerve palsy was made. An urgent CT angiography ruled out posterior communicating artery aneurysm. A repeat MR scan of the brain and orbit showed intermediate T1/T2 signal enhancement related to the left superior orbital fissure, optic nerve canal and orbital apex (figures 4–6). The neuroradiologist suggested that inflammatory, vasculitic and granulomatous conditions to be considered.

Figure 4.

Axial T1 MRI fat saturated post-contrast image showing enhancement involving the left orbital apex and left superior orbital fissure.

Figure 5.

Coronal T1 MRI fat saturated post-contrast image showing enhancement involving the left orbital apex and left superior orbital fissure.

Figure 6.

Coronal STIR MRI showing left optic nerve atrophy (small and hyperintense nerve).

After 4 weeks of his presentation, the headache had significantly improved, the double vision was alleviated by a prism prescribed by our orthoptist and third nerve palsy started to recover. A lumbar puncture was performed which revealed normal cerebrospinal fluid (CSF) analysis.

The site of the lesion described in the MR scan was challenging for getting a biopsy. A whole body PET–CT scan was performed 6 weeks after the initial presentation showed hilar lymphadenopathy with left intense hilar activation. Endobronchial Ultrasound-guided Transbronchial Needle Aspiration (EBUS-TBNA) was recommended as a granulomatous aetiology appears most likely. EBUS-TBNA was performed 2 weeks later which confirmed a non-caseating granulomatous lesion most likely sarcoidosis. The patient was then referred to the neuro-inflammatory clinic which advised the patient that he may need to start an immunosuppressant but he was reluctant to while his symptoms are improving in view of the COVID-19 pandemic.

Discussion

Neurosarcoidosis occurs in up to 5%–15% of cases of sarcoidosis. Optic nerve involvement is an uncommon presentation in neurosarcoid patients.¹ The underlying mechanisms of optic nerve involvement include inflammation, infiltration, compression by a granuloma, secondary involvement through ischaemic complications of retinal and choroidal inflammation, granuloma within the disc itself, meningeal inflammation within optic nerve sheath or consequences of hydrocephalus.²

Neurosarcoidosis can occur either in isolation or associated with other features of systemic sarcoidosis. A case series showed that isolated neurosarcoidosis without systemic involvement represents 17% of neurosarcoidosis.³ Neuro-ophthalmic sarcoidosis has been reported to be associated with a lower incidence of pulmonary involvement.¹ Abdominal involvement is rare in patients presenting with neuro-ophthalmic sarcoidosis. Elnahry et al⁴ reported a case report of a patient who presented with bilateral optic disc granulomas associated with abdominal sarcoidosis with no radiological evidence of pulmonary involvement.

The largest case series of sarcoid-related optic neuropathy to date was described by Kidd et al² and demonstrated that patients commonly present with subacute optic neuropathy resembling optic neuritis. Slowly progressive optic neuropathy was a less common clinical entity. The majority of patients were women with a greater prevalence among African and Caribbean patients.² A wide age range was described ranging from 20 to 80 years in two different studies.^{1 2}

Cranial neuropathy is the most common clinical presentation of neurosarcoidosis.⁵ Any cranial nerve (CN) may be involved in neurosarcoidosis, and multiple cranial nerve involvement is common. Nerves involved in eye movement (CN III, IV and VI) may also be affected.⁶ In a case series of 68 neurosarcoid patients, oculomotor nerve palsy represented 2.5% of presentations.⁷ Based on the MR scan of the orbit, our patient showed a retrobulbar lesion at the superior orbital fissure which well explains the presentation of compressive optic neuropathy and associated third nerve palsy due to the close proximity of the optic nerve and the third cranial nerve at the superior orbital fissure. Isolated third nerve palsy as initial presentation of neurosarcoidosis is rare and usually occur in the context of multiple cranial neuropathies.^7–9

Kidd et al² reported that concurrent ocular inflammation occurs in only 36% of the neurosarcoid patients presenting with optic neuropathy and pain in only 27%. Similarly, our case didn’t show any concurrent ocular inflammation. However, the patient presented with severe unilateral pain which was reported in 9 patients out of 20 in another case series.¹ Neurosarcoid patients presenting with optic neuropathy usually don’t have a previous diagnosis of sarcoidosis (80% in a case series).¹

We believe that our patient represents a rare presentation of sarcoid-related optic nerve involvement in the form of slowly progressive compressive optic neuropathy by a retrobulbar granuloma. We think that NAION was a misdiagnosis and the left altitudinal field defect was not due to an ischaemic neuropathy because of first absence of risk factors such as diabetes and hypertension and second the healthy-looking contralateral optic disc. However, we can’t prove the progressive course due to the lack of the initial photos of the disc, the OCT and the visual field. Altitudinal field defect is not a common visual field defect in sarcoid-related optic neuropathy when compared with central scotoma.²

ACE level is widely used as a biomarker for sarcoidosis. However, its use is limited, as the sensitivity and specificity of elevated ACE in diagnosing sarcoidosis are 41.4% and 89.9%, respectively.¹⁰ In our patient, ACE level was within normal limits. Neuroimaging is a very useful tool in the diagnosis of neurosarcoidosis. However, the definitive diagnosis of sarcoidosis is based on histopathological confirmation. Inaccessible lesions represent a challenge to the physician because of the difficulty to obtain an adequate sample. PET–CT scan helps identify other sarcoid lesions in the body that is more accessible to biopsy. In our patient, the hilar lymphnodes were the biopsy site through EBUS.

Kidd et al² recommended the use of steroids in neurosarcoid patients presenting with optic neuropathy especially those presenting with the subacute optic neuritis form. More studies are required to identify the role of steroids and other immunosuppressant drugs in the treatment of different clinical entities.

Our patient represents a very unusual presentation of neurosarcoidosis, with an absence of systemic features. Considering the clinical signs and pathological progression described, this case represented a very challenging diagnosis, even in a large tertiary centre that regularly sees atypical and complex patients. We therefore advise having a high index of clinical suspicion of sarcoidosis in any patient, especially non-Caucasian, presenting with optic neuropathy.

Learning points.

• Optic neuropathy despite being an uncommon ophthalmic finding in sarcoidosis may be the first presentation of the disease.

• Painful pupil-involving third nerve palsy is commonly due to posterior communicating artery aneurysm. However, other compressive lesions must be ruled out when CT angiogram is normal.

• Always think in a compressive lesion (eg, of sarcoidosis) involving the superior orbital fissure in any patient presenting with both third nerve palsy and optic neuropathy.

• Modern imaging investigations including PET–CT scan may make identification of neurosarcoidosis easier especially lesions involving the orbit.

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