Neuro-ophthalmology Options: Secondary Causes of Eye Pain

Eye pain is frequently encountered in neurology clinics, and primary headache syndromes are an especially common cause (given the rich innervation of the orbit by the trigeminal nerve). In a published series, 51% of people presenting with eye pain to a neurologist’s office had migraine with an additional 4.1% diagnosed with trigeminal neuralgia or other cranial nerve disorder.¹ This review focuses on the pertinent clinical features of secondary etiologies of eye pain that may present to an outpatient neurology practice; see the Red Flag list for eye pain red flags that may signify true emergencies. Taking a localization approach while highlighting salient historical and exam features, we begin with ocular surface causes of eye pain and move posteriorly through the structures of the eye to the optic nerve and orbit.

Ocular Surface

Dry Eye

Dry eye syndrome is a result of insufficient lubrication of the eye and a common cause of ocular discomfort, comprising 3.1% of eye pain presenting to a neurologist.¹ A healthy aqueous and lipid-mucous tear film is required for lubrication and nourishment of the ocular surface as well as flushing of foreign bodies.² Patients with dry eye may complain of mild-to-moderate, typically bilateral ocular discomfort that is vague or burning. Many also endorse a gritty, foreign body sensation in the eye.³ Discomfort can be accompanied by redness and paradoxical watering caused by reflex tearing secondary to irritation from dryness. Resolution of discomfort with topical anesthetic eye drops supports the diagnosis.

Individuals with fascicular or peripheral facial nerve palsies or parkinsonian syndromes are particularly susceptible to dry eye because of inadequate blinking. Anyone under age 65 with accompanying dry mouth and other systemic symptoms should be evaluated for Sjögren syndrome. Use of selective serotonin reuptake inhibitors (SSRIs), anticholinergics, and antihistamines can also contribute to dry eye.⁴

Treatment is aimed at increasing tear production, decreasing tear loss, and reducing ocular surface inflammation. Behavioral coping strategies include frequent blinking and minimizing windy or low-humidity environments. People with dry eye who spend prolonged periods reading or using digital screens should adhere to the 20-20-20 rule (see Clinical Gem). Frequent application of over-the-counter artificial tears (4 times a day) can improve symptoms within days to weeks.⁵ People with dry eye should be followed by a comprehensive ophthalmologist, and those with abnormal eyelid function or anatomy should be referred to an oculoplastic surgeon.

Eye Infections

Stabbing eye pain with purulent discharge from the eye is associated with infectious conjunctivitis or keratitis and more often presents to ophthalmologists.¹ An important infectious cause of eye pain that may present to neurology is herpes zoster ophthalmicus (HZO), which is a reactivation of the varicella zoster virus involving the ophthalmic division of the trigeminal nerve (cranial nerve V-1 [CN V-1]). Patients with HZO may complain of prodromal ocular or periocular pain or dysesthesia in the CN V-1 dermatome before eruption of the classic vesicular shingles rash. The presence of skin lesions near the tip of the nose (Hutchinson sign) is a strong predictor for ocular involvement (Figure).⁶ Treatment includes oral antiviral therapy as well as eye drops. HZO can cause severe sight-threatening inflammation of the eye, and people with HZO must be urgently referred to an ophthalmologist. Unfortunately, even when treated appropriately, over a third of patients over age 60 with HZO can develop postherpetic neuralgia with debilitating and unrelenting pain in and around the eye.⁶

Elevated Intraocular Pressure

Elevated intraocular pressure (IOP) above 40 mm Hg (normal <22 mm Hg) or a sudden, dramatic rise in IOP can cause eye pain, headache, and nausea/vomiting, as well as vision and pupillary changes.⁷ Untreated narrow angle or acute angle closure glaucoma is a common cause. People with chronic insidious elevations in IOP typically do not develop pain.

With elevated IOP, there may be a hard, red eye or blurry vision with glare/haloes around lights because of conjunctival hyperemia and corneal edema.⁸ Head pain accompanying elevated IOP is characteristically described as frontal or cranial pain ipsilateral to the affected eye and may be more severe than the eye pain itself. A study of 11 people with narrow angle glaucoma found initial misdiagnosis of migraine for an average of 2.7 years before proper diagnosis.⁸ Those with elevated IOP have average age 54 at onset, much later than is typical of migraine, and none formally fulfilled the International Classification of Headache Disorders criteria for migraine.⁹ Importantly, topiramate, a first-line agent for migraine preventive treatment, can worsen angle closure.^7,10 Acute angle closure must be treated promptly by an ophthalmologist with pressure-lowering drops and medications as well as procedures to alleviate anatomic angle closure.⁷

Intraocular Inflammation

Uveitis

Inflammation of the anterior chamber of the eye can cause eye pain and is termed anterior uveitis, iritis, or iridocyclitis. People with anterior uveitis will often complain of red eye, blurry vision, photophobia, and moderate-to-severe pain concentrated within the eye with occasional radiation to the face. Individuals with vitreous inflammation, termed vitritis, intermediate uveitis, or pars planitis, or chorioretinal inflammation, termed posterior uveitis, are more likely to complain of painless vision loss or blurred vision. The presence of abnormal cells and protein within the affected eye chamber is evident on slit lamp examination. Uveitis has a vast etiologic differential diagnosis including infectious and systemic immune-mediated diseases, many with neurologic manifestations (eg, multiple sclerosis [MS],¹¹ sarcoidosis, and Behcet disease). Ocular B-cell lymphoma with or without central nervous system (CNS) involvement is an important mimic.

Scleritis

Scleritis or inflammation of the opaque fibrous white outer coat of the eye causes increasingly severe, boring eye pain, often with tenderness to palpation of the affected eye.^12,13 Scleritis can be anterior and visible by examination or posterior with an externally “quiet,” white eye but notable inflammation on orbital ultrasound or CT/MRI imaging. Pain caused by scleritis is often exacerbated by eye movement because the extraocular muscles insert into the sclera. The sclera will be edematous with or without vessel dilation on slit lamp examination with abnormal discoloration. Posterior scleritis can cause optic nerve edema and vision loss because of the sclera’s fusion with the optic nerve sheath posteriorly. Less than half of cases have adjacent anterior uveitis; scleritis is frequently idiopathic or associated with systemic rheumatologic disorder.^12,13

Optic Nerve

Optic Neuritis

Demyelinating optic neuritis is the most common cause of inflammatory optic neuropathy¹⁴ and is often the first manifestation of MS. Classic optic neuritis presents as acute vision loss—blurred or missing vision with dyschromatopsia—progressing over days to weeks and associated with orbital pain or pain on eye movement in women age 20 to 40. Eye pain can precede vision loss by several days and is thought to result from dural contact with an inflamed optic nerve, which is often exacerbated by pulling eye movements.^14,15 Up to 92% of participants enrolled in the Optic Neuritis Treatment Trial reported eye pain.¹⁶ Eye pain or pain with eye movements is more common when longer or intracanalicular segments of the optic nerve are involved.¹⁶ Pain often improves with vision; high-dose steroids accelerates the rate of visual recovery but is not thought to improve visual outcome because most people begin having spontaneous recovery within a month of onset.

Ischemic Optic Neuropathy

Temporal arteritis or giant cell arteritis (GCA) can occasionally cause eye pain but is better known to cause new-onset headache related to ischemia from the inflammatory narrowing or occlusion of superficial extradural blood vessels.^17,18 GCA is the most common systemic vasculitis in adults over age 50 and can rapidly progress to blindness, if not diagnosed and treated early, often from arteritic ischemic optic neuropathy, and other complications.¹⁴ Nonthrobbing headache anywhere over the head¹⁹ or scalp tenderness when brushing or shampooing hair are commonly described. On exam, patients may demonstrate point tenderness, palpable cords, or absent pulses over the temporal arteries and rarely, scalp or tongue ulcers.¹⁴ A careful history should be taken with attention to these signs and constitutional symptoms including fever, malaise, weight loss, proximal myalgias, and jaw claudication with chewing or talking. Prompt initiation of high-dose steroids is critical to prevent further irreversible vascular complications.

Orbit

Orbital disease is characterized by space-occupying hypertrophy or mass lesion and is hallmarked by proptosis or bulging of the eyes as result of forward displacement of the globe. Thyroid-related eye disease (TED) is a frequent cause of orbital dysfunction in adults with Graves thyroiditis and frequently presents with dry eye symptoms. Ocular or periocular discomfort can also occur independently of dry eye in TED and a pressure sensation or feeling of ocular fullness and strain may be described, especially if there is extraocular muscle enlargement. A series of 120 people with TED noted that 30% had eye pain and 15.8% had photophobia.¹⁹ Severe eye pain or pain on eye movements is uncommon in TED.

Idiopathic orbital inflammatory syndrome (IOIS), also known as orbital myositis or orbital pseudotumor, represents 0.5% of people with eye pain presenting to ophthalmology clinics.¹ IOIS involves noninfectious inflammation and lymphocytic infiltration of the orbit, often with irregular thickening of the extraocular muscles. Symptoms include periorbital swelling, unilateral proptosis, double vision, and significant eye pain that worsens with movement in the direction of the inflamed muscle.^20,21 MRI of the orbit, along with accompanying clinical picture, confirms the diagnosis, although other inflammatory and infiltrative disorders should be ruled out. Nonsteroidal anti-inflammatory drugs (NSAIDs) can be used to manage eye pain, but IOIS patients respond most briskly and effectively to oral steroids.