8.1 Diagnosis

The diagnosis of optic neuropathy is based on clinical examination, checking for the following:

• 
  

  Visual loss

  
  
• 
  

  Impaired color vision

  
  
• 
  

  Abnormal visual field

  
  
• 
  

  Relative afferent pupillary defect (RAPD) in all unilateral or asymmetric optic neuropathies (▶ Fig. 8.3)

  
  
• 
  

  Optic nerve head appearance

  
  
  
  
  • 
    

    Acutely: normal or swollen

    
    
  • 
    

    Late (after 4–6 weeks): pale

    
    
    
    

    

    
    

    Fig. 8.3 a, b (a) Right relative afferent pupillary defect (RAPD) from a right optic neuropathy. When the light is shone in the left eye, both pupils constrict briskly; both pupils dilate when the light is shone in the right eye. (b) Pupillary reaction in bilateral and symmetric optic neuropathies. There is no RAPD, but both pupils are sluggish in response to light stimulation.

Electrophysiologic testing is most often unnecessary. However, visual evoked responses and electroretinography are useful when the diagnosis is unclear (e.g., in cases with bilateral visual loss and no RAPD and when there is concern for a retinal disease rather than optic neuropathy). Patients with optic neuropathies have abnormal visual evoked responses. The P100 latency is delayed, and the amplitude is decreased (▶ Fig. 8.4).

8.1.1 Localization of the Lesion

The optic nerve may be affected in the orbit, at the level of the optic canal, or in its intracranial portion. In the orbit, the optic neuropathy may be isolated. The presence of associated symptoms or signs such as diplopia, ptosis, and proptosis suggests a process involving more than just the optic nerve, such as inflammation, infection, or neoplasm (▶ Fig. 8.5 and ▶ Fig. 8.6).

Neurovascular structures enter and exit the orbit through the optic canal and the superior orbital fissure. In the optic canal, the optic nerve exits the orbit, and the ophthalmic artery enters the orbit. In the superior orbital fissure, the superior ophthalmic vein exits the orbit, and cranial nerves III (superior and inferior branches), IV, V1 (lacrimal, frontal, and nasociliary nerves), and VI enter the orbit (▶ Fig. 8.7).

An optic neuropathy may result from a lesion involving the intracranial portion of the optic nerve. When the lesion is close to the optic chiasm, visual field testing demonstrates a junctional scotoma (▶ Fig. 8.8).

8.2 Types of Optic Neuropathies (▶ Table 8.1)

The following lists the main types of optic neuropathies, with subcategories:

• 
  

  Inflammatory (optic neuritis)

  
  
  
  
  • 
    

    Idiopathic demyelinating optic neuritis (associated with multiple sclerosis)

    
    
  • 
    

    Neuromyelitis optica (NMO; Devic disease)

    
    
  • 
    

    Acute disseminated encephalomyelitis

    
    
  • 
    

    Systemic infections

    
    
  • 
    

    Systemic inflammatory diseases (e.g., sarcoidosis)

  
  
• 
  

  Vascular (ischemic optic neuropathy)

  
  
  
  
  • 
    

    Anterior/posterior

    
    
  • 
    

    Arteritic/nonarteritic

  
  
• 
  

  Compressive/infiltrative

  
  
  
  
  • 
    

    Neoplastic

    
    
  • 
    

    Non-neoplastic

  
  
• 
  

  Hereditary

  
  
• 
  

  Toxic/nutritional

  
  
• 
  

  Traumatic

  
  
• 
  

  Raised intracranial pressure (papilledema)

  
  
• 
  

  Glaucomatous

  
  
• 
  

  Anomalous optic nerve

  
  
  
  
  • 
    

    Congenitally anomalous

    
    
  • 
    

    Drusen

Optic neuropathies and maculopathies have overlapping presentations. Both cause central visual loss and dyschromatopsia. Many chronic maculopathies are associated with mild optic nerve pallor. When the macula appears normal, it may be difficult to differentiate an optic neuropathy from a maculopathy (▶ Table 8.2). Autofluorescence imaging of the macula (see ▶ Fig. 4.5) and spectral optical coherence tomography (OCT) (see ▶ Fig. 4.12) are very helpful in distinguishing optic neuropathies from maculopathies when the macula appears normal on funduscopic examination.

8.3 Patient Evaluation

The following clinical characteristics are particularly helpful in determining the mechanism of the optic neuropathy:

• 
  

  Mode of onset of visual loss

  
  
  
  
  • 
    

    Acute (ischemic and inflammatory neuropathies)

    
    
  • 
    

    Progressive (compressive or toxic optic neuropathies)

  
  
• 
  

  Color vision (often relatively spared in ischemic optic neuropathies and usually very abnormal in inflammatory optic neuropathies)

  
  
• 
  

  The presence of pain with eye movements (highly suggestive of an inflammatory mechanism)

  
  
• 
  

  Funduscopic appearance (variable in inflammatory optic neuropathies, reveals a swollen optic nerve in all cases of anterior ischemic optic neuropathy, and shows a sometimes cupped optic nerve in compressive and hereditary optic neuropathies)

  
  
• 
  

  Associated retinal changes in neuroretinitis

Evaluating the patient with suspected optic neuropathy includes the following:

1. 
   

   Confirm the diagnosis of optic neuropathy by clinical examination.

   
   
2. 
   

   Look for associated symptoms and signs.

   
   
3. 
   

   Try to localize the optic nerve lesion (anterior, posterior in the orbit, orbital apex, or intracranial).

   
   
4. 
   

   Determine the presumed etiologic diagnosis.

   
   
5. 
   

   Obtain ancillary testing, such as imaging and laboratory workup, to confirm the diagnosis prior to initiating treatment.

Recommended tests include the following:

• 
  

  Magnetic resonance imaging (MRI) of the brain and orbits with gadolinium (orbital images should be with fat suppression)

  
  
• 
  

  Blood tests

  
  
  
  
  • 
    

    Blood tests will vary, based on the presumed diagnosis.

    
    
  • 
    

    Helpful tests include those for syphilis, sarcoidosis (angiotensin-converting enzyme [ACE]), cat scratch disease (Bartonella antibodies), Lyme disease, human immunodeficiency virus (HIV), inflammatory biologic syndrome (complete blood count [CBC], C-reactive protein [CRP], and erythrocyte sedimentation rate [ESR]), autoantibodies for autoimmune diseases (antinuclear antibodies [ANAs] and antineutrophil cytoplasmic antibodies [ANCAs]), and vitamin B12 and folate (bilateral and progressive painless optic neuropathies), as well as genetic testing for Leber hereditary optic neuropathy (severe unilateral or bilateral optic neuropathies) and for dominant optic atrophy (bilateral and progressive painless optic neuropathies).

  
  
• 
  

  Cerebrospinal fluid (CSF) (lumbar puncture)

  
  
  
  
  • 
    

    Helpful in cases of bilateral optic neuropathies, or when an infectious, systemic inflammatory, or neoplastic cause is suspected

8.4 Inflammatory Optic Neuropathy (Optic Neuritis)

Inflammation of the optic nerve is called optic neuritis. There are several different types of optic neuritis.

8.4.1 Characteristics

Optic neuritis is characterized by subacute, painful loss of central vision that may progress for 7 to 10 days (visual acuity varies from a mild reduction to severe loss); pain that is usually exacerbated by eye movement and may precede or coincide with visual loss; and abnormal color vision that is usually impaired out of proportion to visual acuity.

Optic nerve appearance varies depending on which part of the optic nerve is inflamed. The term retrobulbar optic neuritis is used when the optic nerve appears normal in the acute phase. The terms anterior optic neuritis and papillitis are used when there is optic disc swelling. In both cases, temporal pallor of the disc develops 4 to 6 weeks after visual loss.

Optic nerve enhancement is often seen on orbital MRI.

8.4.2 Causes

There are multiple causes of optic neuritis, including infectious diseases, such as syphilis and cat scratch disease, and noninfectious inflammation, such as sarcoidosis. However, in most cases, optic neuritis remains idiopathic or is associated with multiple sclerosis. Optic neuritis may also be associated with other primary demyelinating diseases, such as NMO (Devic disease) and acute disseminated encephalomyelitis (ADEM).

8.4.3 Patient Evaluation

Evaluation of the patient includes checking for these characteristics:

• 
  

  Cat exposure

  
  
• 
  

  Recent travel

  
  
• 
  

  Tick bite

  
  
• 
  

  Immunosuppression

  
  
• 
  

  Associated systemic symptoms and signs, including fever, lymphadenopathy, weight loss, skin lesions, cough, and arthralgias

  
  
• 
  

  Associated neurologic symptoms and signs, including focal neurologic signs; a history of vertigo, diplopia, numbness, Lhermitte sign, or Uhthoff phenomenon; headaches; and meningismus

  
  
• 
  

  Associated ocular findings, including intraocular inflammation and retinitis

The cause of optic neuritis is often suspected after the history and clinical examination. Ancillary tests are obtained to confirm a presumed diagnosis.

Ancillary tests vary based on the foregoing evaluation and include the following:

• 
  

  MRI of the brain and orbits with contrast (confirms optic nerve enhancement and looks for demyelinating disease in the brain)

  
  
• 
  

  Chest radiograph (looking for sarcoidosis)

  
  
• 
  

  Blood tests (vary based on presumed diagnosis): CBC, platelets, angiotensin-converting enzyme (ACE) level, and syphilis testing

  
  
• 
  

  Lumbar puncture: performed when an infectious cause or underlying systemic inflammatory disease is suspected; should always be obtained when the optic neuritis is bilateral and is obtained in most cases of optic neuritis in children

  
  
• 
  

  MRI of the spine with contrast if neurologic signs suggest spinal cord disease or if NMO is suspected

  
  
• 
  

  NMO antibodies: obtained in the serum of patients with bilateral optic neuritis, recurrent optic neuritis, severe optic neuritis with poor visual recovery, or when there is a spinal cord lesion or symptoms suggesting transverse myelitis

8.4.4 Classification

1. 
   

   Optic neuritis associated with demyelinating disease

   
   
   
   
   • 
     

     Idiopathic optic neuritis

     
     
   • 
     

     Optic neuritis as a manifestation of any of the following:

     
     
     
     
     • 
       

       Multiple sclerosis

       
       
     • 
       

       NMO (Devic disease)

       
       
     • 
       

       ADEM

   
   
2. 
   

   Optic neuritis associated with infectious diseases

   
   
   
   
   • 
     

     Bacterial infections: syphilis, cat scratch disease (Bartonella henselae), Lyme disease, any bacterial meningitis, Mycoplasma pneumoniae, tuberculosis, Whipple disease (syphilis and cat scratch disease are the most common causes)

     
     
   • 
     

     Viral infections: herpes zoster, herpes simplex, HIV, Epstein–Barr virus, coxsackie virus, adenovirus, cytomegalovirus, hepatitis A and B virus, measles, mumps, rubella virus (herpes zoster is the most common cause)

     
     
   • 
     

     Parasitic infections: toxoplasmosis, cysticercosis, toxocariasis, intraocular nematode infection (toxoplasmosis is the most common cause)

     
     
   • 
     

     Fungal infections: cryptococcosis, aspergillosis, mucormycosis, histoplasmosis (cryptococcosis is the most common cause)

   
   
3. 
   

   Post-vaccination optic neuritis

   
   
   
   
   • 
     

     Hepatitis B virus; rabies virus; tetanus toxoid; variola virus; combined smallpox, tetanus, and diphtheria vaccine; combined measles, mumps, and rubella vaccine; influenza vaccine; bacille Calmette-Guérin (BCG)

   
   
4. 
   

   Optic neuritis associated with other inflammatory disorders

   
   
   
   
   • 
     

     Sarcoidosis

     
     
   • 
     

     Systemic lupus erythematosus

     
     
   • 
     

     Sjögren syndrome

     
     
   • 
     

     Polyarteritis nodosa

     
     
   • 
     

     Wegener granulomatosis

     
     
   • 
     

     Inflammatory bowel disease

     
     
   • 
     

     Behçet syndrome

     
     
   • 
     

     Bee and wasp stings

   
   
5. 
   

   Isolated recurrent optic neuritis (autoimmune optic neuritis)

8.4.5 Idiopathic Demyelinating Optic Neuritis

Idiopathic demyelinating optic neuritis is the most common acute optic neuropathy in persons under the age of 45. It is also the most common cause of optic neuritis and often the presenting sign of multiple sclerosis.

Characteristics

Idiopathic demyelinating optic neuritis is more prevalent in young women than men (3:1). It is unilateral (occasionally bilateral) and is characterized by acute to subacute onset (usually rapidly progressive over a few days), decreased visual acuity (variable) and color vision (usually pronounced), pain with eye movements (in > 90% of cases), and exacerbation with heat or exercise (Uhthoff phenomenon).

Patient Evaluation

Examination should include the following:

• 
  

  RAPD (if unilateral or asymmetric)

  
  
• 
  

  Funduscopy:

  
  
  
  
  • 
    

    Normal (two thirds of cases) or swollen (one third of cases) optic nerve head

    
    
  • 
    

    Normal macula and retina (no exudates, no hemorrhages)

    
    
  • 
    

    Optic disc pallor (only if at least 4–6 weeks after onset or if previous episode of optic neuritis)

  
  
• 
  

  Visual field test:

  
  
  
  
  • 
    

    Often central scotoma (diffuse depression on Humphrey visual field test)

In > 90% of cases, spontaneous improvement is seen within several weeks; the absence of improvement should raise concern for another diagnosis. Risk of multiple sclerosis (▶ Fig. 8.9) should also be assessed.

Association between Idiopathic Demyelinating Optic Neuritis and Multiple Sclerosis

Patients diagnosed with idiopathic demyelinating optic neuritis are at high risk of subsequent development of multiple sclerosis after an isolated attack of idiopathic optic neuritis (as high as 74% at 15 years). Initial MRI helps stratify the risk of multiple sclerosis (as per the Optic Neuritis Treatment Trial):

• 
  

  The overall risk of multiple sclerosis at 15 years is 50%.

  
  
• 
  

  If the brain MRI is normal, the 15 year risk of multiple sclerosis is 23%.

  
  
• 
  

  If the brain MRI shows one T2-weighted ovoid > 3 mm in diameter, highly suggestive of multiple sclerosis, the 15 year risk of multiple sclerosis is 56%.

  
  
• 
  

  If the brain MRI shows at least six T2-weighted white matter lesions suggestive of multiple sclerosis, the 15 year risk of multiple sclerosis is 74%.

Lumbar puncture may detect oligoclonal bands in the CSF of patients with idiopathic demyelinating optic neuritis. However, it provides additional information only when the brain MRI is normal (an abnormal brain MRI is the strongest predictor of multiple sclerosis in a patient with optic neuritis).

To determine the prognosis for multiple sclerosis in patients with typical acute isolated optic neuritis, the only test definitely indicated is an MRI scan of the brain with contrast. Other tests are sometimes obtained (vary with patient characteristics and centers), for example, MRI of the orbits with contrast and fat suppression, lumbar puncture for CSF oligoclonal bands, blood tests (syphilis testing and ACE level for sarcoidosis), NMO antibodies, and chest radiograph.

The spontaneous visual prognosis is good without treatment.

Treatment of idiopathic acute optic neuritis should consider the following:

• 
  

  Intravenous methylprednisolone (250 mg, every 6 hours for 3 days) followed by oral prednisone (1 mg/kg/d for 11 days, then tapered off over 3 days):

  
  
  
  
  • 
    

    Hastens the rate of visual recovery by about 2 weeks but does not change the final extent of visual recovery

    
    
  • 
    

    May help alleviate the pain

    
    
  • 
    

    Delays neurologic symptoms and signs from multiple sclerosis for 2 years but does not change the risk of multiple sclerosis after 2 years

  
  
• 
  

  Oral prednisone (1 mg/kg/d) should not be prescribed:

  
  
  
  
  • 
    

    No beneficial effect on recovery of vision or risk of multiple sclerosis

    
    
  • 
    

    Doubles the risk of recurrent optic neuritis (in the Optic Neuritis Treatment Trial)

  
  
• 
  

  Disease-modifying agents decrease the risk of subsequent neurologic symptoms and signs related to multiple sclerosis and should be considered in selected high-risk patients (those with typical idiopathic optic neuritis and white matter lesions highly suggestive of demyelinating disease on brain MRI).

  
  
  
  

  
  

  Pearls

  
  

  
  

  Treatment with intravenous methylprednisolone hastens visual recovery, but it does not change the long-term prognosis of patients with acute isolated optic neuritis.

  
  

  In the Optic Neuritis Treatment Trial, treatment with oral prednisone 1 mg/kg/d alone doubled the risk of recurrent optic neuritis and should not be prescribed to patients with acute isolated optic neuritis.

8.4.6 Neuromyelitis Optica (Devic Disease)

NMO, also known as Devic disease, is the association of acute or subacute severe visual loss in one or both eyes caused by acute optic neuritis. Transverse myelopathy precedes or follows visual loss. NMO is diagnosed with an abnormal cervical spine MRI scan (long T2-weighted hypersignal over more than three segments) and a brain MRI scan that is typically normal or shows T2-weighted hypersignals not typical of multiple sclerosis (not involving the periventricular region and not scattered in the white matter). Positive NMO immunoglobulin G (IgG) antibodies are also a major criterion for the diagnosis of NMO.

The prognosis is usually poor, with permanent, severe visual loss and paraplegia. Treatment usually consists of high-dose intravenous steroids followed by a slow taper of oral prednisone and long-term immunosuppressive therapy. Plasmapheresis is sometimes performed in cases with acute symptoms (▶ Fig. 8.10).

8.4.7 Acute Disseminated Encephalomyelitis

ADEM or subacute encephalomyelitis occurs during the course of various infections, most often as a postinfectious or autoimmune response. It is particularly common in children, but it may occur at any age.

The clinical symptoms and MRI changes may mimic multiple sclerosis; however, unlike multiple sclerosis, which is a relapsing-remitting disorder, patients usually have only one episode of ADEM. Unilateral or bilateral optic neuritis (often with disc edema) may develop during the course of ADEM.

8.4.8 Other Causes of Optic Neuritis

Less commonly, inflammatory optic neuritis is not associated with a primary demyelinating process in the optic nerve or the central nervous system (CNS). Instead, the condition develops in the setting, or as the presenting manifestation, of a systemic infection or a systemic inflammatory disease.

Systemic symptoms and signs, patients’ characteristics, and associated ocular findings such as neuroretinitis should direct the subsequent workup.

Syphilitic Optic Neuritis

Optic neuritis is common in secondary and tertiary syphilis. It is usually associated with lymphocytic meningitis and is a sign of neurosyphilis. Raised intracranial pressure with papilledema is common with syphilitic lymphocytic meningitis. Testing for syphilis (rapid plasma reagin [RPR] and fluorescent treponemal antibody absorption [FTA-ABS]) should be considered in patients with optic neuritis. When blood tests are positive, a lumbar puncture (with opening pressure, CSF analysis, and Venereal Disease Research Laboratories [VDRL] testing) and HIV testing are mandatory. Syphilitic optic neuritis is treated like neurosyphilis. The visual prognosis is usually good (▶ Fig. 8.11).

Optic Neuritis in Patients with HIV

Optic neuritis is a not uncommon cause of visual loss in patients infected with HIV (see Chapter ▶ 20). Syphilis is the most common cause of optic neuritis in patients with HIV.

Most opportunistic infections invading the CNS can produce an optic neuritis. Infections by cytomegalovirus, toxoplasmosis, and cryptococcus are the most classic causes.

A lumbar puncture should always be performed, and CSF should be evaluated for all causes of infections and malignancies (e.g., lymphoma) common in patients with HIV (▶ Fig. 8.12).

Sarcoid Optic Neuritis

Sarcoid optic neuritis may be isolated, or it may develop in a patient with neurosarcoidosis (see discussion in Chapter ▶ 20). The lumbar puncture often shows abnormal CSF (lymphocytic meningitis), and the MRI scan typically demonstrates intense gadolinium enhancement of the affected optic nerve. There is sometimes associated meningeal enhancement.

Workup (general examination, ACE level, chest radiograph, chest computed tomography [CT], gallium scan, or fluorodeoxyglucose positron-emission tomography [FDG-PET] scan) may suggest systemic sarcoidosis. Biopsy of a lesion (usually skin lesion, lymph node, pulmonary lesion, or lacrimal gland) confirms the diagnosis of sarcoidosis.

In sarcoidosis, the optic neuritis may result from lymphocytic meningitis present in neurosarcoidosis. Uni- or bilateral optic nerve edema may be present if there is raised intracranial pressure. Optic neuritis may also result from granulomatous infiltration of the optic nerve head associated with elevation of the optic nerve. Retinal lesions (infiltrates, vasculitis) and vitreous cells are common in this setting. Another cause is granulomatous infiltration of the intracranial portion of the optic nerve and the chiasm.

In most cases, the optic neuropathy responds well to corticosteroids and may be steroid-dependent, requiring long-term treatment with an immunosuppressive agent (▶ Fig. 8.13).

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