eMedicine Specialties > Ophthalmology > Neurologic Disorders

Multiple Sclerosis: Differential Diagnoses & Workup

Author: Andrew G Lee, MD, Professor, Departments of Ophthalmology, Neurology and Neurosurgery, University of Iowa Hospitals and Clinics
Coauthor(s): Fiona Costello, MD, FRCP, Assistant Professor, Departments of Ophthalmology and Medicine (Neurology), Neuro-ophthalmologist, Clinical Neurologist and Clinical Investigator, University of Ottawa; Cecil L Berlie, MD, Consulting Staff, Department of Ophthalmology, Luther Midelfort Eye Clinic
Contributor Information and Disclosures

Updated: Jan 26, 2007

Differential Diagnoses

Other Problems to Be Considered

Ischemic optic neuropathy: The major differential in a case of unilateral and acute optic neuropathy with optic disc edema is either ON or ischemic optic neuropathy. Typically, a younger patient has ON, and an older patient has anterior ischemic optic neuropathy (AION). Although the visual loss is sudden in both ON and AION, pain is less likely to occur in AION unlike in ON, and only mild-to-moderate visual improvement occurs after AION. The disc swelling in AION is typically more severe than in ON, and associated hemorrhages and exudates are features that argue against demyelinating ON.

Infiltrative optic nerve processes: Leukemic infiltration and lymphomatous lesions may create symptoms and a disc appearance similar to that of ON. If a history of such a disorder exists, ruling out either a progression or a relapse of the lymphoproliferative condition is essential. An infiltrate that is visible on the disc head itself is often a clue regarding the underlying etiology. Inflammatory disorders (eg, sarcoid, lupus, other autoimmune disorders) can produce an inflammatory optic neuropathy. The presence of associated anterior or posterior uveitis, a steroid dependent or markedly steroid responsive course, and a history of systemic inflammatory disease are helpful in differentiating these conditions from ON. Magnetic resonance imaging (MRI) is helpful in these cases.

Graves disease: Although thyroid ophthalmopathy (Graves ophthalmopathy) may produce a compressive optic neuropathy, a gradual rather than an acute decrease in visual acuity typically occurs. Usually, the patient has a history of autoimmune thyroid disease and signs of thyroid orbitopathy (eg, upper lid retraction, lid lag, ophthalmoplegia, proptosis). Orbital imaging differentiates compressive optic neuropathy from Graves disease and from ON.

Intraorbital/intracranial compressive lesions: These lesions typically produce painless, progressive, compressive optic neuropathy (eg, optic nerve sheath and intracranial meningiomas, sellar lesions). Neuroimaging studies are important for all cases of atypical ON (eg, chronic ON, pituitary apoplexy, inflammatory or infiltrative ON).

Leber hereditary optic neuropathy: This is a painless, progressive, and typically bilateral optic neuropathy that produces a central or cecocentral scotoma. The disorder is mitochondrially inherited and primarily affects young men.

Toxins and medications: Certain toxins and medications (eg, tobacco, ethanol, methanol, ethambutol, isoniazid, chloroquine, vitamin deficiencies, some anti-neoplastic agents) can produce an optic neuropathy. Typically, these patients have a bilateral and simultaneous central or cecocentral loss.

Neuromyelitis optica

Workup

Laboratory Studies

• In the ONTT, laboratory studies were not deemed helpful in establishing a diagnosis of typical demyelinating ON (ie, acute, unilateral optic neuropathy in a young patient with pain on extraocular movement and improvement over time).
• Laboratory studies can be helpful in patients with features that are atypical for demyelinating ON. These laboratory studies should be performed as a directed evaluation based upon the history and physical examination findings.
  • Complete blood count (CBC)
  • Serum vitamin B-12 level and folate (eg, bilateral central scotoma)
  • Chest radiographs (eg, sarcoidosis, tuberculosis)
  • Lyme titers (eg, endemic area, tick exposure, rash)
  • Tuberculosis (TB) skin test (eg, TB exposure, endemic area)
  • Fluorescent treponemal antibody (FTA) test (eg, syphilis)
  • Venereal Disease Research Laboratory (VDRL) test or rapid plasma reagin (RPR) test (eg, syphilis)
  • Antinuclear antibody (ANA) (eg, systemic lupus erythematosus)
  • Human immunodeficiency virus (HIV) (eg, high-risk patients)
  • Angiotensin-converting enzyme (ACE) level (eg, sarcoidosis)
  • Erythrocyte sedimentation rate (ESR) (eg, inflammatory disorders)
• Although some interest has been shown in HLA typing in ON (eg, HLA-DR2, HLA-B7, HLA-Dr4, HLA-Dw2), the clinical utility of these tests remains unproven.

Imaging Studies

• Typical cases of ON do not warrant extensive investigations. Advances in MRI techniques have improved the ability to visualize damage to the anterior visual axis. Yet the main role for cranial MRI is to identify the future risk of MS, as the presence of asymptomatic white matter lesions on the MRI is a predictor for this diagnosis.
• The most important prognostic imaging study for the development of MS in patients with ON is a cranial MRI. MRI is superior to CT scanning for MS. Although secondary causes of ON, including neoplastic changes, granulomatous lesions, neuropathies, and other inflammatory conditions, may be seen on a cranial MRI, the major rationale for performing a cranial MRI is to evaluate demyelinating lesions.
• In 2001, the International Panel on the Diagnosis of MS put forth the so-called McDonald criteria (named after Dr. Ian McDonald who chaired the panel). These criteria were intended to aid in the diagnostic evaluation of MS by incorporating MRI findings into the evaluation and diagnosis of the disease. According to Polman and colleagues, the McDonald criteria have been extensively assessed and used since 2001, and the 2005 revisions helped to simplify and speed diagnosis, while maintaining adequate sensitivity and specificity.
• The lesions on an MRI are typically bright on T2-weighted imaging and can be highlighted by suppressing the normal cerebrospinal fluid signal using fluid-attenuated inversion recovery (FLAIR).
• MS plaques are usually periventricular, ovoid in shape, large, and multiple. Involvement of the corpus callosum is particularly suggestive of demyelinating disease. Active MS plaques may show enhancement after gadolinium administration.
• The optic nerve in ON often shows enhancement after contrast in T1-weighted MRI. Orbital fat suppression techniques might be useful for visualizing optic nerve enhancement involving the intraorbital portion of the optic nerve.
• Although a high number of white matter lesions present on a cranial MRI are more suggestive of MS, even one white matter lesion may be significant. On the other hand, a normal MRI at onset lessens (<20%) the chance for future development of MS but does not exclude the possibility of MS.

Other Tests

• Visual evoked potentials (VEPs) are not typically necessary for patients with clear clinical evidence of ON. VEPs may be a valuable means of assessing any subclinical fellow eye involvement.

Procedures

• In the ONTT, a lumbar puncture was optional and only showed evidence of demyelinating disease in patients with ON. The cerebrospinal fluid may be useful for diagnostic purposes in atypical cases of ON or in patients in whom a diagnosis of MS requires support from additional paraclinical evidence (eg, elevated immunoglobulin G [IgG] synthesis, oligoclonal bands).

Histologic Findings

The most common form of ON is a unilateral, idiopathic, inflammatory, demyelinative process involving neutrophils, lymphocytes, plasma cells, and macrophages, occurring either anterior or posterior to the lamina cribrosa. Although demyelination is a process that causes a mostly mononuclear infiltration of the perivascular spaces, initial examinations of the axons may show no structural changes until the disease has progressed.

Once the disease has progressed, inflammatory and cellular responses cause the breakdown of myelin into fat globules, thereby altering the structure of the nerve. Ingestion of fat droplets by macrophages causes the stimulation of astrocytes and the formation of glial tissue visualized as plaques on an MRI. This process is responsible for damaging neurons and increasing latency and transmission times along the axons. This process is also responsible for the formation of plaques visualized on T2-weighted imaging.

Thus, the pathologic findings in MS include inflammation, demyelination, and axonal loss. The degree of axonal loss may explain the lack of a complete recovery of function in patients with MS, especially after repeated attacks.

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