Multiple sclerosis (MS) is a neurodegenerative disease of the central nervous system (CNS) that results from the immune-mediated inflammation and demyelination of axons. It is characterized by focal demyelinating lesions in the white matter of the brain or spinal cord that vary temporally and spatially, thereby leading to the classic presentation of episodic neurologic symptoms. These symptoms vary depending on the location of lesions, and can include changes in autonomic, motor or sensory functions. Of interest, MS often presents with ocular manifestations secondary to inflammatory demyelination of the visual pathway, and a majority of patients experience at least one episode of ocular involvement in the course of their disease.
MS affects an estimated 400,000 people in the United States and 2.1 million people worldwide, with a more prevalent geographic distribution among the northern and southern hemispheres.  The average age of onset ranges from 15 to 45 years while the average age at diagnosis is 30 years. Females are more commonly affected than males, at a ratio of about 2 to 1. 
The underlying cause of MS is unknown, though multiple factors have been proposed to contribute to the development and progression of the disease. The leading theories suggest a complex interplay between genetic predisposition and environmental factors.
A genetic component in MS is supported by twin studies showing a concordance rate of 25-30% in monozygotic twins, 5% in dizygotic twins, and 3% in non-twin siblings.  In addition, a number of genome-wide association studies have identified more than 100 risk loci in MS, and a majority of these genes have been found to encode for proteins involved in immune modulation. Although polymorphisms in the human leukocyte antigen (HLA) have been identified as the strongest susceptibility loci, other non-HLA genes have also been found. [4, 5]
Despite data suggesting significant genetic influence in MS, genes alone do not fully contribute to the development of the disease. A number of environmental factors such as infection, location, climate, stress, occupation and diet have been postulated to be involved.  There is evidence suggesting the development or exacerbation of MS following post-viral syndromes, such as those from Epstein-Barr virus (EBV) and human herpes virus (HHV). [7, 8] The geographic variation of MS further supports an environmental role. Although the underlying cause remains unclear, factors such as decreased sun exposure and low levels of vitamin D have been proposed to explain the latitudinal gradient. 
MS is thought to be an autoimmune disease and this theory is supported by its shared characteristics with other autoimmune disorders. These features include the predominance of women affected, the association with HLA polymorphisms, and the presence of autoantibodies to myelin antigens in CSF. 
The chronic inflammation, degeneration and demyelination of axons in the CNS lead to the clinical presentation of neurologic dysfunction. The inflammatory process is mediated by T lymphocytes that recognize myelin as a foreign entity and trigger other immune cells, macrophages, cytokines and antibodies that together lead to myelin and axonal breakdown. These T cells are thought to gain entry into the brain from disruptions in the blood-brain barrier, which can result from post-viral infections.  With the loss of myelin, the protective and insulating fatty sheath that surrounds axons, the conduction of electrical impulses is compromised.
This impaired transmission of neurologic signal can occur anywhere within the CNS, including the visual system. Ophthalmic involvement can be categorized into lesions of the afferent or efferent visual pathways. The afferent pathway is responsible for the transmission of sensory information from the retina to the brain. The optic nerve is most commonly involved and leads to a number of visual symptoms, described below. Infrequently, the optic chiasm and optic tracts are involved which lead to visual field defects such as bitemporal hemianopsia and homonymous hemianopsia, respectively.
The efferent pathway is responsible for motor output to the pupillary muscles and extraocular muscles. Disorders of ocular movement affect more than 40% of patients with MS.  Lesions can involve the brainstem, cerebellum or cranial nerves and result in ocular misalignment and symptoms of oscillopsia, nystagmus and diplopia. A condition termed internuclear ophthalmoplegia (INO) occurs with lesions in the medial longitudinal fasciculus (MLF), a highly myelinated tract between the paramedian pontine reticular formation (PPRF) of the abducting eye to the oculomotor nucleus of the contralateral adducting eye. This facilitates synchronous lateral gaze. Therefore, MLF lesions result in impaired conjugate adduction as well as nystagmus of the abducting eye.
Demographic information such as age, sex, race, country of origin and migration status is relevant as MS is more common in women ages 15-45 who are from areas of northern or southern hemispheres. Family history of MS is also relevant as there is a genetic predisposition to the disease. Recent stressors, viral infections, and the presence of sick contacts should also be explored.
MS is classically described as a condition in which neurologic symptoms vary in time and space. Because demyelination can have diffuse involvement within the CNS, patients often complain of a constellation of seemingly unrelated symptoms. In 75% of patients, the initial presentation of MS involves an isolated complaint—45% are motor or sensory and 20% are visual.  Therefore, a thorough review of systems is crucial, and should involve questions about loss of sensation, muscle weakness, pain, headaches, vision changes, impaired cognition, depression, and loss of bowel, bladder or sexual function.
It is equally important to elicit the onset, duration and temporal relationship of symptoms. Exacerbations or “flare-ups” can be acute or subacute in onset and typically last days to months. These episodes are usually transient, with improvement or even complete resolution of symptoms in 85% of cases. However, symptoms can worsen or become permanent in the remaining 10-15% of those affected. 
The neurologic exam can provide useful information regarding localization of the lesion(s), as well as severity and extent of involvement. The exam consists of the evaluation of cranial nerves, deep tendon reflexes, motor strength, sensation, gait, balance and coordination.
The ophthalmic examination should begin with inspection of the eyes for external ocular findings, range of extraocular muscle movement, pupillary changes, and erythema or inflammation. A slit lamp examination is important for visualization of internal eye structures, notably the optic disc. Other components of the ophthalmic exam involve tests for visual acuity, color vision, contrast sensitivity, afferent pupillary defects and visual field defects. In addition, the use of optical coherence tomography (OCT) and visual evoked responses (VER) can provide information about the extent of involvement and allow for quantitative measures for disease progression over time.
Signs and Symptoms
Neurologic signs and symptoms of MS can be autonomic, visual, motor or sensory. Changes in sensation can present as pain, numbness, tingling, or pins and needles sensation. Motor involvement manifests as muscle weakness, muscle spasms, impaired coordination and balance or difficulty with speech and swallowing. Autonomic symptoms include bowel dysfunction (diarrhea or constipation) and bladder dysfunction (urinary incontinence). Cognitive complaints in MS include fatigue, decreased attention span, concentration, memory, and judgment. Psychological symptoms include depression and mood instability. MS is associated with other clinical findings such as: Charcot triad of dysarthria, ataxia, and tremor; Uhthoff’s phenomenon of worsening of symptoms in higher temperatures; Lhermitte’s sign of an electrical sensation running down the back when the neck is flexed; and trigeminal neuralgia presenting as facial pain or weakness.
Ocular manifestations are common in MS. Up to 20% of patients have optic neuritis as the initial clinical presentation and 75% of patients have at least one episode throughout the course of their lives.  Optic neuritis associated with MS typically presents as a monocular painful vision loss that occurs over hours to days and lasts a few weeks. Changes in visual acuity can range from mild to severe; 10% of patients are 20/20, 25% are 20/30-20/40, 29% are 20/50-20/190 and 36% are 20/200 or worse.  Orbital pain occurs in 92% of patients and is usually worse with extraocular movement. Patients will also present with diminished color vision (dyschromatopsia in 88%, best assessed by red desaturation), diminished contrast sensitivity, visual field loss (most commonly central scotoma) and a relative afferent pupillary defect (RAPD). Slit lamp examination will reveal optic disc swelling in one-third of patients.  Papillitis is more common in postviral and infectious neuritis than demyelinating neuritis, but considerable overlap exists. Retinal nerve fiber layer (RNFL) thinning reflecting axonal damage is observed in about 70% of patients with acute optic neuritis, while visual evoked potential (VEP) increases in latency and decreases in amplitude are found in 65%. [15, 16]
Internuclear ophthalmoplegia occurs in about 30% of patients.  This condition presents with diplopia, nystagmus, and loss of depth perception (stereopsis) secondary to an adduction deficit or adduction lag on conjugate gaze. Other patterns of ocular misalignment include skew deviation, gaze paresis and impaired smooth pursuit.  Uveitis can occur in 1-2% of patients with MS, a rate that is 10 times more common than that of the general population.  Symptoms of uveitis include pain, photophobia, and conjunctival injection.
The 2010 revised McDonald Criteria is widely used for the clinical diagnosis of MS.  The criteria include the presence of two or more attacks involving two or more clinical lesions; two or more attacks of one clinical lesion with evidence for dissemination in space as demonstrated by MRI or CSF; one attack involving two or more lesions demonstrated by MRI or followed by a second attack; one attack of one lesion demonstrated by MRI, CSF or followed by a second attack. An attack is defined as any subjective or objective neurologic disturbance of 24-hour duration occurring 30 days apart, in the absence of fever or infection. MS is classified into four subtypes depending on its clinical course: relapsing-remitting (RRMS), secondary progressive (SPMS), primary progressive (PPMS), and progressive relapsing (PRMS).
Repeated episodes of demyelination result in the formation of plaques that are seen as hyperintense T2 lesions or post-gadolinium enhancement on magnetic resonance imaging (MRI). MRI of the head and spine is performed to evaluate for these demyelinating plaques in the periventricular, juxtacortical, infratentorial or spinal cord white matter. Optic neuritis in MS is typically seen as a unilateral T2 lesion of the optic nerve. Serial imaging is useful for comparing episodes and monitoring disease progression.
Lumbar punctures can be performed for evaluation of the CSF for oliclonal bands and intrathecal immunoglobulin G (IgG). In an atypical presentation of optic neuritis, suspicion for a non-MS cause should prompt additional laboratory testing. Atypical features include bilaterality, painless vision loss, lack of characteristic MRI findings, lack of response to corticosteroids, and presence of severe optic nerve head swelling or peripapillary hemorrhages.  The following laboratory tests should be considered given a patient’s history, risk factors and clinical findings:
- Antinuclear antibody (ANA) for systemic lupus erythematosus
- Angiotensin-converting enzyme (ACE) and lysozyme for sarcoidosis
- Venereal Disease Research Laboratories [VDRL], rapid plasma reagin [RPR] and fluorescent treponemal antibody (FTA-ABS) for syphilis
- Anti-aquaporin 4 [AQP4] IgG antibody for neuromyelitis optica (NMO)
- Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) for inflammatory disorders
- Tuberculin skin test, chest x-ray or Quantiferon-TB for tuberculosis
- Lyme titers for Lyme disease (in an endemic area)
The differential diagnosis for optic neuritis is broad, and accurate assessment is important for the proper treatment of the underlying etiology. [22, 23] They include:
- Inflammatory conditions: NMO or Devic’s disease, acute disseminated encephalomyelitis (ADEM), sarcoidosis
- Infections: Tuberculosis, Syphilis, Lyme and Bartonella
- Compressive lesions: orbital tumors or aneurysms
- Connective tissue or vascular diseases: lupus, granulomatosis with polyangiitis, Sjogrens, Behcet
- Nonarteritic anterior ischemic optic neuropathy (NAION)
- Severe systemic hypertension
- Acute papilledema from increased intracranial pressure
- Leber’s hereditary optic neuropathy (LHON)
- Optic nerve glioma
- Toxic or metabolic optic neuropathy: alcohol, malnutrition, ethambutol, heavy metals
- Central serous retinopathy or other maculopathies
There is no cure for MS. Management involves pharmacotherapy for immune modulation and symptomatic relief. The Optic Neuritis Treatment Trial (ONTT) has shown that high-dose intravenous methylprednisone improves recovery time for visual function, contrast sensitivity and color vision. However, corticosteroids have not been shown to improve final visual outcomes.  Intravenous immunoglobulin (IVIg) has not been shown to improve long-term visual acuity, contrast sensitivity or color vision.  Plasmapheresis may be used short term for severe attacks if steroids are contraindicated or ineffective.  Interfeon-beta and glatiramer acetate are generally used as first-line disease-modifying agents in MS, with relapse reduction rates of 18-34% in some trials.  Other FDA-approved disease-modifying drugs include fingolimod, teriflunomide, dimethyl fumarate, natalizumab and alemtuzumab.
Multiple sclerosis can have severe debilitating effects within 20-25 years of onset. Up to 30% of patients eventually require assistance for ambulation, and 22% become wheelchair bound.  There is a 5 to 10 year decrease in life expectancy, and death secondary to cardiovascular disease, infection and suicide is higher in MS compared to the general population. 
Many of the clinical findings of optic neuritis come from the Optic Neuritis Treatment Trial (ONTT), a multi-institutional study of 454 patients with acute unilateral optic neuritis carried out between 1988 and 1991. The 15-year follow-up of the Optic Neuritis Treatment Trial (ONTT) showed that clinically definite MS developed in 50% of ONTT patients in 15 years. However, the probability of developing clinically definite MS based on MRI scan appearance ranged from 25% for patients with no lesions on the brain MRI to 72% with 1 or more lesions.
Visual prognosis following the first episode of optic neuritis is typically good with or without the use of corticosteroids. Visual symptoms such as decreased visual acuity, visual field defects, and color vision defects recover within weeks to months. A majority of patients achieve 20/20 vision one year after an acute episode while 8% of patients retain a visual acuity worse than 20/40.  However, recurrent episodes are associated with less favorable prognosis.
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