Sclerosis, Multiple

Article Author:
Moavia Ehsan
Article Editor:
Kathryn Xixis
10/27/2018 12:31:44 PM
PubMed Link:
Sclerosis, Multiple


Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) characterized by chronic inflammation, demyelination, gliosis, and neuronal loss. The course may be relapsing-remitting or progressive in nature. Lesions in the CNS occur at different times and in different CNS locations. Because of this, multiple sclerosis lesions are sometimes said to be "disseminated in time and space." The clinical course of the disease is quite variable ranging from a stable chronic disease to a rapidly evolving and debilitating illness. The most common form of the disease is relapsing-remitting multiple sclerosis; however, several other forms exist.


The specific cause of multiple sclerosis is unknown. The most widely accepted theory is that multiple sclerosis is an autoimmune disease that preferentially destroys the CNS while the peripheral nervous system is spared. Demyelination causes the symptoms of multiple sclerosis. Damage to myelin, the protective fatty tissue around the nerves that aids conduction of impulses along the nerves, leads to symptomatic flares in multiple sclerosis. These damaged areas often do not fully recover leading to areas of scarring, damage, and ongoing symptoms.  Over time, these cumulative areas of damage can lead to disability. Of note, patients can also develop subclinical areas of damage that are detectable early in the disease course only by radiographic studies.


Approximately 350,000 individuals in the United States and 2.5 million individuals worldwide have multiple sclerosis. The disease is 3-fold more common in females than in males. While the age of onset is usually between 20 to 40 years, the disease can present at any age. Almost 10% of the cases present before the age of 18.

Classically, multiple sclerosis is more common in populations who live farther from the equator. The highest prevalence of multiple sclerosis is found in Orkney islands north of Scotland. In other temperate areas like North America, northern Europe, southern Australia and southern New Zealand the prevalence of the multiple sclerosis is significantly higher than in areas closer to the equator.

A variety of risk factors for multiple sclerosis have been suggested. In addition to increasing risk with increasing distance from the equator, genetic associations, sunlight exposure, vitamin-D levels, tobacco smoking, viral transmission, and other theories have been evaluated.  No theory has been proven.


Early lesions of multiple sclerosis show mononuclear infiltrate with perivenular cuffing and surrounding white matter infiltration. The blood-brain barrier is disrupted at inflammatory sites. However, the vessel wall is preserved. The humoral immune system may also play a significant role in disease pathogenesis as evident by the presence of B-cells at active sites. The pathological hallmark of multiple sclerosis is demyelination which is often the earliest sign noted in affected neurons. Oligodendrocyte precursor cells usually survive and are often present in greater number when compared to the surrounding normal tissue, but, these cells fail to differentiate into mature oligodendrocytes. In some lesions, there is partial remyelination of surviving neurons, known as shadow plaques. With the evolution of a lesion, astrocytes proliferate resulting in gliosis.

Myelin is known to aid in the conduction of nerve impulses. Because multiple sclerosis is a demyelinating disease resulting in damage to this myelin, conduction speed is often slowed along affected nerves leading to the symptoms seen in multiple sclerosis.


When hematoxylin and eosin (HE) stain is done, the plaques of multiple sclerosis appear pale when compared to normal white matter. Active lesions are also cellular as they contain inflammatory cells like macrophages, lymphocytes, and astrocytes. Often, activity is confined to the borders of the plaques and myelin staining shows complete loss of myelin or palor of the myelin sheaths. The inflammatory cells of the lesions include CD8 T lymphocytes, macrophages, microglia, and astrocytes. B lymphocytes, plasma cells, antibodies, and complement proteins have also been identified in the lesions. Lesions are most frequently found in the periventricular white matter, optic nerves, and the spinal cord in multiple sclerosis.  Lesions in the periventricular white matter often caused "Dawson's fingers."

History and Physical

The presentation of multiple sclerosis is variable. Classic presentations include sensory changes, weakness, or visual changes. The most common presenting symptoms are unilateral sensory disturbances. Unilateral visual changes, often in the form of optic neuritis, are also quite common.

Often patients will present with a history of sensory, weakness, or visual changes which have occurred and resolved. Because symptoms often resolve without specific medical intervention, patients may have a history of several different events prior to presenting for formal medical evaluation.

As stated, sensory changes are common. These can affect any part of the body but are often unilateral. Likewise, weakness may affect any part of the body. Optic neuritis presents with decreased visual activity, dimness of vision, and decreased color perception known as red desaturation. Abnormality of the affected pupil to respond to light called afferent pupillary defect is often seen in cases of optic neuritis. Another common visual complaint is of abnormal eye movement known as internuclear ophthalmoplegia (INO). Patients often complain of diplopia. INO results from a demyelinating lesion of the medial longitudinal fasciculus.

Patients with a history of demyelinating damage may state that symptoms worsen in extreme heat. This is known as Uthoff's phenomenon. Patients may also complain of electrical sensation moving through the spine and limbs. This is known as Lhermitte's sign.

Multiple sclerosis is a complex disease. In addition to sensory changes, weakness, and visual changes, coordination problems or spasticity can be seen. Other complaints related to general health include bladder and bowel dysfunction, cognitive impairment, depression, fatigue, sexual dysfunction, sleep problems, and vertigo.


The diagnosis of multiple sclerosis is a clinical diagnosis. No one test is diagnostic for the disease. Evidence of lesions which have occurred at different times in different locations must be found. This evidence can be clinical or radiographic. When evaluating clinical flares, flares are traditionally defined as symptoms that last for at least 24 hours. The McDonald Criteria is a set of criteria outlining different ways that a patient can meet the criteria for a definite diagnosis of multiple sclerosis.

MRI is the radiologic study of choice. MRI should be completed with and without contrast to help differentiate old lesions from new, active lesions. Cerebrospinal fluid (CSF) analysis may be helpful in pointing toward a diagnosis of multiple sclerosis. Specifically, the presence of oligoclonal bands present in the cerebrospinal fluid which are not present in the serum is concerning for an underlying diagnosis such as multiple sclerosis. It is important to evaluate for other mimickers of multiple sclerosis as well. These include a wide variety of other neurologic diseases, rheumatologic diseases, and infectious diseases.

Treatment / Management

At least partial recovery from acute exacerbations or flares is expected. However, as discussed above, repair of damaged myelin may be incomplete.

Flares are often treated with steroids. Steroids lead to a faster recovery from an acute attack but do not change the ultimate extent of recovery. Furthermore, steroids do not prevent future attacks.

The primary goal in the treatment of multiple sclerosis is to prevent areas of damage by using maintenance therapies. Early maintenance therapies were injectables and first became available in the 1990s. Rapid growth has occurred in this area in the past several years with injection therapies, oral therapies, and infusion therapies now available. Therapies have largely targeted relapsing-remitting multiple sclerosis, the most common form of the disease. However, in 2017, the first therapy was approved for another form of the disease, primary progressive.

Differential Diagnosis

The differential diagnosis for multiple sclerosis is broad. Other related neurologic diseases such as neuromyelitis optica must be ruled out. A wide variety of rheumatologic diseases and infectious diseases must also be screened for when a diagnosis of multiple sclerosis is considered.