Neurodegeneration

Inflammation and Neurodegeneration

The pathogenesis of multiple sclerosis (MS) can be described as 2 separate but interrelated (and often overlapping) phases of inflammation and neurodegeneration. It's been shown that acute relapses in MS result from acute inflammatory axonal demyelination, whereas disease progression reflects neurodegenerative processes such as axonal/neural damage or brain atrophy. The Clinician's Primer on Multiple Sclerosis Immunology and the Basic Mechanisms of Action of Pharmacological and Therapeutic Agents noted that evidence indicates a major role of the innate and adaptive immune systems in the inflammatory phase of MS, and growing evidence also supports significant involvement of immunological factors and cells in the neurodegenerative phase.

Inflammation

Inflammation in MS is mediated by cytokine and chemokine production by T cells infiltrating the central nervous system (CNS). The number of T cells in peripheral blood that react to myelin are similar in healthy individuals and those with MS, but there are important qualitative differences. In MS, T cells possess a memory or activated phenotype compared with a naive phenotype in healthy persons. Myelin-specific T cells in MS are more reactive and inflammatory in relation to specific chemokine receptors and cytokines released.

Neurodegeneration

Although axonal damage has been recognized as a feature of MS lesions, the most prominent pathological findings and concept of disease mechanism seemed related to myelin. The last 20 years provided an understanding of axonal damage that's evolved as a result of studies showing early axonal pathology in MS, detected using advanced MRI techniques and immunostaining for markers of axonal damage. It's been shown that a correlation exists between axonal transection and the degree of inflammation in white-matter lesions undergoing demyelination.

Axonal loss continues constantly during a course of MS, with more than 80% loss in come chronic lesions and is associated with whole-brain atrophy and long-term disability. Evidence of neurodegeneration contributed to the newer standard in the diagnosis of MS and initiation of treatment as early as possible.

Although findings of early axonal damage challenge the concept of axonal loss as a secondary phase of the disease related to inflammation and demyelination. Because of this, some feel that the relationship between inflammation and neurodegeneration shows that there is little evidence that MS is an autoimmune disease caused by an immune response to an environmental trigger. They instead feel that MS may be a primary degenerative disease with secondary immune responses and inflammatory demyelination.

Lesion / Plaque Formation

Lesion or plaque development is believed to originate from peripheral activation of cells specific for myelin antigens in genetically susceptible individuals. This type of activation allows them to be able to enter the normally immunologically protected CNS because of changes in the blood brain barrier (BBB). Activated T cells are able to now enter the CNS and are reactivated when they recognize myelin antigens on the surface of antigen presenting cells (APCs). This in turn triggers proinflammatory cytokine release and events leading to the formation of an inflammatory demyelinating lesion begin.

Heterogeneous pathology of the last 20 years has identified 4 distinct types of lesions based on the type of myelin involved and other specifics as noted in the Clinician's Primer.

Type 1 Lesions
20% - These lesions showed infiltration by T cells, macrophages, and macrophage-related products, with macrophage-related demyelination and equal loss of all myelin antigens.

Type 2 Lesions
50% - The most common, these lesions were similar to Type 1 but were also characterized by deposition of immunoglobulin (Ig) and complement.

Type 3 Lesions
25% - These showed that there was T cell and macrophage infiltration and loss of (MAG) with no remyelination; oligodendroglia apoptosis was extensive suggesting a hypoxic or viral etiology.

Type 4 Lesions
Rare, these lesions are characterized by oligodendrocyte toxicity.

Although typically presented as one type of lesion, it has been reported that individual patients have had more than one type of lesion.

Brain Lesions

A lesion is an area of tissue that has been damaged through injury or disease. Therefore, a brain lesion is an area of injury or disease within the brain. While the definition sounds simple, understanding brain lesions can be complicated. That's because there are many types of brain lesions. They can range from small to large, from few to many, from relatively harmless to life threatening.

Brain lesions can be caused by injury, infection, exposure to certain chemicals, problems with the immune system, and more. Typically, their cause is unknown.

There are many different types of brain lesions. Now although they may be basically an injury or damage to tissue within the brain, but brain lesions vary greatly.

Common brain lesions include:

Abscesses
Brain abscesses are areas of infection, including pus and inflamed tissue. They are not common, but they are life threatening. Brain abscesses often occur after an infection, usually in a nearby area, such as an ear, sinus, or dental infection. They can also appear after injury or surgery to the skull.

Arteriovenous malformations (AVMs)
An AVM is a type of brain lesion that occurs during early development. Arteries and veins in the brain grow in a tangle and become connected by tube-like structures called fistulae. The arteries are not as strong as normal arteries. The veins are often enlarge because of the constant flow of blood directly from the arteries through the fistulae to the veins. These fragile vessels may rupture, leaking blood into the brain. In addition, the brain tissue may not receive enough blood to function properly. Damage to the brain may cause seizures as the first symptoms of an AVM.

Cerebral infarction
Infarction refers to death of tissue. A cerebral infarction, or stroke, is a brain lesion in which a cluster of brain cells die when they don't get enough blood.

Cerebral palsy
This type of brain lesion occurs when a baby is still in the mother's womb. Cerebral palsy does not progress over time. The brain lesions affect the child's ability to move, which can also make communication and related skills difficult. However, many children with cerebral palsy have normal intellectual functioning.

Multiple sclerosis (MS)
With this condition, the immune system attacks and damages the nerve linings (myelin) in the brain and spinal cord. These lesions make it difficult for messages to be sent and received properly between the brain and the rest of the body.

Tumors
Tumors are clumps of cells that grow abnormally from normal tissue. Some tumors in the brain are noncancerous, or benign. Others are cancerous. They may start in the brain, or they may spread from elsewhere in the body (metastatic). They may grow quickly or they may remain stable.

The methods used to find and diagnose brain lesions depend on the symptoms. In many cases, CT and MRI imaging studies help pinpoint the location, size, and characteristics of the lesions. Blood and other lab tests may also be done to look for signs of infection.

Treatment depends on the type of brain lesion. The goals of treatment may be to provide a cure, relieve symptoms, or improve the quality or length of life.

Common approaches for treating brain lesions include the following:

•	"Wait and see;" if the lesion is not causing problems and is not growing, you may only need periodic checkups.
•	Surgical removal of the lesion, if possible; new surgical techniques may make it possible to remove even hard-to-reach lesions.
•	Chemotherapy and radiation therapy for lesions that are cancerous
•	Medication to fight infections, such as antibiotics or other antimicrobial drugs
•	Medication to calm the immune system or otherwise change the immune system's response
•	Medication or other therapies to relieve symptoms associated with the brain lesion