| Demyelinating disease | |
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| Photomicrograph of a demyelinating MS-lesion:Immunohistochemical staining for CD68 highlights numerous macrophages (brown). Original magnification 10×. | |
| Specialty | Neurology  |
Ademyelinating disease refers to anydisease affecting thenervous system where themyelin sheath surroundingneurons is damaged.[1] This damage disrupts the transmission of signals through the affected nerves, resulting in a decrease in their conduction ability. Consequently, this reduction in conduction can lead to deficiencies in sensation, movement, cognition, or other functions depending on the nerves affected.
Various factors can contribute to the development of demyelinating diseases, includinggenetic predisposition,infectious agents,autoimmune reactions, and other unknown factors. Proposed causes of demyelination include genetic predisposition, environmental factors such as viral infections or exposure to certain chemicals. Additionally, exposure to commercial insecticides likesheep dip,weed killers, and flea treatment preparations for pets, which containorganophosphates, can also lead to nerve demyelination.[2] Chronic exposure toneuroleptic medications may also cause demyelination.[3] Furthermore, deficiencies invitamin B12 can result in dysmyelination.[4][5]
Demyelinating diseases are traditionally classified into two types:demyelinating myelinoclastic diseases anddemyelinating leukodystrophic diseases. In the first group, a healthy and normal myelin is destroyed by toxic substances, chemicals, or autoimmune reactions. In the second group, the myelin is inherently abnormal and undergoes degeneration.[6] ThePoser criteria named this second groupdysmyelinating diseases.[7]
In the most well-known demyelinating disease,multiple sclerosis, evidence suggests that the body's immune system plays a significant role.Acquired immune system cells, specificallyT-cells, are found at the site of lesions. Other immune system cells, such asmacrophages (and possiblymast cells), also contribute to the damage.[8]
Symptoms and signs that present in demyelinating diseases are different for each condition. These symptoms and signs can present in a person with a demyelinating disease:[9]
The role of prolonged cortical myelination in human evolution has been implicated as a contributing factor in some cases of demyelinating disease. Unlike other primates, humans exhibit a unique pattern of postpubertal myelination, which may contribute to the development of psychiatric disorders and neurodegenerative diseases that present in early adulthood and beyond. The extended period of cortical myelination in humans may allow greater opportunities for disruption in myelination, resulting in the onset of demyelinating disease.[10] Furthermore, humans have significantly greater prefrontal white matter volume than other primate species, which implies greater myelin density.[11] Increased myelin density in humans as a result of a prolonged myelination may, therefore, structure risk for myelin degeneration and dysfunction. Evolutionary considerations for the role of prolonged cortical myelination as a risk factor for demyelinating disease are particularly pertinent given that genetics and autoimmune deficiency hypotheses fail to explain many cases of demyelinating disease. As has been argued, diseases such as multiple sclerosis cannot be accounted for by autoimmune deficiency alone, but strongly imply the influence of flawed developmental processes in disease pathogenesis.[12] Therefore, the role of the human-specific prolonged period of cortical myelination is an important evolutionary consideration in the pathogenesis of demyelinating disease.[citation needed]
Various methods/techniques are used to diagnose demyelinating diseases:
Demyelinating diseases can be divided in those affecting thecentral nervous system (CNS) and those affecting theperipheral nervous system (PNS). They can also be classified by the presence or absence ofinflammation. Finally, a division may be made based on the underlying cause of demyelination: the disease process can bedemyelinating myelinoclastic, wherein myelin is destroyed; ordysmyelinating leukodystrophic, wherein myelin is abnormal and degenerative.
The demyelinating disorders of thecentral nervous system include:[citation needed]
The myelinoclastic disorders are typically associated with symptoms such asoptic neuritis andtransverse myelitis, because the demyelinating inflammation can affect theoptic nerve orspinal cord. Many areidiopathic. Both myelinoclastic and leukodystrophic modes of disease may result inlesional demyelinations of the central nervous system.
The demyelinating diseases of theperipheral nervous system include:[citation needed]
Treatments are patient-specific and depend on the symptoms that present with the disorder, as well as the progression of the condition. Improvements to the patient's life may be accomplished through the management of symptoms or slowing of the rate of demyelination. Treatment can include medication, lifestyle changes (i.e. smoking cessation, increased rest, and dietary changes), counselling, relaxation, physical exercise, patient education, and in some cases, deep brainthalamic stimulation (to amelioratetremors).[13]: 227–248
Prognosis depends on the condition itself. Some conditions such as MS depend on the subtype of the disease and various attributes of the patient such as age, sex, initial symptoms, and the degree of disability the patient experiences.[15] Life expectancy in MS patients is 5 to 10 years lower than unaffected people.[16] MS is an inflammatory demyelinating disease of the central nervous system (CNS) that develops in genetically susceptible individuals after exposure to unknown environmental trigger(s). The bases for MS are unknown but are strongly suspected to involve immune reactions against autoantigens, particularly myelin proteins. The most accepted hypothesis is that dialogue between T-cell receptors and myelin antigens leads to an immune attack on the myelin-oligodendrocyte complex. These interactions between active T cells and myelin antigens provoke a massive destructive inflammatory response and promote continuing proliferation of T and B cells and macrophage activation, which sustains secretion of inflammatory mediators.[17] Other conditions such ascentral pontine myelinolysis have about a third of patients recover and the other two-thirds experience varying degrees of disability.[18] In some cases, such astransverse myelitis, the patient can begin recovery as early as 2 to 12 weeks after the onset of the condition.[citation needed]
Incidence of demyelinating diseases varies by disorder. Some conditions, such astabes dorsalis appear predominantly in males and begin in midlife.Optic neuritis, though, occurs preferentially in females typically between the ages of 30 and 35.[19] Other conditions such as multiple sclerosis vary in prevalence depending on the country and population.[20] This condition can appear in children and adults.[16]
Much of the research conducted on demyelinating diseases is targeted towards discovering the mechanisms by which these disorders function in an attempt to develop therapies and treatments for individuals affected by these conditions. For example,proteomics has revealed several proteins which contribute to the pathophysiology of demyelinating diseases.[21]For example,COX-2 has been implicated inoligodendrocyte death in animal models of demyelination.[22]The presence of myelin debris has been correlated with damaging inflammation as well as poor regeneration, due to the presence of inhibitory myelin components.[23][24]
N-cadherin is expressed in regions of active remyelination and may play an important role in generating a local environment conducive to remyelination.[25] N-cadherinagonists have been identified and observed to stimulateneurite growth and cell migration, key aspects of promoting axon growth and remyelination after injury or disease.[26]
Immunomodulatory drugs such asfingolimod have been shown to reduce immune-mediated damage to the CNS, preventing further damage in patients with MS. The drug targets the role ofmacrophages in disease progression.[27][28]
Manipulatingthyroid hormone levels may become a viable strategy to promote remyelination and prevent irreversible damage in MS patients.[29]It has also been shown thatintranasal administration ofapotransferrin (aTf) can protect myelin and induce remyelination.[30]Finally, electrical stimulation which activatesneural stem cells may provide a method by which regions of demyelination can be repaired.[31]
Demyelinating diseases/disorders have been found worldwide in various animals. Some of these animals include mice, pigs, cattle, hamsters, rats, sheep, Siamese kittens, and a number of dog breeds (including Chow Chow, Springer Spaniel, Dalmatian, Samoyed, Golden Retriever, Lurcher, Bernese Mountain Dog, Vizsla, Weimaraner, Australian Silky Terrier, and mixed breeds).[32][33]
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