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 |
A demyelinating disease refers to any disease affecting the nervous system where the myelin sheath surrounding neurons 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, including genetic 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 like sheep dip, weed killers, and flea treatment preparations for pets, which contain organophosphates, can also lead to nerve demyelination. [2] Chronic exposure to neuroleptic medications may also cause demyelination. [3] Furthermore, deficiencies in vitamin B12 can result in dysmyelination. [4] [5]
Demyelinating diseases are traditionally classified into two types: demyelinating myelinoclastic diseases and demyelinating 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] The Poser criteria named this second group dysmyelinating 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, specifically T-cells, are found at the site of lesions. Other immune system cells, such as macrophages (and possibly mast 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 the central nervous system (CNS) and those affecting the peripheral nervous system (PNS). They can also be classified by the presence or absence of inflammation. Finally, a division may be made based on the underlying cause of demyelination: the disease process can be demyelinating myelinoclastic, wherein myelin is destroyed; or dysmyelinating leukodystrophic, wherein myelin is abnormal and degenerative.
The demyelinating disorders of the central nervous system include:[ citation needed ]
The myelinoclastic disorders are typically associated with symptoms such as optic neuritis and transverse myelitis, because the demyelinating inflammation can affect the optic nerve or spinal cord. Many are idiopathic. Both myelinoclastic and leukodystrophic modes of disease may result in lesional demyelinations of the central nervous system.
The demyelinating diseases of the peripheral 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 brain thalamic stimulation (to ameliorate tremors). [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. [14] Life expectancy in MS patients is 5 to 10 years lower than unaffected people. [15] 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. [16] Other conditions such as central pontine myelinolysis have about a third of patients recover and the other two-thirds experience varying degrees of disability. [17] In some cases, such as transverse 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 as tabes dorsalis appear predominantly in males and begin in midlife. Optic neuritis, though, occurs preferentially in females typically between the ages of 30 and 35. [18] Other conditions such as multiple sclerosis vary in prevalence depending on the country and population. [19] This condition can appear in children and adults. [15]
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. [20] For example, COX-2 has been implicated in oligodendrocyte death in animal models of demyelination. [21] The presence of myelin debris has been correlated with damaging inflammation as well as poor regeneration, due to the presence of inhibitory myelin components. [22] [23]
N-cadherin is expressed in regions of active remyelination and may play an important role in generating a local environment conducive to remyelination. [24] N-cadherin agonists have been identified and observed to stimulate neurite growth and cell migration, key aspects of promoting axon growth and remyelination after injury or disease. [25]
Immunomodulatory drugs such as fingolimod have been shown to reduce immune-mediated damage to the CNS, preventing further damage in patients with MS. The drug targets the role of macrophages in disease progression. [26] [27]
Manipulating thyroid hormone levels may become a viable strategy to promote remyelination and prevent irreversible damage in MS patients. [28] It has also been shown that intranasal administration of apotransferrin (aTf) can protect myelin and induce remyelination. [29] Finally, electrical stimulation which activates neural stem cells may provide a method by which regions of demyelination can be repaired. [30]
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). [31] [32]
Myelin is a lipid-rich material that surrounds nerve cell axons to insulate them and increase the rate at which electrical impulses pass along the axon. The myelinated axon can be likened to an electrical wire with insulating material (myelin) around it. However, unlike the plastic covering on an electrical wire, myelin does not form a single long sheath over the entire length of the axon. Rather, myelin ensheaths the axon segmentally: in general, each axon is encased in multiple long sheaths with short gaps between, called nodes of Ranvier. At the nodes of Ranvier, which are approximately one thousandth of a mm in length, the axon's membrane is bare of myelin.
Optic neuritis describes any condition that causes inflammation of the optic nerve; it may be associated with demyelinating diseases, or infectious or inflammatory processes.
Multiple sclerosis (MS) is an autoimmune disease in which the insulating covers of nerve cells in the brain and spinal cord are damaged. Being a demyelinating disease, MS disrupts the ability of parts of the nervous system to transmit signals, resulting in a range of signs and symptoms, including physical, mental, and sometimes psychiatric problems. Symptoms include double vision, vision loss, eye pain, muscle weakness, and loss of sensation or coordination. MS takes several forms, with new symptoms either occurring in isolated attacks or building up over time. In relapsing forms of MS, between attacks, symptoms may disappear completely, although some permanent neurological problems often remain, especially as the disease advances. In progressive forms of MS, bodily function slowly deteriorates once symptoms manifest and will steadily worsen if left untreated.
Myelitis is inflammation of the spinal cord which can disrupt the normal responses from the brain to the rest of the body, and from the rest of the body to the brain. Inflammation in the spinal cord can cause the myelin and axon to be damaged resulting in symptoms such as paralysis and sensory loss. Myelitis is classified to several categories depending on the area or the cause of the lesion; however, any inflammatory attack on the spinal cord is often referred to as transverse myelitis.
Oligodendrocytes, also known as oligodendroglia, are a type of neuroglia whose main functions are to provide support and insulation to axons within the central nervous system (CNS) of jawed vertebrates. Their function is similar to that of Schwann cells, which perform the same task in the peripheral nervous system (PNS). Oligodendrocytes accomplish this by forming the myelin sheath around axons. Unlike Schwann cells, a single oligodendrocyte can extend its processes to cover around 50 axons, with each axon being wrapped in approximately 1 μm of myelin sheath. Furthermore, an oligodendrocyte can provide myelin segments for multiple adjacent axons.
Oligodendrocyte progenitor cells (OPCs), also known as oligodendrocyte precursor cells, NG2-glia, O2A cells, or polydendrocytes, are a subtype of glia in the central nervous system named for their essential role as precursors to oligodendrocytes and myelin. They are typically identified in the human by co-expression of PDGFRA and CSPG4.
Experimental autoimmune encephalomyelitis, sometimes experimental allergic encephalomyelitis (EAE), is an animal model of brain inflammation. It is an inflammatory demyelinating disease of the central nervous system (CNS). It is mostly used with rodents and is widely studied as an animal model of the human CNS demyelinating diseases, including multiple sclerosis (MS) and acute disseminated encephalomyelitis (ADEM). EAE is also the prototype for T-cell-mediated autoimmune disease in general.
Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired autoimmune disease of the peripheral nervous system characterized by progressive weakness and impaired sensory function in the legs and arms. The disorder is sometimes called chronic relapsing polyneuropathy (CRP) or chronic inflammatory demyelinating polyradiculoneuropathy. CIDP is closely related to Guillain–Barré syndrome and it is considered the chronic counterpart of that acute disease. Its symptoms are also similar to progressive inflammatory neuropathy. It is one of several types of neuropathy.
Multiple sclerosis is an inflammatory demyelinating disease of the CNS in which activated immune cells invade the central nervous system and cause inflammation, neurodegeneration, and tissue damage. The underlying cause is currently unknown. Current research in neuropathology, neuroimmunology, neurobiology, and neuroimaging, together with clinical neurology, provide support for the notion that MS is not a single disease but rather a spectrum.
Multiple sclerosis and other demyelinating diseases of the central nervous system (CNS) produce lesions and glial scars or scleroses. They present different shapes and histological findings according to the underlying condition that produces them.
Remyelination is the process of propagating oligodendrocyte precursor cells to form oligodendrocytes to create new myelin sheaths on demyelinated axons in the Central nervous system (CNS). This is a process naturally regulated in the body and tends to be very efficient in a healthy CNS. The process creates a thinner myelin sheath than normal, but it helps to protect the axon from further damage, from overall degeneration, and proves to increase conductance once again. The processes underlying remyelination are under investigation in the hope of finding treatments for demyelinating diseases, such as multiple sclerosis.
Inflammatory demyelinating diseases (IDDs), sometimes called Idiopathic (IIDDs) due to the unknown etiology of some of them, are a heterogenous group of demyelinating diseases - conditions that cause damage to myelin, the protective sheath of nerve fibers - that occur against the background of an acute or chronic inflammatory process. IDDs share characteristics with and are often grouped together under Multiple Sclerosis. They are sometimes considered different diseases from Multiple Sclerosis, but considered by others to form a spectrum differing only in terms of chronicity, severity, and clinical course.
Baló's concentric sclerosis is a disease in which the white matter of the brain appears damaged in concentric layers, leaving the axis cylinder intact. It was described by József Mátyás Baló who initially named it "leuko-encephalitis periaxialis concentrica" from the previous definition, and it is currently considered one of the borderline forms of multiple sclerosis.
Myelinogenesis is the formation and development of myelin sheaths in the nervous system, typically initiated in late prenatal neurodevelopment and continuing throughout postnatal development. Myelinogenesis continues throughout the lifespan to support learning and memory via neural circuit plasticity as well as remyelination following injury. Successful myelination of axons increases action potential speed by enabling saltatory conduction, which is essential for timely signal conduction between spatially separate brain regions, as well as provides metabolic support to neurons.
Gap junction beta-1 protein (GJB1), also known as connexin 32 (Cx32), is a transmembrane protein that in humans is encoded by the GJB1 gene. Gap junction beta-1 protein is a member of the gap junction connexin family of proteins that regulates and controls the transfer of communication signals across cell membranes, primarily in the liver and peripheral nervous system. However, the protein is expressed in multiple organs, including in oligodendrocytes in the central nervous system.
Tumefactive multiple sclerosis is a condition in which the central nervous system of a person has multiple demyelinating lesions with atypical characteristics for those of standard multiple sclerosis (MS). It is called tumefactive as the lesions are "tumor-like" and they mimic tumors clinically, radiologically and sometimes pathologically.
Diffuse myelinoclastic sclerosis, sometimes referred to as Schilder's disease, is a very infrequent neurodegenerative disease that presents clinically as pseudotumoural demyelinating lesions, making its diagnosis difficult. It usually begins in childhood, affecting children between 5 and 14 years old, but cases in adults are also possible.
Multiple sclerosis (MS) can be pathologically defined as the presence of distributed glial scars (scleroses) in the central nervous system that must show dissemination in time (DIT) and in space (DIS) to be considered MS lesions.
MOG antibody disease (MOGAD) or MOG antibody-associated encephalomyelitis (MOG-EM) is an inflammatory demyelinating disease of the central nervous system. Serum anti-myelin oligodendrocyte glycoprotein antibodies are present in up to half of patients with an acquired demyelinating syndrome and have been described in association with a range of phenotypic presentations, including acute disseminated encephalomyelitis, optic neuritis, transverse myelitis, and neuromyelitis optica.
Anti-neurofascin demyelinating diseases refers to health conditions engendered by auto-antibodies against neurofascins, which can produce both central and peripheral demyelination. Some cases of combined central and peripheral demyelination (CCPD) could be produced by them.