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Overview

Definition of Myelitis

Myelitis involves the infection or the inflammation of white matter or gray matter of spinal cord which is a part of central nervous system that acts as a bridge between a brain and the rest of a body. During an inflammatory response on the spinal cord, the myelination and axon may be damaged causing symptoms such as paralysis and sensory loss. Myelitis is classified to several categories depending on the area or the cause of the lesion; However, people often refer any inflammatory attack on spinal cord to transverse myelitis.

Types of Myelitis

Myelitis lesions usually occur in a narrow region but can be spread and affect many areas.

Poliomyelitis^[1]: disease caused by viral infection in the gray matter with symptoms of muscle paralysis or weakness
Leukomyelitis: a lesion in the white matter
Transverse Myelitis: caused by axonal demyelination encompassing both sides of the spinal cord
Meningococcal Myelitis (or meningomyelitis): lesions occurring in the regions of meninges and the spinal cord

Symptoms

Depending on the cause of the disease, such clinical conditions manifest different speed in progression of symptoms in a matter of hours to days. Most of myelitis manifests fast progression in muscle weakness or paralysis starting with the legs and then arms with varying degrees of severity. Sometimes the dysfunction of arms or legs cause instability of a posture and difficulty in walking or any movement. Also symptoms generally include paresthesia which is a sensation of tickling, tingling, burning, pricking, or numbness of a person's skin with no apparent long-term physical effect. Adult patients often report pain in the back, extremities, or abdomen. ^[2] Patients also present increased urinary urgency, bowel or bladder dysfunctions such as bladder incontinence, difficulty or inability to void, and incomplete evacuation of bowel or constipation. Others also report fever, respiratory problems and intractable vomiting.^[3]

Cause

Myelitis occurs due to various reasons such as infections. Direct infection by viruses, bacteria, mold, or parasites such as human immunodeficiency virus (HIV), human T cell lymphotropic virus types I and II (HTLV-I/II), syphilis, and tuberculosis can cause the myelitis but it can also be caused due to non-infectious or inflammatory pathway. Myelitis often follows after the infections or after vaccination. These phenomena can be explained by a theory of autoimmune attack which states that the autoimmune bodies attack its spinal cord in response to immune reaction.

Mechanism of Myelitis

The theory of autoimmune attack claims that a person with neuroimmunologic disorders have genetic predisposition to auto-immune disorder, and the environmental factors would trigger the disease. The specific genetics in myelitis is not completely understood. It is believed that the immune system response could be to viral, bacterial, fungal, or parasitic infection; however, it is not known why the immune system attacks itself. Especially, for immune system to cause inflammatory response anywhere in the central nervous system, the cells from immune system must pass through the blood brain barrier. In the case of myelitis, not only does the immune system is dysfunctional, but it also crosses this protective blood brain barrier to affect the spinal cord.^[4]

Infectious Myelitis^[5]

Viral Myelitis

Most viral myelitis are actue, but the retrovirus (HIV, HTLV) can cause chronic myelitis. [[Poliomyelitis, or gray matter myelitis, is usually caused by infection of anterior horn of the spinal cord by the enteroviruses (polioviruses, enteroviruses 70 and 71, echoviruses, coxsackieviruses A and B) and the flaviviruses (West Nile, Japanese enchephalitis, tick-borne encephalitis). On the other hand, transverse myelitis or leukomyelitis, or white matter myelitis, are often caused by the herpesviruses and influenza virus. It can be due to direct viral invasion or via immune mediated mechanisms.

Bacterial Myelitis

Bacterial myelitis include Mycoplasma Pneumoniae, which is a common agent for respiratory tract. Studies have shown respiratory tract infections within 4-39 days prior to the onset of transverse myelitis. Or, tuberculosis, syphilis, and brucellosis are also known to cause myelitis in immunocompromised individuals. Thus myelitis is rare manifestation of bacterial infection.

Fungal Myelitis

Fungi have been reported to cause spinal cord disease either by forming abscesses inside the bone or by granuloma. In general there are two groups of fungi that may infect the CNS and cause myelitis - Primary and Secondary pathogens. Primary pathogens include following: Cryptococcus neoformans, Coccidiodes immitis, Blastomyces drmatitides, Hystoplasma capsulatum; Secondary pathogens are opportunistic agens that primarily infect immunocompromised hosts such as candida species, aspergillus species, and zygomycetes.

Parasitic Myelitis

Parasitic species infect human hosts through larvae that penetrate the skin. Then they enter the lymphatic and circulatory ststem, and migrate to liver and lung. Some reach the spinal cord. Parasitic infections have been reported with Schistosoma species, Toxocara canis, Echinococcus species, Taenia solium, Trichinella spiralis, and Plasmodium species.

Diseases Associated With Myelitis

Demyelinating diseases such as relatively common multiple sclerosis and Devic's disease is known to be causing myelitis. Moreover, autoimmune connective tissue disease such as lupus, antiphospholipid antibody syndrome, and paraneoplastic also cause the myelitis. Other reasons are not discovered yet but usually related to immune disorder.

Acute disseminated encephalomyelitis: autoimmune demyelination of the brain manifesting altered level of consciousness, acute cognitive dysfunction, behavioral changes, and seizures
Multiple Sclerosis: demyelination of the brain and spinal cord
Neuromyelitis optica or Devic's disease: immune attack on optic nerve and spinal cord
Sjögren's syndrome: immune cell destroying the exocrine system of the body
Systemic lupus erythematosus: a systemic autoimmune disease manifesting variety of neurological symptoms such as headaches, depression, seizures, cognitive dysfunction, mood disorder, cerebrovascular disease, polyneuropathy, anxiety disorder, psychosis.
Sarcoidosis^[6]: chronic inflammatory cells form as nodules in multiple organs
Atopy dermatitis, known as eczema: It is prevalent immune disorder in children that is reported to be related to atopy in eastern asian countries such as Japan and Korea. Atopy is characterized by enhanced IgE responses to such common environmental antigens as pollens, foods and house dust mites, and it generally is an underlying mechanism for allergic rhinitis, asthma and dermatitis.^[7] Atopic myelitis show distinctive features such as younger age at onset, non-acute onset and long duration of symptoms at admission, predominant sensory symptoms with mild weakness. ^[8]

There are other associated disease usually that causes the myelitis.

Diagnosis

Myelitis has an extensive differential diagnosis. The type of onset (acute versus subacute/chronic) along with associated symptoms such as the presence of pain, constitutional symptoms that encompass fever, malaise, weight loss or a cutaneous rash may help identify the the cause of myelitis. In order to establish a diagnosis of myelitis, One has to localize the spinal cord level, and exclude cerebral and neuromuscular diseases. Also a detailed medical history, a careful neurologic examination, and imaging studies using magnetic resonance imaging (MRI) are needed. In respect to the etiology of the process, further work-up would help identify the cause and guide treatment. Full spine MRI is warranted, especially with acute onset myelitis, to evaluate for structural lesions that may require surgical intervention, or disseminated disease. ^[9] Adding gadolinium further increases diagnostic sensitivity. A brain MRI may be needed to identify the extent of central nervous system (CNS) involvement. Lumbar puncture is important for the diagnosis of acute myelitis when a tumoral process, inflammatory or infectious etiology are suspected, or the MRI is normal or non-specific. Complementary blood tests are also of value in establishing a firm diagnosis. Rarely, a biopsy of a mass lesion may become necessary when the etiology is uncertain. However, in 15–30% of patients with subacute or chronic myelitis, a clear etiology is never uncovered and their condition is considered idiopathic.^[5]

Treatment

Since each cases are differnet, the followings are possible treatments that patient might receive in the management of myelitis.

Intravenous Steroids
Plasma Exchange (PLEX)^[10]
Immunosupressants/Immunomodulatory Agents

Myelitis with no definite cause seldom arises a recurrence, but for others, myelitis may be a manifestation of another diseases that are mentioned above. In these cases, ongoing treatment with medications that modulate or suppress immune system may be necessary. Or, sometimes there is no specific treatment. Either way, aggressive rehabilitation and long-term symptom management are an integral part of the healthcare plan.

Prospective Research Direction

Central Nervous System Nerve Regeneration would be able to repair or regenerate the damages that were done on the spinal cord. It would restore functions that were lost due to the disease. ^[11]

Engineering Endogenous Repair

Currently, there exist a hydrogel based scaffolds which act as a channel which delievers nerve growth enhancing substrates while providing stuructural support. These factors would promote nerve repairs to the target area. Hydrogels' macroporous properties would enable attachment of cells and enhance ion and nutrient exchange. In addition, hydrogels' biodegradable or bioresorbable would prevent the need for surgical removal of the hydrogel after drug delivery. It means that it would be dissolved naturally due to body's enzymatic reaction.

Biochemical Repair

Neurotrophic Factor Therapy and Gene Therapy Neurotrophic growth factors regulate growth, survival, and plasticity of axon. It benefits nerve regenration after injury to the nervous system. They are a potent initiator of sensory axon growth and is upregulated at the lesion site. The continuous delivery of neurotrophic growth factor (NGF) would increase the nerve regenration in the spinal cord. However, the excessive dosing of NGF often leads to undesired plasticity and sprouting of uninjured sensory nerves. Gene therapy would be able to increase the NGF efficacy by the controlled and sustained delivery in a site-specific manner.

Stem Cell Based Therapies

The possibility for nerve regenration after injury to the spinal cord was considered to be limited because of the absence of major neurogenesis. However, Joseph Altman showed that cell division does occur in the brain which allowed the potential of stem cell therapy for nerve regenration.^[12]^[13]. The stem cell based therapies are used in order to replace the lost and injured cell due to inflmmation, to modulate immune system, and to enhance regenration and remyelination of axons.^[14] Neural stem cells (NSC) have the potential to integrate to the spinal cord because they are investigated in the recent past demonstrating their potential for differentiation into multiple cell types that are crucial to spinal cord. Studies show that NSCs that were transplanted into a demyelinating spinal cord lesion were found to regenrate oligodendrocytes and [[Schwann cells], and completely remyelinated axons.^[15]

References

^ Kelly, H. (2006). Evidence for a causal association between oral polio vaccine and transverse myelitis: A case history and review of the Literature. Journal Of Paediatrics And Child Health, 42(4), 155-159.
^ Thomas, M., & Thomas, J. (1997). Acute transverse myelitis. The Journal Of The Louisiana State Medical Society: Official Organ Of The Louisiana State Medical Society, 149(2), 75-77.
^ Wasay, M., Arif, H., Khealani, B., & Ahsan, H. (2006). Neuroimaging of tuberculous myelitis: analysis of ten cases and review of literature. Journal Of Neuroimaging: Official Journal Of The American Society Of Neuroimaging, 16(3), 197-205.
^ http://myelitis.org
^ ^a ^b Mihai, C., & Jubelt, B. (2012). Infectious myelitis. Curr Neurol Neurosci Rep, 12(6), 633-641. doi: 10.1007/s11910-012-0306-3
^ Baum, J., Solomon, M., & Alba, A. (1981). Sarcoidosis as a cause of transverse myelitis: case report. Paraplegia, 19(3), 167-169.
^ Stenius, B., Wide, L., Seymour, W.M., Holford-Strevens, V. and Pepys, J. (1971) Clinical significance of specific IgE to common allergens. I. Relationship of specific IgE against Dermatophagoides spp. and grass pollen to skin and nasal tests and history. Clin. Allergy, 1: 37–55
^ Yoon, J. H., Joo, I. S., Li, W. Y., & Sohn, S. Y. (2009). Clinical and laboratory characteristics of atopic myelitis: Korean experience. Journal of the Neurological Sciences, 285(1-2), 154-158. doi: 10.1016/j.jns.2009.06.033
^ Kitley, J., Leite, M., George, J., & Palace, J. (2012). The differential diagnosis of longitudinally extensive transverse myelitis. Multiple Sclerosis (Houndmills, Basingstoke, England), 18(3), 271-285.
^ Scott, T., Frohman, E., De Seze, J., Gronseth, G., & Weinshenker, B. (2011). Evidence-based guideline: clinical evaluation and treatment of transverse myelitis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology, 77(24), 2128-2134.
^ Karumbaiah, L., Bellamkonda, R. . Neural Tissue Engineering.
^ Altman J, Das GD (1965) Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol 124(3):319-335
^ Reynolds BA, Weiss S (1992) Generation of neurons and astrocytes from isolated cells from the adult mammalian central nervous system. Science 255(5052):1707-1710
^ Rowland JW, Hawryluk GW, Kwon B, Fehlings MG (2008) Current stauts of actue spinal cord injury pathophysiology and emerging therapies: promise on the horizon. Neurosurg Focus 25(5):E2
^ Keirstead HS, Ben-Hur T, Rogister B, O'Leary MT, Dubois-Dalcq M, Blakemore WF (1999) Polysialylated neural cell adhesion molecule-positive CNS precursors generate both oligodendrocytes and Schwann cells to remyelination the CNS after transplantation. J Neurosci 19(17):7529-7536

[1] Kelly, H. (2006). Evidence for a causal association between oral polio vaccine and transverse myelitis: A case history and review of the Literature. Journal Of Paediatrics And Child Health, 42(4), 155-159.

[2] Thomas, M., & Thomas, J. (1997). Acute transverse myelitis. The Journal Of The Louisiana State Medical Society: Official Organ Of The Louisiana State Medical Society, 149(2), 75-77.

[3] Wasay, M., Arif, H., Khealani, B., & Ahsan, H. (2006). Neuroimaging of tuberculous myelitis: analysis of ten cases and review of literature. Journal Of Neuroimaging: Official Journal Of The American Society Of Neuroimaging, 16(3), 197-205.

[4] ttp://myelitis.org

[Infectious_myelitis-5] Mihai, C., & Jubelt, B. (2012). Infectious myelitis. Curr Neurol Neurosci Rep, 12(6), 633-641. doi: 10.1007/s11910-012-0306-3

[6] Baum, J., Solomon, M., & Alba, A. (1981). Sarcoidosis as a cause of transverse myelitis: case report. Paraplegia, 19(3), 167-169.

[7] Stenius, B., Wide, L., Seymour, W.M., Holford-Strevens, V. and Pepys, J. (1971) Clinical significance of specific IgE to common allergens. I. Relationship of specific IgE against Dermatophagoides spp. and grass pollen to skin and nasal tests and history. Clin. Allergy, 1: 37–55

[8] Yoon, J. H., Joo, I. S., Li, W. Y., & Sohn, S. Y. (2009). Clinical and laboratory characteristics of atopic myelitis: Korean experience. Journal of the Neurological Sciences, 285(1-2), 154-158. doi: 10.1016/j.jns.2009.06.033

[9] Kitley, J., Leite, M., George, J., & Palace, J. (2012). The differential diagnosis of longitudinally extensive transverse myelitis. Multiple Sclerosis (Houndmills, Basingstoke, England), 18(3), 271-285.

[10] Scott, T., Frohman, E., De Seze, J., Gronseth, G., & Weinshenker, B. (2011). Evidence-based guideline: clinical evaluation and treatment of transverse myelitis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology, 77(24), 2128-2134.

[11] Karumbaiah, L., Bellamkonda, R. . Neural Tissue Engineering.

[12] Altman J, Das GD (1965) Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol 124(3):319-335

[13] Reynolds BA, Weiss S (1992) Generation of neurons and astrocytes from isolated cells from the adult mammalian central nervous system. Science 255(5052):1707-1710

[14] Rowland JW, Hawryluk GW, Kwon B, Fehlings MG (2008) Current stauts of actue spinal cord injury pathophysiology and emerging therapies: promise on the horizon. Neurosurg Focus 25(5):E2

[15] Keirstead HS, Ben-Hur T, Rogister B, O'Leary MT, Dubois-Dalcq M, Blakemore WF (1999) Polysialylated neural cell adhesion molecule-positive CNS precursors generate both oligodendrocytes and Schwann cells to remyelination the CNS after transplantation. J Neurosci 19(17):7529-7536

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