Plasmapheresis for neuropathies

Background 

A number of severe progressive neuropathies are based on the autoimmune pathogenesis, which is considered essential in myasthenia gravis, myasthenic Lambert-Eaton syndrome, Guillain-Barre syndrome, IgM-monoclonal demyelinating polyneuropathy, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, multiple sclerosis, inflammatory myopathies, syndrome of muscular hypertonicity, autoimmune neuromyotonia, paraneoplastic cerebellar degeneration and neuropathy, neuropathies associated with systemic vasculitis and viral infection. In these disorders autoantibodiesaffectglial cells, myelin, axon, calcium channels, muscles [DalakasM.C., 1995].

Demyelinating diseases are widespread in the population with an unstoppable trend to "rejuvenation", with rapid incapacitation and uniquely poor prognosis. Demyelination is due to release of control of T-suppressors with the abolition of immune tolerance to myelin basic protein (MBP). Antibodies against MBP stimulate complement which increases the permeability of the blood-brain barrier to components of the immune system. Antibodies to MBP, specifically affecting the oligodendrocytes and myelin, have myelinolitic and myelinotoxic effects. During the incubation of these antibodies with allogenic MBP a pronounced proteolytic effect is revealed[Vostrikova I.L. et al., 2006].

Currently, the most common viral etiology of the concept of demyelinating diseases, which is the data confirming the presence of common antigenic determinants between the encephalitogenic region of MBP, and several viruses (measles, rubella, Epstein-Barr virus, cytomegalovirus, herpes simplex). Obviously, as a result of a viral infection there is the initial startup of autoimmune disorders, leading to failure of tolerance to MBP and development of severe demyelinating disease. An important role in the pathogenesis of autoimmune diseases is played by cytokines, in particular TNF-α, which strengthen the adhesion of T-lymphocytes (CD4+), macrophage activation, cytolysis oligodendrocytes, and thereby promoting demyelination [Körner H. et al., 1997].

In multiple sclerosis, encephalomyelitis, neuromyelitis optica we can observe accumulation of some unidentifiable substances autoimmune or allergic nature, causing the destruction of myelin in the white matter of the brain and spinal cord, the myelin sheath of nerve trunks. Myelin acts as a sort of isolator, allowing the neuro-electrical impulses spread in certain directions. Its elimination leads to multiple "short circuits" in the process, which determines a particular clinical picture of the disease depends on the level of "circuit".

Apheresis therapy, mainly plasmapheresis, removing from an organism such demyelinating agents, promotes if not recovery of the destroyed, then at least a slowing of the progression of these diseases, the stabilization of state [Keegan M. et al., 2002; Yücesan C. et al., 2007, 2008; Kaynar L. et al., 2008; Linker R.A., Gold R., 2008; Llufriu S. et al., 2009;  Voinov V.A., 2010; McDaneld L.M. et al., 2010; Gwathmey K. et al., 2011, 2012; Cortese I. et al., 2012; Heuchler M. et al., 2013; Rahmlow M.R., Kantarci O., 2013; Latov N., 2014; Ohkudo A. et al., 2014].  The plasma exchange with success is used and at emergence of the demylinating diseases at children [Kosiolek M. et al., 2013]. After plasmapheresis course (5-6 sessions up to 1,3-1,5 liters of plasma for each) there are signs of regression paralysis, impaired recovery of sensitivity, increase muscle strength. Repeated annual courses suspend the progression of the disease and improve quality of life for patients [Voinov V.A., 2010].

Let us examine some of these diseases in more detail.

Multiple sclerosis

MS - demyelinating disease of the central nervous system. It is an autoimmune inflammatory disease with diverse clinical manifestations, often leading to severe damage of motor activity, paralysis, vision loss, disorders of the pelvic organs. Although the etiology and pathogenesis are unknown, a number of features support the hypothesis about the role of as yet unidentified infectious agent that triggers an immune response against the distorted own nervous tissue, especially in genetically susceptible individuals. Although the antibody titers detected increase to various viruses (influenza, herpes simplex virus, Epstein-Barr virus, papilloma virus) in plasma and cerebrospinal fluid, but there is no clear guidance for the detection of RNA or viral antigens in the brain tissue itself. However, there are indications of the possible role of retroviruses in multiple sclerosis [Allain J.-P., 1998]. There is a chance of a process of molecular mimicry with the antigenic structure of individual proteins of viruses similar to the proteins of the brain tissue. In this case, a possible autoantigen is influenced by the excited viral antigens of T-lymphocytes, a myelin-oligodendrocyte-glycoprotein, breach of which may underlie the pathogenesis of multiple sclerosis [Bernard C.C.A. et al., 1997].

S. Sriram and collaborators (1997) mark as the main causes of multiple sclerosis T-lymphocytes, which penetrate into microglia and activate secretion and release of myelotoxic factors with direct damage to myelin in oligodendrocytes. Autoantibodies to MBP join in the processes of demyelination in the later stages of the development of multiple sclerosis [Vostrikova I.L. et al., 2006]. Activation of microglia cells also leads to the production of proinflammatory cytokines, chemokines, which in turn drives lymphocytes. In these processes there is also a release of "tumor necrosis factor", nitric oxide and free oxygen radicals, interleukins 1 and 12. Cytokines are detected and cerebro-spinal fluid. The content of IL12 can grow well in advance (4-6 weeks) to the exacerbation of the disease [van Boxel-Dezaire A.H.H. et al., 1999]. It is possible to believe that removal of such mediators of an inflammation by means of a plasma exchange promotes restoration of tolerance of immune cells to autoantibodies [Jamshidian A., Gharagozloo M., 2012]. It is possible to believe that removal of such mediators of an inflammation by means of a plasma exchange has to promote restoration of tolerance of immune cells to autoantibodies [Jamshidian A., Gharagozloo M., 2012].

A number of patients with multiple sclerosis exhibit antinuclear autoantibodies characteristic of systemic lupus erythematosus which rather points to a systemic disease [Fukazawa T., 1997; Hashimoto H., 2010].

Demyelination process is not irreversible, as there is some "nerve growth factor" contributing to the restoration of myelin and nerve cell regeneration. However, the presence of autoantibodies against this factor in multiple sclerosis weakens the process, that is additional incentive for carrying out a plasma exchange.

Currently there are no known reliable methods of treatment that may inhibit the progression of the process. Based on the postulate of autoimmune nature of multiple sclerosis, we can use a lot of immunosuppressive and immunomodulatory agents - corticosteroids, azathioprine, and methotrexate, total irradiation of lymphocytes. There is known some effect of the oral administration of bovine myelin, resulting in reduction of autoreactive T-cells. Also used is intravenous administration of large doses of immunoglobulin. However, character of changes in the immunological multiple sclerosis status indicates immunodeficiency (decrease of T-lymphocytes and reduction ratio CD4+ / CD8+, decrease of IgM), glucocorticoids may therefore contribute further immunosuppression [Orlova Yu.Yu., 1999].

It is proved that injection of recombinant interferon b-1b promotes binding and neutralizing antibodies in some patients with multiple sclerosis[Ric G.P.A. et al., 1999; Plosker G.L., 2011]. However, anti-IFN-β molecules begin to form antibodies that reduce the efficiency of the drug [Majorga C. et al., 1999; Sorensen P.S., 2008; Applebee A., Panitch H., 2009; Zarkou S. et al., 2010]. In addition, there is a number of detected and seriousside effects of such an interferon – the formation of subcutaneous abscesses at the injection site, liver problems, flu-like reaction, weakness, stomatitis, anorexia, decreased hemoglobin, neutrophils and platelets [Soria A. et al., 2007; Nakamura Y., et al., 2008; Okushin H. et al., 2010; Sanford M. et al., 2011; Mahe J. et al., 2013]. This often forces to interrupt this treatment [Clerio M. et al., 2008]. It should be taken into account relatively high cost of courses using interferon b-1b, reaching $400,000 [Bell C. et al., 2007].

Considered to be promising as well areselective inhibitorsof adhesion molecules whose representative is a recombinant monoclonal antibody Natalizumab. Researchers revealed, however, a downside to this treatment – the development of progressive multifocal leukoencephalopathy [Clifford DB et al., 2010; Keene D.L. et al., 2012; Rudick R.A., 2011; Sørensen P.S. et al., 2012; Baldwin K.J., Hogg J.P., 2013; Boster A.L., et al., 2013; Eisele P. et al., 2014; Theódórsdóttir A. et al., 2014[. And, besides a natalizumab, leads treatment to such complication and other preparations on the basis of monoclonal antibodies – efalizumab, infliximab, adalimumab, etanercept, ibiritumomab tiuxetan, bevacizumab, alemtuzumab, cetuximab, brentuximab [Takao M., 2013]. Also lethal outcomes of such complication after long reception of an efalizumab are described [Schwab N. et al., 2012]. At the same time, using plasmapheresis we had to remove the drug and to eliminate such complications thereby[Khatri B.O. et al., 2009; Schröder A. et al., 2010; Tan. I.L. et al., 2011; Takao M, 2013].

 Alongwith this, the methods oftherapeutic apheresis are used, plasmapheresis,in particularin combination withcorticosteroids andcyclophosphamide[Khatri BOet al.,1991; Weinshenker BG, 2000; Ohji S., Nomura K., 2008; Schröder A. et al.,2009; Trebst C. et al.,2009; Hashimoto H., 2010; MagañaS.M. etal., 2011; Heuchler M. et al., 2013], and at the splenic  perfusion (through a column with fragments of a spleen of a pig) promoting activation of T-lymphocytes at the expense of T-suppressors [Roth T.A., 1999], and cryo plasmosorption with processing in this way up to 2,5 volumes of the circulating plasma [Kreynes I.V., 1999]. However E.V.Nedashkovsky et al. (2003) note that use of a plasma exchange  with extracorporeal modified autoplasma  had no advantages before a usual not selective plasma exchange. Indications to a plasma exchange especially increase when pulse therapy by corticosteroids doesn't yield due result [Matsuo H., 2014]

V.I.Chernyet al.(2004) used thesoftwareplasmapheresis-2 sessions perweek, and then at 1, 3, 6 months, a year. Such tacticsfor 10years,7 patientsallowed to achieveremissionof multiple sclerosis. Carrying out such program plasma exchange was more effective than courses of a sporadic plasma exchange 1-2 times a year [Karpov M. I. etc., 2013].We also preferthe tactics ofthe initial courseof4-5 sessionsof plasmapheresis, followed by one sessioneachmonth, whichallows users to securea positive result [Voinov V.A., 2014].Successwas achieved inthe application ofcascade plasmapheresis[Ramunni A.et al.,2008]. Positiveresults were achievedby selectiveIg-apheresis withimmunosorbents. I.M.BarbasandA.A.Skoromets(2003),the bestresults are achieved withcourses of hemocarboperfusion.

Neuromyelitis optica

Neuromyelitis optica, or Devic’s disease – inflammatorydisease characterizedby selectivelesions ofthe opticnerve andspinal cord (extensive transverse myelitiswith paraplegia). Previouslyit was considered assevere variantof multiple sclerosis. However NMO-IgG-antibodies, specific to this disease, a target for which is the aquaporin-4 (AQP4) which is in shoots of astrocytes or covering sites of the vessels which aren't covered with astrocytes legs, participating in formation of a blood-brain barrier are allocated. At its damage it doesn't cope with the function that promotes access and other immune components in CNS, in particular, of the leukocytes allocating toxic cytokines which complete death of oligodendrocytes and neurons [Argyriou A.A, et AL., 2008; Cree B., 2008; Marignier R. et al., 2010; Awad A., 2011].  Usually, primary,visual disturbancesoccurwithsubsequent addition ofthe symptomsof severetransverse myelitis– a coupleandtetrapareses,disorders of pelvicorgans[Karim S., Majithia V.,2009]. Life expectancy thus usually doesn't exceed five years.

Usedfor the treatment aresteroids,immunoglobulinsandplasmapheresisto removecoursesup to 2-3litersof plasmaper session[GreenbergB.M. etal., 2007;Watanabe S.et al.,2007; Bonnan M. et al.,2009, 2012; Magaña S.M. et al.,2009; Trebst C. et al.,2009; CarollW.M., FujiwaraK., 2010; Ochi H., 2010; Wang K.C. et al.,2011; DeviB.V. etal., 2012; KhatriB.O. etal., 2012; MerleH. etal. 2012; Pula JH, MacDonald CJ, 2012; Sato D. et al., 2012; Morgan S.M., 2013, 2014; Cordoba J.P., 2014], followed by a periodicallyrepeatedsessionsof plasmapheresis(programorintermittent plasmapheresis) [Miyamoto K., Kusunoki S.,2009]. S.H.Kim et al. (2013) note that after a plasma exchange course the level of antibodies to aquaporin-4 decreases to 15% of initial level, and the effect of treatment remains also in 6 months. Thisfindsapplication andcascadeplasmapheresis[Yoshida H.et al.,2010; Munemoto M. et al., 2011] and lymphocyte-apheresis [Nozaki I. et al., 2005]. Transversal myelitis can develop and against the system lupus erythematosis complicated by meningitis and the plasma exchange in that case also yielded positive result [Covach A.J., Rose W.N., 2014].

Guillain-Barré syndrome

This is an acute severe disease of the central nervous system, accompanied by progressive muscle weakness and paralysis, including respiratory muscles, which often requires prolonged mechanical ventilation. In such cases, when joining pneumonia, thrombocytopenia and bleeding, mortality can reach 12% [Netto AB et al., 2011]. At the heart of acute disseminated encephalomyelitis lie demyelinating processes. Its connection with chronic demyelinating diseases still debated, its pathogenesis is not clear, but the role of the immune system is undeniable.

Often, such a process is preceded by viral infections and vaccinations, sometimes an infection caused by Campylobacter jejuni [Straub J. et al., 1997; Hao Q. et al., 1999; Rogalewski A. et al., 2007]. At least 41% of patients identify this pathogen [Nachamkin I. et al., 1999]. Some connections are found for acute disseminated encephalomyelitis and previously suffered pneumonia caused by mycoplasma or bac. Legionella [Hagiwara H., et al., 2009; de Lau LM et al., 2010].

Detection of antibodies indicates a possible molecular mimicry between epitopes of the antigen of the infectious agent and the elements of the peripheral nerves, which determines the pathogenesis of this syndrome. Among the patients with this disease there is a large heterogeneity in the severity of neurological disorders of muscle weakness, the degree of sensory disorders, demyelination and axonal degeneration. Anti-GQ1b antibodies increases in severe ophthalmoplegia and Fisher syndrome, anti-GM1 antibodies are more concerned with purely motor variant of the disease, anti-GalNAcGD1a antibodies are detected more frequently in the gastro-intestinal infections before clinical symptoms of Guillain-Barré syndrome with the development of distal paralysis [Hao Q. et al., 1999].

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