Albert Hietala, specialistläk, med dr Neurologen Sahlgrenska

Modellsjukdomar

Myastenia Gravis Thomas Willis 1672 "a woman who temporarily lost her power of speech and became 'mute as a fish.'"

Myastenia Gravis Mary Walker 1934 Kolinesterashämmare fysostigmin

MG - data Prevalens 10/100 000 Debut alla åldrar, peak 20-30 Yngre kv:män 3:1 Äldre kv:män 1:2 <40-år HLA-B8

Ändplattan

Ändplattan

Ändplattans fysiologi •Elektricitet -> Kemi -> Mekanik •Nervimpuls •ACh frisättning •Receptor bindning •Na+ influx ---> aktionspotential

Etiologi

Etiologi Autoantikroppar mot acetylcholinreceptorn (AChR-ak) 90% AChR-ak positiva Thymom 10% Vitiligo, thyreotoxicos, diabetes, RA och andra autoimmuna sjd i 10%

Thymus – "brässen"

Thymus

MG - Diagnostik

Elekromyelografi - EMG MG - Diagnostik Elekromyelografi - EMG

MG - Diagnostik Icepack test Tensilon® - test (edrofonium) 2mg + 3mg + 5mg Vänta 1 min Duration 4-5 min (atropin 0,5mg vb)

MG - Behandling Pyridostigmin (Mestinon®) Biotillgänglighet <10-20% Max plasmakonc 1-2h T ½ 2-4h Utsöndras via njurar

MG - Behandling Thymektomi

MG - Behandling Plasmaferes Kortikosteroider Immunoglobuliner mABs Kortikosteroider Cytostatika Azathioprin Cyklosporin A Takrolimus

MG – olämpliga mediciner Antibiotika Hjärt-kärlmedel Aminoglykosider, linkosamider, fluorokinoloner, tetracyklin, sulfonamider Beta-blockerare, prokainamid, klorokin, kinidin

MG - olämpliga mediciner Psykofarmaka Antiepileptika Övriga Litium, bensodiazepiner, fentiaziner, barbiturat, opiater Fenytoin, karbamazepin, gabapentin D-penicillinamin, thyreoideamedicin, steroider, botox

MG - prognos Kronisk sjukdom Endast ett fåtal blir medicinfria Sjukdomen kan gå i remission Med behandling lever man fullgott liv med fullgod livslängd

Guillain-Barrés syndrom Landry-Guillain-Barré-Strohl The term 'Landry's ascending paralysis' (-59) was first used in 1876 (Westpahl). The usual treatment was with strychnine which probably did the unfortunate patients more harm than good. Landry contributed no more to neurology for he died of cholera just six years after publishing his paper.

Guillain Barré Guillain-Barré-Strohl 1916 "Dissociation albumino-cytologique"

GBS

GBS-data Incidens 2/100 000 Alla åldrar drabbas 2/3 av fallen finns antingen trauma eller infektion 2-4 v innan insjuknande Campylobacter jejuni

GBS - symtom Muskelsvaghet > 50 % har kranialnervspares (facialis) Parestesier Reflexbortfall Autonom dysfunktion – ortostatisk hypotension, takykardi, blåspares,tarmpares Var 6:e pat kräver respiratorvård

GBS diagnostik Likvor Ingen cellstegring (mono <50) Kraftig ökning av albumin

GBS diagnostik EMG

GBS Behandling IvIg Plasmaferes

GBS prognos 90-95% blir helt återställda 5-6% restsymptom med partiell pares 10% får återfall inom veckor, månader el. år

IvIG Poolad plasma från 3-10 000 donatorer Omfattande reningsprocess I vissa fall 100 000 Omfattande reningsprocess Cohn-fraktionering (EtOH) Jonbytar-kromatografi Nanofiltration Inkubation lågt pH + värmebehandling

Innehåll Humant protein 50mg/ml ≥95% är IgG IgA ≤0,2mg/ml IgG

Innehåll Cytokiner Neutraliserande antikroppar? Interferoner: Låga halter av: Cytokiner Neutraliserande antikroppar? Interferoner: IL-1 IL-6 Naturliga antikroppar Lösliga CD4, CD8 och HLA-molekyler Kazatchkine, 2001

Historik Immunglobuliner användes första gången 1952 Behandling av immunbristtillstånd, im 1981 godkänd indikation på ITP Imbach, 1981 Helv Paediatr Acta. 1981 Feb;36(1):81-6.

Autoimmunitet MS

Autoimmunitet CIDP

IgG The IgG Molecule. The site of interactions between IgG and antigen (epitope) is shown, as are binding sites for C1q and activated C3b and C4b and sites of interaction between the heavy (H) chains of IgG and Fc{gamma} receptor types I, II, and III. V denotes variable region, C constant region, and L light chain. Kazatchkine M and Kaveri S. N Engl J Med 2001;345:747-755

Dalakas, M. C. Neurology 2002;59:13-21S Dimerbildning IvIg Schematic drawing of an immunoglobulin molecule and the formation of dimers in immune globulin (IVIg). (Left) Structure of the immunoglobulin molecule. (Right) Immune globulin in a purified preparation derived from multiple donors contains 40% dimers (the result of double-arm and single-arm binding) and 60% monomers. Dalakas, M. C. Neurology 2002;59:13-21S

B och T-cell modulering Immunomodulatory Effects of Immune Globulin on B Cells and T Cells. Arrows indicate the sites targeted for the effect of immune globulin. Immune globulin interferes with the selection of B-cell repertoires, down-regulates or up-regulates antibody production, neutralizes pathogenic autoantibodies and T-cell superantigens, modulates the activation and function of effector T cells and the production by CD4 T cells of cytokines mediated by type 1 and type 2 helper-T-cells, and controls cell growth. Kazatchkine M and Kaveri S. N Engl J Med 2001;345:747-755

Bindning till auto-ak Proposed effect of immune globulin on the anti-idiotypic network. (Left) Idiotypes recognize autoantigen on the surface of a cell. (Right) The variable region of the anti-idiotypic antibodies in the immune globulin preparation binds to the circulating idiotypes and prevents them from reacting with the autoantigen.

Komplement Effect of immune globulin on complement deposition. Activation of the complement pathway on the cell surface begins with the binding of the C1q on the antigenﾐantibody complex, triggering the cascade of C3 activation. This leads to activation of C3b fragments and the formation of MAC, which causes cell lysis. Immune globulin inhibits complement deposition (dotted arrows) by acting on the C3b fragments and preventing the incorporation of C3 molecules into the C5 convertase assembly. The formation of MAC is therefore inhibited and cell lysis is prevented. In addition, IVIg saturates the CR1 and CR3 receptors on activated macrophages (M) and inhibits opsonization of immune complexes by preventing the binding of C3b and C3bi complement fragments.

Fc-R blockad Effect of IVIg on Fc receptor saturation. By saturating the Fc receptors on macrophages (1), IVIg induces blockade of antibody-dependent cell-mediated cytotoxicity (2).

Fcγ-receptorer Members of the Family of Human Fc{gamma} Receptors. Listed below each receptor are the cells on which each receptor is expressed. Semicircular structures in the extracytoplasmic region represent immunoglobulin-like domains. Individual subunits of Fc receptors in the intracytoplasmic region are labeled {alpha} and {gamma}. The immunoreceptor tyrosine-based activation motifs are depicted as blue bands, and the immunoreceptor tyrosine-based inhibition motif of Fc{gamma} receptor RIIB is depicted by the pink circle. Fc{gamma} RIII receptors on natural killer cells bear a {zeta} chain rather than an {alpha} chain.

The Journal of Experimental Medicine,2007, Vol. 204, No. 1, 11-15

Models for the mechanism of IVIG-mediated antiinflammatory activity Models for the mechanism of IVIG-mediated antiinflammatory activity. (A) During an inflammatory response immune complexes consisting of autoantibodies (brown) and self-antigens (green) activate innate immune effector cells (e.g., macrophages) by cross-linking cell surface FcRs, which can lead to the destruction of self-tissues. Serum antibody half-life of normal (light brown) and autoreactive antibodies is regulated by FcRn (purple) expressed on endothelial cells. (B) Three models have been proposed to explain the antiinflammatory activity of IVIG. In the first model, IVIG (consisting of a mixture of sialic acidﾐrich [red] and sialic acidﾐlow [blue] antibodies) binds to activating FcRs on immune effector cells, thereby blocking access of immune complexes to these receptors and inhibiting cell activation. The second model proposes that IVIG competes with serum IgG (including autoreactive antibodies) for recycling mediated by FcRn. Thus, serum and autoreactive antibodies would be cleared more rapidly and not reach the threshold level for initiating tissue destruction. In the third model, IVIG leads to up-regulation of the inhibitory FcRIIB on immune effector cells, thus increasing the threshold level for cell activation by immune complexes

Two-cell model for the mechanism of IVIG activity Two-cell model for the mechanism of IVIG activity. Sialic acidﾐrich antibodies (red) in the IVIG preparation bind to an as yet unknown IVIG receptor on CSF-1ﾐdependent regulatory macrophages. This induces the up-regulation of the inhibitory FcRIIB on effector macrophages, thereby increasing the threshold for cell activation in response to the binding of immune complexes and inhibiting the release of destructive inflammatory and cytotoxic mediators.

Fcγ-receptorer - Nyckeln? Fc-sialyserade IgG påverkar M0- receptorer -> uppreglering av inibitorisk FcγR -> ingen inflammation IvIg har 1-2% sialyserad FC-IgG Vid anrikning till 20% ökar antiinflammatoriska effekten 10x -> dosen kan minskas 10x! The term "sialic acid" (from the Greek σιαλοσ (sialos) 'saliva') was first introduced by Swedish biochemist, Gunnar Blix, in 1952. Ravetch JEM;2007, Vol. 204, No. 1, 11-15 Lazarus, Nat Med, 2006, 12(6);688-92

Dosering Arbiträr dosering baserad på erfarenhet! Ej vetenskap!! Inom neurologin = 2g / kg kroppsvikt 0,4g / kg kroppsvikt under 5 dagar Ofta 3-6 v mellanrum Roifman CM, Levison H, Gelfand EW. High-dose versus low-dose intravenous immunoglobulin in hypogammaglobulinaemia and chronic lung disease. Lancet. 1987 May 9;1(8541):1075-7. Bernatowska E, Madalinski K, Janowicz W, Weremowicz R, Gutkowski P, Wolf HM, Eibl MM. Results of a prospective controlled two-dose crossover study with intravenous immunoglobulin and comparison (retrospective) with plasma treatment. Clin Immunol Immunopathol. 1987 May;43(2):153-62.

Dosering Ev premedicinera inför behandling Paracetamol Kortikosteroider Antihistamin Infusion Network Systems www.infusionsystems.net/article-Office-basedIVIG.html

Farmakokinetik Serum and CSF IgG 3 days after infusion of IVIg. IgG increases five-fold in serum and two-fold in the CSF. Rapid diffusion into the extravascular space follows.

Risker / biverkningar 3x ökning av serum IgG (upp till 6000 mg / dL Serumviskositet ökas 0,1 -> 1,0 centipoise (mPa*s)

Risker / biverkningar Frossa, huvudvärk, feber, kräkn, illamående, artralgi, bl-tr förändr Anafylaxi (ssk IgA brist) Reversibel aseptisk meningit, resp hemolytisk anemi/hemolys Njursvikt Cerebral / kardiell ischemi Diffusion-weighted MR image demonstrates marked symmetric hyperintensity within both parietal and posterior temporal lobes. 70-year old woman, PCV. Byrne, N. P. et al. Neurology 2002;59:458-461

Risker / biverkningar Vänta 3 mån innan vaccinering med levande försvagat virus Interferens med serologisk testning Diffusion-weighted MR image demonstrates marked symmetric hyperintensity within both parietal and posterior temporal lobes. 70-year old woman, PCV. Byrne, N. P. et al. Neurology 2002;59:458-461

Risker / biverkningar Vältolererad och säker immunmodulerande behandling