Comprehensive Children’s Epilepsy Centre
Immunomodulatory Treatment for the Intractable Paediatric Epilepsies Luis E. Bello‐Espinosa, MD Section of Pediatric Neurology Departments of Pediatrics & Clinical Neurosciences Cumming School of Medicine University of Calgary Disclosure
• Faculty: Luis E. Bello‐Espinosa
• Relationships with financial sponsors: • Grants/Research Support: Eisai Pharm. • Speakers Bureau/Honoraria: UCB. • Consulting Fees: None • Patents: • Other: Objectives. • Appraise the data supporting the use of IVIg aand other immune modulatory treatments for the intractable Paediatric Epilepsies. • Clinical Experience of Pediatric IVIg. • Upcoming therapies that have paid the “Toll” and are ready to enter the arena of immunomodulation. Principle
Treatment Immune‐related Resistant Pediatric Epilepsy hypothesis
Is there a role for immuno‐modulation? Immunity in the Central Nervous System. Immunity in the Central Nervous System.
Innate Adaptive Autoimmunity Autoimmunity
Epileptogenic Insult
Often Triggered in the Inflammosome where the IL‐1 is the main CNS trauma, CNS infections, Strokes, HIE, Autoimmune pathological mediator encephalities, CNS tumors, paraneoplasias, metabolic diseases, etc
Involves an antigen‐specific T‐cell and antibody response to a CNS component
The cell biology of inflammasomes: Mechanisms of inflammasome activation and regulation Deepika Sharma, et al J Cell Biol Jun 2016, 213 (6) 617-629; DOI: 10.1083/jcb.201602089 R. Bhat et al Neuron 64.1 (2009): 123‐132. Das ist ja toll!
Nuclear factor kappa-light-chain-enhancer of activated B cells
Nature , 1997, Vol.388(6640), p.394‐397 Leucin‐rich repeat Domain and a cytoplasmic IL‐1 domain
Christiane Nüsslein-Volhard J Leukoc Biol. 2004 Sep;76(3):514-9. Epub 2004 Jun 3. 1995 Nobel Prize Eric Wieschaus Vezzani, Bethan Lang, Eleonora Aronica Cold Spring Harb Perspect Med. 2016 Feb; 6(2): a022699. doi: 10.1101/cshperspect.a022699 Immunity and Inflammation Resting Glia Activated Glia in Epilepsy Brain inflammation in Epilepsy: Experimental Evidence Epilepsia, 46(11):1724–1743, 2005 CD68
GFAP
Triple immunofluore sce confocal images
19‐December 2009
In Humans what are the triggers of the innate autoimmune response? In Humans what are the triggers of the innate autoimmune response?
Unknown in some epilepsies Translational to Therapeutic Application
Immunomodulatory Agents Immunomodulatory Agents Class Drugs Steroids Prednisone, Prednisolone, ACTH
Intravenous Immunoglobulins IVIg
mTOR signalling pathway interference sirolimus, deforolimus, everolimus, temsirolimus, zotarolimus, biolimus A9 Immunomodulatory agents Class Drugs Steroids Prednisone, Prednisolone, ACTH
Intravenous Immunoglobulins IVIg
mTOR signalling pathway interference sirolimus, deforolimus, everolimus, temsirolimus, zotarolimus, biolimus A9
Macrolides and other IL‐2 Inhibitors Tacrolimus, ciclosporin, pimecrolimus, abetimus, gusperimus
Antimetabolites Urine synthesis inhibitors (azathioprine, mycophenolic acid), pyrimidine synthesis inhibitors (leflunomide, teriflunomide) and antifolate drugs (methotrexate) TNF/TNFα Inhibitors Thalidomide, lenalidomide, etanercept, pegsunercept
Monoclonal antibodies Complement component 5 (ecluzimab), TNFs (infliximab, adalimumab, certolizumab pegol, afelimomab, golimumab), IL‐5 (mepolizumab), immunoglobulin (Ig) E (omalizumab) , interferon (faralimomab), IL‐6 (elsilimomab), IL‐12 and IL‐13 (lebrikizumab and ustek‐ inumab), CD3 (muromonab‐CD3, otelixizumab, teplizumab, visilizumab), CD4 (cleno‐ liximab, keliximab, zanolimumab), CD11a (efalizumab), CD18 (erlizumab), CD20 (rituximab, afutuzumab, ocrelizumab, pascolizumab), CD23 (lumiliximab), CD40 (tenelix‐ imab, toralizumab), CD62 L/L‐selectin (aselizumab), CD80 (galiximab), CD147/basigin (gavilimomab), CD154 (ruplizumab), BLyS (belimumab), CTLA‐4 (ipilimumab, tremeli‐ mumab), CAT (bertilimumab, lerdelimumab, metelimumab), integrin (natalizumab), IL‐ 6 receptor (tocilizumab), lymphocyte function‐associated antigen (LFA)‐ 1 (odulimumab) , IL‐2 receptor/CD25 (basiliximab, daclizumab, inolimomab), T‐lymphocyte (zolimomab aritox), miscellaneous (atorolimumab, cedelizumab, dorlixizumab, fontolizumab, gan‐ tenerumab, gomiliximab, maslimomab, morolimumab, pexelizumab, reslizumab, rov‐ elizumab, siplizumab, talizumab, vapaliximab, vepalimomab
IL‐1 Receptor Antagonist Anakinra
Polyclonal antibodies Anti‐thymocyte globulin and anti‐lymphocyte globulin. Immunomodulatory agents for management of epilepsy unomodulatory agents for management of epilepsy ‐yr‐old girl with TRE CAE(ETX,VPA, LTG,TPM, LVT,KD) FS: 10 (> 50‐100/day) MRI : normal Methyprednisolone: • 30 mg/kg/d x 5‐d FS : 1. munomodulatory agents s Drugs ds Prednisone, Prednisolone, ACTH ravenous Immunoglobulins IVIg
sirolimus, deforolimus, everolimus, temsirolimus, zotarolimus, biolimus A9 ravenous Immunoglobulin for Epilepsy
Cochrane Database Syst Rev 2013 Jun 27;(6):CD009945 doi:10 1002/14651858 CD009945 pub2 f interventions erimental interventions included orticosteroids or immunosuppressants: intravenous, intramuscular or sub‐ ous route taken in addition to AEDs. osuppressants: included intravenous oglobulins, azathioprine, mycophenolic acid, mide, teriflunomide, methotrexate, mus, ciclosporin, pimecrolimus, abetimus, mus, thalidomide, lenalidomide,etanercept, ercept, anakinra, etc N=61 patients (adults and children)
Seizure Free on IVIg: 2 IVIg : 52.7 % response vs. Placebo: 27.8 % response
Subgroup analysis of patients with partial epilepsy showed a significant improvement in favor of IVIG treatment (N = 46, P = 0.041)
Authors’ conclusions
It is not possible to draw any conclusions about the role of immunomodulatory interventions in reducing seizure frequency or the safety of these agents in adults with epilepsy. Further randomised controlled trials are needed echanism of action: Multiple g in Treatment‐Resistant Epilepsy in Children sults
Immunomodulatory agents Class Drugs Steroids Prednisone, Prednisolone, ACTH
Intravenous Immunoglobulins IVIg
mTOR signalling pathway interference sirolimus, deforolimus, everolimus, temsirolimus, zotarolimus, biolimus A9
Monoclonal antibodies Complement component 5 (ecluzimab), TNFs (infliximab, adalimumab, certolizumab pegol, afelimomab, golimumab), IL‐5 (mepolizumab), immunoglobulin (Ig) E (omalizumab) , interferon (faralimomab), IL‐6 (elsilimomab), IL‐12 and IL‐13 (lebrikizumab and ustek‐ inumab), CD3 (muromonab‐CD3, otelixizumab, teplizumab, visilizumab), CD4 (cleno‐ liximab, keliximab, zanolimumab), CD11a (efalizumab), CD18 (erlizumab), CD20 (rituximab, afutuzumab, ocrelizumab, pascolizumab), CD23 (lumiliximab), CD40 (tenelix‐ imab, toralizumab), CD62 L/L‐selectin (aselizumab), CD80 (galiximab), CD147/basigin (gavilimomab), CD154 (ruplizumab), BLyS (belimumab), CTLA‐4 (ipilimumab, tremeli‐ mumab), CAT (bertilimumab, lerdelimumab, metelimumab), integrin (natalizumab), IL‐ 6 receptor (tocilizumab), lymphocyte function‐associated antigen (LFA)‐1 (odulimumab), IL‐2 receptor/CD25 (basiliximab, daclizumab, inolimomab), T‐lymphocyte (zolimomab aritox), miscellaneous (atorolimumab, cedelizumab, dorlixizumab, fontolizumab, gan‐ tenerumab, gomiliximab, maslimomab, morolimumab, pexelizumab, reslizumab, rov‐ elizumab, siplizumab, talizumab, vapaliximab, vepalimomab Antimetabolites Urine synthesis inhibitors (azathioprine, mycophenolic acid), pyrimidine synthesis inhibitors (leflunomide, teriflunomide) and antifolate drugs (methotrexate) IL‐1 Receptor Antagonist Anakinra Macrolides and other IL‐2 Inhibitors Tacrolimus, ciclosporin, pimecrolimus, abetimus, gusperimus
TNF/TNFα Inhibitors Thalidomide, lenalidomide, etanercept, pegsunercept
Polyclonal antibodies Anti‐thymocyte globulin and anti‐lymphocyte globulin. Interleukin‐1 (IL‐1) receptor antagonists Anakinra (Kineret)® • Could there be a role for this group of agents?
Using IL‐b antagonists Doses ranging between 1 and 10mg/kg/day SC (maximum typically =100mg/day);
Case Onset Seizure types Failed Treatments Age when OUTCOME and Epilepsy Anakinra Started (dose)
14‐wks CPSs, GTCs, daily >20 AEDs, KD, VNS, IVIg (at 17‐yr) 4‐yr Seizure free 4 mg/kg/d 216‐mGTCs, infection Multiple AEDS, IVIg (at 10‐yr) 2‐yr seizure free triggered (1‐5 3 mg/kg/d day/wk) 3Unk.GTC, LKS, triggered Mult AED, MST, OCS, IVIg (at 10‐yr) 4‐yr Seizure free. by Colitis Thalidomide, 3 mg/kg/d Failed taper x 2 45‐yr ASD, ID, Wheat Mult AEDS (not effective (at 10‐yr) 3‐yr Sz free. Has allergy (Neg Celiac) and hepatotoxicity, IVIg 3 mg/kg failed tapered x 2 SPAD Jyonouchi et at, J Clin Cell Immn 2016, 7:5 What could there be in the horizon??
• Anti‐dendritic Cell Therapy (i.e. vaccines) Conclusion • Despite strong experimental data implying inflammatory mechanisms as cause of epilepsy, the role of immunomodulating agents (IMA) for chronic epilepsies remains equivocal. • If Immunomodulatory agents are considered, perhaps not as last resort especially if there is strong evidence of systemic inflammatory triggers. • More clinical research is needed. Thank you..! Comprehensive Children Epilepsy Team