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CNS Immune Reconstitution-Syndrome IRIS

IRIS Underlying Causes. Start of antiretroviral combination-therapy (cART) in HIV-patients with severe immunosuppressionImmune therapies. cART 2011. NRTIs (Nukleoside-/Nukleotide-Reverse-Transcriptase-Inhibitors)Zidovudine AZT (Retrovir?)Lamivudine 3TC (Epivir?)AZT 3TC (Combivir?)Abacavir A

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CNS Immune Reconstitution-Syndrome IRIS

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    1. CNS Immune Reconstitution-Syndrome (IRIS) Gabriele Arendt Dept. of Neurology, University of Duesseldorf, Medical Faculty

    2. IRIS – Underlying Causes Start of antiretroviral combination-therapy (cART) in HIV-patients with severe immunosuppression Immune therapies

    6. Neurological signs right side accentuation of deep tendon reflexes, no pyramidal tract signs, bradydiadochokinesia of the right hand, muscle spasticity, MRC 3-4 right side hemiparesis, sensorimotor aphasia, ideomotor apraxia of both hands

    8. CSF Findings Cell count, protein content, glucose and lactate: normal HIV-PCR: negative Infectious bodies including JC-Virus-PCR: negative

    9. Neuropathological Diagnosis after Brain Biopsy IRIS-Vasculitis

    10. Therapy 1 g methylprednisolone i.v. for 5 days, then slow oral tapering

    11. Clinical Course Slow clinical improvement cMRT: unchanged except from a slight reduction of contrast medium enhancement

    14. Potential Laboratory Markers for IRIS Pro-inflammatory IL-6 TNF-alpha, IL-1, IL-8 IFN-gamma Human interferon-inducible protein 10 (IP-10, CXCL-10) Monokine-induced IFN-gamma (MIG, CXCL-9) HLA-haplotypes

    20. MRI of a patient with severe HIV-IRIS-PML This patient had high viral loads, aggressive IRIS with seizures, but survived and is recovering, walking, and returning improving (pictures smiling and happy in rehab and with doctor shared)This patient had high viral loads, aggressive IRIS with seizures, but survived and is recovering, walking, and returning improving (pictures smiling and happy in rehab and with doctor shared)

    22. IRIS-Therapy ??? Later start of cART ? Steroid application ? Immunoglobuline application ?

    23. IRIS in the Light of Modern Immune Therapies

    24. Natalizumab (Tysabri™) Recombinant humanized monoclonal a4-integrin antibody Reduces inflammatory cell trafficking to brain in multiple sclerosis by blocking VLA-4 adhesion to vascular cell adhesion molecule (VCAM-1)

    26. Brain Magnetic Resonance Imaging of Immune Therapy-induced-PML Brain MR lesions consistently seen correlating to PML symptoms T2 FLAIR images are excellent for detecting lesions Natalizumab associated PML lesion had Gd+ enhancement on T1 images reported in 15/42 (36%) at diagnosis Please blank out all identifying data on scansPlease blank out all identifying data on scans

    27. Treatment of natalizumab associated PML:Plasma Exchange Rapid reversal of drug effects seems important Should achieve improved immune activity in the brain Plasma exchange (PLEX) or immunoabsorption employed in all but 2 cases Contribution of PLEX uncertain, but supported by strong rationale to restore optimal immune surveillance of CNS as soon as possible1 Plasma exchange is recommended when the diagnosis is considered likely 2 cases did not receive PLEX, both survived. Marked by especially early withdrawal of natalizumab due to sx2 cases did not receive PLEX, both survived. Marked by especially early withdrawal of natalizumab due to sx

    28. Symptoms and Signs suspicious of IRIS in immune therapy-induced PML Despite therapy (PE) more neurological deficits New MRI lesions (may or may not enhance contrast medium)

    29. IRIS is universal and severe in natalizumab associated PML IRIS appears to have occurred in virtually every case Onset of IRIS days to weeks after PLEX Duration of IRIS likely >2 months In rare cases not receiving PLEX, IRIS has been seen several months after natalizumab was stopped, and also been severe.

    30. Therapy plasma-exchange 1g Methylprednisolone i.v. for 5 days

    31. Summary IRIS is a new, yet not fully understood phenomenon. It is seen in immunocompromised patients with rapid changes of the immune status. It presents more or less severely in different patient populations. To date, there is no evidence-based treatment.

    32. References GabrieleArendt & Thorsten Nolting. Immune Reconstitution Inflammatory Syndrome in HIV-positive patients: a review. 2010. HIV Ther 4(5): 577-587 David B Clifford, Andrea de Luca, David M Simpson, Gabriele Arendt, Avindra Nath. Natalizumab-associated progressive multifocal leukoencephalopathy in patients with Multiple Sclerosis: lessons from 28 cases. 2010. The Lancet Neurology Vol 8: 438-446

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