Cacoub p  hcv meh 2014
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  • Diagnosis of neuropathic pain requires identifying the nerve structures that are involved. Pattern recognition is a common means of identifying the location of the deficit. Once the pattern of involvement is recognized, the next step is to identify the etiology.
    Mononeuropathies are usually posttraumatic or caused by entrapment neuropathies.1 Occasionally systemic disease (eg, diabetes or vasculitis) can produce a mononeuropathy.2
    Mononeuropathy multiplex means that a patient has multiple mononeuropathies, usually asymmetric and involving multiple parts of the body. Causes include vasculitis, sarcoidosis, and inflammatory polyneuropathies.2
    Involvement of most of an extremity in the neuropathic process suggests involvement of the plexus, or a plexopathy.2,3 Common causes include trauma, cancer, radiation, and some systemic illnesses.3
    Peripheral polyneuropathy, resulting in a “stocking-and-glove” pattern, is perhaps the pattern most easily recognized.4 It is always the result of a systemic process, such as a toxic exposure, diabetes, or alcohol.1
    1.Boulton AJM, Malik RA. Diabetic neuropathy. Med Clin North Am. 1998;82:909-929.
    2.Portenoy RK. Neuropathic Pain. In: Portenoy RK, Kanner RM, eds. Pain Management: Theory and Practice. Philadelphia, Pa: FA Davis Company; 1996:108-113.
    3.Katz N. Neuropathic pain in cancer and AIDS. Clin J Pain. 2000;16:S41-S48.
    4.Galer BS, Dworkin RH. A Clinical Guide to Neuropathic Pain. Minneapolis, Minn: McGraw-Hill Companies Inc; 2000:100.


  • 1. Extrahepatic Manifestations of Hepatitis C Virus Infection Pr Patrice CACOUB Service de Médecine Interne, et CNRS UMR 7087 Université Pierre et Marie Curie Centre National de Référence Maladies Auto-immunes Hôpital La Pitié-Salpêtrière, Paris, FRANCE
  • 2. Manifestation certainly associated with HCV %  Vasculitis (PAN, cryoglobulinemia) 5-40  Arthralgia-myalgia 25-35  Sicca syndrome 10-25  Auto-antibodies 10-40  Thrombocytopenia 20-40  Lymphoma RR=35
  • 3. Hepatitis C Virus Chronic Infection: More Than One Target Cell Hepatocyte Choo. Science 1989 • Hepatitis • Cirrhosis • Hepatocarcinoma Lymphocyte Zignego. J Hepatol 1992 Ferri. Blood 1993 • Cryoglobulinemia • Auto-Ab • B-NHL
  • 4. Cryoglobulinémies mixtes Infection VHC +++ Saadoun, Arch Intern Med, 2006
  • 5. VASCULARITES: CLASSIFICATION Chapel Hill, révisé en 2012
  • 6. Les cryoglobulines sont des Immunoglobulines qui précipitent à une température < 37°C et se dissolvent lors du réchauffement Ferri C et al. Orphanet J Rare Dis 2008 Brouet J et al. Am J Med 1974
  • 7. Cryoprecipitation Endothelial cells 7
  • 8. Pathogenesis of cryoglobulinaemic vasculitis Roccatello, D. et al. Nephrol. Dial. Transplant. 2004 8
  • 9. Skin Purpura Neuropathy Cryoglobulinemia Vasculitis Membrano-proliferative Glomerulonephritis CNS Vasculitis 9
  • 10. Mixed Cryoglobulin and Neuropathy Distal Polyneuropathy 80% • Chronic progressive course, • Distal, symetric, axonal PN, mainly sensory • Few extra neurological signs : purpura • Severe liver involvement • Moderate inflammatory syndrome Mononeuropathy Multiplex 20% Cacoub P et al, AIDS 2005
  • 11. Cryoglobulinemic Membrano-Proliferative Glomerulonephritis GNMP de type 1 Doubles Contours Pseudo-thrombi IgG/IgM Kappa/ lambda C3 ±C1q
  • 12. HCV Mixed Cryoglobulinemia and Digestive Tract Mesenteric artery stenosis Intestinal wall thickening Terrier B et al, GUT 2011 13
  • 13. Cardiac Involvement in Hepatitis C Virus-Related Vasculitis Terrier B et al, Am J Cardiol 2013 14
  • 14. Central Nervous System Involvement in HCV-Cryoglobulinemia Vasculitis  HCV-vasculitis HCV Controls (n=40) (n=11) (n=36) ------------------------------------------------------------------------------------Gender (F/M) 23/17 6/5 20/16 Age (yrs) 59 ± 13 56 ± 10 58 ± 12 WMHS 7.0 ± 9.9 0.9 ± 1.8 * 2.0 ± 3.1 PVHS 2.5 ± 3.1 0.4 ± 0.5 * 0.8 ± 1.4 NCFD 2.2 ± 1.8 0.9 ± 0.8 * ------------------------------------------------------------------------------------- * P<0.01 WMHS: White Matter Hypersignals Casato MPeriventricular Hypersignals PVHS: et al, J Hepatol 2004
  • 15. Features of Mixed Cr yoglobulinemia Age at disease onset Female/Male ratio Purpura Weakness Arthralgias Arthritis (non-erosive) Raynaud's phenomenon Sicca syndrome Peripheral neuropathy Renal involvement B-cell non-Hodgkin's lymphoma Hepatocellular carcinoma n=250 54 ± 13 (29-72) 3 98% 98% 91% 8% 32% 51% 81% 31% 11% 3% Ferri C, Mascia MT, Saadoun D, Cacoub P. 2009 16
  • 16. Mixed Cryoglobulin and Distal Polyneuropathy Peripheral Nerve Biopsy - important peri-vascular infiltrate of lymphocyte - around small vessels i.e. venules, capillaries - no PMN, no destruction of the vascular wall
  • 17. Cellular Infiltrate in HCV-Vasculitis Who’s the culprit ? HCV Core Protein in Skin Vascular Structures 18
  • 18. Detection of Genomic Viral RNA in Ner ve and Muscle of Patients with HCV Neuropathy  Inflammatory vascular lesions in 26/30 (87%) patients  Positive-strand genomic HCV RNA detected in 10/30 patients (muscle 9, nerve 3)  Negative-strand replicative HCV RNA never detected --> HCV neuropathy probably results from virus-triggered immune-mediated mechanisms rather than direct nerve infection and in situ replication Authier JF et al, Neurology, 2003 19
  • 19. A Role for B Cell Immunity in HCV-Vasculitis Rationale for Rituximab treatment in cryoglobulinemic vasculitis Roccatello, D. et al. Nephrol. Dial. Transplant. 2004 Rocatello D, Nephrol Dial Transplant, 2004 20
  • 20. J Immunol, 2011
  • 21. Expansion des Lympho B CD21-/low CD27+ IgM+ chez les patients VHC-MC
  • 22. Biais de répertoire des Lympho B CD21-/low CD27+ IgM+ avec expression préférentielle de la chaîne lourde d’Ig VH1-69 Accumulation de mutations somatiques témoignant de la maturation d’affinité Terrier B. et al. J Immunol 2011
  • 23. Etude de l’apoptose et de la prolifération Apoptose (expression annexine V) Prolifération (incorporation 3H) Les LymphoB CD21-/low CD27+ IgM+ sont des cellules anergiques