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Immunological Adverse Effects of Anticonvulsants

What is their Clinical Relevance?

  • Review Article
  • Drug Experience
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Summary

Long term administration of anticonvulsants is sometimes associated with impairment of the humoral and/or cellular immune response. Furthermore, certain well known adverse reactions to antiepileptics may have an immunotoxicological origin e.g. lymphadenopathy, pseudolymphoma and systemic lupus erythematosus. However, two important questions remain unresolved. First, the possibility that epilepsy per se might be primarily associated with immune alterations makes it difficult to assess the pathogenetic role of a specific drug, especially in a patient population usually on multiple drug therapy. Secondly, the clinical relevance of some of the observed immunological abnormalities is still highly controversial.

This review is intended to give an outline of the present state of knowledge on the effects of anticonvulsants on humoral, cellular and nonspecific immunity, with particular regard to some of the major clinical conditions that have been ascribed to drug-induced immune dysregulation, such as pseudolymphoma and systemic autoimmune diseases. The immunotoxic potential of anticonvulsants appears to be low, and immunological monitoring is not usually required except in patients with known immune defects.

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References

  • Aarli JA. Changes in serum immunoglobulin levels during phenytoin treatment of epilepsy. Acta Neurologica Scandinavica 54: 423–430, 1976a

    Article  PubMed  CAS  Google Scholar 

  • Aarli JA. Drug-induced IgA deficiency in epileptic patients. Archives of Neurology 33: 296–299, 1976b

    Article  PubMed  CAS  Google Scholar 

  • Aarli JA. Phenythoin-induced depression of salivary IgA and gingival hyperplasia. Epilepsia 17: 283–291, 1976c

    Article  PubMed  CAS  Google Scholar 

  • Aarli JA. Phenytoin-induced depression of salivary IgA. Acta Otolaryngologica 82: 199–201, 1976d

    Article  CAS  Google Scholar 

  • Aarli JA, Tönder O. Effect of antiepileptic drugs on serum and salivary IgA. Scandinavian Journal of Immunology 4: 391–396, 1975

    Article  PubMed  CAS  Google Scholar 

  • Adams JD. Localized cutaneous pseudolymphoma associated with phenytoin therapy: a case report. Australasian Journal of Dermatology 22: 28–29, 1981

    Article  PubMed  CAS  Google Scholar 

  • Adams LE, Hess EV. Drug-related lupus: incidence, mechanisms and clinical implications. Drug Safety 6: 431–449, 1991

    Article  PubMed  CAS  Google Scholar 

  • Alarcón-Segovia D, Palacios R. Differences in immunoregulatory T cell circuits between diphenylhydantoin-related and spontaneously occurring systemic lupus erythematosus. Arthritis and Rheumatism 24: 1086–1092, 1981

    Article  PubMed  Google Scholar 

  • Alberto P, Cougn R, Maurice P, Weber J. Trois cas de lymphome malin ou pseudolymphome chez des épileptiques traités par la diphénylhydantoïne. Schweizerische Medizinische Wochenschrift 101: 1773–1774, 1971

    PubMed  CAS  Google Scholar 

  • Amadori G, Fiore D. Problemi diagnostici dell’immunopatia idantoinica. Minerva Medica 75: 2503–2519, 1984

    PubMed  CAS  Google Scholar 

  • Andersen P, Mosekilde L. Immunoglobulin levels and autoantibodies in epileptics on long-term anticonvulsant therapy. Acta Medica Scandinavica 201: 69–74, 1977

    Article  PubMed  CAS  Google Scholar 

  • Anderson VM, Bauer HM, Kelly AP. Mucocutaneous lymph node syndrome in an adult receiving diphenylhydantoin. Cutis 23: 493–498, 1979

    PubMed  CAS  Google Scholar 

  • Anthony JJ. Malignant lymphoma associated with hydantoin drugs. Archives of Neurology 22: 450–454, 1970

    Article  PubMed  CAS  Google Scholar 

  • Arneborn P, Palmblad J. Drug-induced neutropenia: a survey for Stockholm 1973–1978. Acta Medica Scandinavica 212: 289–292, 1982

    Article  PubMed  CAS  Google Scholar 

  • Arora PK, Hanna EE, Paul SM, Skolnik P. Suppression of the immune response by benzodiazepine receptor inverse agonists. Journal of Neuroimmunology 15: 1–9, 1987

    Article  PubMed  CAS  Google Scholar 

  • Askmark H, Wiholm B. Epidemiology of adverse reactions to carbamazepine as seen in a spontaneous reporting system. Acta Neurologica Scandinavica 81: 131–140, 1990

    Article  PubMed  CAS  Google Scholar 

  • Bardana EJ, Gabourel JD, Anderson CJ, Davies GH. Phenytoininduced suppression of IgA and IgE. Journal of Allergy and Clinical Immunology 65: 167, 1980

    Google Scholar 

  • Bardana EJ, Gabourel JD, Davies GH, Graig S. Effects of phenytoin on man’s immunity. Evaluation of changes in serum immunoglobulins, complement, and antinuclear antibody. American Journal of Medicine 74: 289–296, 1983

    Article  PubMed  Google Scholar 

  • Basaran N, Kansu E, Hincal F. Serum immunoglobulins, complement levels and lymphocyte subpopulations in phenytoin-treated epileptic patients. Immunopharmacology and Immunotoxicology 11: 335–346, 1989

    Article  PubMed  CAS  Google Scholar 

  • Bassanini M, Baez A, Sotelo J. Immunoglobulins in epilepsy. Journal of Neurological Sciences 56: 275–281, 1982

    Article  CAS  Google Scholar 

  • Bercel NA, Finesilver B, Solomon P, Somerfeld-Ziskind E, Ziskind E. Mesantoin in epilepsy. Journal of the American Medical Association 143: 1460–1462, 1950

    Article  PubMed  CAS  Google Scholar 

  • Black DM, Fivenson DP. Case report of antiepileptic drug hypersensitivity reaction: pseudolymphoma syndrome. Family Practice Research Journal 8: 107–111, 1989

    PubMed  CAS  Google Scholar 

  • Bladé Creixenti J, Segura Porta F, Noguéxarau S, Soriano Marín E, García San Miguel J. Asociación de enfermedad de Hodgkin e hidantoínas. Comunicación de un nuevo caso y revisión de la literatura. Medicina Clínica (Barcelona) 15: 24–26, 1980

    Google Scholar 

  • Blanco A, Palencia R, Solis P. Transient phenytoin-induced IgA deficiency and permanent IgE increase. Allergologia et Immunopathologia 14: 535, 1986

    PubMed  CAS  Google Scholar 

  • Blijham GH, Blaauw I, Schutte B, Mendes de Leon DE. Increased numbers of suppressor-cytotoxic cells in a patient with carbamazepine hypersensitivity. Journal of Immunopharmacology 6: 79–85, 1984

    Article  PubMed  CAS  Google Scholar 

  • Boissier MC, Sansonetti P, Dupont B, Lapresle C. Intolérance majeure à la carbamazépine: immunodépression acquise ou allergie? Semaine des Hôpitaux (Paris) 59: 2989–2990, 1983

    CAS  Google Scholar 

  • Botta M, Capra Marzani M, Pavesi M. Linfoadenopatia angioim-munoblastica con disprotidemia (L.A.I.D.) e carbamazepina: a proposito di un caso. Gazzetta Medica Italiana — Archivio Scienze Mediche 144: 711–716, 1985

    Google Scholar 

  • Bradley JM, Sagraves R, Kimbrough AC. Carbamazepine-induced thrombocytopenia in a young child. Clinical Pharmacy 4: 221–223, 1985

    PubMed  CAS  Google Scholar 

  • Brandt L, Nilsson PG. Lymphocytopenia in patients treated with phenytoin. Lancet 1: 308, 1976

    Article  PubMed  CAS  Google Scholar 

  • Burks AW, Charlton R, Casey P, Poindexter A, Steele R. Immune function in patients treated with phenytoin. Journal of Child Neurology 4: 25–29, 1989

    Article  PubMed  CAS  Google Scholar 

  • Charlesworth MEN. Phenytoin-induced pseudolymphoma syndrome: an immunologic study. Archives of Dermatology 113: 477–480, 1977

    Article  PubMed  CAS  Google Scholar 

  • Chennebault JM, Dumont AM, Achard J, Alquier P, Saint-André JP. Insuffisance rénale aiguë, érythrodermie, polyadénopathies au cours d’un traitement par carbamazépine. Thérapie 37: 103–108, 1982

    Google Scholar 

  • Choovivathanavanich P, Wallace EM, Scaglione PR. Pseudolymphoma induced by diphenylhydantoin. Journal of Pediatrics 76: 621–623, 1970

    Article  PubMed  CAS  Google Scholar 

  • Cohen BL, Bovasso GJ. Leukopenia as an unusual component of diphenylhydantoin hypersensitivity: a case with pruritus, rash, fever, lymphadenopathy, but low leukocyte count. Clinical Pediatrics 12: 622–623, 1973

    Article  PubMed  CAS  Google Scholar 

  • Cooke LE, Hardin TC, Hendrickson DJ. Phenytoin-induced pseudolymphoma with mycosis fungoides manifestations. Clinical Pharmacy 7: 153–157, 1988

    PubMed  CAS  Google Scholar 

  • Coope R, Burrows RGR. Treatment of epilepsy with dipheny-lhydantoinate. Lancet 1: 490–492, 1940

    Article  Google Scholar 

  • Danno K, Kume M, Ohta M, Utani A, Ohno S, et al. Erythroderma with generalized lymphadenopathy induced by phenytoin. Journal of Dermatology 16: 392–396, 1989

    PubMed  CAS  Google Scholar 

  • Davies-Jones GAB. Anticonvulsants. In Dukes MNG (Ed.) Meyler’s side effects of drugs, 11th ed., pp. 120–136, Elsevier, Amsterdam, 1988

    Google Scholar 

  • De Marco P, Melchiori G. Carbamazepine and eosinophilia. Annals of Neurology 20: 274, 1986

    Article  PubMed  Google Scholar 

  • Descotes J. Immunotoxicology of drugs and chemicals, 2nd ed., Elsevier, Amsterdam, 1988

  • Descotes J. Drug-induced immune diseases, Elsevier, Amsterdam, 1990

  • Dorfman RF, Warnke R. Lymphadenopathy simulating the malignant lymphomas. Human Pathology 5: 519–550, 1974

    Article  PubMed  CAS  Google Scholar 

  • Dosch H-M, Jason J, Gelfand EW. Transient antibody deficiency and abnormal T suppressor cells induced by phenytoin. New England Journal of Medicine 306: 406–409, 1982

    Article  PubMed  CAS  Google Scholar 

  • Duggan MAK, Court JB. A proposed mechanism of production of the autoimmune and lymphoproliferative side-effects of β-adrenergic-site-blocking drugs and hydantoin anticonvulsants. Annals of Clinical Research 13: 406–418, 1981

    PubMed  CAS  Google Scholar 

  • Eeg-Olofsson O, Janjua NA, Andermann E, Guttmann RD, Osterland K. Immunological and genetic studies in primary generalized corticoreticular epilepsy. Acta Neurologica Scandinavica 74: 425–431, 1986

    Article  PubMed  CAS  Google Scholar 

  • Ferrer Sancho J, Martínez Vázquez JM, Capdevila Morell JA, Ocaña I, Pigrau C, et al. Gammapatía monoclonal transitoria en el curso de una linfadenopatía angioimmunoblástica. Medicina Clinica (Barcelona) 84: 458, 1985

    CAS  Google Scholar 

  • Flowers FP, Araujo OE, Hamm KA. Phenytoin hypersensitivity syndrome. Journal of Emergency Medicine 5: 103–108, 1987

    Article  PubMed  CAS  Google Scholar 

  • Fontana A, Grob PJ. Immunodeficiency in epilepsy: a new view. Journal of Neurology 220: 297–301, 1979

    Article  PubMed  CAS  Google Scholar 

  • Fontana A, Grob PJ, Sauter R. Immunoglobulin abnormalities in relatives of IgA-deficient epileptic. Journal of Neurology 217: 207–212, 1978a

    Article  PubMed  CAS  Google Scholar 

  • Fontana A, Grob PJ, Sauter R, Joller H. IgA deficiency, epilepsy and hydantoin medication. Lancet 2: 228–231, 1976

    Article  PubMed  CAS  Google Scholar 

  • Fontana A, Joller H, Skvaril F, Grob PJ. Immunological abnormalities and HLA antigen frequencies in IgA deficient patients with epilepsy. Journal of Neurology, Neurosurgery, and Psychiatry 41: 593–597, 1978b

    Article  PubMed  CAS  Google Scholar 

  • Fossan GO. Reduced CSF IgG in patients treated with phenytoin (diphenylhydantoin). European Neurology 14: 426–432, 1976

    Article  PubMed  CAS  Google Scholar 

  • Fried MP, Sunwoo Y. Anticonvulsant-induced lymphoma. Laryngoscope 84: 1770–1781, 1974

    Google Scholar 

  • Fujimoto Y, Ikoma R, Shimizu T, Shimizu A. Effect of zonisamide on serum immunoglobulins. Arzneimittel-Forschung 40: 855–858, 1990

    PubMed  CAS  Google Scholar 

  • Gabourel JD, Davies GH, Bardana EJ, Ratzlaff NA. Phenytoin influence on human lymphocyte mitogen response: a prospective study of epileptic and nonepileptic patients. Epilepsia 23: 367–376, 1982

    Article  PubMed  CAS  Google Scholar 

  • Gabrys K, Medras E, Kowalski P, Gola A. Wystapienie chloniaka zlosliwego w przebiegu leczenia przeciwdrgawkowego. Polski Tygodnik Lekarski 38: 505–507, 1983

    PubMed  CAS  Google Scholar 

  • Gams RA, Neal JA, Conrad FG. Hydantoin-induced pseudopseudolymphoma. Annals of Internal Medicine 69: 557–568, 1968

    PubMed  CAS  Google Scholar 

  • Garzon P, Gonzalez-Cornejo S, Hernandez-Hernandez G, Aguirre-Portillo L, Almodovar-Cuevas C, et al. Effects of antiepileptic drugs on concentrations of serum proteins and immunoglobulins of epileptic patients. General Pharmacology 17: 49–55, 1986

    Article  PubMed  CAS  Google Scholar 

  • Gaulier A, Marsan C, Sigal S, Perron J, Loutre JC. Lymphadénopathie dysimmunitaire, érythrodermie et troubles hématologiques au cours d’un traitement par la carbamazépine. Nouvelle Presse Médicale 9: 1388, 1980

    PubMed  CAS  Google Scholar 

  • Gennis MA, Vemuri R, Burns EA, Hill JV, Miller MA, et al. Familial occurrence of hypersensitivity to phenytoin. American Journal of Medicine 91: 631–634, 1991

    Article  PubMed  CAS  Google Scholar 

  • Gerson WT, Fine DG, Spielberg SP, Sensenbrenner LL. Anticonvulsant-induced aplastic anemia: increased susceptibility to toxic drug metabolites in vitro. Blood 61: 889–893, 1983

    PubMed  CAS  Google Scholar 

  • Gilhus NE. The in vitro effect of phenytoin and carbamazepine on subpopulations of human blood mononuclear cells. International Journal of Immunopharmacology 5: 283–288, 1983

    Article  PubMed  CAS  Google Scholar 

  • Gilhus NE. Effect of phenytoin and carbamazepine on subpopulations of mononuclear blood cells as defined by membranc antigens. International Archives of Allergy and Applied Immunology 74: 80–83, 1984

    Article  PubMed  CAS  Google Scholar 

  • Gilhus NE, Aarli JA. The reversibility of phenytoin-induccd IgA deficiency. Journal of Neurology 226: 53–61, 1981a

    Article  PubMed  CAS  Google Scholar 

  • Gilhus NE, Aarli JA. Respiratory disease and nasal immunoglobulin concentrations in phenytoin-treated epileptic patients. Acta Neurologica Scandinavica 63: 34–43, 1981b

    Article  PubMed  CAS  Google Scholar 

  • Gilhus NE, Aarli JA, Thorsby E. HLA antigens in epileptic patients with drug-induced immunodeficiency. International Journal of Immunopharmacology 4: 517–520, 1982a

    Article  PubMed  CAS  Google Scholar 

  • Gilhus NE, Lea T. Carbamazepine: effect on IgG subclasses in epileptic patients. Epilepsia 29: 317–320, 1988

    Article  PubMed  CAS  Google Scholar 

  • Gilhus NE, Matre R. Carbamazepine effects on mononuclear blood cells in epileptic patients. Acta Neurologica Scandinavica 74: 181–185, 1986

    Article  PubMed  CAS  Google Scholar 

  • Gilhus NE, Matre R, Aarli JA. Lymphocyte subpopulations and lymphocyte function in phenytoin-treated patients with epilepsy. International Journal of Immunopharmacology 4: 43–48, 1982b

    Article  PubMed  CAS  Google Scholar 

  • Gilhus NE, Strandjord RE, Aarli JA. The effect of carbamazepine on serum immunoglobulin concentrations. Acta Neurologica Scandinavica 66: 172–179, 1982c

    Article  PubMed  CAS  Google Scholar 

  • Gleichman HIK, Pals ST, Radaszkiewicz T. T cell-dependent B-cell proliferation and activation induced by administration of the drug diphenylhydantoin to mice. Hematological Oncology 1: 165–176, 1983

    Article  Google Scholar 

  • Gouet D, Rouffineau J, Pouget-Abadie JF, Besson I, Becq-Giraudon B. Lymphadénopathie dysimunitaire survenant au cours d’un traitement par la carbamazépine: deux observations. Revue de Médecine Interne 5: 72–74, 1984

    Article  PubMed  CAS  Google Scholar 

  • Grindulis KA, Nichol FE, Oldham R. Phenytoin in rheumatoid arthritis. Journal of Rheumatology 13: 1035–1039, 1986

    PubMed  CAS  Google Scholar 

  • Grob PJ, Herold GE. Immunological abnormalities and hydantoins. British Medical Journal 2: 561–563, 1972

    Article  PubMed  CAS  Google Scholar 

  • Guerra IC, Fawcett WA IV, Redmon AH, Lawrence EC, Rosenblatt HM, et al. Permanent intrinsic B cell immunodeficiency caused by phenytoin hypersensitivity. Journal of Allergy and Clinical Immunology 77: 603–608, 1986

    Article  PubMed  CAS  Google Scholar 

  • Hadzic N, Portman B, Davies ET, Mowal AP, Mieli-Vergani G. Acute liver failure induced by carbamazepine. Archives of Disease in Childhood 65: 315–317, 1990

    Article  PubMed  CAS  Google Scholar 

  • Haldorsen T, Aarli JA. Immunoglobulin concentrations in first-degree relatives of epileptic patients with drug-induced IgA deficiency. Acta Neurologica Scandinavica 56: 608–612, 1977

    Article  PubMed  CAS  Google Scholar 

  • Halevy S, Feuerman EJ. Pseudolymphoma syndrome. Dermatologica 155: 321–327, 1977

    Article  PubMed  CAS  Google Scholar 

  • Haruda F. Phenytoin hypersensitivity: 38 cases. Neurology 29: 1480–1485, 1979

    Article  PubMed  CAS  Google Scholar 

  • Herberman RB. Natural killer cells and their possible roles in host resistance against tumors. Transplantation Proceedings 16: 476–478, 1984

    PubMed  CAS  Google Scholar 

  • Huijgens PC, Thijs LG, Den Ottolander GJ. Pure red cell aplasia, toxic dermatitis and lymphadenopathy in a patient taking diphenylhydantoin. Acta Haematologica 59: 31–36, 1978

    Article  PubMed  CAS  Google Scholar 

  • Hyman GA, Sommers SC. The development of Hodgkin’s disease and lymphoma during anticonvulsant therapy. Blood 28: 416–427, 1966

    PubMed  CAS  Google Scholar 

  • Hyman LR, Ballow M, Knieser MR. Diphenylhydantoin interstitial nephritis: roles of cellular and humoral immunologic injury. Journal of Pediatrics 92: 915–920, 1978

    Article  PubMed  CAS  Google Scholar 

  • Iivanainen M, Syriänen J, Waltimo O, Valtonen VV. Increased bacterial antibody titres and IgA deficiency in epileptic patients. British Medical Journal 294: 677, 1987

    Article  PubMed  CAS  Google Scholar 

  • Isobe T, Tomita M, Matsumoto J, Itoh T, Fujita T. Haematologic and immunologic aberrations in patients under diphenylhydantoin administration. Acta Haematologica Japonica 46: 1–5, 1983

    PubMed  CAS  Google Scholar 

  • Jain KK. Systemic lupus erythematosus (SLE)-like syndromes associated with carbamazepine therapy. Drug Safety 6: 350–360, 1991

    Article  PubMed  CAS  Google Scholar 

  • Josephs SH, Rothman SJ, Buckley RH. Phenytoin hypersensitivity. Journal of Allergy and Clinical Immunology 66: 166–172, 1980

    Article  PubMed  CAS  Google Scholar 

  • Joubert PH, Aucamp AK, Potgieter GM, Verster F. Epilepsy and IgA deficiency: the effect of sodium valproate. South African Medical Journal 52: 642–644, 1977

    PubMed  CAS  Google Scholar 

  • Jungi WF, Senn HJ, Stanisic M, Rösli R. Maligne Lymphome nach jahrelanger Epilepsiebehandlung mit Hydantoinpräparaten? Schweizerische Medizinische Wochenschrift 105: 1735–1737, 1975

    PubMed  CAS  Google Scholar 

  • Kahn HD, Faguet GB, Agee JF, Middleton HM. Drug-induced liver injury: in vitro demonstration of hypersensitivity to both phenytoin and phenobarbital. Archives of Internal Medicine 144: 1677–1679, 1984

    Article  PubMed  CAS  Google Scholar 

  • Kanoh T, Uchino H. Immunodeficiency and epilepsy. Lancet 1: 860–861, 1976

    Article  PubMed  CAS  Google Scholar 

  • Katzin WE, Julius CJ, Tubbs RR, McHenry MC. Lymphoproliferative disorders associated with carbamazepine. Archives of Pathology and Laboratory Medicine 114: 1244–1248, 1990

    PubMed  CAS  Google Scholar 

  • Khayat D, Marty M, Brocheriou C, Jacquillat C. Lymphome non hodgkinien après maladie de Hodgkin chez un malade recevant des hydantoïnes. Nouvelle Presse Médicale 35: 2637–2638, 1982

    Google Scholar 

  • Kleckner HB, Yakulis V, Heller P. Severe hypersensitivity to diphenylhydantoin with circulating antibodies to the drug. Annals of Internal Medicine 83: 522–523, 1975

    PubMed  CAS  Google Scholar 

  • Kornberg A, Kobrin I. IgG antiplatelet antibodies due to carbamazepine. Acta Haematologica 68: 68–70, 1982

    Article  PubMed  CAS  Google Scholar 

  • Lapes MJ, Vivacqua RJ, Antoniades K. Immunoblastic lymphadenopathy associated with phenytoin (diphenylhydantoin). Lancet 24: 198, 1976

    Article  Google Scholar 

  • Leppik IE, Lapora J, Lowenson R. Seasonal incidence of phenytoin allergy unrelated to plasma levels. Archives of Neurology 42: 120–122, 1985

    Article  PubMed  CAS  Google Scholar 

  • Li FP, Willard DR, Goodman R, Vawter G. Malignant lymphoma after diphenylhydantoin (Dilantin) therapy. Cancer 36: 1359–1362, 1975

    Article  PubMed  CAS  Google Scholar 

  • Lillie MA, Yang LC, Honig PJ, August CS. Erythroderma, hypogammaglobulinemia, and T-cell lymphocytosis: occurrence following therapy with phenytoin. Archives of Dermatology 119: 415–418, 1983

    Article  PubMed  CAS  Google Scholar 

  • MacFarlane DG, Clark B, Panayi GS. Pilot study of phenytoin in reumathoid arthritis. Annals of the Rheumatic Diseases 45: 954–956, 1986

    Article  PubMed  CAS  Google Scholar 

  • MacICinney AA, Booker HE. Diphenylhydantoin effects on human lymphocytes in vitro and in vivo. Archives of Internal Medicine 129: 988–992, 1972

    Article  Google Scholar 

  • MacKinney AA, Knobeloch L. Diphenylhydantoin inhibits cortisol-induced lysis of thymocytes. Proceedings of the Society for Experimental Biology and Medicine 182: 474–477, 1986

    PubMed  CAS  Google Scholar 

  • MacKinney AA, Vyas R. The assay of diphenylhydantoin effects on growing human lymphocytes. Journal of Pharmacology and Experimental Therapeutics 186: 37–43, 1973

    PubMed  CAS  Google Scholar 

  • Maguire JH, Wettrell G, Rane A. Apparently normal phenytoin metabolism in a patient with phenytoin-induced rash and lymphadenopathy. British Journal of Clinical Pharmacology 24: 554–557, 1987

    Article  PubMed  CAS  Google Scholar 

  • Marcoli M, Gatti G, Ippoliti G, Lombardi M, Crema A, et al. Effect of chronic anticonvulsant monotherapy on lymphocyte subpopulations in adult epileptic patients. Human Toxicology 4: 147–157, 1985

    Article  PubMed  CAS  Google Scholar 

  • Margaretten NC, Hincks JR, Warren RP, Coulombe Jr RA. Effects of phenytoin and carbamazepine on human natural killer cell activity and genotoxicity in vitro. Toxicology and Applied Pharmacology 87: 10–17, 1987

    Article  PubMed  CAS  Google Scholar 

  • Massimo L, Pasino M, Rosanda-Vadalà C, Tonini GP, De Negri M, et al. Immunological side-effects of anticonvulsants. Lancet 1: 860, 1976

    Article  PubMed  CAS  Google Scholar 

  • Matson JR, Krous HF, Blackstock R. Diphenylhydantoin-induced hypersensensitivity reaction with interstitial nephritis. Human Pathology 16: 94–97, 1985

    Article  PubMed  CAS  Google Scholar 

  • Matzner Y, Polliack A. Lymphoproliferative disorders in four patients receiving chronic diphenylhydantoin therapy: etiologic correlation or chance association? Israel Journal of Medical Sciences 14: 865–869, 1978

    PubMed  CAS  Google Scholar 

  • McCarthy LJ, Aguilar JC, Ransburg R. Fatal benign phenytoin lymphadenopathy. Archives of Internal Medicine 139: 367–368, 1979

    Article  PubMed  CAS  Google Scholar 

  • Meissner O, Joubert HF, Joubert PH, Van der Meyden CH, Studzinski W. IgA in epileptics receiving anticonvulsivant therapy. European Journal of Clinical Pharmacology 25: 491–495, 1983

    Article  PubMed  CAS  Google Scholar 

  • Meissner O, Joubert PH, Joubert HF, Van der Merwe CA. The IgA immune system in epileptics on anticonvulsant therapy. European Journal of Clinical Pharmacology 27: 81–83, 1984

    PubMed  CAS  Google Scholar 

  • Menitove JE, Rassiga AL, McLaren GD, Daniel TM, Mahmoud AAF. Antigranulocyte antibodies and deranged immune function associated with phenytoin-induced serum sickness. American Journal of Rheumatology 10: 277–284, 1981

    CAS  Google Scholar 

  • Michael JR, Mitch WE. Reversible renal failure and myositis caused by phenytoin hypersensitivity. Journal of the American Medical Association 236: 2773–2775, 1976

    Article  PubMed  CAS  Google Scholar 

  • Moutard ML, Bavoux F, Mensire A, Lebourges F, Ponsot G. Nephrite tubulo-interstitielle immuno-allergique secondaire à la prise de carbamazépine. Archives Françaises de Pédiatrie 44: 191–193, 1987

    PubMed  CAS  Google Scholar 

  • Murphy JE, Stewart RB, Springer PK. Carbamazepine-induced leukocytosis. American Journal of Hospital Pharmacy 37: 550–552, 1980

    PubMed  CAS  Google Scholar 

  • Murphy JM, Mashman J, Miller JD, Bell JB. Suppression of carbamazepine-induced rash with prednisone. Neurology 41: 144–145, 1991

    Article  PubMed  CAS  Google Scholar 

  • Musolino R, Natoli M, Gallitto G, Morgante L, Serra S, et al. The effect of chronic n-dipropylacetamide (Depamide) treatment on plasmatic immunoglobulins of epileptic patients. Acta Neurologica 35: 115–120, 1980

    Google Scholar 

  • Neilan BA, Leppik IE. Phenytoin and formation of T lymphocyte rosettes. Archives of Neurology 37: 580–581, 1980

    Article  PubMed  CAS  Google Scholar 

  • Newcom SR, Kadin ME. T-cell leukemia with thymic involution. Cancer 43: 622–626, 1979

    Article  PubMed  CAS  Google Scholar 

  • Oates RK, Tonge RE. Phenytoin and the pseudolymphoma syndrome. Medical Journal of Australia 2: 371–373, 1971

    PubMed  CAS  Google Scholar 

  • Okamoto Y, Shimizu K, Tamura K, Yamada M, Matsui Y, et al. Effects of anticonvulsants on cellular immunity (in Japanese). No To Shinkei 41: 299–304, 1989

    PubMed  CAS  Google Scholar 

  • O’Keane JC. Non Hodgkin lymphoma and carbamazepine. Lancet 2: 1275–1276, 1989

    Article  PubMed  Google Scholar 

  • Olsson R, Zettergren L. Anticonvulsant-induced liver damage. American Journal of Gastroenterology 83: 576–577, 1988

    PubMed  CAS  Google Scholar 

  • Öner A, Topaloglu R, Besbas N, Topaloglu H. Carbamazepine induced systemic lupus erythematosus: another warning. Clinical Neurology and Neurosurgery 92–3: 261–262, 1990

    Article  Google Scholar 

  • Pacifici R, Paris L, Di Carlo S, Pichini S, Zuccaro P. Immunologie aspects of carbamazepine treatment in epileptic patients. Epilepsia 32: 122–127, 1991

    Article  PubMed  CAS  Google Scholar 

  • Paladini G, Marinig L. Effetti collaterali immunoallergici indotti dalla somministrazione di carbamazepina: contribute casistico. Minerva Medica 75: 1651–1655, 1984

    PubMed  CAS  Google Scholar 

  • Pelekanos J, Camfield P, Camfield C, Gordon K. Allergic rash due to antiepileptic drugs: clinical features and management. Epilepsia 32: 554–559, 1991

    Article  PubMed  CAS  Google Scholar 

  • Pellock JM. Carbamazepine side effects in children and adults. Epilepsia 28 (Suppl. 3): S64–S70, 1987

    Article  PubMed  Google Scholar 

  • Penarrocha Diago M, Antolin Rodriguez MA, Alfaro Giner A, Perez Sirvent ML. [Hematologic alterations and reduction in serum folate in epileptics treated with anticonvulsants]. Neurologia 4: 119–123, 1989

    PubMed  CAS  Google Scholar 

  • Pereira A, Cervantes F, Rozman C. Anemia macrocitica por deficit de ácido fólico y linfoma no hodgkiniano asociados a la ingesta prolongada de difenilhidantoina. Medicina Clínica (Barcelona) 85: 503–505, 1985

    CAS  Google Scholar 

  • Pisciotta AV. Carbamazepine: hematologic toxicity. In Woodbury DM (Ed.) Antiepileptic drugs, pp. 533–541, Raven Press, New York, 1982

    Google Scholar 

  • Prosser TR, Lander RD. Phenytoin-induced hypersensitivity reactions. Clinical Pharmacy 6: 728–734, 1987

    PubMed  CAS  Google Scholar 

  • Puppo F, Adami GF, Corsini G, Zavarise GM, Zattoni J. Effect of a single oral dose of phenobarbitone on lymphocyte blastogenic response in man. British Journal of Anaesthesia 52: 1205–1207, 1980

    Article  PubMed  CAS  Google Scholar 

  • Rausing A, Trell E. Malignant lymphogranulomatosis and anticonvulsant therapy. Acta Medica Scandinavica 189: 131–136, 1971

    Article  PubMed  CAS  Google Scholar 

  • Reents SB, Luginbuhl WE, Davis SM. Phenytoin-carbamazepine cross-sensitivity. Drug Intelligence and Clinical Pharmacy 23: 235–236, 1989

    CAS  Google Scholar 

  • Reiffers J. Les pseudo-lymphomes et les lymphomes induits par les hydantoïnes. Nouvelle Revue Française d’Hématologie 20: 131–138, 1978

    PubMed  CAS  Google Scholar 

  • Ricevuti G, Marcoli M, Gatti G, Mazzone A, Lecchini S, et al. Assessment of polymorphonucleate leucocyte functions in adult epileptic patients undergoing long-term phenytoin treatment. Human Toxicology 5: 237–241, 1986

    Article  PubMed  CAS  Google Scholar 

  • Rosenthal CJ, Noguera CA, Coppola A, Kapeiner SN. Pseudolymphoma with mycosis fungoides manifestations, hyperresponsiveness to diphenylhydantoin, and lymphocyte disregulation. Cancer 49: 2305–2314, 1982

    Article  PubMed  CAS  Google Scholar 

  • Rouffineau J, Besson I, Brechoire D, Lebezu M, Pouget-Abadie JF, et al. Lymphadénopathie angio-immunoblastique induite par la carbamazépine: à propos d’une observation d’évolution spontanément favorable. Archives de Médecine de l’Ouest 13: 446, 1981

    Google Scholar 

  • Ruff ME, Pincus LG, Sampson HA. Phenytoin-induced IgA depression. American Journal of Diseases of Children 141: 858–861, 1987

    PubMed  CAS  Google Scholar 

  • Saltzstein SL, Ackerman LV. Lymphadenopathy induced by anticonvulsant drugs and mimicking clinically and pathologically malignant lymphoma. Cancer 12: 164–182, 1959

    Article  PubMed  CAS  Google Scholar 

  • Schlaifer D, Arlet P, Oilier S, Montane P, Le Tallec Y, et al. Carbamazepine update. Lancet 2: 980–981, 1989

    Google Scholar 

  • Schlumpf M, Ramseier H, Lichtensteiger W. Prenatal diazepam induced persisting depression of cellular immune response. Life Sciences 44: 493–501, 1989

    Article  PubMed  CAS  Google Scholar 

  • Schoenfeld Y, Ben Baruch N, Livni E, Santo M, Pinkhas J. Carbamazepine (Tegretol)-induced thrombocytopenia. Acta Haematologica 68: 74, 1982

    Article  Google Scholar 

  • Schweiger F-J, Kelton JG, Messner H, Klein M, Berger S, et al. Anticonvulsant-induced marrow suppression and immune thrombocytopenia. Acta Haematologica 80: 54–58, 1988

    Article  PubMed  CAS  Google Scholar 

  • Schwinghammer TL, Howrie DL. Phenytoin-induced lymphadenopathy. Drug Intelligence and Clinical Pharmacy 17: 460–462, 1983

    PubMed  CAS  Google Scholar 

  • Seager J, Jamison DL, Wilson J, Hayward AR, Soothill JF. IgA deficiency, epilepsy and phenytoin treatment. Lancet 2: 632–635, 1975

    Article  PubMed  CAS  Google Scholar 

  • Seetharam MN, Pellock JM. Risk-benefit assessment of carbamazepine in children. Drug Safety 6: 148–158, 1991

    Article  PubMed  CAS  Google Scholar 

  • Severson GS, Harrington DS, Burnett DA, Linder J. Dermatopathic lymphadenopathy associated with carbamazepine: a case mimicking a lymphoid malignancy. American Journal of Medicine 83: 597–599, 1987

    Article  PubMed  CAS  Google Scholar 

  • Seyfeddinipur N. Lymphoadenopathie bei Phenytoin-Behandlung. Deutsche Medizinische Wochenschrift 101: 1454–1456, 1976

    Article  PubMed  CAS  Google Scholar 

  • Shakir RA, Behan PO, Dick H, Lambie DG. Metabolism of immunoglobulin A, lymphocyte function, and histocompatibility antigens in patients on anticonvulsants. Journal of Neurology, Neurosurgery, and Psychiatry 41: 307–311, 1978

    Article  PubMed  CAS  Google Scholar 

  • Shuttleworth D, Graham-Brown RAC, Williams AJ, Cambell AC, Sewell H. Pseudo-lymphoma associated with carbamazepine. Clinical and Experimental Dermatology 9: 421–423, 1984

    Article  PubMed  CAS  Google Scholar 

  • Silverman AK, Fairley J, Wong RC. Cutaneous and immunologic reactions to phenytoin. Journal of the American Academy of Dermatology 18: 721–741, 1988

    Article  PubMed  CAS  Google Scholar 

  • Singsen BH, Fishman L, Hanson V. Antinuclear antibodies and lupus-like syndromes in children receiving anticonvulsants. Pediatrics 57: 529–534, 1976

    PubMed  CAS  Google Scholar 

  • Sinnige HAM, Boender CA, Kuypers EW, Ruitenberg HM. Carbamazepine-induced pseudolymphoma and immune dysregulation. Journal of Internal Medicine 227: 355–358, 1990

    Article  PubMed  CAS  Google Scholar 

  • Sinues B, Conde B, Martinez P, Cisterna R. Repercussion of antiepileptic treatment with phenobarbitone and phenytoin on some parameters of immunity: comparative study. International Journal of Immunopharmacology 4: 328, 1982

    Article  Google Scholar 

  • Sisca TS. An unusual dual hypersensitivity reaction induced by diphenylhydantoin. American Journal of Hospital Pharmacy 30: 446–449, 1973

    PubMed  CAS  Google Scholar 

  • Slavin BN, Fenton GM, Laundy M, Reynolds EH. Serum immunoglobulins in epilepsy. Journal of Neurological Sciences 23: 353–357, 1974

    Article  CAS  Google Scholar 

  • Smith QT, Hamilton MJ, Biros MH, Pihlstrom BL. Salivary and plasma IgA of seizure subjects receiving phenytoin. Epilepsia 20: 17–23, 1979

    Article  PubMed  CAS  Google Scholar 

  • Smythe MA, Umstead GS. Phenytoin hepatotoxicity: a review of the literature. Drug Intelligence and Clinical Pharmacy 23: 13–18, 1989

    CAS  Google Scholar 

  • Sorrell TC, Forbes IJ. Depression of immune competence by phenytoin and carbamazepine. Studies in vivo and in vitro. Clinical and Experimental Immunology 20: 273–285, 1975

    PubMed  CAS  Google Scholar 

  • Sorrell TC, Forbes IJ, Burness FR, Rischbieth RHC. Depression of immunological function in patients treated with phenytoin sodium (sodium diphenylhydantoin). Lancet 2: 1233–1235, 1971

    Article  PubMed  CAS  Google Scholar 

  • Spiers EM, Potts RC, Simpson JRM, MacConnachie A, Beck JA. Mechanisms by which barbiturates suppress lymphocyte responses to phytohaemagglutinin stimulation. International Journal of Immunopharmacology 9: 505–512, 1987

    Article  PubMed  CAS  Google Scholar 

  • Stanley J, Fallon-Pellicci V. Phenytoin hypersensitivity reaction. Archives of Dermatology 114: 1350–1353, 1978

    Article  PubMed  CAS  Google Scholar 

  • Strandjord RE, Johannessen SI, Aarli JA. Serum concentrations of immunoglobulins in patients with epilepsy treated with carbamazepine. Acta Neurologica Scandinavica 61: 260–263, 1980

    Article  PubMed  CAS  Google Scholar 

  • Stroink AR, Skillrud DM, Kiely JM, Sundt Jr TM. Carbamazepine-induced hemolytic anemia. Acta Haematologica 72: 346–348, 1984

    Article  PubMed  CAS  Google Scholar 

  • Talesnik E, Rivero SJ, Gonzalez B. Serum IgA deficiency induced by prolonged phenytoin treatment. Revista de Investigación Clinica 41: 331–335, 1989

    PubMed  CAS  Google Scholar 

  • Tartara A, Verri AP, Nespoli L, Moglia A, Botta MG. Immunological findings in epileptic and febrile convulsion patients before and under treatment. European Neurology 20: 306–311, 1981

    Article  PubMed  CAS  Google Scholar 

  • Tasaka K, Terao R, Uokawa M, Miyake H, Kamei C. Immunological studies on delayed hypersensitivity to phenytoin-II: the delayed skin reaction induced by BSA-phenytoin conjugate. International Journal of Immunopharmacology 9: 401–409, 1987

    Article  CAS  Google Scholar 

  • Thatcher N, Wan HH, Swindell R, Wilkinson PM, Crowther D. Effects of diphenylhydantoin on killer cell activity and other immunological functions: a sequential study including the interaction of Corynebacterium parvum in melanoma patients. International Journal of Immunopharmacology 4: 167–174, 1982

    Article  PubMed  CAS  Google Scholar 

  • Tomsick RS. The phenytoin syndrome. Cutis 32: 535–541, 1983

    PubMed  CAS  Google Scholar 

  • Travin M, Macris NT, Block JM, Schwimmer D. Reversible common variable immunodeficiency syndrome induced by phenytoin. Archives of Internal Medicine 149: 1421–1422, 1989

    Article  PubMed  CAS  Google Scholar 

  • Tsung SH, Lin JI. Angioimmunoblastic lymphadenopathy in a patient taking diphenylhydantoin. Annals of Clinical and Laboratory Science 11: 542–545, 1981

    PubMed  CAS  Google Scholar 

  • Valli M, Jadot G, Bussiere H, Bouyard P. Immunoglobulines sé-riques et traitement par la phénytoïne. Thérapie 37: 694–695, 1982

    PubMed  CAS  Google Scholar 

  • Vellucci A, Galanti G, Pezzella B, De Longis P, Colacecchi C. Su un caso di pseudo-linfoma esantematico da ipersensibilità alla difenilidantoina, con transitorio deficit immunologico. Clinica Terapeutica 94: 229–237, 1980

    PubMed  CAS  Google Scholar 

  • Verdier F, Brouland JP, Virat M, Descotes J. Phénytoine et test du ganglion poplité chez le rat Sprague Dawley. Journal de Toxicologie Clinique et Expérimentale 10: 161–167, 1990

    PubMed  CAS  Google Scholar 

  • Vesin P, Periac P, Kalifat R, Intrator L, Tulliez M, et al. Lymphadénopathie et anomalies protidiques après traitement par la phénylhydantoïne. Nouvelle Presse Médicale 5: 1125–1127, 1976

    PubMed  CAS  Google Scholar 

  • Webster RO, Goldstein IM, Flick MR. Selective inhibition by phenytoin of chemotactic factor-stimulated neutrophil functions. Journal of Laboratory and Clinical Medicine 103: 22–33, 1984

    PubMed  CAS  Google Scholar 

  • Weedon AP. Diphenylhydantoin sensitivity: a syndrome resembling infectious mononucleosis with a morbilliform rash and cholestatic hepatitis. Australian and New Zealand Journal of Medicine 5: 561–563, 1975

    Article  PubMed  CAS  Google Scholar 

  • Wilden JN, Scott CA. A pseudolymphomatous reaction in soft tissue associated with phenytoin sodium. Journal of Clinical Pathology 31: 761–764, 1978

    Article  PubMed  CAS  Google Scholar 

  • Wolf R, Kahane E, Sandbank M. Mycosis fungoides-like lesions associated with phenytoin therapy. Archives of Dermatology 121: 1181–1182, 1985

    Article  PubMed  CAS  Google Scholar 

  • Yates P, Stockdill G, Mclntyre M. Hypersensitivity to carbamazepine presenting as pseudolymphoma. Journal of Clinical Pathology 39: 1224–1228, 1986

    Article  PubMed  CAS  Google Scholar 

  • Zimmer JP, Lehr HA, Kornhuber ME, Breitig D, Montagnier L, et al. Diphenylhydantoin (DPH) blocks HIV-receptor on T-lymphocyte surface. Blut 53: 447–450, 1986

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Internal Medicine and Therapeutics, Section of Pharmacology, University of Pavia, 2nd Faculty of Medicine, Viale Luigi Borri 57, I-21100, Varese VA, Italy

    Fabrizio De Ponti, Sergio Lecchini, Marco Cosentino, Carlo Maria Castelletti, Anna Malesci &  Gian Mario Frigo

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De Ponti, F., Lecchini, S., Cosentino, M. et al. Immunological Adverse Effects of Anticonvulsants. Drug-Safety 8, 235–250 (1993). https://doi.org/10.2165/00002018-199308030-00005

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