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December 1962, Vol 104, No. 6 >
Article | December 1962

Aplastic Anemia Secondary to Anticonvulsants FREE

M. MORENO ROBINS, M.D.
[+] Author Affiliations

Submitted for publication Jan. 16, 1962.


Am J Dis Child. 1962;104(6):614-624. doi:10.1001/archpedi.1962.02080030614006.
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The physician confronted with aplastic anemia in a patient being treated with anticonvulsant medication wishes to know (1) which medication may have produced the marrow dysfunction, (2) how could the aplasia have been anticipated and avoided, (3) what is the prognosis once the disease has developed, and (4) what therapy is available. The search for an answer to these questions led to the present study.

Since the review in 1950 by Best and Paul1 of 17 cases of aplastic anemia secondary to anticonvulsant medication, articles on this subject have been largely limited to case reports. This report is a summary and discussion of 48 case reports. In addition we are reporting the development of aplastic anemia in a patient who had been receiving multiple anticonvulsants.

Report of a Case  A 7-year-old white girl was admitted to the University of Washington Hospital on Aug. 6, 1960, with a referring

REFERENCES

1 +
Best, W. R., and Paul, J. T.:  Severe Hypoplastic Anemia Following Anticonvulsant Medication , Amer. J. Med. 8:124, 1950;.
2 +
Robins, M. M., and Noyes, W. D.:  Aplastic Anemia Treated with Bone-Marrow Transfusion from an Identical Twin , New Engl. J. Med. 265: 974, 1961;.
3 +
Hasselback, R. C., and Thomas, J. W.:  Aplastic Anemia , Canad. Med. Ass. J. 82:1253, 1960;.
4 +
Swartout, R. III:  Two Cases of Fatal Pancytopenia Following Mesantoin Therapy , Calif. Med. 78:138, 1953;.
5 +
Frank, C. W., and Holland, J. F.:  Pancytopenia from "Mesantoin," J.A.M.A. 138:1148, 1948;.
6 +
Burrell, Z. L.:  Fatal Pancytopenia as a Result of Improperly Supervised Mesantoin Therapy , Amer. Practit. 6:726, 1955;.
7 +
England, N. J., and McEachern, D.:  Acute Aplastic Anemia During Mesantoin Therapy , Canad. Med. Ass. J. 60:173, 1949;.
8 +
Scott, J. L.; Cartwright, G. E., and Wintrobe, M. M.:  Acquired Aplastic Anemia: An Analysis of 39 Cases and Review of the Pertinent Literature , Medicine (Balt.) 38:119, 1959;.
9 +
Mohler, D. N., and Leavell, B. S.:  Aplastic Anemia: An Analysis of 50 Cases , Ann. Intern. Med. 49:326, 1958;.
10 +
Aird, R. B.:  The Treatment of Epilepsy with Methylphenylethyl Hydantoin (Mesantoin) , Calif. Med. 68:141, 1948;.
11 +
Davies, R. R.; Fisch, C., and Tischer, E. P.:  Pancytopenia Due to Mesantoin: Report of a Case , New Engl. J. Med. 242:863, 1950;.
12 +
Nielsen, D. I.:  Aplastic Anemia Following Mesantoin with Recovery , Ann. West. Med. Surg. 6:562, 1952;.
13 +
Stillman, S.; Bedell, S. G., and Leavitt, D.:  Fatal Aplastic Anemia Associated with Mesantoin: Report of a Case with Autopsy , J. Florida Med. Ass. 37:496, 1951;.
14 +
Weller, R. W., and Metcalfe, J.:  Fatal Pancytopenia Following the Use of Mesantoin: Report of a Case , New Engl. J. Med. 241:17, 1949;.
15 +
Bloom, N.; Lynch, J. P., and Brick, H.:  "Mesantoin" Poisoning with Aplastic Anemia and Recovery , J.A.M.A. 138:498, 1948;.
16 +
Witkind, E., and Waid, M. E.:  Aplasia of the Bone Marrow During Therapy: Report of a Fatal Case , J.A.M.A. 147:757, 1951;.
17 +
Merlis, J. K.: Personal communication
18 +
Tyler, M. W., and King, E. Q.:  Phenacemide in Treatment of Epilepsy , J.A.M.A. 147:17, 1951;.
19 +
Dreyer, V. R.:  Therapieschaden durch antiepileptische Mittel unter besonderer Berücksichtigung schwerer Nebenwirkungen an Hand der Literatur und eigener Fälle , Fortschr. Neurol. Psychiat. 27:401, 1959;.
20 +
Spring, M., and Soltz, W. B.:  Fatal Aplastic Anemia Due to Methylphenylethyl Hydantoin (Mesantoin) , New York J. Med. 55:3478, 1955;.
21 +
Weinmann, O.:  Ein weiterer Fall von aplastischer Anämie durch Mesantoin , Wien. Klin. Wschr. 63:587, 1951;.
22 +
Meier, U.:  Knochenmarksschädigung durch moderne Antikonvulsiva (Hydantoinkörper und Tridion) , Deutsch. Med. Wschr. 78:1107, 1953;.
23 +
Hofstatter, L.:  Mesantoin in the Management of the Hospitalized Psychotic Epileptic: Report of Toxic Effects and One Fatality , Southern Med. J. 44:827, 1951;.
24 +
Weiss, H. A., and Hawley, W. D.:  Pancytopenia Following the Use of Mesantoin and Thianton: Report of a Fatal Case , U.S. Armed Forces Med. J. 2:83, 1951;.
25 +
Forster, F. M., and Frankel, K.:  Fatal Aplastic Anemia During Anticonvulsant Therapy , Dis. Nerv. Syst. 10:108, 1949;.
26 +
Klaus, V. E.:  Pancytopenie durch Tridion , Acta Haemat. (Basel) 5:74, 1951;.
27 +
Harrison, F. F.; Johnson, R. D., and Ayer, D.:  Fatal Aplastic Anemia Following Use of Tridione and a Hydantoin , J.A.M.A. 132:11, 1946;.
28 +
Smith, J. C.; Heinle, R. W., and Kimball, O. P.:  Hypoplastic Anemia in a Patient Treated Unfavorably with Tridione: A Case Report , Ohio Med. J. 45:582, 1949;.
29 +
Gentry, E., and Hill, L. F.:  Granulocytopenia and Death Following the Use of Trimethadione , Amer. J. Dis. Child. 75:582, 1948;.
30 +
Briggs, J. N., and Emery, J. L.:  Toxic Effects of Tridione , Lancet 1:59, 1949;.
31 +
Braithwaite, R. F.:  A Fatal Case of Agranulocytosis Associated with Tridione Therapy , Brit. Med. J. 1:14, 1948;.
32 +
Gayle, R. F.; Lynch, J. P., and Scherer, J. H.:  Another Fatality Following the Use of Tridione and Hydantoin , Virginia Med. Monthly 75:288, 1948;.
33 +
Forster, T. W., and Watson, J. W.:  Agranulocytosis and Thrombocytopenia Following the Use of Tridione , Lancet 1:517, 1949;.
34 +
Redin, B.:  Complications During Tridione Treatment of Epilepsy in Children , Nord. Med. 49:563, 1953;.
35 +
Berry, A. N.:  Fatality Following Tridione , Southern Med. J. 42:995, 1949;.
36 +
Carnicelli, T. J., and Tedeschi, C. G.:  Fatal Acute Pancytopenia Following Tridione Treatment , New Engl. J. Med. 238:314, 1948;.
37 +
Kaplan, S. R.; Levy, G., and Schwartz, S. O.:  Fatal Aplastic Anemia Following Tridione Administration , Dis. Nerv. Syst. 10:339, 1949;.
38 +
Mackay, R. P., and Gottstein, W. K.:  Aplastic Anemia and Agranulocytosis Following Tridione , J.A.M.A 132:13, 1946;.
39 +
Michelstein, I., and Weiser, N. J.:  Fatal Agranulocytosis Due to Trimethadione (Tridione) , Arch. Neurol. Psychiat. 62:358, 1949;.
40 +
Mallin, A. W., and Gammon, G. D.:  A Clinical Evaluation of Mesantoin in Epilepsy , J. Nerv. Ment. Dis. 118:193, 1953;.
41 +
Pearson, P. H.; Peck, J. L., and Livingston, S.:  Fatal Pancytopenia Following Therapy with Nuvarone (3-Methyl, 5-Phenylhydantoin): A Case Report , Bull. Johns Hopkins Hosp. 91:341, 1952;.
42 +
Isaacson, S.; Gold, J. A., and Ginsberg, V.:  Fatal Aplastic Anemia After Therapy with Nuvarone (3-Methyl-5-Phenylhydantoin) , J.A.M.A. 160:1311, 1956;.
43 +
Green, R. A., and Gilbert, M. G.:  Fatal Bone Marrow Aplasia Associated with Celontin Therapy , Minnesota Med. 42:130, 1959;.
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Bán, A., and Berczeller, I.:  Tödliche Panmyelopathie durch Hydantoinkörper , Acta Haemat. (Basel) 6:354, 1951;.
45 +
Simpson, T. W.; Wilson, E. B., Jr., and Zimmerman, S. L.:  Fatal Aplastic Anemia Occurring During Anticonvulsant Therapy: Probable Idiosyncrasy to Phenurone , Ann. Intern. Med. 32:1224, 1950;.
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Thomas, E. D.; Lochte, H. L., Jr.; Cannon, J. H.; Sahler, O. D., and Ferrebee, J. W.:  Supralethal Whole Body Irradiation and Isologous Marrow Transplantation in Man , J. Clin. Invest. 38:1709, 1959;.
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McGovern, J. J., Jr.; Russell, P. S.; Atkins, L., and Webster, E. W.:  Treatment of Terminal Leukemic Relapse by Total-Body Irradiation and Intravenous Infusion of Stored Autologous Bone Marrow Obtained During Remission , New Engl. J. Med. 260:675, 1959;.
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References

1 +
Best, W. R., and Paul, J. T.:  Severe Hypoplastic Anemia Following Anticonvulsant Medication , Amer. J. Med. 8:124, 1950;.
2 +
Robins, M. M., and Noyes, W. D.:  Aplastic Anemia Treated with Bone-Marrow Transfusion from an Identical Twin , New Engl. J. Med. 265: 974, 1961;.
3 +
Hasselback, R. C., and Thomas, J. W.:  Aplastic Anemia , Canad. Med. Ass. J. 82:1253, 1960;.
4 +
Swartout, R. III:  Two Cases of Fatal Pancytopenia Following Mesantoin Therapy , Calif. Med. 78:138, 1953;.
5 +
Frank, C. W., and Holland, J. F.:  Pancytopenia from "Mesantoin," J.A.M.A. 138:1148, 1948;.
6 +
Burrell, Z. L.:  Fatal Pancytopenia as a Result of Improperly Supervised Mesantoin Therapy , Amer. Practit. 6:726, 1955;.
7 +
England, N. J., and McEachern, D.:  Acute Aplastic Anemia During Mesantoin Therapy , Canad. Med. Ass. J. 60:173, 1949;.
8 +
Scott, J. L.; Cartwright, G. E., and Wintrobe, M. M.:  Acquired Aplastic Anemia: An Analysis of 39 Cases and Review of the Pertinent Literature , Medicine (Balt.) 38:119, 1959;.
9 +
Mohler, D. N., and Leavell, B. S.:  Aplastic Anemia: An Analysis of 50 Cases , Ann. Intern. Med. 49:326, 1958;.
10 +
Aird, R. B.:  The Treatment of Epilepsy with Methylphenylethyl Hydantoin (Mesantoin) , Calif. Med. 68:141, 1948;.
11 +
Davies, R. R.; Fisch, C., and Tischer, E. P.:  Pancytopenia Due to Mesantoin: Report of a Case , New Engl. J. Med. 242:863, 1950;.
12 +
Nielsen, D. I.:  Aplastic Anemia Following Mesantoin with Recovery , Ann. West. Med. Surg. 6:562, 1952;.
13 +
Stillman, S.; Bedell, S. G., and Leavitt, D.:  Fatal Aplastic Anemia Associated with Mesantoin: Report of a Case with Autopsy , J. Florida Med. Ass. 37:496, 1951;.
14 +
Weller, R. W., and Metcalfe, J.:  Fatal Pancytopenia Following the Use of Mesantoin: Report of a Case , New Engl. J. Med. 241:17, 1949;.
15 +
Bloom, N.; Lynch, J. P., and Brick, H.:  "Mesantoin" Poisoning with Aplastic Anemia and Recovery , J.A.M.A. 138:498, 1948;.
16 +
Witkind, E., and Waid, M. E.:  Aplasia of the Bone Marrow During Therapy: Report of a Fatal Case , J.A.M.A. 147:757, 1951;.
17 +
Merlis, J. K.: Personal communication
18 +
Tyler, M. W., and King, E. Q.:  Phenacemide in Treatment of Epilepsy , J.A.M.A. 147:17, 1951;.
19 +
Dreyer, V. R.:  Therapieschaden durch antiepileptische Mittel unter besonderer Berücksichtigung schwerer Nebenwirkungen an Hand der Literatur und eigener Fälle , Fortschr. Neurol. Psychiat. 27:401, 1959;.
20 +
Spring, M., and Soltz, W. B.:  Fatal Aplastic Anemia Due to Methylphenylethyl Hydantoin (Mesantoin) , New York J. Med. 55:3478, 1955;.
21 +
Weinmann, O.:  Ein weiterer Fall von aplastischer Anämie durch Mesantoin , Wien. Klin. Wschr. 63:587, 1951;.
22 +
Meier, U.:  Knochenmarksschädigung durch moderne Antikonvulsiva (Hydantoinkörper und Tridion) , Deutsch. Med. Wschr. 78:1107, 1953;.
23 +
Hofstatter, L.:  Mesantoin in the Management of the Hospitalized Psychotic Epileptic: Report of Toxic Effects and One Fatality , Southern Med. J. 44:827, 1951;.
24 +
Weiss, H. A., and Hawley, W. D.:  Pancytopenia Following the Use of Mesantoin and Thianton: Report of a Fatal Case , U.S. Armed Forces Med. J. 2:83, 1951;.
25 +
Forster, F. M., and Frankel, K.:  Fatal Aplastic Anemia During Anticonvulsant Therapy , Dis. Nerv. Syst. 10:108, 1949;.
26 +
Klaus, V. E.:  Pancytopenie durch Tridion , Acta Haemat. (Basel) 5:74, 1951;.
27 +
Harrison, F. F.; Johnson, R. D., and Ayer, D.:  Fatal Aplastic Anemia Following Use of Tridione and a Hydantoin , J.A.M.A. 132:11, 1946;.
28 +
Smith, J. C.; Heinle, R. W., and Kimball, O. P.:  Hypoplastic Anemia in a Patient Treated Unfavorably with Tridione: A Case Report , Ohio Med. J. 45:582, 1949;.
29 +
Gentry, E., and Hill, L. F.:  Granulocytopenia and Death Following the Use of Trimethadione , Amer. J. Dis. Child. 75:582, 1948;.
30 +
Briggs, J. N., and Emery, J. L.:  Toxic Effects of Tridione , Lancet 1:59, 1949;.
31 +
Braithwaite, R. F.:  A Fatal Case of Agranulocytosis Associated with Tridione Therapy , Brit. Med. J. 1:14, 1948;.
32 +
Gayle, R. F.; Lynch, J. P., and Scherer, J. H.:  Another Fatality Following the Use of Tridione and Hydantoin , Virginia Med. Monthly 75:288, 1948;.
33 +
Forster, T. W., and Watson, J. W.:  Agranulocytosis and Thrombocytopenia Following the Use of Tridione , Lancet 1:517, 1949;.
34 +
Redin, B.:  Complications During Tridione Treatment of Epilepsy in Children , Nord. Med. 49:563, 1953;.
35 +
Berry, A. N.:  Fatality Following Tridione , Southern Med. J. 42:995, 1949;.
36 +
Carnicelli, T. J., and Tedeschi, C. G.:  Fatal Acute Pancytopenia Following Tridione Treatment , New Engl. J. Med. 238:314, 1948;.
37 +
Kaplan, S. R.; Levy, G., and Schwartz, S. O.:  Fatal Aplastic Anemia Following Tridione Administration , Dis. Nerv. Syst. 10:339, 1949;.
38 +
Mackay, R. P., and Gottstein, W. K.:  Aplastic Anemia and Agranulocytosis Following Tridione , J.A.M.A 132:13, 1946;.
39 +
Michelstein, I., and Weiser, N. J.:  Fatal Agranulocytosis Due to Trimethadione (Tridione) , Arch. Neurol. Psychiat. 62:358, 1949;.
40 +
Mallin, A. W., and Gammon, G. D.:  A Clinical Evaluation of Mesantoin in Epilepsy , J. Nerv. Ment. Dis. 118:193, 1953;.
41 +
Pearson, P. H.; Peck, J. L., and Livingston, S.:  Fatal Pancytopenia Following Therapy with Nuvarone (3-Methyl, 5-Phenylhydantoin): A Case Report , Bull. Johns Hopkins Hosp. 91:341, 1952;.
42 +
Isaacson, S.; Gold, J. A., and Ginsberg, V.:  Fatal Aplastic Anemia After Therapy with Nuvarone (3-Methyl-5-Phenylhydantoin) , J.A.M.A. 160:1311, 1956;.
43 +
Green, R. A., and Gilbert, M. G.:  Fatal Bone Marrow Aplasia Associated with Celontin Therapy , Minnesota Med. 42:130, 1959;.
44 +
Bán, A., and Berczeller, I.:  Tödliche Panmyelopathie durch Hydantoinkörper , Acta Haemat. (Basel) 6:354, 1951;.
45 +
Simpson, T. W.; Wilson, E. B., Jr., and Zimmerman, S. L.:  Fatal Aplastic Anemia Occurring During Anticonvulsant Therapy: Probable Idiosyncrasy to Phenurone , Ann. Intern. Med. 32:1224, 1950;.
46 +
Huguley, C. M., Jr.; Erslev, A. J., and Bergsagel, D. E.:  Drug-Related Blood Dyscrasias , J.A.M.A. 177:23, 1961;.
47 +
Zimmerman, F. T.:  New Drugs in the Treatment of Petit Mal Epilepsy , Amer. J. Psychol. 109:767, 1953;.
48 +
Goodman, L. S., and Gilman, A. Z.: The Pharmacological Basis of Therapeutics , Ed. 2, New York, The Macmillan Company, 1955;, pp. 178-205.
49 +
Middleton, J. W., and Hejtmancik, M. R.:  Severe Leukopenia Due to Diphenylhydantoin Sodium: Case Report , Texas J. Med. 46:520, 1950;.
50 +
Gropper, A. L.:  Diphenylhydantoin Sensitivity: Report of a Fatal Case with Hepatitis and Exfoliative Dermatitis , New Engl. J. Med. 254:522, 1956;.
51 +
Underwood, L. C.:  Fatal Bone Marrow Depression After Treatment with Acetazolamide (Diamox) , J.A.M.A. 161:1477, 1956;.
52 +
Zimmerman, F. T., and Burgemeister, B. B.:  A New Drug for Petit Mal Epilepsy , Neurology (Minneap.) 8:769, 1958;.
53 +
Niswander, G. D., and Karacan, I.:  Amino-Glutethimide in the Treatment of Chronic Psychotic Epileptics , Amer. J. Psychiat. 116:260, 1959;.
54 +
Carter, C. H.:  Evaluating a New Anticonvulsant in a "Therapeutic Community," Dis. Nerv. Syst. 21:50, 1960;.
55 +
Lambros, V. S.:  A New Anticonvulsant, Elipten , Dis. Nerv. Syst. 19:349, 1958;.
56 +
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57 +
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58 +
Millichap, J. G.:  Milontin: A New Drug in the Treatment of Petit Mal , Lancet 2:907, 1952;.
59 +
Davidson, D. T., Jr.; Lombroso, C., and Markham, C. H.:  Methylphenylsuccinimide (Milontin) in Epilepsy , New Engl. J. Med. 253:173, 1955;.
60 +
Millichap, J. G.:  Milontin and Hematuria , J.A.M.A. 157:613, 1955;.
61 +
Zimmerman, F. T.:  Use of Methylphenylsuccinimide in Treatment of Petit Mal Epilepsy , A.M.A. Arch. Neurol. Psychiat. 66:156, 1951;.
62 +
Forrer, G. R.:  Use of Milontin in Treating Mental Patients with Petit Mal Convulsive Disorders , J. Mich. Med. Soc. 53:275, 1954;.
63 +
Carter, C. H.:  Use of Milontin in the Control of Petit Mal Epilepsy , Neurology (Minneap.) 4:935, 1954;.
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65 +
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66 +
Davis, J. P., and Lennox, W. G.:  A Comparison of Paradione and Tridione in the Treatment of Epilepsy , J. Pediat. 34:273, 1949;.
67 +
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68 +
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70 +
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71 +
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72 +
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74 +
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75 +
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76 +
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77 +
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79 +
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80 +
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81 +
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84 +
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87 +
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90 +
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96 +
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97 +
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99 +
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100 +
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