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Beta Blockers for Glaucoma
1064
Beta Blockers for Glaucoma EYE-DROPS of 0.25% or 0.5% timolol maleate, a beta-1 and beta-2 adrenergic blocker, can probably now be rated a standard treatment for open-angle (chronic simple) glaucoma. 1-3 Does this agent work in other glaucomas too-in closed-angle glaucoma, for instance, if or when an operation which includes iridectomy has failed to control the ocular tension, or if the patient has refused operation? Here there is hardly any published proof of efficacy,4though a beneficial effect seems very likely. This new drug has two great advantages: it need be instilled only twice a day and it has little5 or no6 effect on the pupil and accommodation. It is more effective than pilocarpine7,8 and adrenaline,8,9 and has an additive effect to them and also to acetazolamide.lo-12 In the eye, it acts by reducing the amount of aqueous humor produced13 (by the ciliary epithelium) rather than by increasing its outflow;l4 at the molecular level its mechanism is unknown. Timolol reduces intraocular pressure also when given by
mouth. 15 Does timolol lose its effect with time? There is a slight reduction of effect during the first few weeks of treatment but probably no further decrease occurs. 10, 12, 16-18 The drug is used systemically in the treatment of hypertension and arrhyth-
mias, and systemic absorption 19 via conjunctival nasal
for
or
reductions of
slight pulse-rate6,10,20 and possibly of blood-pressure. 16,21 Accordingly, these eye-drops should be prescribed only with great caution in the patient with bradycardia or heart failure, the patient whose heart is dependent on the adrenergic whip, or the patient mucosa
accounts
Katz, I. M., Hubbard, W. A., Getson, A. J., Gould, A. L. Invest. Ophthal. 1976, 15, 489. 2. Zimmerman, T. J., Kaufman, H. E. Archs Ophthal. 1977, 95, 601. 3. Zimmerman, T. J., Kaufman, H. E. ibid. p. 605. 4. Saari, K. M., Airaksmmen, P. J., Jaanio, E. A. T. Lancet, 1978, i, 442. 5. Demailly, P., Lehner, M. A., Etienne, R., Trepsat, C., Haut, J., Raynaud, G., Massin, M., Tatry, C. J. fr. Ophtal. 1978, 1, 727 6. Johnson, S. H., Brubaker, R. F., Trauntman, J. C. Invest. Ophthal. Vis. Sci. 1978, 17, 924. 7. Boger, W. P., Steinert, R. F., Puliafito, C. A., Pavan-Langston, D. Am. J Ophthal. 1978, 86, 8. 8. Katz, I. M. in Timolol Maleate Ophthalmic Solution in the Treatment of Glaucoma (selected papers from XXIII int. Congr. Ophthal., Kyoto); p. 29. Merck Sharpe and Dohme, Rahway, N. J., 1978. 9. Moss, A. P., Ritch, R., Hargett, N. A., Kohn, A. N., Smith, H., Jr., Podos, S. M. Am. J Ophthal. 1978, 86, 489. 10. Boger, W P., Puliafito, C. A., Steinert, R. F., Langston, D. B. Ophthalmology, 1978, 85, 259. 11. Demailly, P. cited by Heel, R. C., Brogden, R. N., Speight, T. M., Avery, G. S. Drugs, 1979, 17, 48. 12. Nielsen, N. V. Acta ophthal. 1978, 56, 504. 13. Yablonski, M. E., Zimmerman, T. J., Waltman, S. R., Becker, B. Exp. Eye Res. 1978, 27, 135 14. Zimmerman, T. J., Harbin, R., Pett, M., Kaufman, H. E. Invest. Ophthal. 1.
Vis. Sci. 15. 16.
1977, 16, 623
Arrata, M., Massin, M., Sfeir, T.J.fr. Ophtal. 1978, 1, 745. Dausch, D., Honegger, H. in Timolol Maleate Ophthalmic Solution in the Treatment of Glaucoma (selected papers from XXIII int. Congr. Ophthal., Kyoto); p. 5. Merck Sharpe & Dohme, Rahway, N.J., 1978. 17. Ritch, R., Hargett, N. A., Podos, S. M.Acta ophthal. 1978, 56, 6. 18. Demailly, P., Lehner, M. A., Pigot, C.J.fr. Ophtal. 1978, 1, 743 19. Vareilles, P., Silverstone, D., Plazounet, B., Le Douarec, J. C., Sears, M. L., Stone, C. A. Invest Ophthal. Vis. Sci. 1977, 16, 987. 20 Demailly, P., Lehner, M. A., Duperre, J.J.fr. Ophtal. 1978, 1, 723 21. Plane, C., Solé, P., Hamard, H., Vidal, R., Ourgard, A. G., Chagnon, A.
whose bronchial muscles require adrenaline’s stimulus to relax. Similarly a byproduct of the systemic use of a beta-blocker for non-ophthalmic reasons will be a fall in ocular tension; fortunately this may be greater than its effect on blood-pressure -an important consideration when we remember that reduction of systemic blood-pressure independent of intraocular pressure can cause progression of field loss in glaucoma. This area of ophthalmic pharmacology has many inconsistencies. Ophthalmologists have used adrenaline drops in glaucoma for many years, but there is no explanation for the odd fact that betaadrenergic blockers also reduce intraocular presAdministration of a beta-blocker before sure. adrenaline does not enhance the action of adrenaline22 although the effects are additive.23 Timolol lowers intraocular pressure more than does adrenaline.24,25 Also puzzling is the fact that salbutamol, a selective beta-2 stimulant, reduces intraocular pressure.27 Another AHLQUIST 21 is needed to make sense of this. However, we should be willing to use timolol eye-drops just as empirically as we have used adrenaline. The new drug can often add to the ocular hypotensive effect of the maximum tolerated doses of cholinergics, carbonic-anhydrase inhibitors, and sympathomimetics.18,26 (Tolerable medical treatment is usually preferable to drainage operation in open-angle glaucoma, provided that field loss can be held in check.) Although the molecular mechanism of action is speculative, some information has accumulated since the surprising report, 12 years ago, of the ocular hypotensive effect of intravenous and oral
propranolol. 29-12 Even more surprisingly, propranolol proved to be active in the form of eyedrops,33,34 but the temporary local anxsthetic effect ruled out topical use in the treatment of glaucoma: this membrane-stabilising property does not explain its effect on ocular tension, nor does its intrinsic sympathomimetic effect.35 Beta-blockers may have a place in the treatment of glaucoma systemically : 40 mg propranolol is as effective as 2s0 mg acetazolamide, both given twice daily,36 and s0 mg atenolol is amide.11 As to
effective than 500 mg acetazoltopical treatment, several other beta-
more
22. Phillips, C. I., Gore, S. M., Gunn, P. M. Br.J. Ophthal. 1978, 62, 296 23. Katz, I. M. Ann. Ophthal. 1978, 10, 847. 24. Sonntag, J. R., Brindley, G. O., Shields, B. M., Arafat, N-I T. Pn C. D. Archs Ophthal 1979, 97, 273. 25. Moss, A. P , Ritch, R , Hargett, N A., Kohn, A N., Smith, H, Podos. S. V.
Am.J. Ophthal. 1978, 86, 489. 26. Zimmerman, T. J., Gillespie, J. E, B. Archs Ophthal. 1979, 97, 278.
Kass, M. A., Yablonski, M. E. Becker
27. Paterson, G D., Paterson, G Postgrad med J. 1971, suppl. 47, p 22 28. Ahlquist, R. P Am.J Physiol. 1948, 153, 586. 29 Phillips, C I , Howitt, G., Rowlands, D. J. Br. J. Ophthal 1967. 51, 222 30. Coté, G., Drance, S. M Can.J Ophthal 1968, 3, 207. 31. Bietti, G.Am J Ophthal. 1972, 73, 475 32 Pandolfi, M, Öhrström, A. Acta ophthal 1974, 52, 464. 33. Bucci, M. G., Missiroli, A., Giraldi, J. P., Virno, M. Boll. Oculist 1958, 47. 51. 34 Vale, J., Gibbs, A. C. C , Phillips, C. I. Br. J Ophthal. 1972, 56, 0 35. Vale, J., Phillips, C. I. Expl Eye Res. 1970, 9, 82. 36. Wettrell, K , Pandolfi, M.Archs Ophthal 1979, 97, 280. 37. Macdonald, M., Gore, S. M, Cullen, P. M, Phillips, C I Br J
0
1065
blockers have been
tested-practolol,38,39 oxpreno101,40,41 atenolol,42 and bupranolol47,48-but for various reasons they will probably be superseded by timolol.
Timolol was released in the U.K. only in January this year, but 2-3 years’ experience from other countries suggests that side-effects are few. Burning, photophobia, blurred vision, and conjunctival redness were encountered much less often than in patients on pilocarpine and adrenaline, the incidence in a timolol group being only 3-4% higher than in a non-treatment control group.49 Further long-term and even short-term side-effects may yet emerge, but it is encouraging that, with the notable exception of practolol, which had a disastrous effect on conjunctiva and cornea in a small proportion of patients, systemic beta-blockers have not given rise to fully proven ophthalmic sideeffects.
PLASMA EXCHANGE IN THROMBOTIC THROMBOCYTOPENIC PURPURA
THROMBOTIC thrombocytopenic purpura (T.T.P.) is a syndrome of fever, thrombocytopenia, microangiopathic hxmolytic ansemia, renal impairment, and diverse neurological abnormalities originally described by Moschowitz.’ The disease may occur at any age but is particularly common amongst females in the second and third decades.2 The clinical diagnosis can be confirmed by gingival biopsy, which reveals hyaline microthrombi occluding terminal arterioles and capillaries, but there is a high false-negative rate and often the pathological diagnosis is not made till necropsy.2,3 For many years T.T.P. was regarded as a usually fatal disease. Patients were treated with antibiotics, steroids and immunosuppressive agents, anticoagulants, and splenectomy, in various combinations and with occasional success.2,4,5 In 1959 Rubinstein and others6 described a case of T.T.P. in which two exchange transfusions with fresh whole blood were followed by rapid and sustained recovery. They postulated that this suc.
38 Vale, J., Phillips, C.I. ibid 1973, 57, 210. 39 Hagedoorn, A , Tjoa, S. T. Lancet, 1974, i, 733. 40. Bucci, M. Boll Oculist, 1976, 54, 235. 41. Sharaf, E. E. D., Haroun, E. A., Ishaac, Z., El Shewy, T. M., Nassef, A. E. H. Expl Eye Res 1974, 19, 223. 42 Phillips, C. I , Macdonald, M. J., Gore, S. M., Cullen, P. M. Br. J. Ophthal. 43 44 45 46 47
1977, 61, 349 Brenkman,R F. ibid. 1978, 62, 287. Phillips, C. I., Macdonald, M. J., Gore, S. M., Cullen, P. M. Br. med. J. 1976, n, 1448 Phillips, C I , Macdonald, M. J., Gore, S. M., Cullen, P. M. Br J. Ophthal. 1977, 61, 349. Wettrell, K., Wilke, K , Pandolfi, M. ibid. 1978, 62, 292. Takase, M, Komuro, S., Nanbu, H, Araie, M. Jap. J. Ophthal. 1978, 22, 142
48
Krieglstein,
G. K.,
Sold-Darseff, J., Leydhecker,
W. Albrecht
v.
Graefes
Arch Klin exp. Ophthal 1977,202,81 49 Katz, I M. m Timolol Maleate Ophthalmic Solution in the Treatment of
Glaucoma selected papers from XXIII int Congr. Ophthal., Kyoto); p. 29. Merck Sharpe & Dohme, Rahway, N. J., 1978. 1 Moschowitz, E. Archs intern. Med. 1925, 36, 89. 2 Bukonski, R. M., Hewlett, J. S., Harris, J. W., et al. Semm. Hemat. 1976,
13, 219 Amorosi, EL., Ultmann,J EMedicine, 1966, 45, 139. Hill, J. B., Cooper, W M.Archsintern.Med. 1968, 122, 353. 5 Schwartz, S. I., Adams, J. T., Bauman, A. W. Current Problems in Surgery; p 29. Chicago, 1971. 6 Rubinstein, M A., Kagan, B. M., MacGillviray, M. H., et al. Ann. intern. Med. 1959, 51, 1409.
3 4
might be due to removal of "antibodies" by the7 exchange procedure. Subsequently, Pisciotta et al.’ reviewed 25 patients who had been treated in this way, of whom only 2 had received no additional therapy: 14 had improved or were in remission, including the 2 patients who had received exchange transfusion alone. The suggestion that the beneficial effect of this process
cedure
was
the removal of a "toxic" substance
was
chal-
lenged by Byrnes and Khurana,8who described a single patient in whom multiple plasma infusions alone could repeatedly induce remission. However, this observation could not be confirmed in other patients9 and plasma exchange has lately been assessed in two trials10,11 as a convenient alternative to manual exchange transfusion. Haematological remission was obtained in a combined total of 6 of 7 patients and it was suggested that this was due to the removal of circulating immune complexes. However, some of the exchanges were performed with fresh frozen plasma, and all but 1 patient received other therapy in addition. The evidence that T.T.P. may be immunologically mediated is largely inferential-for instance, the condition can be initiated by infection or vaccination,12 there is an association with autoallergic disorders such as systemic lupus erythematosus," and complement and immunoglobulins are present in the lesions.14 Serum complement was measured in only 1 of the 7 patients treated by plasma exchange and was normal. Apart from occasional low levels of serum complement there is little to support the proposal that circulating immune complexes could be responsible for initiating vascular endothelial damage, and tests for such complexes have been negative.15,16 In the hsmolytic-uraemic syndrome (H.u.s.) there is rather more convincing evidence that immunopathogenetic mechanisms play a part. The close clinical and pathological correlation between this condition and T.T.P. has often been noted. 17,18 In endemic areas, H.u.s. seems to be an acquired defect in which there is good evidence for classical-pathway complement activation associated with circulating immune complexes.19 However, sporadic H.u.s. is more akin to T.T.P., and reports suggest a hereditary defect with positive family his-
tories.2O
Lately, an alternative hypothesis21 has implicated prostacyclin, an extremely potent endogenous inhibitor of platelet aggregation. It is suggested that patients with H.u.s. and allied conditions lack a plasma factor which stimulates prostacyclin activity, resulting in the widespread formation of platelet thrombi in the microcirculation. In 2 patients, plasma prostacyclin-like activity, absent during relapse, was restored within an hour of plasma exchange. This hypothesis gains support from another study by Lian and others22 in which plasma 7. Pisciotta, A. V., Garthwaite, T., Darin, J., et al. Am. J. Hemat. 1977, 3, 73. 8. Byrnes, J. J, Khurana, M. New Engl.J. Med. 1977, 297, 1386. 9. Arsell, J., Beaser, R. S., Pechet, L. Ann intern. Med. 1978, 89, 647. 10. Bukowski, R. M., King, J. W., Hewlett, J. S. Blood, 1977, 50, 413. 11. Ryan, P. F., Cooper, I. A., Firkin, B. G. Med.J. Aust. 1979, i, 69.
12. Antes, E. H. Ann. intern. Med. 1958, 48, 512. S., Shearn, M. A. Archs intern. Med. 1964, 113, 826 14. Mant, M. J., Cauchi, M. N., Medley, G. Blood, 1972, 40, 416. 15. Celada, A , Perrin, L. H. Blood, 1978, 52, 855 16. Neame, P. B., Hirsh, J. ibid. 1978, 51, 559. 17. Kaplan, B. S., Drummond, K. N.New Engl.J.Med 1978, 298, 964 18. Hepstinall, R. H Pathology of the Kidney; chap 18. Boston, 1974. 19. Koster, F., Levin, J., Walker, L., et al. New Engl J. Med. 1978, 298, 927. 20. Karlsberg, R. P., Lacher, J W, Bartecchi, C. E. Archs intern Med. 1977, 13. Levine,
137, 1155. 21. Remuzzi, G , Misiani, R , Marchesi, D., et al. Lancet, 1978, n, 871 22 Lian, E. C-Y., Harkness, D. R, Byrnes, J. J., et al Blood, 1979, 53, 333.
Beta Blockers for Glaucoma EYE-DROPS of 0.25% or 0.5% timolol maleate, a beta-1 and beta-2 adrenergic blocker, can probably now be rated a standard treatment for open-angle (chronic simple) glaucoma. 1-3 Does this agent work in other glaucomas too-in closed-angle glaucoma, for instance, if or when an operation which includes iridectomy has failed to control the ocular tension, or if the patient has refused operation? Here there is hardly any published proof of efficacy,4though a beneficial effect seems very likely. This new drug has two great advantages: it need be instilled only twice a day and it has little5 or no6 effect on the pupil and accommodation. It is more effective than pilocarpine7,8 and adrenaline,8,9 and has an additive effect to them and also to acetazolamide.lo-12 In the eye, it acts by reducing the amount of aqueous humor produced13 (by the ciliary epithelium) rather than by increasing its outflow;l4 at the molecular level its mechanism is unknown. Timolol reduces intraocular pressure also when given by
mouth. 15 Does timolol lose its effect with time? There is a slight reduction of effect during the first few weeks of treatment but probably no further decrease occurs. 10, 12, 16-18 The drug is used systemically in the treatment of hypertension and arrhyth-
mias, and systemic absorption 19 via conjunctival nasal
for
or
reductions of
slight pulse-rate6,10,20 and possibly of blood-pressure. 16,21 Accordingly, these eye-drops should be prescribed only with great caution in the patient with bradycardia or heart failure, the patient whose heart is dependent on the adrenergic whip, or the patient mucosa
accounts
Katz, I. M., Hubbard, W. A., Getson, A. J., Gould, A. L. Invest. Ophthal. 1976, 15, 489. 2. Zimmerman, T. J., Kaufman, H. E. Archs Ophthal. 1977, 95, 601. 3. Zimmerman, T. J., Kaufman, H. E. ibid. p. 605. 4. Saari, K. M., Airaksmmen, P. J., Jaanio, E. A. T. Lancet, 1978, i, 442. 5. Demailly, P., Lehner, M. A., Etienne, R., Trepsat, C., Haut, J., Raynaud, G., Massin, M., Tatry, C. J. fr. Ophtal. 1978, 1, 727 6. Johnson, S. H., Brubaker, R. F., Trauntman, J. C. Invest. Ophthal. Vis. Sci. 1978, 17, 924. 7. Boger, W. P., Steinert, R. F., Puliafito, C. A., Pavan-Langston, D. Am. J Ophthal. 1978, 86, 8. 8. Katz, I. M. in Timolol Maleate Ophthalmic Solution in the Treatment of Glaucoma (selected papers from XXIII int. Congr. Ophthal., Kyoto); p. 29. Merck Sharpe and Dohme, Rahway, N. J., 1978. 9. Moss, A. P., Ritch, R., Hargett, N. A., Kohn, A. N., Smith, H., Jr., Podos, S. M. Am. J Ophthal. 1978, 86, 489. 10. Boger, W P., Puliafito, C. A., Steinert, R. F., Langston, D. B. Ophthalmology, 1978, 85, 259. 11. Demailly, P. cited by Heel, R. C., Brogden, R. N., Speight, T. M., Avery, G. S. Drugs, 1979, 17, 48. 12. Nielsen, N. V. Acta ophthal. 1978, 56, 504. 13. Yablonski, M. E., Zimmerman, T. J., Waltman, S. R., Becker, B. Exp. Eye Res. 1978, 27, 135 14. Zimmerman, T. J., Harbin, R., Pett, M., Kaufman, H. E. Invest. Ophthal. 1.
Vis. Sci. 15. 16.
1977, 16, 623
Arrata, M., Massin, M., Sfeir, T.J.fr. Ophtal. 1978, 1, 745. Dausch, D., Honegger, H. in Timolol Maleate Ophthalmic Solution in the Treatment of Glaucoma (selected papers from XXIII int. Congr. Ophthal., Kyoto); p. 5. Merck Sharpe & Dohme, Rahway, N.J., 1978. 17. Ritch, R., Hargett, N. A., Podos, S. M.Acta ophthal. 1978, 56, 6. 18. Demailly, P., Lehner, M. A., Pigot, C.J.fr. Ophtal. 1978, 1, 743 19. Vareilles, P., Silverstone, D., Plazounet, B., Le Douarec, J. C., Sears, M. L., Stone, C. A. Invest Ophthal. Vis. Sci. 1977, 16, 987. 20 Demailly, P., Lehner, M. A., Duperre, J.J.fr. Ophtal. 1978, 1, 723 21. Plane, C., Solé, P., Hamard, H., Vidal, R., Ourgard, A. G., Chagnon, A.
whose bronchial muscles require adrenaline’s stimulus to relax. Similarly a byproduct of the systemic use of a beta-blocker for non-ophthalmic reasons will be a fall in ocular tension; fortunately this may be greater than its effect on blood-pressure -an important consideration when we remember that reduction of systemic blood-pressure independent of intraocular pressure can cause progression of field loss in glaucoma. This area of ophthalmic pharmacology has many inconsistencies. Ophthalmologists have used adrenaline drops in glaucoma for many years, but there is no explanation for the odd fact that betaadrenergic blockers also reduce intraocular presAdministration of a beta-blocker before sure. adrenaline does not enhance the action of adrenaline22 although the effects are additive.23 Timolol lowers intraocular pressure more than does adrenaline.24,25 Also puzzling is the fact that salbutamol, a selective beta-2 stimulant, reduces intraocular pressure.27 Another AHLQUIST 21 is needed to make sense of this. However, we should be willing to use timolol eye-drops just as empirically as we have used adrenaline. The new drug can often add to the ocular hypotensive effect of the maximum tolerated doses of cholinergics, carbonic-anhydrase inhibitors, and sympathomimetics.18,26 (Tolerable medical treatment is usually preferable to drainage operation in open-angle glaucoma, provided that field loss can be held in check.) Although the molecular mechanism of action is speculative, some information has accumulated since the surprising report, 12 years ago, of the ocular hypotensive effect of intravenous and oral
propranolol. 29-12 Even more surprisingly, propranolol proved to be active in the form of eyedrops,33,34 but the temporary local anxsthetic effect ruled out topical use in the treatment of glaucoma: this membrane-stabilising property does not explain its effect on ocular tension, nor does its intrinsic sympathomimetic effect.35 Beta-blockers may have a place in the treatment of glaucoma systemically : 40 mg propranolol is as effective as 2s0 mg acetazolamide, both given twice daily,36 and s0 mg atenolol is amide.11 As to
effective than 500 mg acetazoltopical treatment, several other beta-
more
22. Phillips, C. I., Gore, S. M., Gunn, P. M. Br.J. Ophthal. 1978, 62, 296 23. Katz, I. M. Ann. Ophthal. 1978, 10, 847. 24. Sonntag, J. R., Brindley, G. O., Shields, B. M., Arafat, N-I T. Pn C. D. Archs Ophthal 1979, 97, 273. 25. Moss, A. P , Ritch, R , Hargett, N A., Kohn, A N., Smith, H, Podos. S. V.
Am.J. Ophthal. 1978, 86, 489. 26. Zimmerman, T. J., Gillespie, J. E, B. Archs Ophthal. 1979, 97, 278.
Kass, M. A., Yablonski, M. E. Becker
27. Paterson, G D., Paterson, G Postgrad med J. 1971, suppl. 47, p 22 28. Ahlquist, R. P Am.J Physiol. 1948, 153, 586. 29 Phillips, C I , Howitt, G., Rowlands, D. J. Br. J. Ophthal 1967. 51, 222 30. Coté, G., Drance, S. M Can.J Ophthal 1968, 3, 207. 31. Bietti, G.Am J Ophthal. 1972, 73, 475 32 Pandolfi, M, Öhrström, A. Acta ophthal 1974, 52, 464. 33. Bucci, M. G., Missiroli, A., Giraldi, J. P., Virno, M. Boll. Oculist 1958, 47. 51. 34 Vale, J., Gibbs, A. C. C , Phillips, C. I. Br. J Ophthal. 1972, 56, 0 35. Vale, J., Phillips, C. I. Expl Eye Res. 1970, 9, 82. 36. Wettrell, K , Pandolfi, M.Archs Ophthal 1979, 97, 280. 37. Macdonald, M., Gore, S. M, Cullen, P. M, Phillips, C I Br J
0
1065
blockers have been
tested-practolol,38,39 oxpreno101,40,41 atenolol,42 and bupranolol47,48-but for various reasons they will probably be superseded by timolol.
Timolol was released in the U.K. only in January this year, but 2-3 years’ experience from other countries suggests that side-effects are few. Burning, photophobia, blurred vision, and conjunctival redness were encountered much less often than in patients on pilocarpine and adrenaline, the incidence in a timolol group being only 3-4% higher than in a non-treatment control group.49 Further long-term and even short-term side-effects may yet emerge, but it is encouraging that, with the notable exception of practolol, which had a disastrous effect on conjunctiva and cornea in a small proportion of patients, systemic beta-blockers have not given rise to fully proven ophthalmic sideeffects.
PLASMA EXCHANGE IN THROMBOTIC THROMBOCYTOPENIC PURPURA
THROMBOTIC thrombocytopenic purpura (T.T.P.) is a syndrome of fever, thrombocytopenia, microangiopathic hxmolytic ansemia, renal impairment, and diverse neurological abnormalities originally described by Moschowitz.’ The disease may occur at any age but is particularly common amongst females in the second and third decades.2 The clinical diagnosis can be confirmed by gingival biopsy, which reveals hyaline microthrombi occluding terminal arterioles and capillaries, but there is a high false-negative rate and often the pathological diagnosis is not made till necropsy.2,3 For many years T.T.P. was regarded as a usually fatal disease. Patients were treated with antibiotics, steroids and immunosuppressive agents, anticoagulants, and splenectomy, in various combinations and with occasional success.2,4,5 In 1959 Rubinstein and others6 described a case of T.T.P. in which two exchange transfusions with fresh whole blood were followed by rapid and sustained recovery. They postulated that this suc.
38 Vale, J., Phillips, C.I. ibid 1973, 57, 210. 39 Hagedoorn, A , Tjoa, S. T. Lancet, 1974, i, 733. 40. Bucci, M. Boll Oculist, 1976, 54, 235. 41. Sharaf, E. E. D., Haroun, E. A., Ishaac, Z., El Shewy, T. M., Nassef, A. E. H. Expl Eye Res 1974, 19, 223. 42 Phillips, C. I , Macdonald, M. J., Gore, S. M., Cullen, P. M. Br. J. Ophthal. 43 44 45 46 47
1977, 61, 349 Brenkman,R F. ibid. 1978, 62, 287. Phillips, C. I., Macdonald, M. J., Gore, S. M., Cullen, P. M. Br. med. J. 1976, n, 1448 Phillips, C I , Macdonald, M. J., Gore, S. M., Cullen, P. M. Br J. Ophthal. 1977, 61, 349. Wettrell, K., Wilke, K , Pandolfi, M. ibid. 1978, 62, 292. Takase, M, Komuro, S., Nanbu, H, Araie, M. Jap. J. Ophthal. 1978, 22, 142
48
Krieglstein,
G. K.,
Sold-Darseff, J., Leydhecker,
W. Albrecht
v.
Graefes
Arch Klin exp. Ophthal 1977,202,81 49 Katz, I M. m Timolol Maleate Ophthalmic Solution in the Treatment of
Glaucoma selected papers from XXIII int Congr. Ophthal., Kyoto); p. 29. Merck Sharpe & Dohme, Rahway, N. J., 1978. 1 Moschowitz, E. Archs intern. Med. 1925, 36, 89. 2 Bukonski, R. M., Hewlett, J. S., Harris, J. W., et al. Semm. Hemat. 1976,
13, 219 Amorosi, EL., Ultmann,J EMedicine, 1966, 45, 139. Hill, J. B., Cooper, W M.Archsintern.Med. 1968, 122, 353. 5 Schwartz, S. I., Adams, J. T., Bauman, A. W. Current Problems in Surgery; p 29. Chicago, 1971. 6 Rubinstein, M A., Kagan, B. M., MacGillviray, M. H., et al. Ann. intern. Med. 1959, 51, 1409.
3 4
might be due to removal of "antibodies" by the7 exchange procedure. Subsequently, Pisciotta et al.’ reviewed 25 patients who had been treated in this way, of whom only 2 had received no additional therapy: 14 had improved or were in remission, including the 2 patients who had received exchange transfusion alone. The suggestion that the beneficial effect of this process
cedure
was
the removal of a "toxic" substance
was
chal-
lenged by Byrnes and Khurana,8who described a single patient in whom multiple plasma infusions alone could repeatedly induce remission. However, this observation could not be confirmed in other patients9 and plasma exchange has lately been assessed in two trials10,11 as a convenient alternative to manual exchange transfusion. Haematological remission was obtained in a combined total of 6 of 7 patients and it was suggested that this was due to the removal of circulating immune complexes. However, some of the exchanges were performed with fresh frozen plasma, and all but 1 patient received other therapy in addition. The evidence that T.T.P. may be immunologically mediated is largely inferential-for instance, the condition can be initiated by infection or vaccination,12 there is an association with autoallergic disorders such as systemic lupus erythematosus," and complement and immunoglobulins are present in the lesions.14 Serum complement was measured in only 1 of the 7 patients treated by plasma exchange and was normal. Apart from occasional low levels of serum complement there is little to support the proposal that circulating immune complexes could be responsible for initiating vascular endothelial damage, and tests for such complexes have been negative.15,16 In the hsmolytic-uraemic syndrome (H.u.s.) there is rather more convincing evidence that immunopathogenetic mechanisms play a part. The close clinical and pathological correlation between this condition and T.T.P. has often been noted. 17,18 In endemic areas, H.u.s. seems to be an acquired defect in which there is good evidence for classical-pathway complement activation associated with circulating immune complexes.19 However, sporadic H.u.s. is more akin to T.T.P., and reports suggest a hereditary defect with positive family his-
tories.2O
Lately, an alternative hypothesis21 has implicated prostacyclin, an extremely potent endogenous inhibitor of platelet aggregation. It is suggested that patients with H.u.s. and allied conditions lack a plasma factor which stimulates prostacyclin activity, resulting in the widespread formation of platelet thrombi in the microcirculation. In 2 patients, plasma prostacyclin-like activity, absent during relapse, was restored within an hour of plasma exchange. This hypothesis gains support from another study by Lian and others22 in which plasma 7. Pisciotta, A. V., Garthwaite, T., Darin, J., et al. Am. J. Hemat. 1977, 3, 73. 8. Byrnes, J. J, Khurana, M. New Engl.J. Med. 1977, 297, 1386. 9. Arsell, J., Beaser, R. S., Pechet, L. Ann intern. Med. 1978, 89, 647. 10. Bukowski, R. M., King, J. W., Hewlett, J. S. Blood, 1977, 50, 413. 11. Ryan, P. F., Cooper, I. A., Firkin, B. G. Med.J. Aust. 1979, i, 69.
12. Antes, E. H. Ann. intern. Med. 1958, 48, 512. S., Shearn, M. A. Archs intern. Med. 1964, 113, 826 14. Mant, M. J., Cauchi, M. N., Medley, G. Blood, 1972, 40, 416. 15. Celada, A , Perrin, L. H. Blood, 1978, 52, 855 16. Neame, P. B., Hirsh, J. ibid. 1978, 51, 559. 17. Kaplan, B. S., Drummond, K. N.New Engl.J.Med 1978, 298, 964 18. Hepstinall, R. H Pathology of the Kidney; chap 18. Boston, 1974. 19. Koster, F., Levin, J., Walker, L., et al. New Engl J. Med. 1978, 298, 927. 20. Karlsberg, R. P., Lacher, J W, Bartecchi, C. E. Archs intern Med. 1977, 13. Levine,
137, 1155. 21. Remuzzi, G , Misiani, R , Marchesi, D., et al. Lancet, 1978, n, 871 22 Lian, E. C-Y., Harkness, D. R, Byrnes, J. J., et al Blood, 1979, 53, 333.