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OCULAR INVOLVEMENT IN LEUKÆMIA
829
whose loss of vision was thought to be due to infiltration of the optic nerve by malignant cells. Diagnosis was based on the ophthalmoscopic appearance which is characteristic. The mode of presentation and the response to radiotherapy and cytotoxic drugs in these three patients are the subject of this paper.
OCULAR INVOLVEMENT IN LEUKÆMIA Report of Three Cases FRANCO PAOLINO* KATHERINE H. MURRAY DAVID A. G. GALTON M. GOLDMAN JOHN C. F. JOHN GRINDLE Medical Research Council Leukœmia Unit, Hammersmith
Hospital, London W12 0HS, and Department of Clinical Ophthalmology, Institute of Ophthalmology, Moor fields Eye Hospital, London EC1V 2PD
patients with treated acute lymphoblastic leukæmia acquired visual believed to be caused by ocular infiltration by symptoms All cells. three patients had other evidence of malignant disease including bone-marrow involvement at systemic One the time. patient had a previous history of meningeal leukæmia and none had received "prophylactic" cranial irradiation. The ophthalmoscopic appearances were similar in each case and were thought to have been caused by obstruction of axoplasmic flow associated with infiltration of the optic nerve by neoplastic cells. The three patients were treated by local irradiation and two also received intrathecal chemotherapy. Response to treatment was variable but the use of radiotherapy combined with intrathecal cytotoxic drugs is probably the best available approach.
Summary
Three
Introduction VISUAL symptoms in patients with leukaemia are not and may be associated with retinal haemorrhages, exudates, or papillredema 12 for which specific therapy may not be required. Leukaemia may, however, involve the eye by direct infiltration. In the past ten years we have seen three patients with acute leukaemia uncommon
Present address: Servizio di Bramante 90, Turin, Italy.
Ematologia, Ospedale Maggiore,
C.
Case-reports Patient1 A 5-year-old boy was found to have acute lymphoblastic leukaemia (A.L.L.) in June, 1966. Clinical details are given in the accompanying table. 6 months after systemic remission had been obtained with cytotoxic drugs he developed meningeal leukaemia. A lumbar puncture showed cerebrospinal fluid (c.s.F.) under increased pressure with blast cells of 1270/µl. He was treated successfully with cytotoxic drugs administered intrathecally. 6 months later routine examination of the fundus showed a homogeneous opalescent area spreading outward from the right optic disc. At that time he had no visual symptoms. Over the next 4 weeks the opaque area enlarged and enveloped blood-vessels. A similar lesion then developed in the left eye. After 2 further months his vision began to deteriorate and radiotherapy (1500 rads first to the right and then to the left eye) was administered with improvement to his vision and in the appearance of the fundus. 2 months later visual symptoms recurred in both eyes and ophthalmoscopy showed recurrence of peripapillary opacity and swelling in both eyes. Further radiotherapy (1800 rads) was administered to the whole cranium including the eyes. There was some improvement in vision, and the opaque areas regressed until they involved only the areas of the discs. There was no further change over the following 4 months. Patient 2 A 3-year-old girl complained of impaired vision 9 months after the diagnosis of A.L.L. in November, 1969. On examination she apparently had bilateral fields defects. Both discs appeared pale and opaque swelling covered the optic cups. The c.s.F. pressure and cell content were normal. She was treated initially with methotrexate without response. Radiotherapy was administered to both eyes (1150 rads). Her vision improved and the appearance of both fundi returned to normal.
CLINICAL AND HAEMATOLOGICAL DETAILS OF 3 PATIENTS WITH FUNDAL CHANGES CAUSED BY LEUKAEMIC INVOLVEMENT OF THE OPTIC NERVE
A.L.L. Acute lymphoblastic leukzmia. N.A.=Not available. B.M.=Bone-marrow. methotrexate. R.T.=Radiotherapy. *Typed as T=lymphoblastic. &dag er; After some treatment. =
c.R.=Complete remission. M.T.X. !/T.=Intrathecal ’
830 Patient 3
21-year-old male with A.L.L. was started on treatment repeated 5-day courses of cyclophosphamide, vincristine, cytosine arabinoside, and prednisolone according to the Medical Research Council UKALL IV trial in June, 1976. He achieved complete remission. "Prophylactic" cranial irradiation was scheduled but delayed for personal reasons. 3 months after diagnosis he noticed blurring of vision in the right eye while abroad. 10 days later he lost vision in the right eye and developed blurred vision in the left eye. On his return home a week later he could only perceive light in the right eye and distinguish hand movements in the left eye. Ophthalmoscopy showed opaque shiny white areas involving both optic discs and spreading as far as the macular regions (see accompanying figure). At the disc blood-vessels were buried in the opacity and A
with
therefore invisible. The veins
were
distended. Lumbar punc-
ture revealed clear c.s.F. under normal pressure. Peripheralblood and bone-marrow examination showed relapse of acute leukaemia. The patient was treated with radiotherapy (2400 rads) to the eyes, optic nerves, and cranium. Cytotoxic drugs were continued systemically. An Ommaya reservoir3 was inserted to communicate with the right lateral ventricle of the brain and methotrexate and cytosine arabinoside were injected by this route. The visual acuity in the left eye improved to 6/6 and the appearance of the left fundus returned to normal. Acuity in the right eye remained impaired (6/30) and ophthalmoscopy showed optic atrophy.
Discussion least three mechanisms by which the and retina may be involved in patients with leukaemia. There may be (1) papilloedema secondary to There
optic
are at
nerve
Appearances of right and left optic discs in patient 3: (A) Before treatment; (B)6 days after start of treatment. (A) shows opaque swelling of the disc and surrounding retina. The veins are engorged and there are haemorrhages in the nerve-hbre layer. (B) shows resolution of the areas of opaque swelling and reduction in the calibre of the veins. The haemorrhages in the nerve-hbre layer remam.
831
raised intracranial pressure, (2) direct infiltration of the retina by leuksmia cells, or (3) the presence of neoplastic cells in the optic nerve without retinal involvement. Papilloedema, usually bilateral, is a common sign of raised intracranial pressure in patients in whom malignant cells have proliferated in the subarachnoid space. In these circumstances the main visual signs are enlargement of the blind spot and reduction in peripheral visual fields. Patients with localised leukæmic involvement restricted to the retina may have some focal visual loss but visual acuity should not be impaired provided that the macula is spared and the pressure of C.S.F. is not raised. Neither of these mechanisms adequately explains the features described in our three patients. Most descriptions of leukaemic infiltration of the retina and optic nerve are based on appearances at necropsy.1Our limited experience suggests that the ophthalmoscopic appearance of leukaemic involvement of the optic nerve is characteristic and the diagnosis may be made during life. Typically there are areas of opaque swelling and these may develop asymmetrically and involve one eye before the other. The borders are often well defined but there may be extension outwards to surround blood-vessels. Visual acuity may not be reduced in the affected eye or eyes and there may be a central scotoma. These features, together with the normal C.S.F. pressure, serve to distinguish optic-nerve infiltration from papillcedema on the one hand and from uncomplicated retinal involvement on the other. The changes seen in the fundus are then explained by infiltration by leukaemic cells in the retrolaminar portion of the optic nerve where they produce mechanical or ischaemic effects on nerve-fibres. This in turn leads to severe localised nerve-fibre swelling with accumulation of axoplasmic material at the disc secondary to obstruction of orthograde axoplasmic transport in ganglion cell axons. Certainly the ophthalmoscopic appearances in our patients are indistinguishable from those seen when axoplasmic transport in the optic nerve is obstructed in other conditions such as acute ischaemic optic neuro-
pathy.6-s Two of the three patients were first seen at a time when the importance of prophylactic treatment to prevent spread of disease to the central nervous system was not fully appreciated. Cranial irradiation with intrathecal chemotherapy is part of the UKALL IV protocol but the radiotherapy field deliberately excludes the eyes. One cannot therefore say whether such prophylactic treatment would have prevented the onset of ocular infiltration in patient 3 but it appeared not to have done so in three patients recently reported by Rosenthal et al.1 One of our patients (patient 1) had evidence of meningeal involvement before involvement of the retina but two patients (patients 1 and 2) had meningeal leukaemia subsequently. In contrast although all three patients had achieved initial remission of their systemic disease all had evidence of bone marrow involvement when they presented with eye symptoms. Similarly all of Rosenthal’s five patients were in systemic relapse when they developed signs of leukaemic involvement of the optic nerve.9 It thus appears that infiltration of the optic nerve is more closely related in time to (and may represent spread from) systemic rather than meningeal disease.
Although meningeal
leukaemia is sometimes treated
with intrathecal cytotoxic drugs only, such an approach the therapy of ocular disease is illogical since the subarachnoid space ends just posterior to the globe. In a recent report of a necropsy on an 11-year-old girl treated with intrathecal methotrexate for leukaemic involvement of the fundus, residual leukaemic cells were demonstrated only outside the subarachnoid space.10 The combined use of radiotherapy and intrathecal cytotoxic drugs was successful in four of the five patients with leukaemic involvement of the eye reported recently by Eichholtz" and our two patients treated in this manner obtained benefit. The use of the two modalities together should give the best chance of controlling or curing leuksemic involvement of the eye. to
We thank Mr Peter Fells (Moorfields Eye Hospital) for helpful advice during the preparation of this manuscript and Dr Eva Kohner for the retinal photographs. Dr D. Catovsky performed immunological tests on the leukasmic cells in patient 3. Radiotherapy was administered under the care of the late Dr L. Szur and Dr A. W. G. Goolden. Requests for reprints should be addressed to J. M. G., M. R. C. Leukaemia Unit, Hammersmith Hospital, Ducane Road, London W12 OHS. REFERENCES
Culler, A. M. Trans. Am. ophth. Soc. 1951, 49, 445. Allen, R. A., Straatsma, B. R. Arch. Ophthalmol. 1961, 66, 490. 3. Spiers, A. S. D., Booth, A. E. Lancet, 1973, i, 1263. 4. Goldstein, I., Wexler, D. Archs Ophthalmol. 1935, 13, 26. 5. Kuwabara, T., Aiello, L. ibid. 1964, 72, 494. 6. McLeod, D. Lancet, 1975, ii, 954. 7. McLeod, D. Trans. ophthal. Soc. U.K. 1976, 96, 313. 8. Tso, M. O. M., Fine, B. S. Am. J. Ophthalmol. 1975, 82, 424. 9. Rosenthal, A. R., Egbert, P. R., Wilbur, J. R., Probert, J. C. Trans. Pacific Coast oto-ophthalmol. Soc. 1974, 55, 137. 10. Ellis, W., Little, H. L. Am. J. Ophthalmol. 1973, 75, 867. 11. Eichholtz, W. Ophthalmologica, Basel, 1975, 170, 494. 1. 2.
Preliminary Communication A CONTROLLED TRIAL OF D-PENICILLAMINE THERAPY IN PRIMARY BILIARY CIRRHOSIS STEPHAN JAIN S. SAMOURIAN
P. J. SCHEUER J. O’D. MCGEE
SHEILA SHERLOCK
Departments of Medicine and Histopathology, Royal Free Hospital, London, and Department of Pathology, Radcliffe Infirmary, Oxford 900 mg daily, was used randomised controlled trial for treatment of patients with primary biliary cirrhosis. 19 patients received D-penicillamine and 13 received placebo. The two groups were similar in age, duration of illness, liver function tests, and liver histology. Before entry into the trial liver-copper concentration was raised in 25 of the 27 patients in whom it was measured. After three months patients taking D-penicillamine showed a significant reduction in serum-aspartate-transaminase concentrations compared with the placebo group, and this reduction seemed to be sustained. In the 4 patients on D-penicillamine for a year, a second liver biopsy showed that mean liver-copper concentration fell from
Summary
D-penicillamine,
in
310±128 (S.E.M.)
a
to
84±36
µg/g dry liver, compared
with a reduction from 511±169 to 454±128 in the 7 patients in the placebo group in whom serial liver-copper measurements were available. Liver histology demonstrated a comparative improvement in cholestasis in pa-
whose loss of vision was thought to be due to infiltration of the optic nerve by malignant cells. Diagnosis was based on the ophthalmoscopic appearance which is characteristic. The mode of presentation and the response to radiotherapy and cytotoxic drugs in these three patients are the subject of this paper.
OCULAR INVOLVEMENT IN LEUKÆMIA Report of Three Cases FRANCO PAOLINO* KATHERINE H. MURRAY DAVID A. G. GALTON M. GOLDMAN JOHN C. F. JOHN GRINDLE Medical Research Council Leukœmia Unit, Hammersmith
Hospital, London W12 0HS, and Department of Clinical Ophthalmology, Institute of Ophthalmology, Moor fields Eye Hospital, London EC1V 2PD
patients with treated acute lymphoblastic leukæmia acquired visual believed to be caused by ocular infiltration by symptoms All cells. three patients had other evidence of malignant disease including bone-marrow involvement at systemic One the time. patient had a previous history of meningeal leukæmia and none had received "prophylactic" cranial irradiation. The ophthalmoscopic appearances were similar in each case and were thought to have been caused by obstruction of axoplasmic flow associated with infiltration of the optic nerve by neoplastic cells. The three patients were treated by local irradiation and two also received intrathecal chemotherapy. Response to treatment was variable but the use of radiotherapy combined with intrathecal cytotoxic drugs is probably the best available approach.
Summary
Three
Introduction VISUAL symptoms in patients with leukaemia are not and may be associated with retinal haemorrhages, exudates, or papillredema 12 for which specific therapy may not be required. Leukaemia may, however, involve the eye by direct infiltration. In the past ten years we have seen three patients with acute leukaemia uncommon
Present address: Servizio di Bramante 90, Turin, Italy.
Ematologia, Ospedale Maggiore,
C.
Case-reports Patient1 A 5-year-old boy was found to have acute lymphoblastic leukaemia (A.L.L.) in June, 1966. Clinical details are given in the accompanying table. 6 months after systemic remission had been obtained with cytotoxic drugs he developed meningeal leukaemia. A lumbar puncture showed cerebrospinal fluid (c.s.F.) under increased pressure with blast cells of 1270/µl. He was treated successfully with cytotoxic drugs administered intrathecally. 6 months later routine examination of the fundus showed a homogeneous opalescent area spreading outward from the right optic disc. At that time he had no visual symptoms. Over the next 4 weeks the opaque area enlarged and enveloped blood-vessels. A similar lesion then developed in the left eye. After 2 further months his vision began to deteriorate and radiotherapy (1500 rads first to the right and then to the left eye) was administered with improvement to his vision and in the appearance of the fundus. 2 months later visual symptoms recurred in both eyes and ophthalmoscopy showed recurrence of peripapillary opacity and swelling in both eyes. Further radiotherapy (1800 rads) was administered to the whole cranium including the eyes. There was some improvement in vision, and the opaque areas regressed until they involved only the areas of the discs. There was no further change over the following 4 months. Patient 2 A 3-year-old girl complained of impaired vision 9 months after the diagnosis of A.L.L. in November, 1969. On examination she apparently had bilateral fields defects. Both discs appeared pale and opaque swelling covered the optic cups. The c.s.F. pressure and cell content were normal. She was treated initially with methotrexate without response. Radiotherapy was administered to both eyes (1150 rads). Her vision improved and the appearance of both fundi returned to normal.
CLINICAL AND HAEMATOLOGICAL DETAILS OF 3 PATIENTS WITH FUNDAL CHANGES CAUSED BY LEUKAEMIC INVOLVEMENT OF THE OPTIC NERVE
A.L.L. Acute lymphoblastic leukzmia. N.A.=Not available. B.M.=Bone-marrow. methotrexate. R.T.=Radiotherapy. *Typed as T=lymphoblastic. &dag er; After some treatment. =
c.R.=Complete remission. M.T.X. !/T.=Intrathecal ’
830 Patient 3
21-year-old male with A.L.L. was started on treatment repeated 5-day courses of cyclophosphamide, vincristine, cytosine arabinoside, and prednisolone according to the Medical Research Council UKALL IV trial in June, 1976. He achieved complete remission. "Prophylactic" cranial irradiation was scheduled but delayed for personal reasons. 3 months after diagnosis he noticed blurring of vision in the right eye while abroad. 10 days later he lost vision in the right eye and developed blurred vision in the left eye. On his return home a week later he could only perceive light in the right eye and distinguish hand movements in the left eye. Ophthalmoscopy showed opaque shiny white areas involving both optic discs and spreading as far as the macular regions (see accompanying figure). At the disc blood-vessels were buried in the opacity and A
with
therefore invisible. The veins
were
distended. Lumbar punc-
ture revealed clear c.s.F. under normal pressure. Peripheralblood and bone-marrow examination showed relapse of acute leukaemia. The patient was treated with radiotherapy (2400 rads) to the eyes, optic nerves, and cranium. Cytotoxic drugs were continued systemically. An Ommaya reservoir3 was inserted to communicate with the right lateral ventricle of the brain and methotrexate and cytosine arabinoside were injected by this route. The visual acuity in the left eye improved to 6/6 and the appearance of the left fundus returned to normal. Acuity in the right eye remained impaired (6/30) and ophthalmoscopy showed optic atrophy.
Discussion least three mechanisms by which the and retina may be involved in patients with leukaemia. There may be (1) papilloedema secondary to There
optic
are at
nerve
Appearances of right and left optic discs in patient 3: (A) Before treatment; (B)6 days after start of treatment. (A) shows opaque swelling of the disc and surrounding retina. The veins are engorged and there are haemorrhages in the nerve-hbre layer. (B) shows resolution of the areas of opaque swelling and reduction in the calibre of the veins. The haemorrhages in the nerve-hbre layer remam.
831
raised intracranial pressure, (2) direct infiltration of the retina by leuksmia cells, or (3) the presence of neoplastic cells in the optic nerve without retinal involvement. Papilloedema, usually bilateral, is a common sign of raised intracranial pressure in patients in whom malignant cells have proliferated in the subarachnoid space. In these circumstances the main visual signs are enlargement of the blind spot and reduction in peripheral visual fields. Patients with localised leukæmic involvement restricted to the retina may have some focal visual loss but visual acuity should not be impaired provided that the macula is spared and the pressure of C.S.F. is not raised. Neither of these mechanisms adequately explains the features described in our three patients. Most descriptions of leukaemic infiltration of the retina and optic nerve are based on appearances at necropsy.1Our limited experience suggests that the ophthalmoscopic appearance of leukaemic involvement of the optic nerve is characteristic and the diagnosis may be made during life. Typically there are areas of opaque swelling and these may develop asymmetrically and involve one eye before the other. The borders are often well defined but there may be extension outwards to surround blood-vessels. Visual acuity may not be reduced in the affected eye or eyes and there may be a central scotoma. These features, together with the normal C.S.F. pressure, serve to distinguish optic-nerve infiltration from papillcedema on the one hand and from uncomplicated retinal involvement on the other. The changes seen in the fundus are then explained by infiltration by leukaemic cells in the retrolaminar portion of the optic nerve where they produce mechanical or ischaemic effects on nerve-fibres. This in turn leads to severe localised nerve-fibre swelling with accumulation of axoplasmic material at the disc secondary to obstruction of orthograde axoplasmic transport in ganglion cell axons. Certainly the ophthalmoscopic appearances in our patients are indistinguishable from those seen when axoplasmic transport in the optic nerve is obstructed in other conditions such as acute ischaemic optic neuro-
pathy.6-s Two of the three patients were first seen at a time when the importance of prophylactic treatment to prevent spread of disease to the central nervous system was not fully appreciated. Cranial irradiation with intrathecal chemotherapy is part of the UKALL IV protocol but the radiotherapy field deliberately excludes the eyes. One cannot therefore say whether such prophylactic treatment would have prevented the onset of ocular infiltration in patient 3 but it appeared not to have done so in three patients recently reported by Rosenthal et al.1 One of our patients (patient 1) had evidence of meningeal involvement before involvement of the retina but two patients (patients 1 and 2) had meningeal leukaemia subsequently. In contrast although all three patients had achieved initial remission of their systemic disease all had evidence of bone marrow involvement when they presented with eye symptoms. Similarly all of Rosenthal’s five patients were in systemic relapse when they developed signs of leukaemic involvement of the optic nerve.9 It thus appears that infiltration of the optic nerve is more closely related in time to (and may represent spread from) systemic rather than meningeal disease.
Although meningeal
leukaemia is sometimes treated
with intrathecal cytotoxic drugs only, such an approach the therapy of ocular disease is illogical since the subarachnoid space ends just posterior to the globe. In a recent report of a necropsy on an 11-year-old girl treated with intrathecal methotrexate for leukaemic involvement of the fundus, residual leukaemic cells were demonstrated only outside the subarachnoid space.10 The combined use of radiotherapy and intrathecal cytotoxic drugs was successful in four of the five patients with leukaemic involvement of the eye reported recently by Eichholtz" and our two patients treated in this manner obtained benefit. The use of the two modalities together should give the best chance of controlling or curing leuksemic involvement of the eye. to
We thank Mr Peter Fells (Moorfields Eye Hospital) for helpful advice during the preparation of this manuscript and Dr Eva Kohner for the retinal photographs. Dr D. Catovsky performed immunological tests on the leukasmic cells in patient 3. Radiotherapy was administered under the care of the late Dr L. Szur and Dr A. W. G. Goolden. Requests for reprints should be addressed to J. M. G., M. R. C. Leukaemia Unit, Hammersmith Hospital, Ducane Road, London W12 OHS. REFERENCES
Culler, A. M. Trans. Am. ophth. Soc. 1951, 49, 445. Allen, R. A., Straatsma, B. R. Arch. Ophthalmol. 1961, 66, 490. 3. Spiers, A. S. D., Booth, A. E. Lancet, 1973, i, 1263. 4. Goldstein, I., Wexler, D. Archs Ophthalmol. 1935, 13, 26. 5. Kuwabara, T., Aiello, L. ibid. 1964, 72, 494. 6. McLeod, D. Lancet, 1975, ii, 954. 7. McLeod, D. Trans. ophthal. Soc. U.K. 1976, 96, 313. 8. Tso, M. O. M., Fine, B. S. Am. J. Ophthalmol. 1975, 82, 424. 9. Rosenthal, A. R., Egbert, P. R., Wilbur, J. R., Probert, J. C. Trans. Pacific Coast oto-ophthalmol. Soc. 1974, 55, 137. 10. Ellis, W., Little, H. L. Am. J. Ophthalmol. 1973, 75, 867. 11. Eichholtz, W. Ophthalmologica, Basel, 1975, 170, 494. 1. 2.
Preliminary Communication A CONTROLLED TRIAL OF D-PENICILLAMINE THERAPY IN PRIMARY BILIARY CIRRHOSIS STEPHAN JAIN S. SAMOURIAN
P. J. SCHEUER J. O’D. MCGEE
SHEILA SHERLOCK
Departments of Medicine and Histopathology, Royal Free Hospital, London, and Department of Pathology, Radcliffe Infirmary, Oxford 900 mg daily, was used randomised controlled trial for treatment of patients with primary biliary cirrhosis. 19 patients received D-penicillamine and 13 received placebo. The two groups were similar in age, duration of illness, liver function tests, and liver histology. Before entry into the trial liver-copper concentration was raised in 25 of the 27 patients in whom it was measured. After three months patients taking D-penicillamine showed a significant reduction in serum-aspartate-transaminase concentrations compared with the placebo group, and this reduction seemed to be sustained. In the 4 patients on D-penicillamine for a year, a second liver biopsy showed that mean liver-copper concentration fell from
Summary
D-penicillamine,
in
310±128 (S.E.M.)
a
to
84±36
µg/g dry liver, compared
with a reduction from 511±169 to 454±128 in the 7 patients in the placebo group in whom serial liver-copper measurements were available. Liver histology demonstrated a comparative improvement in cholestasis in pa-