Documenta Ophthalmologica 40, 2: 287-300, 1976. MEASLES (MORBILLI) AND OCULAR COMPLICATIONS NORA I. R E G E N S B U R G & H. E. HENKES (Rotterdam)
INTRODUCTION Measles or morbilli, known in the Western world as a children's disease, is caused by a labile, highly infective virus with neurotropic properties. Not until 1954 was this virus isolated. One of the complications of measles is encephalitis that occurs in 0.1 tot 0.4 % of cases. Allegedly, optic neuritis occurs in 7.5 % of the cases of encephalitis. Most authors believe that the optic neuritis has a favorable prognosis (Walsh & Hoyt, 1969; Duke-Elder, 1966), but Capolongo (quoted by Haydn, 1970) reported total blindness in 25 out of 38 cases! Sporadic unilaterality of the optic neuritis has been reported (Srivastava et al., 1963). Retinal lesions resulting from a measles infection appear to occur less often. There have been reports in the literature, however, of patients with retinal lesions occurring in the course of many different acute viral infections, including measles; the latter occurrence was described for the first time by Leber in 1916 (see review paper by Doise, 1955; Franceschetti, Franqois & Babel, 1963;Heutz & Kfilz, 1969; Scheie, 1972). In the course of measles retinopathy, three stages can be distinguished (Doise, 1955): 1. The acute stage, which occurs between the 4th and the 1 l t h day of the disease. The duration of the acute stage is mostly given as varying from 10 days to 2 months. The visual acuity is reduced to bilateral amaurosis occurring within 2 4 4 8 hours.
The fundus appearance resembles that of occlusion of the central retinal artery, viz.: pale papillae, narrow vessels and retinal oedema, either at the posterior pole alone or of the retina as a whole. The cherry-red macula is not always seen in these cases; other aspects that have been described are
Department of Ophthalmology, Erasmus University, Schiedamse Vest 180, Rotterdam, The Netherlands, phone: 0.10 - 110402.
287
scattered hemorrhages, small white exudates, greyish-white foci and/or a stellate figure, at the macula (e.g. Weigelinm, 1923; Duke-Elder, 1966; Doise, 1955; Heath, 1932; Schlossberg & Prizer, 1940; Scheie, 1972 and Crone, 1973). The observed differences of the fundus appearance are probably to be attributed to the different times of first examination of the fundus. The visual fields cannot be determined in this stage. Electroretinographically no responses can be recorded.
2. The phase o f recovery: The duration is stated as varying between 14 days and a few months. The visual acuity is restored to a considerable extent, but the ultimate result depends on the duration of the amaurosis and of the macular abnormalities that have developed. Complete restoration of the visual acuity to normal is rare. The fundus picture in this stage is characterized by disappearance of the retinal oedema and the appearance of small white spots, simulating retinopathia punctata albescens, retinitis stellata or drusen. Pigment alterations occur later, in central and/or peripheral localizations. These pigment alterations give the fundus a salt-and-pepper appearance. The visual fields: concentric limitation, even tubular, may be seen. Annular scotomas and central scotomas with varying peripheral impairment have also been described. The last-mentioned findings depend on the localization of the lesions in the retina. The ERG in this stage often reveals partial restoration of the activity; the EOG in our case showed no increase of the light adaptation of the resting potential. Dark adaptation is found to be impaired. The possibility of disorders of the color vision depends on the extent of the macular lesions. This stage of restoration is followed - according to the literature at any rate - by a period of latency (e.g. Heutsch & Kfilz, 1970; Scheie, 1972), during which the retinal functions do not change. The pigment alterations, however, grow coarser during this period. In this stage, the patient is often lost from sight. 3. The late phase (described, for instance, after 18 and 14 years (Franceschetti, Dieterler & Schwarz, 1958) and after 17 years (Scheie, 1972)). The visual acuity begins to decrease once more. The fundus picture is characterized by a pale papilla; the retinal vessels may be narrow, but are sometimes normal. If the macula is affected, it shows the
288
a p p e a r a n c e o f a c e n t r a l t a p e t o r e t i n a l d e g e n e r a t i o n , as o b s e r v e d , for i n s t a n c e , in S t a r g a r d t ' s disease. T h e p e r i p h e r y s h o w s t h e p i c t u r e o f a t a p e t o - r e t i n a l d e g e n e r a t i o n w i t h coarse p i g m e n t a c c u m u l a t i o n s a n d t r a b e c u l a r s t r u c t u r e s . T h e visual fields s h o w e x t e n s i o n o f t h e p r e - e x i s t e n t s c o t o m a s . In t h e E R G , n o r e s p o n s e s can be r e c o r d e d a n y longer, or t h e r e are o n l y rudim e n t a r y c o n e - s y s t e m responses. Dark a d a p t a t i o n s h o w s an increase o f the p h o t o p i c as well as of t h e s c o t o p i c threshold. CASE REPORTS
Case 1. KM (fem.), born 26.9.1957. This girl contracted measles on 10.1.1965, as the third in her family. After 2 days, the child complained of bad eyesight (very intelligent girl, so could describe it clearly), followed the next day by almost complete blindness. On 20.1.1965 she was examined by an ophthalmologist, who found a visual acuity in both eyes of -;/4/ 60 (= finger counting at 25 cm.). The fundus was not definitely abnormal: the arteries were possibly somewhat narrowed and there was some doubtful pallor of the papillae, OS)'OD. Retrobulbar neuritis ODS was diagnosed. The child was admitted to a general hospital on 22.1.1965. Internal examination revealed no abnormalities. In particular, the blood picture and lumbar puncture were normal. Roentgen examination of the skull: normal findings. Neurological examination showed no abnormalities. EEG: mild diffuse disorders with dysrhythmias in the occipital area. Treatment: vit. B complex, gammagiobulin. 24.1.1965 ophthalmologically: VOD = 1/60; VOS = ~ / 6 0. Fundus: narrowed retinal vessels, progressive atrophy OD and OS. Treatment: Prednison, vit. B6, paraxine, vit. C. 26.1.1965: Fever due to unknown cause. Probably: 'drug fever'. 3.2.1965: Transfer to the Ophthalmological Hospital of Rotterdam.
Findings: Fundus: pale papillae; narrowed retinal vessels; in both maculae, fine crystalliform deposits and diffuse pigment changes. Periphery: normal appearance. Visual fields (Fig. 1): both eyes centro-caecal scotoma, slightly reduced retinal sensitivity in the periphery. Dark adaptation (Fig. 2): reduced photopic adaptation and almost complete loss of scotopic adaptation. EOG: LP/DT ratio: OD 1.50 and OS 1,45 (lower limit of normal: 1.85). ERG: rod responses absent. Cone responses rudimentary. Visually evoked cortical potentials (VECP's): demonstrable but very slight.
Conclusion." Combined infection of the retina and optic nerve due to measles. The patient was re-examined 8 years later. Vision: OD 3/60 and OS 5/60. Fundus: papilla OS normal color, OD slightly pale temporaUy with normal retinal vessels. The retina on both sides shows the appearance of a central tapeto-retinal degeneration. Periphery: normal retinal areas alternating with areas of atrophy of retina and choroid, with coarse pigment shifts, grouped around the retinal vessels. Here and there, the pigmentations show a trabecular appearance (see Figs. 3a, b and c). Visual field: no essential alteration compared with 1965. Dark adaptation: normal photopic and scotopic adaptation.
289
'0926 1.1965
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/
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/ / Fig. 1. Case 1 (KM). Visual fields (Goldmann perimeter) one month after onset of the diseaese. Below: 8 years later.
EOG: LP/DT ratio OD 1.60 and OS 1.84. ERG: rod responses OD 60 % of normal (based on the scheme of the department of electro-ophthalmology of the Rotterdam Ophthalmological Hospital) and OS, 35 % of normal. Cone responses ODS 30 % of normal. VECP's: slight responses. Case 2. AA (fem.), born 28.8.1953. Measles on 16.4.1957; 1 day later, free from fever; after 2 days recurrence of fever, rambling talk, vomiting, headache and progressive drowsiness. According to the anamnesis, the patient at this time started to squint, which she had never done before. On 21.4.1957 admission to a general hospital. Internal examination showed bronchitis; blood picture: leukocytosis with relative granulocytosis. Neurological examination showed drowsiness, Kernig doubtful, low reflexes. With regard to the eyes, only strabismus was recorded without further specification. CSF: pressure slightly increased. 8/3 cells. Diagnosis: measles encephalitis. Therapy: Atarax tablets, ACTH injections, penicillin. Atarax was subsequently replaced by Miltown.
290
Fig. 2. Case 1 ; darkadaptationcurve one month after onset of disease. Disturbance of photopic and scotopic adaptation. Below: 8 years later a normal photopic and scotopic darkadaptation is found.
29.4.1957: Increased and pathological reflexes in the legs, pronounced disorders of movement coordination and mental confusion. 16.5.1957: exanthema of unknown origin. After discharge on 19.8.1957, the patient had to be hospitalized in a special children's clinic because of disorders of behavior. She functions at the level of disability. Ophthalmological examination November 1966: VOD with correction (+ 1.50) = 1.0; VOS = 1/60, improvement impossible. Fundus both sides: pale papilla. Examination on 18.9.1973 (as a part of a study of retinal abnormalities in children who have had measles encephalitis) VOD with correc-
291
a
9Fig. 3a and b. Case 1 ; 8 years after onset of measles. Fundus photographs of right and left eye, showing considerable pigmentary derangement of the posterior pole. Striking resemblance to Stargardt's disease.
Fig. 3c. Case. Peripheral fundus. Bone curpuscles and pigment clusters on and around the vessels.
fion S + 1.50 = 2.0; VOS = 1/60, improvement impossible. Color vision: AO-HRR: OD slight red-green disorder, OS markedly abnormal, 'unclassified' disorder of the color vision. Position of the eyes: convergent strabismus OS. Fundi: pale papilla; normal retinal vessels. In both maculae, light-colored and white spots; fine pigment alterations. (Figs. 4a and b). Periphery, salt-and-pepper appearance.
292
b Fig. 4a and b. Case 2 (AA). Foveal region of right and left eye. Small white dots, disturbed foveal reflex and fine pigmentary disturbances are visible.
Visual fields: OD enlarged blind spot, concentric limitation, partial loss of the upper nasal quadrant. OS centro-caecal scotoma and partial loss of the nasal visual field (Fig. 5). Dark adaptation: both the photopic and scotopic curves run 1 log. U above the normal hminal value (Fig. 6).
293
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Fig. 5. Case 2. Visual fields (Goldmann perimeter). Marked defects probably related to lesions in the optic pathways.
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Fig. 6. Case 2. Darkadaptationcurve showing an increase of photopic and scotopic
EOG: LP/DTratio ODS: 1.75. ERG: rod responses: normal. Cone responses: normal. VECP's: subnormal. Neither patient had a history of hereditary predisposition. No consanguinity was found in the family. Both patients had developed normally prior to the measles infection. DISCUSSION In the first case, KM, there was a clear-cut combination of a retinopathy and a lesion of the optic nerve. This patient has been examined for the first time during the stage of recovery and is now probably in the latent period. It cannot be predicted whether this situation will remain unchanged. Case 2, AA. In this case, a lesion situated higher in the visual tract undoubtedly plays an important part, but the fundus abnormalities and the abnormal EOG show that here, also, a retinal component is involved. Repetition of the examination after a number of years will possibly yield additional information in these cases. It should be kept in mind, however, that in neither case was 'measles' proved beyond doubt, since no serological tests with measles antigen were carried out.
DIFFERENTIAL DIAGNOSIS According to Franceschetti, Franqois & Babel (1963) and Slezak (1969) the alterations of the fundus encountered after the acute stage, are to be distinguished from: 1. primary tapeto-retinal degeneration 2. alterations of the pigmented epithelium in other hereditary diseases, e.g. carriers of choroideremia Stargardt's disease 3. secondary tapeto-retinal degeneration: congenital:
post-natal:
296
viral (especially important, rubella; cytomegaly) syphilis toxoplasmosis viral (poliomyelitis, mumps, variola, varicella, vaccinia) syphilis trauma old age (senility)
4. alterations of the pigmented epithelium caused by drugs: chloroquine streptomycin phenothiazine indomethacin In the majority of the cases the anamnestic data, however vague, will have to serve as a basis for the conclusion. Family anamnesis and/or examination is of particular importance for the differentiation of the hereditary affections. Earlier authors on the basis of the histological findings obtained by Blum & Babel (1948) believed that a simple differentiation between primary and secondary tapeto-retinal degeneration can be made with the aid of the ERG. However, the ERG only reflects deep retinal lesions. In making the distinction between primary and secondary tapeto-retinal degeneration, the return of the electro-retinographic response undoubtedly constitutes an argument in favor of a secondary form (case 1).
PATHOGENESIS The hypotheses advanced in regard to the occurrence of the acute phase of measles retinopathy may be concisely summarized (Haydn, 1970) as follows: 1. Vascular genesis: direct or indirect action of the virus or of its toxins on the vascular wall, as the result of which a generalized spasm occurs and/ or the vascular wall grows permeable; 2. Direct or indirect action of the virus on the retinal metabolism by blocking the glycolytic enzymes (Schupfer, 1951); 3. As provocation of a familial hereditary degeneration (Franceschetti, 1964). Owing to the almost complete lack of histopathological material, no definite conclusion has been drawn so far. It may be mentioned, however, that Babel in 1958, in the discussion following the paper by Franceschetti, Dieterle & Schwarz, stated that histological study of one case had shown that in measles retinopathy, the neuro-epithelium is affected first. In this connection he postulated a retinal ischemia.
297
CONSIDERATIONS The forms of retinopathy described in subacute sclerosing panencephalitis or SSPE (Otradovec, 1969; Robb & Watters, 1970; Nelson et al., 1970; Karel et al., 1971; Landers & Klintworth, 1971) show great resemblance to the cases of measles retinopathy hitherto described, both as regards the pigment alterations and as regards the course. In SSPE, in which it is known that the occurrence is correlated with a measles vaccination infection, inclusions have been encountered in the retinal neurons (Landers & Klintworth, 1971), which proved to be identical to the measles virus. It may be assumed (e.g. Kapselberg & Ronde-Verloop, 1973) that the measles virus is the etiological agent. This renders it probable that the measles virus itself is also the etiological agent for the development of a retinopathy. In SSPE, the deterioration of the visual acuity and the onset of pigment retinopathy may precede the neurological symptoms. Timely diagnosis of this state (acute chorioretinitis, central and/or peripheral, with secondary pigment alterations after the acute phase caused.by measles virus) may be of great importance. It is also plausible to suppose that many cases of unexplained juvenile tapetoretinal degeneration have been due to the measles virus. The question to what extent a particular predisposition may play a part has not yet been studied (Nelson, 1970, case 2: female SSPE whose older brother had also died from this disease). CONCLUSIONS 1. Measles retinopathy appears to be a specific neuro-retinal disorder caused by the measles virus. 2. The prognosis must always be interpreted with due prudence, in view of the fact that the long-term evolution is unknown. 3. The frequency of the condition may be higher than has been believed so far, which view is corroborated by the findings in SSPE. 4. An agreement concerning uniform nomenclature for the pathological condition 'measles' would help reduce the confusion in the literature (in Anglo-Saxon literature, the term 'rubeola' sometimes wrongly applied to rubella as well as to measles).
298
REFERENCES Blum, J. D. & Babel, J. Diagnostic diff~rentiel des r&inites et des pseudo-r&fifites pigmentaires au point de rue histologique. Ann. d'Oculist. 181 : 468 (1948). Crone, R. A. Personal communication (1973). Doise, P. La r&inite pigmentaixe post-morbilleuse. Th~se Lille (1955). Duke-Elder, S. Textbook of ophthalmology. Vol. X, p. 266 ; Vol. XII, p. 124. London, Kimpton (1966). Franceschetti, A., Francois, J. & Babel, J. Les h~rgdoddg~n~rescences chorio-r~tiniennes, tome II, p. 1412. Paris, Masson (1963). Franceschetti, A., Dieterle, P. & Schwarz, A. R&inite pigmentaire /t virus. Ophthalmologica 135 : 545 (1958). Franceschetti, A. et al. Pigmentary pseudoretinopathy after measles, an acute manifestation of familial hereditary conditions. Bull. Soc. ft. Ophtal. 77 : 549 (1964). Haydn, M. Erblindung beider Augen nach Masernerkrankung. Klin. Mbl. Augenheilk. 156 : 539 (1970). Heath, P. Measles encephalitis, a clinical report of some eye findings. Amer. J. Ophthal. 15 : 130 (1932). Heutsch, R. & Kfilz, J. Beitrag zur sekund/iren Pigmentdegenerationen der Netzhaut nach Masern. Klin. Mbl. Augenheilk. 154 : 706 (1969). Kapsenberg, J. G. & Ronde-Verloop, F. M. de. Subacute scleroserende panencephalitis; isolatie van mazelenvirus. Ned. T. Geneesk. 117 : 1880 (1973). Karel, 1. et al. Fluoroangiographic picture of the macular lesion in subacute sclerosering leukoencephalifis. Ophthalrnolog4ca 162 -348 (1971). Landers, M. B. & Klintworth, G. K. Subacute sclerosing panencephalitis (SSPE). Arch. Ophthal. 86 : 156 (1971). Nelson, D. A. et al. Retinal lesions in subacute sclerosing panencephalitis. Arch. Ophthal. 84 : 613 (1970). Otradovec, J. Das klinische Bild der zentralen chorioretinalen Ver~inderungen bei subakuten sklerosierenden Leukoenzephalitis. Ophthalmologica 157 : 427 (1969). Robb, R. M. & Watters, G. V. Ophthalmic manifestation of S.S.P.E. Arch. Ophthal. 83 : 426 (1970). Scheie, M. G. & Morse, P. H. Rubeola retinopathy. Arch. Ophthal. 88 : 341 (1972). Schlossberg, F. R. & Prizer, M. Retinal changes with marked impairment of vision in measles.Amer. J. Ophthal. 23 : 948 (1940). Schupfer, F. Retiniti pigmentose consecutive a malattie infettive acute. Boll. Oculist. 30 : 424 (1951). Slezak, H. & Hommer, K. Fundus pulverulentus. Graef Arch. Ophthal. 178 : 177. (1969). Srivastava, S. P. & Nema, H. V. Optic neuritis in measles. Brit. J. Ophthal. 47 : 180 (1963). Walsh, F. B. & Hoyt, W. F. Clinical neuro-ophthalmology; Vol. II. Baltimore, Williams & Wilkins, 1969.
DISCUSSION Crone has recently seen a 2-year-old girl with a mild measles rash. She became suddenly blind and was examined a few hours later. There were yellowish-white oedematous spots, mostly in the periphery, with scattered small, mostly streaked hemorrhages. The papillae were slightly oedematous. As early as the next day, the oedema had largely disappeared. After 9 days, it had disappeared altogether and the retinal vessels were markedly narrowed. In the albinotic fundi, only mild pigment shifting was seen. The eyesight failed to return.
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Answer: The fundus image largely depends on the m o m e n t of examination o f a child. Hemorrhages and oedema have been described b u t disappear very rapidly. The amaurosis m a y continue for up to 6 months. Leffertstra: Do y o u know of any mass screenings of measles patients to detect any formes f m s t e s or cases running an abortive course? Answer: I have n o t heard o f any studies o f this kind. We ourselves have studied cases already k n o w n as measles encephalitis, since they constituted a circumscribed, accessible group. In view o f the high frequency of measles, it is practically impossible to examine all the children with this infection. Janssons Capriles: This interesting observation corresponds directly to an article on SSPE in the latest issue of the Nederlands Tijdschrift voor Geneeskunde (Dr. Kapsenberg). What was the age of onset of the measles in y o u r cases? Answer: Both children were 5 years old when they contracted measles.
300
INTRODUCTION Measles or morbilli, known in the Western world as a children's disease, is caused by a labile, highly infective virus with neurotropic properties. Not until 1954 was this virus isolated. One of the complications of measles is encephalitis that occurs in 0.1 tot 0.4 % of cases. Allegedly, optic neuritis occurs in 7.5 % of the cases of encephalitis. Most authors believe that the optic neuritis has a favorable prognosis (Walsh & Hoyt, 1969; Duke-Elder, 1966), but Capolongo (quoted by Haydn, 1970) reported total blindness in 25 out of 38 cases! Sporadic unilaterality of the optic neuritis has been reported (Srivastava et al., 1963). Retinal lesions resulting from a measles infection appear to occur less often. There have been reports in the literature, however, of patients with retinal lesions occurring in the course of many different acute viral infections, including measles; the latter occurrence was described for the first time by Leber in 1916 (see review paper by Doise, 1955; Franceschetti, Franqois & Babel, 1963;Heutz & Kfilz, 1969; Scheie, 1972). In the course of measles retinopathy, three stages can be distinguished (Doise, 1955): 1. The acute stage, which occurs between the 4th and the 1 l t h day of the disease. The duration of the acute stage is mostly given as varying from 10 days to 2 months. The visual acuity is reduced to bilateral amaurosis occurring within 2 4 4 8 hours.
The fundus appearance resembles that of occlusion of the central retinal artery, viz.: pale papillae, narrow vessels and retinal oedema, either at the posterior pole alone or of the retina as a whole. The cherry-red macula is not always seen in these cases; other aspects that have been described are
Department of Ophthalmology, Erasmus University, Schiedamse Vest 180, Rotterdam, The Netherlands, phone: 0.10 - 110402.
287
scattered hemorrhages, small white exudates, greyish-white foci and/or a stellate figure, at the macula (e.g. Weigelinm, 1923; Duke-Elder, 1966; Doise, 1955; Heath, 1932; Schlossberg & Prizer, 1940; Scheie, 1972 and Crone, 1973). The observed differences of the fundus appearance are probably to be attributed to the different times of first examination of the fundus. The visual fields cannot be determined in this stage. Electroretinographically no responses can be recorded.
2. The phase o f recovery: The duration is stated as varying between 14 days and a few months. The visual acuity is restored to a considerable extent, but the ultimate result depends on the duration of the amaurosis and of the macular abnormalities that have developed. Complete restoration of the visual acuity to normal is rare. The fundus picture in this stage is characterized by disappearance of the retinal oedema and the appearance of small white spots, simulating retinopathia punctata albescens, retinitis stellata or drusen. Pigment alterations occur later, in central and/or peripheral localizations. These pigment alterations give the fundus a salt-and-pepper appearance. The visual fields: concentric limitation, even tubular, may be seen. Annular scotomas and central scotomas with varying peripheral impairment have also been described. The last-mentioned findings depend on the localization of the lesions in the retina. The ERG in this stage often reveals partial restoration of the activity; the EOG in our case showed no increase of the light adaptation of the resting potential. Dark adaptation is found to be impaired. The possibility of disorders of the color vision depends on the extent of the macular lesions. This stage of restoration is followed - according to the literature at any rate - by a period of latency (e.g. Heutsch & Kfilz, 1970; Scheie, 1972), during which the retinal functions do not change. The pigment alterations, however, grow coarser during this period. In this stage, the patient is often lost from sight. 3. The late phase (described, for instance, after 18 and 14 years (Franceschetti, Dieterler & Schwarz, 1958) and after 17 years (Scheie, 1972)). The visual acuity begins to decrease once more. The fundus picture is characterized by a pale papilla; the retinal vessels may be narrow, but are sometimes normal. If the macula is affected, it shows the
288
a p p e a r a n c e o f a c e n t r a l t a p e t o r e t i n a l d e g e n e r a t i o n , as o b s e r v e d , for i n s t a n c e , in S t a r g a r d t ' s disease. T h e p e r i p h e r y s h o w s t h e p i c t u r e o f a t a p e t o - r e t i n a l d e g e n e r a t i o n w i t h coarse p i g m e n t a c c u m u l a t i o n s a n d t r a b e c u l a r s t r u c t u r e s . T h e visual fields s h o w e x t e n s i o n o f t h e p r e - e x i s t e n t s c o t o m a s . In t h e E R G , n o r e s p o n s e s can be r e c o r d e d a n y longer, or t h e r e are o n l y rudim e n t a r y c o n e - s y s t e m responses. Dark a d a p t a t i o n s h o w s an increase o f the p h o t o p i c as well as of t h e s c o t o p i c threshold. CASE REPORTS
Case 1. KM (fem.), born 26.9.1957. This girl contracted measles on 10.1.1965, as the third in her family. After 2 days, the child complained of bad eyesight (very intelligent girl, so could describe it clearly), followed the next day by almost complete blindness. On 20.1.1965 she was examined by an ophthalmologist, who found a visual acuity in both eyes of -;/4/ 60 (= finger counting at 25 cm.). The fundus was not definitely abnormal: the arteries were possibly somewhat narrowed and there was some doubtful pallor of the papillae, OS)'OD. Retrobulbar neuritis ODS was diagnosed. The child was admitted to a general hospital on 22.1.1965. Internal examination revealed no abnormalities. In particular, the blood picture and lumbar puncture were normal. Roentgen examination of the skull: normal findings. Neurological examination showed no abnormalities. EEG: mild diffuse disorders with dysrhythmias in the occipital area. Treatment: vit. B complex, gammagiobulin. 24.1.1965 ophthalmologically: VOD = 1/60; VOS = ~ / 6 0. Fundus: narrowed retinal vessels, progressive atrophy OD and OS. Treatment: Prednison, vit. B6, paraxine, vit. C. 26.1.1965: Fever due to unknown cause. Probably: 'drug fever'. 3.2.1965: Transfer to the Ophthalmological Hospital of Rotterdam.
Findings: Fundus: pale papillae; narrowed retinal vessels; in both maculae, fine crystalliform deposits and diffuse pigment changes. Periphery: normal appearance. Visual fields (Fig. 1): both eyes centro-caecal scotoma, slightly reduced retinal sensitivity in the periphery. Dark adaptation (Fig. 2): reduced photopic adaptation and almost complete loss of scotopic adaptation. EOG: LP/DT ratio: OD 1.50 and OS 1,45 (lower limit of normal: 1.85). ERG: rod responses absent. Cone responses rudimentary. Visually evoked cortical potentials (VECP's): demonstrable but very slight.
Conclusion." Combined infection of the retina and optic nerve due to measles. The patient was re-examined 8 years later. Vision: OD 3/60 and OS 5/60. Fundus: papilla OS normal color, OD slightly pale temporaUy with normal retinal vessels. The retina on both sides shows the appearance of a central tapeto-retinal degeneration. Periphery: normal retinal areas alternating with areas of atrophy of retina and choroid, with coarse pigment shifts, grouped around the retinal vessels. Here and there, the pigmentations show a trabecular appearance (see Figs. 3a, b and c). Visual field: no essential alteration compared with 1965. Dark adaptation: normal photopic and scotopic adaptation.
289
'0926 1.1965
os /
/
~
OD OV 1972
/ / Fig. 1. Case 1 (KM). Visual fields (Goldmann perimeter) one month after onset of the diseaese. Below: 8 years later.
EOG: LP/DT ratio OD 1.60 and OS 1.84. ERG: rod responses OD 60 % of normal (based on the scheme of the department of electro-ophthalmology of the Rotterdam Ophthalmological Hospital) and OS, 35 % of normal. Cone responses ODS 30 % of normal. VECP's: slight responses. Case 2. AA (fem.), born 28.8.1953. Measles on 16.4.1957; 1 day later, free from fever; after 2 days recurrence of fever, rambling talk, vomiting, headache and progressive drowsiness. According to the anamnesis, the patient at this time started to squint, which she had never done before. On 21.4.1957 admission to a general hospital. Internal examination showed bronchitis; blood picture: leukocytosis with relative granulocytosis. Neurological examination showed drowsiness, Kernig doubtful, low reflexes. With regard to the eyes, only strabismus was recorded without further specification. CSF: pressure slightly increased. 8/3 cells. Diagnosis: measles encephalitis. Therapy: Atarax tablets, ACTH injections, penicillin. Atarax was subsequently replaced by Miltown.
290
Fig. 2. Case 1 ; darkadaptationcurve one month after onset of disease. Disturbance of photopic and scotopic adaptation. Below: 8 years later a normal photopic and scotopic darkadaptation is found.
29.4.1957: Increased and pathological reflexes in the legs, pronounced disorders of movement coordination and mental confusion. 16.5.1957: exanthema of unknown origin. After discharge on 19.8.1957, the patient had to be hospitalized in a special children's clinic because of disorders of behavior. She functions at the level of disability. Ophthalmological examination November 1966: VOD with correction (+ 1.50) = 1.0; VOS = 1/60, improvement impossible. Fundus both sides: pale papilla. Examination on 18.9.1973 (as a part of a study of retinal abnormalities in children who have had measles encephalitis) VOD with correc-
291
a
9Fig. 3a and b. Case 1 ; 8 years after onset of measles. Fundus photographs of right and left eye, showing considerable pigmentary derangement of the posterior pole. Striking resemblance to Stargardt's disease.
Fig. 3c. Case. Peripheral fundus. Bone curpuscles and pigment clusters on and around the vessels.
fion S + 1.50 = 2.0; VOS = 1/60, improvement impossible. Color vision: AO-HRR: OD slight red-green disorder, OS markedly abnormal, 'unclassified' disorder of the color vision. Position of the eyes: convergent strabismus OS. Fundi: pale papilla; normal retinal vessels. In both maculae, light-colored and white spots; fine pigment alterations. (Figs. 4a and b). Periphery, salt-and-pepper appearance.
292
b Fig. 4a and b. Case 2 (AA). Foveal region of right and left eye. Small white dots, disturbed foveal reflex and fine pigmentary disturbances are visible.
Visual fields: OD enlarged blind spot, concentric limitation, partial loss of the upper nasal quadrant. OS centro-caecal scotoma and partial loss of the nasal visual field (Fig. 5). Dark adaptation: both the photopic and scotopic curves run 1 log. U above the normal hminal value (Fig. 6).
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Fig. 5. Case 2. Visual fields (Goldmann perimeter). Marked defects probably related to lesions in the optic pathways.
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Fig. 6. Case 2. Darkadaptationcurve showing an increase of photopic and scotopic
EOG: LP/DTratio ODS: 1.75. ERG: rod responses: normal. Cone responses: normal. VECP's: subnormal. Neither patient had a history of hereditary predisposition. No consanguinity was found in the family. Both patients had developed normally prior to the measles infection. DISCUSSION In the first case, KM, there was a clear-cut combination of a retinopathy and a lesion of the optic nerve. This patient has been examined for the first time during the stage of recovery and is now probably in the latent period. It cannot be predicted whether this situation will remain unchanged. Case 2, AA. In this case, a lesion situated higher in the visual tract undoubtedly plays an important part, but the fundus abnormalities and the abnormal EOG show that here, also, a retinal component is involved. Repetition of the examination after a number of years will possibly yield additional information in these cases. It should be kept in mind, however, that in neither case was 'measles' proved beyond doubt, since no serological tests with measles antigen were carried out.
DIFFERENTIAL DIAGNOSIS According to Franceschetti, Franqois & Babel (1963) and Slezak (1969) the alterations of the fundus encountered after the acute stage, are to be distinguished from: 1. primary tapeto-retinal degeneration 2. alterations of the pigmented epithelium in other hereditary diseases, e.g. carriers of choroideremia Stargardt's disease 3. secondary tapeto-retinal degeneration: congenital:
post-natal:
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viral (especially important, rubella; cytomegaly) syphilis toxoplasmosis viral (poliomyelitis, mumps, variola, varicella, vaccinia) syphilis trauma old age (senility)
4. alterations of the pigmented epithelium caused by drugs: chloroquine streptomycin phenothiazine indomethacin In the majority of the cases the anamnestic data, however vague, will have to serve as a basis for the conclusion. Family anamnesis and/or examination is of particular importance for the differentiation of the hereditary affections. Earlier authors on the basis of the histological findings obtained by Blum & Babel (1948) believed that a simple differentiation between primary and secondary tapeto-retinal degeneration can be made with the aid of the ERG. However, the ERG only reflects deep retinal lesions. In making the distinction between primary and secondary tapeto-retinal degeneration, the return of the electro-retinographic response undoubtedly constitutes an argument in favor of a secondary form (case 1).
PATHOGENESIS The hypotheses advanced in regard to the occurrence of the acute phase of measles retinopathy may be concisely summarized (Haydn, 1970) as follows: 1. Vascular genesis: direct or indirect action of the virus or of its toxins on the vascular wall, as the result of which a generalized spasm occurs and/ or the vascular wall grows permeable; 2. Direct or indirect action of the virus on the retinal metabolism by blocking the glycolytic enzymes (Schupfer, 1951); 3. As provocation of a familial hereditary degeneration (Franceschetti, 1964). Owing to the almost complete lack of histopathological material, no definite conclusion has been drawn so far. It may be mentioned, however, that Babel in 1958, in the discussion following the paper by Franceschetti, Dieterle & Schwarz, stated that histological study of one case had shown that in measles retinopathy, the neuro-epithelium is affected first. In this connection he postulated a retinal ischemia.
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CONSIDERATIONS The forms of retinopathy described in subacute sclerosing panencephalitis or SSPE (Otradovec, 1969; Robb & Watters, 1970; Nelson et al., 1970; Karel et al., 1971; Landers & Klintworth, 1971) show great resemblance to the cases of measles retinopathy hitherto described, both as regards the pigment alterations and as regards the course. In SSPE, in which it is known that the occurrence is correlated with a measles vaccination infection, inclusions have been encountered in the retinal neurons (Landers & Klintworth, 1971), which proved to be identical to the measles virus. It may be assumed (e.g. Kapselberg & Ronde-Verloop, 1973) that the measles virus is the etiological agent. This renders it probable that the measles virus itself is also the etiological agent for the development of a retinopathy. In SSPE, the deterioration of the visual acuity and the onset of pigment retinopathy may precede the neurological symptoms. Timely diagnosis of this state (acute chorioretinitis, central and/or peripheral, with secondary pigment alterations after the acute phase caused.by measles virus) may be of great importance. It is also plausible to suppose that many cases of unexplained juvenile tapetoretinal degeneration have been due to the measles virus. The question to what extent a particular predisposition may play a part has not yet been studied (Nelson, 1970, case 2: female SSPE whose older brother had also died from this disease). CONCLUSIONS 1. Measles retinopathy appears to be a specific neuro-retinal disorder caused by the measles virus. 2. The prognosis must always be interpreted with due prudence, in view of the fact that the long-term evolution is unknown. 3. The frequency of the condition may be higher than has been believed so far, which view is corroborated by the findings in SSPE. 4. An agreement concerning uniform nomenclature for the pathological condition 'measles' would help reduce the confusion in the literature (in Anglo-Saxon literature, the term 'rubeola' sometimes wrongly applied to rubella as well as to measles).
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REFERENCES Blum, J. D. & Babel, J. Diagnostic diff~rentiel des r&inites et des pseudo-r&fifites pigmentaires au point de rue histologique. Ann. d'Oculist. 181 : 468 (1948). Crone, R. A. Personal communication (1973). Doise, P. La r&inite pigmentaixe post-morbilleuse. Th~se Lille (1955). Duke-Elder, S. Textbook of ophthalmology. Vol. X, p. 266 ; Vol. XII, p. 124. London, Kimpton (1966). Franceschetti, A., Francois, J. & Babel, J. Les h~rgdoddg~n~rescences chorio-r~tiniennes, tome II, p. 1412. Paris, Masson (1963). Franceschetti, A., Dieterle, P. & Schwarz, A. R&inite pigmentaire /t virus. Ophthalmologica 135 : 545 (1958). Franceschetti, A. et al. Pigmentary pseudoretinopathy after measles, an acute manifestation of familial hereditary conditions. Bull. Soc. ft. Ophtal. 77 : 549 (1964). Haydn, M. Erblindung beider Augen nach Masernerkrankung. Klin. Mbl. Augenheilk. 156 : 539 (1970). Heath, P. Measles encephalitis, a clinical report of some eye findings. Amer. J. Ophthal. 15 : 130 (1932). Heutsch, R. & Kfilz, J. Beitrag zur sekund/iren Pigmentdegenerationen der Netzhaut nach Masern. Klin. Mbl. Augenheilk. 154 : 706 (1969). Kapsenberg, J. G. & Ronde-Verloop, F. M. de. Subacute scleroserende panencephalitis; isolatie van mazelenvirus. Ned. T. Geneesk. 117 : 1880 (1973). Karel, 1. et al. Fluoroangiographic picture of the macular lesion in subacute sclerosering leukoencephalifis. Ophthalrnolog4ca 162 -348 (1971). Landers, M. B. & Klintworth, G. K. Subacute sclerosing panencephalitis (SSPE). Arch. Ophthal. 86 : 156 (1971). Nelson, D. A. et al. Retinal lesions in subacute sclerosing panencephalitis. Arch. Ophthal. 84 : 613 (1970). Otradovec, J. Das klinische Bild der zentralen chorioretinalen Ver~inderungen bei subakuten sklerosierenden Leukoenzephalitis. Ophthalmologica 157 : 427 (1969). Robb, R. M. & Watters, G. V. Ophthalmic manifestation of S.S.P.E. Arch. Ophthal. 83 : 426 (1970). Scheie, M. G. & Morse, P. H. Rubeola retinopathy. Arch. Ophthal. 88 : 341 (1972). Schlossberg, F. R. & Prizer, M. Retinal changes with marked impairment of vision in measles.Amer. J. Ophthal. 23 : 948 (1940). Schupfer, F. Retiniti pigmentose consecutive a malattie infettive acute. Boll. Oculist. 30 : 424 (1951). Slezak, H. & Hommer, K. Fundus pulverulentus. Graef Arch. Ophthal. 178 : 177. (1969). Srivastava, S. P. & Nema, H. V. Optic neuritis in measles. Brit. J. Ophthal. 47 : 180 (1963). Walsh, F. B. & Hoyt, W. F. Clinical neuro-ophthalmology; Vol. II. Baltimore, Williams & Wilkins, 1969.
DISCUSSION Crone has recently seen a 2-year-old girl with a mild measles rash. She became suddenly blind and was examined a few hours later. There were yellowish-white oedematous spots, mostly in the periphery, with scattered small, mostly streaked hemorrhages. The papillae were slightly oedematous. As early as the next day, the oedema had largely disappeared. After 9 days, it had disappeared altogether and the retinal vessels were markedly narrowed. In the albinotic fundi, only mild pigment shifting was seen. The eyesight failed to return.
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Answer: The fundus image largely depends on the m o m e n t of examination o f a child. Hemorrhages and oedema have been described b u t disappear very rapidly. The amaurosis m a y continue for up to 6 months. Leffertstra: Do y o u know of any mass screenings of measles patients to detect any formes f m s t e s or cases running an abortive course? Answer: I have n o t heard o f any studies o f this kind. We ourselves have studied cases already k n o w n as measles encephalitis, since they constituted a circumscribed, accessible group. In view o f the high frequency of measles, it is practically impossible to examine all the children with this infection. Janssons Capriles: This interesting observation corresponds directly to an article on SSPE in the latest issue of the Nederlands Tijdschrift voor Geneeskunde (Dr. Kapsenberg). What was the age of onset of the measles in y o u r cases? Answer: Both children were 5 years old when they contracted measles.
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