Journal of the Neurological Sciences 27 (1976) 323-345 © Elsevier ScientificPublishing Company,Amsterdam - Printed in The Netherlands

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EALES' DISEASE WITH NEUROLOGICAL INVOLVEMENT Part 2. Pathology and Pathogenesis

D A R A B K. D A S T U R and B. S. S I N G H A L

Neuropathology Unit and Department of Neurology, Grant Medical College and Sir J.J. Group of Hospitals, Bombay-8 (India) (Received 18 July, 1975)

SUMMARY

Detailed neuropathologic examination was carried out on 1 case of Eales' disease with CNS involvement, in the form of retinal vasculopathy, followed first by signs of brain stem and cerebellar disease and then by a myelopathy, with death 4 years later from renal infection. There was mild chronic inflammation in the retina, and sub-total demyelination of one optic nerve. The brain stem and cerebellum showed extensive vasculopathy, with various stages of venous change extending from proliferation and dilatation to haemorrhage, or to thickening with hyalinisation. The perivenular brain tissue, particularly of the cerebellum, often showed demyelination, with relative axon preservation, but no inflammation. Similar, but less pronounced venopathy was seen in the dorsal cord. There was ascending degeneration of Goll's columns and descending degeneration of the lateral columns. The condition possibly represents a separate syndrome of "venopathy with episodic demyelinating retino-encephalo-myelopathy" (VEDREM), arising as a hypersensitivity mechanism. An inflammatory agent, either bacterial or viral, might be responsible for the first episode of retinopathy which preceded the CNS involvement. There is some pathogenetic similarity with neurotuberculosis, especially where tuberculous encephalopathy develops as a second episode after sensitization of the brain to myelinogenous proteins liberated during prior tuberculous meningitis. In the present syndrome, the first episode could liberate proteins from neuroglial tissues of retina and optic nerve, to which the brain is sensitized and responds with demyelination during the second episode. There is also some similarity of this syndrome to multiple sclerosis, notably the demyelination with axon preservation. Thirdly, the constant venous involvement and perivenous myelin loss are reminiscent of allergic encephalomyelitis. However, none of these 3 possible mechanisms has been proven.

324 INTRODUCTION

In the preceding p a p e r the clinical features o f 9 patients manifesting the s y n d r o m e o f Eales' disease with n e u r o l o g i c a l i n v o l v e m e n t , were r e c o r d e d (Singhal and D a s t u r 1976). H e r e we r e p o r t the n e u r o p a t h o l o g i c findings in t o f these patients on w h o m necropsy was available. This a p p e a r s to be the first detailed pathological a c c o u n t to be published, on the c o m b i n a t i o n o f Eales' disease o f the eye an d a neurologic disorder. On a c c o u n t o f its rarity a n d also the fascinating array o f changes that were e n c o u n t e r e d in the central n e r v o u s system o f this 1 case, the h i st o p at h o l o g i cal acco u n t is given in some detail, a n d the p r o b a b l e p a t h o g e n e t i c mechanisms o f what appears to be a separate s y n d r o m e are presented.

CASE REPORT Case 1

S.M., male, 23 years (J.J.H. 26126/66). In September 1966 he had a sudden onset of vertigo with vomiting for which he was admitted to the M.G.M. Hospital in Bombay. In addition he complained of diplopia, nasal regurgitation, dysarthria and weakness of the left side of the body. There was no complaint of visual impairment. On 20 October 1966 he was transferred to the J.J, Hospitals. On examination his right fundus showed mild pallor of the disc with perivenous sheathing along the upper nasal and upper temporal veins. The left fundus showed more pronounced pallor of the disc with perivenous sheathing of veins and neovascular formation. Visual acuity (V.A.) in the right eye was 6/36 and in the left 6/24. The peripheral fields of vision showed mild constriction but there was no scotoma. The other positive findings were mild dysarthria, left Homer's syndrome, bilateral partial 6th nerve palsy, coarse horizontal nystagmus, left palatal and vocal cord paresis, trunkal ataxia and left-sided cerebellar incoordination. There was no convincing weakness of any limb; sensation and tendon reflexes were normal. Plantars were flexor. Blood pressure was 140/90 mm Hg. Rest of the systemic examination was unremarkable. It was felt that this patient had changes of Eales' disease in the fundi and an acute lesion in the brain stem. Routine blood count, urine, blood sugar, blood urea, electrocardiogram (ECG), chest and skull X-rays were normal. Blood VDRL was negative. First cerebrospinal fluid (CSF) (19 September 1966) showed normal pressure, protein 156 mg/100 ml, sugar 35 mg/100 ml, cells 80, mainly lymphocytes. Audiogram and caloric studies were normal, electroencephalogram (EEG) and pneumoencephalogram (PEG) were normal. Vertebral angiography was unsuccessful. In view of the CSF findings the physicians at M.G.M. Hospital treated the patient with antituberculous medication; however, he improved only slightly. Nasal regurgitation and dysarthria cleared and diplopia was reduced. CSF examination on 21 October 1966 showed proteins 60 rag/100 ml, sugar 57 mg/100 ml and 36 lymphocytes/mm3. On 22 December 1966, while he was still in the hospital and on antituberculous medication, he developed sudden weakness in both lower limbs with retention of urine. On examination the fundal appearances were unchanged; a mild degree of Homer's syndrome, nystagmus, bilateral 6th nerve palsy, and mild incoordination in the left upper limb persisted. Both lower limbs showed marked hypotonic weakness, with loss of superficial sensation below T10. Position and vibration sense were unaffected, but knee and ankle jerks were now absent, and both plantars were extensor. CSF (22 Dec. 1966): protein 60 mg/100 ml, sugar 60mg/10Oml, and cells 30 tymphocytes/mm3. Antitaberculous medication was continued and the patient was also given a course of ACTH injections. Reexamination a week later showed spasticity in both lower limbs with exaggerated knee and ankle jerks. The findings were essentially unchanged when re-examined on 14 April 1967. Repeat CSF on 13 April 1967 showed protein 50 mg/100 ml, sugar 56 mg/100 ml, with cell 1/mm a. Mantoux test was positive. Myelography was not done. The patient was readmitted on 15 October 1969 (J.J.H. 29277). Re-examination showed that the neurological findings were unchanged, except for slight improvement in power in the right lower limb. The patient had evidence of urinary infection, chronic pyelonephritis and renal failure. Haemoglobin was 8.5 g/100 ml. Blood urea was consistently

325 elevated, and ranged from 82 to 250 mg/100 ml. Finally the patient died of chronic renal failure on 13 January 1970. The final clinical impression was of Eales' disease with two episodes of a possible vascular or demyelinating lesion in the brain stem and spinal cord, respectively, with death due to chronic renal failure.

Pathologicalfindings On gross examination, the brain was somewhat small, weighing only 980 g. The leptomeninges were slightly congested, but the superolateral surface of the brain was otherwise unremarkable. The blood vessels of the carotid and the vertebrobasilar system were unremarkable. The left optic nerve was slightly thinner than the right. Coronal slices through the cerebral hemispheres showed pale prominent white matter, moderately narrowed lateral ventricles and slightly dilated sulci of the frontal lobes. Horizontal slices through the brain stem and cerebellum revealed areas of greyish discolouration in the tegmentum of both sides in the pons, and paramedially in the floor of the fourth ventricle in the lower half of the medulla oblongata. The spinal cord was unremarkable on the external surface. Horizontal sections through the cord at about half-inch intervals showed lack of distinction between grey and white matter in the D2-D3 region. The entire dorsal cord, but more its upper half, showed some greyish discolouration or congestion, paracentrally at the junction of grey and white matter or more peripherally in the lateral columns. Greyish discolouration was also suggested in the paramedian portions of the posterior columns of the mid-dorsal cord. As permission for removal of the whole eye was not available, only about the posterior one-third of each eye, along with the intraorbital part of the optic nerve, could be obtained. The retina appeared unremarkable macroscopically.

Microscopic examination All the above tissues were fixed in formalin and representative parts of the cerebrum, cerebellum, brain stem, spinal cord and optic nerves were blocked in paraffin. Sections (about 30 in all) were routinely stained with haematoxylin-eosin, Luxol fast blue and cresyl violet (Klfiver-Barrera's method), Holmes' silver for axons and phosphotungstic acid-haematoxylin (PTAH). Occasional sections were stained by the picro-Mallory method for connective tissues. Celloidin sections of the posterior part of the eye (provided through the courtesy o f Professor N. Ashton), showed stray inflammatory foci made up of small mononuclear cells (Fig. 1) in the retina. There was only slight prominence of some of the retinal blood vessels, with thickening, but haemorrhages were not seen. The general organization of the retina, including the neurons, was otherwise well-preserved. The optic nerve head showed some glial cell reaction. The proximal 1.5 cm of the optic nerve, sectioned along with the eye, showed mild diffuse gliosis in PTAH preparations. The intraocular muscles and the nerves and vessels in them were quite normal. As the whole eye was not available, the vitreous could not be examined. The left optic nerve, which was grossly thinner, showed, at its point of exit from the orbit, a small area of demyelination in one part of the nerve, the rest of the

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Fig. 1. Left eye: focus of lymphocytic reaction in outer part of retina, with thickening and gliosis of the plexiform layer in the centre, which also bears thickened hyalinised blood vessels. PTAH, 120; celloidin section.

Fig. 2. Left optic nerve: transverse section at point of exit from orbit showing a small elongated area of partial demyelination, a little above the mid-zone. KlOver-Barrera, • 40. bundles being well-myelinated (Fig. 2). The same nerve, a b o u t I cm onwards, i.e., close to the optic chiasma, showed obvious shrinkage of size, lack of distinction of the nerve bundles a n d diffuse d e m y e l i n a t i o n with glial cell prominence. There was greater loss of axons too in this part of the nerve than in the part closer to the eye. P r o m i n e n t b u t n o t particularly thickened veins were seen at sites of demyelination. The right

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Fig. 3. a: cerebellar white matter showing proliferated prominent veins but no demyelination; subtotal loss of Purkinje cells in cerebellar cortex, b: closer view of same area of white matter showing marked thickening and hyalinisation of the walls of veins, with narrowing of their lumina. KlfiverBarrera, x 40 (a), x 250 (b). optic nerve s h o w e d only s o m e fine v a c u o l a t i o n , the myelin a n d axons being otherwise preserved. Histopathologie examination o f b r a i n a n d spinal c o r d revealed the m o r e severe changes in the b r a i n stem a n d spinal cord. W h i l e the m i d b r a i n a p p e a r e d relatively spared, the pons, m e d u l l a a n d cerebellum showed clear changes in the b l o o d vessels a n d p a r e n c h y m a . Since the changes here represent the p a t h o l o g i c a l process observed

328 throughout the central nervous system, they will be described in detail, the finer" variations elsewhere being mentioned briefly later. A vasculopathy appeared to be the basic change, and this involved veins and venules almost exclusively. Various stages of changes were found in these veins, the most frequent being a chronic change in the form of smooth, hyaline thickening or fibrosis of the wall of the small and medium-sized veins (Figs. 3 a and b). There was generally proliferation of the veins at the affected sites. The homogenous appearance of the wall is seen clearly in Figs. 3b and 4. Fig. 4 shows another important neuropathological feature, demyelination. It was most pronounced in the cerebellar white matter, especially of the vermis. As seen in Figs. 4 and 5 the demyelination was partial and either diffuse or perivenous. There were no sharply defined plaques. The periphery of the folial white matter retained the myelin, while the central part showed the loss (Figs. 4 and 5). The remaining myelinated fibres appeared well-preserved and there were no myelin breakdown products anywhere. The axons in such demyelinated areas appeared relatively better preserved, but thin and crowded between the thickened veins (Fig. 6). The cerebellar folia in general, i.e., of the vermis and the hemispheres appeared thin and atrophic. Both the grey and the white matter were involved, the molecular layer, the granular layer and the white matter being appreciably thin, and the Purkinje cells showing sub-total loss. Prominent veins were occasionally seen in the molecular layer and in the leptomeninges covering the folia. Rarely a thickened blood vessel showed haematogenous pigment in the vessel wall, with or without an enlarged Virchow-Robin space (Fig. 7).

Fig. 4. Same section, showing subtotal myelin loss around thickened hyalinised veins in the centre of vermis white matter; note better preserved myelin at periphery and thinned granular layer of cortex on either side. Klfiver-Barrera, × 165.

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Fig. 5. Same section, peripheral part of vermis white matter at one end, showing patchy perivenous demyelination and some loss of Purkinje cells. KliJver-Barrera, x 40.

Fig. 6. Fine, smooth, possibly regenerated, axons crowding the area of demyelination seen in Fig. 5. Note also smooth hyalinised venous walls. Holmes' silver, x 250. The pons showed a variety o f small lesions o f different stages. In one lateral angle o f the fourth ventricle, there was a small but prominent area o f haemorrhagic necrosis, the haemorrhage having obviously resulted from a distended ruptured vein on one side (Fig. 8a). The opposite angle showed mainly distension (Fig. 8b), proliferation o f small veins, but diffuse glial cellular and fibrillar reaction was seen even a r o u n d such veins (Fig. 8B). In the pontine tegmentum there were other forms o f

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Fig. 7. Cerebellar white matter: thickened narrowed vein with its walt showing irregular deposits of blood pigment and wide perivascular space; better preserved vein at lower border. Hematoxylin eosin, • 250. vasculopathy and necrotic lesions. In one such lesion, where the haemorrhage had resorbed and only an eosinophilic area with degeneration of parenchymal elements and glial reaction remained, there were prominent collapsed veins, only the walls of which showed up, even in serial sections. On the opposite side only the walls of thickened hyalinised vessels could be recognised amidst areas of nerve fibre toss and astrocytic proliferation (Fig. 9). Rarely, groups of degenerated swollen axons alone remained. Most of these lesions were seen in the transversely cut descending corticospinal tracts, which showed some vacuolation even at sites removed from frank lesions. The vasculopathy and the associated parenchymal changes were also in evidence in symmetrical parts of the medulla oblongata. Here hyalinisation of still patent veins, in a manner similar to that seen in the cerebellum, was encountered (Fig. 10a), rather than haemorrhagic necrosis. The veins here showed distention only and not thickening (Fig. 10b), possibly representing an earlier stage of the vasculopathy. The fibrous thickening of the wall was best seen with connective tissue stains (Fig. 10c). Some demyelination was also witnessed in the vicinity of affected veins. Thus, the medial longitudinal bundle and the medial lemniscus were partially demyelinated, while the thickened veins were present paramedially among fibres with both wellpreserved myelin and axons (Figs. l la and b). The axons here were clearly thicker and more normal looking than those in the demyelinated areas, as is appreciated by contrasting Figs. 6 and 1 lb. There was also some demyelination of and around the posterior part of the inferior olivary nucleus, with partial loss of its neurones. Two other lesions were encountered in the medulla oblongata. There was some patchy loss of myelin in the pyramids, especially on one side. While prominent veins

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Fig. 8. a: section through pons showing haemorrhagic necrosis in lateral angle of fourth ventricle. Note the rupture of the distended vein on one side. b: enormous distension and thinning of a vein with glial cell reaction round about. HE, × 10O (a), × 250 (b). were not encountered here, there were clearly proliferated vessels in the floor o f the 4th ventricle on b o t h sides,particularly paramedially in the medulla, i.e., in and a r o u n d the hypoglossal nuclei (Fig. 12a). There was relatively greater loss o f myelin here, both the neurons and axons being better preserved (Fig. 12b). In the lower part o f the medulla oblongata, the nuclei gracilis showed considerable depletion o f neurons and degeneration o f axons. The cerebral hemispheres were relatively unaffected in respect o f both cerebral

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Fig. 9. Pontine tegmentum showing a lesion with glial cell reaction around fibrous scars, possibly representing old hyalinised or ruptured vessels. HE, Y 100. cortex and white matter. The only change seen in the latter was the presence o f small bleached lesions in the deeper white matter, especially o f the insula (Fig. 13). These lesions were o f an oedematous nature, a r o u n d or near small blood vessels, and showing either distended or depleted oligodendroglia and a shredded appearance o f the fibres in them. There was no significant area o f demyelination in either cerebral white matter, corpus callosum or internal capsule. Basal ganglia were unremarkable. While the lumen o f the superior sagittal sinus was patent, with a normal endothelial lining, the fibrous wall o f the sinus showed recent confluent and discrete haemorrhages and was thickened on that account. The cervico-medullary junction showed symmetrical demyelination in the posterior and lateral columns (Fig. 14). In addition, there was a midline lesion, just behind the central canal, which showed some demyelination (Fig. 14). The axons in these areas were relatively better preserved but very fine. A little lower, at about the C2 level, more clearly defined posterior and lateral column demyelination was noticeable (Fig. 15). The myelin and axon loss was confined to Goll's tracts and less than in the lateral columns. In these tracts a fair complement o f fibres was f o u n d preserved in both myelin and axon preparations, the former showing intact and degenerating myelinated fibres (Fig. 16) and the latter revealing the remaining thick and thin axons. This contrasted strikingly with the full

Fig. 10. a: cluster of distended slightly thickened veins on one side of upper medulla, b: lesion on opposite side showing only proliferated thin walled veins, c: dense collagenosis of the hyalinised veins in the same area. HE (a and b), picro-Mallory; (c), x lO0.

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Fig. 1la. axon population observed in the normal Burdach's column. This appears to be a degenerative change, in the form of an ascending degeneration of Goll's tracts, which were maximally affected in the upper dorsal region, as seen for example in the T.S. of cord at D2 level (Fig. 17). Burdach's tracts were well-myelinated throughout (Figs. 14, 15, 17). In the upper dorsal cord the entire lateral part of the cord from the periphery up to the posterior horns showed partial demyelination (Fig. 17). Even at

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Fig. llb. Fig. 11. a: mid-zone of medulla at the same level showing demyelination in the median raphe in the region of decussation of medial lemnisci, with well-myelinated paramedian fibres and thickened veins. b: well-preserved axons in the same paramedian region except when they are interrupted by thickened veins, a: Kltiver-Barrera, z 70; b: Holmes' silver, x 250.

the very low magnification of Fig. 17, prominent veins can be seen especially along the outer border of the right posterior horn. Closer examination showed the venous change to be similar to that described earlier in the brain, taking the form of proliferation with distension (Fig. 18), or fibrosis of the vessel wall. Either enlargement of the Virchow-Robin space or moderate perivascular oedema and shredding of the white matter were seen. The lateral columns were maximally affected in the mid-dorsal region of the cord, with almost total demyelination. In such degenerated areas there was no appreciable venous thickening but only an occasional dilated vessel, and showing only a few glial cell nuclei but no reactive astrocytes. Here the axon loss was commensurate to that of myelin. In this region the lateral border-zone was frankly spongy and degenerative. The lower dorsal and the upper lumbar cord continued to show descending degeneration of the pyramidal tracts. Among the other organs, the only noteworthy change was in the kidneys, which showed severe chronic inflammatory and degenerative changes, with extensive lymphocytic infiltration, and fibrosis or frank hyalinisation of the majority of the glomeruli, with loss of the peripheral renal tubules. DISCUSSION

The salient features emerging from the clinical study of this 1 patient with Eales' disease with involvement of the nervous system, comprised a characteristic retinal vasculopathy followed by 2 episodes of a neurological disorder affecting brain stem

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b Fig. 12. a: partial loss of myelin and thickened venules in region of hypoglossal nucleus, b: remaining neurons and relatively well-preserved axons in the same lesion, a: HE, 100; b: Holmes' silver, "~ 250. and cerebellum and then the spinal cord, within a total period of 3 months, with subsequent persistence of this condition and death due to renal failure 4 years later. The essential pathological changes were mild chronic inflammation and gliosis in the retina (only the posterior third of the eye was available) with demyelination and some gliosis in 1 optic nerve; a vasculopathy of varying stages, almost restricted to the veins in the brain stem, 'cerebellum and spinal cord, with a tendency to their fibrosis and hyalinisation, or distension leading to rupture and microhaemorrhages; patchy

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Fig. 13. Few small scattered bleached lesions in otherwise well-preserved cerebral white matter. HE, x 100.

Fig. 14. Transverse section through cervico-medullary junction showing symmetrical demyelination in both tracts of Goll and sparing of tracts of Burdach. KliJver-Barrera, x 8.

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Fig. 15. Transverse section through C2 level of spinal cord showing partial demyelination of columns of Goll and more severe demyelination of the lateral columns. Klfiver Barrera, 10.

Fig. 16. Paramedian portions of both columns of Goll showing depletion of myelinated fibres and active demyelination of many of the remaining fibres. Kltiver-Barrera, x 250.

p a r t i a l d e m y e l i n a t i o n at sites showing the v a s c u l o p a t h y , a n d ascending o r descending d e g e n e r a t i o n o f the sensory tracts a n d m o t o r p a t h w a y s respectively in the spinal cord. Before p r o c e e d i n g to a c o n s i d e r a t i o n o f the pathogenesis o f the c o n d i t i o n described, it is necessary to e x a m i n e a n d interpret the p a t h o l o g i c a l changes observed.

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Fig. 17. Transverse section through D1 level of spinal cord showing diffuse demyelination in lateral column and medial part of posterior columns. Note dilated veins in the right posterior horn. KliiverBarrera, x 9.

Pathology The 3 pathological features which merit critical assessment are the changes in the blood vessels, the nature of the myelopathy and encephalopathy, and the possible relationship between the two. The vasculopathy was restricted to venules and small veins and occurred in various stages. The earliest stage took the form of proliferation and dilatation, with only some perivascular oedema. The next phase of the vasculopathy appeared to manifest in one of two ways. There was either rupture of the vessel wall leading to a microhaemorrhage, or a tendency to thickening of the vessel wall. This led to its fibrosis with subsequent hyalinisation and, at times, occlusion. The entire process appeared to be free of an inflammatory reaction; possibly, it occurred but was transient. The only place where it was seen clearly in our patient was in the retina. At times a shrunken remnant of the affected vein was found in a distended Virchow-Robin space. Focal microscopic areas of necrosis seemed to be the result of the microhaemorrhages, and constituted one of the parenchymal changes observed. The nature of the glial cell reaction indicated the stage of such necrotic lesions, most of which showed destruction of parenchyma and astrocytic reaction. When this glial reaction was seen around hyalinised veins alone, it suggested a preceding haemorrhage or necrosis around these vessels, but which had now cleared. The successive stages of the vasculopathy leading to fibrous hyalinisation can be seen through Figs. 10a, 10b and 10c on the one hand, and to haemorrhage through Figs. 8a and 8b on the other. The

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Fig. 18. Upper dorsal spinal cord showing proliferated congested venules and veins in and around the posterior horn. (The posterior root is at upper border). HE, × 40. venopathy seen here was comparable to that reported in the retina in Eales' disease with involvement of the eye only, such as that described and reviewed by Ashton (1962), and by Duke-Elder (1967). Both these authors very well illustrate the various stages of the changes in retinal veins. In addition to the post-haemorrhagic necrotic reaction mentioned above, there were two other clearly recognizable changes in the CNS parenchyma. One was demyelination and the other was degeneration. The demyelination was almost always seen at sites of vascular proliferation although, at times, the myelin remained intact in spite of excessive venous proliferation and thickening (as in Figs. 3a and b). The more usual change is represented by Figs. 4 and 5. At these sites the demyelination was perivenous and indubitable, but of unclear outline and not in plaques. Again, any inflammatory or even gitter cell reaction was conspicuous by its absence and there were no myelin break-down products. All these changes suggested a chronicity of the pathologic process, consistent with the long survival of the patient for over 3 years after the onset of neurologic symptoms. That the change described here was a form of primary demyelination

341 was further suggested by the relative preservation and possible proliferation of axons as seen in Fig. 6. The distribution of these demyelinative lesions, notably in the white matter of the brain stem and cerebellum, gave no clue as to their pathogenesis which will be considered later. The other parenchymal change observed was a symmetrical degeneration of certain long tracts in the spinal cord. There was a descending degeneration of the cortico-spinal tracts from the pons and lower medulla down to the lumbar cord, with maximal involvement in the mid-dorsal region. The axon and myelin loss were commensurate. Likewise, there was an ascending degeneration of the tracts of Goll from the lower dorsal cord to the nuclei gracilis and the lemniscal decussation in the medulla, with the maximal involvement again in the mid-dorsal cord. The posterior column degeneration was less severe and extensive than that of the lateral column and was not accompanied by overt clinical signs or symptoms. Venopathy appeared responsible for the cord lesions also, though this was not as evident as in the brain. A remarkable feature of the disease was the occurrence of the vascular and related lesions on both sides of the brain stem. That they occurred at different times was evident from the different stages of the vasculopathy in both pons and medulla oblongata. There was greater symmetry in the spinal cord lesions, but one lateral column showed more degeneration and gliosis than the other. There was fair correlation between the greater weakness and ataxia on one side as noted on clinical examination, and the severer (more established) pathological change also on one side. The optic nerve change was clearly asymmetrical, being more pronounced on the left side, where fundoscopic examination during life had revealed a paler optic disc. The optic nerve change too was primarily demyelinative with secondary atrophy.

Pathogenetic mechanisms The pathogenesis of the case under report and of other cases of the association of Eales' disease with CNS involvement can best be considered in 2 stages. One has first to account for the pathogenesis of the primary retinal or retino-optic nerve disorder, and then to consider the possible mechanism of the secondary involvement of the brain and/or cord. The pathogenetic factors that have so far been advanced to explain the ocular changes in Eales' disease, and which must be considered here too, have been tuberculosis and a form of multiple sclerosis. The proponents of a tuberculous aetiology, especially Elliot (1954, 1958), have based their argument on the occurrence of focal reactions in the retina after injection of tuberculin. Elliot (1958) reported active or healed tuberculosis in 35 ~ of his cases and the skin tuberculin test was positive in all except one. On the basis of this he suggests that Eales' disease "occurs in individuals who have been previously sensitized to tuberculo-protein, and the haemorrhage and exudation are a local reaction in a hyper-sensitive vessel wall". In 2 eyes that were available to him for pathological examination, being removed for glaucoma, a nonspecific perivascular lymphocytic cuffing was noted. White (1961) also reported a high degree of cutaneous sensitivity to old tuberculin in 10 of 15 cases of retinal vasculitis, and felt that tuberculin hypersensitivity is a more likely aetiological agent

342 than the tubercle bacillus itself. Occasionally giant cells and granulation tissue havc been found around retinal vessels (Ashton 1962); very rarely tubercle bacilli have been demonstrated in the vicinity of retinal vessels (e.g., Stock 1937); and there have been a few attempts at experimental production of retinal periphlebitis by the injection of tubercle bacilli (e.g., Finnoff 1924). As Ashton (1962) has commented, it is inconceivable that infection with tubercle bacilli could give rise to such a restrained inflammatory reaction as is seen in retinal periphlebitis. Diabetic vasculopathy was considered in our case in view of the microhaemorrhages, but there were no clear microaneurysms and arterioles or capillaries were not involved as they are in diabetic microangiopathy. Moreover, microaneurysm formation in diabetes is found only in the retinal vasculature and not elsewhere (Cook 1966), and they were not seen in the retina in our case. Haarr (1948) described 4 cases of retinal vasculitis with primary pulmonary tuberculosis. He pointed out that the histology of retinal vasculitis is not characteristic of tuberculosis but is similar to that of erythema nodosum. It is generally accepted that erythema nodosum is a nonspecific vascular reaction to a variety of infective and toxic agents (Perry 1944). However, angiitis is not always present (Haber 1966), and in any event there were no cutaneous lesions of any sort in our patients. In White's (1961) series a positive brucellin intradermal reaction was observed in 50~'/~ of tests made. He concludes, "considered alongside reports of associated sarcoidosis, primary tuberculosis, brucellosis, infectious mononucleosis and torulosis, these observations suggest that retinal vasculitis is a nonspecific tissue response to a variety of antigens, mainly bacterial". An early stage of the vasculopathy in the brain, viz. the clustered proliferation of veins in the medulla (as in Fig. 10a), raised the remote possibility of cerebral angiomatosis. However, this appears unlikely in view of the clinical and pathological evidence of venopathy at multiple sites and of varying stages, the clear picture of Eales' disease of the eye, and the presence of areas of demyelination in the optic nerve and CNS. Conscious of the fact that a high incidence of tuberculosis in general (Handbook 1968) and of neurotuberculosis in particular prevails in our country (Dastur, Lalitha and Prabhakar 1968; Udani, Bhat and Dastur 1974), in this patient and in 7 of the other 8 patients with Eales' disease with CNS involvement reported in the first paper (Singhal and Dastur 1976), antituberculous treatment was given for several weeks to months. This was done despite the absence of any overt tuberculous lesion, the only suggestive evidence of an inflammatory process in the CNS being the elevated CSF cell count in 5 of our 9 patients. There was no evidence that the antituberculous treatment had any effect on the course of the disease. A tuberculous aetiology was also considered for the second stage of the syndrome, viz., the involvement of the central nervous system. Keeping in mind the predominant myelopathy in our patients, and the occasional occurrence of tuberculous spinal meningitis in our population, this condition was thought of, but the pathology here is entirely different (Dastur and Wadia 1969) from that observed in the present material. An even stronger argument that led us to consider a tuberculous aetiology and,

343 more specifically, a hypersensitivity mechanism operating in the eye or the CNS in response to tuberculo-protein, was the earlier description by Dastur and Udani (1966) of the entity called tuberculous encephalopathy. In this condition, usually in a child or young adult, the predominant feature is a generalised brain oedema with occasional perivascular mononuclear cell reaction, but only mild or minimal tuberculous meningitis, and resulting in death with signs of a diffuse brain disorder. Recently Dastur and Lalitha (1973), were impressed by the occurrence of tuberculous encephalopathy during a second attack of tuberculous meningitis. This suggested the development of the rapidly progressive encephalopathy as an allergic manifestation to myelinogenous proteins, to which the brain had been sensitized during the first episode of tuberculous meningitis, when some damage to the brain surface invariably occurs. Wi~niewski and Bloom (1975) have recently confirmed this by producing demyelinative lesions in the brain and nerves of guinea pigs injected with tubercle bacilli, old tuberculin or purified protein derivative in Freund's adjuvant. The myelin damage was said to have resulted as a nonspecific consequence of a delayed type hypersensitivity reaction to bacillary antigens. Such a condition was lacking in all our patients with Eales' disease. Moreover, the brain in the case under report showed small areas of demyelination in the brain stem and cerebellum and not a diffuse myelin loss due to oedema. Meningitis was also absent. Thus, we have no clear evidence of a tuberculous aetiology in our patients with Eales' disease and CNS involvement. Nevertheless, the two-stage pattern of tuberculous encephalopathy is recapitulated in our patient with Eales' disease and CNS involvement. The breakdown of myelin in the optic nerve in the first stage might render the CNS hypersensitive to second and subsequent attacks by the original agent. The other possible pathogenetic mechanism in the development of this syndrome, i.e., both the primary ocular disease and the subsequent neurologic disorder, is multiple sclerosis. The proponents of this are Rucker (1947) and Haarr 0964). Chronic "periphlebitis retinae", as the condition is often called, is believed by these investigators to be an infrequent but reliable concomitant of multiple sclerosis (MS). Rucker concluded that "sheathing of the retinal veins occurring away from the optic disc and without visible cause appears to represent an entity worthy of being regarded as a retinopathy of MS". According to Haarr (1964) "the ophthalmoscopic picture of periphlebitis retinae in MS suggests that we are dealing with a perivascular cell infiltration in the active stage and thickening of the wall of the vein and/or its sheaths in the arrested stage. These changes tally so well with the vascular changes to be seen in certain plaques in the central nervous system that it is not unlikely that they are identical". The preservation of axons in demyelinated lesions also favours the possibility of MS. A third possible pathogenetic mechanism that must needs be considered is allergic encephalomyelitis. The association, and even a possible causal relationship, between this immunologic disorder and MS has been discussed recently by Lumsden (1972) and Poser (1972). The occurrence in our case of clear perivenous demyelination, the hallmark of human and experimental allergic encephalomyelitis, provided evidence in favour of this possibility. The absence of perivascular lymphocytic reaction, except

344 in the retina, might be a reflection of the late stage at which most of the lesions in our patient were examined. However, the fact that retinopathy was the primary manifestation, that even the recent lesions in our patient were haemorrhagic rather than inflammatory, and that there was no history in this or any other patient of this group (Singhal and Dastur 1976) of a viral exanthem or vaccination preceding the first episode, militated against this possibility but did not rule it out completely. All the above considerations lead us to make three suggestions. Firstly, that Eales' disease with CNS involvement constitutes a separate syndrome of "vasculopathy with episodic demyelinating retino-encephalo-myelopathy" (VEDREM), which should be recognised as such, and not confused with other brain/cord disorders which present some clinical similarities to this syndrome. Secondly, this syndrome perhaps develops as a hypersensitivity mechanism similar to that encountered in tuberculous encephalopathy, so that an infective agent, viral or bacterial but not necessarily tuberculosis, might act as the initial allergen. The blood vessels in the neuroglial tissue of the retina and optic nerve exhibit a predilective susceptibility to the noxious agent, and constitute the basis for the invariably primary retinopathy which characterises this syndrome. Thirdly, the possible liberation of proteins from the breakdown of these tissues, renders susceptible the blood vessels and parenchyma of the white matter of the spinal cord and brain, resulting in the second and subsequent episodes of vasculopathy and demyelination which also typify this syndrome. Thus, this syndrome of Eales' disease with neurologic involvement might be an immunologic disorder, with a unique venopathy resulting in haemorrhages or hyalinisation and also with some features similar to thos~ of multipl.~ sclerosis and of allergic encephalomyelitis. ACKNOWLEDGEMENTS Thanks are due to U K Medlars and the British High Commission in Bombay for generously providing us part of the bibliography. It is a pleasure to acknowledge the technical assistance of Mr. V. P. Kate for the histology preparations, and of Mr. N. Solanki for the photographic printing. We are grateful to Professor N o r m a n Ashton, F.R.S., of the Institute of Ophthalmology for providing celloidin sections of the eye and for his comments on them.

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