Two unusual neuropathologically proven cases of multiple sclerosis from bombay

Journal of the neurological Sciences, 1973, 20:397-414

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© Elsevier Scientific Publishing C o m p a n y , A m s t e r d a m - Printed in The Netherlands

Two Unusual Neuropathologically Proven Cases of Multiple Sclerosis from Bombay DARAB K. DASTUR AND B. S. SINGHAL .V~,to'opathoh~gr Unit and Department of Neurology, Grant Medical College and J. J. Group oJ Hospitals, Bombay-8 (India)

INTRODUCTION

A consideration of the epidemiological data from different parts of the world has led a number of investigators, notably Kurland (1965), to the conclusion that multiple sclerosis (MS) is uncommon in the tropical and subtropical zones. Acheson (1972) also concludes, from a survey of world literature, that an increasing incidence of MS accompanies an increase in latitude, and that "environmental" factors appear more important than "genetic" in the causation of MS. Alter (1972), while confirming this, has revealed that a higher percentage of MS patients had enjoyed better sanitary facilities than controls in the childhood home. The implications of this are relevant to a possible infectious aetiology of MS (See Discussion). A survey of the published literature from India, which consists mainly of clinical reports and impressions, has failed to reveal any pathologically proven case of multiple sclerosis. A recent painstaking clinical report on "demyelinating disease in India" has been published by Mathew, Mathai, Abraham and Taori (1972). A current careful review of 74 personally examined "possible cases" of MS from the Bombay region by Singhal and Wadia (1972), revealed 45 "clinically definite" cases of MS or neuromyelitis optica. Only 2 of these came to necropsy and were studied neuropathologically. Both these conform to acceptable diagnostic criteria of MS in manifesting dissemination of lesions in time and in space. Although the tempo of the disease was rapid in both, between the 2 of them almost the whole spectrum of neuropathological changes of MS was represented. Hence they are reported here in some detail. CASE REPORTS

M. G. (J. J, H. 1940/1968), a w o m a n aged 27 years, was first examined on 12 April, 1968.

Clinicalfeatures She was Hindu, unmarried, dark in complexion and a vegetarian. She was a resident of Bombay, of average build and well-nourished. There was no noteworthy illness prior to 1968. In the first week of

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January 1968 she was revaccinated for smallpox. On 12th February 1968, she complained ol pain m 1he right supra-orbital region. On 15 February she developed total visual loss in the right eye. With ~ tentative: diagnosis of "optic neuritis", she was treated with oral corticosteroids by an ophthalmologist at another hospital in Bombay. Her vision improved to finger-counting at 6 feet distance. On 7 April 1968, she complained of mild weakness of the right upper and lower limbs, with a feeling of heaviness and numbness on that side. On 12 April she complained of weakness in left leg, and of parasthesiae on the right side of neck (C2 ('3 region). On examination that day, she showed pallor of the right optic disc, mild weakness (grade 4 power) m the right upper and lower limbs, with mild incoordination on finger-nose test on that side. There was impairment of position sense in the fingers of the right hand, with normal vibration sense. There was impairment of pinprick and thermal sensibility below the T6 spinal level on the right. The tendon jerks were brisk in the right upper limb and both lower limbs. The abdominal reflexes were absent and the plantar response was extensor on both sides. The rest of the examination revealed nothing abnormal, and the blood pressure was 110/70 mm Hg. It was felt that she had an upper cervical cord lesion, possibly of a demyelinating variety, despite the rarity of this condition in Bombay. Her routine blood counts, ESR and urinalysis were within normal limits. Serological tests for syphilis (Kahn, VDRL and WR) were negative. Chest and cervical spine X-rays were normal. Cerebrospinal fluid (CSF) manometrics were normal. The CSF protein was 50 mg/100ml, with positive Pandy's and NonneApelt reactions; the glucose content was 60 mg/100 rnl, chloride 700 rag/100 ml, and there were 18 cells per mm 3 (16 lymphocytes and 2 polymorphonuclears). The CSF WR was negative, and Lange's colloidal gold curve gave a reading of 1120000000. She was treated with intramuscular injections of ACTH (40 units twice a day for 7 days, 20 units twice a day for 7 days and 20 units daily for 10 days). There was partial improvement : the paraesthesiae subsided and weakness diminished, but the objective sensory impairment and reflex changes persisted. On 26 May 1968, she had an episode of acute vertigo and hiccups, which was treated with phenothiazines. It subsided in 2 days. On 10 June 1968 she had a recurrence of weakness on the right side, and also complained of weakness on the left for the first time. These symptoms progressed over the next 3 weeks. She developed retention of urine and difficulty in breathing. Examination on 5 July showed severe pallor of the right optic disc and doubtful pallor of the left; there was also mild nystagmus and severe weakness of all 4 limbs, with weakness of respiratory muscles. Position and vibration sense were lost in all 4 limbs. Cutaneous sensations of light touch, temperature and pain to prick were impaired up to the C4 spinal segment, Tracheostomy was done, she was put on positive pressure respiration, and ACTH was re-started. There was no improvement. On 15 July she had profuse bleeding from the tracheostomy wound and died.

Pathological findings Gross examination of the brain and spinal cord revealed clear changes only in the latter and in the brain stem. The cerebral and cerebellar hemispheres were grossly unremarkable, except for minimal convolutional atrophy of the frontal grey matter with slight prominence of the white matter of the frontal lobes. There were neither gliotic plaques nor areas of softening anywhere. There was no evidence of meningitis, and the optic nerves (of which only the chiasmal halves were available) and the optic chiasma were grossly unremarkable. The middle of the medulla oblongata showed an irregular greyish sclerotic lesion across the middle of its right half, behind and medial to the inferior olive with a tongue extending in front of the olive (Fig. 1A). There was also a smaller circular plaque around the central canal. The pyramidal tracts appeared unremarkable, but there was some diffuse softening of the cervico-medullary junction. A 9.5 cm long specimen of the cervico-dorsal cord. from about C3-T1 was available. Cross sections throughout this portion showed either softening with obliteration of grey-white distinction, or frank necrosis with grey horns not recognisable as such. The cervical enlargement from C5-C7 was maximally affected, the cord here being bulky, measuring 1.6 cm across, with a firm feel and a greyish gliotic appearance. An 11 cm length of the dorso-lumbar spinal cord from about the TI0 level to the cauda equina was also available, but showed nothing grossly remarkable. Thus the gross pathological examination appeared to confirm the clinical impression of a demyelinating disorder with lesions of different stages, in the cervical cord and the brain stem. Paraffin sections were prepared of several levels of the spinal cord and of different parts of the brain and optic nerves, and were stained with haematoxylin and eosin for cells, Klfiver-Barrera's method for cells (cresyl violet) and myelin (luxol-fast blue), phosphotungstic acid-haematoxylin for glial cells and fibres, and Holmes' AgNO 3 impregnation for axons. Selected portions were also subjected to frozen sections and stained for fat. Microscopic examination confirmed the absence of lesions in the cerebral or cerebellar hemispheres. The plaques in the medulla oblongata showed total absence of myelin with moderate diffuse glial reaction and vascular proliferation, and no intact axons, only argyrophilic knots remaining. Denser gliosis was noticed in the pericentral plaque (Figs. 1A and B).

Fig. 1. (NP/E567) A: cross section through lower half of medulla oblongata showing one large tri-radiate plaque of total demyelination in the region of the inferior olive, and another in front of the small central canal; Kliiver-Barrera, x 7. B: dense gliosis in the smaller plaque around the central canal, mild cellular and vascular reaction behind it and normal decussation of the lemnisci ; phosphoungstic acid-haematoxylin (PTAH), × 40.

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Fig. 2. (Same case) Affected right optic nerve, A : retro-orbital part, showing large plaque of total demyelination: Kl~iver-Barrera, :,: 20. B: few remaining smooth axons: Holmes' A g N O 3 . . 625. The normal left optic nerve showed well-myelinated nerve bundles throughout. In contrast, the right optic nerve (affected) showed some blotchiness and myelin pallor in the part near the chiasma and an area of total demyelination in the retro-orbital portion (Fig. 2A) (the intra-orbital part was not available for examination). There was diffuse astrocytic reaction in the plaque, but still some preservation of axons even in the tot'aily demyelinated zone (Fig. 2B). Sections through the uppermost level of the cervical cord available (about the C2 levelj showed a large plaque just outside and involving the grey horns on 1 side and several smaller plaques along the periphery or in the midst of anterior, lateral and posterior columns (Fig. 3). Closer examination of the large demyelinated area showed diffuse prominence of small glial nuclei, mainly astrocytic, capillary proliferation and congestion and occasionally frank sponginess (Figs. 4A and B). In contrast, some of the smaller peripheral ~c,ions were paler and less cellular, indicating chronicity.

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Fig. 3. (NP/E/567(3)) Transverse section through cervical cord at about C3 level, showing a large plaque all around the right anterior and posterior grey horns, and smaller scattered plaques mainly at or under the surface of the cord; Kliiver-Barrera, x 10. At about the level of the C7 cord the demyelination was more severe and irregular, both along the surface and toward the centre of the cord. The cellular reaction here was similar but with more glial fibrillar reaction as well as larger astrocytes with abundant cytoplasm (Fig. 5) and which, in appropriately stained frozen sections, showed sudanophilic myelin breakdown products. Only a few scattered oligodendroglia were seen. The severe parenchymal disintegration observed here persisted down to the lower part of the cervical cord where 2 large irregular and confluent areas of demyelination were seen (Fig. 6A). A feature of note was the presence of small blood vessels, though without perivascular inflammatory cuffs, in the centre of one of the plaques in the lateral column (Fig. 6B). The rest of the cellular reaction was identical to that described above. One of the spinal ganglia from the affected portion of the cervical cord showed some loss of ganglion cells, chromatolysis of many of the remainder and prominence of capsule cells. The spinal roots in this ganglion showed increased sheath nuclei, depleted myelin and relative preservation of axons. Case 2 R. T. A. (J. J. H. 14757/1972), a woman aged 20 years, was first examined on 3 June, 1972. Clinical jeatures She was Christian, married 6 months ago, dark in complexion, and a non-vegetarian. She was a resident of Jalgaon (200 miles east of Bombay). She was of average build and well-nourished. There was no significant illness in the past. On 8 April 1972, she complained of a tingling sensation in the right thigh, which spread to the whole of right lower extremity over a week. On 28 April, she experienced similar paraesthesiae in the left lower limb, and also complained of weakness in both lower limbs. By 3 May, she was totally paralysed in both lower limbs. On 29 May, the paraesthesiae, spread up to the mid-chest. On 1 June, she developed retention of urine with overflow incontinence ; she was admitted to the Neurology wards of the J.J. Hospitals on 3 June. On examination that day, higher functions, fundi, cranial nerves and upper limbs were normal. She was totally paralysed in both lower limbs, which were spastic. There was total loss of all sensation, both superficial and deep, below the T6-T7 spinal segments. The tendon jerks were exaggerated in both lower limbs. Abdominal reflexes were lost and the plantar response was extensor on both sides. The rest of the examination revealed nothing abnormal and the blood pressure was 120/60 mm Hg. At this stage it was felt that she had spinal cord compression.

Fig. 4. (NP/E/567(3)) A : area ofdem~elination showing l'rank sponginess clo~cl t~ the surface and vascular and cellular reaction: B: ci~sc~ xi~'~ ,,J I SI'It)V. ilI~2 coHgcsti~n ol !~h,,~d \c..-~:i. ~nd diffuse glial cellular

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Fig. 5. (NP/E/567(4) Cord at about C5 level. Large, plump astrocytes and glial fibrils in one of the demyelinated zones and congested vessels, scattered lymphocytes and few stray oligodendroglia. HE, ,: 250.

Fig. 6. (NP/E/567 (8) Cord at C'LC8 level. A : large irregular areas of demyelination ; B : closer view of the lesion in the left lateral segment showing several blood vessels in the central plaque but only slight cellular reaction. Klfiver-Barrera, x 10 (A) and x 40 (B).

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~. SINCIHAI

Fig. 7. (N P/G/727) A : coronal slice through both hemispheres showing large pale-grey, alsmost symmetrical, periventricular areas of demyelination in the centrum ovale, with puckering and softening of the corpus callosum (which was slit prior to fixation). Also note pale prominent non-demyelinated white matter: B: coronal slice through frontal lobes showing larger areas of demyelination, with frank necrosis in the upper half of left lobe.

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Her routine blood count, ESR and urinalysis, as well as the blood urea and blood sugar were within normal limits. Her blood VDRL was negative. Chest X-ray and dorsal spine X-rays were normal. Myelography, done by the lumbar route, on the same day, showed no abnormality. CSF examination showed 8 lymphocytes/mm a, protein 30 rag/100 ml, sugar 60 rag/100 ml and chloride 720 rag/100 ml. CSF VDRL and WR were negative. Lange's test was not done. As spinal cord compression was excluded, and on the assumption she had some form of transverse myelitis or demyelinating disease, she was treated with ACTH. Initially she received 40 units intramuscularly twice a day ; this was gradually tapered off over 5 weeks. She started improving on 8 June 1972, by m m in; her lower limbs. By4 July she had regained bladder control. By 23 July, she was able to walk with support and the power in the lower limbs was grade 4. The level of sensory loss, however, was unchanged, and the tendon jerks in the lower limbs remained brisk, with both plantars extensor. During the following week she started to develop headache and occasional vomiting. On 3 August bilateral papilloedema was noticed, and she occasionally became drowsy. Her neurological status was unchanged otherwise. At this stage, an intracranial space-occupying lesion was considered, especially a tuberculoma, and the patient was given antituberculous treatment. EEG examination, on 4 August, showed intermittent delta potentials in both anterior regions, but more on the left side. On 10 August, a left carotid angiogram showed nothing abnormal. The patient continued to deteriorate over the next 2 weeks. She became disinterested, apathetic, and incontinent. The neurosurgeon called into consultation (Dr. S. N. Bhagwati). carried out Conray ven triculography on 26 August, to rule out a space-occupying lesion. This showed a slight depression of the roof of the anterior half of both lateral ventricles. The ventricular fluid showed a protein of 40 mg/100 ml, but was otherwise normal. It was felt that she had either a glioma of the corpus callosum, spreading on both sides, or a tuberculoma. On account of this location, the neurosurgeon did not advise surgery and advised continuation of anti-tuberculous treatment. However, she continued to deteriorate and, on 2 October, she showed a supranuclear palsy of the left facial nerve, marked weakness of left upper limb, a grasp reflex of the right hand, and again severe weakness of the lower limbs. Although drowsy, she was obeying simple commands. Her neurological condition worsened, she became comatose on 13 October, and she died 3 days later.

Pathological findings Gross examination of the brain and spinal cord showed changes in both. The brain appeared large and weighed 1260 g (which is considerably more than the usual brain weight in women, as noted at this Unit*).

Fig. 8. (Same case) Section showing spongy part in Fig, 7 : luxol-fast blue positive material in the cavitory lesions and large glial cells filled with similar material in the surrounding white matter. Kliiver-Barrera. ×100. * The average brain weight of adults at autopsy, as noted in this Bombay Unit, is 150 g less than that observed in Western countries.

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suggesting diffuse oedema. The gyri of both cerebral hemispheres, but most "of the left fl~ontal lobe. appcm cd swollen and felt soft. The leptomeninges and the blood vessels of the circle of Willis and the basilar s~s~em appeared unremarkable. The brain stem and cerebellum were grossly unremarkable. Coronal slices through the brain showed large pale-grey areas of demyelination in the centrum semiovale, almost symmetrically, but the larger lesion was on the left side (Fig. 7A). The lesions were clearIx

Fig. 9. (Same case) A : upper half of anterior part of right parietal lobe showing demyelination of the greater part of the white matter with preservation of many of the U-fibres. Note total demyelination of anterior corpus callosum ; B: upper and medial quadrant of posterior part of right parietal lobe showing demyelination confined to supra-eallosal gyri and well-myetinated corpus callosum. Kltiver-Barrera, . 1.7~

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periventricular and extended through the corpus callosum which, in its anterior two-thirds, looked puckered and felt soft like the hemispheric lesions. These areas extended from almost the frontal pole up to the posterior limit of the parietal poles. The greater part of the white matter of the frontal lobes was involved and the upper half of the left frontal lobe was actually breaking down (Fig. 7B). In thick unstained frozen sections this area appeared frankly spongy. The brain stem and the cerebellar grey and white matter were grossly unremarkable. Only 2 small portions of spinal cord were available for examination ; (a) a separate 2 cm long piece of the upper lumbar cord; and (b) a larger 15 cm long piece from the mid-lumbar portion down to the distal part of the cauda equina. There was a gross lesion, in the form of a triangular yellowish plaque involving both anterior columns symmetrically, in the lower part of specimen (a) and the upper part of specimen (b). The entire lumbar cord felt somewhat soft. Histological methods used were identical to those described for the first case, the KliJver-Barrera proce-

Fig. 10. (Same case) A: parietal lobe: large luxol-fast blue-positive astrocytes and other smaller glia; Kl/-iver Barrera, x 250. B: one hypertrophic astrocyte and gliosis in this region: PTA H, × 625.

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dure for combined staining ol cells and myelin again proving to be most uselul. Microscopic examination of the spongy part of the frontal lobe showed frank cavitary necrosis of the ~viiE, matter which was otherwise uniformly demyelinated with diffuse glial cell reaction (Fig. 8). The spaces in Ihc spongy areas were full of large irregular deposits of myelin breakdown products, as seen in luxol-fasl-bluc. and Sudan black preparations. The surrounding white matter also contained histiocytic glia laden \~ith such lipidic material, in addition to diffuse astrocytic reaction. Fibrillary gliosis was more pronounced in the lower, grossly firmer, part of the frontal white matter. There was extensive severe demyelination of the parietal lobe also. only the U-fibres remaining and. at times, even some of these lacked myelin (Figs. 9A and B). Kliiver-Barrera preparations through this area showed the demyelinated white matter replete with cell~

Fig. 11. (Same case) A: remaining smooth thin axons in demyelinated white matter; Holmes' A g N t ) 3, x 250. B : demyelinated area showing diffuse glial cell increase, including astrocytes and some oligodendroglia, and dense perivascular cuff of mononuclear cells; HE, x 100.

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full of Luxol-fast-blue-positive material (Fig. 10A). These cells were large and mononuclear and closer examination revealed short radiating processes arising from most of them, indicating that they were astrocytes of the gemistocytic variety (Fig. 10B). PTAH preparations revealed glial fibrils in varying density throughout the demyelinated region, and demonstrated hypertrophic astrocytes to be their progenitors (Fig. 10B). Frozen sections stained for fat demonstrated copious sudanophilic material in large

Fig. 12. (Same case) A : cross section of upper lumbar cord showing symmetrical demyelination of anterior columns, especially along the medial aspect of the anterior horns; Kli.iver-Barrera, x 8. B: the lumbar cord one segment lower showing diffuse glial cell reaction including some preserved oligodendroglia in one anterior column and moderate vascular-inflammatory reaction in the meninges in the anterior median fissure; HE, x 100.

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"'histiocytes" (?-gitter cells and gemistocytes) and lying free, with only rare perivascular accumulation, i)~ the totally demyelinated area; and small and large fat-laden cells reaching up to the subcortical white mattcr. Smaller cells, mainly small astrocytes and some oligodendroglia, formed the remaining cell population ~i the white matter (Fig. 11B). While Holmes' Ag preparations revealed some reduction in axon density, several smooth, intact axons were seen running throughout the demyelinated white matter (Fig. 11A). Another noteworthy reaction was lymphocytic infiltration of the vessel and the Virchow-Robin space of several of the small blood vessels in the white matter (Fig. 1 IB). The anterior corpus callosum was totally demyelinated and rarefied with only glial nuclei and fibres and stray axons remaining. The cerebellar white matter did not show any demyelination and the grey matter was also unremarkablc. Sections through the brain stem showed nothing remarkable, except 1 tiny plaque of demyelination and gliosis, just behind the central canal in the lower third of the medulla oblongata. Sections through both portions (a) and (b), including the greater part of the lumbar cord, showed total symmetrical demyelination of the anterior columns, with rather striking sparing of the posterior and lateral columns (Fig. 12A). There was fair axon preservation, and only the late remains of products of myelin breakdown. This was accompanied by a small glial cell reaction, mainly astrocytic but with some preserved oligodendroglia, throughout this region (Fig. 12B), with mild inflammatory and vascular reaction in the anterior leptomeninges. This was an older and milder demyelination than the severe breakdown observed in the cerebrum. DISCUSSION

Both the patients reported manifested clear evidence of dissemination of their neurological illness in time and in space. They fulfilled all the 6 criteria for the clinical diagnosis of MS, laid down by Schumacher, Beebe, Kibler, Kurland, Kurtzke, McDowell, Nagler, Sibley, Tourtellotte and Willman (1965). In addition, they also showed a "tendency to remission", as emphasized by McAlpine (1972), for the diagnosis of"probable multiple sclerosis". In their report on "Profile of MS in the Bombay region" on the basis of a "critical clinical appraisal", Singhal and Wadia (1972) have deemed it necessary that all the criteria of Schumacher et al. (1965) and McAlpine (1972) be fulfilled before a clinical diagnosis of MS is arrived at, especially in parts of the world where the disease is known to be rare. In both our patients who were young women, the disease was characterised by a rapid tempo, with death ensuing within 6 months of onset of the first neurological symptom. In the first patient, the neurological disorder simulated what has been described as neuromyelitis optica (Devic's disease). However, even clinically, there were features of MS, viz. a remission of the spinal cord symptoms followed by a relapse, and evidence of involvement of the brain stem manifesting as vertigo. In the second patient, the initial disease of the spinal cord, which progressed and remitted, made one consider transverse myelitis or a demyelinating disease. The subsequent involvement of the brain with signs of raised intracranial pressure misled us into considering an unrelated intracerebral space-occupying lesion. There was no remission of cerebral symptoms, and only necropsy later showed the first impression to be correct. In retrospect, the cerebral features could be considered a form of diffuse cerebral sclerosis (Schilder's disease), but the associated spinal cord lesion indicated the disease to be a form of multiple sclerosis. Both gross and microscopic pathological examination confirmed the dissemination of the lesions in different parts of the CNS. In the first patient, 3 different sites were involved, viz. the right optic nerve, the medulla oblongata and the cervical spinal cord. In the second patient, at least 2 separate areas were involved, namely the cerebral

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centrum ovale and the spinal cord. The rapid clinical progression of the disease, with remissions in between, was also confirmed pathologically in both the patients, with appropriate cellular reactions indicating different stages of the disease. Thus, the medulla and optic nerve in the first patient and the spinal cord in tile second, showed clearly more chronic lesions with astrocytic and glial fibrillar reactions predominating. The clearly gliotic and sharply defined lesions in the medulla oblongata of the first patient, their site (near the inferior olive and around the central canal, respectively) and character, reproduced the pattern described by Shiraki, Yamamoto and Hamada (1958) in all their 6 cases of disseminated demyelinating disease. On the other hand, the spinal cord in the first patient and the cerebrum in the second, evidenced more active lesions with necrosis and histiocytic reaction predominating. The modifying role of tempo on the demyelinative processes was stressed earlier by Ferraro (1944) and Lumsden (1951), and more recently by Poser (1968). Our first patient with clinical and pathologic features simulating neuromyelitis optica, finds reflection in some of the more acute cases of MS described in the literature. As Shiraki et al. (1958) rightly surmised 15 years ago, "differences of clinico-pathological features of neuromyelitis optica from multiple sclerosis could reasonably be attributed to differences in tempo and intensity of the same process". Okinaka, McAlpine, Miyagawa, Suwa, Kuroiwa, Shiraki, Araki and Kurland (1960) concluded, on the basis of a critical evaluation of the then published Japanese cases, that many of those described as "neuromyelitis optica" could be validly considered to be cases of MS. Our second patient, with her cerebral disease showing, both clinically and pathologically, features of diffuse cerebral sclerosis, was reminiscent not so much of classical "Schilder's disease" as of the "diffuse disseminated or transitional sclerosis", as described by Poser and Van Bogaert (1956), and Poser (1957). Heernu, Martin and Van Bogaert (1945) and Roizin, Helfland and Moore (1946) appear to be the first to have suggested that Schilder's sclerosis and MS were slightly different expressions of the same disease process. All these conditions fall readily into the category of "myelinoclastic diseases" (Poser 1968). As Zimmerman and Netsky (1950) so rightly inferred, the more fulminating course of the disease and the larger size of the lesion in diffuse sclerosis may account for some of the differences in microscopic details between it and MS, but essentially these 2 conditions can be grouped together. A concurrent glioma of the cerebrum, such as the astrocytomas described by Russell and Rubinstein (1971) and others in association with plaques of MS, was not detected in this patient. However, it is interesting to recall that Schilder's cerebral sclerosis often appears as a progressive form with signs of an intracranial space-occupying lesion (Poser 1968), such as were noted in this patient. But the associated spinal cord demyelination of an earlier stage, brings this case legitimately into tile wider spectrum of MS. Three of the recent noteworthy reviews of the neuropathology of MS, based on autopsy studies are those of Zimmerman and Netsky (1950), Greenfield and Norman (1963) and Peters (1968). All these authors stress the good preservation of axons in demyelinated plaques of various stages, severe axon loss being present in only a small proportion. These features have been evident in our 2 cases also; regenerating axons were not seen. The absence or paucity of Wallerian degeneration in parts of

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tracts distal to a lesion in the spinal cord has also been discussed in the above publications and was noticed by us too. A third comment of relevance, by Greenfield and Norman (1963) particularly, is on the nature of the cellular reaction in recent plaques, consisting first of lipid-laden microglia and then of swollen astrocytes. The latter were quite pronounced in the large cerebral lesions in our second case, and were probably invoked by the myelin breakdown products. The "gliofibrillogenesis" which is responsible for the development of plaques of MS and for the designation of this disease is, as aptly stated by Lumsden (1972), "in some unexplained way 'turned on' by the myelin injury". The relation of demyelination to a depletion of oligodendroglia (Peters 1968 and Lumsden 1972) was also noticeable in our material. Peters conceived of the spread of demyelination by perivascular diffusion, like "an ink stain on blotting paper". On the basis of immunofluorescent studies, Lumsden (1972) shows that perivenous demyelination spreads radially in the form of sleeves and, together with "a coalescence of contiguous sleeves", leads to the formation of plaques. The exudation of antigenic proteinaceous material from the central venules of the plaque (Lumsden 1972), may or may not be accompanied by a perivascular inflammatory cell reaction depending on the stage which the demyelination has reached (Peters 1968 ; Poser 1968). That such reaction was present in the cerebral lesions of our second case points to their activity and not necessarily to an infectious aetiology. A relevant question that may be raised here concerns the significance of the frequent surface lesions in the spinal cord (as in our first case), and of the periventricular location of the cerebral plaques (as in our second case), in MS. The increase in immunoglobulin-G now reported from the CSF and the brain of some patients, though originating from immunocytes outside the brain and not from the plaques (Lumsden 1972), and the hypothesis that it is a myetinotoxic antigen, can be accounted for by such superficially placed lesions in the CNS. As Peters (1968) states, the first manifestation or an exacerbation of MS after an infection or vaccination or serum treatment is compatible with the assumption of an antigen-antibody mechanism. The history of re-vaccination against smallpox, about 5 weeks before the onset of optic neuritis in our first patient, raises the possibility of a post-infectious allergic disorder of the CNS as a pathogenetic mechanism. The association, and even the causal relationship, of MS to a well-accepted immunologic disturbance such as allergic encephalomyelitis, has been discussed for a number of years, notably by Lumsden (1972) and Poser (1968, 1972). This patient, however, did not show selective perivenous demyelination or vascular cuffs of inflammatory cells, typical of post-vaccinal encephalomyelitis, and the clinical picture was also not indicative of this condition. The other possibility that this patient raises is of the virus infection (the vaccination) acting as a trigger mechanism precipitating the true aetiological process of MS. Peters (1968) also concludes that the anatomical distribution of, as well as the histological alterations in the lesions of MS do not show any analogy to the characteristic pathological changes, (involvement of neurons and grey matter), caused by viruses. Lumsden (1972) can now see a virus only "in the role of co-factor initiating, along with myelin autoantigen, a myelin sensitization process", and this too only occasionally. The close similarity between morphologic lesions of MS in Japan and of "rabies

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post-vaccinal encephalomyelitis of the encephalitic type", and the possible allergic role of anti-rabies inoculation in the production of MS, have been discussed by Uchimura and Shiraki (1957). Other older evidence on the possible role of vaccines and sera in the pathogenesis of multiple sclerosis was reviewed by P~ilffy and M6rei (1961), who added 6 cases of their own. In their patients previous single or repeated injections of typhoid vaccine, BCG, Mantoux or autogenous vaccine from throat material were administered. They postulated an allergic basis for the subsequent signs and symptoms of multiple sclerosis which developed in all these patients after varying periods of time. However, the only other report of multiple sclerosis developing shortly after revaccination for smallpox, as in our first patient, is that of Miller and Schapira (1959). They contrast this case with 27 other patients with other neurological complications following upon primary vaccination, and who did not develop MS subsequently. SUMMARY

Two unusual cases of multiple sclerosis (MS), both from Bombay, have been reported with detailed clinical and histopathological findings, which evidenced dissemination in time and in space. They were both women in their twenties, with total duration of the neurological illness of 5-6 months. The first patient had initial signs related to the optic nerves and then, after remission, to the brain stem and spinal cord. There were chronic plaques in the medulla, in 1 optic nerve and lesions of varying stages throughout the cervical spinal cord, with glial cellular and fibrillar reaction, and some preservation of axons. This appeared to be a case of MS with features simulating neuromyelitis optica. The second patient had initial signs related to the lumbar cord, like a transverse myelitis and then, after a remission, evidence of a progressive cerebral disorder with clinical and ventriculographic findings suggesting a space-occupying lesion in the corpus callosum and frontal lobes. The more chronic demyelination was in the spinal cord. The brain showed large, recent, symmetrical, periventricular plaques, with total absence of myelin except in some of the U-fibres, throughout the frontal and parietal lobes and anterior corpus callosum. There was moderate lymphocytic reaction in and around the vessels, extensive accumulation of myelin breakdown products in histiocytes (gemistocytes and gitter cells) with some preservation of axons and early gliosis. This appeared to be a case of MS with some features of diffuse cerebral sclerosis, or what is often called transitional type of MS. A history of smallpox vaccination 5 weeks before the illness in the first case, and the chronic inflammatory reaction in the second, together with the rapid tempo of the disease in both, which determined the characteristic patterns of clinical and pathological changes, has led us to discuss the infectious and allergic hypotheses of aetiology in MS. ACKNOWLEDGEMENTS

Thanks are due to Mr. V. P. Kate and Mr. V. Talwadkar for the histopathological technical assistance and to Mr. N. Solanki for the photographic prints.

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