Multiple sclerosis with amyotrophy complicated by oligodendroglioma

Journal of the neurological Sciences

441

Elsevier PublishingCompany,Amsterdam-Printedin The Netherlands

Multiple Sclerosis with Amyotrophy Complicated by Oligodendroglioma History of Recurrent Herpes Zoster R. O. BARNARD AND E. H. JELLINEK Maida Vale Hospital for Nervous Diseases, London W9 (Great Britain)

(Received 16 November, 1966)

The development of glial tumours in and around the plaques of demyelination in multiple sclerosis is a recognized but rare phenomenon (SCHERER1938; RUSSELLAND RUBINSTEIN 1963): in the cases recorded the tumours concerned were usually astrocytomas or glioblastomas. Since the oligodendrocytes may have a role in myelination and in the demyelinating process, it is a point of interest that in the case now described the tumour is an oligodendroglioma undergoing de-differentiation to a primitive ceil-type. The patient who developed this complication had suffered from multiple sclerosis for 16 years. She also had a solitary dorsal neurofibroma and had had two attacks of zoster. CASEREPORTJ. H. (M.V.H. No. 37468) A married white woman, without relevant past or family history, had an attack of shingles on the right side of the neck extending from the clavicle up to the angle of the jaw in 1940 (age 20). Thereafter she was well until 1948 (age 28) when she developed symptoms of multiple lesions of the nervous system with giddiness, some disorder of vision and a sensory disturbance. Her general practitioner found nystagmus and other neurological signs and referred her to Dr. S. P. Meadows at the Westminster Hospital. By the time she was seen there all her signs and symptoms had subsided but Dr. Meadows suspected that she had had an episode of demyelination. On 27 June, 1950 (age 30) she was seen in Dr. E. A. Carmichael's outpatients at the National Hospital, Queen Square, complaining of numbness from the waist downwards for 2 weeks; about 18 months previously she had a similar episode. On examination she had impairment of sensation to pin prick below the seventh dorsal segment, but no other signs. A diagnosis of multiple sclerosis was again suggested. It appears from a letter from her general practitioner that she suffered transient visual symptoms in 1950, 1952 and 1953. E. H. Jellinek: Present address: Northern General Hospital, Ferry Road, Edinburgh-5. J. neurol. Sci. (1967) 5:441-455

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In September 1955 she was living in the same house as a man who had to be admitted to the local fever hospital with an attack of poliomyelitis. The patient herself developed sudden symptoms of weakness, nausea and diplopia and two days later complained of loss of power of the right arm; she was afebrile. When admitted to a fever hospital on 19 September she had nystagmus and weakness of the right upper limb muscles, with increased reflexes in the right upper limb. The right plantar response was doubtfully extensor. Lumbar puncture on admission produced CSF which contained 144 white cells per mm z and a protein of 80 mg/100 ml. During the first month of her stay in hospital her neurological disorder became progressively worse. She developed first of all weakness of the right internal rectus muscle and then a complete external ophthalmoplegia. Her weakness continued to spread and she was no longer able to raise her legs off the bed. She developed paraesthesiae in the fingers and toes and a sensory level atTs. Both plantar responses were extensor. By October 6th the weakness had progressed; she was drowsy and confused, with retention of urine and a clear sensory level at Ts. She was seen by Dr. R. E. Kelly a week later, who thought that the illness could be interpreted as an acute episode of demyelination. She had ataxic nystagmus and paralysis of the limbs except for some residual movement in the left upper limb. She had sensory levels at T4 and Tlz. The presence of a shadow in the chest X-ray (the dorsal neurofibroma) was noted. Thereafter she began to improve and by 17 October had regained bladder control; external ocular movements began to recover on 28 October and she was walking with two sticks on discharge from the fever hospital on 6 January 1956. During the next few months improvement was maintained and all numbness disappeared; sphincter control was normal though she still experienced frequency of micturition. When seen in October 1956 by Dr. Douglas McAlpine she thought that she had lost ground during the previous fortnight and complained of an irritation inside the left breast and just below it. On examination there was no nystagmus and ocular movements were normal. She had slight weakness of abduction of the right shoulder, gross weakness of the right triceps with wasting, and slight weakness of the extensors of the right wrist and fingers. She had well-marked wasting and weakness of the intrinsic muscles of the right hand and slight wasting of the muscles of the left hand. The right triceps and supinator jerks were absent. The lower limbs were slightl2¢ weak and the plantar responses were extensor. Vibration sense was diminished below T8. Dr. McAlpine arranged for her admission to Maida Vale Hospital where in November 1956 she was investigated. The cerebrospinal fluid contained 5 white cells per mm z and 42 mg/100 ml of protein. The Lange curve was fiat. The X-ray of the chest again showed a rounded opacity alongside the fifth dorsal vertebra on the right. During 1957 she was observed as an outpatient: her gait improved slowly. In the first half of 1958 she continued to get better especially with respect to the use of her right upper limb, but in September 1958 she complained of increasing frequency and urgency of micturition which lasted a month or two. In February 1959 there was an episode of weakness of the right hip muscles and pain in the right groin; this later recovered. In November 1959 she suffered a further attack of herpes zoster affecting J. neurol. Sci.

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the second right cervical dermatome. In June 1960 she complained of a numb patch on the right side of the chest thought probably to be due to the thoracic neurofibroma; this could be seen in the X-rays to have enlarged slowly. In September she complained of"jumping" of her legs in bed; on examination the right leg was slightly spastic. In January 1961 she noticed increased frequency of micturition and in April found that her legs were getting worse. In January 1962 she experienced difficulty in visual fixation; on examination no new signs were found. In June she noticed abnormal sensations in the legs; vibration sense was found to be absent up to the anterior superior iliac spine and both plantar responses were now extensor. By September the sensory deficit had improved; there was no spasticity and the left plantar response was flexor, the right extensor. In September 1963 she complained of a pounding headache in the right eye and right temple, nausea and attacks of diplopia especially on waking. Her husband said that she had been confused and abnormally sleepy for the previous 6 weeks. Skull X-ray was normal, but an electroencephalogram (EEG) suggested a lesion in the right hemisphere. She was admitted to Maida Vale Hospital under the care of the late Dr. P. H. Sandifer (10 September); arteriography demonstrated a right temporal space-occupying lesion. Mr. Valentine Logue performed a temporal lobectomy and found a glial tumour which extended into the inferior parietal zone and could not be completely removed. There was uncal herniation and the brain stem was displaced to the left. Post-operative progress was satisfactory apart from a right third nerve paresis which, however, was recovering at time of discharge (15 October). Eight months later she complained of unsteadiness and recurrent headaches behind the right eye; her memory had deteriorated. She was re-admitted and was found to be completely disorientated, with a left homonymous hemianopia and fine nystagmus, especially on looking to the right. External ocular movements were full; there was a mild left facial weakness. Ataxia in the right arm and leg was now worse than on the left and she had a slight cerebellar dysarthria. A fine tremor of the outstretched hands was seen, worse on the right. Right carotid arteriography showed a large circular mass in the posterior temporal region, with pathological vessels seen in the antero-posterior views extending deeply towards the midline. On 29 June 1964 Mr. Lindsay Symon needled the brain and found a cystic cavity from which he aspirated 17 ml of oily-looking fluid. After this procedure her condition was reasonably satisfactory until 9 July when she suddenly collapsed with dilatation of the right pupil and died shortly afterwards. Pathology Biopsy (September 1963) (laboratory reference No. 191/63). A portion of temporal lobe 6.5 cm x 6.5 cm x 3.0 cm was received, containing a mass of abnormal pale grey and yellow tissue extending from the subcortical white matter to penetrate the cortex in some places. Histology. The tumour mass was composed of large polyhedral cells with oval nuclei showing prominent nucleoli and coarsely granular nuclear chromatin. A "boxed-in" appearance of nuclei enclosed in a well-defined framework was often seen and there J. neuroL Sci. (1967) 5:441-455

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were foci of mucinous degeneration. While much of the tumour was arranged in lobules intersected by thin-walled blood-vessels there were areas of cells of more elongated shape radiating from the walls of the blood-vessels in "pseudo-rosette" formation. Mitotic figures were fairly common and there were occasional foci of necrosis. There was no calcification. The appearances were those of an oligodendroglioma of "polymorphic" type, with some features resembling ependymoma. Second biopsy (June 1964) (laboratory reference No. 137/64). Two tiny morsels of pale grey and brown tissue were received. Histology. The biopsy consisted of fragments of grey matter and of glial tumour. In the latter there was fairly marked cellular pleomorphism and vascular endothelial hyperplasia; the regularity of cell disposition was lost. In comparison with the earlier biopsy the tumour demonstrated progressive anaplasia.

Fig. 1. A mass of recurrent tumour refills the operation site in the temporal lobe. Around the margins of the ventricles areas of gliosis can be seen. J. Neurol. Sci. (1967) 5:441 455

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Post-mortem examination was carried out within 12 hours of death. The body was that of a plump, very well-built woman with no stigmata of neurofibromatosis. The intrinsic muscles of both hands and the right triceps appeared wasted. The craniotomy scar was well-healed - - a recent burrhole was placed close to it. The intrathoracic tumour was an encapsulated solitary neurofibroma immediately adjacent to the spinal column and attached to the fifth dorsal root. No other relevant changes were found outside the central nervous system; the lungs showed congestion and purulent bronchitis. The brain was cut after fixation and showed great swelling of the right hemisphere with cingulate herniation and a marked cerebellar cone. There were two distinct tumour masses: the first refilled the excavated temporal lobe, infiltrated the central grey matter up to the fibres of the internal capsule and was firmly adherent to the upper surface of the tentorium (Fig. 1). At the level of the pineal gland this mass measured 5 cm supero-inferiorly by 6 cm across and had burst the ependymal lining to gain the free surface of the ventricle; it was composed of finn, pink-streaked grey tissue. The second mass was softer and partly necrotic; it replaced much of the right cerebellar hemisphere and was adherent to the lower surface of the tentorium. It appeared that the tumour had spread round the free margin of the tentorium; the vermis cerebelli was swollen and displaced and a "reverse pressure cone" had formed (Fig. 2).

Fig. 2. A granular mass of tumour invading the cerebellum. Both lateral ventricles were dilated and in the white matter close to their margins were discrete areas of grey gliosis. The spinal cord was of normal length; from T1 to the lumbar enlargement the external surface was shrunken and congested; the leptomeninges were opaque. On section areas of grey gliosis could be seen at all levels. Nerve roots and posterior root ganglia appeared normal. Histology

(In addition to routine methods representative brain slices were embedded in celloidin and silver impregnation methods were employed on plaques and on specimens of the tumour tissue.) J. neurol. Sci. (1967) 5:441-455

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Brain. The leptomeninges showed focal collagenous thickening and adjacent gyri were often united by fine strands of connective tissue, with a light exudate of lymphocytes and monocytes. The major arterial branches were healthy; the veins were frequently congested. In the periventricular white matter there was a narrow band of demyelination that followed the outline of the lateral ventricles extending on either side from the anterior part of the frontal lobe to the posterior parietal; it was of variable thickness and from it circumscribed areas of partial myelin loss (shadow-plaques) extended into the white matter (Fig. 3). Often a small vein was present close to the centre of these lesions.

Fig. 3. There are numerous foci of complete or partial demyelination in the periventricular white matter. At this level the tumour is contained within the margin of the cortex. (Myelin, natural size.) Distant from the dilated ventricular cavity there were various other foci of demyelination, often appearing at the junction of cortex and white matter or projecting into the cortex over a short distance. With Holzer's crystal violet many of the areas showed an abundance of dense glial fibres. In the discrete plaques a proportion of the myelin sheaths was usually preserved, but in the periventricular areas the loss was often virtually total and the number of axons appeared markedly reduced when metallic impregnations were examined (Fig. 4). A number of lesions appeared "active" with lymphocytic cuffing of small blood-vessels. Astrocytes were sometimes conspicuous at the margins of the lesions, showing swelling of their cell-bodies and formation of glial fibres; near the centres they commonly showed loss of processes and contraction of a darkly-stained cell body. OligodenJ. neurol. Sci.(1967) 5:441-455

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Fig. 4. Axis cylinders and oligodendrocytes disappear abruptly at the edge of an area of myelin loss. (Silver carbonate, × 130.)

Fig. 5. Close to the edge of a plaque of demyelination oligodendrocyte nuclei are numerous and fibrous astrocytes show some activity. (Silver carbonate, x 500.) drocytes were sparse within the a r e a o f myelin loss, b u t close to the m a r g i n s they a p p e a r e d very n u m e r o u s (Figs. 5 a n d 6) a n d sometimes showed the a p p e a r a n c e s o f " a c u t e swelling". However, in all the areas e x a m i n e d the m o r p h o l o g y o f the oligodenJ. neurol. Sci. (1967) 5:441-455

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Fig. 6. At the centre of the same area of demyelination no oligodendrocytes remain; the outlines of astrocyte cell-bodies can sometimes be made out, but glial processes are almost entirely destroyed. Two axons are recognized. (Silver carbonate, x 500.) drocytes was entirely typical and no loci of tumour formation were found at the margins of the plaques of demyelination. The anterior limit of the right hemisphere tumour was at the level of the optic chiasm, where a nodule was present in the white matter of the orbital gyrus. Posteriorly it expanded to form a large mass (up to 6 cm × 5 cm), refilling the temporal lobectomy site and infiltrating the central grey matter, to reach the posterior parietal area. The centre of the mass was necrotic; the viable periphery was composed of a densely cellular structure in a great part of which the cells were elongated and slender, tending to be arranged in parallel rows. Very few glial fibres could be demonstrated by metallic impregnations or by Mallory's P T A H stain. Elsewhere the cells were sometimes arranged round blood vessels in perivascular "pseudo-rosettes" and in places the " h o n e y c o m b " appearance of an oligodendroglioma was preserved (Fig. 7). The cerebellar tumour was similar; but here necrosis was more extensive. The tentorium separating the two deposits was not permeated. Microglia were fairly numerous in and around the tumour tissue, often showing active phagocytosis. In the mid-brain the areas of demyelination were well-circumscribed. The aqueduct was dilated and bordered by an area of myelin loss. In the pons there were areas of pallor of myelin-staining in both middle cerebellar peduncles and in the central tegmental tract; the corticospinal fibres also appeared pale. The cavity of the IVth J. neurol. Sci.

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Fig. 7. "Polymorphic" oligodendroglioma. (Haematoxy|in--eosin, × 130.) ventricle was deformed by the proximity of the tumour in the cerebellum; some cells of the dentate nuclei showed accumulated lipochrome pigment; the granule cells and Purkinje cells of the folia of the left hemisphere were within normal limits. Areas of myelin loss in the medulla were seen in the corticospinal pathways in both pyramids, at the hilum of each inferior olive, in the inferior peduncles and in the periventricular white matter. Occasional "glial knots" and lightly cuffed blood vessels were present in the white matter. The neurons of the inferior olive contained abundant lipochrome. Spinal cord. The cervical segments were of normal size and shape. The leptomeninges were thickened with collagen and contained perivascular foci oflymphocytes; the anterior spinal artery and its branches were healthy. Myelin loss was variable in distribution and intensity; in the upper cervical segments it was maximal in fasciculus gracilis. The lateral and anterior columns also showed a consistent loss with a tendency for preservation of myelinated fibres at the periphery. In the affected areas cellular constituents were sparse and were mainly astrocytes or microglia; sometimes the astrocytic nuclei were paired. Holzer's method demonstrated a marked fibrous gliosis in the demyelinated areas. Axons were much reduced in number in the areas where demyelination was marked. For the most part the neuronal population was normal, but at C7 there were lesions consisting of focal loss of myelinated axons and motor neurons from the anterior horns (Fig. 8). These areas were clearly demarcated and roughly ovoid; at their J. neurol. Sci. (1967) 5:441-455

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Fig. 8. Spinal cord C7 showing extensive myelin loss. There are clear-cut lesions in the anterior horns. (Heidenhain's myelin, × 3.~

Fig. 9. Anterior horn, C7, showing a circumscribed area of pallor with disappearance of ganglion cells. (Davenport's axonal stain, × 60.) m a r g i n s a few n o r m a l a n t e r i o r h o r n cells survived (Fig. 9). Their m o r p h o l o g y was similar to the plaques in the white matter. The lesions d i d n o t extend to the a n t e r i o r horns at T1, t h o u g h there was here a diffuse loss o f large m o t o r neurons. F o c a l a n d diffuse myelin loss was seen in all parts o f the white m a t t e r at this level. T h e lower t h o r a c i c c o r d was shrunken a n d meningeal thickening was m a r k e d , J. neurol. Sci. (1967) 5:441-455

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myelin loss was extensive; at T5 only a portion of the posterior columns was preserved, at Ts the loss was most intense in the lateral columns where only some blood vessels and scattered glial cells remained. Gliosis was dense. Axons were reduced in number and often appeared abnormally thick and darkly-stained. There were no softenings or fat-laden phagocytes. Neurons of the anterior and lateral horns were normal. The lumbar enlargement was of normal shape; poverty of myelin was most marked in the lateral columns and in the anterior part of the posterior columns. Anterior horn cells were within normal limits. The posterior roots and root entry zones in the cervical cord showed a marked loss of myelinated axons especially at C4; in the lumbar enlargement the posterior roots were mainly preserved. In the posterior root ganglia a varying proportion of neurons was undergoing dissolution with proliferation of capsule cells; this was most evident in the cervical region. The triceps showed groups of small fibres with prominent subsarcolemmal nuclei typical of denervation atrophy; a few groups of denervated fibres were seen in the intrinsic hand muscles. The intrathoracic tumour showed the typical appearances of a benign neurofibroma.

DISCUSSION

The multiplicity of neurological afflictions in one patient calls for some comment; she first suffered an attack of herpes zoster, later developed multiple sclerosis, was noted to have a dorsal neurofibroma, subsequently had a second attack of zoster and finally died of a recurrent oligodendroglioma. No connection between the demyelinating disease and the neurofibroma is suggested, though multiple neurofibromatosis is certainly linked with a high incidence of certain types of glioma (RUSSELL AND RUBINSTEIN 1963). The neurofibroma, first noted in 1955, probably doubled in size during the next 9 years: the only symptom referable to it was the local disturbance of skin sensation. Histologically it was typical and no others were found at necropsy. The patient's multiple sclerosis ran a fairly typical course between 1948 and her death in 1964; during the first 7 years she had several episodes with subsequent remissions. In 1955 she had an exacerbation of the disease which took several months to clear and left residual symptoms and signs including weakness and wasting in the right arm and hand. Poliomyelitis was at the time considered a diagnostic possibility since there was a history of contact, but the clinical course and cerebrospinal fluid were not typical of this disease. On four occasions between 1956 and 1962 she had further episodes suggesting fresh demyelination. The histological findings confirmed the diagnosis of chronic multiple sclerosis with symmetrical periventricular myelin loss in the hemispheres and various discrete plaques; the lesions varied in age and intensity, sometimes showing lymphocytic cuffing of blood-vessels. No large confluent areas of myelin loss were found and little sudanophilic material could be demonstrated. The spinal cord showed extensive demyelination and gliosis; at the seventh cervical segment there were well-demarcated areas in the anterior horns showing destruction of motor neurons together with axons and myelin sheaths. The lower thoracic cord was shrunken and here the disease process appeared most intense in the lateral columns where J. neurol. Sci.

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only a few glial cells and blood vessels survived. The posterior roots, especially in the cervical region, showed loss of myelinated fibres; posterior root ganglia showed some cell loss. Lesions in the spinal cord in which anterior horn cells are destroyed are more often illustrated in Devic's disease (OPPENHEIMER1962) than in multiple sclerosis. GARCIN et aL (1962) reviewed existing recorded cases and described three examples of amyotrophy resulting from anterior horn cell destruction in plaques similar to the present case. Histologically the anterior horn lesions resemble those in the white matter and there are no features which suggest infection with either poliomyelitis or zoster, but the possibility remains that the additional presence of a virus could have in some way altered the pattern of the demyelinating disease. ALAJOUANINEAND GRIEFITHS(193 l) described the case of a girl aged 17 with multiple sclerosis in whom the first attack of paralysis (of the right leg) coincided with shingles in the L1-4 dermatomes. They argued that this was an episode of demyelination with symptomatic herpes zoster rather than of zoster myelopathy on account of her rapid recovery; she had apparent typical multiple sclerosis episodes at the ages of 21, 23 and 26. They did not consider that herpes zoster could have caused the multiple sclerosis but rather that it represented the anatomical localisation " o f the virus of scl6rose en plaques". DENNY-BROWNet al. (1944) described thepost-mortem findings in 3 cases of herpes zoster and confirmed the earlier findings (WortLWILL 1924; LJJERMIXTEAND VERMES 1930) of inflammatory lesions in the central nervous system as well as in the posterior root ganglia. The patient under discussion had an upper cervical eruption of zoster at the age of 20, 8 years before the apparent onset of the demyelinating disease and a second eruption in the same territory at the age of 39, at a time when her demyelinating disease showed no particular sign of activity. Second attacks of zoster are unusual; HEAD AND CAMPBELL(1900) reported 3 among 400 cases, HOPE-SIMPSON(1965) 8 among 162; in half of HOPE-SIMPSON'S cases the second attack involved the same ganglia. While the combination of zoster and demyelination in the same case could clearly have been due to chance, two other possibilities merit attention; the zoster could have been symptomatic of the demyelinating process as is envisaged by ALAJOUANINE AND GRIFFITHS(1931); this is improbable here as the first attack preceded the symptoms of multiple sclerosis by 8 years. The other possibility is that the virus of zoster plays some part in the pathogenesis of demyelinating disease. It is impossible to date the onset of the cerebral turnout with accuracy since it arose in a relatively silent area of the brain. The patient died from its effects within a year of its discovery. A histological comparison of biopsy and necropsy specimens showed that it was an atypical oligodendroglioma undergoing anaplasia with predominance of a primitive cell-type. SCHERER (1938) published an account of a case of acute multiple sclerosis in a woman aged 29, with a diffuse periventricular glioblastoma supervening on the "reactive" glial proliferation at the margins of the areas of myelin loss. The boundary between "reaction" and "neoplasia" was not well-defined and a progressive transition could be observed. Elsewhere in the brain there were various lesions of demyelination, some resembling the concentric pattern of Von Balo's type, without associated tumour J. neurol. Sci. (1967) 5:441455

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formation. SCHERER believed that the glioblastoma in his case was the result of multifocal malignant transformation of reactive glia. The case described by MONCH-PETERSEN (1949) concerned a woman aged 49 who died suddenly 3 years after a clinical diagnosis of multiple sclerosis had been made. The left cerebral hemisphere was much expanded by the presence of a tumour containing large recent haemorrhages. It was growing downwards from the region of the external capsule to reach the mesencephalon and was composed of cells with little cytoplasm and fine fibrils radiating toward vessels to form "pseudo-rosettes". Some blepharoplasts were observed and the tumour was diagnosed as an ependymoma. Various plaques of demyelination were found, some of which were not sharply defined. Axons had often largely disappeared, but fibrillary gliosis was not marked, the astrocytes showing mainly regressive changes. The author considered that transformation of astrocytes to cells of ependymoma type as seen in the tumour was improbable and that the association of the two lesions was best considered as fortuitous. RUSSELL AND RUBINSTEIN(1963) described 2 cases. The first of these concerned a woman aged 36 in whom two distinct gliomas had arisen at the borders of plaques of demyelination. The larger, a fibrillary astrocytoma undergoing anaplastic change, was situated in the right frontal lobe; the smaller a glioblastoma multiforme lying above the left border of the genu of the corpus callosum measured only 0.4 cm together with its associated plaque. The second case was of a man aged 66 with a left occipital glioblastoma and a pedunculated tumour, apparently a subependymoma, attached to the head of the right caudate nucleus. It was not possible to relate either tumour directly to a plaque, though the authors commented that the growth of the glioblastoma, which had attained massive size, would have destroyed any visible link. Another case was reported by BRIHAYE et al. (1963). Their patient, a man of 62, presented with a short history of headache, vomiting, progressive hemiparesis and "seizures". The cerebrospinal fluid showed 160 cells per mm a and a protein of 120 mg/ 100 ml. A right temporal lobe tumour was partly removed at operation. Histological examination showed it to be a pilocytic astrocytoma corresponding to grade II or III of Kernohan's classification. The patient died 10 days later and at p o s t m o r t e m examination numerous lesions typical of multiple sclerosis were found both in the white matter close to the ventricular system and close to the cortex. Some of the patches of demyelination merged into the tumour, but in the main the "glial wall" at the margins of the plaques appeared dissimilar from the tissue forming the tumour. In only one area could a possible transition between tumour and reactive glia be seen. The authors did not believe that their case substantiated the hypothesis of neoplastic change occurring in the glial reaction to lesions of demyelination. In the case we have described oligodendrocytes are mainly deficient in the demyelinated areas, but are abundant in the nearby white matter. PAYLINGWRIGHT (1961) and other authors have stressed the importance of the question of the maintenance of myelin: if constant attention by specialized cells is required then failure of these cells would result in myelin loss. LUMSDEN (1951)believed that oligodendrocytes disappear from the areas affected in demyelination; subsequent studies have shown that while oligodendrocytes tend to be scanty near the centres of plaques they are abnormally numerous at the margins where they show increased enzymic activity (IBRAHIM AND J. neurol. Sci. (1967) 5:441-455

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ADAMS 1963). If, as seems likely, their initial reaction in multiple sclerosis is a proliferative one it would be reasonable to predict that if the reaction became uncontrolled it could result in neoplasia. In this context, it is o f interest that in an electronmicroscopic study o f brain tumours, RAIMONDI et al. (1962) found polygonal crystalline bodies with the m o r p h o l o g y o f a virus in the cytoplasm of cells from an oligodendroglioma, and not in the other gliomas examined. It thus seems possible that a virus could be a pathogenetic factor c o m m o n to all the neurological diseases suffered by the patient we have described; accordingly, the history of recurrent infection with herpes zoster is given some prominence.

ACKNOWLEDGEMENTS We would like to thank Professor W. H. M c M e n e m e y for his continuous help and encouragement; Mr. V. Logue for kindly placing his notes at our disposal and for criticising the manuscript. Mr. T. Scott was responsible for m a n y of the histological preparations while working under a grant from the British Empire Cancer Campaign to w h o m we are indebted and Mr. G. Cox was responsible for the photomicrographs.

SUMMARY (1) The case is described of a w o m a n whose first s y m p t o m o f multiple sclerosis appeared 16 years before her death, 8 years after an attack o f herpes zoster. A second attack of zoster occurred 19 years after the first. S y m p t o m s of a cerebral turnout appeared less than l year before her death; biopsy showed a pleomorphic oligodendroglioma which recurred rapidly. A thoracic neurofibroma is regarded as an incidental finding. (2) Existing accounts o f cerebral tumours associated with demyelinating disease are reviewed. N o other examples o f oligodendroglioma are reported. (3) The relationship o f multiple sclerosis with herpes zoster is discussed.

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J. neurol. Sci. (1967) 5:441--455