Acute with massiveJ. clin. Path. (1962), 15, 314 Acutedisseminated encephalomyelitis, with massive necrosis ofthe spinal cord, probably due to antitetanus serum A. A. MILLERANDF. RAMSDEN

J. clin. Path. (1962), 15, 314

Acute disseminated encephalomyelitis, with massivenecrosis of the spinal cord, probably due

to antitetanus serum

A. A. MILLER AND F. RAMSDEN

From the Group Laboratory, Preston Royal Infirmary

SYNOPSIS The clinical and pathological findings are described of a fatal case of acute haemorrhagicleucoencephalitis and disseminated encephalomyelitis with acute necrosis of the white matter ofthe spinal cord. It is suggested that the reaction was a severe immunological response of an allergicnature, probably due to antitetanus serum.

The case described in this paper is of great interestfor the following reasons: Acute disseminatedencephalomyelitis and acute haemorrhagic leuco-encephalitis with massive necrosis of the whitematter of the spinal cord is an extremely rare con-dition which we have not found described in man inthe available literature. Demyelinating encephalo-myelitis after the administration of prophylacticserum has been reported only infrequently. In thiscase the onset of the neurological symptoms was notheralded by any local upset or skin eruption.

CASE REPORT

The patient, a healthy girl aged 23 years, was admitted tothe North Lonsdale Hospital following a scooter accident:injuries were a simple fracture of the mid shaft of the leftfemur with abrasions of the left thigh and right elbow.Immediate treatment included the intramuscular in-jection of penicillin, subcutaneous injection of 1 ml. ofantitetanus serum, and I grain of morphia.Her condition remained satisfactory until the fifteenth

day when she developed acute retention of urine fol-lowed, some hours later, by flaccid paraplegia, weaknessof the left arm, unequal pupils, and sensory loss belowthe second thoracic segment.On the seventeenth day she was transferred to the

Neurosurgical Unit of Preston Royal Infirmary under thecare of Mr. R. A. Daws. At the time of admission shewas fully conscious, cooperative, and well orientated.There was flaccid paraplegia; the only reflex demon-strable in the legs was a depressed right knee jerk. Lossof sensation to pin prick reached to the level of thesecond thoracic segment and there was dulling of lighttouch sensation over this area. Upper limb reflexes were

Received for publication 15 November 1962.

grossly exaggerated; the left arm was weak and inco-ordinated; the jaw jerk was brisk. Upward movement ofthe eyes was restricted and bilateral papilloedema waspresent.

Radiological examination of the skull and spinalcolumn and a right carotid angiogram showed noabnormality; the transverse fracture of the mid shaft ofthe left femur was confirmed radiologically.

Cerebrospinal fluid was under normal pressure; cellularand chemical constituents were normal. Serologicaltests, including the Wassermann reaction and P.P.R.,were negative. Haematological investigations did notshow any evidence of anaemia: white cells were increased(23,000 per c.mm.) due to polymorphonuclear leuco-cytosis; the erythrocyte sedimentation rate was slightlyraised; serum electrolytes were normal apart from aslightly low chloride level (91-6 mEq./l.); blood urea was185 mg. per 100 ml.The urine contained numerous pus cells and gave a

profuse growth of a coliform organism when cultured.The patient was examined by Dr. N. Gordon, the

consultant neurologist, who diagnosed acute encephalo-myelitis, probably of allergic origin. Treatment withantihistamines was instituted and tetracyclines weregiven to control urinary infection.Her condition deteriorated rapidly, extensive paralysis

developed; the patient became drowsy and confused.Lumbar puncture on the twenty-second day showedpressure within the normal range. Examination of thecerebrospinal fluid did not show abnormality. On thetwenty-third day intravenous steroids were given. Thepatient died in coma early next morning. Death was onthe twenty-fourth day after the administration of serumand nine days after the onset of neurological symptoms.During life she worked in a pharmaceutical laboratory

where most of her time was spent in washing up dutiesinvolving innocuous substances; more recently she hadsampled penicillin and streptomycin. She had never beenexposed to poisonous substances such as cyanides.

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Acute disseminated encephalomyelitis, with massive necrosis of the spinal cord

NECROPSY

The examination was carried out about 48 hoursafter death, the body being refrigerated in theinterim period. The deceased was a sparely built,well-nourished young woman. Abrasions on theleft thigh and right elbow were noted; the fractureof the left femur was not united. Injuries to the scalp,skull, spine, and other bones were not found.The lungs showed congestion of all lobes with

bilateral, basal haemorrhagic bronchopneumonia.The heart was structurally normal: the left ventricularmyocardium was flaccid, toneless and congested.Abdominal organs were congested. The spleen wasenlarged, soft, congested, and contained a largeamount of pulp. The bladder showed haemorrhagiccystitis and the kidneys the appearances of pyelone-phritis. All the endocrine glands appeared normal.The cause of death was respiratory failure, due to

-acute disseminated encephalomyelitis with maximalinvolvement of the spinal cord.

PATHOLOGY OF THE CENTRAL NERVOUS SYSTEM

MACROSCOPIC FINDINGS The brain weighed 1,185 g.The leptomeninges were acutely congested; pin-point haemorrhages were seen on both cerebralconvexities but without exudate. The main cerebralarteries appeared normal; cerebral veins and duralsinuses contained fluid blood with small post-mortem clots. On coronal section the ventricles wereof normal size; the grey and white matter cf bothcerebral hemispheres and, to a lesser extent thebrain-stem, showed slight diffuse congestion andoedema. Numerous petechial haemorrhages wereseen in the white matter of the posterior frontal andanterior parietal regions of both sides and in bothcorpora striata; diffuse haemorrhages were presentin the right postero-lateral region of the pons andthe white matter of the right cerebellum. Macro-scopic lesions were not seen in the corpus callosum.Areas of softening were not found in the brainsubstance.The spinal cord, from lower cervical to upper

lumbar segnents, was swollen and soft; the lepto-meninges were intensely congested but there wasno meningeal exudate (Fig. 1). Section of the dorsalsegments after fixation showed soft grey necroticsurfaces: the cervical and lumbo-sacral parts wereoedematous and congested but were firmer than thedorsal cord.

MATERIALS AND METHODS Samples were taken from everysegment of the cord together with nerve roots and rootganglia; from the lower and upper medulla oblongata,the pons, cerebellum, brain-stem, basal ganglia, the

FIG. 1. Posterior aspect ofspinal cord showing congestionof leptomeninges and oedematous swelling of the dorsalcord.

frontal, parietal and occipital cortex and white matterand the corpus callosum; and from the cranial nerves.Paraffin, celloidin, and freezing methods were usedto prepare sections which were stained by a varietyof techniques including haematoxylin and eosin, vanGieson's stain, and phosphotungstic acid haematoxylin.Loyez haematoxylin and Weigert-Pal preparations wereused for demonstration of myelin. Frozen sections weretreated by Weil Davenport's method and by Penfield'smodification of Hortega's silver carbonate technique todemonstrate neuroglial cells and neurofibrils.Sudan III and IV, sudan black B, and periodic acid-

Schiff methods were used to demonstrate myelin break-down products.

MICROSCOPIC FINDINGS The leptomeninges appearednormal apart from congestion and extravasation ofred blood cells. In the brain substance the mainfinding was numerous foci of perivascular demyelina-tion and cellular cuffing around small veins; thecellular sleeve consisted of histiocytes and granularamoeboid microglial cells with irregularly lobed

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A. A. Miller and F. Ramsden

FIG. 2 FIG. 3

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Vessel

FIG. 2. Blood vessel in frontal white matter showing wide intra- and peri-adventitial infiltra-tions. The lumen of the vessel, containing red blood cells, is in the lower right-hand corner.(Phosphotungstic acid-haematoxylin x 650.)

FIG. 3. Subcortical frontal white matter showing perivascular demyelination forming an'anaemic' zone. (Phosphotungstic acid-haematoxylin x 140.)

nuclei and scanty cytoplasm, also fat granule cellsin various stages of formation (Fig. 2).

In general the foci were not haemorrhagic andwere found in the white matter of the posteriorfrontal, anterior parietal and occipital lobes, also inthe internal capsule, caudate and lenticular nuclei,the thalamus, mid-brain, pons, and cerebellum. Theseverity of the process varied throughout the brain;the mildest form, seen in the posterior part of thepons, was a narrow perivascular cuff of histiocyteswith slight transudate in the adjacent neural tissue.In the more severely affected areas the perivasculardemyelination had become confluent or diffuse,producing ill-defined, pale foci which showed wellon Loyez and phosphotungstic-acid-haematoxylin-

stained sections (Fig. 3). In the subcortical whitematter of the frontal lobes, the internal capsulesnear the corona radiata, the thalamus, brain-stemand medulla, the demyelination was accompaniedby wide perivascular sleeves of cells (Figs. 4 and 5).In one area of the right frontal lobe, the cellularsleeves were confluent and occupied an area mea-suring 12 x 4 mm. (Fig. 6).

In the right dorsolateral part of the pons and thewhite matter adjacent to the dentate nucleus therewas a large diffuse haemorrhagic focus of recentorigin.The lower medulla oblongata and the spinal cord

showed a severe degenerative lesion (Figs. 8 to 17).The motor decussation of the pyramids at the

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317Acute disseminated encephalomyelitis, with massive necrosis of the spinal cord

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FIG. 4 FIG. 5

FIG. 4. Blood vessel near corona radiata showing narrow advetititial and wide periadventitial infiltrations. (Phosphotungsticacid-haematoxvlin x 140.)FIG. 5. Blood vessel in the thalamus showing perivascular cellular infiltration. (Phosphotungstic acid-haematoxvlin x 150.)

FIG. 6. A large area of confluent perivascular demyelination in subcorticalwhite matter. (Phosphotungstic acid-haematoxvlin x 20.)



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FIG. 8. Medulla oblongata at middle level of motordecussation. (Weigert-Pal x 15.)

FIG. 9. Medulla at caudal level of motor decussation.(Loyez haematoxylin x 15.)

FIG. 10. Upper cervical cord showing symmetrical fociof demyelination in both posterior horns. (Weigert-Palx 15.)

caudal and middle levels of the medulla oblongatashowed large areas of demyelination extending dorso-laterally from both sides of the central canal. Thelesions followed a perivascular pattern and involvedthe griseum centrale, the lateral cortical andposterior spinocerebellar tracts, the trigeminalspinal tract and nucleus, the cuneate nucleus andfuniculus, and most of the gracilis.The upper cervical segment showed confluent

demyelination of crossed pyramidal tracts, with lessmarked degeneration in posterior white columns,and also a small demyelinated focus in the centralgrey matter. In the lower cervical region the greymatter of both posterior horns was affected.

FIG. 1 1. Lower cervical cord showing demyelination.(Weigrert-Pal xi )..

The lumbo-sacral regions contained wide con-fluent areas of perivascular demyelination in most ofthe white matter but with sparing of the rightposterior and lateral columns. Loss of myelin wasmost severe in both anterior columns: there weresmall foci in the spinothalamic tract region and in thecentral grey matter of the anterior and posteriorhorns.

In sum, there was perivascular demyelination,either focal or confluent, in the lower medullaoblongata and at all levels of the cord. WVhite matterwas mainly affected, and changes were most markedin the lower cervical, dorsal, and upper lumbarregions.Many anterior horn neurones, at all levels of the

cord showed varying degrees of chromatolysis; theremainder were well preserved.The demyelinated areas contained predominantly

mature and immrature histiocytes together with fatgranule cells. Distribution was mainly perivascularbut some cells were in tissue spaces. Plasma cellswere not seen. With silver carbonate stains, the

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FIG. 12

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FIG. 14

FIGS. 12, 13, and 14. The upper, mid, and lower dorsalcord segments showing general loosening, disintegration,and recent acute necrosis of grey and white matter: alsomyelin degeneration ofposterior nerve roots. (Weigert-Palx 15.)

FIG. 15

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FIG. 15. Another section of the dorsal cord showing lessmarked necrosis and demyelination. Posterior nerve rootsare affected. (Weigert-Pal x 15.)

FIG. 16. Mid-lumbar cord showing widespread demyelina-tion. Note the loss ofmyelin in anterior andposterior nerveroots. (Weigert-Pal x 15.)

FIG. 17. Lower sacral cord showing demyelination inanterior and posterior horns, central grey matter, anteriorwhite columns, anterior andposterior nerve roots. (Weigert-Pal x is.)



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FIG. 7 FIG. 18

FIG. 7. Blood vessel in caudal medulla surrounded by wide cellular zone. (Phosphotungstic acid-haematoxylin x 200.)FIG. 18. Recent demyelinated area in anterior white column of lumbar cord showing numerous perivascular and a fewinterstitially distributed histiocytes laden with lipid granules. (Sudan black B x 460.)

necrosed denuded areas of the white columns in thedorsal and lumbar regions showed scanty astro-cytes with swollen lobed nuclei and normal fibrils.Elsewhere in the white matter the astrocytes werebetter preserved.The products of myelin catabolism stained orange

red with sudan III and grey black with sudan blackB; the sudanophilic material had been taken up bylarge histiocytes (Figs. 7 and 18) which were oftenarranged around blood vessels but also lay free inthe necrotic tissues. Sudan black B showed marginalfat droplets in histiocytes and also demonstratedbroken fragments of myelin amongst the cellularinfiltration. Examination of sudan-stained sectionsby polarized light showed myelin balls, neutral fatdroplets, anisotropic lipid droplets, and crystalswhich were probably cholesterol. Protein drops anddecaying myelin sheaths were well shown by theperiodic acid-Schiff stain.

Considering that myelin disintegration and solu-tion is more rapid in allergic than Wallerian degen-

eration (Greenfield, 1930), the stage of myelinbreakdown seen in this case is compatible with thenine-day period between the onset of symptoms anddeath.

Silver impregnation techniques showed con-siderable fragmentation of some axis cylinders in thecord; elsewhere they were well preserved.

In the necrosed white matter of the dorsal andlumbar segments the perivascular demyelination andcellular infiltration was accompanied by fibrinoidnecrosis of the walls of small perforating bloodvessels with considerable extravasation of fibrin intosurrounding neural tissues (Figs. 19, 20, and 21).These changes were also seen in a posterior nerveroot. Blood vessels were intensely congested;petechial and perivascular haemorrhages werepresent. The leptomeninges showed little abnormalityapart from slight cellular infiltrations around bloodvessels in the cervical and dorsal regions.

Demyelination in the cranial nerves was markedin the third, moderately severe in the seventh and

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FIG. 19 FIG. 20

FIG. 19. Necrosed area in dorsal cord s!,owing perivascular haemorrhages and infiltrations: blood vessels show fibrinoilnecrosis and extravascular fibrin. (Phosphotungstic acid-haematoxylin x 220.)FIG. 20. A high-power view of one of the blood vessels in Fig. 19 demonstrating partial fibrinoid necrosis of the walland extravasation offibrin (stained black). (Phosphotungstic acid-haematoxylin x 660.)

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FIG. 21. Blood vessel in dorsal cord showing passage of fibrin through thenecrosed wall. (Phosphotungstic acid-haematoxylin x 520.)

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FIG. 22. Oculomotor nerve showing perivascular de-myelination: cellular infiltration is absent. (Loyez hae-matoxylin x 230.)

eighth, and less marked in the fifth and sixth. Lossof myelin was patchy and variable in the optictracts.The third cranial nerve showed focal and con-

fluent perivascular demyelination without cellularinfiltration (Fig. 22). There was considerable frag-mentation of myelin with swollen and nodularfibres, and fat droplets and fat granule cells werepresent. Silver impregnation showed considerablenecrosis of axis cylinders in some areas.

Posterior nerve roots at all cord levels showedpatchy demyelination: the changes were severe inthe dorsal and lumbo-sacral regions where myelinbreakdown extended almost to the dura. Loss ofmyelin sheaths with the presence of myelin break-down products was demonstrated, as was axonaldecomposition. Posterior root ganglia were notaffected.A few anterior nerve roots in the lumbo-sacral

region showed loss of myelin but elsewhere theyappeared normal. Peripheral nerves were notexamined.

PATHOLOGY OF OTHER ORGANS

The spleen was swollen and pulpy and on sectionshowed intense congestion with an increased numberof plasma cells, some of which were atypical,probably plasmablasts. The thyroid gland alsoshowed plasma cell infiltration. Plasma cells werenot found in sections of the lungs, heart, adrenalglands, and kidneys.

DISCUSSION

Hurst (1941) was the first to recognize acute hae-morrhagic leucoencephalitis as a distinct entity, butmost workers since that time have linked it withdisseminated demyelinating encephalomyelitis andregard the two conditions as being kindred statesdiffering mainly in the violence of the assault on thecentral nervous system. Russell (1955) presentedthree cases which support this view; all are essentiallysimilar to the case reported here but her third casecorresponds most closely in that there was severedamage to the brain-stem and spinal cord.The histological features of the present case bear

a resemblance to the disseminated encephalomyelitiswhich can follow acute virus diseases such as small-pox and measles, can result from vaccinationagainst smallpox and rabies, and has also been seenas a sequel to an 'influenza-like' illness (Greenfield,1930). In the post-vaccinal cases reported by Turnbulland McIntosh (1926) the characteristic zones ofdemyelination and cellular infiltration were accom-panied by petechial haemorrhages (Russell, 1943).One of the two 'post-influenza' cases reported byGreenfield (1930) showed petechial haemorrhage,but extravasation of fibrin, as seen in the casedescribed here, was not present in either.The confluent demyelination of the medulla

oblongata and the massive necrosis of the whitematter of the cord which are prominent features ofthis case were not found in any of the cases reportedby Russell (1955), nor in previous cases reviewed byher in the same paper: since that time there is norecord of a similar case.

In the numerous sections examined it wouldappear that the lesions throughout the brain,medulla, and spinal cord were about the same age.These findings make the diagnosis of multiple,diffuse, or disseminated sclerosis untenable, as doesthe presence of fibrinoid necrosis in blood vessels.Acute necrotic encephalopathy, as described by

Adams (1959), shows necrotizing lesions of varyingages and is thus dissimilar to the case reported here.The clinical and pathological features of acutenecrotic myelopathy (Hoffman, 1955) are essentiallydifferent from our findings. The vascular changes

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Acute disseminated encephalomyelitis, with massive necrosis of the spinal cord

present in this case also rule out neuromyelitis opticaalthough there is some similarity in the patchydemyelination of the optic tracts.The findings of haemorrhage, perivascular demye-

lination, and cellular infiltration, together withfibrinoid necrosis of blood vessel walls and extrava-sation of fibrin, adequately fit the diagnostic pictureof acute disseminated encephalomyelitis and hae-morrhagic leucoencephalitis. The features of thiscase appear to support the tenet that these twoconditions are facets of the same pathologicalentity.The many parallels between experimental en-

cephalomyelitis and some aspects of humandemyelinating diseases warrant the view that thelatter are essentially allergic disorders. Wolf (1952),Russell (1955), and Adams (1959), and many otherEuropean and American workers, are satisfied thatexperimental allergic encephalitis represents a satis-factory laboratory model for acute disseminatedencephalomyelitis and haemorrhagic leucoencepha-litis in man.The findings in this case suggest that the process

was a neuroallergic reaction of unusual severity.The acutely inflamed spleen which, together with thethyroid gland, contained an excess of plasma cells,support the allergic theory (Campbell and Good,1950).The only possible antigenic substance in this case

was a single subcutaneous injection of antitetanusserum given 15 days before the onset of symptoms.There is no evidence in the available literature thatpenicillin can produce such phenomena.The patient had never before received horse serum.

The only prophylactic injections given were ofpoliomyelitis vaccine: she had not been vaccinated.There are many reported cases of neurological

sequelae following injections of serum. Baker (1942)described 12 cases of tetanus, some treated withantitoxin, which showed perivascular demyelinationin the brain: Putman, McKenna, and Morrison(1931) produced similar results in dogs by repeatedinjections of tetanus antitoxin. Csermely (1950)described one case of haemorrhagic and non-

haemorrhagic lesions of acute disseminated demyeli-nating encephalomyelitis following the use of anti-tetanus serum: the reactions were less severe than in

this case but were essentially similar. Miller andStanton (1954), in a review of the literature onneurological sequelae of prophylactic innoculation,include three cases in which antitetanus serumwasused.A case of acute necrotizing haemorrhagic

encephalopathy following the administration oftetanus antitoxin is described by Toogood (1960)but histological findings are not given. Williamsand Chafee (1961) describe demyelinating encephalo-myelitis in a case of tetanus, treated with antitoxin,in a boy aged 13 who showed urticaria and angio-edema on the eighth and eleventh days after theinjections. He became comatose and died on thethirteenth day.The case reported here, along with the others

mentioned, appear to represent manifestations of thedelayed type of allergic response (Waksman, 1959).

Our thanks are due to H.M. Coroner for permission topublish this case. We are most indebted to Dr. L.Rubinstein for reviewing the histology, making thediagnosis, and referring us to the literature; to Dr. H.Urich for many helpful suggestions and for reading themanuscript; to Mr. R. A. Daws and Mr. R. S. Gardenfor access to clinical history; to Messrs. J. H. Wilkinsonand J. Urquhart for preparing the large amount of histo-logical material, and Mr. John King of the LondonHospital for photomicrographs.

REFERENCES

Adams, R. D. (1959). In "Allergic" Encephalomyelitis, ed. M. W.Kies and E. C. Alvord, pp. 187-207. Thomas, Springfield, Ill.

Baker, A. B. (1942). J. Neuropath. exp. Neurol., 1, 394.Campbell, B., and Good, R. A. (1950). Arch. Neurol. Psychiat.

(Chicago), 63, 298.Csermely, H. (1950). Ibid., 64, 676.Greenfield, J. G. (1930). J. Path. Bact., 33, 453.Hoffman, H. L. (1955). Brain, 78, 377.Hurst, E. W. (1941). Med. J. Aust., 2, 1.Miller, H. C., and Stanton, JL B. (1954). Quart. J. Med., 23, 1.Putman, T. J., McKenna, J. B., and Morrison, L. R. (1931). J. Amer.

med. Ass., 97, 1591.Russell, D. S. (1943). Proc. roy. Soc. Med., 36, 321.

(1955). Brain. 78, 369.Toogood, J. H. (1960). Canad. med. Ass. J., 82, 907.Turnbull, H. M., and McIntosh, J. (1926). Brit. J. exp. Path., 7,

181.Waksman, B. H. (1959). In "Allergic" Encephalomyelitis, ed. M. W.

Kies and E. C. Alvoid. Thomas, Springfield, Illinois.Williams, H. W., and Chafee, F. H. (1961). New Engl. J. Med., 264,

489.Wolf, A. (1952). Proa. First int. Congr. Neuropath., Rome, 1952, vol.

1, 121.

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Acute with massiveJ. clin. Path. (1962), 15, 314 Acutedisseminated encephalomyelitis, with massive necrosis ofthe spinal cord, probably due to antitetanus serum A. A. MILLERANDF. RAMSDEN