Acute encephalitis in infectious mononucleosis

SHORT ARTICLES

ACUTE ENCEPHALITIS I N INFECTIOUS MONONUCLEOSIS

M. J. SWORN AND H. URICH The London Hospital

PLATES LXXVI-LXXIX

INVOLVEMENT of the nervous system in glandular fever is rare and probably occurs in about 1 per cent. of cases, although some series suggest a higher incidence (Gautier-Smith, 1965). Complete recovery is the rule, but occasional fatalities have been reported, neurological complications ranking second as a cause of death after splenic rupture (Custer and Smith, 1948; Werner, 1954). Post-mortem studies of the central nervous system have yielded conflicting results, only minimal or non-specific changes being found in most cases. This has led to the conclusion that encephalopathy and not encephalitis is the cause of the cerebral manifestations (Bergin, 1960). In presenting a case in which florid inflammatory changes were found in the cerebral cortex both on biopsy and at necropsy, we wish to adduce evidence for the occurrence of a true encephalitis in infectious mononucleosis.

W. H., male, L.H. record no. 1

The Datient. an 8-vr-old bov.

CASE REPORT 7804.

Clinical history presented with generalised convulsions, a pyrexia of

101"F, a id a week's history of-tender lumps in his neck. On examination, generalised lymphadenopathy, injected fauces, injected red right ear-drum and palpable liver and spleen were noted. There was a slight increase in tone in the right arm, but no meningism.

Haematological examination showed WBC 15,500 per PI, with 36 per cent. leucocytes and 10 per cent. monocytes. The presence of atypical lymphocytes suggested glandular fever, and a screening test for glandular fever was positive. By the day after admission, he was alert and orientated. Five days later he became sleepy with nausea, vomiting and headache. Lumbar puncture yielded cerebrospinal fluid (CSF) at normal pressure with WBC 3 per pl and a protein concentration of 30 mg per 100 ml.

A few hours later he suffered a generalised convulsion, after which he remained unconscious. The pupils did not react to light. There was a generalised hypertonia associated with opisthotonos and increase of all reflexes. Both plantar responses were extensor. Ten minutes later there was a sudden change to a hypotonic state associated with a sudden increase in pulse rate to 180 per min. and increase in systolic blood pressure to 240 mm Hg. Both optic discs were noted to be swollen and the retinae oedematous. Spontaneous breathing soon ceased, and respiration had to be maintained artificially. Bilateral frontal burr-holes revealed a tight, soft, oedematous brain. The CSF pressure was over 600 mm H20. Both lateral ventricles were tapped, and appeared small, but symmetrical. A cortical biopsy was taken (S.D. 2272168). This showed patchy infiltration of the cerebral cortex with mononuclear inflammatory cells that formed cuffs around small blood vessels and were also scattered diffusely through the parenchyma. Many of these cells were atypical, with fairly large, round, oval or slightly indented vesicular nuclei. There was also some microglial activation with formation of rod-cells. The appearances were those of an encephalitis.

Received 27 Aug. 1969; accepted 25 Sept. 1969. J. PATH.-VOL. 100 (1970) 201

202 M. J. SWORN AND H. URICH

After the operation the patient remained deeply unconscious. His body temperature fell to 91WF, his pulse rate was 84 per min. and his systolic blood pressure 80 mm Hg. An electro-encephalograph recording showed no evidence of cerebral activity apart from a transient ripple of theta waves from the right side. The examination was repeated on the following day when a completely flat record was obtained. The patient died soon afterwards.

Necropsy (P.M. no. 126/68) There were surgical incisions on the scalp, with sutures in situ, overlying burr-holes.

The tonsils were moderately enlarged. The liver (1120 g) was enlarged and its architecture was normal. The spleen (215 g) was firm and showed prominent Malpighian bodies on a red background. All lymph-nodes were discrete, enlarged, with pale-brown cut surfaces. The thymus (11 g) was normal. Serial slices of both lungs after formalin fixation failed to show any abnormality. The middle ears contained a little glairy fluid.

Brain and cord (after fixation). The brain, which weighed 1420 g, was swollen and showed deep symmetrical uncal grooving with mild bilateral hippocampal herniation. The cerebellar tonsils showed prominent symmetrical herniation. The leptomeninges appeared normal. Coronal sections confirmed the diffuse swelling. The brain had a soft consistency and the white matter was faintly mottled. The pattern and demarcation of grey and white matter were preserved. The spinal cord appeared normal. A P a d Bunnell test performed on blood obtained at necropsy gave an unabsorbed titre of 1 in 320, unaffected by absorption with guinea-pig kidney. After absorption with ox red cells the serum gave a negative test at 1 in 10. Material from brain, spleen and faeces inoculated on monkey kidney and HeLa cells produced no changes in the culture.

Histology The lymph-nodes showed marked lymphocytic and reticulo-endothelial hyperplasia with

lymphocytic infiltration of sinuses and lymph-node capsules. The peripheral sinuses were distended with closely packed mononuclear cells (fig. 1). Demarcation between medullary cords and sinuses was blurred. The mononuclear infiltrate was composed predominantly of normal lymphocytes in association with larger cells, some with vesicular nuclei, others with coarse nuclear chromatin. Those with vesicular nuclei were approximately three times the size of normal lymphocytes. The nuclei, which occupied about one-third of each cell area, had prominent nucleoli and well-demarcated nuclear membranes surrounded by abundant pale eosinophilic cytoplasm which was sometimes vacuolated. Hence these cells had the appearance of rather rounded reticulum cells. In those cells with coarse nuclear chromatin the nucleus occupied about three-quarters of the cell and the chromatin was irregularly distributed, giving a mottled appearance with occasional bars. The nuclear membrane, which in some cases was infolded or crenated, was well demarcated and blended with the peripheral chromatin particles. A thin rim of homogeneous basophilic or faintly eosinophilic cytoplasm surrounded the nucleus.

In the spfeen lymphocytic infiltration of the capsule, subendothelial infiltration of trabecular veins and adventitial infiltration of trabecular arteries were present. Malpighian bodies were on the whole devoid of Flemming centres. Atypical lymphocytes could be identified in sinusoids, and in red and white pulp.

The medulla of the thymus showed a diffuse infiltration of degenerating polymorphs in association with cystic change of Hassall's corpuscles, which contained polymorphs and debris. There was no evidence of acute involution and no convincing atypical lymphocytes were identified.

The tonsils showed an admixture of normal and atypical lymphocytes, plasma cells and polymorphs. Necrosis was present in the centre of the lymphoid follicles. Lymphocytic infiltration of peritonsillar tissues and into adjacent glands was present.

The submandibular salivary glands contained prominent, mainly periductal foci of mononucleosis (fig. 2).

The liver architecture was well preserved. The parenchymal cells had pale granular

SWORN AND U R l C H

ACUTE ENCEPHALITIS IN INFECTIOUS MONONUCLEOSIS

PLATE Lxxvr

FIG. 1 .-Lymph-node. Infiltration of peripheral sinus by mixed mononuclear cells. Haematoxylin and eosin (HE). x 200.

FIG. 2.-Submandibular gland. Periductal lymphocytic infiltration. HE. x 200.

SWORN AND URICH


PLATE LXXVII

FIG. 3.-Liver. Infiltration of portal tracts by inflammatory cells. HE. x 200.

FIG. 4.-Brain. Sparse lymphocytic infiltration of leptomeninges in a sulcus. Lux01 fast blue and cresyl violet (LFB, CV). x 200.

SWORN AND URICH


PLATE LXXVIII

FIG 5.--Brain. Low-power view of cortex of cingulate gyrus: patchy inflammatory infiltration. LFB, CV. x9.

FIG. &-Brain. Higher-power view of cortical lesion : perivascular cuffing and infiltration of parenchyma. LFB, CV. x 200.

SWORN A N D URICH


PLATE LXXIX

FIG. 7.-Brain. Cuffing of blood vessel by typical small lymphocytes. HE. x 375.

FIG. %--Brain. Blood vessel cuffed by atypical mononuclear cells. HE. x 375.

FIG. 9.-Brain. Proliferation of microglial rod-cells. HE. )c 420.

ACUTE ENCEPHALITIS IN INFECTIOUS MONONUCLEOSIS 203

and clear cytoplasm with intact liver cell plates and only occasional cells were necrotic. Kupffer cells were prominent, and the sinuses were congested and dilated and contained many mononuclear cells including some atypical forms. The portal tracts were expanded by a dense accumulation of mononuclears including atypical forms and degenerating polymorphs (fig. 3). Blood vessels showed prominent endothelial cells.

Heart. The myocardium contained scattered groups of mononuclear cells with a few minute foci of necrosis. Both the lungs were normal.

Genito-urinary system. The kidneys showed congested capillaries, which contained clumps of mononuclear cells. Scattered mononuclear-cell foci were present in the medulla and at the corticomedullary junction. In the bladder a subepithelial collection of lymphocytes, including atypical forms, was present.

Endocrine glands. The anterior lobe of the pituitary showed extensive necrosis. There was a minute mononuclear-cell focus containing atypical forms in the medulla of one adrenal.

Central nervous system. The leptomeninges showed sparse inflammatory infiltration, mainly perivascular in distribution and largely confined to the sulci (fig. 4).

Representative sections of the cerebral cortex showed patchy inflammatory lesions with dense perivascular cuffing and diffuse infiltration of the parenchyma (figs. 5 and 6) . The appearance of the mononuclear cells varied: in some areas typical small lymphocytes predominated (fig. 71, in others larger cells abounded. These had oval or slightly irregular nuclei with a sparse, mainly peripheral chromatin network, and pale, faintly granular or vacuolated cytoplasm (fig. 8). The fine cytoplasmic granules in some cells were PAS- positive. The infiltration of the parenchyma consisted partly of similar mononuclear cells and partly of microglial cells, mainly in rod-cell form, most abundant in the periphery of the areas of lymphocytic infiltration (fig. 9). The neurones were generally well preserved, though there was some disorganisation of cortical architecture in areas of heavy infiltration suggesting patchy loss of nerve cells. No evidence of acute necrosis was seen. There was no astrocytic proliferation or fibrillary gliosis. Topographically the lesions were predominantly cortical in distribution and most abundant in the frontal and motor cortex and in the cingulate gyrus. The temporal cortex and the island of Reil were affected in a patchy fashion; no lesions were seen in the occipital cortex. The hippocampal formation was normal. In the deeper structures of the grey matter small foci of inflammatory infiltration were seen in the claustrum and the body of the caudate nucleus. Otherwise the basal ganglia, brain-stem and cerebellum were unaffected.

The white matter was generally free of inflammatory infiltration except for a few areas where the cortical lesion encroached upon the superficial subcortical fibres. There was severe oedema of the white matter of the cerebral hemispheres with separation of fibres and pallor of myelin staining.

The spinal cord was normal at all levels examined.

DISCUSSXON With the exception of the unusual cerebral lesions the pathological findings in our

case corresponded accurately to those previously described in fatal cases of infectious mononucleosis (Custer and Smith, 1948). The appearances of the lymph-nodes were those usually seen at the height of the disease when the germinal centres in the lymphoid follicles are still prominent and show incipient necrosis, but the invasion by mononuclear cells has begun to obliterate the hyperplastic and dilated sinuses (Reinauer, 1959). The appearances of the liver were those most commonly seen in biopsies taken between the tenth and thirtieth days of the disease (Wadsworth and Keil, 1952).

The lesions in the central nervous system were those of an acute, predominantly cortical, polio-encephalitis, as seen in a variety of virus infections. One striking feature was the presence of a large number of atypical cells in the inflammatory exudate, both in the perivascular spaces and in the cerebral parenchyma. Though it was impossible to identify these cells in histological sections with any degree of certainty, it is probable that most of them were atypical lymphocytes and were distinct from the equally abundant microglia.

204 M. J. SWORN AND H. URICH

This picture of a florid encephalitis differs considerably from findings hitherto reported. Although the clinical diagnosis of encephalitis is frequently made (Epstein and Dameshek, 1931; Johansen, 1931; and many others, reviewed by Gautier-Smith, 1965) most of the post-mortem lindings suggested a non-inflammatory nature of the process (Thomsen and Vimtrup, 1939; Peters et al., 1947; Dolgopol and Husson, 1949; Bergin, 1960). Some of the abnormalities described are indistinguishable from post-mortem artefacts, others represent terminal phenomena, others still may be ascribed to encephalopathies, anoxic, post-convulsive, hyperpyrexial or unexplained, sometimes loosely termed " allergic ". On the other hand, minimal inflammatory changes, mostly confined to perivascular cuffing, were found in some cases in which there was no clinical evidence of involvement of the nervous system (Allen and Kellner, 1947; Custer and Smith). The case of Gastaut et a!. (1956) stands apart, in that it showed a florid meningitis and a limited encephalitis. This case was rejected by Bergin on the grounds of unsatisfactory diagnostic criteria. Indeed the diagnosis of glandular fever had not been made during life, and the post-mortem examination was limited to the brain. It was based on the presence of numerous atypical lymphocytes in the inflammatory exudate. Similar findings in our case suggest that the diagnosis may well have been correct.

Our findings support the view that true encephalitis may occur in glandular fever. This, however, does not invalidate the observation that death in cases with cerebral involvement is usually due to encephalopathies. Even in our case the fatal outcome was probabfy precipitated by anoxic encephalopathy with total loss of cortical function rather than due directly to the inflammatory process.

SUMMARY

During the 2nd wk of an attack of glandular fever an 8-yr-old boy developed a syndrome suggesting cerebral changes. This was ushered in by convulsions, followed by gradual decline in the level of consciousness leading to coma and death from respiratory failure. A cortical biopsy revealed an acute encephalitis, which was subsequently confirmed at necropsy. The florid inflammatory lesions differed from the changes found in previously reported cases, in which evidence of acute inflammation was absent or minimal.

We are indebted to Dr A. D. M. Jackson for permission to publish the case and to use his clinical records, to Professor I. Doniach for his interest and encouragement and to Dr A. H. E. Marshall for his helpful advice and criticism.

REFERENCES ALLEN, F. H., JR, AND KELLNER, A. 1947. Infectious mononucleosis; an autopsy report.

Amer. J. Path., 23, 463. BERGIN, J. D. 1960. Fatal encephalopathy in glandular fever. J . Neurol. Neurosurg.

Psychiat., 23, 69. CUTER, R. P., AND S ~ H , E. B. 1948. The pathology of infectious mononucleosis. Blood,

3, 830. DOLGOPOL, VERA B., AND HUSSON, G . S. 1949. Infectious mononucleosis with neurologic

complications; report of fatal case. Archs intern. Med., 83, 179. EPSTEIN, S. H., AND DAMESHEK, W. 1931. Involvement of the central nervous system in

a case of glandular fever. New Engl. 3. Med., 205, 1238. GASTAUT, H., RADERMECKER, J., VIGOUROUX, R., AND VAN BOGAERT, L. 1956. une

meningoenckphalite suraigue dans la mononuclkose; ktude anatomoclinique et klectro- enckphalographique. Revue neurol., 94, 23.

GAUTIER-SMITH, P. C. 1965. Neurological complications of glandular fever (infectious mononucleosis). Brain, 88, 323.

JOHANSEN, A. H. 1931. Serous meningitis and infectious mononucleosis. Acta med. scand., 76, 269.

ANAPLASTIC CARCINOMA IN XENOPUS 205

PETERS, C. H., WIDERMAN, A., BLUMBERG, A., AND RICKER, W. A. 1947. Neurologic manifestations of infectious mononucleosis, with special reference to Guillain-Barre syndrome. Archs Intern. Med., 80, 366.

REINAUER, H. 1959. Morphologische Befunde an Lymphknoten bei infektioser Mono- nukleose. Virchows Arch. path. Anat. Physiol., 332, 56.

THOMSEN, S., AND VIMTRUP, B. 1939. Six fatal cases of infectious mononucleosis com- plicated by central respiratory paralysis. Nord. Med., 4, 3295.

WADSWORTH, R. C., AND KEIL, P. G. 1952. Biopsy of the liver in infectious mononucleosis. Amer. J . Path., 28, 1003.

WERNER, W. 1954. Zur Pathologie der Mononucleosis infectiosa. Virchows Arch. path. Anat. Physiol., 326, 155.

A S P O N T A N E O U S ANAPLASTIC INTESTINAL METASTASISING C A R C I N O M A I N A S O U T H A F R I C A N CLAWED T O A D ( X E N O P U S LAEVIS D A U D I N )

E. ELKAN Shrodells Hospital, Watford, Herts.

PLATE LXXX

SINCE Hogben (1930) established its usefulness for the purpose of pregnancy tests, the South African Toad (Xenopus laevis Daudin) has, year by year, increased its reputation as a most useful laboratory animal, easy to keep, easy to feed and even easy to breed. Exigencies of husbandry have produced many studies on the biology of this toad, but the papers on its physiology far outnumber those on its pathology. This is explained by the astonishing resistance of the species to diseases of all kinds even if, as frequently happens in laboratories with limited space, the toads are kept in unnaturally crowded or otherwise unsuitable conditions.

Malignant tumours are rare in lower vertebrates and even in collections where necropsy is carried out on every specimen that dies are extremely rarely seen in Xenopus. The scanty literature on the subject has been reviewed by Reichenbach-Klinke and Elkan up to 1965. The lymphoid tumours occurring in the Amphibia have been reviewed by Balls and Ruben in 1968 and Elkan reported one further case, an ophthalmic adenocarcinoma, in the same year.

In view therefore of the great paucity of oncological material on Xenopus, a record of the necropsy findings in a recent case may be of interest.

Pathology The specimen, a fully adult female, had for at least 5 yr lived in a 2 x 2 ft (60 x 60 cm)

tank, at a controlled temperature of 24"C, together with 24 other toads of the same species. It died without having shown any preliminary symptoms of distress and has remained the only casualty from this tank so far. On dissection the stomach as well as the pancreas were found abnormally bulky, but there were no signs of inflammation, no adhesions and no peritoneal effusion. The fat body was vestigial, a sign that the toad had been starving for some time. The ovaries too were abnormally small; the liver, spleen and lungs looked normal. The substance of both kidneys was partly replaced by round, white

Received 19 Aug. 1969; revised version accepted 31 Oct. 1969.

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Acute encephalitis in infectious mononucleosis