J. Neurol. Neurosurg. Psychiat., 1971, 34, 341-347

Fatal encephalopathy complicating lymphoidinterstitial pneumonia

MICHAEL JEFFERSON, D. RIDDOCH,' AND W. THOMAS SMITH

From the Departmenit of Neurology, United Birmingham Hospitals; Department of Pathology,University of Birmingham

SUMMARY The case is reported of a young woman who suffered from lymphoid interstitialpneumonia. Involvement of the brain by what appeared to be an identical pathological process ledto her death, and the orbital tissues were also involved at one stage. The cause of this condition isunknown, but the hypotheses are put forward that it may represent one facet of delayed hyper-sensitivity or that a slow virus is the responsible aetiological agent. Although lymphoid interstitialpneumonia has previously been reported as an isolated entity, the evidence from this case suggeststhat it might represent part of a pluri-systemic disease.

Lymphoid interstitial pneumonia (LIP) was describedby Liebow (1968) as a distinct variety of interstitialpneumonia. He noted that in LIP the histologicalappearances in the lung may resemble those ofHashimoto's thyroiditis and also that anti-lungantibodies may be elevated; he suggested, therefore,that the process might be an autoimmune pheno-menon. This report describes a patient sufferingfrom LIP who subsequently developed a relapsing-remitting and eventually fatal neurological illnessthat resulted from an encephalitic process charac-terized by a cellular infiltrate in the brain resemblingthat in the lung.

CASE REPORT

A 22 year old married woman was first admitted tohospital in February 1965. One week previously, for thefirst time in her life, she had had a major fit in which herhead and eyes turned to the left. This was followed inthe next few days by five brief attacks of focal left-sidedsensory epilepsy, each starting with tingling in the handspreading to involve the face, trunk and leg.As a child her tonsils, adenoids, and appendix had

been removed. At the age of 13, she was taken to achest clinic with a history of persistent cough for onemonth. Chest radiographs showed an opacity at theleft base and some pleural reaction; the Heaf test waspositive. Treatment with penicillin resulted in complete

Applications for reprints should be addressed to D.R.

clinical and radiological resolution in six weeks. Forsome years she had been subject to mild eczema.

Clinical examination on admission was normal.Investigations showed: Hb 12-7 g/100 ml.; WBC 4,200/c.mm, with a normal differential count; ESR 2 mm/hr(Westergren); blood Wassermann reaction negative.The CSF was clear and under normal pressure, with5 WBC /c.mm, protein. 40 mg/100 ml., Lange curvenormal, and WR negative; EEG, radiographs of thechest and skull, and a right carotid angiogram were allnormal.She was discharged from hospital on phenobarbitone

30 mg b.d. Over the following year she remained welland free of fits, until she developed uncomplicated herpeszoster of the right chest, which was followed by anisolated epileptic attack; the dose of phenobarbitonewas increased to thrice daily. She later became pregnant,and during labour deep transverse arrest of the foetusrequired forceps delivery. Afterward she began taking anoral contraceptive (Lyndiol).

In May 1967, over a period of a week, she developedswelling and closure of the right eyelids, with milderchanges on the left. When admitted to hospital, threeweeks later, her signs had partially resolved, but she stillshowed bilateral ptosis, more marked on the right,deficient elevation of the right eye, and a slightly dilatedright pupil. There was also oedema of both eyelids, of theconjunctivae, and of the forehead. There was post-herpetic scarring of the right chest wall, and a mildeczematous rash on the neck and elbows. The spleenwas palpable but there was no hepatomegaly or significantlymphadenopathy. The heart and lungs were normal andthe blood pressure 130/70 mm Hg.

Laboratory investigations now revealed the following:341

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Hb 14-0 g/100 ml.; WBC 5,600/c.mm with a normaldifferential count; platelets 145,000/c.mm; ESR 9 mm/hr.Serum urea, electrolytes, cholesterol, alkaline phos-phatase, glutamic-oxaloacetic transaminase, uric acid,and protein-bound-iodine were all normal; serumalbumin 4-2 g and globulin 2-2 g/100 ml. with a normalelectrophoretic pattern; LE cells were not seen in twospecimens of blood. The Paul-Bunnell, Rose-Waaler,and latex fixation tests were negative, as were tests forfluorescent anti-nuclear factor, and complement fixationsfor viruses and autoimmune tissue antibodies. The CSFpressure, chemistry, and cytology were normal. TheEEG and electrocardiogram were normal. Vertebralangiography was unremarkable. However, radiographsof the chest now revealed multiple soft opacities at bothlung bases, which persisted in serial films. Sputumexamination showed no evidence of tuberculosis or otherinfection. Lung function was normal, The Mantoux testwas negative at I in 1,000.The ocular symptoms and signs gradually subsided,

but in view of the persistently abnormal chest radio-graphs, lung biopsy was carried out. At thoracotomy,both upper and lower lobes were studded with smalldark nodules. Histologically the biopsy showed that thesenodular foci (Fig. 1) consisted of areas in which therewas alveolar collapse and extensive lymphocytic in-filtration, particularly around bronchioles and smallarteries (Fig. 2), and in the interlobular septa. Germinalcentres were present and variable numbers of plasmacells and foamy macrophages were admixed with thelymphocytic infiltrate. There was mild fibrosis withinthe nodules but the intervening lung looked normal. Noorganisms or birefringent particles were seen. It was

concluded that the process was probably inflammatoryand not a reticulosis.By the time the patient was discharged from hospital

her ptosis, ocular paralysis, and the local oedema had allvirtually gone, but the diagnosis was still obscure. Itseemed that she might have some unusual inflammatoryaffection, conceivably of the delayed hypersensitivityvariety (type IV, Gell and Coombs, 1968), involving theorbital tissues as well as the lungs. Treatment withprednisone 30 mg daily was initiated, the dose being soonreduced to 5 mg daily, which was continued for thenext 12 months. During this time she remained well(except for three brief attacks of left-sided paraesthesia)though serial radiographs of the chest showed littlechange.

In June 1968 she again had a major fit, preceded bythree attacks of focal twitching, this time right sided.After a few days she was noticed to be a little confusedand she complained of intense headaches. On admissionto hospital a fortnight later she looked unwell but wasafebrile. Neurological examination revealed dysphasia,right homonymous hemianopia, mild right hemiparesis,and early papilloedema on the right. The chest was clearclinically. There was moderate hepatosplenomegaly butno lymphadenopathy. Investigation showed: Hb 14-0g/100 ml.; normal WBC; ESR 7 mm/hr; no LE cells;urinalysis negative; normal serum urea, electrolytes,calcium, phosphorus, sugar, proteins, and liver functiontests. Serum protein immunophoresis revealed low levelsof IgG (340 mg/100 ml.) and IgA (18 mg/100 ml.), butnormal IgM (80 mg/100 ml.) and no detectable IgD.Bleeding, clotting, and prothrombin times were normal,Coombs's test was negative and there was a normal

FIG. 1. Lung biopsy showinglymphocytic infiltration.E andE, x 18.

'p.

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Fatal encephalopathy complicating lymphoid interstitial pneumonia

FIG. 2. Enlarged view ofFig. 1, showing peribronchiolarand perivascular lymphocyticinfiltration. H and E, x 120.

haptoglobin level; serum vitamin B,2 level was700 pg/ml.; serum iron 18 mglOO ml. Toxoplasma dyetest was negative; viral and tissue complement-fixationtests were negative. Chest radiographs showed essentiallythe same appearance as before.

Needle biopsy of the liver was taken which onlyshowed mild lymphocytic cuffing of the portal tracts;there was no evidence of reticulosis, sarcoidosis orother lesions.

EEG revealed a delta wave focus centred over the lefttemporal lobe, and carotid angiography confirmed anavascular space occupying lesion in this situation. Whenexploratory craniotomy was performed, the temporallobe was seen to be swollen and soft, the macroscopicappearance suggesting a malignant glioma. Biopsy wastaken and the skull closed. Histologically there was adiffuse encephalitic process (Fig. 3) with extensivedemyelination, and proliferation of large atypical

FIG. 3. Cerebral biopsy show-ing perivascular and morediffuse infiltration of the whitematter with chronic in-flammatory cells. There isdiffuse demyelination. Luxolfast blue-cresylfast violet

b ~~~~~x120.

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multinucleated and feebly fibre-forming gemistocyticastrocytes (Fig. 4). There was a pronounced infiltrationwith lymphocytes and plasma cells, forming broad cuffsaround small blood vessels and spreading out beyondthe Virchow-Robin spaces into the cerebral substance.There were many large binucleate intensely pyrinophilicplasma cells (? plasmablasts). The tissue disorganizationwas so severe that it was not possible to differentiatebetween grey and white matter. Organisms were notidentified. A few oligodendrocytes contained eosinophilicintranuclear inclusions and the question of progressivemultifocal leucoencephalopathy was raised. With this inmind the previous lung biopsy was re-assessed but itwas again concluded that the lesions present could notbe regarded as those of a reticulosis. An inflammatoryprocess (? allergic) affecting the brain was the finalconclusion.

After craniotomy her condition steadily improved.Three weeks later the only neurological signs were a mildexpressive dysphasia, and weakness of the left lateralrectus muscle which had appeared after admission andwas now subsiding. She was allowed home on prednisone2-5 mg daily along with phenobarbitone.A week later she had to be readmitted on account of

violent headache and vomiting which had developedthree days previously. At this time the only abnormalneurological sign was the residual weakness of the leftlateral rectus muscle, but two days later acute bilateralpapilloedema was seen and on the same day she collapsedwith cardiorespiratory arrest. Despite intubation andartificial pulmonary ventilation, she remained un-conscious and hypotensive with fixed dilated pupils. Anechoencephalogram showed no shift of midline structures,and attempts to needle the lateral ventricles were un-successful. Bilateral subtemporal decompression wasperformed, and the brain was found to be very swollen.

*9

Biopsy material was taken from both temporal regions.That from the left side showed microscopic featuresidentical with those previously seen; the cortex wasseverely affected but there were no intraneuronal in-clusions. Tissue from the right temporal biopsy was muchless affected. There was also evidence of mild meningealinfiltration. Terminal cardiac arrest occurred two daysafter the operation.

NECROPSY FINDINGS The body (173 cm) was thin(41 kg) and showed no relevant external abnormalities.The teeth, tongue, mouth cavity, cervical lymph nodes,

salivary glands, and thyroid were all unremarkable. Theinnominate, carotid, subclavian, and vertebral arteriesappeared to be free from disease.

Respiratory tract Pleural cavities were normal. Theperibronchial, subcarinal, and paratracheal lymph nodeswere all moderately enlarged, of soft fleshy consistencyand discrete. The trachea and proximal bronchi showedmucosal congestion and oedema and contained muco-purulent exudate. There were numerous nodules, varyingfrom a few mm to about 2 to 3 cm in diameter, scatteredthroughout both lungs, especially in the basal zones.The nodules were firm, bulged above the pleural and cutsurfaces, were paler than the surrounding lung, and didnot exude pus. The smaller nodules were mainly alongthe lung margins. There was no diffuse fibrosis, 'honey-comb', or cystic degeneration or emphysema.The heart (250 g) showed no right-sided hypertrophy

or other relevant changes.The thymus was replaced by enlarged lymph nodes.

Abdominal lymph nodes The mesenteric, para-aortic,and iliac groups, were enlarged but of normal con-sistency, resembling the thoracic nodes.fi§\ FIG. 4. Demyelinated white

matter showing nodular andt j diffuse infiltration with

A.........X Slymphocytes and plasma cells.Note large stellate astrocytes(arrows). Luxolfast blue-cresylfast violet x 300.

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Fatal encephalopathy complicating lymphoid interstitial pneumonia

The spleen (350 g) was enlarged (23 x 13 x 5 cm)showing a soft, mushy pulp but no other changes.The liver (2,100 g) was enlarged, pale yellow in colour,

and had a slightly greasy cut surface. There were nofocal lesions.The gall bladder was normal. The bile-ducts were

patent.The kidneys (280 g), ureters, stomach, intestines,

pancreas, adrenals, peritoneal cavity, bladder, uterus,Fallopian tubes, ovaries, abdominal aorta and inferiorvena cava, skeletal muscles, and peripheral nerves wereall unremarkable.

Brain The dura mater was extremely tense. The venoussinuses were patent. There was gross symmetricalswelling of both cerebral hemispheres with flattening ofthe convolutions and obliteration of sulci. Both temporallobes bulged for about 2 cm through bilateral temporal-craniotomy decompression sites. The cerebral hemi-spheres were extremely soft and friable and showedpink-blue ('bruised') discolouration due to 'respiratorautolysis'; as a result, the cerebrum was difficult toremove and tended to disintegrate on handling. Thecerebellum was similar but the brain-stem was firmer.The floor of the third ventricle was tense and bulged overa flattened pituitary gland.

HISTOLOGY Lungs These showed numerous, interstitialnodules similar to those seen in the biopsy material butless florid. Mild suppurative bronchopneumonia wassuperimposed.

Heart The myocardium showed intermuscular oedemaand mild to moderate diffuse infiltration with lympho-cytes and plasma cells (Fig. 5). The muscle fibres showed

fatty degeneration. The appearances indicated a non-specific myocarditis.

Liver The portal tracts showed mild infiltration withlymphocytes and plasma cells (Fig. 6), and the liver cellsshowed fatty vacuolation. There was fine portal fibrosisbut no necrosis of liver cells.

Adrenals These showed cortical atrophy (on steroids).

Spleen and lymph nodes They showed non-specificreactive hyperplasia with follicular enlargement and sinuscatarrh. The tissue architecture was retained and therewas no evidence of reticulosis.The uterus, pancreas, pituitary, tongue, skeletal

muscles, and peripheral nerves were all unremarkable.

Brain Widespread autolytic changes made interpretationdifficult. A diffuse encephalitis was nevertheless stillrecognizable and particularly prominent in the temporaland parietal areas. The subependymal regions andmeninges also showed heavy infiltration with inflam-matory cells. The character of the inflammation wasidentical with that seen in the biopsies. Both grey andwhite matter were involved.

DISCUSSION

Throughout three and a half years during whichthis young woman was under observation, the natureof her relapsing and remitting illness remained amystery. There was doubt, never finally resolved,about its exact duration, as it was not clear whetherthe pulmonary affection at the age of 13 might have

FIG. 5. Myocardium showingintermuscular oedema andinfiltration with lymphocytesandplasma cells. H and E,x 300.

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as

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FIG. 6. Liver showing focalinfiltration with chronicinflammatory cells. H and E,x 300.

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marked the opening phase of her illness, or whetherthis incident was aetiologically unrelated. It wasthought most likely that she was suffering from someform of allergic inflammatory disorder, possiblyWegener's granulomatosis or sarcoidosis, and onthis assumption she was given steroid therapy butwithout detectable benefit. Later the diagnosis ofreticulosis with predominantly cerebral mani-festations and superficial lymph node escape wasconsidered to be an alternative possibility. The finaldiagnosis of lymphoid interstitial pneumonia (LIP)with widespread dissemination of lesions outside thelung was only reached after post-mortem study.

Histologically, the lung lesions in this case areunequivocally those of LIP as described by Liebow(1968). The presence of lymphoid follicles andplasma cells, many of the latter being atypical,suggests a microscopical resemblance to autoimmunedisorders such as Hashimoto's thyroiditis andSj6gren's syndrome. There is also some histologicalaffinity to the pulmonary lesions of farmer's lung(Seal, Hapke, Thomas, Meek, and Hayes, 1968),though in the latter condition the pathologicalchanges are not usually focal, and are accompaniedby cystic and emphysematous areas as well as byvascular lesions from pulmonary hypertension andcor pulmonale. But there is no evidence that theyoung woman had been exposed to risk from inhaledantigenic material, to cause a hypersensitivityreaction as in farmer's lung.With regard to the histological picture found in

the brain at necropsy, although there were wide-spread autolytic changes due to 'respirator death',

this did not conceal a diffuse encephalitic processmost marked temporoparietally and identical withthat seen originally in the cerebral biopsy material;there was also meningeal and ependymal involve-ment.

There was some histological similarity to pro-gressive multifocal leucoencephalopathy, notably inthe presence of large bizarre astrocytes, oligo-dendrocytic inclusions, and demyelination. Theclinical evolution of the illness was atypical of thataffection, and there were no signs of reticulosis,blood dyscrasia, or the other disorders that havemost often been linked with it. Organisms suggestiveof an infective or parasitic process were not seen inthe cerebral tissue.A slow or latent virus infection merits con-

sideration. There are two points of special interestin this connexion, which might predicate a viralcause, arising against a background of diminishedhost resistance. Firstly, the A and G immuno-globulin factors of her serum were both distinctlylow, a feature that may reflect an underlying weak-ness of bodily defence mechanisms. Secondly, duringher illness she had an attack of herpes zoster, andit is recognized that herpetic infections occur withgreater frequency than normal in people sufferingfrom illness in which there is depression or in-competence of immunological reactions.The myocardial and hepatic lymphocytic cellular

infiltrates suggest involvement of the heart and liverin the same way as the lungs and brain, thoughmore mildly. Further, it is possible that the orbitaland periorbital tissue swelling which was present at

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one stage had a similar pathological basis, and it isinteresting that clinical and histological features ofa hypersensitivity reaction have previously beennoted in orbital pseudotumours (Easton and Smith,1961).Both the clinical and the pathological aspects of

this case of LIP are unusual. Histologically thepulmonary lesions were unequivocally those oflymphoid interstitial pneumonia. The affectionof the brain by similar lesions, which was the im-mediate cause of death, and the milder simultaneousinvolvement of the heart and liver have notpreviously been described, and suggest that LIPmay be a part of a more widely dispersed process.Our case offers clues suggesting that the diseaseprocess most likely resulted either from allergichypersensitivity of cell-mediated type (type IV), or

from invasion by a slow or latent virus.

REFERENCES

Easton, J. A., and Smith, W. T. (1961). Non-specific granu-

loma of orbit (Orbital Pseudotumour). J. Path. Bact.,82, 345-354.

Gell, P. G. H., and Coombs, R. R. A. (1968). Classificationof allergic reactions responsible for clinical hypersensitivityand disease. In Clinical Aspects of Immunology, pp.

575-596. 2nd edn. Edited by P. G. H. Gell and R. R. A.Coombs. Blackwell: Oxford.

Liebow, A. A. (1968). New concepts and entities in pul-monary disease: lymphoid interstitial pneumonia (LIP).In The Lung, pp. 349-351. Edited by A. A. Liebow andD. E. Smith. Williams and Wilkins: Baltimore.

Seal, R. M. E., Hapke, E. J., Thomas, G. O., Meek, J. C.,and Hayes, M. (1968). The pathology of the acute andchronic stages of farmer's lung. Thorax, 23, 469-489.

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