J. clin. Path. (1968), 21, 422-431

Proteus and coliform meningoencephalitis inneonates

W. R. SHORTLAND-WEBB

From the Children's Hospital, Birmingham

SYNOPSIS The characteristic necropsy and histological appearances are described of nine cases ofProteus meningoencephalitis in neonates. One case which was not due to Proteus has been includedbecause of the close similarity of the gross appearances of the brain. Umbilical sepsis in half thecases indicated that this is a common portal of entry of these organisms. That epidemiologicalfactors may be of importance in the aetiology was suggested by the distribution of cases.

Proteus organisms are widely distributed in nature.They play an important role in the decay of organicmatter of animal origin, including sewage, andexist as saprophytes in the alimentary tract of man.Under certain circumstances they may becomepathogenic and in particular they may infect theurinary tract, the ear, and burns and scalds. Menin-gitis due to Proteus is extremely uncommon, andin adults and older children it appears to be limitedto a few cases following otitis media and sinusthrombosis (Kaplan and Poweleit, 1949); otherwiseit occurs almost exclusively in neonates though itis still a rarity even at this relatively susceptibleage. The few reported cases indicate that neonatalmeningitis due to Proteus is an extremely lethalcondition and this is also the experience in Birming-ham. The purpose of this paper is to describe thecharacteristic findings at necropsy and on histolo-gical examination and to comment on the aetiology.

CASE REPORTS

CASE 1 A male infant was born at 33 weeks to a para2 mother aged 23 years. There was hyperemesis butpregnancy was otherwise unremarkable. Spontaneousvertex delivery followed an uncomplicated labourlasting 12 hours. At birth the infant weighed 1,814 gand was in fair general condition. The onset of respira-tory distress a few hours later necessitated transfer to apremature baby unit where the infant was noticed tohave a feeble cry and a rash on his chest. Gradualimprovement followed treatment in humidified oxygen,the removal of 12 ml of blood by umbilical catheter,digitalization, achromycin, and chloramphenicol. Onthe second day the blood sugar level was 70 mg% andthe serum bilirubin 8-6 mg%; blood culture grew Proteus

Received for publication 25 October 1967.

mirabilis which were sensitive to streptomycin, chloro-mycetin, neomycin, albamycin, and partially sensitiveto novobiocin. On the third day he became pale, cyanosed,jaundiced, tense and rigid, and had a squeaky cry; hedied a few hours later aged 65 hours.Necropsy was performed 91 hours after death. The

body measurements corresponded to 33 to 34 weeks'gestation; weight 1,590 g, length 43 cm, head circum-ference 29 cm.The cranial cavity had a foul smell and both cerebral

hemispheres were greyish in colour and grossly softened,much of the cerebral substance having the consistencyof thick sauce. There was extensive, bilateral, subduralhaemorrhage with no tentorial tears, and both occipitalpoles showed localized subarachnoid haemorrhages.The hindbrain appeared normal.

There was widespread congestion and collapse of bothlungs with subpleural haemorrhages and bloodstainedfroth in the bronchi.

Bacteriology Swabs taken from the left and rightcerebral hemispheres grew Proteus mirabilis. Proteuswas present in small numbers in a portion of the rightlower lobe of lung; cultures on solid media failed togrow this organism but subcultures of a glucose brothculture gave a growth of Proteus mirabilis.

Histology The periventricular cerebral tissue showedextensive necrosis with haemorrhage and intravascularhaemolysis but no inflammatory reaction. The lungsshowed a little granular eosinophilic debris and mono-nuclear cells within the alveolar ducts.

CASE 2 A female infant was born at home to a para 3mother. Pregnancy was uneventful but delivery wasprecipitate. The birth weight was 2,722 g. Towards theend of the first month of life the infant began to refuseher feeds. On admission to the Birmingham Children'sHospital she was an ill, wasted, cold infant with a rectaltemperature of 25°C (77-0°F). She showed peripheralcyanosis, had a feeble cry, swollen eyelids, candidalinfection of the mouth, and a napkin rash. The pulse

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rate was 40/minute and the heart rate was 88/minuteand irregular. Respirations were shallow, the respiratoryrate was 32/minute, and there was dullness and dimin-ished air entry at the right base. Treatment includedpenicillin, streptomycin, nystatin, and hydrocortisone.After eight hours' slow warming the rectal temperaturewas 31 7°C (89-0°F). Attacks of apnoea and cyanosisoccurred approximately every three hours and she died13 hours following admission.Necropsy was performed 11i hours after death. The

body weighed 2,394 g, measured 47-5 cm in length, andhad a head circumference of 33 cm. There was moderatewasting, superficial ulceration of the lower lip, and aslight napkin rash. On opening the cranial cavity therewas a foul smell but there was no gross evidence ofmeningitis or haemorrhage. The brain was soft andswollen with a dull, purple-black discoloration over theleft temporo-parietal region, and the cerebral whitematter was greyish-pink in appearance. The lungsshowed generalized collapse and congestion. There wasthoracic scoliosis due to hemivertebrae.

Bacteriology A swab of the left cerebral hemisphereshowed a heavy growth of proteus and a few Klebsiella;the lung showed a heavy growth of Klebsiella togetherwith a few Proteus and viridans streptococci; the surfaceof the pour plate of heart blood was covered withProteus; subculture of the liquid glucose broth fluidculture grew Klebsiella with a few Proteus vulgaris andviridans streptococci. Isolation of these organismssuggested that this postmortem blood culture mighthave been contaminated.

Histology The brain and spinal cord showed almostgeneralized infiltration with filamentous, Gram-negativebacilli (proteus); this was most marked in the areas notedto be softened at necropsy and was least in the lowerspinal cord. There was no accompanying inflammatorycell reaction even in the meninges, nor was there anyvascular lesion in spite of the fact that the bacteria wereoften seen to colonize the small blood vessels. Therewere, however, many swollen microglia which on frozensections were shown to contain sudanophilic material.Neurones in the cortex of the softened areas showedshrinkage of cytoplasm and homogeneous, deeplybasophilic nuclei. The lungs showed acute broncho-pneumonia in two lobes.

CASE 3 A male infant was born at 38 weeks to a para 3,Rhesus-negative mother. Delivery was complicated byplacenta praevia and antepartum haemorrhage. Birthweight was 2,381 g. The cord blood was group A,Rhesus-positive, Coombs test positive. Haemoglobinwas 98% and the bilirubin 3-1 mg%. The general con-dition of the infant was poor and he developed jaundicewith a maximum bilirubin level of 20-0 mg% on thefifth day. During the 24 hours preceding death he refusedfeeds and developed pyrexia, restlessness, grunting, andneck stiffness. He died on the seventh day. Lumbarpuncture several hours before he died produced turbidyellow fluid which had a protein content of 325 mg% andcontained 2,920 polymorphs, 500 lymphocytes, and 2,620erythrocytes per cmm. No organisms were seen in aGrar-i-stained film of the centrifuged cerebrospinal fluid

* -0ik-. ..*

FIG. 1. Case 2. Cerebral white matter showing masses ofbacilli. Giemsa x 1,930.

but cultures grew Proteus sensitive to penicillin, strepto-mycin, chloramphenicol, novobiocin, and ampicillin,and also coagulase-negative staphylococci. It wassuggested that these latter organisms might have beencontaminants.

Necropsy was performed four days after death. Thebody was moderately jaundiced, weighed 2,040 g,measured 47 cm, and had a head circumference of 30 5cm. The umbilicus was clean but there was an erythe-matous, slightly haemorrhagic rash on the trunk. Thecerebral hemispheres were brownish, soft, swollen, andfoul smelling. A thick layer of exudate covered the pos-terior aspect of the cerebellum but there was none sur-rounding the spinal cord. The brain showed extensivesoftening and reddening on slicing; there was no kernic-terus of the brain stem or cerebellar nuclei but therewas slight yellow staining of the basal nuclei. The lungsshowed collapse at the bases. The liver was slightlyenlarged and congested. The spleen was congested but notenlarged and gave a positive Prussian Blue reaction.

Bacteriology Swabs from the brain showed a moderategrowth of Proteus. Cultures of the lung were sterile.

Histology There was marked acute inflammation ofthe meninges and many vessels within the brain showedperivascular cellular exudate and haemorrhage or werenecrotic and filled with fibrin thrombus. Inflammatorycells, mainly mononuclear, extended into surroundingbrain tissue in which much of the cerebral white matterwas necrotic. There was much proliferation and swellingof glial cells. There were abundant Gram-negative rods,especially in the perivascular infiltrates. The lungsshowed alveolar oedema but no pneumonia. There washaemosiderosis of the liver and spleen with only asmall amount of erythropoiesis.

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CASE 4 A male infant was born at 30 weeks to a primi-parous mother aged 26 years. Pregnancy and labourwere normal. He weighed 1,134 g at birth, and becauseof grunting respirations was admitted to a prematurebaby unit. He was nursed in an incubator and fed onexpressed mother's milk. On the third day he becamejaundiced and on the following day there was an offen-sive umbilical discharge. He died at 92 hours followingfrequent apnoeic attacks. Blood culture showed amixture of E. coli and Proteus; both organisms wereinsensitive to penicillin and tetracyclines but sensitive tostreptomycin and chloramphenicol.Necropsy was performed six and a half hours after

death. The body was that of a moderately jaundiced,premature infant of estimated maturity of 29 weeks.Weight was 975 g, length 37cm, head circumference 27cm.Both cerebral hemispheres were represented by extremelysoft, chocolate-coloured tissue with a foul smell butmeningeal exudate was not seen. The lungs showeddiffuse congestion and collapse. The umbilical veinappeared normal but both umbilical arteries werefilled with pus.

Bacteriology Proteus of the same serological typeisolated during life was found on culture of brain,lung, and umbilical arteries.

Histology There was extensive necrosis of the brainwith intravascular haemolysis but no inflammatoryreaction. All areas, including apparently normal brainand meninges, showed abundant Gram-negative rods.The lungs showed congestion and intraalveolar haemor-rhage with no inflammatory change.JThe intraabdominalsegments of the umbilical arteries contained septicthrombus; one showed necrosis of the intima withmany Gram-negative rods but no cellular reaction.

CASE 5 A female infant was delivered spontaneouslyby the vertex at 32 weeks' gestation to a 32-year-oldpara 2 mother. There was antepartum haemorrhage. Theinfant weighed 1,474 g and required oxygen by mask.On transfer to a premature baby unit when 3j hoursold she had grunting respirations and cyanosis. Jaundicewas noticed on the third day when the plasma bilirubinlevel was 10-3 mg%. On the fifth day she developedpallor and apnoeic attacks and she died the following day.Treatment included humidified oxygen by mask duringcyanotic episodes, terramycin, kanamycin, and caffeinesodium benzoate.Necropsy was performed five days after death. The

body was that of a premature infant with an estimatedmaturity of 31 weeks. Weight was 1,237 g, length 39 5cm, head circumference 28 cm. On opening the cranialcavity there was a foul smell. The brain was purple-black, discoloured, and extensively softened but therewas no gross meningeal exudate. Both umbilical arteriescontained pus, the right more than the left.

Bacteriology Proteus vulgaris was cultured from brain,umbilicus, lung, and heart blood.

Histology The cerebral white matter particularlyshowed gross haemorrhagic disorganization with haemo-lysis of red cells. The architecture of the hindbrain andcerebral cortex was fairly well preserved but the nervecells generally were shrunken with intensely basophilic

FIG. 2. Case 5. Coronal slice of left cerebral hemisphereshowing complete blackening and necrosis.

nuclei. The meninges, particularly over the ventralsurface of the hindbrain, showed an exudate of fibrin,polymorphs, and mononuclear cells. All sections showedabundant Gram-negative bacilli; in the brain stem thesewere particularly numerous in the descending cortico-spinal tracts and intra-vascular haemolysis was alsoparticularly marked in these areas, suggesting that theinfection had tracked down from the cerebral hemi-spheres along this route. Lung sections showed haemo-lysis of red cells with Gram-negative rods in the walls ofmany blood vessels. There were focal haemorrhages butno evidence of pneumonia. Both intraabdominal umbi-lical arteries were filled with acute inflammatory debrisand there was much oedema and infiltration withpolymorphs and mononuclear cells in and around theirwalls. Smears from the umbilical arteries showed abun-dant pus cells and many Gram-negative bacilli.

CASE 6 A male infant was born to a para 1 mother.Both medical and surgical induction were employed toterminate this pregnancy at 36 weeks by dates becauseof maternal preeclampsia and delivery was assisted byforceps. Labour lasted three and a quarter hours, theinfant weighed 1,474 g, and his general condition wasfair. Two days later he was transferred from a prematurebaby unit to the Birmingham Children's Hospitalbecause he failed to pass meconium and had developedsigns of intestinal obstruction with a mass in the right

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loin. The blood sugar was 17 mg %; radiological exa-mination showed gas in the rectum and an umbilicalswab showed a heavy growth of Proteus sensitive tostreptomycin, neomycin, and polynoxylin. The infantwas treated conservatively with intravenous fluids,penicillin, streptomycin, tetracyclines, and chloram-phenicol but he died on the fourth day.

Necropsy was performed 24 hours after death. Thebody weighed 1,394 g, measured 42 cm in length, andthe head circumference was 28-5 cm. There was muchwasting and the umbilicus was reddened. On openingthe cranial cavity foul-smelling gas escaped and thebrain was almost completely liquefied. The meninges,dural venous sinuses, and middle ears were normal.The lungs were deep purple and partially collapsed. Onopening the abdominal cavity foul-smelling gas escapedand there was fibrino-purulent peritonitis. The mesen-tery of the ileocaecal region was unfixed and there wasa volvulus with strangulation but no perforation. Theright kidney was greatly enlarged and cystic.

Bacteriology Proteus was grown in large numbersfrom swabs from the brain and peritoneal cavity andin small numbers from a portion of the lung.

Histology The lungs showed marked congestion, amacrophage intraalveolar exudate, and a few pus cellsin the large bronchi. As the brain was completely necroticand liquefied none was taken for histology.

CASE 7 The first of twins was born at 34 weeks to a25-year-old gravida 2 mother. Labour lasted four hoursand there was spontaneous vertex delivery of a maleinfant. Birth weight was 1,588 g. He was transferred to apremature baby unit where he remained well for thefirst three days. He then developed a rash on the skinof the abdomen, repeated apnoeic attacks, and slightjaundice. The serum bilirubin level was 11 mg°%. Atthis stage Proteus vulgaris was cultured from the blood,an umbilical swab, and cerebrospinal fluid. He wastreated with colomycin and tetracyclines but died aged41 days following an attack of vomiting and convulsions.Periumbilical erythema was noticed a few hours beforedeath.Necropsy was performed six days after death. The

body weighed 1,385 g, measured 41 cm in length, andhad a head circumference of 28-5 cm. The stump ofthe umbilical cord appeared to be clean. There was adirty-green discoloration of the scalp and calvariumand a foul odour escaped on opening the cranial cavity.The left cerebral hemisphere was firm and blackenedthroughout, but the rest of the brain was soft and necroticand altered blood covered the surface of the rightcerebral hemisphere. The lungs had a slightly mottledappearance macroscopically. The peritoneal cavitycontained a few millilitres of foul-smelling, turbid fluidbut was otherwise unremarkable. The intima of thegreat vessels was stained greyish-red indicating haemo-lysis.

Bacteriology Meninges and lung showed a heavygrowth of Proteus with very few Ps. pyocyanea. A swabfrom the peritoneal cavity showed a scanty pure growthof Proteus.

Histology All sections of brain showed areas of

necrosis, softening, and cellular degeneration and manyneurones remained as cell ghosts. The glial cells showedsmall, dark, irregular, pyknotic nuclei. Sections fromthe most severely affected areas showed complete loss ofidentifiable cellular contents and boundaries, cuffing ofthe meningeal vessels by Gram-negative rods and ovalbacilli, antemortem thrombus in the lumen of some ofthese vessels and extensive intracerebral haemorrhage.There was little polymorph response to the infection.The lungs were moderately congested, irregularly ex-panded, and showed a scanty mononuclear cell, intra-alveolar exudate together with occasional amnioticsquames and small clumps of bacteria. There was noacute inflammatory response though some alveoli con-tained oedema fluid.The other twin was normal and progressing well

when last seen at the age of 14 months. The placentawas dichorionic with fused membranes and with unequalcomponents.

CASE 8 The first of twins was born at 36 weeks to a33-year-old para 6 Indian mother. There was hydram-nios but labour and delivery were normal. The infantweighed 1,744 g and was in fair condition. Progress wasunremarkable until the seventh day when there wassudden onset of grunting, convulsions, and cyanosis.He was treated with oxygen but died an hour after theonset of symptoms.Necropsy was performed 53 hours after death. Weight

was 1,685 g, length 43 cm, head circumference 31 cm.The estimated maturity was 34 weeks. There was aslight but distinct pungent aroma on opening the thoraciccavity. Both lungs were markedly congested but therewas no consolidation. Upon opening the cranial cavitythere was a foul, rancid smell akin to that of stale fish.The meninges appeared to be oedematous but there wasno gross purulent exudate. Both cerebral hemispheres,particularly the frontal lobes, were softened and discol-oured purplish-black. Examination after fixation showedthat there was considerable softening of both cerebralhemispheres, the cerebral peduncles, and the midbrain,together with greyish-black discoloration of the frontaland anterior part of the parietal lobes. The cerebralpeduncles and the midbrain were unavoidably disruptedduring removal from the skull. The hindbrain was intactand showed no obvious meningitis.

Bacteriology There were heavy growths of Proteusmirabilis from lung and meninges.

Histology Sections from the frontal necrotic tissueshowed much formalin pigment and small cystic spacesfilled with haemolysed red cells. The normal corticalarchitecture was recognizable and there was a relativelyscanty leucocytic infiltration of the meninges. Theoccipital lobes showed no haemorrhage or haemolysisand no inflammatory exudate. A section from the mid-brain showed generalized necrosis recognizable bynuclear pyknosis and loss of structural detail of the braintissue; most vessels in this region were abnormal, somewere cuffed by degenerate inflammatory cells, and manyshowed fibrinous material replacing the vessel wall;many of the smaller vessels showed abundant smallbacilli in and around their walls easily recognizable

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FIG. 4. Case 8. Brain after fixation. Inferior surfaceshowing blackening of frontal lobes and disruption ofcerebral peduncles.

FIG. 3. Case 8. Right cerebral hemisphere in situ showingblackening offrontal and parietal lobes.

FIG. 5. Case 8. Cerebral white matter. Masses of bacilliin and around vessel walls. Giemsa x 780.

*..0~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~.....

FIG. 6. Case 8. Cerebral white matter. Fibrinous necrosisof vessel wall with perivascular exudate. Haematoxylinand eosin x 780.

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FIG. 7. Case 8. Bacilli in intact cerebellar cortex. Giemsax 780.

even in haematoxylin and eosin preparations. Thehindbrain showed none of these features and cellularmorphology was well retained; the only abnormalityconsisted of cytoplasmic swelling of many astrocytesin the white matter of the cerebellum and brainstem.Gram and Giemsa preparations showed enormousnumbers of Gram-negative bacilli; they were especiallyabundant in the frontal lobes and around the vessels ofthe midbrain. Rather surprisingly there were also nume-rous filamentous bacilli throughout the otherwise normalcerebellum and brain stem. The lungs showed a fewsquames and macrophages together with small quanti-ties of bile pigment in the air sacs.

The other twin Apart from slight icterus in the firstfew days the surviving twin remained well; birth weightwas 1,857 g. His weight gain was satisfactory and heattained the weight of 2,495 g upon discharge. Furtherprogress of the surviving twin was not recorded as themother did not take him to the follow-up clinic. Theplacenta was dichorionic and showed no unusual

features. Histological examination of the placenta,membranes, and cords related to both twins showed noinflammatory changes or other features of note.

CASE 9 A female infant was born at 43 weeks to aprimiparous mother. Pregnancy, labour, and deliverywere normal. The infant weighed 3,359 g. On the eighthday she became restless, irritable, and did not take herfeeds. On the following day she kept moaning and wouldnot sleep; she rolled her eyes from side to side and criedas though frightened; there were twitching movementsof the head and she was very pale. On admission to theBirmingham Children's Hospital she was moribund,grey, cyanosed, apnoeic, and unresponsive but herperipheral circulation remained good. The anteriorfontanelle was bulging and the umbilicus was septic.The pupils were fixed in mid-position and the discs werenormal. The pulse was regular at 160/minute. Therewas some respiratory stridor with indrawing of the ribsand moist sounds over both lungs. Lumbar punctureproduced xanthochromic fluid which was under increasedpressure and contained 3,850 polymorphonuclear leuco-cytes per cmm, protein 800 mg%, and sugar 20 mg %.Two Gram-negative bacilli were seen in smears andcultures provided a few colonies of Proteus mirabilis.Blood culture grew Proteus mirabilis and the pour plateblood culture showed 114 haemolytic colonies permillilitre of blood. Subcultures showed that these wereall Proteus which had the same antibiogram as thosecultured from the cerebrospinal fluid and which weresensitive to streptomycin, chloramphenicol, neomycin,ampicillin, and cephaloridine. The infant was treatedwith chloramphenicol, sulphadimidine, penicillin, amy-lobarbitone, and hydrocortisone but she failed to respondand died on the morning following admission.Necropsy was performed 11 hours after death. Weight

was 3,300 g, length 52 cm, head circumference 37 cm.The anterior fontanelle was wide and slightly bulging.The umbilicus appeared to be clean and healthy. Theumbilical vein was patent and unremarkable as was theductus venosus. The left umbilical artery appeared tobe normal. A segment of the right umbilical artery inits course alongside the bladder and within the pelviswas firm and swollen, with reddening of the surroundingtissues. Slicing of this segment showed pus within itslumen. Both lungs were firm and congested throughout.On reflecting the scalp the slightly bulging fontanellewas confirmed. Both the scalp and pericranium overlyingthe fontanelle had a dusky orange-black discoloration.There was a distinct, foul, fishy odour which was moreintense when the skull was opened. Much of the cerebralhemispheres was blackish discoloured, extremely softened,and easily disrupted on attempted removal. Many of thecerebral veins contained firm thrombi but the cranialvenous sinuses were clear. There was thick, dark-greyexudate in the interpeduncular cistern at the base of thebrain and occluding the fourth ventricular foramina.The middle ears were clear. Slicing of the brain followingfixation showed the same dark-grey colour throughoutthe cut surface except for a little cortical tissue in theright temporal lobe. The periventricular structures andthe basal ganglia were grossly softened and easily

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FIG. 10.

.4 4 4

FIG.8.Case 9.Discoloratio ofscalp and anWe fonta-.

FIG. 1 C .

FIG. 8. Case 9. Discoloration of'scalp and anterior fonta-nelle.

FIG. 9. Case 9. Brain after fixation. Coronal slice showingextensive blackening and necrosis.

FIG. 10. Case 9. Exudate surrounding brain stem.

FIG. 11. Case 9. Cerebral white matter. Thrombosis in avenule with surrounding inflammatory exudate. Giemsax 193.

FIG. 8.

FIG. 9.

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FIG. 12. Case 9. Right umbilical artery. The dark area represents an abscess in the wall. Haematoxylinand eosin x 6-5.

disrupted. The hindbrain was similarly discolouredthroughout but not softened.

Bacteriology A very heavy growth of Proteus wasobtained from a meningeal swab, a heavy pure growthfrom the right umbilical artery and a heavy growthfrom an umbilical swab.

Histology Sections from three lobes of lung showedareas of pneumonia, apparently of recent origin with asparse polymorphonuclear exudate. Organisms were notseen in Gram and Giemsa preparations. Two sectionsof the umbilicus showed complete epithelialization ofthe umbilical pit. One section included the umbilicalvein which was almost totally occluded by asepticgranulation tissue. The other section from the centre ofthe umbilicus between the vein and arteries showed anacute abscess cavity lying immediately underneath thesubepidermal granulation tissue. The umbilical abscesscontained a few Gram-negative bacilli whilst the um-bilical pit contained only a few Gram-positive cocciamong desquamating cells. The right umbilical arteryin its suprapubic segment showed acute inflammation ofits wall extending into the surrounding fibro-adiposetissue and an acute abscess cavity which contained nu-merous Gram-negative rods. A block from the infra-umbilical segment showed acute inflammatory infil-tration involving the wall and the granulation tissuewhich partly occluded the lumen; the remains of thelumen were occupied by fibrino-purulent material.Similar changes were seen in the left umbilical arteryat this level, but they were relatively slight. The in-flammatory material within the two arteries near theumbilicus contained many Gram-negative rods. Sectionsof brain showed a polymorphonuclear and mono-nuclear exudate in the piaarachnoid over the cerebrumand hindbrain. Much of the cerebrum was franklynecrotic and there were many small cystic spaces of

liquefaction. A zone of necrotic inflammatory cellssurrounded many of the vessels, the walls of some ofwhich were represented by structureless, eosinophilicrims of fibrinous appearance. There was no cellularinfiltration of the intervascular necrotic parenchyma.All these areas showed many Gram-negative rods. Thelateral ventricles showed acute exudate over the choroidplexus and considerable acute inflammatory infiltrationin the subependymal zone.The hindbrain showed none of the frank necrosis

seen in the cerebral hemispheres, and the fourth ventricleshowed no ependymitis. Many blood vessels, however,showed a narrow cuff of inflammatory cells in theVirchow-Robin spaces; this was especially so in theventral half of the pons. There were numerous Gram-negative rods around these vessels and also in theintervening apparently normal parenchyma. Numerousorganisms were also seen in the cerebellar folia eventhough the cortical cells appeared normal and therewas no inflammatory change. The anterior lobe of thepituitary was normal and contained no organisms whilstthe posterior lobe showed a peculiar homogeneouseosinophilic change of the matrix, pyknosis, and frag-mentation of many nuclei and numerous Gram-negativerods.

CASE 10 A male infant was born at 32 weeks to a healthy20-year-old primiparous mother. Pregnancy and labourwere normal. Birth weight was 1,899 g. For the firstfew days he did not suck well, had oedema of the eyes,hands, and feet, with slight cyanosis of the extremitiesand slight jaundice which cleared spontaneously. At 5weeks he became irritable and cyanotic; he was unableto open his mouth and had rotary nystagmus, generalizedstiffness, and an odd cry with wheezing respirations. He

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was thought to have meningitis and lumbar punctureproduced bloody fluid which on culturing grew Kleb-siella which were sensitive to tetracyclines, streptomycin,and chloramphenicol. Blood culture produced non-lactose fermenting bacilli which were members of thecitrobacter group. He was treated with oxygen, chloro-mycetin, sulphadimidine, and cloxacillin but died about20 hours after the onset of symptoms.

Necropsy was performed 35 hours after death. Thebody was that of a pale, premature infant weighing2,340 g and measuring 49 cm in length, with a headcircumference of 33 cm. The umbilicus was well healedand clean. There was a foul smell both on reflecting thescalp and on opening the cranial cavity. Purulent exudatecovered the cerebellum and both cerebral hemisphereswhich were softened and blackened. The lungs showedbasal congestion. The abdominal contents, especiallythe umbilical vessels, were unremarkable.

Bacteriology Direct smears of the meninges showedpus cells and short, Gram-negative rods. Culturingshowed these organisms to be non-lactose fermenting;they were not easy to classify but were subsequentlylabelled by the Salmonella Reference Laboratory asbeing members of the citrobacter group. These organismswere insensitive to penicillin, tetracyclines, erythromycin,sulphadimidine, and ampicillin.

In addition to a scanty growth of non-lactose fermen-ting bacilli a heavy growth of Lancefield group Ahaemolytic streptococci was obtained from a portion oflung.

Histology There were numerous Gram-negative,short rods scattered diffusely in the substance of thebrain and in clumps within cerebral blood vessels.Haematoxylin and eosin preparations of the cerebralcortex showed vascular congestion and some exudatecomposed of pus cells and macrophages. The exudatewas rather less marked than expected from naked eyeappearances. The lungs showed extensive, intraalveolar,mononuclear exudate.

DISCUSSION

With one exception the cases described were eitherpremature or dysmature neonates in whom therewere symptoms and signs referrable to the res-piratory and central nervous systems and in four ofwhom there was evidence of umbilical sepsis.Eight of the 10 infants succumbed within thefirst 10 days of life.The characteristic features of Proteus meningo-

encephalitis were the smell and the gross andhistological appearances of the cranial contents atnecropsy. Primary infection by Proteus was esta-blished beyond doubt by bacteriological isolationof these organisms during life in six of the cases.Proteus organisms are motile and are known toflourish at room temperature, one of their charac-teristics being the ability to swarm under favourableconditions. For these reasons the possibility ofsecondary invasion by these organisms must be

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1961 62 63 '64 65 66Year

ED Total number_Cases due to proteus

FIG. 13. Graph showing the number of casesof neonatal meningitis necropsied at theChildren's Hospital, Birmingham, from1961 to 1966. Two cases of Proteus menin-gitis that originated in the same nursery ascase 9, but examined elsewhere, are alsoincluded. Case JO, which was not due toProteus, is the case recorded in 1965.

considered in the three remaining cases in whichProteus was isolated from material obtained atnecropsy.As case 2 was necropsied less than 12 hours after

death and heavy, though not pure growths ofProteus were obtained from the softened, discol-oured, and offensive smelling brain and fromheart blood, it was felt that the primary infection inthis case was due to Proteus. There was histologicalevidence of meningitis and umbilical sepsis in case5 and histological evidence of meningitis in case 8;this evidence, together with bacteriological isolationof Proteus, seems strong evidence in favour ofProteus sepsis having been the primary conditionin both these cases too.The remaining case has been included in order to

illustrate that variants of E. coli may rarely beresponsible for similar necropsy appearances of thebrain and that whilst there are characteristic patho-logical features by which Proteus meningo-encephalitis may he recognized, bacteriologicalconfirmation is necessary in every case.The 10 cases described were encountered from

1961 to 1966 during which time, excluding caseswith spina bifida, there were 30 necropsies onneonates with acute meningitis. Groover et al. (1961)found that Proteus was the cause in approximately4s0 of reported cases of neonatal meningitis. The

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Proteus and coliform meningoencephalitis in neonates

relatively high incidence of Proteus in necropsycases of meningitis is an indication of the severityof this condition. There are few reports of successfultreatment (Becker, 1962; Tolmas and Winter, 1957),and there have been no survivors in the Birminghamarea.During this period there have been only two

other known cases in this area; they are included inthe graph (Fig. 13) as they originated in the samenursery as case 9. The graph shows two smallclusters, one in 1963 and the other in 1966, indica-ting that epidemiological factors may be of impor-tance in the aetiology. It is not intended to pursuethis aspect here, but the finding of Proteus sepsis ofthe umbilicus or of the intraabdominal segmentsof the umbilical arteries in half of the cases isimportant. It indicates that this is commonly theportal of entry and possibly that the method usedin the routine treatment of the umbilical stump

may be a predisposing factor. This aspect is currentlyunder further investigation.

I am indebted to Dr A. H. Cameron, the instigator ofthis paper, for all the encouragement and advice thathe has given me in its preparation. I would like to thankDr K. B. Rogers for his advice concerning the bacterio-logy on the 10 cases presented. The Salmonella ReferenceLaboratory, Central Public Health Laboratory, London,was responsible for finally labelling the causative or-ganism in case 10.

I am grateful to Mr R. H. Bailey for technical assis-tance, Mr F. Mehta for photography, and Miss A. E.Arnold for secretarial assistance.

REFERENCES

Becker, A. H. (1962). Amer. J. Dis. Child., 104, 355.Groover, R. V., Sutherland, J. M., and Landing, B. H. (1961). New

Engl. J. Med., 264, 1115.Kaplan, M. Z., and Poweleit, A. C. (1949). Amer. J. Dis. Child., 77,

454.Tolmas, H. C., and Winter, J. (1957). Ibid., 94, 574.

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