2 S . A. MED I C A L J o· URN A L January 12, 1946

Torula Infection of the CentralNervous System: Four Recent Cases

By w. LEWIN AND P. Roux(South African Institute for Medical Research, Johannesburg).

Torula (Oryptococcus) histolytica infection of the centralnervous syst.em in man is a comparative rarity; only approxi·mately lOO cases have been reported since Zenker recordedthe first case in 1861 (Freeman, 1931). Cases have beendescribed by Shapiro and Teal (1925), Freeman (1931), Levin(1937), Watts (1932), Crone, de Groat and Wahlin (1937),Longmire and Goodwin (1939), Magruder (1939), Reeves, Buttand Hammack (1941), Binford (1941), Stiles and CurtisS (1941),Marshall and Teed (1942), Warvi and Rawson (1942), Ohampionde Crespigny (1944), and Burger and 'Morton (1944). The

Oase History No. 1 (Dr. Hutchinson): The patient, a non·European, was admitted to hospital on 6/8/44 with markedneck·rigidity and positive Kernig. Lumbar puncture revealedthe cerebrospinal fluid under. markedly increased pressure;SO·60 c.c. were withdrawn. M & B 693 was administered forfour days (28 tablets) and the headache and neck paindiminished. On 11/8/44 lumbar puncture was repeated anda further SO c.c. removed as neck.rigidity ~ecame very markedand severe headache recurred. The fluid was submitted to thelaboratory. where the condition was diagnosed as Torulah·jstolytica infection on microscopic examination of ~he

specimen. Potassium iodide gr. xx...x: t.d.s. was administeredand a further 70 C.c. of spinaLfluid removed, but tHe patient'scondition deteriorated, and death occurred on the eleventh dayof illness. ThrouShout the illness the temperature variedbetween 97° to 99 F., pulse 70·80, and respiration 17-18.At autopsy the brain showed some generalised congestion andthe entricular fluid turbid. No gelatinous mattlrial was

FIG. No. I.-Torula in cerebrospinal fluid showing mucilouscapsule and occasional budding form.

first South African case was reported by Aneck-Hahn (1933).Gray (1940) gave a full account of two cases occurring in thePort Elizabeth area and described the laboratory findings indetail. The fourth South African case was -reported bySampson and Farren (1942). Five further unreported caseshave been observed in South Africa by F. W. Simson (1935),during the last ten years. Within the past eleven monthswe have conducted the laboratory investigations on four furthercases, which form the subject of this· commamcation. Weare indebted La Dr. G. Hutchinson, Rand Leases, Florida; toLt.·Col. A. Tinker, Cottesloe Military Hospital; to Dr. P. J. J.Barnard, Consolidated Goldfields Group; and to Dr. M. J.eohen, Johannesburg, for their help and permission to publishthese notes OIl their cases.

FIG. No. 2.-Old.standing Torula lesion in the lung.

observed. Microscopic examination of the fluid showednumerous cellular elements of Torula histolytica (Fig. No. 1).

Oase History No. 2 (Col. A. Tinker) : The patient, an adultEuropean; became ill on 14/1/45 complaining of headache andvomiting He was admitted to hospital on the eighth day ofillness-temperature 100.4° F., pulse 84-with m<j:rked photo­phobia and intense headache, controlled only by morphia. On23/1/45 headache was still marked and neck-rigidity present.Lumbar puncture revealed the fluid' slightly turbid and underpressure. The cerebrospinal fluid was submitted to the SouthAfrican Institute for Medical Research and the conditiondiagnosed as Torula histolytica infection on microscopicexamination of the fluid. Sulphapyridine had been administered,and on 27/1/45 penicillin was given intrathecally and intra­muscillarly. ~ total of 2,000,000 quits of penicillin was

r

Januarie 12 194.6 S.A. TYDSKRIF VIR GENEESKUNDE 3

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administered by 10/2/45. On 27/2/45 potassium iodide wasgiven, gr. XXX t.d.s., and later increased to 150 grains daily.On 12/;V45 10. c.c. ?f 50 per cent. sodium .iodide was ~i:,enill 1,000 c.c. drIp saline. On 2.4/4/45 the patIent was receivmg200 grains potassium iodide daily; this ·was reduced to 150grains on 15/5/45, and on 23/5/45 was still being taken.During the -whole of this period the patient had a stormypassage and repeated lumbar punctures. On 2/6/45 the patienthad sufficiently recovered to be allowed to leave hospital for

. some hours, and on 26/6/45 was discharged from hospital on28 days' sick leave. Eleven months after the onset of symptomsthe patient was actiYe and well, and cerebrospinal fluidexamination showed the presence of 24 lymphocytes per c.mm.,but no Torula bodies were seen.

FIG. No 3.-Stroke cultures across plat-e of four strains ofTorulu. histolytica, with Staphylococcm aureus (Oxford5traiu) . in centre. Sensitivity to penicillin illustrated .bylysis of Staphylococcu culture only; Torula stramsresistant.

Ca$e History No. 3 (Dr. P. J. J. Barnard) : A non-Eu~~n

adult male was admitted to hospital on 17/3/45 complammgof headache which had been present to a lesser degr.ee f?rseveral weekS before admission. Th1l headaches varIed mintensity, ~nd vomiting .occurred· on several occasions. ~eck-

. rigidity was present. Lumbar puncture revealed the flUld tobe under moderate pressure and slightly turbi~. On 27/3/45sulphadiazine was gIven per os four-hourly until a total of 40gm. had been given. No improvem~nt was noted, the te~p.e~­ture rose and the drug was discontmued. On 1/5/45 perncillillwas giv:~n intrath~lly twi.ce daily un~il. a total of 4~,.OOOunits had been_ gIven Without allevlat~g the cond.lt!o?Potassium iodide gr. XXX t.d.s. was then given after pemclllmadministration had ceased. Dr. Barnard states that after 10days of this treatment deterioration of the patient's condition

appeared to be arres~d, but ultimately deatb occurred. Thelung, liver, -spleen, kidney and brain were examined, andTorula histolytica was found in the substance of the lungsurrounded by fibrous tissue; this· lesion was obviously ?f old.standing (Fig. Nq. 2). We are indebted to pr. F .. W. Slillson,who examined the lung post-mortem, for this findmg. Torulabodies were detected in the brain.

Case History No. 4 (Dr. M. J. Cohen): This patient, aEuropean male, became ill in May, 1945, and was treated withsulphadiazine, which appeared to relieve the condition for atime. After a short period, however, blindness occurred, andhis general condition deteriorated. A specimen of cerebrospinalfluid examined on 20/7/45. showed the presence of Torulahistolytica. Large doses of potassium iodide were given by

FIG. No. 4.-Guinea-pig showin~ large grape-like masses of. Torula infected tissue involvmg omentum. Normal bowel

visiblE only at extreme periphery of ab~ominal contents~

mouth and some was given intrathecally, but the patient died.Post-mortem examination revealed a generalised congestion .ofthe brain and a thick ~eenish exudate in the sulci, with anaccumulation in. the regiOn of the optic chiasma. This exudatewas not gelatinous in appearance. .

Autopsy of guinea-pigs and lnice, inoculated intraperitoneallyand subcutaneously on two occasions with cerebrospinal fluid,showed no microscopic lesions after a period of six weeks,and Torula bodies were not observed in the tissues lnicro­scopically or culturally.

LABORATORY OBSERVATIO~S.

Cultural Findings: The cerebrospinal fluid from the firsttwo and the fourth cases was tnrbid, and that from the thirdcase only slightly so. The morphology of the organismsdetected in the cerebrosllinal fluid was identical in all cases.UnstaineJ wet preparatiOns showed numerous large, ~ighly-

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4 S.A. MEDICAL JOURNAL - January 12, 1946

refractile bodies varying from 51" to 151" in diameter. A well­defined clear capsule surrounded each cell, and. some formsshowed budding (Fig. No. 1). When stained by Gram'smethod, the organism stained deeply Gram-positive, and thewide, clear surrounding mucoid coat stained red, with anirregular periphery. Culture on the usual laboratory mediawas successflil in all cases. After 24 hours' incubation at37° C. small moist colonies d.eveloped, and after four days atroom temperature became cream in colour. Growth occurredwell on blood agar, nutrient agar, Sabouraud's medium andglucose agar. . After seven days' growth on Loeffier's serumcultures '1, 3.:and 4 showed a confluent, moist growth; culture2 appeared· t-<t be less moist in appearance. Culture 1 had aslightly '~olden, and the remaining three a cream colour. Inbroth growth 'oocurred best at the bottom of the tube, where

Animal Inoculation: Specimens of cerebrospinal flnid andsuspensions of pure culture from the four cases were inoculatedsubcutaneously, intraperitoneally and intrapleurally into guinea­

'pigs, mice and rabbits with varying results. None of the aninlalsinoculated with strains Jos. 1, 3 and 4 became infected. Fig.No. 4 shows masses of infected tissue .invading the omentumof a guinea-pig inoculated intraperitoneally with a culture fromCase No. 2. The microscopic appeareance of the fluid fromthis tissue is shown in Fig. No. 5. Another pig inoculatedsubcutantously in the thigh died eigh~ months later andshowed extensive invasion of the inguinal lymph glands, spleen,liver, lung and brain. Apparently trains of Torula histolyticavary greatly in -their infectivity to laborat-ory animals. Strainsof the three fatal human cases failed to infect the ·testanimals.

----1----1------1----1----

BIOCHEMIC_U, CEREBROSPTh'AL fLUID FINDINGS.

The biochemical fihdlngs in the cerebrospinal fluid of the fonrpatients are tabulated below:

•

6-11

slightexcess

Case 4

28 1{.53

4 8-25

,slightexcess

Case 3

Veryslightly Turbid.turbid.

40 mgm. 5 mgm.

32-42

49-96

Case 2

Turbid.

moderateexcess"

nil

moderateexcess

660 mgm.640-735 mgm_ 700 mgm.675 mgm.

Disintegrated

Case 1

numerous

Prot-ein

Sugar

Chlorides

Appearance. Turbid.

CellsLymphocytes 12PlHymorpho-

nuclears . . 33-

DISCUSSION.

Diagnosis': Human infection with Torula histolytica has been. reported to involve nearly all the tissues ·and organs of the

body, and in some reported ca·ses the infection was localisedto certain parts of the body, with recovery after drainage andother treatment. The organism appears t-o have a predilectionfor the central nervous system,' and, owing to the comparativerarity 9f -the condition, cases may be missed. Binforcr (1941)states' . that "ante-mortem r.ecognition of the d,ise!!Jle - willprobably become more frequent when physicians consider itamong the diagnostic possibilities of obscure cerebral con­ditions and laborat-ory workers learn to recognise this yeast".Clinically, cases are stated to resemble tuberculous meningitisand brain tllmours more commonly, with encephalitis, brainabscess, dementia psychosis and dementia paralytica simulatedless frequently. Our four cases all showed symptoms ofmeningitis. The laboratory diagnosis is simple and rests onthe recognition of the yeast in the cerebrospinal fluid on directexalI?-~ation.

The typical feature is the presence of the mucilous C9psuleof clear material surrounding the yeast bodies, budding, andthe absence of -mycelium and ascospores (Figs. Nos. 1, 5 and6). We experienced no difficulty in culturing the organismfrom the cerebrospinal. fluid in all cases. Levin (1937) r.ecordsthat of' 60 cases, 10 were diaguosed ante-mortem by culture.Crone, DeGroat' .and Wahlin (1937) recommend that miceshould be inocqJated intraperitoneally as a routine measure.Excluding the presence of the causative organism, other cerebro­spiual fluid findings are not pathognomonic. The fluid maybe clear, xanthochromic or turbid and under pressure. Thecell count varies from 3 to 1,000 per c.uun. and averages 200 to300, chiefly lymphocytes. Protein is inc~eased; the sugarcontent varies, but may be decreased (LeVIn, 1937).

FIG. No. 5.-Fluid from Torula tissue in guinea-pig.

it prasented a thick creamy layer. Of the many carbohydratemedia inoculated with the four strains, glucose was fermented ­with the production of acid ouly. Lrevulose produced the same'change to a lesser degree, and only after prolonged incubation.lndol was not produced, and the M.H.. and V.P. reactions we~e

negative. Litmus milk was unchanged and no hremolyslSoccurred on horse blood agar. Stab cultures showed no growthalong thu needle track. Gelatin and inspissated .serum wtrenot liquefied. No mycelium was' produced on culture, and theorganisms lost their mucoid capsule. .

Penicillin Sensitivity: The organisms were tested -for sensi­tivity to penicillin by means. of stroke cultures on nutrientagar and were found to be penicillin-resistant (Fig. No. 3).Stroke cultures were made' on the plate and penicillin insolution superimpose~ .on half. of the inoculated strea~. TheOxford penicillin-sensItIve st.rarn of staphylococcus was mcludedas a control.

Januarje 12 1946 S.A. TYDSKRIF VIR GENEESKUNDE 5

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Prog7UJsis: Most observers record that Torula meningo;encephalitis is almost invariably fatal. De Crespigny (1944)states that the duration of the illness varies from three to fourweeks to two and a half years. Warvi and Rawson. (1942)state that all treatment has been ineffective in 100 per cent.of cases and that death usually occurs within 16 months of theonset of definite symptoms. Magruder (1939) states. that thelongest duration of the illness recorded was five and a halfyears, and quotes Levin as giving the average duration as fiveto six months. Stiles and- Curtiss (1941) observe that acutecases are rare, and in their review.have found ouly three otherreported instances of torulosis of less than a month's duration.It is to be noted that three of our four recorded cases endedfatally after an acute illness.

Treat'ment: Various-methods of treatment. have beendescribed: repeated withdrawal of cerebrospinal flnid and dailyintrathecal administration of acriflavin hydrochloride (Warvi

FIG. No. 6.-Torula body found in fluid from lung puncture.(Dr. F. W. Simson.)

and Rawson, 1942),- sulphadiazine administration followed bypotassium iodide (Marshall and Teed, 1942), and various sub­stances .have been tried to inhibit growth in vitro, such asgentian violet, gold thiosulphate, X-rays and _acriflavine(Shapiro and Neal, 1925). Penicillin has recently been tried;our four strains have proved to be penicillia-resistant (Fig.No. 3).

It would appear that the administration of massive doses ofpotassium iodide is, at the present stage of our knowledge, thetherapeutic measure offering the best chance of .reco~ery.

-Etwlogy: The mode of entry of the organlSIU lUto thebody is of interest. Fig. No. 2 shows the presence of Torulabodies in the lung snbstance in an old-standing lesion in oneof our cases of acute meningo-encephalitis (Case _TO. 2). Dr.

F. W. Simson has acquainted us of a further case of pul­monary infection in which the lesion is at present confined tothe lung and where the organism has been demonstrated in thefluid obtained by lung puncture (Fig. No. 6). It would thusappear that, in some cases at least, the organism gains accesst{) the budy by inhalation and produces a pulmonary lesionwhich must be the primary focus. The possibility of directinfection through the cribriform plate must also be consideredin other cases where no pulmonary lesions can be detected.

SUMMARY.

Four cases of meningo-encephalitis-three fatal-due toTorula histolytica are recorded, together with the laboratoryinvestigations. The primary pulmonary focus has definitelybeen demonstrated in one case, and reference made to another(Simson, 1945). The four strains of Ponda histolyticaare penicillin-resistant. A short review of the diagnosis,prognosis and treatment obtained from the literature is given.

ACfu-';OwqDGME.-.;rs.We wish to record our indebtedness to Dr. G. Hutchinson,

Lt.-Col. A. Tiuker, Dr. P. J. J. Barnard and Dr. M. J.Cohen foJ' the notes they have supplied and their permissionto use these; and to Dr. F. W. Simson, of the South AfricanInstitute for Medical Research, for his advjce and help andthe production of the photographic plates, in which he wasassisted by Mr. F. Brandt.

BIBLIOGRAPHY.

Anecl:-Hahn, H. G. L. (1933): S. A/r. Med. J., 7, 369.Bin/ord, C. H. (1941): ,4mer. J. Clin. Path., 11, 242. _Burger, R. E., and MO'rton, C. B. (1944): Surgery, 15, 312.Ch01npion de Crespigny, C. T. (1944): Med. J. Aust., 11, 605.Crone, J. T., DeGroat, A. F., and Wahlin, J. G. (1937) : .Amer.

J. Path., 13, 863.Freeman, W. (1931): J. Psychol. Neurol. Lpz., 43, 236.Gray, F: C. (1940): S. A/r. Med. J., 14, 65.Levin, E. A. (1937): ArcIJ-. Int. Med., 59, 667.Long'mire, W. P., and Goodw'in, '1'. C. (1939): Bull. Jolms

Hopk. Hosp., 64,.22.Magruder, R. G. (1939): J. Lab. Olin. Med., 24, 495.Marshall. M., and Teed, R. W. (1942): J. Amer. Med. .Ass.,

120, 527.Ree-ves, D. L., Butt, E. M., and Hammack, R. W. (1941):

Arcl~. Int. Med., 68, 57. .Sampson, B. F., and Far-rel1, J. E. (1942): . A/r. Med. J., 16,

245.Shapiro, L. L., and Neal, J. B. (1925) : Arch. :Veurol. Psychiat.,

1], 174.Sirnson, F. W. (1945): Personal communication.Stil!!s, W. W., and Curtiss, A. N. (1941) : J. Amer. Med. Ass.,

116, 1633.Wa:nvi, W. N., and Rawson, R. W. (1942): Arcl~. Tnt. Med.,

69, 90.Watts, J. W. (1932): Amer. J. Path.,' 8, 167.

•Pneumococcus l\Ieitingitis in the New..,born: Report of aCase with R'<lCovery and a Review of the Literature.

This is the report of a 13-day-old new-born who had pneumococcus meningitis' and survived. According to the review of allavailable literatlll'e this is the third case with recovery to bepresented. Twenty-eight cases of pneumococcus meningitis inthe new-born have been reported. The diagnosis of meningitis'in the new-born is not always suspected because the findingsare 'not typical. In the 28 cases reviewed, in 11 of them (40per cent.) a diagnosis was made during life by lumbar punctureand in 17 (60 per cent.) by autopsy. W€uty-three (82 percent.) were primary in origin. Ouly four wer!! secondary inorigin.' In three uf these pneumonia was found at autopsy,and in the other one otitis media was found. This patient wastreated ,with sulfadiazine. Of the other two cases thatrecovered, one was treated by spinal punctnre, and the othermade a spontaneous recovery

(Hogg, P., and Bradley, C. D. : JouTlIal 0/ Pediatrics, 26,406, April, 1945.)