J. Neurol. Neurosurg. Psychiat., 1967, 30, 580

Encephalopathy due to visceral larva migransDAVID SUMNER and ELLIS G. F. TINSLEY

From the Departments of Neurology and Pathology,St. James's Hospital, Leeds

For some time a syndrome of massive eosino-philia associated with respiratory and other symp-toms has been recognized. The condition carries onthe whole a good prognosis, is self-limiting and ismost commonly seen in children, often occurring inseveral members of the same family. Frequentlyobserved in the tropics or the subtropics, it has beenvariously described as Loeffler's syndrome, tropicaleosinophilia, familial eosinophilia, or benign eosino-philic leukaemia. In 1940 this syndrome was shownto be associated with multiple eosinophilic granu-lomata in the liver, and in 1950, Mercer and hiscolleagues (Mercer, Lund, Bloomfield, and Caldwell,1950) found that with this eosinophilia, Nematodelarvae were sometimes to be seen in the tissues. In1952, Beaver, Snyder, Carrera, Dent, and Laffertysuggested that the syndrome resulted from infectionin man by a Nematode normally parasitic upon alower animal; under these conditions the normalNematode life cycle does not take place but isblocked by an eosinophilic granulomatous reactionat the stage where the larvae are in the tissues. Atthis point systemic symptoms and signs may appear,in addition to an eosinophilia, and it was for thisstage that they coined the term 'visceral larvamigrans'.The condition has been reported most frequently

from the more southern states of the U.S.A. and inaddition to the eosinophilia, the clinical featuresinclude malaise, pyrexia, bronchitis, 'pneumonitis',enlargement of the liver (and less commonly thespleen), lymphadenopathy, skin rashes, and sub-cutaneous granulomata. In view of the wide distri-bution of the larvae in the viscera, it would besurprising if the brain were to escape and indeed,Dent, Nichols, Beaver, Carrera, and Staggers in1956, describing the necropsy findings in a child whosuffered from this condition but had died fromanother illness, found five larvae per gram of wetbrain tissue. Despite this, clinical involvement of thenervous system has rarely been reported. Reviewing58 cases Lewis, Yadav, and Kern (1962) foundmention of convulsions in but three patients, onein Britain (Dickson and Woodcock, 1959) and two

in America (Milburn and Ernst, 1953), whileMoore (1962) described a further example whichpresented with convulsions and encephalitis.For an adult to be affected is equally rare and

Lorentz (1962), who made the diagnosis in a WestIndian immigrant in London, could find but threeexamples in the literature, and none in an English-born individual. In 1964, Brain and Allan describedthe case of a young Englishwoman who had viscerallarva migrans presenting essentially the picture ofvarying focal epilepsy. Although the larva was notfound it seemed likely that the infecting parasitewas a Toxocara and it is of interest that five yearsbefore the onset of her illness she had gone to livein Calcutta.The present example is reported not only because

of the paucity of accounts of clinical involvementof the nervous system but also because of theapparent rarity of the condition in the adult.

CASE REPORT

The patient was a 57-year-old school mistress, teachingsixth form mathematics. She had never visited thetropics and has lived all her life in the north of England.She had never kept any pets and denied any but the mostcasual contact with cats or dogs, but she was a patho-logical hoarder and as a result of this had lived for someyears in considerable squalor. The hoarding had beengoing on for many years and she collected not only newand unwanted objects (as, for example, four unusedparaffin heaters, a 20-ft. extending ladder, and 87 poundjars of Bovril), but all rubbish and uneaten food. Nothinghad been placed in a dustbin for 10 years but the fullextent of the hoarding only came to light when she wasadmitted to hospital and her house could be visited.Figure 1, which shows some of the 3,600 full milkbottles which were stored in the bedrooms and Figure 2,which shows her kitchen, give some idea of what thehouse was like. Although it is not our contention thather recent encephalopathy was directly related to thislongstanding psychological abnormality (in the sense ofsharing the same pathology), it seems reasonable toconclude that the state of her house may well haveprovided a route for Nematode infection. For manyyears she had lived apart from her husband, but he

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Encephalopathy due to visceral larva migrans

I' i.. .

FIG. 1. The patient's bedroom.

nevertheless visited her about twice a week and was thusable to say that in September 1965, she began to look illand at the beginning of October, she stopped work andretired to bed, where she lay confused and incontinent.The day before her admission to hospital (25 October)she was found to have a temperature of 103°F. but within24 hours she became apyrexial and remained so. Sheherself could give no clear account of her condition and

FIG. 2. The patient's kitchen.

although she knew the day and the date, she had norecollection of the events of the preceding week. She hadno knowledge of current affairs and was totally unableto carry out the serial seven test. On the other hand, sheknew that the area ofa circle was wrr. On general examina-tion the only abnormality was in the chest, where therewas diminished air entry at the right lung base and inthis area scattered expiratory rhonchi could be heard.

wrCI#S,# ; Big -ftc, AC lb ( e I7I0I

Temporal montage

1 second I 50 pV

FIG. 3. The E.E.G. recorded on admission showing an increase in slow wave activity in anterior leads, particularly onoverbreathing.

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David Sumner and Ellis G. F. Tinsley

-V:;<Wt>s, Neither the liver nor the spleen was palpable. In the,1k.11 ~.114- central nervous system the only abnormality (apart of

course from confusion) was the presence of blateralA.~~~~~extensor plantar responses.

The cerebrospinal fluid was normal, but the E.E.G.showed some diffuse abnormality, particularly on over

~~~~~~~~~~ breathing (Fig. 3).z4>>t̂$>t The striking finding on investigation was a considerable

JN v {. @ ;"" W g> eosinophilia of 47% of a total W.B.C. count of 9,800per c.mm., the eosinophilia persisting throughout her

$*s--<>sWBa* R g ¢ % stay in hospital, and a search for helminth parasites wasA~i. m...EX.....commenced. Faeces were examined on many occasions

by concentration methods but no ova, larvae, or adultts;i worms were discovered. Twice the stomach was washed

vAI:.t -X.t.ifl ^' '%'>t*v-sbf4out in the early morning and the aspirate similarly4Xt : ;t<;<1!,searched with negative results. However, an x-rayS %,* Xs e9sskmi : ;tabtx§examinationof the chest showed a high right diaphragm,

46f Ri,:which suggested that there might be some enlargementt t a :> > * of the liver, although this could never be felt. Liver+"' .-^t)t,.;^t function tests at this time were abnormal, suggesting

~a~. considerable liver damage: serum bilirubin 0-5 mg./1004 A4g ml.; serum alkaline phosphatase 28 K.A. units; thymolW flo~~~cculation weakly positive; thymol turbidity and zinc

sulphate turbidity at the upper limit of normal; S.G.P.T.127 units; S.G.O.T. 62 units; total serum proteins

a ~.e ; 6 . ss¢58.ei^ef: .rt *R9.W.444 '..........6-2g/100 ml.; (albumin 3-3, globulin 2-9); electrophoreticZ.a..I;! A4'tsi7'$.. pattern normal.:e.....*R4¢..,ti...............Three weeks after admission to hospital a needle

biopsy of the liver was performed. A small white nodulewas seen in the middle of the specimen, and microsco-

FIG. 4. Liver biopsy showing the granuloma and Nematode pically it consisted of an inflammatory granuloma some

larva. 3 mmn. in diameter (Fig. 4). Necrotic liver cells and

Temporal montage

1.s J10&nV1 second

FIG. 5. The E.E.G. recorded three weeks after admission showing considerable resolution in the changes seen earlier.

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Encephalopathy due to visceral larva migrans

breaking down polymorphs and eosinophils made upthe centre, together with numerous Charcot-Leydencrystals. Embedded in the necrotic mass was a Nematodelarva. Surrounding the centre was a narrow band ofeosinophil leucocytes and outside this a broader area ofyoung fibrous tissue, heavily infiltrated with eosinophilsand other chronic inflammatory cells. The rest of theliver biopsy showed normal liver tissue.The greatest length of larva seen in any one section

measured about 620/i and the maximum diametermeasured 54,4. Apart from nuclear debris and a chi-tinous coat, no identifiable structures were noted in thelarva. It appeared to be in process of dissolution.

Later the deltoid muscle was biopsied. Part of thespecimen was digested and examined for larvae and therest was cut up into several blocks and many sectionswere taken. No evidence of any inflammation or of anylarvae was seen.

Following success with the liver biopsy, specimens ofserum were sent for serological tests for filariasis, hy-datid disease, and ascariasis. All were negative. Skin testsusing specific Nematode antigens were also performed.Trichinella gave a positive reaction, Ascaris gave adoubtful positive, while Toxocara and Hydatid antigenswere negative.Over the course of the next few weeks the patient's

confusion cleared spontaneously and the plantar res-ponses became flexor. This change was reflected in theE.E.G. recorded three weeks after her admission tohospital (Fig. 5).She was discharged from hospital two months after

admission, having continued to make a steady andspontaneous recovery both clinically and biochemically.Her convalescence was complicated by an episode ofdepression which responded well to drugs, and sixmonths after the onset of her illness she was back atwork teaching A level mathematics with complete con-fidence and success.By mid-January 1966 the white blood cell count was

6,000 per c.mm. with only 1% eosinophils. Stools wereexamined periodically for a further eight months but noova, larvae, or adult worms were seen.

DISCUSSION

Despite the non-specific pattern of neurologicaldisease and the apparent rarity of central nervoussystem involvement in visceral larva migrans, therecan be little doubt that this is the correct diagnosis.The combination of a self-limiting disease withtransitory signs in the chest, transitory pyrexia,and a massive eosinophilia, to say nothing of thepresence of an eosinophilic granuloma containinglarval remnants in the liver, can point in no otherdirection. No alternative explanation is forth-coming to account for the encephalopathy andindeed it would be extremely unlikely for this and thesystemic illness to be unrelated. In view of the veryfew recorded examples of central nervous system in-

volvement in visceral larva migrans, any attemptto delineate a clinical pattern is obviously impossible.It is of interest, however, that the few previousexamples in the literature presented with epilepsyor 'convulsions'. In this connexion, the importantwork of Woodruff, Bisseru, and Bowe (1966) mustbe mentioned. They found positive skin tests toToxocara in 7-5% of a population of epileptics asagainst an incidence of 2-1 % in normals and postu-lated that the epilepsy was due to the presence ofgranulomata in the brain. If this is indeed so, thenit seems quite possible that with the passage oftime our patient may herself develop epilepsy.More than 150 cases of visceral larva migrans

have been reported in the literature. In the greatmajority of cases where the infecting Nematodehas been identified, Toxocara canis was the cause(Beaver et al., 1952) although other Nematodes havebeen shown to cause a similar clinical syndrome.Some cases of visceral larva migrans have beendiagnosed on clinical grounds in association withaltered serum protein levels, haematological and sero-logical evidence. In many cases liver biopsy, eitherat laparotomy or by needle aspiration, has sub-stantiated the diagnosis by showing the typicaleosinophilic infiltration and granulomata in theliver tissue. Larvae have been seen in only a fewof these cases and anatomical identification of thelarva has been undertaken on probably less than40 occasions (Beaver et al., 1952). The second stagelarva of Toxocara canis, the form of larva causingvisceral larva migrans, measures up to 400 jp x 20 ,u(Nichols, 1956). In only one previous case (Beaverand Danaraj, 1958) has a larva similar in size tothat described in this paper been noted as causingvisceral larva migrans. Here typical granulomatawere found in the liver, but the larvae (fourth stagelarvae of Ascaris lumbricoides) were seen in thebronchioles only, in association with charac-teristic inflammatory changes. The larva from ourpatient cannot be identified anatomically as it hasundergone internal autolysis and only a part of itslength is available for measurement.Normally the larval forms of Toxocara canis can

remain viable for periods up to a year in the tissuesof its natural host the dog, while a similar long lifeis possible in unnatural hosts, as has been shownexperimentally in mice, guinea-pigs, monkeys, andman. This is, no doubt, the cause of the persistenteosinophilia which occurs in human infection. Inthis case the eosinophilia lasted a few weeks onlyand histologically the larva appears to have beendead at the time of biopsy. It would seem probable,therefore, that our patient is permanently cured ofthis infection.

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On the other hand clinical and experimentalevidence suggests that an initial systemic infectionby larval Nematodes not normally associated withthat host results in little systemic illness but thatre-infection results in severe systemic illness of anallergic type (Kerr, 1938). The two forms of theinfection are also associated with rather differentpatterns of local reaction of the tissues to the larvae.Only on re-infection are the typical eosinophilicand epithelioid cell granulomata produced. Ourcase shows these features both clinically and histo-logically. In at least one described case re-infectionresulted in an ill-defined encephalopathy. Itwould seem more common for nervous systeminvolvement to be due either to the presence oftypical granulomata causing epilepsy (Dickson andWoodcock, 1959; Woodruff et al., 1966; Moore,1962; Snyder, 1961; Dent and Carrera, 1953) or toassociated encephalitis probably viral in origin(Woodruff et al., 1966; Mochizuki, Tomimura, andOka, 1954). The latter seems to have some peculiarassociation with Nematode infections. Our patientrecovered spontaneously from the encephalopathyand never showed the cerebrospinal fluid changesassociated with encephalitis, suggesting that thereaction was a form of allergy.

CONCLUSION

An adult woman presented with an encephalo-pathic syndrome due to visceral larva migrans. Thediagnosis was substantiated by needle biopsy of theliver, which showed a typical granuloma of epithe-lioid cells and eosinophil leucocytes surrounding acentral area of necrosis containing a dead Nematodelarva larger than any previously described in thissite. The larva remains unidentified. It is suggestedthat this may not be the first occasion on whichthis patient has been infected with such a Nematode.As no evidence of continuing infection remainsdespite the fact that she was given no treatment,

it is concluded that man is an unnatural host forthis parasite.

Our thanks are due to Dr. Leahy, of the Department ofPsychiatry, who referred this patient in the first instance;to Dr. Exley, of the Department of Electro-encepha-lography, who was responsible for the E.E.G. recordingsand interpretation; to Dr. Losowski, of the Departmentof Medicine, who carried out the liver biopsy with suchstriking success; and to Mr. Howard, of the Departmentof Medical Photography, for his invaluable assistance.

REFERENCES

Beaver, P. C., and Danaraj, T. J. (1958). Pulmonary ascariasis resemb-ling eosinophilic lung; autopsy report with description of larvaein the bronchioles. Amer. J. trop. Med. Hyg., 7, 100-111.Snyder, C. H., Carrera, G. M., Dent, J. H., and Lafferty, J. W.(1952). Chronic eosinophilia due to visceral larva migrans;report of three cases. Pediatrics, 9, 7-19.

Brain, R., and Allan, B. (1964). Encephalitis due to infection withToxocara canis. Lancet, 1, 1355-57.

Dent, J. H., and Carrera, G. M. (1953). Eosinophilia in childhoodcaused by visceral larva migrans. J. La med. Soc., 105, 275-280.

-, Nichols, R. L., Beaver, P. C., Carrera, G. M., and Staggers, R. J.(1956). Visceral larva migrans, with a case report. Amer. J.Path., 32, 777-803.

Dickson, W., and Woodcock, R. C. (1959). Visceral larva migrans.Arch. Dis. Childh., 34, 63-67.

Kerr, K. B. (1938). The cellular response in acquired resistance inguinea pigs to an infection with pig ascaris. Amer. J. Hyg., 27,28-51.

Lewis, P. L., Yadav, V. G., and Kern, J. A. (1962). Visceral larvamigrans (Larval granulomatosis). Report of a case and reviewof the literature. Clin. Pediat., 1, 19-26.

Lorentz, I. T. (1962). Visceral larva migrans. Report of a case. J. trop.Med. Hyg., 65, 112-116.

Mercer, R. D., Lund, H. Z., Bloomfield, R. A., and Caldwell, F. E.(1950). Larval ascariasis as a cause of eosinophilia withvisceral manifestations. Amer. J. Dis. Child., 80, 46-58.

Milburn, C. L., Jr., and Ernst, K. F. (1953). Eosinophilia-hepatomegalysyndrome of infants and children; report of a case due toinvasion of liver by nematode larvae. Pediatrics, 11, 358-367.

Mochizuki, H., Tomimura, T., and Oka, T. (1954). Cerebrospinalnematodiasis as a provoking factor in Japanese B enceohalitis:an experimental approach. J. infect. Dis., 95, 260-266.

Moore, M. T. (1962). Human toxocara encephalitis with leadencephalopathy. J. Neuropath. exp. Neurol., 21, 201-218.

Nichols, R. L. (1956). The etiology of visceral larva migrans: I.Diagnostic morphology of infective second-stage toxocaralarvae. J. Parasit., 42, 349-362.

Snyder, C. H. (1961). Visceral larva migrans. Ten years' experience.Pediatrics, 28, 85-91.

Woodruff, A. W., Bisseru, B., and Bowe, J. C. (1966). Infection withanimal helminths as a factor in causing poliomyelitis andepilepsy. Brit. med. J., 1, 1576-79.

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