Four documented cases of eosinophilic meningoencephalitis due to Angiostrongylus cantonensis in Hong Kong

TRANSACTIONS OF THE ROYAL SOCIETY OF

TROPICAL MEDICINE ANDHYGIENE (1987)

Four documented cases of eosinophilic meningoencephalitis due to Angiostrongylus cantonensis Hong Kong R. C. Ko’*,

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81, 807-810

S. W. CHANT, K. W. CHAN’, K. LAME, M. FARRINGTON~,H. W. WON@AND

in

P.

YUEN~

‘Dept of Zoology, ‘Dept of Pathology, 3Dept of Medicine, University of Hong Kong; 4Dept of Microbiology, ‘Dept of Paediatics, Chinese University of Hong Kong; 6Paediatric A Unit, Queen Elizabeth Hospital, Hong Kong

Abstract

4 cases of eosinophilic meningoencephalitis in Hong Kong are described. The major clinical features of the patients, who were 2-60 years old, were low grade fever, headache, mild meningeal signs, right facial palsy or hemiplegia. Eosinophilia in the peripheral blood and eosinophilic pleocytosis were prominent. Computerized tomography scans of brain showed a small area of attenuation with surrounding hypodense area; the lesion was resolved l-2 months after admission to hospital. Electroencephalograms revealed abnormally slow dysrhythmia. Sections of a nematode observed in the brain of a patient who died were identified as those of young adult Angiostrongylus cantonensis. High ELISA titres against the crude antigens of this nematode were also noted in the serum of 3 patients. The disease is probably under-recognized in Hong Kong.

Introduction

Eosinophilic meningoencephalitis was not known to occur in Hong Kona until KO et al. (1984) diagnosed the first-case 07 human angiostrong$iasis by computerized tomography (CT) scanning and serology. KO (1984) suggested that, due to the high prevalence of Angiostrongylus cantonensis in the local molluscs, rats and other animals, more cases of angiostrongyliasis would be encountered in Hong Kong. Since then, 3 more cases have been found. The present paper compares the clinical features and laboratory data of all 4 cases and presents evidence concerning the aetiological agent and local epidemiology of this infection. This is important as most local physicians are still unaware of this disease and not familiar with its diagnosis. Materials and Methods The enzyme-linkedimmunosorbentassay(ELISA) was used to test for anti-A. cantonensis, anti-Toxocara canis, and anti-Gnuthostonta hispidum IgG antibodies in the sera and cerebrospinal fluid (CSF) according to Ko et al. (1985) an4 KUM & KO (1985). The indirect fluorescent antibody test (IFAT) was used on brain sections of patient no. 4. The brain tissues, preserved in formalin, were originally stained with haematoxylin and eosin; after destaining, the sections were incubated with anti-A. cantonemisand anti-G. hispidum sera raised in rabbits. The optimal dilutions for the antisera and fluorescein isothiocyanate (FITC) goat anti-rabbit IgG (Wellcome) were 1:40 and 1:lOOrespectively. Normal rabbit serum was used as the control serum. For comparison, the brain of a rat experimentally infected with A. canronensis 25 days previously was also studied. Case Reports

2 of the 4 patients were children (see Table). The patients were initially treated with antibiotics (ampicillin to patients nos 1, 3, 4; chloroamphenicol to patients nos 1, 3, 4; penicillin, cloxacillin, cephalor*Address for reprints.

idin and gentamicin to patient no. 1) but showed no response. Gram stain and cultures of CSF did not show any organisms. The patients all had low grade fever and neurological symptoms. The major clinical features were headache(patients nos 2, 3); projectile vomiting after eating (no. 3); right facial palsy (nos 1, 4); neck stiffness (nos 1, 4); brisk tendon jerks on right side (no. 4), calf pain for 2 weeks, sweating, shivering, weakness of lower limbs (no. 3), left hemiplegia (no. 2); tremor of hands, decrease in spontaneousmovements and coma (no. 4). CT scans of the brain showed a small area of increased attenuation with surrounding hypodense area, without significant contrast enhancement, located in the left basal ganglia lateral to the basal capsule (no. l), right parietal lobe (no. 2) and occipito-parietal regions (no. 3). Subsequent scans l-2 months later showed a complete resolution of the lesion. The electroencephalograms (EEG) showed delta discharges over the right posterior quadrant (no. 1) and precentral and frontal regions (no. 4). The peripheral white cell count (WBC) was normal except lor patient no. 3 whose counts changed from 16 x lO’/litre on admission to 22 x lo9 and 10 x lO’/litre 3 and 10 d later. Except for no. 4, the eosinophil counts in the blood were high, varying from 12-45%. The eosinophils in the CSF were 72-80%. An increase in serum IgE (684 iu/ml) was noted in patient no. 2. The ELISA test on the sera of patients nos 1-3 and the CSF of no. 1 showed high positive titres against crude extracts of A. cantonensis. Serafrom nos 2 and 3 were also tested against extracts of Gnathostoma and Toxocara; high positive titres were obtained against the former (Figs 1, 2). A higher optical density (OD) value was noted when the sera were tested against Gnathoswma compared with Angiostrongylus antigens. The positive cut-off OD value was set at 0.3. Patients l-3 recovered completely about one month

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EOSINOPHILIC

Table-Laboratory

data for four patients

MENING~ENCEP~LITIS

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A. cantonmsis

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in Hong Kong, 1982-85 CSF

Patient no., sex and age (years) 1.M(2) Z.F(30) 3.M(lO)

Fever (“0

(Z& he) 9.1 16,223 10 8,94

IOW’

low’ 37.5

4.F(60)

Eosinophils (%)

38.4

37 18 26,343 45 1,64

Appearante Turbid Turbid Clear, Turbid’

WBC1u.f

Eosirphils(%)

10’ 28 111,583 190 56,3664

80 78 70,703 80 72

Glucose (mmol/litre)

Protein (g/litre)

ELISA titres

1.6 BN’ 2.3

iI2 0.6

25 600 3200 12 800

3.2

0.7 1.44

‘Low grade fever. *BN=below normal; N=normal. ‘Taken 3 and 10 days apart. ?aken 1 week apart. 5Postmortem. s No.1 Angio '. '\*

0'

8

I 400

8

I 1600

I

I 6400

SERUM OllUllON

II

3

1 ?5600

t

I 120400

I

Fii. 1. Mean ELISA absorbance (OD) values obtained at various dihnions of sera from patients 1 & 2. Serum from no. 1 was tested against crude antigens of Angbstro&u cmuonmis (Angio). Serum from no. 2 was tested against Angio, Toxocaro canis (Toxo) and Gnathostot~ hirpidum (Gnatho). Cut-off value set at 0.3.

----

LOO

1600

1st Serum 2nd Serum

64iO

SERUM OllUIlON

25600

102400

I1 1

Fig. 2. Mean ELISA absorbance (OD) values obtained at various dilutions of 2 serum samples(taken 2 weeks apart) from patient no. 3, tested against crude extracts of Angiosnongylus canron& (Angie), Toxocma canti (Toxo) and Gnarhostoma hispidum (Gnatho). Cut-off value set at 0.3.

after admission to hospital. Patients 1 and 3 did not receive further treatment after the withdrawal of antibiotics. Patient no. 2 was given thiabendazole, 1000 mg twice daily for 5 days, and she showed marked improvement in motor power and subsidence

Fig. 3. Cross-section of a nematode, identified as young fifth-stage larva of Angiosnongdus cant, in the white matter of cerebellum of patient no. 4, showing somatic musculature (S), intestine (I) and regions of developing reproductive tract (R). X190.

of headache. However, 4 h after the tirst dose of thiabendazole, a sudden severeperiorbital swelling of the right eye associatedwith a mild decreasein visual acuity occurred, attributed to an acute reaction to a retrobulbar parasitic granuloma, and was treated successfully with dexamethasone. Patient no. 4 died of unknown causes 18 d after admission to the Queen Mary Hospital in late 1981. 5 days before hospitalization, she showed drowsiness, anorexia, productive coughs, tremor of hands and decrease in spontaneous movements. The initial haematological study, renal and liver function tests and CSF examination were normal. Eosinophilic pleocytosis was seen only during a subsequent examination 7 d later. She lapsed into a coma on the next day and never recovered. Post-mortem, a large blood clot (O-3 x 2 x 2.5 cm) with sharp demarcation from the brain substance, was noted caudal to the left lentiform nucleus. About 40 random haemorrhagic streaks were located in the grey and white matter of the cerebrum, cerebellum and pons. After KO (1984) reported the first case of angiostrongyliasis in Hong Kong, slides prepared from the brain of patient no. 4 were re-studied. Sections of a nematode were found in the white matter of the parietal lobe in 5 sections, 2 worm sections in each tissue section. The nematode, with opposite diameters measuring 206 urn X 120 um, had a smooth cuticle and a polymyarian-coelomyarian somatic musculature (Fig. 3). The pseudocoele contained an intestine with distinct epithelial cells and digested

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R. c. ~0 et al.

food contents, and various regions of a developing reproductive tract which indicated a young fifth-stage worm. Around the worm sections, there were mild leucocytic infiltrations. In the neuroparenchyma there were also numerous random and large haemorrhagic tracks. Heavy infiltrations consisting mainly of eosinophils were seenin the subarachnoid region especially around blood vessels. IFAT study of the worm sections revealed grade 2 positive fluorescence in the hypodermis, edgesof the somatic musculature, membranes of the cells of the reproductive tract and curicular surface of the nematode when anti-A. cantonensis serum was applied. When the anti-Gnathostomaserum was used, similar results were obtained except for the absence of fluorescence on the cuticular surface. Normal rabbit serum yielded negative reactions. Discussion

This is the first report of endemic eosinophilic meningoencephalitis in Hong Kong. The 4 casesare considered asangiostrongyliasis mainly on the basis of clinical symptoms, which are typical of an infection with Angiostrongylus (see PUNYAGUPTA, 1979), and serological evidence. Gnathostomiasis, which is also endemic in south-east Asia, is usually in the form of eosinophilic myeloencephalitis characterized by transverse or ascendingmyelitis following the symptoms of nerve root pain. The CSF is bloody or xanthochromic (PUNYAGUPTA, 1979). Also, due to the visceral migration of the larvae, there are signs and symptoms referable to other organs besides the central nervous systemwhich have not been seenin angiostrongyliasis (CHITANONDH & ROSEN, 1967). However, hemiple-

gia, seen in patient no. 2, is not a common feature. studied 484 cases but hemiplegia was not observed and only 1% of the patients experienced general weaknessof the extremities. Similarly, of the 125casesstudied in Taiwan, 6% had flaccid paralysis of the extremities associatedwith coma (YII, 1976). Patients 1-3 had a mild infection. Patient no. 4, who becamecomatoseand died, most probably had a heavy worm burden, although only a single worm was noted in the neuroparenchyma. Such a low recovery of worms was probably due to the fact that angiostrongyliasis was not considered at the post-mortem examination and no effort was made to search for the worms. However, the nematode in the neuroparenchyma can be positively identified as a young fifth-stage A. cantonensis. The morphology and size of the worm are similar to those of worms recovered from experimentally infected animals 25 days after infection (Ko, 1979). The negative ELBA results rule out toxocariasis for patients 2 and 3. Although highly positive PUNYAGUPTA et al. (1975)

reactions were observed when Gnathosroma antigens

were used, this is not surprising as the crude antigens of helminths are well known to be non-specific. For the IFAT study, a positive reaction was observed on the cuticular surface of worms only when anti-A. cantonensis serum was used, which provides further evidence that the worm sections belong to Angiostron-

P&S. KUM & KO (1985) found that cuticular surface gf A. cantonensis reacted specifically to homologous anti-serum.

Patients 1 and 3, both children, lived in village homes in the rural New Territories district. Since Achatina fulica, the major snail intermediate host, abounds in their home environment, it is possible that the boys acquired the infection by accidentally ingesting or contacting the infective larvae on contaminated vegetation or freshly killed molluscs. These larvae can also reach the brain through skin lacerations (Ko, 1981). Patient no. 2 had a history of eating freshwater molluscs from a food-stall within 2 weeks before the onset of symptoms. Patient no. 4 lived in a rehabilitation centre and there was no record of her eating habits. Judging by the size, extent of development, and condition of the worm, her infection was about one month old; i.e., she probably acquired the parasite one week before the onset of symptoms. The timing of the onset correlates well with the usual increase in pathogenicity when the third-stage A. cantonensis moults into the larger 4-stage larva. Angiostrongyliasis should be more frequently encountered in Hong Kong, as it is in Taiwan and south-east Asian countries, if the local physicians were more familiar with parasitic diseases.About 10% of the rat population is naturally infected and many species of the local terrestrial and aquatic molluscs, including those which are commonly consumed as food, can serve as intermediate hosts (Ko, 1978). Many local Chinese are fond of eating molluscs. Another possible source of infection is the “drunken prawn”, a local delicacy eaten after placing the crustacean briefly in wine. This study shows that CT scanning can help to diagnose the disease.However, the size and location of the observedlesions are variable, probably depending on the number and movement of worms and extent of the haemorrhages. The resolution of the lesion about one month after the onset of symptoms also serves as a diagnostic feature.

References

Chitonandh,H. & Rosen, L. (1967). Fatal encephalomyeli-

tis caused by the nematode, Gnathostomaspinigatm. American Journal of Tropical Medicine and Hygiene, 16, 638-645. Ko, R. C. (1978). Occurrence of Angiostrongvlus cantonensis p2th;2h9eartof a spider monkey. Journal ofHeLminthology,

Ko, R. C. (1979). Host-parasite relationship of Angrostron~Zuscanronensis.1. Intracranial transplantation into various hosts. Journal of Helminthologv, 53, 121-126. Ko, R. C. (1981). Host-parasite relationship of Angiostrongylus canronensis.2. Angiotropic behaviour and abnormal sites development. Zeitschrift ftir Parasitenkunde, 64, 195-202. Ko, R. C. (1984). Are there parasitic disease problems in Hong Kong? In: Current Perspectives of Parasitic Diseases, Ko, R. (editor). Hong Kong: Depts of Zoology and Medicine, University of Hong Kong, pp. 29-51. Ko, R. C., Chiu, M., Kum, W. & Chart,,S. H. (1984). First report of human angiostrongyliasis in Hong Kong diagnosedby computerized axial tomography (CAT) and enzyme-linked immunosorbent assay. Transactions of the Rqal

Society of Tropical Medicine and Hygiene, 78,

354-35s. Kum, W. & Ko, R. C. (1985). Isolation of specific antigens from Angiostrongylus cantontxsis. 1. By preparative isoelectric focussing. Zeitschrift fiir Parasitenkunde, 71, 789-800.

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Punyagupta, S. (1979). Angiostrongyliasis: clinical features and human pathology. In: Studieson Angiastmgyliasis in Eastern Asia and Australia, Cross, J. (editor). Special publication of the U.S. Naval Medical Research Unit No. 2, pp. 138-150. Punyagupta, S., Juttijudata, P. & Bunnag, T. (1975). Eosinophilic meningitis in Thailand. Clinical studies of 484 typical cases probably caused by Angiasrrangylus

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A. cantonensis

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cantonensis.American Jmmal of Tropical Medicine and Hygiene, 24, 921-931. Yii, C. Y. (1976). Clinical observations on eosinophilic meningitis and meningoencephalitis caused by Angiostrangylus cantmmsis in Taiwan. American Journal of Tropical Medicine and Hygiene, 25, 233-249. Accepted for publication 16 September 1986