Journal of the Neurological Sciences, 1990, 96:241-256

241

Elsevier JNS 03320

Eosinophilic meningitis in Thailand Clinical and epidemiological characteristics of 162 patients with myeloencephalitis probably caused by Gnathostoma spinigerum S o m p o n e P u n y a g u p t a 1, T h a n o n g s a k Bunnag 2 and Pipat Juttijudata 3 J IVichaiyut Hospital. Bangkok (Thailand), 2School of Tropical Medicine, Mahidol University, Bangkok (Thailand), and 3Department of Tropical Medicine, Pra Mongkutklao Hospital, Bangkok (Thailand)

(Received 26 January, 1989) (Revised, received 28 December, 1989) (Accepted 28 December, 1989)

SUMMARY The clinical and epidemiological characteristics of 162 patients with eosinophilic myeloencephalitis, believed to be caused by invasion of the central nervous system by Gnathostoma spinigerum, are described. The case mortality rate was at least 12%, and probably higher. Single live young adult G. spinigerum were recovered from the brains of 2 patients at autopsy and from the eye lids of 2 other living patients. The disease caused by this parasite can be distinguished from that caused by Angiostrongylus cantonensis by characteristic acute nerve root pain, signs of spinal cord and cerebral involvement, and the presence of bloody or xanthochromic cerebrospinal fluid. As judged by its prevalence and mortality, central nervous system disease caused by G. spinigerum is the most important parasitic disease of the central nervous system in Thailand. Since invasion of the nervous system by this parasite is a significant cause of intracranial hemorrhage in Thailand, it should be kept in mind by internists, neurologists, neurosurgeons, and pathologists who care for patients residing in, or who have visited, areas where G. spinigerum occurs.

Key words: Eosinophilic meningitis; Myeloencephalitis; Gnathostoma spinigerum; Thailand

Correspondence to: Dr. S. Punyagupta,Director, VichaiyutHospital, 114/4 Setsiri Road, Phyathai, Bangkok 10400, Thailand.

0022-510X/90/$03.50 © 1990Elsevier Science Publishers B.V. (BiomedicalDivision)

242 INTRODUCTION In the course of a study in Thailand from 1965 to 1968 of patients with an eosinophilic pleocytosis, two clinical entities were clearly defined, namely, typical eosinophilic meningitis and eosinophilic myeloencephalitis (Punyagupta et al. 1975). The clinical and epidemiological characteristics of the 484 patients with typical eosinophilic meningitis, probably caused by Angiostrongylus cantonensis, have been described previously (Punyagupta et al. 1970, 1975). This report describes the clinical and epidemiological characteristics of the 162 patients with eosinophilic myeloencephalitis, probably caused by Gnathostoma spinigerum. Clinical aspects of the first 9 cases (Punyagupta et al. 1968b), the neuropathology of 9 fatal cases (Bunnag et al. 1970), and the clinical and pathological findings in 2 patients from whose brains G. spinigerum was recovered at autopsy (Punyagupta et al. 1968a) have been published previously.

MATERIALS AND METHODS The plan of the study and the criteria for differentiating typical eosinophilic meningitis from eosinophilic myeloencephalitis have been published previously (Punyagupta et al. 1970, 1975). In brief, patients considered to have eosinophilic myeloencephalitis were those with an eosinophilic pleocytosis who (1)experienced acute nerve root pain of the extremities and/or trunk (often followed in a few days by paralysis of the involved limbs), or (2) experienced sudden impairment of the sensorium or headache with or without localizing neurologic signs and had bloody or xanthochromic cerebrospinal fluid.

RESULTS Clinical data Symptoms Patients (114 males and 48 females) could be classified in one of 3 groups on the basis of their predominant clinical manifestations, namely, (1) myelitis, (2) encephalitis, or (3) hemiplegia. Some of the characteristics of the patients in each of these groups are shown in Table 1. Group 1 : patients with myelitis A total of 89 patients (62 males and 27 females) whose symptoms were predominately those of spinal cord involvement, with or without nerve root pain, are included in this group. All but 4 had symptoms typical of radiculitis as their chief complaint, 2-15 days (average 5) before admission. They were well until they experienced a sudden agonizing nerve root pain, described as sharp and shooting,

243 TABLE 1 NUMBER OF PATIENTS WITH EOSINOPHILIC MYELOENCEPHALITIS BY CLINICAL GROUP AND TYPE OF CLINICAL SYMPTOM Clinical features

Myelitis group No. (%)

Encephalitisgroup No. (%)

Hemiplegicgroup No. (%)

Totals No. (%)

Number of cases Males/females Age range (years) Root pain before admission Root pain after admission Headache Stiffness of neck Vomiting Paraesthesia Blurred vision Diplopia Eyelid swelling High fever Convulsion Impair sensorium Urinary retention Incontinence urine Motor weakness Migration swelling

89 62/27 12-65 85 8 (9) 43 (48) 20 (22) 18 (20) 0 (0) 5 (6) 6 (7) 1 (1) 2 (2) 3 (3) 11 (12) 39 (44) 7 (8) 89 (100) 7 (8)

56 38/18 8-57 0 (0) 3 (5) 55 (98) 43 (77) 42 (75) 7 (12) 10 (18) 9 (16) 3 (5) 20 (36) 8 (14) 19 (34) 0 (0) 2 (3) 12 (21) 4 (7)

17 14/3 6-57 0 (0) 0 (0) 17 (100) 7 (41) 5 (29) 3 (17) 5 (29) 1 (6) 2 (12) 6 (35) 3 (18) 10 (59) 0 (0) 2 (12) 17 (100) 1 (6)

162 114/48 6-65 85 (52) 11 (7) 115 (71) 70 (43) 65 (40) 10 (6) 20 (12) 16 (10) 6 (4) 28 (17) 14 (8) 40 (25) 39 (24) 11 (7) 101 (62) 12 (7)

similar to an electrical shock, from the spine to the trunk, limbs, or perineum. Attacks lasted from half an hour to a few hours and occurred several times each day. Muscular weakness o f extremities was noted 3 - 6 days after onset of pain. Pain ran from the groin or buttock down both legs in 23 patients, down one leg in 12 patients, and from the neck to one arm in 11 patients. Pain was felt only at the neck or shoulder by 10 patients, only at the chest wall by 8 patients, and only at the abdomen by 21 patients. Fourteen of the above 85 patients also experienced nerve root pain from the lower back to the anus, perineum, or scrotum a few days after admission. Within a few days of their initial pain, 12 patients noted that the site o f pain moved upward and 34 noted that it m o v e d downward. Four patients had symptoms compatible with a transverse spinal cord lesion without definite symptoms of nerve root pain. The severe pain in the chest or abdomen could mimick that o f a medical and surgical emergency, such as an acute myocardial infarction or an acute peptic perforation and, at the beginning of the study, m a n y patients were admitted to surgical wards. Usually, however, the correct diagnosis could be made by the history ofradicular pain followed by lower motor neuron paralysis of the involved extremities and by the sensory level of those patients with transverse spinal cord lesions. Difficulties in urination were frequently noted with lower limb paralysis. Symptoms of cerebral lesions such as headache, stiffness o f the neck, visual impairment, and changes in sensorium were commonly observed in patients with evidence of high spinal cord lesions. In 8 patients in w h o m nerve root pain had disappeared, it later recurred at a different site.

244 Three patients experienced the recurrence at the abdomen, 2 each at the neck and chest, and one in an arm.

Group 2: patients with encephalitis Patients in this group (38 males and 18 females), in contrast to those in the myelitis group, did not have typical nerve root pain prior to admission, but most (77~o) did complain of tightness or stiffness of the neck associated with their chief complaint of severe headache. Other symptoms of brain involvement were impairment of the sensorium (34 ~ of patients), convulsions (14 ~o), and vomiting (75 ~o)- Generalized motor weakness of all extremities was observed in 12 ~ of the group. Some patients could have been misdiagnosed as eosinophilic meningoencephalitis caused by A. cantonensis were it not for the characteristic finding of grossly bloody or xanthochromic spinal fluid. Only one patient in the group had clear colorless spinal fluid on admission, but bloody fluids were observed on subsequent spinal taps. Group 3: patients with hemiplegia The symptomatology of the patients (14 males and 3 females) in this group was similar to that of the group with encephalitis except that they had only unilateral paralysis of one or both limbs. With one exception, all these patients had bloody or xanthochromic spinal fluid on admission. The single exception did have it later. Patients in this group usually were diagnosed initially as having an ordinary cerebral hemorrhage. However, only 4 patients were older than 40 years of age and all were normotensive. Awareness of the possibility of Gnathostoma infection and thorough examination of the spinal fluid for eosinophilic leucocytes were important factors in establishing the correct diagnosis. Of the total number of patients in all groups, 63 ~ was admitted to hospital within 5 days of onset and 83~o within 10 days. Headache, a complaint of 71 ~o of all patients, was characterized as throbbing by 56~o, stabbing by 25~o, and dull and aching by 19~. Headache was localized to the occipital area in 58 ~o of patients, to the temporal area in 2 5 ~ , to the ocular area in 6 ~ , and generalized in 11 ~ . High fever was not common but was frequently observed in groups 2 and 3, probably because of cerebral involvement. Paraesthesiae were noted only by 6~o of patients. Generalized convulsions occured in 8 ~o of patients, all of whom had markedly impaired sensoria. Typical nerve root pain was observed in 8 and 3 patients from groups 1 and 2, respectively, many days after admission. A history of painless cutaneous migratory swelling and the unilateral eyelid swelling, which are typical manifestations of cutaneous gnathostomiasis, were experienced by only 7 and 4 ~ of patients, respectively, while failing vision and diplopia were experienced by 12 and 10~o, respectively. Signs The major physical findings for all 3 groups of patients are summarized in Table 2. The impairment of muscular power was present in both groups 1 and 3 but was different in character. Hemiplegia or hemiparesis was, by definition, characteristic of group 3.

245 TABLE 2 NUMBER OF PATIENTS WITH EOSINOPHILIC MYELOENCEPHALITIS BY CLINICAL GROUP AND TYPE OF CLINICAL SIGN

Number of cases Motor involvement Paralysis Paraesis Sensorinmimpalrment Lethargy Semieoma Coma Stiffness of neck Kernig's sign Aphasia Cranial nerves Involvement Blurred disc Papilledema Nystagmus Facial paralysis Ptosis Lateral rectal paralysis High fever Hypertension Eyelid swelling

Myelitis group No. (%)

Encephalitisgroup No. (%)

Hemiplegicgroup No. (%)

Totals No. (%)

89 89 66 23 11 2 3 6 15 0 0

(100) (100)

56 12 0 12 24 10 9 5 34 11 0

(61) (20) (0)

17 (100) 17 (100) 9 8 10 (59) 4 3 3 2 (12) 1 (6) 1 (6)

162 (100) 118 (73) 75 43 45 (28) 16 15 14 51 (32) 12 (7) 1 (0.6)

7 3 1 1 1 1

(8)

23 (41) 10 6 1 3 1

17 (100) 4 3 0 7 0

47 (29) 17 10 2 11 2

0 13 (15) 0 (0) 3 (3)

2 8 (14) 1 (2) 3 (5)

3 6 (35) 0 (0) 2 (12)

5 21 (17) 1 (0.6) 8 (5)

(12)

(17) (0) (0)

(100) (21) (43)

The motor impairment was observed in all 89 cases o f myelitis group; involvement of both legs in 57 cases, two legs and one arm in 13 cases, all extremities in 4 cases, one leg in 8 cases and one arm in 7 cases. In group 2 (those with encephalitis), generalized weakness of all extremities was observed in 12 patients. Signs o f meningeal irritation (neck stiffness and a positive Kernig's sign) were more c o m m o n in this group than in the others. As would be expected, impairment of the sensorium and involvement of cranial nerves was more frequent in groups 2 and 3. Blood pressure higher than 145/90 m m H g was observed in only one patient (from group 2). Impairment of the sensations o f touch and pain was observed in all patients who had m o t o r involvement and corresponded to the level of nerve root or spinal cord lesions. Unilateral eyelid swelling (Fig. 1) was observed in 8 patients, in 2 of w h o m it developed after admission.

Laboratory data Leucocytosis (10000 cells/ml or more) and eosinophilia of 10% or more were observed in 54 and 57 % o f cases, respectively. However, moderately high eosinophilia of over 21% was seen in only 26?/0 o f cases. The pattern o f eosinophilia was similar in the 3 clinical groups. The gross findings of the initial spinal fluid examination are summarized in

246

Fig. 1. Left eyelid swelling in a patient of eosinophilic myeloencephalitis at the time of admission. Table 3. Bloody or xanthochromic spinal fluid was observed initially in 104 patients (64~o), mostly in groups 2 and 3. In 3 patients with spinal fluids that were initially xanthochromic and in 2 patients with spinal fluids initially clear, subsequent spinal taps revealed blood fluid. Initial spinal fluid pressure was increased in 53 ~o of patients, 35 having a pressure of 200-300 m m H 2 0 and 1 8 ~ having a pressure of greater than 300 m m H 2 0 . More than half of the patients had pleocytosis of less than 500 cells/ml and 16 ~o had less than 100 cells/ml. In 9 patients the first spinal fluid examination revealed less than 20 cells/ml but subsequent spinal taps showed a higher number. Eosinophilia of

TABLE 3 NUMBER OF PATIENTS WITH EOSINOPHILIC MYELOENCEPHALITIS BY CLINICAL GROUP AND GROSS CHARACTER OF CSF Character

Myelitis ~oup No.(%)

Encephalitis ~oup No.(%)

Hemiplegic group No.(%)

Totals No.(%)

Bloody Xanthochromic Clear-turbid Totals

9 24 56 89

40 (71) 15 (27) 1 (2) 56 (100)

8 (47) 8 (47) 1 (6) 17 (I00)

57 47 58 162

(10) (27) (63) (100)

(35) (29) (36) (100)

247 the spinal fluid greater than 1 0 ~ was eventually seen in all patients, including the 11 patients with initial percentages of less than 10 ~ . Eosinophilia of the spinal fluid was similar in each of the 3 clinical groups and eosinophilic pleocytosis of over 30~o was seen in 109 cases (64~). The sugar content of spinal fluid was low only in 16 patients, but the protein content was higher than 50 mg/100 ml in 72°/o of patients. A random sample of spinal fluids (total of 48) was cultured for bacteria but none was found. Stool examination for ova of helminthic parasites was positive in 50~o, of patients, 34~o having Opisthorchis, 13~o hookworm, and 1 ~ each ofAscaris, Taenia,

and Enterobius. X-ray examination of the spine was carded out on 19 paraplegic patients with negative results. Electroencephalography (EEG) performed on 7 patients in group 1, 4 patients in group 2, and 3 in group 3 revealed localized abnormalities on one side in 10 instances. Carotid angiography done in 5 patients with localized E E G abnormalities was inconclusive.

Treatment and course of illness Since patients were hospitalized at different institutions and attending physicians at those hospitals were responsible for their care, treatment varied. In addition to the treatment of symptoms, oral prednisolone at a dosage of 40-60 mg dally or 5 mg dexamethasone intravenously every 4 - 6 h was given to a total of 118 patients for about one week. No definite benefit was seen when comparisons were made with patients who did not receive steroids. Aqueous penicillin was given intravenously at a dally dose of 6-12 million units to 72 patients who had moderately high fever. Again, the results were inconclusive. The clinical course of patients in the 3 clinical groups is summarized in Table 4. T h o s e who recovered did so slowly and had partial neurological deficits. They could

TABLE 4 NUMBER OF PATIENTS WITH EOSINOPHILIC MYELOENCEPHALITISBY CLINICAL GROUP AND CLINICAL COURSE Clinical course

Myelitis g r o u p No. (~)

Encephalitisgroup No. (~)

Hemiplegicgroup No. (~)

Totals No. (%)

Totals Improved on discharge Not improved on discharge Dead Postmortem Gnathostome recovered

89 (100)

56 (100)

17 (100)

162 (100)

52 (59)

42

(75)

11 (65)

105 (65)

7 (12.5) 7 (12.5) 3

4 (24) 2 (11) 2

38 (23) 19 (12) 10

Ia

1a

27 (30) 10 (I1) 5 2b

Parasite recovered from the swollen eye-lid. b Parasite recovered from the brain at post mortem.

4

248 walk with help and could urinate. The case fatality ratio was 19/162 and was similar (11-12~o) for each clinical group. Actually, the case fatality ratio was probably much higher since 38 patients were taken home unimproved and many were critically ill. Patients who died had either progressive cerebral depression or an abrupt loss of consciousness. Four patients were much improved and ready to leave hospital when they suddenly experienced severe headache, lapsed into coma, and died within a few hours. Postmortem examination of 10 patients revealed multiple subarachnoid, cortical, or intraventricular hemorrhages, brain necrosis, and necrotic tracks (Fig. 2a,b,c). Massive hemorrhages were the cause of death. A single G. spinigerum was recovered from each of 2 patients and both parasites were still alive at the time of death of the patient (Fig. 3). The neuropathology has been described in detail elsewhere (Punyagupta et al. 1968b; Bunnag et al. 1970). Epidemiological data Distribution of cases by age group and sex Patients ranged in age from 6 to 65 years and their distribution by age group and sex is shown in Table 5.

Fig. 2. (a) Coronal section of a brain showing cortical hemorrhage. (b) Brain of another case died of intraventricular hemorrhage. (c) Spinal cord of an eosinophilic myelitis case showing grossly necrotic tracks.

249

Fig. 2b.

Fig. 2e.

250

Fig. 3. A living adult Gnathostomaspinigerumrecovered from the choroid plexus of the fourth ventricle of a patient who died of massive cerebral hemorrhages. TABLE 5 NUMBER OF PATIENTS WITH EOSINOPHILIC MYELOENCEPHALITIS BY AGE-GROUP AND SEX Age group (years)

Male

Female

Totals

0-9 10-19 2o-29 30-39 40-49 50-59 60-69 Totals

3 18 19 34 20 15 5 114

2 5 20 12 5 3 1 48

5 23 39 46 25 18 6 162

Distribution of cases in time Eighty-one percent of patients had the onset of their disease between May and September, the rainy season. The correlation between the distribution o f cases in time and rainfall is shown in Fig. 4.

Distribution of cases by place of residence Patients resided in 16 different provinces representing all regions of Thailand except the most southern part. However, the prevalence o f the disease was by far the highest, with 140 o f the total of 162 cases, in the northeast. Both eosinophilic myeloencephalitis and typical eosinophilic meningitis, presumably caused by A. cantonensis,

251 35.

[]

ALL CASES

~UBON 30,

=

CASES

=RAINFALL

25-

- 1200

t~J

0

20-

-I000

-

[1~ W

15-

Z

I0-

800

E

600

.J .J

z 400

,~

5' 200

O

JAN FEB MAR APR MAY JUN JUL AUG SEP OCT NOV DEC MONTHS

Fig. 4. Distribution of cases by month of admission and the amount of rainfalls. were seen in the same areas, but with different frequencies. The ratio between the former and the latter was 1/12 in Korat, 1.7/1 in Ubon, and 1/3 (162/484) in all localities studied.

Incubation period N o definite information on the incubation period of eosinophilic myeloencephalitis was obtained because of uncertain or confusing dietary histories. The infective larvae of G. spinigerum are found in many kinds of food animals and it is not known how soon after ingestion the nematodes can enter the central nervous system, though it is suspected that it may be 30 days or more. N o n e of the 162 patients was from the same household or ate the same dishes of raw food together.

History of previous similar illness A history of similar previous illness was obtained from 18 patients but there were no available clinical records to document the illness. Only 4 patients could remember the time of the previous attacks which ranged from 3-10 years beforehand.

Food habits of patients Of the total of 162 patients, 49 (30~o) could not furnish reliable information on their diet because of the state of their sensorium. Of the remaining patients, 9 denied having eaten any raw food, 19 had eaten only one kind of raw food in the 30 days prior to the onset of their first symptom. Of the latter, 37 ~o ate raw snails, 33 ~o raw freshwater fish, 25 ~o raw freshwater shrimp, and 5 ~ other types of raw animals. The frequency with which various kinds of raw food were eaten by the 85 patients who ate more than one kind of raw food 30 days prior to onset was as follows: raw vegetables, 121 times; raw fish or raw fish preparations, 164 times; freshwater shrimp, 45 times; freshwater snails, 52 times; raw beef, 43 times; other miscellaneous raw food, 26 times. Almost all patients ( 9 6 ~ ) drank untreated water from ponds or canals.

252

Distribution of cases by occupation The disease did not seem to be limited to any particular occupation but appeared to be most prevalent among farmers (62~o of patients). Eosinophilic myeloencephalitis and intracranial hemorrhage Since bloody and xanthochromic spinal fluid is commonly observed in eosinophilic myeloencephalitis, we tried to determine the frequency of the disease among patients with intracranial hemorrhage. The study was carried out in April and October 1968, in 3 provincial hospitals in Saraburi, Pra Phuttabat, and Lopburi in central Thailand about 130 km north of Bangkok. These provinces were known endemic areas for cutaneous gnathostomiasis. All patients who were admitted during the study period with a clinical diagnosis of cerebral vascular accident (CVA) and bloody or xanthochromic spinal fluid were examined for pleocytosis and eosinophils in their spinal fluid. Of a total of 54 patients studied, 12 (22~) could be diagnosed as having eosinophilic myeloencephalitis. The percentages were 27 at Saraburi, 14 at Pra Phuttabat, and 30 at Lopburi.

DISCUSSION The disease described here is distinguished from the well known eosinophilic meningitis caused by A. cantonensis by nerve root pain, paralysis of extremities, sudden loss of consciousness, spinal cord lesions, bloody and xanthochromic spinal fluid, and a clinical course with a high fatality rate. Thus, it is a more severe disease than that caused by A. cantonensis and has a higher mortality rate. The fatality rate which we observed, 12~o, is almost certainly an underestimate, since many of the 38 patients taken home from the hospital in critical condition probably died. The absence of treatment for the disease is also discouraging. Eosinophilic myeloencephalitis is a newly recognized disease whose clinical features were briefly described by us in 1968 (Punyagupta et al. 1968a,b) and proven by post-mortem findings (Punyagupta et al. 1968a). In the past, invasion of the central nervous system (CNS) by Gnathostoma had been suspected but never confirmed (Daengsvang, 1949; Tansurat, 1955; Bodhidat and Punyagupta, 1956). Also, in retrospect, it appears probable from the clinical descriptions that some patients from Thailand reported to have had eosinophilic meningitis, in fact had Gnathostorna infections, namely, one of 11 patients from Roi Ed described by Benjapongs (1964), one of 32 patients from Udorn described by Jittayasothorn et al. (1965), 5 of 30 patients from Bangkok described by Hongladarom and Indarakoses (1966), and 6 of 22 patients from Bangkok described by Sorasuchart et al. (1968). Post mortem findings for 3 cases described in the latter 2 papers were typical of the neuropathology of gnathostomiasis which we have described (Ptmyagupta et al. 1968a; Bunnag et al. 1970;). One might ask whether or not all our 162 patients were infected with the same parasite, Gnathostoma, and if so, why 3 different types of clinical manifestation were observed. However, the clinical features observed correlate well with the post-mortem

253 findings of proven Gnathostoma infections. Nerve root necrosis and hemorrhages induce the typical agonizing nerve root pain of the extremities and trunk. Gnathostoma can migrate along the spinal nerve and damage the nerve root before entering the CNS at any level from the lumbosacral plexus to the cervical plexus. The parasite can also enter the CNS without damaging the nerve root, which explains the absence of nerve root pain in some patients. Parasites also may leave the CNS via a spinal nerve as indicated by the recurrence of root pain at a higher level later on in the course of illness. Boongird et al. (1977) reported two cases of radicular pain of the buttock and chest wall, respectively, 4 and 17 days after onset of paraplegia. G. spinigerum were recovered 3-6 h later from subcutaneous tissue in the areas affected by the pain. The optic nerve may also serve as a route of entry or exit for the parasite as shown by the presence of unilateral swelling and hemorrhage of periorbital tissue before or after CN S involvement. In fact, Gnathostoma parasites were removed surgically from near the swollen eyelids of 2 patients (Bunnag et al. 1968). Paralysis of the extremities and urinary retention can be explained by the grossly hemorrhagic and necrotic tracts observed in the spinal cord (Fig. 2c). In fact, Chitanondh and Rosen (1967) recovered Gnathostoma from the spinal cord of a patient who died of eosinophilic encephalomyelitis. The headache, neck stiffness, impairment of the sensorium, and the bloody and xanthochromic spinal fluid characteristic of patients in group 2 are probably the result of brain hemorrhages and necrosis caused by a migrating parasite. Multiple subarachnoid hemorrhages (Fig. 2b) are typical post-mortem findings. The presence of hemiplegia and bloody spinal fluid in group 3 patients are explained by the massive subcortical hemorrhages caused by a migrating parasite (Fig. 2a). Patients probably die of massive or multiple hemorrhages. Intraventricular hemorrhage (Fig. 2b) may be the cause of sudden death in some patients showing considerable improvement. Unlike A. cantonensis, G. spinigerum is not a neurotropic parasite. Consequently, involvement of the CNS is an accidental, not a regular, feature of infection with the latter parasite. In animal experiments, we were able to demonstrate the parasite in the spinal cord following oral feeding only once out of many trials. Generally, the clinical diagnosis of typical gnathostomiasis is based on the cutaneous migratory swellings and the associated eosinophilia of the peripheral blood. However, in our patients skin manifestations were observed only in 12 patients, swelling of the eyelids in another 8 patients, and a peripheral eosinophilia of less than 10~o in 69 patients. Therefore one cannot use the criteria for typical guathostomiasis to diagnose gnathostomiasis of the CNS. Bloody spinal fluid was observed in 57 of our patients and the special study of 3 hospitals indicated that 22Yo of "cerebral vascular accidents" in Thais are probably caused by Gnathostoma. The majority of the latter patients were young and normotensive. It is, therefore, important to examine bloody spinal fluid for the presence of an increased number of leucocytes and eosinophils. We believe that, previously, most cases of cerebral gnathostomiasis were misdiagnosed as cerebral hemorrhage from other causes, such as cerebral arteriosclerosis or aneurysm. Similarly, the finding of a low leucocyte count and a high level of protein in the spinal fluid of patients with signs and symptoms of spinal cord lesions may lead to an erroneous diagnosis of Guillaln-Barr6 syndrome or viral myelitis. The search for eosinophils in the spinal fluid is obviously of great importance to avoid misdiagnoses.

254 Unlike A. cantonensis, a single Gnathostoma parasite only is responsible for CNS diseases. Therefore, aside from considerations of size, it is very unlikely that the parasite could be recovered from the spinal fluid. The intradermal test for Gnathostoma is not specific enough and immunological studies of serum and spinal fluid for antibodies against Gnathostoma have not been conclusive (Egashira 1953; Punyagupta and Pacheco 1961 ; Tungkanak et al. 1972). Fortunately, the diagnosis of myeloencephalitis caused by Gnathostoma can be made with reasonable ease by the typical clinical features and the eosinophilic pleocytosis. G. spinigerum has been found in nature in many countries in Asia, and human disease caused by this parasite has been reported in Japan (Miyazaki 1960), China (Chen 1949), the Philippines (Yogore and Juliano 1951), Malaysia (Sandosham 1949), India (Sen and Ghose 1944), Burma (Gyi 1960), Palestine (Witenberg et al. 1950), and Indonesia (Lie 1949). Consequently, invasion of the CNS by the parasite may also occur in the same countries. In reviewing reports of eosinophific meningitis from some of the countries, it appears that some patients had signs and symptoms which, in retrospect, are suggestive of disease caused by G. spinigerum. For example, one of 4 cases reported by Sison et al. (1951) from the Philippines had hemiplegla, as did one of 8 reported by Smith from Sumatra, Indonesia (1963). Kishida and Sakagami (1961) reported coma and aphasia in a patient from Japan following cutaneous gnathostomiasis and suggested that the parasite had damaged the cerebral cortex. Of course, similar signs and symptoms might also be the result of other helminthic diseases, namely, schistosomiasis, echinococcosis, paragonimiasis, and trichinosis. Of these, Schistosoma has also been reported to produce paraplegia, nerve r o o t pain, and xanthochromic spinal fluid (Budsilovich et al. 1964; Bird 1965). The cases reported here occurred throughout the year but with increased incidence from May to December, corresponding to the rainy season. The manner in which patients acquired their infection is still unknown and the difference in the incidence between the sexes probably only reflects a difference in exposure. Human infection with G. spinigerum is generally attributed to ingestion of the infective third stage larvae of the parasite in the flesh of intermediate or transport hosts, which include fish, frogs, turtles, shrimp, snakes, birds (including chickens), pigs, etc. (Daengsvang 1949, 1968; Miyazaki 1960; Daengsvang et al. 1966). The diet histories of our patients did not allow us to incriminate any particular food. In fact, we do not even know the incubation period from the time of infection to the appearance of neurological symptoms. None of the patients described here lived in the same household or shared the same food. However, among another group of 6 patients who developed hypereosinophilia following the common ingestion of a suspect fish preparation, one patient died of CNS disease 72days after eating the food (Punyagupta 1967). The proven case of eosinophilic encephalomyelitis caused by G. spinigerum reported by Chitanondh and Rosen (1967) developed general systemic symptoms about 3 months prior to the onset of CNS symptoms. Presumably, several months may elapse between the time of infection and the onset of CNS involvement. We know from experimental work (Miyazaki 1960) that several months are required for the third stage G. spinigerum larva to reach the immature adult stage, the stage of the parasites which have been recovered from man.

255 Since the peak of seasonal occurrence of the disease in the northeast of Thailand is so definite, it is possible that most patients there acquired the disease from eating a particular infected food several months before the onset of the disease. It is known that second stage G. spinigerum larvae in copepods develop into early infective (third) stage larvae after 10 days. Since 96~ of our patients drank untreated ground water from ponds or canals, it is possible that they became infected by ingesting water containing infected copepods. In the summer months of February to May, water in reservoirs in the northeast is low and, consequently, the concentration of pollutants, including copepods increases. It is also true, however, that aquatic animals that become infected by ingesting copepods, such as fish and shrimp, also would be more likely to become infected during the same period. At present, it is not possible to decide which of the two possible explanations is the more likely to be correct.

ACKNOWLEDGEMENTS

We thank Dr. Leon Rosen, Director, Arbovirus Program, University of Hawaii for his support of this project and for his critical review of the manuscript. We should also like to thank Mrs. S. Pinnoi, Miss A. Pisithpun, Mr. A. NaNakorn, M.C. Pungmoengdee, and Lieut. S. Binkani for their valuable help.

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Eosinophilic meningitis in Thailand. Clinical and epidemiological characteristics of 162 patients with myeloencephalitis probably caused by Gnathostoma spinigerum.

The clinical and epidemiological characteristics of 162 patients with eosinophilic myeloencephalitis, believed to be caused by invasion of the central...
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