Parasitology International 63 (2014) 544–549
Contents lists available at ScienceDirect
Parasitology International journal homepage: www.elsevier.com/locate/parint
Angiostrongylus cantonensis eosinophilic meningitis: A clinical study of 42 consecutive cases in French Polynesia Erwan Oehler a, Frédéric Ghawche b, Alex Delattre c, Anthony Berberian d, Marc Levy e, Florent Valour a,⁎ a
Department of Internal Medicine, French Polynesia Hospital Center, 98716 Pirae, Tahiti, French Polynesia Department of Neurology, French Polynesia Hospital Center, 98716 Pirae, Tahiti, French Polynesia Department of Pneumology, French Polynesia Hospital Center, 98716 Pirae, Tahiti, French Polynesia d Laboratory of Pathology, French Polynesia Hospital Center, 98716 Pirae, Tahiti, French Polynesia e Laboratory of Microbiology, French Polynesia Hospital Center, 98716 Pirae, Tahiti, French Polynesia b c
a r t i c l e
i n f o
Article history: Received 30 September 2013 Received in revised form 8 February 2014 Accepted 16 February 2014 Available online 26 February 2014 Keywords: Angiostrongylus cantonensis Meningitis Eosinophils
a b s t r a c t Introduction: In endemic areas, eosinophilic meningitis is mainly caused by Angiostrongylus cantonensis. We describe a series of this poorly-known condition. Methods: Retrospective cohort study (2000–2012) including all patients diagnosed with eosinophilic meningitis in French Polynesia. Results: Forty-two patients (males: 61.9%, age: 22 (IQR 17–32)) were diagnosed with a serologically proven (n = 13) or probable A. cantonensis meningitis, mostly during the dry season (66.6%) and following the consumption of or prolonged contact with an intermediate/paratenic host (64.3%). No differential diagnosis was found in probable cases, in whom serological tests were performed earlier (7.5 days (6.5–10)) compared to positive patients (7.5 (6.5–10) versus 11 (7–30) days, p = 0.02). The most commonly reported symptom was headache (92.8%). Fever (7.1%) and biological inflammatory syndrome (14.3%) were rare. Blood eosinophil count was 1200/mm3 (900–2548). Cerebrospinal fluid (CSF) analysis disclosed a protein level of 0.9 g/L (0.7–1.1), a CSF/plasma glucose ratio of 0.50 (0.40–0.55), and 500 leucocytes/mm3 (292–725; eosinophils: 42.0% (29.5– 60); lymphocytes: 46.5% (32.5–59.0)). Thirteen cases (31.0%) were severe, with 11 focal neurological deficits. A delayed hospital referral (OR 1.13, p = 0.05) was associated with severity. Conclusions: A. cantonensis meningitis must be evocated in young patients with meningitic syndrome, severe headache, and CSF inflammation with predominance of eosinophils. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Eosinophilic meningitis is a rare condition, mainly related to central nervous system (CNS) infection by parasitic agents [1,2]. The nematode Angiostrongylus cantonensis, whose larvae are neurotropic, is the most frequent etiology of eosinophilic meningitis in endemic areas, including Southeast Asia and Pacific basin [1]. A. cantonensis normally affects rodents (and especially rats) in which larvae pass through the bowel wall, migrate to the brain, and develop into adult worms that reach the pulmonary arteries after 4 weeks where eggs are laid by adult worms (Fig. 1). First stage larvae migrate to the pharynx and are swallowed and excreted in the stool. They can survive for months in the environment, be ingested by snails or slugs and reach the fibromuscular tissues and mucus secretions of these intermediate hosts, which then become infective for rodents or paratenic hosts such as land crabs, frogs, lizards, planarians, fishes or freshwater shrimps [3,4]. Humans may be infected by eating raw or undercooked infested ⁎ Corresponding author. Tel.: +689 48 59 90; fax: +689 48 59 92. E-mail address: fl[email protected] (F. Valour).
http://dx.doi.org/10.1016/j.parint.2014.02.001 1383-5769/© 2014 Elsevier Ireland Ltd. All rights reserved.
snails or slugs included in local traditional food of endemic areas, by ingestion of infected paratenic animals, or by handling directly to the mouth in contact with hosts, and especially molluscs [5–8]. Humans constitute a parasitic impasse. Larvae migrate to the brain or the eye chamber (rarely, the lungs) and die, leading to intense inflammatory lesions responsible for clinical manifestations, mainly represented by transient meningitis with severe headache and paresthesias or hyperesthesias [1]. We here report a large series of eosinophilic meningitis in French Polynesia, aiming to describe the clinical features of this rare condition, with emphasis on severe presentations and their risk factors. 2. Patients and methods This retrospective cohort study was based on the examination of medical records registered in our institution from 2000 to 2012 under the codification B83.2 (“Angiostrongyloidosis to Parastrongylus cantonensis”) and G05.2 (“Encephalitis, myelitis and encephalomyelitis in other infectious and parasitic diseases classified elsewhere”) according to the International Statistical Classification of Diseases and Related
E. Oehler et al. / Parasitology International 63 (2014) 544–549
545
Fig. 1. Angiostrongylus cantonensis life cycle.
Health Problem (ICD-10) of the World Health Organization. The following inclusion criteria were used: i) compatible clinical manifestations i.e. meningitis symptoms (defined as the association of at least two of the following symptoms: headache, neck stiffness, and photophobia), or meningoencephalitis (i.e., meningitis symptoms with confusion, neurologic deficit, and/or visual disturbance), or myeloradiculitis (paresthesias, hyperesthesias); ii) plasmatic hypereosinophilia, defined as blood eosinophil count N 500/mm3; and iii) the presence of more than 10 eosinophils/mm3 of CSF, and/or eosinophils accounting for more than 10% of the total CSF leukocyte count [1,9,10]. A. cantonensis serological tests were performed using enzyme linked immunosorbent assay (ELISA) detecting the 29 kDa antigenic polypeptide of A. cantonensis [11]. Files were excluded if clinical and biological manifestations were not sufficiently suggestive of the diagnosis, or when a differential diagnosis cannot be excluded. Clinical, biological and radiological data were collected from medical records and nursing charts according to a standardized case report form, including sex, age, ethnic group, urban or rural dwelling place, supposed mode of transmission, date of appearance of symptoms, clinical manifestations, laboratory values, radiographic studies and treatment. Severe forms were defined according to the presence of encephalitis and/or neurological deficit including cranial nerve involvement symptoms. Descriptive statistics were used to estimate the frequencies of the study variables, described as median and interquartile ranges (IQR). For the percentage calculation of each variable, the number of missing values was excluded from the denominator. Non-parametric statistical methods were used to compare the study groups (Chi2, Fisher exact test, Mann–Whitney U test), as appropriate, with a significance level of 0.05. Risk factors for severe forms were assessed using a linear mixed regression model. After exclusion of interacting variables, those with a p-value b 0.15 in univariate analysis were included in the final multivariate model. All analyses were performed using SPSS software version 16.0 (SPSS, Chicago, IL). 3. Results From 2000 to 2012, 70 files were registered under the G05.2 and/or B83.2 codes in our institution, corresponding to 57 patients. Fifteen files were excluded, including 3 medical records with insufficient data and 12 patients with differential diagnosis for eosinophilic meningitis: five complications of HIV infection (three toxoplasmosis, a JC virus infection and an encephalitis of undetermined etiology), a congenital toxoplasmosis, three other viral meningoencephalitis (H1N1 influenza virus,
varicella-zoster virus, and dengue fever), one tuberculous meningitis, a Rasmussen encephalitis and a Devic's optic neuromyelitis. Hence, 42 patients with eosinophilic meningitis were finally enrolled in the study, including 13 (31.0%) serologically proven cases of A. cantonensis CNS infection (positive plasma and/or CSF serological tests). No differential diagnosis existed for the 29 remaining patients, which are included as probable cases. 3.1. Demographic and epidemiological features Twenty-six patients were male (61.9%, sex ratio: 1.5), with a median age of 22 years (IQR 17–32). Seven (16.3%) were under 15 year-old (Table 1). Thirty-nine patients (92.8%) were Polynesian; others (7.2%) were from metropolitan France. All cases were initially referred to the emergency department, and then hospitalized with a median stay of 5 days (IQR 3–6). A majority of cases (n = 28, 66.6%) were diagnosed during the dry and cool seasons (May–October). Twelve patients (28.5%) lived in an urban area whereas the others lived in rural conditions (71.5%). Exposure risk was specified in 27 cases (61.9%): 22 persons (81.5%) reported eating shrimps (including 16 eating taioro, a traditional Polynesian meal made with head shrimps fermented in coconut milk and sea water, and 6 eating raw shrimps), one had eaten snails (3.7%) and one ate raw crab (3.7%). Indirect risk factors were found among 3 other patients: 2 (7.4%) reported eating raw vegetables in fields without washing them and one (3.7%) worked in a shrimp farming factory. Three persons were infested during the same meal (taioro). The delay between the presumptive infesting meal and the beginning of the symptomatology was available in only 10 cases (40.0%), ranging from 3 days to one month. 3.2. Clinical features Patients were admitted at the hospital within a median of 7 days (IQR 5–10) after the onset of symptoms. Headaches were the most frequently reported complain (92.8%). When specified, the distribution of headache was frontal and/or retro-orbital (33.3%), temporal or parietal (12.8%), occipital (7.2%), or generalized (15.4%). Headache was defined as severe, intensive or intolerable in 17 cases (41.5%). When evaluated by analogic visual scale (n = 13), pain was at a median of 7 (IQR 6–8). Other meningitis symptoms included photophobia (n = 22, 52.4%), neck stiffness (n = 18, 42.8%) or neck pain (n = 17, 40.4%), and nauseas (n = 29, 69.0%) or vomiting (n = 24, 57.1%). History of chills or fever was reported in 11 cases (26.2%) but fever was objectively measured
546
E. Oehler et al. / Parasitology International 63 (2014) 544–549
Table 1 Characteristics of patients and assessment of severe form determinants. All patients (n = 42)
Demographic characteristics Sex (male) Age (years) Polynesian origin Urban life mode Clinical presentation Evolution delay (days) Fever Headaches Paresthesia, hyperesthesia Muscular pain Meningitis symptoms Encephalitis symptoms Focal neurological deficit Cranial nerve injury Convulsions Blood laboratory tests Biological inflammatory syndrome WBC count (/mm3) Eosinophil count (/mm3) (% of total WBC) Na (mmol/L) Positive angiostrongyliasis serology CSF characteristics Turbidity Protein (g/L) Glucose (mmol/L) (% of FBG) Leucocytes (/mm3) Neutrophils (%) Lymphocytes (%) Eosinophils (%) Positive angiostrongyliasis serology CT and/or MRI abnormality Management Length of hospital stay (days) Corticosteroids Initial dosage (mg/kg/day) Total duration (days) Antihelmintic therapy
Severe forms (n = 13)
p
Univariate analysis
Multivariate analysis
OR (95% CI)
p
26 (61.9%) 22 (17–32) 39 (92.9%) 12 (28.6%)
9 (69.2%) 22 (17–36) 9 (69.2%) 3 (23.1%)
0.382 0.978 0.222 0.446
1.588 (0.395–6.379) 0.994 (0.944–1.047)
0.514 0.832
7 (5–10) 12 (28.6%) 39 (92.9%) 12 (28.6%) 11 (26.2%) 29 (69.0%) 13 (31.0%) 11 (26.2%) 8 (19.0%) 1 (2.4%)
9 (7–19.3) 3 (23.1%) 10 (76.9%) 5 (38.5%) 3 (23.1%) 7 (53.8%) 13 (100%) 11 (84.6%) 8 (61.5%) 1 (7.7%)
0.063 0.446 0.025 0.277 0.538 0.144 NA NA NA NA
1.129 (1.000–1.276) 1.500 (0.331–6.798)
0.050 0.599
0.509 (0.125–2.073) 1.270 (0.276–5.839) 2.694 (0.679–10.739)
0.346 0.759 0.160
6 (14.3%) 11,350 (9400–14,000) 1200 (900–2547) 14.2 (8.0–23.7) 139 (137–140) 11/28 (39.3%) 25 (59.5%) 0.9 (0.7–1.1) 2.6 (2.2–2.9) 50.0 (40.2–54.5) 500 (292–725) 0.0 (0.0–2.3) 46.5 (32.5–59.0) 42.0 (29.5–60.0) 7/23 (30.4%) 11/38 (28.9%) 5 (3–6) 17 (40.5%) 1.4 (1.2–1.8) 4.5 (3.0–12.0) 7 (16.7%)
2 (15.4%) 10,700 (8300–13,900) 1496 (880–2050) 18.8 (7.0–23.6) 138 (135–139) 4/9 (44.4%)
0.615 0.414 0.744 0.989 0.036 0.507
0.880 (0.140–5.539) 1.000 (1.000–1.000) 0.418 (0.000–360.389)
0.892 0.495 0.800
0.720 (0.533–0.973) 0.729 (0.146–0.3654)
0.032 0.701
7 (53.8%) 0.9 (0.8–1.1) 2.5 (2.2–2.7) 48.4 (36.4–52.4) 500 (268–700) 1.0 (0.0–2.5) 40.0 (32.0–58.0) 45.0 (34.0–62.0) 4/9 (44.4%) 5/13 (38.5%)
0.433 0.446 0.270 0.413 0.684 0.793 0.707 0.740 0.239 0.457
1.403 (0.373–5.269) 0.855 (0.314–2.334) 0.981 (0.926–1.039)
0.616 0.760 0.506
0.999 (0.998–1.001) 0.942 (0.775–1.147) 0.996 (0.961–1.031) 1.007 (0.973–1.041) 0.341 (0.055–2.131) 0.505 (0.119–2.145)
0.395 0.544 0.805 0.699 0.250 0.355
6 (5–9) 7 (53.8%) 1.4 (1.0–1.7) 14.5 (7.3–15.0) 3 (23.1%)
0.002 0.200 0.560 0.019 0.456
OR (95% CI)
p
1.121 (0.985–1.277)
0.084
0.791 (0.545–1.149)
0.218
Descriptive results are presented as n (%) and as median (IQR). Comparisons were run using non-parametric statistical methods (Chi2, Fisher exact test or Mann–Whitney U-test, as appropriate). Determinants of severe forms were assessed using logistic regression and are presented using odd ratios (OR) and their 95% confidence interval (95% CI). CSF: cerebrospinal fluid; CT: computed tomography; FBG: fasting blood glucose; MRI: magnetic resonance imaging; Na: sodium; WBC: white blood cell.
above 38.3 °C in only 3 cases (7.1%). Other symptoms included asthenia (n = 8, 19.0%), dry cough (n = 4, 9.5%), blurred vision or visual acuity defect (n = 3, 7.2%), abdominal pain (n = 3, 7.2%) and/or transit disorders (n = 3, 7.2%, including 2 patients with diarrheas and one with constipation), pruritus (n = 3, 7.2%), and radiculalgia (sciatica and cervicobrachial neuralgia), arthralgia, erythematous eruption, extremity edema, and palpebral edema in one case each (2.4%) (Table 1). 3.3. Biological features Twenty-nine patients (69.0%) had leukocytosis (N10,000/mm3). The median initial and maximal blood eosinophil counts were 1177/mm3 (IQR 780–2058) and 1200/mm3 (IQR 900–2548), respectively, corresponding to 10.4% (IQR 6.5–17.5) and 14.2% (IQR 8.0–23.7) of total WBC. Only 6 patients (14.3%) presented a biological inflammatory syndrome (CRP N 5 mg/L), with a median CRP plasmatic level of 13.4 mg/L (IQR 9.5–17.0). Four patients (9.5%) had hyponatremia (b135 mmol/L). All patients underwent a lumbar puncture, which was performed within a median delay of 7.0 days (IQR 5.5–9.5) after the onset of symptoms (Table 1). Plasmatic and CSF eosinophil counts were not correlated (Pearson correlation coefficient: 0.176, p = 0.278). Median spinal fluid protein concentration was 0.9 g/L (IQR 0.7–1.1 g/L), and 18 of the 39 patients (46.1%) in whom blood glucose value was available were considered to have low CSF glucose level (ratio CSF/plasma
b 0.5). When available (n = 9), CSF lactate level was slightly elevated, at a median level of 185 mg/L (IQR 181–227) (Table 1).
3.4. Radiographic features Cerebral computed tomography (CT-scan) was performed in 36 cases (85.7%), and considered as normal in 31 (86.1%) patients. In other cases, CT-scan disclosed a moderate cerebral edema (n = 3, 8.3%) or a minimum cerebral hyperdensity related to bleeding (n = 1, 2.7%). Magnetic resonance imaging (MRI) was performed in 13 cases (30.0%). It was considered as normal in 5 (38.5%) patients, and showed a minimum meningeal thickening and abnormal enhancement of diffuse localization in 3 cases (23.1%), with right ocular nerve abnormal enhancement in 1 of them, and a left cerebellar localization with an abnormal enhancement of the acousticofacial complex in 1 additional case. Other MRI abnormalities consisted of sub-meningeal hyperintensities (n = 2, 15.4%), images suspect for bleeding (n = 2, 15.4%), and centromedular hyperintensity at the T12 medullary level (n = 1, 7.7%) (Fig. 2). Electroencephalography was normal in 5 of 6 patients, whereas one showed discrete signs of left temporal suffering. Electromyography was performed in 3 cases and disclosed a neuropathy mainly affecting the lower limbs as a sensory impairment.
E. Oehler et al. / Parasitology International 63 (2014) 544–549
547
Fig. 2. Cerebral magnetic resonance imaging findings in two patients with A. cantonensis meningitis. A: Axial T1-weighted MRI disclosing a diffuse leptomeningeal enhancement after gadolinium injection (arrows). B: Axial T2-weighted Flair MRI showing hyperintense lesion of the rolandic cortices (arrow).
One of the patients presenting a dry cough benefited from a chest ray showing a bilateral interstitial syndrome. 3.5. Severe forms Clinical presentation was considered as severe with clinical encephalitis in 13 cases (31.0%). Two cases presented isolated consciousness impairment with hypotonia. Focal neurological deficit was present in 11 other patients (26.2%), including seizures in one case and cranial nerve palsy in 8 cases (19.0%). Implicated cranial nerves were the abducens (n = 3, 37.5%), facial (n = 2, 25.0%) and oculomotor (n = 1, 12.5%). Multiple cranial nerve implications were seen in 2 cases (25.0%) (III, IV, VI, IX and XII for the first patient, and VI, VII and IX for the second one). Clinical presentation of severe cases did not greatly differ from other patients (Table 1). The only identified differences were a lower prevalence of headaches (76.9% versus 100%, p = 0.025) and a slightly lower plasmatic sodium level (138 mmol/L versus 139 mmol/L, p = 0.036). In univariate analysis, a delayed hospital referral (OR 1.13, 95% CI 1.00–1.28, p = 0.05) was associated with severity, whereas hypernatremia was protective (OR 0.72, 95% CI 0.53–0.97, p = 0.032). None of these variables was found to be a predictive factor of severity in multivariate analysis (Table 1). 3.6. A. cantonensis serological tests Thirty-two patients benefited from at least one A. cantonensis serological test in blood (n = 28) and/or CSF (n = 23) within a median delay of 9.5 (IQR 7.0–12.5) and 7.0 (IQR 5.5–9.5) days after the onset of symptoms. Plasmatic and CSF serological tests were positive in
Table 2 Plasmatic and CSF serological test results. CSF serological test
Plasmatic serological test
Total
Total
NR
Positive
Negative
NR Positive
10 3
1 5
3 3
Negative
6
1
10
7 Delay: 13 (8–26.5)
16 Delay: 6.5 (5–7.5)
19
CSF: cerebrospinal fluid; NR: not realized.
14 11 Delay: 11 (7.5–32.5) 17 Delay: 9 (7–11) 42
11 (39.3%) and 7 (30.4%) cases, respectively, leading to 13 “confirmed cases” (Table 2). The delay of serological test realization was significantly higher in positive patients (11 (IQR 7–30) versus 7.5 (IQR 6.5–10) days; p = 0.02). 3.7. Treatment and outcome All but one patient (97.6%) required antalgics, including level 2 analgesics or morphinics in 23 and 8 cases, respectively. Seventeen patients (40.5%) benefited from corticosteroids for 4.5 days (IQR 3.0–12.0) at a median daily dose of 1.4 mg/kg (IQR 1.2–1.8). Only 7 patients (16.7%) received a specific therapy, including albendazole (n = 4), flubendazole (n = 2) or ivermectin (n = 1). The symptoms improved within a few days in all patients, allowing a rapid discharge to home. One patient with a confirmed A. cantonensis meningoencephalitis presented recurrent symptoms leading to 3 consecutive hospitalizations, despite corticosteroid and albendazole therapies. Outcome was finally favorable more than two months after the onset of the disease. 4. Discussion These findings confirmed that A. cantonensis infection can lead to severe forms of eosinophilic meningoencephalitis. If angiostrongyliasis was confirmed by serological tests in only 13 patients (31.0%), the diagnosis was very likely in the others because i) other parasitic etiologies of eosinophilic meningitis (i.e. Gnathostoma spinigerum, Baylisascaris procyonis, cysticercosis, Paragonimus westermani, schistosomiasis, and fascioliasis) have never (or exceptionally) been described in French Polynesia; ii) other differential diagnoses (i.e. cryptococcosis, malignant hemopathy, ventriculoperitoneal shunt, drug adverse reactions) were excluded in all patients; iii) the patients did not meet the diagnosis criteria of idiopathic hypereosinophilic syndromes; and iv) plasmatic and/or CSF serological tests were realized at the beginning of disease evolution (especially in seronegative patients), which can explain their negativity [2,9]. Unfortunately, serological tests could not be repeated in negative patients, due to the short hospitalization and to the geographical isolation of patients in Polynesian islands. Since the discovery of A. cantonensis in 1935 in China, more than 2800 cases have been reported worldwide, mostly in endemic areas, including Southeast Asia and the Pacific islands. French Polynesia constitutes the third country regarding the number of reported cases (9% of all cases), before the USA with its pacific islands (Hawaii and Samoa), Australia, Micronesia and Melanesia [7,12–16]. Global incidence is not known and seems to greatly vary according to the prevalence of reservoir and intermediate/paratenic hosts, their infestation rate, and their
548
E. Oehler et al. / Parasitology International 63 (2014) 544–549
intentional consumption in traditional food. Few local studies gave the incidence in their own area, evaluated at 2.1 per 100,000 person-years in Hawaii for example [17]. Seroprevalence of A. cantonensis in China had been estimated at 0.8% of the general population and was significantly higher (7.4%) in the population specifically in contact with intermediate hosts [18]. Contrary to what was observed in our study, the incidence is generally higher during rainy season when intermediate hosts are abundant. Other demographic results observed in our series are consistent with data available in literature [1]: most cases of A. cantonensis meningitis occur in young adults or in children in whom disease is more frequently severe, probably due to a higher worm load relative to body size [19]. After an incubation period ranging from one day to several months, but usually comprised within one and two weeks, the onset of the disease is frequently sudden and presents as meningitis. Usually described clinical manifestations are similar to those highlighted in our series [1]. The most frequent initial symptom is acute severe headache (62–100% of cases), resulting from an increase in intracranial pressure relative to the widespread meningeal inflammatory reaction [1,20]. Other clinical features of meningitis syndrome, especially fever, are rarer, confirming another clinical evaluation by Sawanyawisuth et al. in which fever, stiff neck, and clinical evidence of meningitis were found in 23%, 47% and 9% of patients, respectively [20]. Paraesthesia and hyperesthesia (12–54%), relative to nerve root inflammation, are highly evocative of the diagnosis in a patient with a meningitic syndrome in an endemic area. Other neurological signs can include cranial nerve palsies (4–11%), other focal neurologic deficit, and muscle pains (6%). Diplopia and/or blurred vision are seen in 9 to 38% of cases and can correspond to cranial nerve palsies or, more rarely, to ocular angiostrongyliasis (1.1%) [21,22]. Extraneurologic symptoms may include digestive manifestations, proceeding from A. cantonensis itself [23]. Lungs may also be involved due to the migration of larvae, but clinical manifestations are generally absent or mild [24]. When realized, thoracic CT-scan shows ground-glass opacities in the sub-pleural areas in the early period whereas parenchymal nodules and fibrosis, or pleural pachynsis, adhesion, or indentations are more characteristic of late-phase disease [24]. Despite our study failed to disclose any clinical relevant risk factor for severity other than a long evolution delay, some authors found an association between encephalitis and age, prolonged headaches and fever (37-fold increased risk of encephalitis) [25]. There is usually no biological inflammatory syndrome. In severe forms, and especially in meningoencephalitis, hyponatremia can be seen, probably resulting from an inappropriate antidiuretic hormone secretion syndrome [26]. Although significant, the difference in natremia level found in our series was not clinically relevant. Moreover, to our knowledge, there is no explanation for the implication of natremia in severe forms of the disease, and our analysis did not find if it was an independent predictor of severe presentation. Proteinorachia is elevated but rarely exceed 1 g/L, and glycorachia appears to be frequently lower than the two thirds of glycemia. CSF cytological examination generally discloses a pleocytosis with variable percentage of eosinophils, usually ranging within 20 and 70%. As pinpointed by our results, CSF eosinophil count is often unrelated with the blood eosinophilia. Eosinophilia has been reported to disappear within 3 to 4 weeks after the onset of the disease, but can be detected earlier as shown by our results [27]. The cerebral CT-scan is usually normal but may show indirect signs of intracranial hypertension or enhancing ring or disk lesions, resembling tuberculomas [28]. Almost half of patients have abnormalities on MRI, including multiple enhancing nodules in the brain parenchyma, linear leptomeningeal enhancement, and hyperintense lesions in T2-weighted sequences [29,30]. These abnormalities appear to be correlated with the presence of worms in the CSF, severity of headache, CSF pleocytosis, and CSF and blood eosinophilia. Complete resolution of these abnormalities typically occurs within 4 to 8 weeks [30]. A. cantonensis larvae are exceptionally found in the CSF [31]. Although the diagnosis is usually made clinically, serological diagnostic
tests have been developed and are based on the detection of antibodies against the 29 or 31 kDa proteins of A. cantonensis in the serum and/or the CSF [32]. To date, their accuracy is still subject to debate. New diagnostic methods allow i) direct detection of A. cantonensis using immunofluorescence techniques which become more sensitive and specific (N90%) since the use of monoclonal antibodies against parasitespecific antigens; and ii) molecular detection by use of immuno-PCR, which sensibility and specificity are very high (98 and 100% respectively), but not actually of common use [32–35]. As seen in our series, the disease spontaneously resolves within 2 to 3 weeks. The mortality rate, when estimated in large cohort studies, is less than 0.05% [27,36]. In addition to symptomatic medical treatment, repeated lumbar puncture can be required to decrease intracranial pressure. Prednisolone at a daily dose of 1 mg/kg for 2 weeks seems to significantly reduce the severity of headache, the duration of symptoms, and the need for repeated lumbar puncture by decreasing CNS inflammation [10,37]. The use of antihelmintics such as albendazole is still controversial, because of the theoretical risk of exacerbation of CNS inflammation related to pro-inflammatory antigen release [10,38]. Hence, decreased symptom intensity and duration observed in some studies contrast with a worse evolution with albendazole–corticosteroid regimen compared with corticosteroids alone [10,36,39–42]. In our series, with the exception of one case with recurrent symptoms despite corticosteroids and antihelmintic therapies, all patients presented a favorable outcome without specific treatment. 5. Conclusions A. cantonensis is the leading cause of eosinophilic meningitis in endemic areas and must be evocated in young patients with a meningitic syndrome and CSF inflammation with predominance of eosinophils. No predictors for severe presentations could be highlighted. Diagnosis is confirmed by plasmatic and/or CSF serological tests, which must be repeated if negative. The importance of a specific treatment is debated, since all cases presented a favorable outcome, including severe forms, and despite the prescription of antihelmintic in a limited number of cases. Preventive methods should be enhanced in endemic areas, including eradication of infested hosts and educational campaigns about the risk of consuming undercooked intermediate/paratenic hosts and vegetables. Acknowledgment None. References [1] Graeff-Teixeira C, da Silva AC, Yoshimura K. Update on eosinophilic meningoencephalitis and its clinical relevance. Clin Microbiol Rev 2009;22:322–48. [2] Lo Re III V, Gluckman SJ. Eosinophilic meningitis. Am J Med 2003;114:217–23. [3] Graeff-Teixeira C. Expansion of Achatina fulica in Brazil and potential increased risk for angiostrongyliasis. Trans R Soc Trop Med Hyg 2007;101:743–4. [4] Mackerras MJ, Sandars DF. Lifehistory of the rat lung-worm and its migration through the brain of its host. Nature 1954;173:956–7. [5] Lindo JF, Escoffery CT, Reid B, Codrington G, Cunningham-Myrie C, Eberhard ML. Fatal autochthonous eosinophilic meningitis in a Jamaican child caused by Angiostrongylus cantonensis. Am J Trop Med Hyg 2004;70:425–8. [6] Lv S, Zhang Y, Liu HX, Hu L, Yang K, Stelnmann P, et al. Invasive snails and an emerging infectious disease: results from the first national survey on Angiostrongylus cantonensis in China. PLoS Negl Trop Dis 2009;3:e368. [7] Tsai HC, Lee SS, Huang CK, Yen CM, Chen ER, Liu YC. Outbreak of eosinophilic meningitis associated with drinking raw vegetable juice in southern Taiwan. Am J Trop Med Hyg 2004;71:222–6. [8] Wang JJ, Chung LY, Lin RJ, Lee JD, Lin CW, Yen CM. Eosinophilic meningitis risk associated with raw Ampullarium canaliculatus snails consumption. Kaohsiung J Med Sci 2011;27:184–9. [9] Kuberski T. Eosinophils in the cerebrospinal fluid. Ann Intern Med 1979;91:70–5. [10] Sawanyawisuth K, Sawanyawisuth K. Treatment of angiostrongyliasis. Trans R Soc Trop Med Hyg 2008;102:990–6. [11] Maleewong W, Sombatsawat P, Intapan PM, Wongham C, Chotmongkol V. Immunoblot evaluation of the specificity of the 29-kDa antigen from young adult female worms
E. Oehler et al. / Parasitology International 63 (2014) 544–549
[12] [13]
[14]
[15]
[16] [17]
[18] [19] [20]
[21] [22]
[23]
[24] [25]
[26]
[27]
Angiostrongylus cantonensis for immunodiagnosis of human angiostrongyliasis. Asian Pac J Allergy Immunol 2001;19:267–73. Diaz JH. Helminthic eosinophilic meningitis: emerging zoonotic diseases in the South. J La State Med Soc 2008;160:333–42. Kliks MM, Palumbo NE. Eosinophilic meningitis beyond the Pacific Basin: the global dispersal of a peridomestic zoonosis caused by Angiostrongylus cantonensis, the nematode lungworm of rats. Soc Sci Med 1992;34:199–212. Malvy D, Ezzedine K, Receveur MC, Pistone T, Crevon L, Lemardeley P, et al. Cluster of eosinophilic meningitis attributable to Angiostrongylus cantonensis infection in French policemen troop returning from the Pacific Islands. Travel Med Infect Dis 2008;6:301–4. Thiengo SC, Maldonado A, Mota EM, Torres EJ, Caldeira R, Carvalho OS, et al. The giant African snail Achatina fulica as natural intermediate host of Angiostrongylus cantonensis in Pernambuco, northeast Brazil. Acta Trop 2010;115:194–9. Wang QP, Lai DH, Zhu XQ, Chen XG, Lun ZR. Human angiostrongyliasis. Lancet Infect Dis 2008;8:621–30. Hochberg NS, Park SY, Blackburn BG, Sejvar JJ, Gaynor K, Chung H, et al. Distribution of eosinophilic meningitis cases attributable to Angiostrongylus cantonensis, Hawaii. Emerg Infect Dis 2007;13:1675–80. Chen MX, Zhang RL, Ai L, Chen JX, Chen SH, Huang DN, et al. Seroprevalence of Angiostrongylus cantonensis infection in humans in China. J Parasitol 2011;97:144–5. Hwang KP, Chen ER. Clinical studies on angiostrongyliasis cantonensis among children in Taiwan. Southeast Asian J Trop Med Public Health 1991;22(Suppl.):194–9. Sawanyawisuth K, Sawanyawisuth K, Senthong V, Limpawattana P, Intapan PM, Tiamkao S, et al. Peripheral eosinophilia as an indicator of meningitic angiostrongyliasis in exposed individuals. Mem Inst Oswaldo Cruz 2010;105:942–4. Sawanyawisuth K, Kitthaweesin K. Optic neuritis caused by intraocular angiostrongyliasis. Southeast Asian J Trop Med Public Health 2008;39:1005–7. Sawanyawisuth K, Kitthaweesin K, Limpawattana P, Intapan PM, Tiamkao S, Jitpimolmard S, et al. Intraocular angiostrongyliasis: clinical findings, treatments and outcomes. Trans R Soc Trop Med Hyg 2007;101:497–501. Sawanyawisuth K, Pugkhem A, Mitchai J, Intapan PM, Anunnatsiri S, Limpawattana P, et al. Abdominal angiostrongyliasis caused by Angiostrongylus cantonensis: a possible cause of eosinophilic infiltration in human digestive tract. Pathol Res Pract 2010;206:102–4. Cui Y, Shen M, Meng S. Lung CT findings of angiostrongyliasis cantonensis caused by Angiostrongylus cantonensis. Clin Imaging 2011;35:180–3. Sawanyawisuth K, Takahashi K, Hoshuyama T, Sawanyawisuth K, Senthong V, Limpawattana P, et al. Clinical factors predictive of encephalitis caused by Angiostrongylus cantonensis. Am J Trop Med Hyg 2009;81:698–701. Kittimongkolma S, Intapan PM, Laemviteevanich K, Kanpittaya J, Sawanyawisuth K, Maleewong W. Eosinophilic meningitis associated with angiostrongyliasis: clinical features, laboratory investigations and specific diagnostic IgG and IgG subclass antibodies in cerebrospinal fluid. Southeast Asian J Trop Med Public Health 2007;38:24–31. Yii CY. Clinical observations on eosinophilic meningitis and meningoencephalitis caused by Angiostrongylus cantonensis on Taiwan. Am J Trop Med Hyg 1976;25:233–49.
549
[28] Tsai HC, Liu YC, Kunin CM, Lai PH, Lee SS, Chen YS, et al. Eosinophilic meningitis caused by Angiostrongylus cantonensis associated with eating raw snails: correlation of brain magnetic resonance imaging scans with clinical findings. Am J Trop Med Hyg 2003;68:281–5. [29] Jin EH, Ma Q, Ma DQ, He W, Ji AP, Yin CH. Magnetic resonance imaging of eosinophilic meningoencephalitis caused by Angiostrongylus cantonensis following eating freshwater snails. Chin Med J 2008;121:67–72. [30] Jin E, Ma D, Liang Y, Ji A, Gan S. MRI findings of eosinophilic myelomeningoencephalitis due to Angiostrongylus cantonensis. Clin Radiol 2005;60:242–50. [31] Prociv P, Spratt DM, Carlisle MS. Neuro-angiostrongyliasis: unresolved issues. Int J Parasitol 2000;30:1295–303. [32] Wilkins PP, Qvarnstrom Y, Whelen AC, Saucier C, da Silva AJ, Eamsobhana P. The current status of laboratory diagnosis of Angiostrongylus cantonensis infections in humans using serologic and molecular methods. Hawaii J Med Public Health 2013;72:55–7. [33] Chen MX, Zhang RL, Chen JX, Chen SH, Li XH, Gao ST, et al. Monoclonal antibodies against excretory/secretory antigens of Angiostrongylus cantonensis. Hybridoma 2010;29:447–52. [34] Chye SM, Lin SR, Chen YL, Chung LY, Yen CM. Immuno-PCR for detection of antigen to Angiostrongylus cantonensis circulating fifth-stage worms. Clin Chem 2004;50:51–7. [35] Vitta A, Yoshino TP, Kalambaheti T, Komalamisra C, Waikagul J, Ruangsittichai J, et al. Application of recombinant SMR-domain containing protein of Angiostrongylus cantonensis in immunoblot diagnosis of human angiostrongyliasis. Southeast Asian J Trop Med Public Health 2010;41:785–99. [36] Punyagupta S, Juttijudata P, Bunnag T. Eosinophilic meningitis in Thailand. Clinical studies of 484 typical cases probably caused by Angiostrongylus cantonensis. Am J Trop Med Hyg 1975;24:921–31. [37] Chotmongkol V, Sawanyawisuth K, Thavornpitak Y. Corticosteroid treatment of eosinophilic meningitis. Clin Infect Dis 2000;31:660–2. [38] Hidelaratchi MD, Riffsy MT, Wijesekera JC. A case of eosinophilic meningitis following monitor lizard meat consumption, exacerbated by anthelminthics. Ceylon Med J 2005;50:84–6. [39] Chotmongkol V, Sawadpanitch K, Sawanyawisuth K, Louhawilai S, Limpawattana P. Treatment of eosinophilic meningitis with a combination of prednisolone and mebendazole. Am J Trop Med Hyg 2006;74:1122–4. [40] Jitpimolmard S, Sawanyawisuth K, Morakote N, Vejjajiva A, Puntumetakul M, Sanchaisuriya K, et al. Albendazole therapy for eosinophilic meningitis caused by Angiostrongylus cantonensis. Parasitol Res 2007;100:1293–6. [41] Zhou Z, Barennes H, Zhou N, Ding L, Zhu YH, Strobel M. Two outbreaks of eosinophilic meningitis in Yunann (China) clinical, epidemiological and therapeutical issues. Bull Soc Pathol Exot 2009;102:75–80. [42] Chotmongkol V, Kittimongkolma S, Niwattayakul K, Intapan PM, Thavornpitak Y. Comparison of prednisolone plus albendazole with prednisolone alone for treatment of patients with eosinophilic meningitis. Am J Trop Med Hyg 2009;81:443–5.
Contents lists available at ScienceDirect
Parasitology International journal homepage: www.elsevier.com/locate/parint
Angiostrongylus cantonensis eosinophilic meningitis: A clinical study of 42 consecutive cases in French Polynesia Erwan Oehler a, Frédéric Ghawche b, Alex Delattre c, Anthony Berberian d, Marc Levy e, Florent Valour a,⁎ a
Department of Internal Medicine, French Polynesia Hospital Center, 98716 Pirae, Tahiti, French Polynesia Department of Neurology, French Polynesia Hospital Center, 98716 Pirae, Tahiti, French Polynesia Department of Pneumology, French Polynesia Hospital Center, 98716 Pirae, Tahiti, French Polynesia d Laboratory of Pathology, French Polynesia Hospital Center, 98716 Pirae, Tahiti, French Polynesia e Laboratory of Microbiology, French Polynesia Hospital Center, 98716 Pirae, Tahiti, French Polynesia b c
a r t i c l e
i n f o
Article history: Received 30 September 2013 Received in revised form 8 February 2014 Accepted 16 February 2014 Available online 26 February 2014 Keywords: Angiostrongylus cantonensis Meningitis Eosinophils
a b s t r a c t Introduction: In endemic areas, eosinophilic meningitis is mainly caused by Angiostrongylus cantonensis. We describe a series of this poorly-known condition. Methods: Retrospective cohort study (2000–2012) including all patients diagnosed with eosinophilic meningitis in French Polynesia. Results: Forty-two patients (males: 61.9%, age: 22 (IQR 17–32)) were diagnosed with a serologically proven (n = 13) or probable A. cantonensis meningitis, mostly during the dry season (66.6%) and following the consumption of or prolonged contact with an intermediate/paratenic host (64.3%). No differential diagnosis was found in probable cases, in whom serological tests were performed earlier (7.5 days (6.5–10)) compared to positive patients (7.5 (6.5–10) versus 11 (7–30) days, p = 0.02). The most commonly reported symptom was headache (92.8%). Fever (7.1%) and biological inflammatory syndrome (14.3%) were rare. Blood eosinophil count was 1200/mm3 (900–2548). Cerebrospinal fluid (CSF) analysis disclosed a protein level of 0.9 g/L (0.7–1.1), a CSF/plasma glucose ratio of 0.50 (0.40–0.55), and 500 leucocytes/mm3 (292–725; eosinophils: 42.0% (29.5– 60); lymphocytes: 46.5% (32.5–59.0)). Thirteen cases (31.0%) were severe, with 11 focal neurological deficits. A delayed hospital referral (OR 1.13, p = 0.05) was associated with severity. Conclusions: A. cantonensis meningitis must be evocated in young patients with meningitic syndrome, severe headache, and CSF inflammation with predominance of eosinophils. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Eosinophilic meningitis is a rare condition, mainly related to central nervous system (CNS) infection by parasitic agents [1,2]. The nematode Angiostrongylus cantonensis, whose larvae are neurotropic, is the most frequent etiology of eosinophilic meningitis in endemic areas, including Southeast Asia and Pacific basin [1]. A. cantonensis normally affects rodents (and especially rats) in which larvae pass through the bowel wall, migrate to the brain, and develop into adult worms that reach the pulmonary arteries after 4 weeks where eggs are laid by adult worms (Fig. 1). First stage larvae migrate to the pharynx and are swallowed and excreted in the stool. They can survive for months in the environment, be ingested by snails or slugs and reach the fibromuscular tissues and mucus secretions of these intermediate hosts, which then become infective for rodents or paratenic hosts such as land crabs, frogs, lizards, planarians, fishes or freshwater shrimps [3,4]. Humans may be infected by eating raw or undercooked infested ⁎ Corresponding author. Tel.: +689 48 59 90; fax: +689 48 59 92. E-mail address: fl[email protected] (F. Valour).
http://dx.doi.org/10.1016/j.parint.2014.02.001 1383-5769/© 2014 Elsevier Ireland Ltd. All rights reserved.
snails or slugs included in local traditional food of endemic areas, by ingestion of infected paratenic animals, or by handling directly to the mouth in contact with hosts, and especially molluscs [5–8]. Humans constitute a parasitic impasse. Larvae migrate to the brain or the eye chamber (rarely, the lungs) and die, leading to intense inflammatory lesions responsible for clinical manifestations, mainly represented by transient meningitis with severe headache and paresthesias or hyperesthesias [1]. We here report a large series of eosinophilic meningitis in French Polynesia, aiming to describe the clinical features of this rare condition, with emphasis on severe presentations and their risk factors. 2. Patients and methods This retrospective cohort study was based on the examination of medical records registered in our institution from 2000 to 2012 under the codification B83.2 (“Angiostrongyloidosis to Parastrongylus cantonensis”) and G05.2 (“Encephalitis, myelitis and encephalomyelitis in other infectious and parasitic diseases classified elsewhere”) according to the International Statistical Classification of Diseases and Related
E. Oehler et al. / Parasitology International 63 (2014) 544–549
545
Fig. 1. Angiostrongylus cantonensis life cycle.
Health Problem (ICD-10) of the World Health Organization. The following inclusion criteria were used: i) compatible clinical manifestations i.e. meningitis symptoms (defined as the association of at least two of the following symptoms: headache, neck stiffness, and photophobia), or meningoencephalitis (i.e., meningitis symptoms with confusion, neurologic deficit, and/or visual disturbance), or myeloradiculitis (paresthesias, hyperesthesias); ii) plasmatic hypereosinophilia, defined as blood eosinophil count N 500/mm3; and iii) the presence of more than 10 eosinophils/mm3 of CSF, and/or eosinophils accounting for more than 10% of the total CSF leukocyte count [1,9,10]. A. cantonensis serological tests were performed using enzyme linked immunosorbent assay (ELISA) detecting the 29 kDa antigenic polypeptide of A. cantonensis [11]. Files were excluded if clinical and biological manifestations were not sufficiently suggestive of the diagnosis, or when a differential diagnosis cannot be excluded. Clinical, biological and radiological data were collected from medical records and nursing charts according to a standardized case report form, including sex, age, ethnic group, urban or rural dwelling place, supposed mode of transmission, date of appearance of symptoms, clinical manifestations, laboratory values, radiographic studies and treatment. Severe forms were defined according to the presence of encephalitis and/or neurological deficit including cranial nerve involvement symptoms. Descriptive statistics were used to estimate the frequencies of the study variables, described as median and interquartile ranges (IQR). For the percentage calculation of each variable, the number of missing values was excluded from the denominator. Non-parametric statistical methods were used to compare the study groups (Chi2, Fisher exact test, Mann–Whitney U test), as appropriate, with a significance level of 0.05. Risk factors for severe forms were assessed using a linear mixed regression model. After exclusion of interacting variables, those with a p-value b 0.15 in univariate analysis were included in the final multivariate model. All analyses were performed using SPSS software version 16.0 (SPSS, Chicago, IL). 3. Results From 2000 to 2012, 70 files were registered under the G05.2 and/or B83.2 codes in our institution, corresponding to 57 patients. Fifteen files were excluded, including 3 medical records with insufficient data and 12 patients with differential diagnosis for eosinophilic meningitis: five complications of HIV infection (three toxoplasmosis, a JC virus infection and an encephalitis of undetermined etiology), a congenital toxoplasmosis, three other viral meningoencephalitis (H1N1 influenza virus,
varicella-zoster virus, and dengue fever), one tuberculous meningitis, a Rasmussen encephalitis and a Devic's optic neuromyelitis. Hence, 42 patients with eosinophilic meningitis were finally enrolled in the study, including 13 (31.0%) serologically proven cases of A. cantonensis CNS infection (positive plasma and/or CSF serological tests). No differential diagnosis existed for the 29 remaining patients, which are included as probable cases. 3.1. Demographic and epidemiological features Twenty-six patients were male (61.9%, sex ratio: 1.5), with a median age of 22 years (IQR 17–32). Seven (16.3%) were under 15 year-old (Table 1). Thirty-nine patients (92.8%) were Polynesian; others (7.2%) were from metropolitan France. All cases were initially referred to the emergency department, and then hospitalized with a median stay of 5 days (IQR 3–6). A majority of cases (n = 28, 66.6%) were diagnosed during the dry and cool seasons (May–October). Twelve patients (28.5%) lived in an urban area whereas the others lived in rural conditions (71.5%). Exposure risk was specified in 27 cases (61.9%): 22 persons (81.5%) reported eating shrimps (including 16 eating taioro, a traditional Polynesian meal made with head shrimps fermented in coconut milk and sea water, and 6 eating raw shrimps), one had eaten snails (3.7%) and one ate raw crab (3.7%). Indirect risk factors were found among 3 other patients: 2 (7.4%) reported eating raw vegetables in fields without washing them and one (3.7%) worked in a shrimp farming factory. Three persons were infested during the same meal (taioro). The delay between the presumptive infesting meal and the beginning of the symptomatology was available in only 10 cases (40.0%), ranging from 3 days to one month. 3.2. Clinical features Patients were admitted at the hospital within a median of 7 days (IQR 5–10) after the onset of symptoms. Headaches were the most frequently reported complain (92.8%). When specified, the distribution of headache was frontal and/or retro-orbital (33.3%), temporal or parietal (12.8%), occipital (7.2%), or generalized (15.4%). Headache was defined as severe, intensive or intolerable in 17 cases (41.5%). When evaluated by analogic visual scale (n = 13), pain was at a median of 7 (IQR 6–8). Other meningitis symptoms included photophobia (n = 22, 52.4%), neck stiffness (n = 18, 42.8%) or neck pain (n = 17, 40.4%), and nauseas (n = 29, 69.0%) or vomiting (n = 24, 57.1%). History of chills or fever was reported in 11 cases (26.2%) but fever was objectively measured
546
E. Oehler et al. / Parasitology International 63 (2014) 544–549
Table 1 Characteristics of patients and assessment of severe form determinants. All patients (n = 42)
Demographic characteristics Sex (male) Age (years) Polynesian origin Urban life mode Clinical presentation Evolution delay (days) Fever Headaches Paresthesia, hyperesthesia Muscular pain Meningitis symptoms Encephalitis symptoms Focal neurological deficit Cranial nerve injury Convulsions Blood laboratory tests Biological inflammatory syndrome WBC count (/mm3) Eosinophil count (/mm3) (% of total WBC) Na (mmol/L) Positive angiostrongyliasis serology CSF characteristics Turbidity Protein (g/L) Glucose (mmol/L) (% of FBG) Leucocytes (/mm3) Neutrophils (%) Lymphocytes (%) Eosinophils (%) Positive angiostrongyliasis serology CT and/or MRI abnormality Management Length of hospital stay (days) Corticosteroids Initial dosage (mg/kg/day) Total duration (days) Antihelmintic therapy
Severe forms (n = 13)
p
Univariate analysis
Multivariate analysis
OR (95% CI)
p
26 (61.9%) 22 (17–32) 39 (92.9%) 12 (28.6%)
9 (69.2%) 22 (17–36) 9 (69.2%) 3 (23.1%)
0.382 0.978 0.222 0.446
1.588 (0.395–6.379) 0.994 (0.944–1.047)
0.514 0.832
7 (5–10) 12 (28.6%) 39 (92.9%) 12 (28.6%) 11 (26.2%) 29 (69.0%) 13 (31.0%) 11 (26.2%) 8 (19.0%) 1 (2.4%)
9 (7–19.3) 3 (23.1%) 10 (76.9%) 5 (38.5%) 3 (23.1%) 7 (53.8%) 13 (100%) 11 (84.6%) 8 (61.5%) 1 (7.7%)
0.063 0.446 0.025 0.277 0.538 0.144 NA NA NA NA
1.129 (1.000–1.276) 1.500 (0.331–6.798)
0.050 0.599
0.509 (0.125–2.073) 1.270 (0.276–5.839) 2.694 (0.679–10.739)
0.346 0.759 0.160
6 (14.3%) 11,350 (9400–14,000) 1200 (900–2547) 14.2 (8.0–23.7) 139 (137–140) 11/28 (39.3%) 25 (59.5%) 0.9 (0.7–1.1) 2.6 (2.2–2.9) 50.0 (40.2–54.5) 500 (292–725) 0.0 (0.0–2.3) 46.5 (32.5–59.0) 42.0 (29.5–60.0) 7/23 (30.4%) 11/38 (28.9%) 5 (3–6) 17 (40.5%) 1.4 (1.2–1.8) 4.5 (3.0–12.0) 7 (16.7%)
2 (15.4%) 10,700 (8300–13,900) 1496 (880–2050) 18.8 (7.0–23.6) 138 (135–139) 4/9 (44.4%)
0.615 0.414 0.744 0.989 0.036 0.507
0.880 (0.140–5.539) 1.000 (1.000–1.000) 0.418 (0.000–360.389)
0.892 0.495 0.800
0.720 (0.533–0.973) 0.729 (0.146–0.3654)
0.032 0.701
7 (53.8%) 0.9 (0.8–1.1) 2.5 (2.2–2.7) 48.4 (36.4–52.4) 500 (268–700) 1.0 (0.0–2.5) 40.0 (32.0–58.0) 45.0 (34.0–62.0) 4/9 (44.4%) 5/13 (38.5%)
0.433 0.446 0.270 0.413 0.684 0.793 0.707 0.740 0.239 0.457
1.403 (0.373–5.269) 0.855 (0.314–2.334) 0.981 (0.926–1.039)
0.616 0.760 0.506
0.999 (0.998–1.001) 0.942 (0.775–1.147) 0.996 (0.961–1.031) 1.007 (0.973–1.041) 0.341 (0.055–2.131) 0.505 (0.119–2.145)
0.395 0.544 0.805 0.699 0.250 0.355
6 (5–9) 7 (53.8%) 1.4 (1.0–1.7) 14.5 (7.3–15.0) 3 (23.1%)
0.002 0.200 0.560 0.019 0.456
OR (95% CI)
p
1.121 (0.985–1.277)
0.084
0.791 (0.545–1.149)
0.218
Descriptive results are presented as n (%) and as median (IQR). Comparisons were run using non-parametric statistical methods (Chi2, Fisher exact test or Mann–Whitney U-test, as appropriate). Determinants of severe forms were assessed using logistic regression and are presented using odd ratios (OR) and their 95% confidence interval (95% CI). CSF: cerebrospinal fluid; CT: computed tomography; FBG: fasting blood glucose; MRI: magnetic resonance imaging; Na: sodium; WBC: white blood cell.
above 38.3 °C in only 3 cases (7.1%). Other symptoms included asthenia (n = 8, 19.0%), dry cough (n = 4, 9.5%), blurred vision or visual acuity defect (n = 3, 7.2%), abdominal pain (n = 3, 7.2%) and/or transit disorders (n = 3, 7.2%, including 2 patients with diarrheas and one with constipation), pruritus (n = 3, 7.2%), and radiculalgia (sciatica and cervicobrachial neuralgia), arthralgia, erythematous eruption, extremity edema, and palpebral edema in one case each (2.4%) (Table 1). 3.3. Biological features Twenty-nine patients (69.0%) had leukocytosis (N10,000/mm3). The median initial and maximal blood eosinophil counts were 1177/mm3 (IQR 780–2058) and 1200/mm3 (IQR 900–2548), respectively, corresponding to 10.4% (IQR 6.5–17.5) and 14.2% (IQR 8.0–23.7) of total WBC. Only 6 patients (14.3%) presented a biological inflammatory syndrome (CRP N 5 mg/L), with a median CRP plasmatic level of 13.4 mg/L (IQR 9.5–17.0). Four patients (9.5%) had hyponatremia (b135 mmol/L). All patients underwent a lumbar puncture, which was performed within a median delay of 7.0 days (IQR 5.5–9.5) after the onset of symptoms (Table 1). Plasmatic and CSF eosinophil counts were not correlated (Pearson correlation coefficient: 0.176, p = 0.278). Median spinal fluid protein concentration was 0.9 g/L (IQR 0.7–1.1 g/L), and 18 of the 39 patients (46.1%) in whom blood glucose value was available were considered to have low CSF glucose level (ratio CSF/plasma
b 0.5). When available (n = 9), CSF lactate level was slightly elevated, at a median level of 185 mg/L (IQR 181–227) (Table 1).
3.4. Radiographic features Cerebral computed tomography (CT-scan) was performed in 36 cases (85.7%), and considered as normal in 31 (86.1%) patients. In other cases, CT-scan disclosed a moderate cerebral edema (n = 3, 8.3%) or a minimum cerebral hyperdensity related to bleeding (n = 1, 2.7%). Magnetic resonance imaging (MRI) was performed in 13 cases (30.0%). It was considered as normal in 5 (38.5%) patients, and showed a minimum meningeal thickening and abnormal enhancement of diffuse localization in 3 cases (23.1%), with right ocular nerve abnormal enhancement in 1 of them, and a left cerebellar localization with an abnormal enhancement of the acousticofacial complex in 1 additional case. Other MRI abnormalities consisted of sub-meningeal hyperintensities (n = 2, 15.4%), images suspect for bleeding (n = 2, 15.4%), and centromedular hyperintensity at the T12 medullary level (n = 1, 7.7%) (Fig. 2). Electroencephalography was normal in 5 of 6 patients, whereas one showed discrete signs of left temporal suffering. Electromyography was performed in 3 cases and disclosed a neuropathy mainly affecting the lower limbs as a sensory impairment.
E. Oehler et al. / Parasitology International 63 (2014) 544–549
547
Fig. 2. Cerebral magnetic resonance imaging findings in two patients with A. cantonensis meningitis. A: Axial T1-weighted MRI disclosing a diffuse leptomeningeal enhancement after gadolinium injection (arrows). B: Axial T2-weighted Flair MRI showing hyperintense lesion of the rolandic cortices (arrow).
One of the patients presenting a dry cough benefited from a chest ray showing a bilateral interstitial syndrome. 3.5. Severe forms Clinical presentation was considered as severe with clinical encephalitis in 13 cases (31.0%). Two cases presented isolated consciousness impairment with hypotonia. Focal neurological deficit was present in 11 other patients (26.2%), including seizures in one case and cranial nerve palsy in 8 cases (19.0%). Implicated cranial nerves were the abducens (n = 3, 37.5%), facial (n = 2, 25.0%) and oculomotor (n = 1, 12.5%). Multiple cranial nerve implications were seen in 2 cases (25.0%) (III, IV, VI, IX and XII for the first patient, and VI, VII and IX for the second one). Clinical presentation of severe cases did not greatly differ from other patients (Table 1). The only identified differences were a lower prevalence of headaches (76.9% versus 100%, p = 0.025) and a slightly lower plasmatic sodium level (138 mmol/L versus 139 mmol/L, p = 0.036). In univariate analysis, a delayed hospital referral (OR 1.13, 95% CI 1.00–1.28, p = 0.05) was associated with severity, whereas hypernatremia was protective (OR 0.72, 95% CI 0.53–0.97, p = 0.032). None of these variables was found to be a predictive factor of severity in multivariate analysis (Table 1). 3.6. A. cantonensis serological tests Thirty-two patients benefited from at least one A. cantonensis serological test in blood (n = 28) and/or CSF (n = 23) within a median delay of 9.5 (IQR 7.0–12.5) and 7.0 (IQR 5.5–9.5) days after the onset of symptoms. Plasmatic and CSF serological tests were positive in
Table 2 Plasmatic and CSF serological test results. CSF serological test
Plasmatic serological test
Total
Total
NR
Positive
Negative
NR Positive
10 3
1 5
3 3
Negative
6
1
10
7 Delay: 13 (8–26.5)
16 Delay: 6.5 (5–7.5)
19
CSF: cerebrospinal fluid; NR: not realized.
14 11 Delay: 11 (7.5–32.5) 17 Delay: 9 (7–11) 42
11 (39.3%) and 7 (30.4%) cases, respectively, leading to 13 “confirmed cases” (Table 2). The delay of serological test realization was significantly higher in positive patients (11 (IQR 7–30) versus 7.5 (IQR 6.5–10) days; p = 0.02). 3.7. Treatment and outcome All but one patient (97.6%) required antalgics, including level 2 analgesics or morphinics in 23 and 8 cases, respectively. Seventeen patients (40.5%) benefited from corticosteroids for 4.5 days (IQR 3.0–12.0) at a median daily dose of 1.4 mg/kg (IQR 1.2–1.8). Only 7 patients (16.7%) received a specific therapy, including albendazole (n = 4), flubendazole (n = 2) or ivermectin (n = 1). The symptoms improved within a few days in all patients, allowing a rapid discharge to home. One patient with a confirmed A. cantonensis meningoencephalitis presented recurrent symptoms leading to 3 consecutive hospitalizations, despite corticosteroid and albendazole therapies. Outcome was finally favorable more than two months after the onset of the disease. 4. Discussion These findings confirmed that A. cantonensis infection can lead to severe forms of eosinophilic meningoencephalitis. If angiostrongyliasis was confirmed by serological tests in only 13 patients (31.0%), the diagnosis was very likely in the others because i) other parasitic etiologies of eosinophilic meningitis (i.e. Gnathostoma spinigerum, Baylisascaris procyonis, cysticercosis, Paragonimus westermani, schistosomiasis, and fascioliasis) have never (or exceptionally) been described in French Polynesia; ii) other differential diagnoses (i.e. cryptococcosis, malignant hemopathy, ventriculoperitoneal shunt, drug adverse reactions) were excluded in all patients; iii) the patients did not meet the diagnosis criteria of idiopathic hypereosinophilic syndromes; and iv) plasmatic and/or CSF serological tests were realized at the beginning of disease evolution (especially in seronegative patients), which can explain their negativity [2,9]. Unfortunately, serological tests could not be repeated in negative patients, due to the short hospitalization and to the geographical isolation of patients in Polynesian islands. Since the discovery of A. cantonensis in 1935 in China, more than 2800 cases have been reported worldwide, mostly in endemic areas, including Southeast Asia and the Pacific islands. French Polynesia constitutes the third country regarding the number of reported cases (9% of all cases), before the USA with its pacific islands (Hawaii and Samoa), Australia, Micronesia and Melanesia [7,12–16]. Global incidence is not known and seems to greatly vary according to the prevalence of reservoir and intermediate/paratenic hosts, their infestation rate, and their
548
E. Oehler et al. / Parasitology International 63 (2014) 544–549
intentional consumption in traditional food. Few local studies gave the incidence in their own area, evaluated at 2.1 per 100,000 person-years in Hawaii for example [17]. Seroprevalence of A. cantonensis in China had been estimated at 0.8% of the general population and was significantly higher (7.4%) in the population specifically in contact with intermediate hosts [18]. Contrary to what was observed in our study, the incidence is generally higher during rainy season when intermediate hosts are abundant. Other demographic results observed in our series are consistent with data available in literature [1]: most cases of A. cantonensis meningitis occur in young adults or in children in whom disease is more frequently severe, probably due to a higher worm load relative to body size [19]. After an incubation period ranging from one day to several months, but usually comprised within one and two weeks, the onset of the disease is frequently sudden and presents as meningitis. Usually described clinical manifestations are similar to those highlighted in our series [1]. The most frequent initial symptom is acute severe headache (62–100% of cases), resulting from an increase in intracranial pressure relative to the widespread meningeal inflammatory reaction [1,20]. Other clinical features of meningitis syndrome, especially fever, are rarer, confirming another clinical evaluation by Sawanyawisuth et al. in which fever, stiff neck, and clinical evidence of meningitis were found in 23%, 47% and 9% of patients, respectively [20]. Paraesthesia and hyperesthesia (12–54%), relative to nerve root inflammation, are highly evocative of the diagnosis in a patient with a meningitic syndrome in an endemic area. Other neurological signs can include cranial nerve palsies (4–11%), other focal neurologic deficit, and muscle pains (6%). Diplopia and/or blurred vision are seen in 9 to 38% of cases and can correspond to cranial nerve palsies or, more rarely, to ocular angiostrongyliasis (1.1%) [21,22]. Extraneurologic symptoms may include digestive manifestations, proceeding from A. cantonensis itself [23]. Lungs may also be involved due to the migration of larvae, but clinical manifestations are generally absent or mild [24]. When realized, thoracic CT-scan shows ground-glass opacities in the sub-pleural areas in the early period whereas parenchymal nodules and fibrosis, or pleural pachynsis, adhesion, or indentations are more characteristic of late-phase disease [24]. Despite our study failed to disclose any clinical relevant risk factor for severity other than a long evolution delay, some authors found an association between encephalitis and age, prolonged headaches and fever (37-fold increased risk of encephalitis) [25]. There is usually no biological inflammatory syndrome. In severe forms, and especially in meningoencephalitis, hyponatremia can be seen, probably resulting from an inappropriate antidiuretic hormone secretion syndrome [26]. Although significant, the difference in natremia level found in our series was not clinically relevant. Moreover, to our knowledge, there is no explanation for the implication of natremia in severe forms of the disease, and our analysis did not find if it was an independent predictor of severe presentation. Proteinorachia is elevated but rarely exceed 1 g/L, and glycorachia appears to be frequently lower than the two thirds of glycemia. CSF cytological examination generally discloses a pleocytosis with variable percentage of eosinophils, usually ranging within 20 and 70%. As pinpointed by our results, CSF eosinophil count is often unrelated with the blood eosinophilia. Eosinophilia has been reported to disappear within 3 to 4 weeks after the onset of the disease, but can be detected earlier as shown by our results [27]. The cerebral CT-scan is usually normal but may show indirect signs of intracranial hypertension or enhancing ring or disk lesions, resembling tuberculomas [28]. Almost half of patients have abnormalities on MRI, including multiple enhancing nodules in the brain parenchyma, linear leptomeningeal enhancement, and hyperintense lesions in T2-weighted sequences [29,30]. These abnormalities appear to be correlated with the presence of worms in the CSF, severity of headache, CSF pleocytosis, and CSF and blood eosinophilia. Complete resolution of these abnormalities typically occurs within 4 to 8 weeks [30]. A. cantonensis larvae are exceptionally found in the CSF [31]. Although the diagnosis is usually made clinically, serological diagnostic
tests have been developed and are based on the detection of antibodies against the 29 or 31 kDa proteins of A. cantonensis in the serum and/or the CSF [32]. To date, their accuracy is still subject to debate. New diagnostic methods allow i) direct detection of A. cantonensis using immunofluorescence techniques which become more sensitive and specific (N90%) since the use of monoclonal antibodies against parasitespecific antigens; and ii) molecular detection by use of immuno-PCR, which sensibility and specificity are very high (98 and 100% respectively), but not actually of common use [32–35]. As seen in our series, the disease spontaneously resolves within 2 to 3 weeks. The mortality rate, when estimated in large cohort studies, is less than 0.05% [27,36]. In addition to symptomatic medical treatment, repeated lumbar puncture can be required to decrease intracranial pressure. Prednisolone at a daily dose of 1 mg/kg for 2 weeks seems to significantly reduce the severity of headache, the duration of symptoms, and the need for repeated lumbar puncture by decreasing CNS inflammation [10,37]. The use of antihelmintics such as albendazole is still controversial, because of the theoretical risk of exacerbation of CNS inflammation related to pro-inflammatory antigen release [10,38]. Hence, decreased symptom intensity and duration observed in some studies contrast with a worse evolution with albendazole–corticosteroid regimen compared with corticosteroids alone [10,36,39–42]. In our series, with the exception of one case with recurrent symptoms despite corticosteroids and antihelmintic therapies, all patients presented a favorable outcome without specific treatment. 5. Conclusions A. cantonensis is the leading cause of eosinophilic meningitis in endemic areas and must be evocated in young patients with a meningitic syndrome and CSF inflammation with predominance of eosinophils. No predictors for severe presentations could be highlighted. Diagnosis is confirmed by plasmatic and/or CSF serological tests, which must be repeated if negative. The importance of a specific treatment is debated, since all cases presented a favorable outcome, including severe forms, and despite the prescription of antihelmintic in a limited number of cases. Preventive methods should be enhanced in endemic areas, including eradication of infested hosts and educational campaigns about the risk of consuming undercooked intermediate/paratenic hosts and vegetables. Acknowledgment None. References [1] Graeff-Teixeira C, da Silva AC, Yoshimura K. Update on eosinophilic meningoencephalitis and its clinical relevance. Clin Microbiol Rev 2009;22:322–48. [2] Lo Re III V, Gluckman SJ. Eosinophilic meningitis. Am J Med 2003;114:217–23. [3] Graeff-Teixeira C. Expansion of Achatina fulica in Brazil and potential increased risk for angiostrongyliasis. Trans R Soc Trop Med Hyg 2007;101:743–4. [4] Mackerras MJ, Sandars DF. Lifehistory of the rat lung-worm and its migration through the brain of its host. Nature 1954;173:956–7. [5] Lindo JF, Escoffery CT, Reid B, Codrington G, Cunningham-Myrie C, Eberhard ML. Fatal autochthonous eosinophilic meningitis in a Jamaican child caused by Angiostrongylus cantonensis. Am J Trop Med Hyg 2004;70:425–8. [6] Lv S, Zhang Y, Liu HX, Hu L, Yang K, Stelnmann P, et al. Invasive snails and an emerging infectious disease: results from the first national survey on Angiostrongylus cantonensis in China. PLoS Negl Trop Dis 2009;3:e368. [7] Tsai HC, Lee SS, Huang CK, Yen CM, Chen ER, Liu YC. Outbreak of eosinophilic meningitis associated with drinking raw vegetable juice in southern Taiwan. Am J Trop Med Hyg 2004;71:222–6. [8] Wang JJ, Chung LY, Lin RJ, Lee JD, Lin CW, Yen CM. Eosinophilic meningitis risk associated with raw Ampullarium canaliculatus snails consumption. Kaohsiung J Med Sci 2011;27:184–9. [9] Kuberski T. Eosinophils in the cerebrospinal fluid. Ann Intern Med 1979;91:70–5. [10] Sawanyawisuth K, Sawanyawisuth K. Treatment of angiostrongyliasis. Trans R Soc Trop Med Hyg 2008;102:990–6. [11] Maleewong W, Sombatsawat P, Intapan PM, Wongham C, Chotmongkol V. Immunoblot evaluation of the specificity of the 29-kDa antigen from young adult female worms
E. Oehler et al. / Parasitology International 63 (2014) 544–549
[12] [13]
[14]
[15]
[16] [17]
[18] [19] [20]
[21] [22]
[23]
[24] [25]
[26]
[27]
Angiostrongylus cantonensis for immunodiagnosis of human angiostrongyliasis. Asian Pac J Allergy Immunol 2001;19:267–73. Diaz JH. Helminthic eosinophilic meningitis: emerging zoonotic diseases in the South. J La State Med Soc 2008;160:333–42. Kliks MM, Palumbo NE. Eosinophilic meningitis beyond the Pacific Basin: the global dispersal of a peridomestic zoonosis caused by Angiostrongylus cantonensis, the nematode lungworm of rats. Soc Sci Med 1992;34:199–212. Malvy D, Ezzedine K, Receveur MC, Pistone T, Crevon L, Lemardeley P, et al. Cluster of eosinophilic meningitis attributable to Angiostrongylus cantonensis infection in French policemen troop returning from the Pacific Islands. Travel Med Infect Dis 2008;6:301–4. Thiengo SC, Maldonado A, Mota EM, Torres EJ, Caldeira R, Carvalho OS, et al. The giant African snail Achatina fulica as natural intermediate host of Angiostrongylus cantonensis in Pernambuco, northeast Brazil. Acta Trop 2010;115:194–9. Wang QP, Lai DH, Zhu XQ, Chen XG, Lun ZR. Human angiostrongyliasis. Lancet Infect Dis 2008;8:621–30. Hochberg NS, Park SY, Blackburn BG, Sejvar JJ, Gaynor K, Chung H, et al. Distribution of eosinophilic meningitis cases attributable to Angiostrongylus cantonensis, Hawaii. Emerg Infect Dis 2007;13:1675–80. Chen MX, Zhang RL, Ai L, Chen JX, Chen SH, Huang DN, et al. Seroprevalence of Angiostrongylus cantonensis infection in humans in China. J Parasitol 2011;97:144–5. Hwang KP, Chen ER. Clinical studies on angiostrongyliasis cantonensis among children in Taiwan. Southeast Asian J Trop Med Public Health 1991;22(Suppl.):194–9. Sawanyawisuth K, Sawanyawisuth K, Senthong V, Limpawattana P, Intapan PM, Tiamkao S, et al. Peripheral eosinophilia as an indicator of meningitic angiostrongyliasis in exposed individuals. Mem Inst Oswaldo Cruz 2010;105:942–4. Sawanyawisuth K, Kitthaweesin K. Optic neuritis caused by intraocular angiostrongyliasis. Southeast Asian J Trop Med Public Health 2008;39:1005–7. Sawanyawisuth K, Kitthaweesin K, Limpawattana P, Intapan PM, Tiamkao S, Jitpimolmard S, et al. Intraocular angiostrongyliasis: clinical findings, treatments and outcomes. Trans R Soc Trop Med Hyg 2007;101:497–501. Sawanyawisuth K, Pugkhem A, Mitchai J, Intapan PM, Anunnatsiri S, Limpawattana P, et al. Abdominal angiostrongyliasis caused by Angiostrongylus cantonensis: a possible cause of eosinophilic infiltration in human digestive tract. Pathol Res Pract 2010;206:102–4. Cui Y, Shen M, Meng S. Lung CT findings of angiostrongyliasis cantonensis caused by Angiostrongylus cantonensis. Clin Imaging 2011;35:180–3. Sawanyawisuth K, Takahashi K, Hoshuyama T, Sawanyawisuth K, Senthong V, Limpawattana P, et al. Clinical factors predictive of encephalitis caused by Angiostrongylus cantonensis. Am J Trop Med Hyg 2009;81:698–701. Kittimongkolma S, Intapan PM, Laemviteevanich K, Kanpittaya J, Sawanyawisuth K, Maleewong W. Eosinophilic meningitis associated with angiostrongyliasis: clinical features, laboratory investigations and specific diagnostic IgG and IgG subclass antibodies in cerebrospinal fluid. Southeast Asian J Trop Med Public Health 2007;38:24–31. Yii CY. Clinical observations on eosinophilic meningitis and meningoencephalitis caused by Angiostrongylus cantonensis on Taiwan. Am J Trop Med Hyg 1976;25:233–49.
549
[28] Tsai HC, Liu YC, Kunin CM, Lai PH, Lee SS, Chen YS, et al. Eosinophilic meningitis caused by Angiostrongylus cantonensis associated with eating raw snails: correlation of brain magnetic resonance imaging scans with clinical findings. Am J Trop Med Hyg 2003;68:281–5. [29] Jin EH, Ma Q, Ma DQ, He W, Ji AP, Yin CH. Magnetic resonance imaging of eosinophilic meningoencephalitis caused by Angiostrongylus cantonensis following eating freshwater snails. Chin Med J 2008;121:67–72. [30] Jin E, Ma D, Liang Y, Ji A, Gan S. MRI findings of eosinophilic myelomeningoencephalitis due to Angiostrongylus cantonensis. Clin Radiol 2005;60:242–50. [31] Prociv P, Spratt DM, Carlisle MS. Neuro-angiostrongyliasis: unresolved issues. Int J Parasitol 2000;30:1295–303. [32] Wilkins PP, Qvarnstrom Y, Whelen AC, Saucier C, da Silva AJ, Eamsobhana P. The current status of laboratory diagnosis of Angiostrongylus cantonensis infections in humans using serologic and molecular methods. Hawaii J Med Public Health 2013;72:55–7. [33] Chen MX, Zhang RL, Chen JX, Chen SH, Li XH, Gao ST, et al. Monoclonal antibodies against excretory/secretory antigens of Angiostrongylus cantonensis. Hybridoma 2010;29:447–52. [34] Chye SM, Lin SR, Chen YL, Chung LY, Yen CM. Immuno-PCR for detection of antigen to Angiostrongylus cantonensis circulating fifth-stage worms. Clin Chem 2004;50:51–7. [35] Vitta A, Yoshino TP, Kalambaheti T, Komalamisra C, Waikagul J, Ruangsittichai J, et al. Application of recombinant SMR-domain containing protein of Angiostrongylus cantonensis in immunoblot diagnosis of human angiostrongyliasis. Southeast Asian J Trop Med Public Health 2010;41:785–99. [36] Punyagupta S, Juttijudata P, Bunnag T. Eosinophilic meningitis in Thailand. Clinical studies of 484 typical cases probably caused by Angiostrongylus cantonensis. Am J Trop Med Hyg 1975;24:921–31. [37] Chotmongkol V, Sawanyawisuth K, Thavornpitak Y. Corticosteroid treatment of eosinophilic meningitis. Clin Infect Dis 2000;31:660–2. [38] Hidelaratchi MD, Riffsy MT, Wijesekera JC. A case of eosinophilic meningitis following monitor lizard meat consumption, exacerbated by anthelminthics. Ceylon Med J 2005;50:84–6. [39] Chotmongkol V, Sawadpanitch K, Sawanyawisuth K, Louhawilai S, Limpawattana P. Treatment of eosinophilic meningitis with a combination of prednisolone and mebendazole. Am J Trop Med Hyg 2006;74:1122–4. [40] Jitpimolmard S, Sawanyawisuth K, Morakote N, Vejjajiva A, Puntumetakul M, Sanchaisuriya K, et al. Albendazole therapy for eosinophilic meningitis caused by Angiostrongylus cantonensis. Parasitol Res 2007;100:1293–6. [41] Zhou Z, Barennes H, Zhou N, Ding L, Zhu YH, Strobel M. Two outbreaks of eosinophilic meningitis in Yunann (China) clinical, epidemiological and therapeutical issues. Bull Soc Pathol Exot 2009;102:75–80. [42] Chotmongkol V, Kittimongkolma S, Niwattayakul K, Intapan PM, Thavornpitak Y. Comparison of prednisolone plus albendazole with prednisolone alone for treatment of patients with eosinophilic meningitis. Am J Trop Med Hyg 2009;81:443–5.
