How Can Clinicians Ensure the Diagnosis of Meningitic Angiostrongyliasis?

Introduction

A ngiostrongyliasis, caused by Angiostrongylus cantonensis, is endemic mainly in Southeast Asia and Pacific islands but is currently spreading worldwide (Wang et al. 2008). Until 2008, over 2800 cases have been reported in 30 countries. Thailand is the heaviest endemic country where nearly half of the cumulative human cases in the world have been recorded (Wang et al. 2008). The three main clinical manifestations are meningitis, encephalitis, and ocular disease. Among all, meningitis is the most common form, and the patients almost exclusively suffer from acute severe headache (Sawanyawisuth and Sawanyawisuth 2008).

In clinical practice, the diagnosis of meningitic angiostrongyliasis (MA) is primarily made by clinical criteria (Punyagupta et al. 1970, Chotmongkol et al. 2000, 2004, 2006, Jitpimolmard et al. 2007, Ramirez-Avila et al. 2009). The cerebrospinal fluid (CSF) eosinophilia of ≥10% in association with the history of exposure to A. cantonensis larvae are the fundamental clinical criteria. History of eating undercooked or raw snails or contaminated food was commonly noted by the physicians. Serologic tests such as immunoblotting technique have been used to confirm the diagnosis. Besides the need for extensive performance evaluations, immunodiagnostic methods are usually available only in research laboratories, thus preventing the widespread use in clinical settings. Here, we would like to define the diagnostic significance of various clinical parameters that is predictive for the positive serologic test for A. cantonensis. The results will give more confidence to clinicians to diagnose MA by clinical parameters before confirmation by immunological tests.

Materials and Methods

The study was performed at Srinagarind Hospital, Khon Kaen, Thailand, which is an endemic area of angiostrongyliasis. The protocol was approved by the institutional review board and the ethics committee of Khon Kaen University.

All patients in whom MA had been diagnosed and who had serologic tests for both A. cantonensis (Maleewong et al. 2001) and Gnathostoma spinigerum (Intapan et al. 2010) were enrolled. The diagnosis of MA was made by the clinical criteria (Punyagupta et al. 1970, Chotmongkol et al. 2000, Sawanyawisuth and Sawanyawisuth 2008) as follows: (1) white blood cell count in CSF ≥10 cells/mm³, (2) eosinophils in CSF ≥10% of the total CSF white blood cell count, (3) negative tests for CSF by Gram-, acid-fast-, and Indian ink staining, cryptococcal antigen test and cultures, and (4) history of ingesting raw freshwater snails or other paratenic hosts, such as shrimps and monitor lizards. Additionally, we included the negative immunoblot test for the 24-kDa antigen band for G. spinigerum as the inclusion criterion in this study.

Exclusion criteria applied to eliminate other possible causes of CSF eosinophils including history of raw fish consumption, history of migratory swelling, clinical diagnosis of subarachnoid hemorrhage or myeloencephalitis, positive serologic test for cysticercosis, symptomatic or serology-positive HIV infection, and active or previous history of tuberculosis or malignancy. In addition, we excluded the subjects who had a history of previous lumbar puncture or previous treatment.

The participating patients were divided into sero-positive and negative groups according to the results of immunoblot test against the 29-kDa antigen diagnostic band for A. cantonensis (Maleewong et al. 2001). We compared all clinical parameters between these two groups including baseline characteristics, physical signs, and laboratory results.

Univariate logistic regression analyses were applied to calculate the crude odd ratios of individual variables for the association with positive serologic tests. All potential clinical parameters were included in subsequent multivariate logistic regression analyses. All variables with p>0.20 in the multivariate model were excluded with the stepwise approach, whereas those with p<0.15 were retained in the final model. All data analyses were performed with SAS software version 8.2.

Results

There were 75 eligible patients with 26 (34.7%) sero-negative and 49 (65.3%) sero-positive values. Baseline characteristics and laboratory results of both groups were presented in Tables 1 and 2. Approximately three-fourths of the subjects in each group were men. The median age of sero-negative and -positive group was 34 and 32 years, respectively. Most of the subjects had headache for 7 days with the range of incubation period of 1–60 days in both groups.

In the sero-positive group, the number of patients with history of paresthesia, fever, cranial nerve palsy, papilledema, and stiff neck was higher. There were also more patients with leucocytosis (≥10,000 cells/mm³), peripheral blood eosinophilia (≥10%), high opening CSF pressure (≥300 mmH₂O), CSF eosinophilia (≥40%), decreased CSF glucose level (<50 mg/dL), and the decreased CSF/plasma glucose ratio (<50%) in the sero-positive group.

By univariate analysis, none of the clinical parameters were significantly correlated with the positive serological test. In a multivariate model, three variables remained in the final model including male gender, CSF protein >100 mg/dL, and CSF eosinophils ≥40% (Table 3). Among those three factors, only CSF eosinophils ≥40% was significantly predictive for positive serologic test with the adjusted odd ratio of 4.970 (95% confidence interval of 1.337–18.477).

Discussion

Our results show that the CSF eosinophilia of >40% is significantly associated with the positive serological test in patients with clinically diagnosed MA, suggesting that CSF eosinophilia of >40% have a diagnostic value of MA in the endemic area.

Most clinical signs and symptoms of the patients in the sero-positive and negative groups were quite similar (Tables 1 and 2). Only the CSF eosinophilia of ≥40% was significantly associated with the positive serological test. The history of exposure to A. cantonensis larvae is also crucial for the diagnosis of MA.

Hypereosinophilia of CSF (≥40%) does not completely exclude the possibility of other neuroparasitoses such as G. spinigerum, Paragonimus westernmani, or Toxocara canis exclusion. For example, CSF eosinophils in neurognathostomiasis may be as high as 90% (Schmutzhard et al. 1988), and raw freshwater snails may contain G. spinigerum larvae (Komalamisra et al. 2009). However, neurognathostomiasis and MA can be differentiated by overall clinical manifestations. Neurognathostomiasis is almost always accompanied by radicular pain, bloody CSF, and pertinent neurological deficit such as hemiparesis or paraparesis (Schmutzhard et al. 1988, Sawanyawisuth and Sawanyawisuth 2008). Eosinophilic meningitis due to Paragonimus infection has been reported at times, but is usually accompanied by pleuro-pulmonary lesions (Solomon et al. 2006). Eosinophilic meningitis can also be seen in toxocariasis, but typically neurotoxocariasis causes the deterioration of consciousness (Solomon et al. 2006).

In the present study, we used the results of serological tests for the construction of the patients groups and also for the exclusion criteria of gnathostomiasis. Thus, although CSF eosinophilia of ≥40% is highly suggestive of possible MA, the development of a more sensitive, specific, and field-applicable multivalent immunodiagnosis kit is necessary for differential diagnosis of neurohelminthiasis.

In conclusion, with limitations of facilities and accessibility to serological tests, the CSF eosinophils level ≥40% will be a helpful tool to diagnose the MA together with clinical background in the endemic area.