| Summary: | 博士 === 高雄醫學大學 === 醫學研究所博士班 === 96 === Angiostrongylus cantonensis is the most common cause of eosinophilic meningitis worldwide. Human infection occurs following ingestion of the worms in raw snails or fish that serve as intermediate hosts. Three outbreaks of central nervous system infection with A. cantonensis occurred in Kaoshiung, Taiwan during 1998, 1999 and 2001 among 17 Thai laborers who ate raw snails and 5 native Taiwanese who drank raw vegetable juice. We performed a retrospective cohort study to enhance case findings with eosinophilic meningitis, as well as environmental surveillance of larvae in snails and testing for antibodies of A. cantonensis in the blood and cerebrospinal fluids. We enrolled 22 patients with severe headache and eosinophilia within 4 to 90 days after eating raw snails and drinking raw vegetable juice. Sixteen (73 %) developed eosinophilic meningitis. Third stage larvae were found in the cerebrospinal fluids of 2 patients and 12/12 snails. Specific antibodies were detected in serum and cerebrospinal fluids. The severity of illness and eosinophilia were associated with amount of snails ingested. Eighteen of twenty-two of these cases underwent magnetic resonance imaging (MRI) of the brain. MRI imaging revealed high signal intensities over the globus pallidus on TI-weighted imaging, leptomeningeal enhancement, ventriculomegaly and punctate areas of abnormal enhancement within the cerebral and cerebellar hemisphere on gadolinium enhancing T1 imaging, and a hyperintense signal on T2-weighted images. There was a significant correlation between severity of headache, CSF pleocystosis and CSF and blood eosinophilia with MRI signal intensity in T1-weighted imaging (p <0.05). Among the five native Taiwanese who drank raw vegetable juice, risk factors identification showed that consumption of raw vegetable juice was associated with illness (Pearson correlation test r = 0.867, P= 0.01). There was association between the presence of raw vegetable juice and CSF eosinophilia (Spearman’s correlation test r=0.816, P= 0.004).
Vascular endothelial growth factor (VEGF) is a potent vascular permeability factor and a mediator of brain edema. To assess the role of VEGF in eosinophilic meningitis, VEGF was measured in the cerebrospinal fluid (CSF) and blood of 9 patients with eosinophilic meningitis in a cohort study. VEGF CSF was detected in 8 (90%) of 9 eosinophilic meningitis patients (range, 45–2190 pg/mL) at presentation. The mean VEGF CSF at presentation, one week and two weeks after admission was 568 pg/mL, 751 pg/mL and 1031 pg/mL, respectively. There was an association between VEGFCSF, CSF protein, white cell count, and eosinophil counts. The VEGFSERUM fluctuated during the 6-month follow up period. These results indicate that VEGF may be associated with blood-brain barrier disruption in patients with eosinophilic meningitis.
Our another study is designed to evaluate the possibility of blood-brain barrier (BBB) dysfunction caused by matrix metalloproteinase-9 (MMP-9) and its regulation by tissue inhibitors of metalloproteinase (TIMPs) in patients with eosinophilic meningitis caused by the infection with A. cantonensis, 40 patients and 28 controls were included in this study. Concentrations of MMP-2, MMP-9, TIMP-1 and CSF/serum albumin ratio (QAlb values) are significantly increased in patients than those in controls, however, TIMP-4 is significantly lower in patients. Contrarily to MMP-2, proteolytic activity of MMP-9 detected by gelatin zymography was only observed in patients with eosinophilic meningitis. It was observed that the higher the antibody levels specific to A. cantonensis in CSF of patients with eosinophilic meningitis, the higher the QAlb values and MMP-9 concentrations in CSF of patients. Furthermore, the increase in QAlb value was significantly correlated with the increase of MMP-9 in patients. In parallel with CSF MMP-9, patients also showed an increase of CSF white blood cell counts. Gradual decrease levels of QAlb, MMP-9 and TIMP-1 and increase levels of TIMP-4 were observed in 6 patients during recovery from eosinophilic meningitis. These results propose that the source of MMP-9 in CSF of patients with eosinophilic meningitis was probably associated with leukocytes migrating from peripheral blood to CSF. The activity of MMP-9 in CSF of patients could not completely inhibited because of the decrease of TIMP-4 which had the chance to cause BBB dysfunction as proven by the higher QAlb values found in patients.
In conclusion, BBB dysfunction may occur in patients with eosinophilic meningitis due to the infection of A. cantonensis because patients show significantly higher QAlb which significantly correlates with the concentrations of MMP-9 in CSF of patients. And also VEGF may be associated with blood-brain barrier disruption in patients with eosinophilic meningitis. The increase of MMP-9 in CSF of patients probably derives from leukocytes because they appeared a large number in CSF. Although TIMP-1 increased in the CSF of patients to neutralize the MMP-9, the proteolytic activity of MMP-9 still showed high levels. The reason why TIMP-4 in CSF of patients suddenly steeply dropped in the acute phase of eosinophilic meningitis and its role in BBB dysfunction of this parasitic disease should be clarified in further studies.
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