Case Report
Severe eosinophilic meningitis owing to Angiostrongylus cantonensis in young Jamaican children: case report and literature review Tracy Evans-Gilbert1, John F. Lindo2, Sonia Henry3, Paul Brown4, Celia D. C. Christie5 1
Department of Paediatrics, Cornwall Regional Hospital, Montego Bay, 2Department of Microbiology, University of the West Indies, Mona, Kingston, 3Bustamante Hospital for Children, Kingston, 4Department of Basic Medical Sciences University of the West Indies, Mona, Kingston, 5Department of Child Health, University of the West Indies, Mona, Kingston, Jamaica, West Indies Eosinophilic meningitis caused by Angiostrongylus cantonensis is an endemic and emerging disease that affects adults and children in Jamaica. Most cases resolve without sequelae, but young children are at high risk of neurological damage and death. Treatment with corticosteroids and albendazole is considered safe for adults and children, but protocols for its use in children have not been established. A 19-month-old infant with permanent neurological sequlae caused by Angiostrongylus cantonensis meningitis is reported, and five other Jamaican cases are summarized. A review of the literature of children with permanent neurological sequlae and death is presented. Children ,5 years (especially ,2) were at increased risk of incomplete recovery and death if they presented with bulbar signs, flaccid paresis and coma. None of the severe or fatal cases received early intervention with anthelminthics, and disease progression was not altered with corticosteroids. In view of the pathophysiology, necropsy reports and animal studies, it seems that the early use of larvicidals may change the course of severe presentations.
Keywords: Eosinophilic, Meningitis, Angiostrongylus cantonensis, Severe, Infectious disease, Children
Introduction Eosinophilic meningitis caused by Angiostrongylus cantonensis is an emerging disease in Jamaica.1 First reported in the Western Hemisphere in Cuba in 1981, A. cantonensis is endemic in South-east Asia and the Pacific Islands.2 Owing to its spread by international travel and the ship-borne migration of rats, there have been reports of the disease in the Caribbean, South America and other parts of the Western Hemisphere. Humans are incidentally infected by consuming the intermediate hosts (slugs, snails and molluscs) or vegetables containing third-stage larvae. The main clinical manifestations include eosinophilic meningitis and ocular angiostrongyliasis which demonstrate self-limited clinical courses. Reversible neurological sequelae may develop, such as cranial nerve palsy and radiculomyelopathy, and fatal outcomes and irreversible neurological injuries have been reported. Treatment with corticosteroids and albendazole is considered Correspondence to: T Evans-Gilbert, Cornwall Regional Hospital, Montego Bay, Jamaica, West Indies. Email: [email protected]
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safe for adults and children, but protocols for its use in children have not been established because most cases naturally resolve. A 19-month-old infant with meningitis caused by A. cantonensis is presented. Five other cases of confirmed A. cantonensis meningitis in Jamaican children are also summarised, and reports of seven cases in the literature with permanent neurological sequelae (including fatal cases) are compared in order to determine the risk factors associated with incomplete recovery and death.
Case Report A previously healthy 19-month-old girl from rural Jamaica presented at Bustamante Hospital for Children, Kingston with a 1-week history of refusal to walk, excessive crying and, 2 days later, refusal to crawl. The antenatal history and delivery had been normal, she had reached age-appropriate developmental milestones, and had been immunised according to local guidelines. There was no history of trauma, medication, preceding infectious symptoms,
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Figure 1 Male Angiostrongylus cantonensis worm removed from the CSF of the patient with severe eosinophilic meningitis. Note the large copulatory bursa and long copulatory spicules
or familial neurological illness and her three siblings aged 3–6 years were well. Her growth parameters were normal (weight, head circumference and height were on the 25th, 50th and 90th per centiles for age, respectively), and there were no dysmorphic or neurocutaneous lesions. She became irritable when her lower limbs were handled and demonstrated grade 4/ 5 muscle power, decreased tone and hyporeflexia in the lower limbs. The remainder of the examination was unremarkable. Hyperparesthesia, bone pain and acute flaccid paralysis were suspected as causes of the lower limb symptoms. Haemoglobin (Hb) was 11.1 g/dl and peripheral white blood cells (WBC) 8.16109/L (32% lymphocytes, 67% neutrophils and 1% eosinophils). Platelets, erythrocyte sedimentation rate (ESR 20 mm/hr) and sickle cell test were normal. On day 3 of admission, she developed meningism associated with fever, runny nose and cough. Temperature was 38.8uC. Once focal neurological deficits were excluded, lumbar puncture (LP) using a 25-gauge needle was performed. An opening pressure was not assessed. CSF demonstrated 640 WBC/mm3 (30% lymphocytes, 50% neutrophils, 20% eosinophils), 0.18 g/L protein, 3.6 mmol/L glucose and blood glucose was 5.8 mmol/L. Six-to-eight living worms were seen in slightly turbid cerebrospinal fluid (CSF). After assessing their morphometric characteristics, these were identified by a parasitologist as A. cantonensis juvenile male worms (Fig. 1). Toxocara canis and Taenia solium were ruled out by serology. CSF, blood and urine cultures were sterile. Serial LPs demonstrated CSF pleocytosis (WBC 292–2710/mm3) with eosinophilia (10–23%) which peaked at week 7. The peripheral WBC counts were normal (7.2–8.46109/ L) but eosinophil counts increased from 1% to 7% after the 4th week.
Angiostrongylus cantonensis meningitis
The fever persisted for 9 weeks, peaking during weeks 2 and 5–6 in spite of a 10-day course of antibiotics (ceftriaxone commencing on day 3, ceftazidime day 15, erythromycin day 25) and corticosteroids (dexamethasone 0.6 mg/kg q.i.d. for 3 days and oral prednisone 1 mg/kg for 4 weeks). Her lower limb weakness and hyporeflexia resolved but the hyperparesthesia persisted and she refused to sit or stand. We were reluctant to use albendazole earlier in the disease course because of limited available guidelines. The patient developed visual impairment (squinting in both eyes) and a left seventh cranial nerve palsy over weeks 3–4. Computed tomography (CT) scan of the brain was normal. These impairments and the ophthalmic palsy resolved over weeks 4–5, but cortical blindness developed. Wheezing and respiratory distress developed during week 4, and chest radiography was opaque in the right middle zone. Respiratory distress worsened despite the administration of erythromycin on day 25. During week 4 the WBCs in the CSF were 470/ mm3 (59% lymphocytes, 30% neutrophils, 11% eosinophils). When the fever was peaking during weeks 5–6, WBCs in the CSF were 2030/mm3 (31% lymphocytes, 59% neutrophils, 10% eosinophils). Albendazole (10 mg/kg/day for 3 weeks) was administered on day 42 with intravenous dexamethasone (0.6 mg/kg q.i.d. for 5 days). The patient became less irritable within 24 hours of receiving this combination, and the fever subsided during week 9. A visit to the patient’s home in the countryside revealed that she lived in a house with a hardened dirt floor. Silver snail tracks were noted on the floor along with numerous Thelidomous aspera snails in the yard. The child is currently visually impaired, sits only with support, communicates with a limited vocabulary and lives in a children’s home. Table 1 summarizes six cases of A. cantonensis meningitis in Jamaica which were confirmed using DNA PCR and morphometric analysis between 2004 and 2009. Table 2 presents the clinical findings of severe and fatal cases of paediatric A. cantonensis meningitis that were available on PubMed, including one fatal case report in a Jamaican child.
Discussion The patients with A. cantonensis meningitis described in the literature were primarily toddlers who are known to place objects indiscriminately in the mouth. In Table 1, the children were primarily ,24 months of age and infected between May and November 2004–2009. Previous studies in Taiwan report a seasonal predilection for infection during the rainy season when the intermediate host is active.3 In Jamaica, there have been too few human cases to recognise a pattern. All patients developed fever and
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Recovery
Recovery
Prednisone
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Prednisone through week 4, albendazole after week 6
Antibiotics
Hemiparesis
Recovery
Albendazole and prednisone
irritability or headache. The level of CSF pleocytosis did not correlate with disease severity in any patient. In cases 3, 5 and 6 CSF eosinophilia was not noted on the initial LP and cases 1, 3 and 6 had prolonged fever, progressive neurological signs and pulmonary disorders in the absence of worsening CSF pleocytosis. In Table 2, the common characteristics and findings in those who developed sequelae included age ,5 years (the majority were ,2 years), paresis (e.g. hemiparesis, quadriparesis, lower limb paresis), bulbar signs, coma and large larval burden at necropsy. Humans can be infected by A. cantonensis by ingesting the intermediate hosts of A. cantonensis, such as slugs, snails, and molluscs. Adult A. cantonensis worms have been found in branches of rats’ pulmonary arteries. A. cantonensis worms lay eggs that hatch into first-stage larvae and then enter the alveoli and ascend into the trachea; there they are swallowed and then excreted in the faeces. Certain snail and slug species ingest the first-stage larvae, which moult twice as they develop into infective third-stage larvae. Once ingested again, third-stage larvae penetrate the intestinal tissues of humans and are carried by the blood to the liver, heart, lungs and central nervous system (CNS). In the CNS, larvae continue to develop to the fourth and fifth stages, rarely migrating back to the lungs for further development.4 In a 2000 outbreak in 12 North American tourists, the source was traced to vegetables which had been infected with enzootic A. cantonensis by Jamaican rats and snails.5 In children there is earlier onset of illness and higher frequencies of meningo-encephalitis, sixth and seventh cranial nerve palsy, papilloedema and fever than in adults.3,6 In 37 Taiwanese patients diagnosed over an 18-year period (two were children), neurological sequelae developed in only one 2-year-old child.7 Amongst 82 Taiwanese children, 7% developed neurological deficits8 and 12% did not recover completely.3 In Thailand, the only death in a report of 484 mostly adult cases was a 2-year-old.9 Among the 82 Taiwanese children with eosinophilic A. cantonensis meningitis, the mortality rate was 4.9%.3 Of the six Jamaican patients (Table 1), four with meningism and ataxia but without paresis recovered completely. Neurological presentation and severity varied in all patients, which might have been owing to larval burden, host immune response, or the sites of larval development and migration. In Taiwan, among 82 patients, larval recovery is more likely in young patients (73% larval recovery in children 0–2 years of age, 42% in children 3–5 years, and 18% in children 6–8 years).3 This, along with necropsy findings of numerous dead and viable larvae in the pulmonary vessels of the brain and gut,4,6,10
8 live worms, 640 WBC/mm (30%lymphocytes, 50% neutrophils, 20% eosinophils) 104 WBC/mm3 (29%lymphocytes, 52% neutrophils, 19% eosinophils) 1st CSF: 248 WBC/mm3 (50% lymphocytes, 50% neutrophils) 2nd CSF: 376 WBC/mm3 (11% eosinophils) WBC 80/mm3 (35% lymphocytes, 15% eosinophils) 1st CSF: 2 live worms, 16 WBC/mm3 3rd CSF: 277 WBC/mm3 (30%lymphocytes, 12% eosinophils) 1st CSF: 270 WBC/mm3 (98% neutrophils) 2nd CSF: 210 WBC/mm3 (11% eosinophils)
Prednisone through week 5, albendazole after week 6
Cortical blindness, global developmental delays Recovery
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CN, cranial nerve.
6
12
F
Jan
Prolonged fever, vomiting, ataxia, pulmonary signs Dec 19 5
M
Headache, fever, meningism Nov 96 4
M
Fever, irritability, vomiting, ptosis, ataxia Nov 18 3
M
24 2
M
March
Prolonged fever, CN IV and VII palsy, cortical blindness, pulmonary signs, lower limb weakness Headache, fever, irritability, ataxia Feb 19 1 (present case)
F
CSF findings Clinical features Month of infection Sex Age/mths Case
Table 1 Demographic and clinical features of Jamaican children infected with A. cantonensis during 2004–2009
3
Treatment
Outcome
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WBC 200/mm3 (40% lymphocytes, 60% eosinophils) WBC 30/mm3 (98% neutrophils) Punyagupta9 Thailand 1975 Lindo4 Jamaica 2004
36
72
11
24
14
3
4
5
6
7
None of the reported cases received albendazole. Supportive care included antibiotics, multiple lumbar punctures and analgesics.
Supportive
55 lymphocytes, 2 polymorphonucleocytes Cooke-Yarborough10 Fiji 1999
24 60 1 2
Yii6 Taiwan 1975
WBC 50/mm3 (77% lymphocytes, 23% eosinophils, WBC 130/mm3 20% lymphocytes, 39% eosinophils) Yii6 Taiwan 1975
Abdominal distension, flaccid paresis, bulbar involvement, coma, death and dead and viable worms at necropsy
Supportive
Corticosteroids
Supportive
Supportive
Supportive Supportive
Lower limb weakness Lower limb weakness, coma, large larval load at necropsy in brain and lung vessels Semi-comatose, quadriparesis, aphasia, blindness with optic atrophy, death Fever, meningism, semi-comatose, lower-limb paresis, upper-limb flaccid paralysis, death Flaccid quadriparesis, bulbar and pulmonary involvement; larvae identified in brain, lungs and spinal cord at necropsy Convulsions, coma, death Not reported WBC 530/mm3 (3% lymphocytes, 97% eosinophils) Tseng7 Thailand 2011 Yii6 Taiwan 1975
Sequelae CSF findings Author/location Age/mths Case
Table 2 Epidemiological and clinical findings of patients with severe or fatal A. cantonensis infection in the literature
Treatment
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suggests that children (especially those ,5 years) may carry a larger larval burden than older children and adults. Our case had three siblings aged 3–6 who were unaffected. A home visit showed numerous Thelidomous aspera snails which is one of the main intermediate hosts for A. cantonensis in Jamaica. It is possible that the child came into direct contact with infected snails, accounting for the high burden. According to necropsy findings in adults, extensive tissue damage is the result of an inflammatory reaction to any dead parasites, along with the tracks made by viable larvae as they move through the brain.11 No published studies report an association between blood or CSF pleocytosis and severity of sequelae or death. Pleocytosis was not unusually severe in the four fatal cases in Taiwan,6 nor was this a feature of the fatal Jamaican case or the case reported.4 This may have been the result of variations in the host responses or a biphasic course that causes CSF pleocytosis to peak during weeks 3 and 5–9 which did not correlate with clinical relapse.6 Mild presentations during the early phases of eosinophilic meningitis may be overlooked. Variation in the immune responses of children to a large larval load may result in unchecked larval migration and severe neurological sequelae. Of 125 patients who were primarily Taiwanese children, four cases developed coma before death, seven with flaccid paralysis and coma received a grave prognosis, and three of seven patients developed sequelae after coma or semi-coma.6 These findings are similar to three of the four deaths that occurred in a study of 82 Taiwanese children, all preceded by coma.3 Site and larval burden, rather than the inflammatory response (as suggested by the degree of pleocytosis)6 may have a greater influence on neurological outcome. The pathophysiological mechanism of A. cantonensis larvae has been proposed on the basis of necropsy findings. Nematodes cause extensive tissue damage by moving through the brain parenchyma, creating migratory tracks and inducing blood vessel dilation; when dead, they cause thrombotic lesions and eosinophilic and granulomatous inflammatory reactions.11 Studies evaluating the use of corticosteroids and albendazole to treat A. cantonensis meningitis report that both are safe for adults and children.6,12,13 Adult studies suggest that a 2-week course of prednisone relieves headaches but that the addition of albendazole confers no added benefits.12,13 These studies, however, excluded patients with altered conscious states; therefore, the potential impact of albendazole or corticosteroids on such severe cases requires further evaluation.12,13 In children, most symptoms are alleviated after spinal tap and disappear within 4 weeks of onset
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References
without sequelae.3,6 None of the severe or fatal cases received early intervention with anthelminthics. Corticosteroids alone did not prevent morbidity or death in patients demonstrating bulbar signs, CNS depression or progressive neurological signs. In the case presented here, antihelminthics were not used early in the disease owing to the risk of a potential adverse inflammatory response caused by dead worms. No complications were observed in any of the 22 Taiwanese children who were treated with 10 mg/kg albendazole for 3 weeks or in the children from whom live worms were recovered and who were treated only with albendazole.6 In animal studies, larval burden is significantly reduced along with severity of infection when albendazole is administered within the first 2 weeks of infection.14,15 The use of 10 mg/kg albendazole for 3 weeks, commencing at presentation, can be of value in reducing larval burden and offsetting the deleterious effects of migrating worms in children at risk. In Jamaica, a heightened sense of awareness is needed to better detect eosinophilic meningitis. Children ,5 years (especially ,2 years) with eosinophilic meningitis caused by A. cantonensis face a grave clinical outcome and risk the development of neurologic sequelae, including paresis, semi-coma/ coma, bulbar involvement, and visual impairment. Further studies are required to evaluate the impact of early larvicidal use on the natural clinical course in children with poor prognostic markers.
1 Slom TJ, Cortese MM, Gerber SI, Jones RC, Holtz RC, Lopez AS, et al. An outbreak of eosinophilic meningitis caused by Angiostrongylus cantonensis in travelers returning from the Caribbean. N Engl J Med. 2002;346:668–75. 2 Aguiar PH, Morera P, Pascual J. First record of Angiostrongylus cantonensis in Cuba. Am J Trop Med Hyg. 1981;30:963–5. 3 Hwang KP, Chen ER. Clinical studies on Angiostrongylus cantonensis among children in Taiwan. Southeast Asian J Trop Med Public Health. 1991;22:194–9. 4 Lindo JF, Escoffrey CT, Reid B, Codrington G, CunninghamMyrie C, Eberhard ML, et al. Fatal autochthonous eosinophilic meningitis in a Jamaican child caused by Angiostrongylus cantonensis. Am J Trop Med Hyg. 2004;70:425–8. 5 Lindo JF, Waugh C, Hall J, Cunningham-Myrie C, Ashley D, Eberhard ML. Enzootic Angiostrongylus cantonensis in rats and snails after an outbreak of human eosinophilic meningitis, Jamaica. Emerg Infect Dis. 2002;8:324–6. 6 Yii CY. Clinical observation on eosinophilic meningitis and meningoencephalitis caused by Angiostrongylus cantonensis in Taiwan. Am J Trop Med Hyg. 1976;25:233–49. 7 Tseng YT, Tsai HC, Sy CL, Lee SS, Wann SR, Wang YH, et al. Clinical manifestations of eosinophilic meningitis caused by Angiostrongylus cantonensis 18 years’ experience in a medical centre in southern Taiwan. J Microbial Infect. 2011;44;382–9. 8 Hwang KP, Chen ER, Chen TS. Eosinophilic meningitis and meningoencephalitis in children. Acta Paediatr Sinica. 1994;35:124–35. 9 Punyagupta S, Juttijudata P, Bunnang, T. Eosinophilic meningitis in Thailand: clinical studies of 484 typical cases probably caused by Angiostrogylus cantonensis. Am J Trop Med Hyg. 1975;25:233–49. 10 Cooke-Yarborough CM, Kornberg AJ, Hogg GG, Spratt DM, Forsyth JR. A fatal case of angiostrongyliasis in an 11-monthold infant. Med J Aust. 1999;170:541–3. 11 Tangchai P, Nye S, Beaver P. Eosinophilic meningitis caused by Angiostrongyliasis in Thailand: autopsy report. Am J Trop Med Hyg. 1967;16:454–61. 12 Chotmongkol V, Wongjitrat C, Sawadpanit K, Sawanyawisuth K. Treatment of eosinophilic meningitis with a combination of albendazole and corticosteroid. Southeast Asian J Trop Med Public Health. 2004;35:172–4. 13 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. 14 Chen KM, Lai SH. Biochemical and pathological evaluation of albendazole/thalidomide co-therapy against eosinophilic meningitis or meningoencephalitis induced by Angiostrongylus cantonensis. J Antimicrob Chemother. 2007;59:264–76. 15 Hwang KP, Chen ER. Larvicidal effect of albendazole against Angiostrongylus cantonensis in mice. Am J Trop Med Hyg. 1988;39:191–5.
Acknowledgment We would like to thank Drs Barbara Herwaldt and Michele Hlavsa of the Division of Parasitic Diseases, Centers for Disease Control and Prevention (CDC), Atlanta, USA for providing helpful literature during initial communications on this case, and Dr Mark Eberhard, also of the Division of Parasitic Diseases, CDC, for identifying the worm.
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Severe eosinophilic meningitis owing to Angiostrongylus cantonensis in young Jamaican children: case report and literature review Tracy Evans-Gilbert1, John F. Lindo2, Sonia Henry3, Paul Brown4, Celia D. C. Christie5 1
Department of Paediatrics, Cornwall Regional Hospital, Montego Bay, 2Department of Microbiology, University of the West Indies, Mona, Kingston, 3Bustamante Hospital for Children, Kingston, 4Department of Basic Medical Sciences University of the West Indies, Mona, Kingston, 5Department of Child Health, University of the West Indies, Mona, Kingston, Jamaica, West Indies Eosinophilic meningitis caused by Angiostrongylus cantonensis is an endemic and emerging disease that affects adults and children in Jamaica. Most cases resolve without sequelae, but young children are at high risk of neurological damage and death. Treatment with corticosteroids and albendazole is considered safe for adults and children, but protocols for its use in children have not been established. A 19-month-old infant with permanent neurological sequlae caused by Angiostrongylus cantonensis meningitis is reported, and five other Jamaican cases are summarized. A review of the literature of children with permanent neurological sequlae and death is presented. Children ,5 years (especially ,2) were at increased risk of incomplete recovery and death if they presented with bulbar signs, flaccid paresis and coma. None of the severe or fatal cases received early intervention with anthelminthics, and disease progression was not altered with corticosteroids. In view of the pathophysiology, necropsy reports and animal studies, it seems that the early use of larvicidals may change the course of severe presentations.
Keywords: Eosinophilic, Meningitis, Angiostrongylus cantonensis, Severe, Infectious disease, Children
Introduction Eosinophilic meningitis caused by Angiostrongylus cantonensis is an emerging disease in Jamaica.1 First reported in the Western Hemisphere in Cuba in 1981, A. cantonensis is endemic in South-east Asia and the Pacific Islands.2 Owing to its spread by international travel and the ship-borne migration of rats, there have been reports of the disease in the Caribbean, South America and other parts of the Western Hemisphere. Humans are incidentally infected by consuming the intermediate hosts (slugs, snails and molluscs) or vegetables containing third-stage larvae. The main clinical manifestations include eosinophilic meningitis and ocular angiostrongyliasis which demonstrate self-limited clinical courses. Reversible neurological sequelae may develop, such as cranial nerve palsy and radiculomyelopathy, and fatal outcomes and irreversible neurological injuries have been reported. Treatment with corticosteroids and albendazole is considered Correspondence to: T Evans-Gilbert, Cornwall Regional Hospital, Montego Bay, Jamaica, West Indies. Email: [email protected]
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safe for adults and children, but protocols for its use in children have not been established because most cases naturally resolve. A 19-month-old infant with meningitis caused by A. cantonensis is presented. Five other cases of confirmed A. cantonensis meningitis in Jamaican children are also summarised, and reports of seven cases in the literature with permanent neurological sequelae (including fatal cases) are compared in order to determine the risk factors associated with incomplete recovery and death.
Case Report A previously healthy 19-month-old girl from rural Jamaica presented at Bustamante Hospital for Children, Kingston with a 1-week history of refusal to walk, excessive crying and, 2 days later, refusal to crawl. The antenatal history and delivery had been normal, she had reached age-appropriate developmental milestones, and had been immunised according to local guidelines. There was no history of trauma, medication, preceding infectious symptoms,
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Figure 1 Male Angiostrongylus cantonensis worm removed from the CSF of the patient with severe eosinophilic meningitis. Note the large copulatory bursa and long copulatory spicules
or familial neurological illness and her three siblings aged 3–6 years were well. Her growth parameters were normal (weight, head circumference and height were on the 25th, 50th and 90th per centiles for age, respectively), and there were no dysmorphic or neurocutaneous lesions. She became irritable when her lower limbs were handled and demonstrated grade 4/ 5 muscle power, decreased tone and hyporeflexia in the lower limbs. The remainder of the examination was unremarkable. Hyperparesthesia, bone pain and acute flaccid paralysis were suspected as causes of the lower limb symptoms. Haemoglobin (Hb) was 11.1 g/dl and peripheral white blood cells (WBC) 8.16109/L (32% lymphocytes, 67% neutrophils and 1% eosinophils). Platelets, erythrocyte sedimentation rate (ESR 20 mm/hr) and sickle cell test were normal. On day 3 of admission, she developed meningism associated with fever, runny nose and cough. Temperature was 38.8uC. Once focal neurological deficits were excluded, lumbar puncture (LP) using a 25-gauge needle was performed. An opening pressure was not assessed. CSF demonstrated 640 WBC/mm3 (30% lymphocytes, 50% neutrophils, 20% eosinophils), 0.18 g/L protein, 3.6 mmol/L glucose and blood glucose was 5.8 mmol/L. Six-to-eight living worms were seen in slightly turbid cerebrospinal fluid (CSF). After assessing their morphometric characteristics, these were identified by a parasitologist as A. cantonensis juvenile male worms (Fig. 1). Toxocara canis and Taenia solium were ruled out by serology. CSF, blood and urine cultures were sterile. Serial LPs demonstrated CSF pleocytosis (WBC 292–2710/mm3) with eosinophilia (10–23%) which peaked at week 7. The peripheral WBC counts were normal (7.2–8.46109/ L) but eosinophil counts increased from 1% to 7% after the 4th week.
Angiostrongylus cantonensis meningitis
The fever persisted for 9 weeks, peaking during weeks 2 and 5–6 in spite of a 10-day course of antibiotics (ceftriaxone commencing on day 3, ceftazidime day 15, erythromycin day 25) and corticosteroids (dexamethasone 0.6 mg/kg q.i.d. for 3 days and oral prednisone 1 mg/kg for 4 weeks). Her lower limb weakness and hyporeflexia resolved but the hyperparesthesia persisted and she refused to sit or stand. We were reluctant to use albendazole earlier in the disease course because of limited available guidelines. The patient developed visual impairment (squinting in both eyes) and a left seventh cranial nerve palsy over weeks 3–4. Computed tomography (CT) scan of the brain was normal. These impairments and the ophthalmic palsy resolved over weeks 4–5, but cortical blindness developed. Wheezing and respiratory distress developed during week 4, and chest radiography was opaque in the right middle zone. Respiratory distress worsened despite the administration of erythromycin on day 25. During week 4 the WBCs in the CSF were 470/ mm3 (59% lymphocytes, 30% neutrophils, 11% eosinophils). When the fever was peaking during weeks 5–6, WBCs in the CSF were 2030/mm3 (31% lymphocytes, 59% neutrophils, 10% eosinophils). Albendazole (10 mg/kg/day for 3 weeks) was administered on day 42 with intravenous dexamethasone (0.6 mg/kg q.i.d. for 5 days). The patient became less irritable within 24 hours of receiving this combination, and the fever subsided during week 9. A visit to the patient’s home in the countryside revealed that she lived in a house with a hardened dirt floor. Silver snail tracks were noted on the floor along with numerous Thelidomous aspera snails in the yard. The child is currently visually impaired, sits only with support, communicates with a limited vocabulary and lives in a children’s home. Table 1 summarizes six cases of A. cantonensis meningitis in Jamaica which were confirmed using DNA PCR and morphometric analysis between 2004 and 2009. Table 2 presents the clinical findings of severe and fatal cases of paediatric A. cantonensis meningitis that were available on PubMed, including one fatal case report in a Jamaican child.
Discussion The patients with A. cantonensis meningitis described in the literature were primarily toddlers who are known to place objects indiscriminately in the mouth. In Table 1, the children were primarily ,24 months of age and infected between May and November 2004–2009. Previous studies in Taiwan report a seasonal predilection for infection during the rainy season when the intermediate host is active.3 In Jamaica, there have been too few human cases to recognise a pattern. All patients developed fever and
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Antibiotics
Hemiparesis
Recovery
Albendazole and prednisone
irritability or headache. The level of CSF pleocytosis did not correlate with disease severity in any patient. In cases 3, 5 and 6 CSF eosinophilia was not noted on the initial LP and cases 1, 3 and 6 had prolonged fever, progressive neurological signs and pulmonary disorders in the absence of worsening CSF pleocytosis. In Table 2, the common characteristics and findings in those who developed sequelae included age ,5 years (the majority were ,2 years), paresis (e.g. hemiparesis, quadriparesis, lower limb paresis), bulbar signs, coma and large larval burden at necropsy. Humans can be infected by A. cantonensis by ingesting the intermediate hosts of A. cantonensis, such as slugs, snails, and molluscs. Adult A. cantonensis worms have been found in branches of rats’ pulmonary arteries. A. cantonensis worms lay eggs that hatch into first-stage larvae and then enter the alveoli and ascend into the trachea; there they are swallowed and then excreted in the faeces. Certain snail and slug species ingest the first-stage larvae, which moult twice as they develop into infective third-stage larvae. Once ingested again, third-stage larvae penetrate the intestinal tissues of humans and are carried by the blood to the liver, heart, lungs and central nervous system (CNS). In the CNS, larvae continue to develop to the fourth and fifth stages, rarely migrating back to the lungs for further development.4 In a 2000 outbreak in 12 North American tourists, the source was traced to vegetables which had been infected with enzootic A. cantonensis by Jamaican rats and snails.5 In children there is earlier onset of illness and higher frequencies of meningo-encephalitis, sixth and seventh cranial nerve palsy, papilloedema and fever than in adults.3,6 In 37 Taiwanese patients diagnosed over an 18-year period (two were children), neurological sequelae developed in only one 2-year-old child.7 Amongst 82 Taiwanese children, 7% developed neurological deficits8 and 12% did not recover completely.3 In Thailand, the only death in a report of 484 mostly adult cases was a 2-year-old.9 Among the 82 Taiwanese children with eosinophilic A. cantonensis meningitis, the mortality rate was 4.9%.3 Of the six Jamaican patients (Table 1), four with meningism and ataxia but without paresis recovered completely. Neurological presentation and severity varied in all patients, which might have been owing to larval burden, host immune response, or the sites of larval development and migration. In Taiwan, among 82 patients, larval recovery is more likely in young patients (73% larval recovery in children 0–2 years of age, 42% in children 3–5 years, and 18% in children 6–8 years).3 This, along with necropsy findings of numerous dead and viable larvae in the pulmonary vessels of the brain and gut,4,6,10
8 live worms, 640 WBC/mm (30%lymphocytes, 50% neutrophils, 20% eosinophils) 104 WBC/mm3 (29%lymphocytes, 52% neutrophils, 19% eosinophils) 1st CSF: 248 WBC/mm3 (50% lymphocytes, 50% neutrophils) 2nd CSF: 376 WBC/mm3 (11% eosinophils) WBC 80/mm3 (35% lymphocytes, 15% eosinophils) 1st CSF: 2 live worms, 16 WBC/mm3 3rd CSF: 277 WBC/mm3 (30%lymphocytes, 12% eosinophils) 1st CSF: 270 WBC/mm3 (98% neutrophils) 2nd CSF: 210 WBC/mm3 (11% eosinophils)
Prednisone through week 5, albendazole after week 6
Cortical blindness, global developmental delays Recovery
Angiostrongylus cantonensis meningitis
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Prolonged fever, hemiparesis
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CN, cranial nerve.
6
12
F
Jan
Prolonged fever, vomiting, ataxia, pulmonary signs Dec 19 5
M
Headache, fever, meningism Nov 96 4
M
Fever, irritability, vomiting, ptosis, ataxia Nov 18 3
M
24 2
M
March
Prolonged fever, CN IV and VII palsy, cortical blindness, pulmonary signs, lower limb weakness Headache, fever, irritability, ataxia Feb 19 1 (present case)
F
CSF findings Clinical features Month of infection Sex Age/mths Case
Table 1 Demographic and clinical features of Jamaican children infected with A. cantonensis during 2004–2009
3
Treatment
Outcome
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WBC 200/mm3 (40% lymphocytes, 60% eosinophils) WBC 30/mm3 (98% neutrophils) Punyagupta9 Thailand 1975 Lindo4 Jamaica 2004
36
72
11
24
14
3
4
5
6
7
None of the reported cases received albendazole. Supportive care included antibiotics, multiple lumbar punctures and analgesics.
Supportive
55 lymphocytes, 2 polymorphonucleocytes Cooke-Yarborough10 Fiji 1999
24 60 1 2
Yii6 Taiwan 1975
WBC 50/mm3 (77% lymphocytes, 23% eosinophils, WBC 130/mm3 20% lymphocytes, 39% eosinophils) Yii6 Taiwan 1975
Abdominal distension, flaccid paresis, bulbar involvement, coma, death and dead and viable worms at necropsy
Supportive
Corticosteroids
Supportive
Supportive
Supportive Supportive
Lower limb weakness Lower limb weakness, coma, large larval load at necropsy in brain and lung vessels Semi-comatose, quadriparesis, aphasia, blindness with optic atrophy, death Fever, meningism, semi-comatose, lower-limb paresis, upper-limb flaccid paralysis, death Flaccid quadriparesis, bulbar and pulmonary involvement; larvae identified in brain, lungs and spinal cord at necropsy Convulsions, coma, death Not reported WBC 530/mm3 (3% lymphocytes, 97% eosinophils) Tseng7 Thailand 2011 Yii6 Taiwan 1975
Sequelae CSF findings Author/location Age/mths Case
Table 2 Epidemiological and clinical findings of patients with severe or fatal A. cantonensis infection in the literature
Treatment
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suggests that children (especially those ,5 years) may carry a larger larval burden than older children and adults. Our case had three siblings aged 3–6 who were unaffected. A home visit showed numerous Thelidomous aspera snails which is one of the main intermediate hosts for A. cantonensis in Jamaica. It is possible that the child came into direct contact with infected snails, accounting for the high burden. According to necropsy findings in adults, extensive tissue damage is the result of an inflammatory reaction to any dead parasites, along with the tracks made by viable larvae as they move through the brain.11 No published studies report an association between blood or CSF pleocytosis and severity of sequelae or death. Pleocytosis was not unusually severe in the four fatal cases in Taiwan,6 nor was this a feature of the fatal Jamaican case or the case reported.4 This may have been the result of variations in the host responses or a biphasic course that causes CSF pleocytosis to peak during weeks 3 and 5–9 which did not correlate with clinical relapse.6 Mild presentations during the early phases of eosinophilic meningitis may be overlooked. Variation in the immune responses of children to a large larval load may result in unchecked larval migration and severe neurological sequelae. Of 125 patients who were primarily Taiwanese children, four cases developed coma before death, seven with flaccid paralysis and coma received a grave prognosis, and three of seven patients developed sequelae after coma or semi-coma.6 These findings are similar to three of the four deaths that occurred in a study of 82 Taiwanese children, all preceded by coma.3 Site and larval burden, rather than the inflammatory response (as suggested by the degree of pleocytosis)6 may have a greater influence on neurological outcome. The pathophysiological mechanism of A. cantonensis larvae has been proposed on the basis of necropsy findings. Nematodes cause extensive tissue damage by moving through the brain parenchyma, creating migratory tracks and inducing blood vessel dilation; when dead, they cause thrombotic lesions and eosinophilic and granulomatous inflammatory reactions.11 Studies evaluating the use of corticosteroids and albendazole to treat A. cantonensis meningitis report that both are safe for adults and children.6,12,13 Adult studies suggest that a 2-week course of prednisone relieves headaches but that the addition of albendazole confers no added benefits.12,13 These studies, however, excluded patients with altered conscious states; therefore, the potential impact of albendazole or corticosteroids on such severe cases requires further evaluation.12,13 In children, most symptoms are alleviated after spinal tap and disappear within 4 weeks of onset
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References
without sequelae.3,6 None of the severe or fatal cases received early intervention with anthelminthics. Corticosteroids alone did not prevent morbidity or death in patients demonstrating bulbar signs, CNS depression or progressive neurological signs. In the case presented here, antihelminthics were not used early in the disease owing to the risk of a potential adverse inflammatory response caused by dead worms. No complications were observed in any of the 22 Taiwanese children who were treated with 10 mg/kg albendazole for 3 weeks or in the children from whom live worms were recovered and who were treated only with albendazole.6 In animal studies, larval burden is significantly reduced along with severity of infection when albendazole is administered within the first 2 weeks of infection.14,15 The use of 10 mg/kg albendazole for 3 weeks, commencing at presentation, can be of value in reducing larval burden and offsetting the deleterious effects of migrating worms in children at risk. In Jamaica, a heightened sense of awareness is needed to better detect eosinophilic meningitis. Children ,5 years (especially ,2 years) with eosinophilic meningitis caused by A. cantonensis face a grave clinical outcome and risk the development of neurologic sequelae, including paresis, semi-coma/ coma, bulbar involvement, and visual impairment. Further studies are required to evaluate the impact of early larvicidal use on the natural clinical course in children with poor prognostic markers.
1 Slom TJ, Cortese MM, Gerber SI, Jones RC, Holtz RC, Lopez AS, et al. An outbreak of eosinophilic meningitis caused by Angiostrongylus cantonensis in travelers returning from the Caribbean. N Engl J Med. 2002;346:668–75. 2 Aguiar PH, Morera P, Pascual J. First record of Angiostrongylus cantonensis in Cuba. Am J Trop Med Hyg. 1981;30:963–5. 3 Hwang KP, Chen ER. Clinical studies on Angiostrongylus cantonensis among children in Taiwan. Southeast Asian J Trop Med Public Health. 1991;22:194–9. 4 Lindo JF, Escoffrey CT, Reid B, Codrington G, CunninghamMyrie C, Eberhard ML, et al. Fatal autochthonous eosinophilic meningitis in a Jamaican child caused by Angiostrongylus cantonensis. Am J Trop Med Hyg. 2004;70:425–8. 5 Lindo JF, Waugh C, Hall J, Cunningham-Myrie C, Ashley D, Eberhard ML. Enzootic Angiostrongylus cantonensis in rats and snails after an outbreak of human eosinophilic meningitis, Jamaica. Emerg Infect Dis. 2002;8:324–6. 6 Yii CY. Clinical observation on eosinophilic meningitis and meningoencephalitis caused by Angiostrongylus cantonensis in Taiwan. Am J Trop Med Hyg. 1976;25:233–49. 7 Tseng YT, Tsai HC, Sy CL, Lee SS, Wann SR, Wang YH, et al. Clinical manifestations of eosinophilic meningitis caused by Angiostrongylus cantonensis 18 years’ experience in a medical centre in southern Taiwan. J Microbial Infect. 2011;44;382–9. 8 Hwang KP, Chen ER, Chen TS. Eosinophilic meningitis and meningoencephalitis in children. Acta Paediatr Sinica. 1994;35:124–35. 9 Punyagupta S, Juttijudata P, Bunnang, T. Eosinophilic meningitis in Thailand: clinical studies of 484 typical cases probably caused by Angiostrogylus cantonensis. Am J Trop Med Hyg. 1975;25:233–49. 10 Cooke-Yarborough CM, Kornberg AJ, Hogg GG, Spratt DM, Forsyth JR. A fatal case of angiostrongyliasis in an 11-monthold infant. Med J Aust. 1999;170:541–3. 11 Tangchai P, Nye S, Beaver P. Eosinophilic meningitis caused by Angiostrongyliasis in Thailand: autopsy report. Am J Trop Med Hyg. 1967;16:454–61. 12 Chotmongkol V, Wongjitrat C, Sawadpanit K, Sawanyawisuth K. Treatment of eosinophilic meningitis with a combination of albendazole and corticosteroid. Southeast Asian J Trop Med Public Health. 2004;35:172–4. 13 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. 14 Chen KM, Lai SH. Biochemical and pathological evaluation of albendazole/thalidomide co-therapy against eosinophilic meningitis or meningoencephalitis induced by Angiostrongylus cantonensis. J Antimicrob Chemother. 2007;59:264–76. 15 Hwang KP, Chen ER. Larvicidal effect of albendazole against Angiostrongylus cantonensis in mice. Am J Trop Med Hyg. 1988;39:191–5.
Acknowledgment We would like to thank Drs Barbara Herwaldt and Michele Hlavsa of the Division of Parasitic Diseases, Centers for Disease Control and Prevention (CDC), Atlanta, USA for providing helpful literature during initial communications on this case, and Dr Mark Eberhard, also of the Division of Parasitic Diseases, CDC, for identifying the worm.
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