Angiostrongylus Cantonensis

Angiostrongylus cantonensis is the parasitic nematode (roundworm) that causes Angiostrongyliasis, the most common cause of eosiniphilic meningitis in Southeast Asia and the Pacific Basin [1]. It commonly resides in the pulmonary arteries of rats, giving it the nickname the “rat lungworm.” Snails are the primary intermediate hosts, where larvae develop until they are infective. Humans are incidental hosts, and may become infected through ingestion of larvae in raw or undercooked snails or other vectors, or contaminated water and vegetables. The larvae are then transported via the blood to the central nervous system (CNS), where they are the most common cause of eosiniphilic meningitis, a serious condition that can lead to death or permanent brain and nerve damage [2]. Identified in 1964, Angistrongyliasis is an infection of increasing public health importance as globalization aids in the geographic spread of the disease.

Infectious Agent

Angiostrongylus cantonensis is a helminth of the phylum Nematoda, order strongylida, and superfamily metastrongyloidea, but is commonly referred to as the rat lungworm. Nematodes are roundworms characterized by a tough outer cuticle, unsegmented bodies, and a fully developed GI tract. The order Strongylida includes hookworms and lungworms. Metastrongyloidea are characterized as long, slender, threadlike worms that reside in the lungs of the definitive host [3]. Angiostrongylus costaricensis is a closely related worm that causes intestinal Angiostrongyliasis in Central and South America.

History of Discovery

Nematodes suspected to be A. cantonensis were first identified in the cerebrospinal fluid of a patient with eosiniphilic meningitis by Nomura and Lim in Taiwan in 1944. They called the parasite Haemostrongylus ratti, and noted that raw food eaten by the patient may have been contaminated by rats. This paper, however, was not translated from Japanese to English until 1964, just a few years after the parasite had been defined, so their discovery was not widely recognized.

In 1955, Mackerass and Sanders identified the life cycle of the worm in rats, defining snails and slugs as the intermediate host and noting the path of transmission through the blood, brain, and lungs in rats.

In 1961, an epidemiological study of eosiniphilc meningitis in humans was conducted by Rosen, Laigret, and Bories, who hypothesized that the parasite causing these infections was carried by fish. However Alicata noted that raw fish was consumed by large numbers of people in Hawaii without apparent consequences, and patients presenting with mengitis symptoms had a history of eating raw snails or prawns in the weeks before presenting with symptoms. This observation along with epidemiology and autopsy of infected brains confirmed A. cantonensis infection in humans as the cause of the majority of eosiniphilic meningitis cases in Southeast Asia and the Pacific Islands [4].

Clinical Presentation in Humans

In humans, Angiostrongylus is the most common cause of eosiniphilic meningitis [1]. Frequently the infection will resolve without treatment or serious consequences, but in cases with a heavy load of parasites the infection can be so severe it can cause permanent damage to the CNS or death [5].

Early Symptoms

Infection first presents with severe abdominal pain, nausea, vomiting, and weakness, which gradually lessens and progresses to fever, and then to CNS symptoms and severe headache and stiffness of the neck. Occasionally patients present with cranial nerve palsies, usually in nerves 7 and 8, and rarely larvae will enter ocular structures [6].

Severe CNS Infection

CNS symptoms begin with mild cognitive impairment and slowed reactions, and in a very sever form often progress to unconsciousness [2]. Patients may present with neuropathic pain early in the infection. Eventually severe infection will lead to ascending weakness, quadriparesis, areflexia, respiratory failure, and muscle atrophy, and will lead to death if not treated [2]. Even with treatment, damage to the CNS may be permanent and result in a variety of negative outcomes depending on the location of the infection, and the patient ay suffer chronic pain as a result of infection [2].

Eye Invasion

Symptoms of eye invasion include visual impairment, pain, keratitis, and retinal edema. Worms usually appear in the anterior chamber and vitreous and can sometimes be removed surgically.

The parasite is rarely seen outside of endemic areas, and in these cases patients generally have a history of travel to an endemic area.

Transmission

Transmission of the parasite is usually from eating raw or undercooked snails or other vectors [2]. Infection also occurs from ingestion of contaminated water or unwashed salad that may contain small snail and slugs, or have been contaminated by them. Therefore it is very important to avoid raw snails, wash and cook vegetables thoroughly, and avoid open water sources that may be contaminated.

Third stage (infective) larvae taken from snail host [2].

Reservoirs

Rats are the definitive host and the main reservoir for A. cantonensis, though other small mammals may also become infected. While angiostrongylus can infect humans, humans do not act as reservoirs because the worm cannot reproduce in humans and humans do not, therefore, contribute to their life cycle [5].

Vectors

A. cantonensis has many vectors, with the most common being several species of snails, including the giant African land snail (Achatina fulica) in the Pacific islands and snails of the genus Pila in Thailand and Malaysia. The golden apple snail, A. canaliculatus, is the most important vector in areas of China [2]. Freshwater prawns, crabs, or other paratenic, or transport, hosts can also act as vectors [5].

A. canaliculatus, the Golden Apple Snail, is an important vector for A. cantonensis in China [2].

Incubation Period

The incubation period in humans is usually from 1 week to 1 month after infection, and can be as long as 47 days [6]. This interval varies, since humans are intermediate hosts and, the life cycle does not continue predictably as it would in a rat [5].

Morphology

A. cantonensis is a nematode roundworm with 3 outer protective collagen layers, and a simple stomal opening with no lips or buccal cavity leading to a fully developed gastrointestinal tract [1]. Males have a small copulatory bursa at the posterior. Females have a “barber pole” shape down the middle of the body, which is created by the twisting together of the intestine and uterine tubules. The worms are long and slender - males are 15.9-19 mm in length, and females are 21-25 mm in length [7].

Adult male (top) and female (bottom) A. cantonensis worms. Note copulatory bursa at posterior of male, and characteristic “barber pole” spiral in female [10, 11].

Life Cycle

The adult form of A. cantonensis resides in the pulmonary arteries of rodents, where it reproduces. After the eggs hatch in the arteries, larvae migrate up the pharynx and are then swallowed again by the rodent and passed in the stool. These first stage larvae then penetrate or are swallowed by snail intermediate hosts, where they transform into second stage larvae and then into third stage infective larvae. Humans and rats acquire the infection when they ingest contaminated snails or paratenic (transport) hosts including prawns, crabs, and frogs, or raw vegetables containing material from these intermediate and paratenic hosts. After passing through the gastrointestinal tract, the worms enter circulation [6]. In rats, the larvae then migrate to the meninges and develop for about a month before migrating to the pulmonary arteries, where they fully develop into adults [5].

Humans are incidental hosts; the larvae cannot reproduce in humans and therefore humans do not contribute to the A. cantonensis life cycle. In humans, the circulating larvae migrate to the meninges, but do not move on to the lungs. Sometimes the larvae will develop into the adult form in the brain and CSF, but they quickly die, inciting the inflammatory reaction that causes symptoms of infection [5].

Life cycle of Angiostrongylus cantonensis [10].

Diagnostic Tests

Diagnosis of angiostrongyliasis is complicated due to the difficulty of presenting the angiostrongylus larvae themselves, and will usually be made based on the presence of eosiniphilic meningitis and history of exposure to snail hosts. Eosiniphilic meningitis is generally characterized as a meningitis >= 10 eosiniphils/mL in CSF or at least 10% eosiniphils in the total CSF leukocyte count [6]. Occasionally worms found in the cerebrospinal fluid or surgically removed from the eye can be identified in order to diagnose Angiostrongyliasis.

Lumbar Puncture

Lumbar puncture should always be done is cases of suspected meningitis. In cases of eosiniphilc meningitis it will rarely produce worms even when they are present in the CSF, because they tend to cling to the end of nerves. Larvae are present in the CSF in only 1.9-10% of cases [2]. However, as a case of eosiniphilic meningitis progresses, intracranial pressure and eosiniphil counts should rise. Increased levels of eosinophils in the CSF is a trademark of the eosiniphilic meningitis [2].

Brain Imaging

Brain lesions, with invasion of both gray and white matter, can be seen on a CT or MRI. However MRI findings tend to be inconclusive, and usually include nonspecific lesions and ventricular enlargement. Sometimes a hemorrhagic, probably produced by migrating worms, is present and of diagnostic value.

MRI findings in a patient with A. cantonensis. Images show (A) MRI with typical non-specific lesions, with hyperintense lesion in the right cerebellum and a resolving lesion (black arrow) in the left cerebellum, (B) Typical potentially diagnostic haemoragghic tract in left frontal cortex, (C) A worm in the vitreous of the eye, and (D) 40x anterior end of adult worm, showing stomal opening onto GI tract [1].

Serology

In patients with elevated eosiniphils, serology can be used to confirm a diagnosis of angiostrongyliasis rather than infection with another parasite[1]. There are a number of immunoassays that can aid in diagnosis, however serologic testing is available in few labs in the endemic area, and is frequently too non-specific. Some cross reactivity has been reported between A. cantonensis and trichinosis, making diagnosis less specific.

The most definitive diagnosis always arises from the identification of larvae found in the CSF or eye, however due to this rarity a clinical diagnosis based on the above tests is most likely.

Management and Therapy

Treatment of angiostrongylus is not well defined, but most strategies include a combination of anti - parasitics to kill the worms, steroids to limit inflammation as the worms die, and pain meds to manage the symptoms of meningoencephalitis.

Anti-Helminthics

Anti-helminthics are often used to kill off the worms, however in some cases this may cause patients to worsen due to toxins released by the dying worms. Albendazole, ivermectin, mebendazol, and pyrantel are all commonly used, though albendazole is usually the drug of choice. Studies have shown that anti-helminthic drugs may shorten the course of the disease and relieve symptoms. Therefore anti-helminthics are generally recommended, but should be administered gradually so as to limit the inflammatory reaction [2].

Anti-Inflammatories

Anti-helminthics should generally be paired with corticosteroids in severe infections to limit the inflammatory reaction to the dying parasites. Studies suggest that a two week regimen of a combination of mebedizole and prednisolone significantly shortened the course of the disease and length of associated headaches without observed harmful side effects [8]. Other studies suggest that albendazole may be more favorable, because it may be less like to incite an inflammatory reaction [9]. The Chinese herbal medicine long-dan-xie-gan-tan (LDGXT) has also been shown to have a similar anti inflammatory effect, and in mild cases may be used alone to relieve symptoms while infection resolves itself [9].

Symptomatic Treatment

Symptomatic treatment is indicated for symptoms such as nausea, vomiting, headache, and in some cases, chronic pain due to nerve damage or muscle atrophy. Repeat lumbar puncture may be required to lower intracranial pressure and relieve headaches.

Epidemiology

A. cantonensis and its vectors are endemic to Southeast Asia and the Pacific Basin [1]. The infection is becoming increasingly important as globalization allows it to spread to more and more locations, and as more travelers encounter the parasites. The parasites probably travel effectively through rats traveling as stowaways on ships, and through the introduction of snail vectors outside endemic areas.

Although mostly found in Asia and the Pacific where asymptomatic infection can be as high as 88%, human cases have been reported in the Caribbean, where as much as 25% of the population may be infected. In the US, cases have been reported Hawaii, which is in the endemic area [5]. The infection is now endemic in wildlife and a few human cases have also been reported in areas where the parasite was not originally endemic, such as New Orleans and Egypt.

Map illustrating the spread of the Achatina fulica vector, demonstrating the importance of vector control and containment in transmission of the parasite.

Public Health and Prevention Strategies and Vaccines

There are many public health strategies that can drastically limit the transmission of A. cantonensis by limiting contact with infected vectors. Vector control may be possible, but has not been very successful in the past. Education to prevent the introduction of rats or snail vectors outside endemic areas is important to limit the spread of the disease [4]. There are no vaccines in development for angiostrongyliasis.

Recommendations for individuals traveling in endemic areas:

• Avoid consumption of uncooked vectors, such as snails and freshwater prawns
• Avoid drinking water from open sources, which may have been contaminated by vectors
• Prevent young children from playing with or eating live snails

Useful Web Links –

http://www.dpd.cdc.gov/DPDx/HTML/Angiostrongyliasis.htm

http://www.dpd.cdc.gov/DPDx/HTML/ImageLibrary/Angiostrongyliasis_il.htm

http://www.cdc.gov/ncidod/dpd/parasites/angiostrongylus/factsht_angiostrongylus.htm

http://animaldiversity.ummz.umich.edu/site/accounts/information/Angiostrongylus_cantonensis.html

References

[1] Baheti NN & Sreedharan M et al (2008). “Eosinophilic meningitis and an ocular worm in a patient from Kerala, south India” J. Neurol. Neurosurg. Psychiatry 79 (271).

[2] Hua Li, Feng Xu, Jin-Bao Gu and Xiao-Guang Chen (2008). “Case Report: A Severe Eosinophilic Meningoencephalitis Caused by Infection of Angiostrongylus cantonensis”. Am. J. Trop. Med. Hyg., 79(4): 568–570.

[3] http://www.path.cam.ac.uk/~schisto/helminth_taxonomy/taxonomy_nematoda.html, Accessed 2/26/09.

[4] JE Alicata (1991). “The Discovery of Angiostrongylus Cantonensis as a Cause of Human Eosiniphilc Meningitis”. Parasitology Today, 7(6): 151-153.

[5] David, John T. and Petri, William A Jr. Markell and Voge’s Medical Parasitology. St. Louis, MO: El Sevier, 2006.

[6] L. Ramirez-Avila (2009). “Eosinophilic Meningitis due to Angiostrongylus and Gnathostoma Species”. Emerging Infections, 48: 322-327.

[7]http://animaldiversity.ummz.umich.edu/site/accounts/information/Angiostrongylus_cantonensis.html, Accessed 2/26/09

[8] V Chotmongkol and K Sawadpanitch et al. (2006). “Treatment of Eosiniphilic Meningitis with a Combination of Prednisolone and Mebendazole”. Am. J. Trop. Med. Hyg., 74(6): 1122–1124.

[9] SC Lai, KM Chen, YH Chang and HH Lee (2008). “Comparative efficacies of albendazole and the Chinese herbal medicine long-dan-xie-gan-tan, used alone or in combination, in the treatment of experimental eosinophilic meningitis induced by Angiostrongylus cantonensis”. Annals of Tropical Medicine & Parasitology, 102(2): 143–150.

[10] http://www.dpd.cdc.gov/DPDx/HTML/Angiostrongyliasis.htm

[11]http://ecurriculum.mv.ac.th/health/m.5/lesson5/liver5/tropical-meningoencep.htm