Angiostrongylus Cantonensis Infection

Etiology

Rats are definitive hosts for the nematode. The adult nematode enters the rat's bloodstream and matures there. Fertilization occurs, followed by the production of eggs, which are released into the blood. The eggs are lodged in the smaller pulmonary vessels and hatch. The first-stage nematodes break into the airways and then migrate to the upper airways and pharynx. First-stage larvae in the pharynx are swallowed and passed down the gastrointestinal tract and finally into the feces. Snails and slugs (intermediate hosts) ingest these larvae, which mature into the third-stage larvae (infective form) that are passed on to the definite hosts again when the definite hosts consume infected intermediate hosts. Third-stage larvae are neurotropic and develop into young adults in the brains of definite hosts. They then migrate to the venous system and finally reach the pulmonary vasculature, where they sexually mature, and the female worm lays eggs. Some other transport (paratenic) hosts, such as snails, frogs, lizards, prawns, crabs, and freshwater shrimps, pick up the third-stage larvae by ingesting the infected intermediate hosts, which are then passed on to the definite host that ingest these paratenic hosts. Vegetables covered with snail slime can also be a source of infection.[1][2]

Humans become incidental hosts by consuming the infected intermediate or paratenic hosts (or ingestion of snail slime). As these are lung flukes, their method of infection is similar in humans as in rats. It occurs mainly through the fecal-oral route. When larvae are ingested, they travel from the intestinal mucosa into the bloodstream, where they mature, and adult female flukes lay eggs in the terminal branches of the pulmonary arteries. The eggs hatch and the larvae move into the pharynx. They are coughed and subsequently swallowed and travel to the intestinal mucosa, where they are expelled through feces. The intermediate hosts (snails) ingest these eggs and first-stage larvae. They then mature into third-stage larvae. At this point, the definitive hosts, rats/humans, ingest the intermediate hosts containing the third-stage larvae that enter the bloodstream and travel to the brain. This is the site of maturation into the adult phase. They travel via the venous drainage of the brain to the heart, where they mature into mature adults in the terminal branches of the pulmonary arteries and lay eggs. The worm inside the central nervous system, especially in the subarachnoid space, elicits intense eosinophilic inflammation and causes acute eosinophilic meningitis. When the infestation is more severe, it results in other inflammatory manifestations in the human hosts, including radiculitis, cranial neuropathy, myelitis, encephalopathy, coma, and even death. The nematode eventually dies in the nervous system, so humans do not transmit the worms.[3] The incubation period usually ranges from 1 to 3 weeks but can be as long as 6 weeks.

Epidemiology

Angiostrongylus spp. are classically endemic to the Asia-Pacific regions, with the highest incidence in Thailand and Malaysia. Additional areas of inhabitance include the Pacific basin, China, Vietnam, the Phillippines, Taiwan, and Hawaii. Dissemination of infected rats has contributed to spreading the parasite to non-endemic areas such as Africa, S. America, Australia, Caribbean islands, New Orleans, and Louisiana. Travel-related exposures have been attributed to sporadic cases detected in Europe and the United States.

Angiostronglyiasis is known as the rat lungworm. It is a nematode. It is passed between rodents and slugs/snails in its natural transmission lifecycle. However, it can still infect sea animals such as crabs and shrimp frogs. In these organisms, the parasite is not reproduced, but transmission to humans is possible by the consumption of the affected organisms. Humans are dead-end hosts.

Given that the concentration of this infection is mostly in east Asia, the likely method of transfer to the western countries would be by the travel of contaminated rats and mollusks by ship. Typical mollusks include the giant African land snail, Achatina fulica, and Parmoarion martensi (from southeast Asia), which have become prominent in Hawaii. In Hawaii, infection with A cantonensis is a reportable disease, and several outbreaks have been reported. To support this, there is also retrograde movement noted from South America during ship transport to Taiwan and China with subsequent disease outbreaks of A cantonensis.

Pathophysiology

Clinical pathology caused by Angiostrongylus cantonensis is localized to the central nervous system (CNS). In the CNS, these flukes produce an intense inflammatory response with an eosinophilic reaction, resulting in the classic presentation of eosinophilic meningitis. When the inflammation is more severe or affects other areas of the CNS, it results in cranial nerve deficits, radiculitis, encephalitis, and death. The eye may occasionally be the site of infection.[4]

History and Physical

The clinical syndrome seen with A cantonensis is due to the intense inflammatory reaction of the dying parasites. Eosinophilic meningitis (EoM) remains the most common presentation of angiostrongyliasis. Headache is the most common symptom of neck stiffness, nausea, and vomiting. Paresthesias and hyperesthesias can be associated with symptoms lasting several weeks. Eosinophilic encephalitis (EoE) is rare but usually fatal due to late diagnosis. Rarely, ocular involvement can manifest with foreign body sensation and blurred vision from the anterior chamber and intravitreal invasion of larvae, respectively.[5][6][7]

CNS features of infection include new-onset severe headaches resistant to NSAID therapy and paraesthesias (such as touch hypersensitivity, tingling, and burning sensation). Shifting paresthesias are a notable characteristic, along with migratory pain in the trunk and limbs (not in a dermatological distribution). Sixth or seventh cranial nerve palsy may occur. It is not clear why patients may also present with urinary retention. Before CNS symptoms become prominent, changes usually start with the GI tract. The incubation period for infection occurs over 1 to 3 weeks (but can extend up to 6 weeks), and during this time, patients may develop nonspecific abdominal pain, nausea, and vomiting. This occurs due to the infiltration of the intestinal wall by the larva. They then circulate through the blood and ultimately penetrate the brain through the blood-brain barrier when the neurological symptoms occur. This period takes 1 to a few weeks to occur, so patients may have a resolution of the initial GI symptoms and be asymptomatic during this period, or there may be the persistence of the GI symptoms. Emesis can also occur due to meningeal involvement. More nonspecific symptoms include lethargy, low-grade fever, difficulty sleeping, and confusion. Children tend to have less prominent neurological findings and more gastrointestinal involvement. The physical exam should focus on a complete neurological and abdominal exam.

Evaluation

Diagnosis of neuro-angiostrongyliasis is made of clinical history, suggestive signs and symptoms, and supporting laboratory findings. Clinical history should focus on travel to or from an endemic area, consumption of poorly cooked foods or raw vegetables contaminated with snail/slug components, crab, shrimp, etc. Although not confirmatory, CSF eosinophilia (usually exceeds 10%, can be as high as 70%) is required for diagnosing in the right clinical setting. Eosinophilia in the CSF is defined as 10 or more eosinophils per microliter of CSF fluid or greater than 10% of total CSF leukocytes (with at least 6 in absolute count per microliter of fluid). CSF opening pressure and protein are usually elevated, with CSF leucocytosis typically ranging from 150-2000 cells/mm. Peripheral eosinophilia is often reported but does not correlate well with CSF eosinophilia or the clinical course. The editor has personally encountered and made the diagnosis by observing a larva coming out of the spinal needle with the CSF during lumbar puncture, quite a memorable experience. Brain imaging with CT or MRI is generally not helpful in making the etiological diagnosis.[8][9]

Serological immunoassays such as dot blot ELISA or western blot can aid the diagnosis but are not widely available. PCR and real-time PCR-based tests are reported to have good sensitivities, but again not as readily available.[10] The important differential diagnosis is gnathostomiasis, another cause of eosinophilic meningitis. Gnathostomiasis usually presents with radicular pain, non-traumatic bloody or xanthochromic CSF, with brain imaging revealing subarachnoid or intracerebral hemorrhage. Imaging may sometimes reveal myelitis, but this is not found in the case of A cantonensis. The diagnostic immunoblot band is usually 29 kDa.

Treatment / Management

The severity and duration of clinical manifestations are variable and dependent on the parasitic burden. Most patients have spontaneous resolution of the symptoms with conservative measures. The goal is to decrease the meningeal inflammation and lower the intracranial pressure by removing the spinal fluid and symptomatic relief of headaches. The administration of steroids (prednisolone or dexamethasone) to depress the inflammatory reaction has been associated with decreasing the duration of headaches and the requirement for serial CSF drainage.[11] Anti-helminthic medications were traditionally not recommended for the potential risk of an exaggerated inflammatory response to releasing antigens from dying parasites. Although the addition of anti-helminthic therapy to steroids has not shown benefit in the outcome of treatment compared to steroids alone, it is safe. It should be considered in those patients with high parasite load.[9][12](B3)

Ocular angiostrongyliasis has been reported in about 1% of all reported case reports. It occurs when the larva enters the anterior or posterior chamber. The exact mechanism of entry into the eye is unclear but has been thought to be secondary to travel along the retinal artery between the optic nerve and sheath. Usually, only 1 larva is present, and symptoms include blurred vision, blindness, and pain. Usually, eosinophilic meningitis is also present in these cases. Ocular involvement requires laser treatment to kill the larva before surgical removal.

There are no official guidelines for treatment; however, on the premises of evidence-based medicine, the following recommendations are followed. In Hawaii, a real-time PCR test can be performed on CSF fluid that detects DNA from A cantonensis. If negative during early infection states, this test and repeat LP should be done if there is strong suspicion. Serological testing against antibodies in the serum or CSF is not recommended. If added, Albendazole may provide benefits but should be used with steroids to dampen the intense inflammatory response created by the dying parasites. Careful attention should be paid to adequate glycemic control in diabetic patients.

Differential Diagnosis

The most important point in the diagnosis is a high index of suspicion in patients who have likely been exposed to the nematode during the previous few weeks, which can extend up to 6 weeks prior. Other infections that can cause eosinophilic meningitis include gnathostomiasis and baylisascariasis.

• Gnathostomiasis is associated with consuming undercooked fish, poultry, or snake meat.
• The consumption of parasites causes baylisascariasis (Baylisascaris procyonis) eggs (usually in children by ingesting soil), usually transmitted in raccoon feces.
• Cysticercosis caused by Tinea solium or other diseases caused by lung flukes such as schistosomiasis and paragonimiasis are other important differentials.
• Coccidioidomycosis is also associated with eosinophilic meningitis.
• Non-infectious causes of eosinophilic leptomeningeal enhancement include non-Hodgkin lymphoma, myeloproliferative disorders, disseminated glioblastoma, and paraneoplastic manifestation from bronchogenic carcinoma.
• Drugs associated with eosinophilic meningitis include trimethoprim-sulphamethoxazole, ciprofloxacin, ibuprofen, intraventricular vancomycin, and gentamicin.[13]
• Encephalopathy and neurological deficits have been reported to be associated with idiopathic hypereosinophilic syndrome.

Prognosis

The prognosis depends on the timing of the correct diagnosis as eosinophilic meningitis is rare and requires good clinical suspicion to suspect A cantonensis as the cause and appropriate CSF findings. Sometimes, the course of infection can be self-limiting; other times, depending on the disease burden, it may be fatal. There is an overall lack of national surveillance of this disease, and due to the limited diagnostic testing and poor general awareness among healthcare providers, it is difficult to quantify the outcomes.

Complications

Complications include death from eosinophilic meningitis or permanent blindness. Ocular angiostrongyliasis has been reported in about 1% of all reported case reports. It occurs when the larva enters the anterior or posterior chamber. The exact mechanism of entry into the eye is unclear but has been thought to be secondary to travel along the retinal artery between the optic nerve and sheath. Usually, only 1 larva is present, and symptoms include blurred vision, blindness, and pain. Usually, eosinophilic meningitis is also present in these cases.