The finding of even some eosinophils in human cerebrospinal fluid (CSF) raises the suspicion of certain pathologic states. Helminthic infestation of the central nervous system (CNS), particularly with the rat lungworm Angiostrongylus cantonensis, is the most common cause of eosinophilic meningitis worldwide. However, the differential diagnosis of CSF eosinophilia is broad and includes infestation by other parasites ; reaction to placement, malfunction or infection of a ventriculoperitoneal shunt ; medications ; malignancies , ; hypereosinophilic syndrome ; and an unusual manifestation of a more common parasitic, fungal, bacterial, or viral infection of the CNS. Table 47.1 lists the causes of eosinophilic meningitis.

TABLE 47.1
Eosinophilic Meningitis Etiologies
Etiology Association With EM Possible Transmission Country Comments
NEMATODES (ROUNDWORMS) Most common causes
Angiostrongylus cantonensis Contact with rat lungworm; consumption of snail, slug, crustacean, mollusk, crab; frogs, fish, lizards; lettuce and vegetable South Pacific, Africa, Australia, Caribbean, Hawaii, US port cities Neurotropic
Usually self-limited
Baylisascaris procyonis Contact with raccoon or feces; rarely dogs, rodents, small mammals, birds US Neurotropic
Prolonged, profound encephalitis
Young children with pica are typical patients
Gnathostoma spinigerum Contact with dog, cat; consumption of raw fish, poultry, crustaceans, amphibians Southeast Asia, Japan, China, Mexico, Central and South America, Africa, and the Middle East Peripheral eosinophilia common
Ascaris lumbricoides Exposure to embryonated eggs in human feces Worldwide Rarely associated with EM
Trichinella spiralis Consumption of raw or undercooked meat Worldwide; endemic in Japan and China Larvae usually found in skeletal muscle
Rarely associated with EM
Toxocara canis, catis Exposure to eggs in feces dogs, cats Worldwide Rarely associated with EM
CESTODES (TAPEWORMS) Occasional causes
Taenia solium Exposure to eggs in human feces Worldwide Neurocysticercosis a rare cause of EM
Echinococcus granulosus Exposure to eggs in feces sheep; wolves, dogs, moose, reindeer Europe; northern North America and Eurasia Rarely infects CNS and associated with EM
OTHER PARASITES Rare
Toxoplasma gondii Consumption of undercooked meat; exposure to oocyst in cat feces Worldwide Anecdotal report
Schistosoma japonicum Contaminated water Worldwide, tropical and subtropical; most cases Africa
Paragonimus westermani Contaminated water Far East Lung fluke but can invade CNS and other sites
Fasciola hepatica Contaminated water Worldwide; southeast Asia
FUNGI Occasional
Coccidioides immitis Exposure to aerosolized arthroconidia Southwestern United States, Mexico, South America Low level of CSF eosinophils common; EM also reported
Cryptococcus neoformans Environmental exposure Diabetes is a risk factor
BACTERIA AND VIRUSES Case reports
Treponema pallidum Exposure to infected person Worldwide EM is rarely associated with neurosyphilis
Mycobacterium tuberculosis Exposure to infected person Worldwide EM is a questionable association with direct CNS infection versus treatment drug effect
Rickettsia rickettsii Tick bite North, Central, and South America EM is rare
Lymphocytic choriomeningitis virus Exposure to rodents Worldwide EM association made through serologic studies
Ventricular shunt bacterial infections Same pathogens as in shunt infections without eosinophils
NONINFECTIOUS ETIOLOGIES Occasional or case reports Not applicable All or not applicable
Ventricular shunt complications/reaction to shunt material
Bovine dural graft
No infection and improvement with removal of shunt
Systemic drugs Reported with fluoroquinolones, trimethoprim-sulfamethoxazole, nonsteroidal anti-inflammatory drugs and illicit drugs intravenously
CNS neoplasms Reported with Hodgkin lymphoma, acute lymphoblastic leukemia, and primary CNS tumors
Hypereosinophilic syndrome Reported in patients without other cause
Immunologic/hypersensitivity reaction Reported with sarcoidosis, rabies vaccine, myelography contrast agents
CNS, central nervous system; CSF, cerebrospinal fluid; EM, eosinophilic meningitis.

Eosinophilic meningitis is defined as (1) at least 10 eosinophils/μL in the CSF or (2) eosinophils comprising at least 10% of the CSF white blood cells (WBCs), but the presence of eosinophils in the CSF should always be considered an abnormal finding. Diagnostic examination of the CSF should include Giemsa, Wright, or other stain of a cytocentrifuged specimen to delineate the composition of pleocytosis, as well as routine CSF examination, including Gram stain, quantitative cell count, and biochemical tests.

Infectious Etiologies

Helminths

Angiostrongylus cantonensis

The rat lungworm, A. cantonensis, is the most common cause of eosinophilic meningitis worldwide. Angiostrongylus infestation has been the subject of several reviews. , , , , CNS migration is characteristic of the lungworm’s normal life cycle in the rat as well as in the accidental human host. Adult worms live in the rat pulmonary arteries and lay eggs in the lung. After hatching, larvae make their way through the alveolar spaces and up the trachea, from which they are swallowed and then excreted in rat feces.

Many species of slugs and snails serve as intermediate hosts, in which the larvae develop into infectious third-stage larvae. When third-stage larvae are ingested by rats, the definitive host, larvae migrate across the intestinal wall and are carried by the circulatory system to the brain. Juvenile worms have been found in the eyes, brain, and spinal cord in human infections. In the CNS, larvae undergo two more moltings then mature into adult worms; the worms return to the pulmonary arteries to renew the cycle.

Human infection occurs after consumption of raw or undercooked snails, shrimp, or fish that have fed on infected snails. Likewise, infectious larvae can be ingested accidentally on raw vegetables, raw vegetable juice, or fomites contaminated with snail slime. , , , , , Travelers to endemic areas should be warned about the risks of dietary indiscretions. CNS tropism is retained in human infection; however, the life cycle is disrupted, and generally, the disease is self-limited, with larvae dying in the CNS.

Human infection by A. cantonensis has been found in Asia, notably in Thailand, Malaysia, and China; the South Pacific, including Taiwan, Hawaii, American Samoa, New Guinea, Indonesia, and Australia; India, Egypt, Brazil, and the Caribbean. , , Infection likely is more widespread than is recognized. Worms can migrate on ships within their natural hosts (the rat) to distant countries, including mainland US. The first published, nonimported case in the US was a child from New Orleans who reported eating a raw snail “on a dare.” The child had meningitis that abated with supportive care.

In adults, symptoms classically begin 2–35 days after infection, with acute onset of headaches. Other common complaints are nausea and vomiting, weakness, paresthesia or hyperesthesia, pruritus, somnolence, and cranial nerve palsies, especially optic nerve and cranial nerves VII and VIII. , , About 20% of patients also have nuchal rigidity. Severe radiculomyelitis and quadriparesis is rare. Fever, if present, is usually low grade. Hearing loss, retinal detachment or hemorrhage have been reported. , Periorbital cellulitis can occur. Most patients recover completely, with symptoms beginning to abate within several weeks of the initial neurologic manifestations. Headache and paresthesia can be more persistent. , , Neurologic symptoms may be due to mechanical damage caused by worm migration in the brain as well as the neurotoxicity of eosinophil-derived basic proteins. Magnetic resonance imaging findings of the brain can be normal or nonspecific. , , ,

Infected children may not complain of headache. Clinical manifestations in younger patients can be more insidious, with upper respiratory symptoms, cough, and prolonged fever preceding mental status changes, seizures, or focal neurologic abnormalities. , , , Psychiatric changes also have been reported. One series of 16 young adults consuming raw infected great African Achatina fulica snails in American Samoa was notable for the absence of headache as a major complaint. All of the patients experienced severe radiculomyeloencephalitis and one died. Unlike other intermediate hosts or contaminated vegetables, A. fulica snails can harbor thousands of parasites, possibly accounting for the more fulminant course in patients infected from consuming these snails. Fatalities or sequelae are observed primarily in young children who are at risk for acquiring a relatively higher infectious load. , , , ,

CSF examination reveals pleocytosis typically between 150 and 2000 WBCs/μL. , , Peak eosinophilia occurs between 2 and 4 weeks of illness, with CSF eosinophils representing a median of 49% of the total WBCs (range, 15%–97%). , , , The CSF protein value is often elevated, and the glucose value is normal or mildly decreased. , Peripheral blood eosinophilia is common but does not correlate with the extent of CNS eosinophilia. , , Coincident infections with other parasites may contribute to peripheral eosinophilia.

A diagnosis of eosinophilic meningitis is usually made on the basis of clinical presentation in patients who are from or are traveling from an area enzootic for A. cantonensis and have a consistent dietary history. The history of eating raw seafood can be absent in young children who have a propensity for pica. , , Rarely, worms are found in the CSF, especially if a large-bore cannula is used to extract the CSF or if the CSF is aspirated rather than allowed to flow by gravity. Enzyme immunosorbent assays and immunochromatographic tests to detect antibody in serum or CSF have been developed but are not widely available. Polymerase chain reaction testing of the CSF can sensitively detect parasite DNA and is available by contacting the Centers for Disease Control and Prevention, Parasitic Diseases Hotline for Healthcare Providers (770-488-7100). , Detection of Angiostrongylus cell-free based DNA using next-generation microbial sequencing of plasma has recently been described. ,

Baylisascaris procyonis

The ascarid parasite of the raccoon, Baylisascaris procyonis, is found in 20%–90% of both rural and urban raccoons in the US. , Evidence of raccoon latrines near human habitation increases the concern for this emerging infection, which has been highlighted in several reviews. , Like A. cantonensis, this ascarid migrates through the CNS during its normal life cycle and is neurotropic in humans. , , , The ascarid causes little disease in the raccoon, but ingestion of eggs by aberrant hosts, such as foxes, rabbits, birds, and humans, can result in CNS migration of larvae, causing severe neurological damage. Experimental disease in nonhuman primates consists of eosinophilic meningitis, neurologic deterioration, coma, and death (discussed in references , , ). Despite the high prevalence of this parasite in raccoons, B. procyonis is rarely documented in humans. In the US, just more than a dozen clinical cases have been reported, most commonly in young children, resulting in eosinophilic meningoencephalitis with dramatic eosinophilic CSF pleocytosis, severe neurologic devastation, and death in 6 patients. , , , Ocular larva migrans and visceral larva migrans can also occur. , Exposure to raccoon droppings near nesting sites is the expected mode of acquisition. Behavior related to substance abuse has been identified as a possible risk factor. Because clinician awareness of this parasite is limited and diagnosis is not straightforward, it is possible that the disease is more widespread and that less severe clinical presentations remain undiagnosed. Asymptomatic infection has been suspected by finding a low level of seropositivity in otherwise healthy children (reviewed in references , ). As improved serodiagnostic assays become more readily available, the true incidence and clinical array will become more apparent. Currently serologic testing of serum and CSF is available from the Department for Veterinary Pathobiology at Purdue University, West Lafayette, IN (765-494-7558) and from the Centers for Disease Control and Prevention (www.cdc.gov/laboratory/specimen-submission/detail.html?CDCTestCode=CDC-10457; www.cdc.gov/laboratory/specimen-submission/pdf/form-50-34.pdf ). Definitive diagnosis can be made by identifying larvae in biopsy specimens; however, this can be impeded by the formulation of granulomas in tissue.

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