Eosinophilic meningitis

INTRODUCTION — Eosinophilic meningitis is defined as the presence of more than 10 eosinophils/mm³ in the cerebrospinal fluid (CSF) and/or eosinophils accounting for more than 10 percent of CSF leukocytes [1]. Reliable detection of eosinophils in the CSF requires examination of centrifuged cell preparations stained with Wright's, Giemsa, or other eosinophil appropriate stains. Eosinophils are found in the CSF in a limited number of diseases, including certain parasitic diseases and coccidioidal meningitis (table 1) [2,3]. The etiologies of eosinophilic meningitis will be reviewed here, with emphasis on the parasitic causes of this condition.

Some of the infectious agents that cause eosinophilic meningitis are parasites that are historically endemic outside of North America and Europe but now have a global distribution due to commerce and travel. In addition, cases of eosinophilic meningitis due to these parasites may occur among travelers to both well-known and less known endemic regions [4-10].

PARASITIC ETIOLOGIES — There are three important parasitic infections associated with eosinophilic meningitis: Angiostrongylus cantonensis, Baylisascaris procyonis, and Gnathostoma spinigerum. These are parasites for which humans are incidental hosts. Localization to nervous tissue is a typical manifestation of A. cantonensis and B. procyonis infection for both natural and incidental hosts. G. spinigerum can cause meningeal or extrameningeal infection. In general, human infection due to these organisms is self-limited because larvae do not replicate or mature to adult worms. Eosinophilic meningitis occurs as a result of larval migration within the nervous system; peripheral eosinophilia is also observed.

Angiostrongylus cantonensis — A. cantonensis is the most common parasitic cause of eosinophilic meningitis [11,12]. A. cantonensis larvae are neurotropic [13].

Epidemiology — Eosinophilic meningitis due to A. cantonensis occurs principally in Southeast Asia, particularly Thailand and Malaysia but also Southern Vietnam, and throughout the Pacific basin, including Indonesia, the Philippines, Taiwan, China, Japan, Papua New Guinea, Hawaii, and several smaller Pacific islands. Due in part to ship-borne dissemination of infected rats, the parasite has also been found outside of this broad area in regions of Africa, South America, Australia, Cuba, Puerto Rico, and the Caribbean [13-20]. In the United States, infections have spread from New Orleans into other areas of Louisiana and southeastern states [21]. Sporadic cases have been recognized more broadly in Europe and the United States, only some of which are due to travel-related exposures [13,21,22].

The life cycle of A. cantonensis begins with eggs laid by adult worms in the pulmonary arteries of rats (figure 1) [23]. The first-stage larvae migrate to the pharynx where they are swallowed and passed in the stool. These larvae are ingested by a snail or slug (intermediate host), in which larvae develop to a third stage. When the mollusk is ingested by the rat, the third-stage (infective larvae) migrate to the brain where they develop into adult worms; these worms return to the venous system and then the pulmonary arteries.

Humans can acquire the infection by eating raw or undercooked snails or slugs infected with the parasite [24]; they may also acquire the infection by eating raw produce containing a small snail or slug [25]. Infection can also be transmitted by ingestion of infected paratenic animals, such as crab or freshwater shrimp, or by ingestion of infected centipedes [26]. In humans, worms migrate to the brain (or rarely, the lungs) but do not produce eggs.

The incubation period of A. cantonensis averages one to three weeks but has ranged from one day to greater than six weeks [27].

Children who play in the dirt in endemic areas are at increased risk for infection. Visitors to endemic areas who partake of local foods are also at risk [28]. Outbreaks of infection are uncommon even in endemic areas. One outbreak of eosinophilic meningitis due to A. cantonensis was reported among travelers returning from Jamaica [16].

Clinical manifestations — A. cantonensis larvae migrate into neurologic or ocular tissues. Neurologic symptoms develop 2 to 35 days following infection. Infection usually presents as transient meningitis or, less commonly, as severe disease involving the brain, spinal cord, and nerve roots [12,29,30]. Excruciating headache is the most common presenting symptom in more than 90 percent of patients and is usually frontal, occipital, or bitemporal. The headache typically is relieved by lumbar puncture. Opening cerebrospinal fluid (CSF) pressures are often elevated [7].

Neck stiffness, nausea, vomiting, and paresthesias are also common; fever may be absent [31]. In an outbreak among 12 individuals, paresthesias or hyperesthesias of the arms, legs, trunk, or all three sites were present in 75 percent of cases [16]. Paresthesias with residual areas of hyperesthesia can persist for several weeks, even after other symptoms have resolved. Paralysis of the extraocular muscles or facial nerves develops in 4 to 9 percent of patients but generally resolves with time [32-36]. Fatalities are rare [37]; in one study of 484 cases of eosinophilic meningitis in Thailand, the mortality rate was less than 0.5 percent [38].

Ocular involvement due to intravitreal larvae is less common than neurologic involvement and may be manifest by unilateral blurring of vision without signs of meningitis [39,40].

Diagnosis — In general, the diagnosis of cerebral angiostrongyliasis is based upon the clinical presentation, presence of CSF eosinophilia, and an epidemiologic history of known or possible exposure to infective A. cantonensis larvae.

●CSF findings − The diagnosis requires the presence of CSF eosinophilia. The CSF is usually cloudy but not grossly turbid or xanthochromic. The CSF leukocyte count ranges from about 20 to 5000 cells/mm³ and is usually between 150 and 2000 cells/mm³. CSF eosinophilia is usually 20 to 70 percent; it exceeds 10 percent in approximately 95 percent of cases [32-35]. The CSF protein concentration is usually elevated. The CSF glucose concentration is normal or only minimally reduced [32-35].

Polymerase chain reaction (PCR)-based assays are sensitive for detection of parasite deoxyribonucleic acid (DNA) in CSF [41]. In two study of patients eosinophilic meningitis, real-time PCR detected A. cantonensis DNA in the CSF in 67 percent of cases [41,42]. Newer PCR assays may have even greater sensitivity [43,44].

Enzyme-linked immunosorbent assay (ELISA) testing may be used for diagnosis [45]. Newer immunoassays can sensitively discriminate between eosinophilic meningitis due to A. cantonensis and gnathostomiasis [46,47]. However, these assays are not widely available.

A few case reports have described use of next-generation molecular sequencing CSF analysis [48,49].

The diagnosis does not depend on direct identification; A. cantonensis larvae have only rarely been recovered from the CSF antemortem.

●Peripheral eosinophilia − Peripheral blood eosinophilia usually accompanies the eosinophilic CSF pleocytosis; in the majority of patients, it is >3 percent. Blood eosinophilia does not correlate with CSF eosinophilia or with the clinical course.

●Radiographic imaging − Computed tomography (CT) is generally unremarkable; the absence of focal lesions on CT scan helps to distinguish eosinophilic meningitis due to A. cantonensis from gnathostomiasis or neurocysticercosis [50]. Magnetic resonance imaging (MRI) may demonstrate high signal intensities over the globus pallidus and cerebral peduncle on T1-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 [51-53].

Treatment — The treatment of cerebral angiostrongyliasis should involve supportive measures. In the absence of reinfection, migrating larvae die over time, and the accompanying inflammation subsides. Most patients with cerebral angiostrongyliasis have a self-limited course and recover completely.

Analgesics, corticosteroids, and periodic removal of CSF can relieve symptoms due to elevated intracranial pressure [7,54]. In one randomized trial including 110 patients with eosinophilic meningitis, those who received prednisolone (60 mg daily for two weeks) were less likely to have persistent headache or require repeat lumbar puncture for symptomatic relief [55].

The role of specific anti-helminthic therapy in treating humans with A. cantonensis infection is uncertain [55-66]. A. cantonensis worms are susceptible to benzimidazole anthelmintics, such as albendazole and mebendazole, in animal models; however, use of these agents alone in humans can lead to clinical worsening, presumably due to the induction of an inflammatory response due to dying worms [58]. Once the diagnosis is made or suspected, many clinicians treat with both steroids and albendazole, although in a randomized trial including 104 patients with eosinophilic meningitis due to A. cantonensis, prednisolone plus albendazole was no better than prednisolone alone for alleviation of headache [59].

In the setting of ocular disease, treatment options include surgery or laser therapy [60].

Gnathostomiasis — G. spinigerum larvae can migrate in subcutaneous, visceral, or neural tissues; unlike A. cantonensis larvae, G. spinigerum larvae are not primarily neurotropic.

Epidemiology — Gnathostomiasis is endemic in Southeast Asia and parts of China and Japan; it also occurs in Europe, Central and South America, Africa, and the Middle East. Gnathostomiasis has also been described among travelers to endemic areas [6,10,67-69].

The life cycle of gnathostomiasis begins with eggs laid by adult worms in the natural definitive host (pigs, cats, or dogs), where they reside in the gastric wall (figure 2). Eggs are passed in the stool and become embryonated in water.

First-stage larvae are ingested by a small crustacean (Cyclops, the first intermediate host), where second-stage larvae develop and are subsequently ingested by a fish, frog, or snake (second intermediate host). There they develop into third-stage larvae, which are ingested by a definitive host. Alternatively, the second intermediate host may be ingested by a paratenic host (a bird, snake, or frog), in which the larvae do not develop further but remain infective to the next predator.

Humans become infected by eating undercooked fish, poultry, or snake meat containing third-stage larvae [70] or by drinking water containing infective second-stage larvae in Cyclops.

Clinical manifestations — Gnathostoma larvae migrate in cutaneous, visceral, neural, or ocular tissues. Gnathostomiasis most frequently presents with migratory cutaneous swellings [71]; eosinophilic meningoencephalitis or inflammatory masses in visceral organs are less common [69,72-78].

Larval penetration into the brain usually occurs as a result of migration along a nerve tract. Affected patients typically present with sudden onset of severe radicular pain or headache as well as paresthesias in the trunk or a limb, followed shortly by paralysis of extremities or cranial nerves. Eosinophilic meningoencephalitis due to gnathostomiasis is usually more fulminant than infection due to angiostrongyliasis. In addition, tissue destruction and severe inflammation may result in acute cerebral hemorrhages, which can be large and rapidly fatal.

Diagnosis — The CSF is often xanthochromic or bloody with an eosinophilic pleocytosis. The CSF protein concentration is elevated but the glucose concentration is usually normal. Larvae can almost never be recovered from the CSF. Peripheral blood eosinophilia is often quite pronounced and greater than that seen in angiostrongyliasis.

CT scans can demonstrate areas of hemorrhage, and gnathostomiasis may be mistaken for cerebral hemorrhage due to primary cerebrovascular disease [50]. MRI may demonstrate abnormal enhancement and enlargement in cauda equina gnathostomiasis [79] and hemorrhage in intracerebral gnathostomiasis [80]. Ultrasound biomicroscopy has been reported to be effective in diagnosis of intraocular gnathostomiasis [81].

Serologic tests have been developed but are not readily available outside of highly endemic areas. Newer immunoassays can sensitively discriminate between eosinophilic meningitis due to A. cantonensis and gnathostomiasis [46].

Treatment — The treatment of central nervous system (CNS) infection due to gnathostomiasis consists of supportive measures [72,73,75,76,78]. It is uncertain whether anthelminthic treatment of CNS gnathostomiasis is beneficial; there are concerns that it may be deleterious due to augmented inflammation from dying larvae [7,69,82]. There are no controlled trials evaluating the efficacy of albendazole. Of nine patients reported to have been treated with varying regimens of albendazole, five fully recovered, two partially recovered, and two patients did not recover [78]. The use of corticosteroids is generally favored for suppression of inflammation, but there are no randomized control trials to ascertain their benefit and the optimal dosing is uncertain [54,78]. The opening pressure is often elevated [7]; in such cases, serial therapeutic lumbar punctures are appropriate.

Issues related to treatment of cutaneous gnathostomiasis are discussed separately. (See "Skin lesions in the returning traveler", section on 'Gnathostomiasis'.)

Baylisascariasis — Baylisascaris procyonis is a parasite of raccoons that has tropism for the central nervous system [83]. The parasites are neurotropic in both natural and incidental hosts.

Epidemiology — Human infection due to B. procyonis is relatively uncommon. The parasite is prevalent in raccoons in the United States; proximity of raccoons to areas of human habitation provides opportunity for human infection [84]. In a study in California, 28 to 49 percent of residential properties surveyed harbored for B. procyonis eggs [85]. Another study in Atlanta, Georgia, noted that 22 percent of raccoons were infected [86]. Raccoons in Europe also harbor B. procyonis [87,88]. In addition to raccoons, dogs and other procyonids, including pet kinkajous, can be infected with B. procyonis and serve as sources of human infections [89]. Moreover, a study in Santa Barbara county in California found 11 of 150 healthy adult residents (none animal care workers) were seropositive for B. procyonis antibodies, suggesting that subclinical infection occurs [90].

The life cycle of baylisascariasis begins with shedding of eggs laid by adult worms in the intestine of raccoons or dogs (figure 3). Eggs become infective after two to four weeks in the environment and are ingested by raccoons. Over 100 species of birds and mammals (especially rodents) can act as paratenic hosts for this parasite. Eggs ingested by these hosts hatch, and larvae penetrate the gut wall and migrate into various tissues where they encyst. The life cycle is completed when raccoons eat these hosts. Humans become infected when they ingest infective eggs from the environment; typically, this occurs among young children playing in the dirt.

Migration of the larvae through a variety of tissues (liver, heart, lungs, brain, eyes) results in visceral larva migrans and ocular larva migrans syndromes, similar to toxocariasis. Tropism of larvae for nervous tissues can lead to severe nervous tissue damage; the signs and symptoms of baylisascariasis are often severe.

Eosinophilic meningoencephalitis due to B. procyonis is relatively rare. More than a dozen cases of human eosinophilic meningoencephalitis due to B. procyonis have been described in children who probably ingested dirt contaminated with parasite eggs [83,91-95]. Several children died and others had permanent neurologic sequelae. A pediatric case of spinal cord involvement has been described [96]. An adult in California with meningoencephalitis due to B. procyonis has been reported [97].

The prevalence of subclinical cases is unknown.

Clinical manifestations — The larvae of B. procyonis are capable of invading the human spinal cord, brain, and eyes, resulting in permanent neurologic damage, blindness, or death.

Ocular findings, diffuse unilateral subacute neuroretinitis and choroidal infiltrates in association with neurologic disease, have been described in two cases [93]. Ocular involvement may occur in the absence of other neurologic manifestations [98].

Diagnosis — Baylisascariasis should be considered in patients, especially children, in the setting of meningitis, blood and CSF eosinophilia, and potential exposure to raccoon-contaminated soil. Definitive diagnosis requires morphologic identification of larvae on tissue biopsy or autopsy specimens (picture 1). Serologic tests based on excretory-secretory antigen ELISA assays and western blots have been used; although to obviate issues of antigenic cross-reactivity, a newer recombinant antigen-based ELISA offers better sensitivity and specificity [99].

Treatment — The efficacy of anthelminthic treatment in the setting of established baylisascariasis infection is poor, but albendazole (25 mg/kg/day orally on empty stomach for 20 days) has been shown to be preventative if administered promptly (up to three days) after exposure (ingestion of raccoon stool or contaminated soil) [100,101]. Steroid therapy is also appropriate for reduction of inflammation [82].

Other parasites — Other helminthic parasites whose eggs or larvae can localize to the CNS may elicit an eosinophilic pleocytosis. These include toxocariasis (visceral larva migrans) [102], trichinellosis, echinococcosis [103], neurocysticercosis [104], fascioliasis, paragonimiasis [105-107], and rarely a Dirofilaria species [108]. (See related topics.)

NONPARASITIC INFECTIOUS ETIOLOGIES — Eosinophilic meningitis may occur in the context of fungal infection:

●Coccidioidomycosis (see "Coccidioidal meningitis")

●Cryptococcosis (particularly in patients with human immunodeficiency virus [HIV] infection) (see "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in patients with HIV")

On rare occasions, cerebrospinal fluid (CSF) eosinophilia has been reported in case reports of viral, rickettsial, and bacterial infections, although it is uncertain whether these infections were etiologic or coincident, and the individual infectious agents are not commonly associated with eosinophilic meningitis [105].

Prototheca wickerhamii, which may cause eosinophilic meningoencephalitis in dogs, has been reported as a cause of chronic eosinophilic meningoencephalitis in an immunocompetent child [109].

Visceral myiasis (invasion of the central nervous system by larvae of cattle botflies) may elicit a CSF eosinophilia. (See "Skin lesions in the returning traveler", section on 'Myiasis'.)

NONINFECTIOUS ETIOLOGIES — Noninfectious etiologies of eosinophilic meningitis include hematologic disorders, hemorrhagic cerebrovascular syndromes, adverse drug reactions, mechanical shunt malfunction, and other causes [110-112].

The hypereosinophilic syndromes are disorders characterized by a sustained blood eosinophilia in excess of 1500/mm³ without apparent parasitic, allergic, or other etiologies. While eosinophilic meningitis has been described in association with these disorders, it is relatively uncommon [113]. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis".)

Neoplastic diseases, most frequently Hodgkin lymphoma, can have an associated eosinophilic cerebrospinal fluid (CSF) pleocytosis. CSF eosinophilia also has been noted infrequently with carcinomatous or non-Hodgkin lymphomatous meningitis, basophilic-eosinophilic meningitis with undifferentiated myeloproliferative disorders or leukemia, acute lymphocytic leukemia, disseminated glioblastoma, and an apparent paraneoplastic manifestation of a bronchogenic carcinoma [105]. (See "Clinical features and diagnosis of leptomeningeal disease from solid tumors".)

Eosinophilic meningitis may be observed as a result of medication including ibuprofen (and other nonsteroidal anti-inflammatory drugs), ciprofloxacin, trimethoprim-sulfamethoxazole, and intraventricular vancomycin or gentamicin [105,114-118].

Sterile CSF eosinophilia has also been described after myelography with contrast agents [105]. It can also accompany ventriculoperitoneal shunt implantation or malfunction [119-121]. In one series of children with ventriculoperitoneal shunts, approximately one-third had CSF eosinophilia (>8 percent eosinophils) in the absence of peripheral blood eosinophilia; these patients were more likely to have shunt infections and require revision [121]. (See "Secondary central nervous system lymphoma: Clinical features and diagnosis".)

Other conditions rarely described with eosinophilic meningitis include sarcoidosis, amyloid-beta related angiitis, eosinophilic granulomatosis with eosinophilia, and cerebral eosinophilic granuloma [122-125]. Eosinophilia may accompany immunoglobulin (Ig)G4-related disease that uncommonly involves the meninges [126].

SUMMARY AND RECOMMENDATIONS

●Eosinophilic meningitis is defined as the presence of >10 eosinophils/mm³ in the cerebrospinal fluid (CSF) and/or eosinophils accounting for >10 percent of CSF leukocytes. Parasitic etiologies of eosinophilic meningitis include angiostrongyliasis, gnathostomiasis, and baylisascariasis. (See 'Introduction' above and 'Parasitic etiologies' above.)

●Humans are incidental hosts. The life cycle of angiostrongyliasis consists of transmission between rodents and snails or slugs (figure 1). The life cycle of gnathostomiasis consists of transmission between definitive hosts (pigs, cats, or dogs), intermediate hosts (Cyclops, fish, frogs, or snakes) and paratenic hosts (birds, snakes, or frogs) (figure 2). The life cycle of baylisascariasis consists of transmission between definitive hosts (raccoons or dogs) and paratenic hosts (other mammals and rodents) (figure 3). (See 'Epidemiology' above and 'Epidemiology' above and 'Epidemiology' above.)

●The diagnosis is based upon the clinical presentation, presence of CSF eosinophilia, and epidemiologic history of exposure to infective larvae. Larvae can almost never be recovered from the CSF but can be identified on tissue biopsy or autopsy specimens. (See 'Diagnosis' above and 'Diagnosis' above and 'Diagnosis' above.)

●For treatment of angiostrongyliasis, we recommend NOT administering anthelminthic agents (Grade 1B); these may elicit an inflammatory response due to dying organisms. Analgesics, corticosteroids, and periodic removal of CSF can relieve symptoms due to elevated intracranial pressure. (See 'Treatment' above.)

●For treatment of CNS infection due to gnathostomiasis, we suggest NOT administering anthelminthic agents (Grade 2B); these may elicit an inflammatory response due to dying organisms. Analgesics and corticosteroids can alleviate symptoms. For treatment of cutaneous gnathostomiasis, we suggest treatment with albendazole or ivermectin (Grade 2C); dosing is outlined above. (See 'Treatment' above.)

●For treatment of baylisascariasis, we suggest NOT administering anthelminthic agents (Grade 2C); these may elicit an inflammatory response due to dying organisms. Analgesics and corticosteroids can alleviate symptoms. For asymptomatic individuals with known exposure to raccoon stool or contaminated soil, we suggest prophylactic treatment with albendazole (Grade 2C); dosing is outlined above. (See 'Treatment' above.)

●Coccidioidomycosis is an important nonparasitic infectious cause of eosinophilic meningitis. Noninfectious etiologies of eosinophilic meningitis include hematologic disorders, adverse drug reactions, mechanical shunt malfunction, and other causes. (See 'Nonparasitic infectious etiologies' above and 'Noninfectious etiologies' above.)