Eosinophilic meningitis

Eosinophilic Meningitis PETERF.WELLER,M.D., Boston,Massachusetts

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lthough mononuclear or polymorphonuclear leukocytes may be elicited within the cerebrospinal fluid (CSF) in association with a variety of infectious and infknmatory conditions, eosinophilic leukocytes are found in the CSF only with a limited number of diseases. One of these diseases associated with an eosinophilic CSF pleocytosis, coccidioidal meningitis, is evaluated by Ragland and colleagues [l] in tbis issue of the Journal. Dissemination of the fungus Coccidioides immitis outside of the lungs occurs infrequently, but the recently increased numbers of infections with this fungus within California [2] have led to more cases of coccidioidal meningitis. The detection of CSF eosinophilia can provide a compelling diagnostic clue that leads to a consideration of those diseases causing eosinophilic meningitis, including coccidioidal meningitis as well as other entities that are generally less prevalent within the United States (Table I). If the presence of eosinophils within the CSF is to serve as a diagnostic touchstone important to the recognition of any of the parasitic, fungal, or other diseases associated with eosinophilic meningitis, then eosinophils must be identified if they are present. A skilled microscopist may be able to distinguish eosinophils from other leukocytes in unstained preparations of CSF, based on the eosinophil’s generally bilobed nucleus and its prominent cytoplasmic granules; but, as noted by Ragland et al [l], reliable detection of eosinophils in the CSF will require examination of cytocentrifuged cell preparations appropriately stained with Wright’s, Giemsa, or other stains. Only with stained leukocytes will it be possible to reliably detect and enumerate eosinophils within the CSF. Although it is abnormal to have any eosinophils in the CSF, the entity of eosinophilic meningitis, the subject of several reviews [3-71, can be more precisely defined by the presence of greater than or equal to 10 eosinophils/pL CSF and/or greater than or equal to 10% eosinophilia among CSF leukocytes [S]. Most of the infectious agents that elicit eosinophilia in the CSF are parasitic. Although these parasites are not principally endemic to North America, casesof eosinopbilic meningitis due to these parasites may be encountered in the Americas. Angiostrongylus cantonensis, a principal agent of eosinophilic meningitis and a natural parasite From the Infectious Diseases Division, Department of Medicine, Beth Israel Hospital, Harvard Medical School, Boston, Massachusetts. Requests for reprints should be addressed to Peter F. Weller, M.D., Beth Israel Hospital DA-617, 330 Brookline Avenue, Boston, Massachusetts 02215. Manuscript submitted February 10, 1993, and accepted February 19, 1993.

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of rats, has spread progressively throughout the Pacific Basin and is now found in regions of North America, due to ship-borne intercontinental dissemination of infected rata. Baylisascaris procyonis is a parasite of raccoons that exhibits a predilection for nervous system involvement. Human infections have been infrequent, but the high prevalence of this parasite within raccoons in the U.S. and the proximity of these mammals to areas of human habitation will provide opportunities for human infections to occur.

PARASITICETIOLOGIESOF EOSINOPHILIC MENINGITIS A. cantonensis, baylisascariasis, and gnathostomiasis are the three predominant parasitic infections associated with eosinophilic meningitis. The causative agents are hehninthic parasites, the multicellular metamans or “worms,” which, in contrast to unicellular protozoan parasites, are typically associated with eosinophilia [9]. Since the three hehninths are naturally parasites of animals, human infections are zoonoses. Larvae within the human host do not replicate and do not mature to adulthood. These human infections, therefore, are inherently self-limited. With each of these parasitic infections, eosinophilic meningitis is caused by the migration of larvae within the nervous system. For both A. cantonensis and B. procyonis, parasite development in natural animal hosts involves localization within the nervous system, and larvae of these two parasites continue to exhibit their distinct neurotropism when infecting humans. In gnathc&xniasis, larvae can migrate anywhere, penetrating the nervous system and/or non-nervous tissues. A. can tonensis

Eosinopbilic meningitis due to A. cantonensis occurs principally in Southeast Asia, particularly Thailand and Malaysia, and throughout the Pacific Basin, including Hawaii, Indonesia, the Philippines, Taiwan, Japan, Papua New Guinea, and several smaller Pacific islands. A. cantonensis has been found outside of this broad area in rats in regions of Africa, Cuba, Puerto Rico, and New Orleans, Louisiana Human infections have occurred in Cuba. Thus, although the Pacific region, including Hawaii, is the primary endemic area for eosinophilic meningitis due to this parasite, the infection can occur in other locales where ship-borne rats have been introduced into local ports. The life cycle of A. cantonensis, the rat lungworm, involves its natural mammalian host, the rat, and intermediate molluscan hosts. Larvae are passed in the feces of rats, and many species of snails and slugs, which

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TABLE I

Causesof Eosinophilic Meningitis* Infectious, parasitic causes Roundworm (nematode) infections: commonly presenting as eosinophilic meningitis Angiostrongylus cantonensis Gnathostoma spinigerum Baylisascaris procyonis Tapeworm (cestode) infections: may present as eosinophilic meningitis Cysticerosis Fluke (trematode) infections: occasionally causing eosinophilic meningitis Paragonimos westermani Schistosomiasis Fascioliasis Other nematode infections occasionally causingeosinophilic meningitis Toxocariasis Nonparasitic, infectious causes Coccidioidomycosis Cryptococcosis Myiasis Virus and bacteria

Migrating larvae inherently neurotropic Migrating larvae in visceral and/or neural tissues Migrating larvae inherently neurotropic Cysts develop in CNS and/or visceral tissues Ectopic spinal or cerebral localization Ectopic spinal or cerebral localization Ectopic CNS localization Migrating larvae

CSFeosinophilia rare With CNS penetration Rare and uncertain causality

Noninfectious causes Idiopathic hypereosinophilicsyndrome Ventriculoperitoneal shunts Leukemia or lymphoma with CNS involvement Nonsteroidal anti-inflammatory agents Antibiotics Myelography contrast agents CP6 = central nervous system *A,daptedfrom t71.

feed on rat feces, serve as intermediate hosts. In these molluscan hosts, larvae mature to form infective thirdstage larvae. Humans become infected by ingesting raw infected terrestrial mollusks, ground vegetables contaminated by mollusk slime or infected planaria, or csrrier hosts that have themselves eaten infected mollusks, including freshwater and terrestrial crabs and freshwater shrimp. Common garden snails and slugs that may be infected in endemic areas are a risk to young children who may ingest them or to others who may unwittingly ingest them on unwashed ground produce. Infection may be acquired by the consumption of snails, including the African land snail, Achatina fdica, as a dietary staple or a delicacy, escargots [lo]. Thus, residents in endemic areas as well as tourists or visitors who may partake of local foods are at risk for infection. Larvae of A. cantonensis are inherently neurotropic, and after ingestion by humans, migrate into neurologic or ocular tissues. Clinical manifestations develop after a period ranging from 2 to 35 days following infection. The disease presents usually as transient meningitis or, less frequently, as a more severe disease involving the brain, spinal cord, and nerve roots. Headache, experienced by % to 9% of patients, is the most common presenting symptom and is usually an excruciating frontal, occipital, or bitemporal headache. Headache typically is rapidly relieved following lumbar puncture. Neck stiffness, nausea and vomiting, and paresthesias are also frequent. Paresthesias with residual areas of hyperesthesia often persist for several weeks, even after other symptoms have resolved. Most patients do not have a fever of greater than 38’C. Paralysis of the extraocular muscles or facial nerves develops in only 4% to September

%. In the absence of reinfection, migrating larvae will die over time and the accompanying inflammation will subside. Most patients with cerebral angiostrongyliasis have a self-limited course and recover completely. Fatalities are uncommon. The treatment of cerebral angiostrongyliasis consists principally of supportive measures without administration of an anthehninthic agent. The diagnosis of cerebral angiostrongyliasii requires examination of the CSF, and the finding of CSF eosinophilia is of cardinal importance. CSF may be clear or more often cloudy, but not grossly turbid or xanthochromic. The CSF leukocyte count ranges from about 20 to 5,000 cells/~L and is usually between 150 and 2,009 cells/pL. CSF ecsinophilia exceeds 10% in about 95% of cases and is usually in the range of 20% to 70%. The protein concentration is usually elevated, but the CSF glucose is normal or only mimmally low. Peripheral blood eosinophilia usually accompanies the eosinophilic CSF pleocytosis but may be mild (greater than 3% in 99% of patients). Blood eosinophilia does not correlate with CSF eosmopbilia or with the clinical course. Since larvae of A. cantonensis have only rarely been recovered from the CSF antemortem, the diagnosis cannot depend on detecting and identifying the causative agent. EInzymelinked immunosorbent assay serologic tests help confirm the diagnosis, and the usual absence of focal lesions on computed tomographic (CT) scan helps distmguish this form of eosinophilic meningitis from neurocysticercosis or gnathostomiasis. Thus, the diagnosis is generally based on a clinical presentation and CSF eosinophilia compatible with eosinopbilic meningitis together with an epidemiologic history of known or possible exposure to infective A. cantonensis larvae. 1993

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Gnathostomiasis This infection results from the migration of larvae of Gnathostoma spinigerum within human tissues. In contrast to A. cantonensis larvae, G. spinigerum larvae are not inherently neurotropic, but rather may migrate in subcutaneous, visceral, or neural tissues. Consequently, gnathostomiasis can present as migratory cutaneous swellings, eosinophilic meningoencephalitis, or inflammatory masses in visceral organs. Gnathostomiasis is endemic in Southeast Asia and parts of China and Japan and occurs sporadically in Europe, the Americas, Africa, and the Middle East. Adult G. spinigerum worms are gastrointestinal parasites of domestic and wild dogs and cats. Eggs passed in canine and feline feces hatch in water to release first-stage larvae, which are ingested by Cyclops species of water fleas. Infective third-stage larvae develop in the flesh of many animal species, including fmh, frogs, eels, snakes, chickens, and ducks, that have eaten either infected Cyclops or another infected second intermediate host. Humans usually acquire the infection by eating raw or undercooked fish or poultry. Clinical symptoms are elicited by the migration of a single Gnathostoma larva in cutieous, visceral, neural, or ocular tissues. Larval penetration into the brain usually results from migration along a nerve track. Characteristically, patients present with sudden onset of severe radicular pain or headache as well as pare&he&s in the trunk or a limb, followed shortly by paralysis of extxemities or cranial nerves. Thus, the syndrome of eosinophilic meningoencephalitis due to gnathostomiasis is usuaJly distinct from the more indolent manifestations of eosinophilic meningitis due to angiostrongyliasis. Moreover, the tissue destruction and severe inflammation in gnathcstomiasis may result in acute cerebral hemorrhages, which can be large and rapidly fatal. At present, spinocerebral involvement is managed with supportive measures and generally a course of corticosteroids. Diagnosis of CNS gnathostomiasis entails evaluation of the CSF, which contains an eosinophilic pleocytais and is often xanthochromic or bloody. Larvae can almost never be recovered from the CSF. CSF protein is elevated and the glucose level is usually normal. Peripheral blood eosinophilia is often quite pronounced and greater than occurs with angiostrongyliasis. CT scans can demonstrate areas of hemorrhage. The abrupt onset of symptoms and the prominence of nerve root pain, in the appropriate geographic and epidemiologic setting, usually make this form of eosinophilic meningoencephalitis distinguishable from eosinopbilic meningitis due to angiostrongyliasis. Gnathmto&is may be mistaken for cerebral hemorrhage due to primary cerebrovascular disease. Serologic tests have been developed but are not readily available outside of highly endemic areas. Baylisascariasis B. procyonis 252

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is widely prevalent within raccoon populations in regions of the U.S. but to date has only rarely caused human eosinophihc meningoencephalitis. B. procyonis eggs are shed in raccoon feces, and ingestion of infectious eggs is followed by release of larvae that have a predilection to migrate into the spinal cord and brain. Two cases of human eosinophilic meningoencephalitis due to B. procyonis, both of which occurred in children who had likely ingested raccoon feces, have been recognixed [11,12]. Thus, this syndrome can be considered a form of visceral larva migrans, and those at risk include children with their proclivity for pica and, less likely, adults who consume foodstuffs or other items contaminated with Baylisascaris eggs derived from raccoon feces. The diagnosis at present is made by the clinical features in concert with prominent blood and CSF eosinopbilia in individuals with a potential exposure to raccoon-contaminated soil. Definitive diagnosis would require morphologic identification of larvae, which would necessitate examination of biopsy tissue samples. Eosinophilic Meningitis From Other Helminthic Parasites Parasites, whose eggs or larvae can sometimes be localized within the CNS, may elicit an eosinophilic pleocytosis. These include cerebral and spinal cord schistosomiasis, toxocariasis (visceral larva migrans due to Toxocara canis or Toxocara catis), trichinosis, neurocysticercosis, fascioliasis, and cerebral and spinal paragonimiasis [7].

NONPARASITIC,INFECTIOUSETIOLOGIESOF EOSINOPHILICMENINGITIS Coccidioidomycosis, as exemplified by the patients reported by Hagland et al [l], is the one fungal infection that is notably associated with CSF eosinopbilia when infection disseminates to involve the meninges [3,13-X5]. CNS cryptococcosis is only rarely accompanied by CSF eosinophilia [16]. Although some viral, rickettsial, and bacterial infections have been reported to be associated with CSF eosinophilia, these infections are not likely, and definitely not common, etiologies for eosinophilic meningitis [7]. Visceral myiasis, with central nervous system invasion by larvae of cattle bottlies, may elicit a CSF eosinophilia

NONINFECTIOUSETIOLOGIESOF EOSINOPHILICMENINGITIS The idiopathic hypereosmopbilic syndrome is a leukoproliferative disorder characterized by a sustained blood eosinophilia in excess of 1,5OO/~L for more than 6 months without apparent parasitic, allergic, or other etiologies. Although eosinophilic meningitis has been described with the idiopathic hypereosinophilic syndrome, eosinophihc meningitis is not one of the more frequent neurologic manifestations of this disorder [17]. Neoplastic diseases, most frequently Hodgkin’s 95

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disease, can have an associated eosinophilic CSF pleocyto&. CSF eosinophilia has been noted infrequently with carcinomatous or non-Hodgkin’s 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 [7]. Eosinophilia in the CSF has developed with medicinal and diagnostic agents [7], including ibuprofen and specific antimicrobial agents, such as systemic ciprofloxacin and intraventricular vancomycin or gentamicin. CSF eosinophilia has been noted after myelography with contrast agents. Sterile CSF eosinophilia can accompany ventriculoperitoneal shunt implantation or malfunction. In children with ventriculoperitoneal shunts, about a third in one series experienced a CSF eosinophilia of 8% or greater, and these children, none of whom developed peripheral blood eosinophilia, were more likely to require shunt revisions and to experience shunt infections [18]. Other conditions described with eosinophilic meningitis include sarcoidosis and cerebral eosinophilic granuloma.

THE SIGNIFICANCEOF CSF EOSINOPHILIA Just as an exuberant neutrophilic exudate in bacterial meningitis can contribute to the adverse sequelae of such infections, one must be concerned that an elicited eosmophilic exudate in the various disorders associated with eosinophilic meningitis may be contributing to neurologic damage. Eosinophils with their distinct cationic granule proteins may cause tissue damage and dysfunction in other organs [19,20]. Two of the eosinophil granule cationic proteins are eosinophil cationic protein (ECP) and eosinophil-derived neurotoxin (EDN), which are similar, but structurally distinct, proteins. Both ECP and EDN can elicit the Gordon phenomenon, which constituted the basis for naming EDN. The Gordon phenomenon, first described as a cerebrocerebellar dysfunction in test rabbits after intracerebral injection of the lymph nodes of patients with Hodgkin’s disease and subsequently shown to be attributable to eosinophils infiltrating these lymph nodes, is evoked when either eosinophil granule constituent, ECP or EDN, is injected into the CSF or brains of rabbits or guinea pigs [19]. Although the neurotoxicity of these eosinophil proteins when admiitered to test animals is clear, it has not yet been ascertained that naturally released eosinophil proteins contribute to damage to human neural tissues in vim The potential exists, however, for eosinophil-derived granule proteins or other compounds, such as cytokines or oxidants, to contribute to damage of the nervous system. The seriousness of coccidioidal meningitis is apparent from the 27 patients reported by Regland et al September

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[l], since 70% developed hydrocephalus and cranial or peripheral nerve palsies. Neither the presence nor levels of CSF eosinophilia could be correlated with outcome. Nevertheless, these findings do not exonerate the eosinophil from potentially contributing to the adverse outcomes. Eosinophil counts were performed on CSF obmined from lumbar sites, whereas the serious pathology and adverse sequelae of coccidioidal meningitis occur at the base of the brain and in the ventricles. Thus, local eosinophilia and inflammatory events at these central sites are not available for evaluation. What the roles of eosinopbils are in the host response to Coccidioides remain uncertain, whether they in some fashion help contain infection and/or contribute to local damage. What is certain, however, is that detection of eosinophils within the CSF can serve as a helpful means of identifying those limited conditions associated with an eosinophil CSF pleocytosis, including coccidioidal meningitis and specific helminthic infections.

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