Curr Infect Dis Rep (2013) 15:600–611 DOI 10.1007/s11908-013-0383-8

CENTRAL NERVOUS SYSTEM (J LYONS, SECTION EDITOR)

Central Nervous System Infections in Travelers H. L. Kirsch & K. T. Thakur & G. L. Birbeck

Published online: 5 November 2013 # Springer Science+Business Media New York 2013

Abstract International travelers commonly contract infections while abroad, many of which are primary neurological diseases or have potential neurological sequelae. The implications of these neuroinfectious diseases extend beyond the individual, since returning travelers may contribute to the spread of infection in novel areas. In this review, we discuss signs, symptoms, treatments, and prophylaxes for these infections, as well as emerging trends with regard to neuroinfectious diseases of the returning traveler. Keywords Travel . Central nervous system infection . Encephalitis . Meningitis . Malaria . Dengue . Chikungunya . Rabies . Sleeping sickness

Introduction According to the recent GeoSentinel study, approximately 15 returning traveler patients per 1,000 present with neurological symptoms and signs [1]. Not only are there numerous primary neurological conditions contracted abroad, but also many common infectious diseases in travelers have potential neurological sequelae. In this article, we provide information Authors’ Contribution H. L. Kirsch: design, writing, and editing of the manuscript. K. T. Thakur: design, writing, and editing of the manuscript. G. L. Birbeck: design and editing of the manuscript. H. L. Kirsch (*) New York University School of Medicine, New York, NY 10016, USA e-mail: [email protected] K. T. Thakur Department of Neurology, Johns Hopkins Hospital, Baltimore, MD, USA G. L. Birbeck Department of Neurology, University of Rochester School of Medicine, Rochester, NY, USA

on significant and recently emerging neuroinfectious diseases in returning travelers. Discussed are signs, symptoms, and treatment of these diseases, options for prophylaxis, and recommendations for vaccination when available.

Viral Infections Dengue Transmitted by the Aedes mosquito, the dengue virus is a flavivirus with four distinct serotypes [2]. This most common arbovirus infection in the world is present throughout Latin America, Southeast Asia and the South Pacific, the Caribbean, and sub-Saharan Africa [2]. The disease is most often contracted in Southeast Asia, although this may reflect high rates of travel to this popular tropical destination [3–5]. Incidence rates among travelers to endemic regions range from 0.3 % to 16 %, all of which are likely underestimates [2, 6]. The number of cases of the disease has increased dramatically over the past 30–50 years as the disease has spread geographically across endemic continents and to North America [7–9]; an estimated 20,000 deaths and 50–100 million cases of the disease occur annually [9]. Viremic travelers returning from original endemic areas are thought to account for much of the spread of dengue virus and potentiate delayed outbreaks of the disease in nonendemic areas [7–9]. While the disease is not traditionally neurotropic, neurological complications that occur include acute pure motor weakness, intracerebral hemorrhage, and, most commonly, encephalopathy [10, 11]. There are also cases of meningoencephalitis and, rarely, myelitis due to dengue [10, 12, 13]. Recent reports of reversible hypokalemic quadriparesis and diaphragmatic paralysis associated with dengue infection have been described [14, 15]. The virus is traditionally difficult to detect, both because serologic tests frequently cross-react for other flaviviruses and because IgM and IgG levels vary throughout the course of the disease [16].

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Recent advances in using the dengue nonstructural protein 1 (NS1) ELISA along with traditional anti-DENV IgM ELISA to confirm DENV infection help facilitate early diagnosis [17]; ELISA may also be combined with real-time PCR [18]. Treatment for all forms of dengue is supportive. There have been several recent successful phase II trials of dengue vaccine in endemic countries [19, 20]. One small study in previously vaccinated subjects showed that all five recipients of the vaccine showed no response to subcutaneous DENV-1 inoculation, and two showed no response to DENV-3 inoculation [21]. If successful, up to 59–89 million doses may be needed for travelers in the first 5 years after the vaccine is approved [8]. Japanese Encephalitis This mosquito-borne flavivirus accounts for at least 50, 000 clinically apparent infections worldwide annually [22], with a case fatality rate of up to 30 % and a high rate of neurological sequelae [22, 23]. Most cases occur in continental south Asia and Indonesia, although Japan, China, the Philippines, Papua New Guinea, and Australia have also been affected [22]. Estimated encephalitis rate in travelers has ranged from under 1 per million [24, 25] to 1 in 400,000 [24]. Perhaps unsurprisingly, most reported cases come from the most-traveled countries, including Bali and Thailand [24]. Importantly, while in more northern endemic areas Japanese encephalitis virus (JEV) outbreaks tend to occur seasonally, between May and October [22, 26], in hotter tropical regions transmission can occur year round [24, 26]. Clinical illness becomes apparent after about a 2-week incubation period, with relatively nonspecific symptoms including fever and vomiting that progress to meningeal signs, altered mental status, extrapyramidal signs, flaccid paralysis, and a characteristic masklike facies [24, 27, 28]. Diagnosis is frequently made clinically, although available confirmatory tests include hemagglutination inhibition test, enzyme-linked immunosorbent assay, and the technically difficult but very specific virus isolation from blood or CSF [22]. Classic MRI findings include FLAIR hyperintensities in the bilateral thalami, basal ganglia, and/or midbrain [29, 30] (Fig. 1). Unfortunately, while minocycline has potential as a JEV treatment [28], currently there is no effective treatment beyond supportive care for JEV [26, 28]. There are two licensed JE vaccines in the United States, the Vero cell culture-derived vaccine for adults and mouse brain-derived vaccine approved for children less than 17 years of age23. While the pediatric vaccine is no longer in production and supplies are consequently limited, the adult JE vaccine is available and recommended for travelers who plan to spend at least 1 month in JE-endemic areas during transmission season and travelers to areas with active JEV outbreaks [23].

Fig. 1 The MRI features of Japanese encephalitis: T2 axial brain MRI depicting symmetrical hyperintense signals in the bilateral thalamus and basal ganglia in a patient with Japanese encephalitis. (FromVerma R., MRI Features in Japanese Encephalitis. BMJ Case Reports, 2012)

According to a March 2013 study surveying travelers to JE-endemic areas in Asia, only 11 % of higher-risk travelers and 1.8 % of lower-risk travelers received the vaccine; the majority attributed this to being unaware of or not advised to receive JE vaccine [31]. Thirty-seven percent of surveyed travelers reported seeing a primary care or travel medicine physician in preparation for the trip [31], suggesting a need for increased awareness of JE vaccination recommendations even among travel physicians. Chikungunya Chikungunya virus (CHIKV) is an alphavirus that, like dengue virus, is spread by the Aedes mosquito. The disease reemerged after several decades of few to no cases in endemic countries. This resurgence is thought to be influenced by a recently discovered mutation in the envelope protein gene E1A226V, which increases infectivity of the viral vector and transmission to host animals [32]. India alone has seen 1–3 million cases since 2005 [33]. Recent outbreaks have also occurred in Yemen, China, Cambodia, Bangladesh, and a number of other African and South Asian countries [33–38]. As the endemic incidence of CHIKV infection has increased, so has infection in travelers. According to the multinational Geosentinel survey of 53 travel or tropical medicine clinics, there were 164 cases of CHIKV reported in returning travelers between 2007 and 2011 [1], contracted primarily in India, Malaysia, Indonesia, and Thailand [1]. One study identified 109 laboratory-confirmed cases of chikungunya in the United States from 1995 to 2009, 97 % of which occurred after 2006 [39]; while no locally transmitted cases were identified, there is a theoretical risk of spreading the virus to close contacts via direct contact with blood or via Aedes mosquitoes [39, 40].

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CHIKV’s initial clinical manifestations strongly resemble those of dengue, with sudden-onset fever, headache, and maculopapular rash after an approximate 3- to 7-day incubation period [41]. Unlike dengue, nearly all patients with CHIKV develop an extremely painful symmetrical polyarthralgia in the extremities, which may persist for months or years [42]. In general, neurological manifestations of CHIKVare rare, perhaps due to the rapid induction of type I interferons and activation of the innate immune system upon central nervous system (CNS) invasion by the virus [43]. There is no known receptor mediating CHIKV entry, but it has been shown in animal models that the virus can infect and cause apoptosis in neurons, astrocytes, meningeal cells, and ependymal cells, as well as remain in macrophages as a reservoir [43, 44]. When neurologic symptoms occur, patients present acutely with an encephalopathy associated with lymphopenia and thrombocytopenia, Guillain–Barré syndrome, and meningoencephalitis associated with prominent white matter lesions and seizure [43, 44]. There have been some reports of long-term cognitive dysfunction in patients with chronic arthralgia due to CHIKV who did not suffer any acute neurological complications [45]. A recent large outbreak in Reunion Island included 23 patients with neurological symptoms in the acute phase of infection, associated with CSF positive for IgM or viral genetic material by RT-PCR [46]. Altered mental status, headache, and seizure were the most common presentations. Neurological improvement was dramatic as the infection was treated with IVIG; all five deaths in this cohort were in elderly patients who had preexisting comorbidities or who became increasingly debilitated due to persistent polyarthralgias [46]. In general, elderly patients, the immunocompromised, or otherwise ill patients are at higher risk of developing neurological manifestations of CHIKV [43, 47, 48], which should be considered when advising patients who plan to travel to chikungunya-endemic regions. Rabies Rabies is caused by infection with members of the genus Lyssavirus and carries a nearly 100 % case fatality rate [49]. Lyssavirus is transmitted via the saliva of infected animals, usually dogs, and requires direct inoculation via a bite or salivary contact with mucous membranes. The disease is endemic to countries on all continents, with most reported deaths occurring in Africa and Southeast Asia [49]. The incidence of rabies in travelers is likely underestimated, since the diagnosis can be difficult to obtain when death occurs abroad [50, 51]. Rabies should be considered in patients with even a remote history of animal bite, since the incubation period for rabies ranges from days to months or, rarely, years [52]. The patient may experience 2–10 days of prodromal symptoms of intense pruritus or neuropathic pain at the site

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of inoculation [52]. Following the prodrome, two thirds of patients will develop encephalitic or furious rabies, characterized by hyperactivity, deteriorating mental status, autonomic hyperactivity, and phobic spasms. Hypersalivation and hydrophobic attacks are particularly indicative of encephalitic rabies [52]. Paralytic rabies does not include the prominent aggression of encephalitic rabies and resembles Guillain–Barré syndrome; the presence of persistent fever, intact sensorium, and percussion myoedema may help to differentiate this form of rabies from GBS [52]. Preexposure prophylaxis (PrEP) for rabies has long been available in the form of three intradermal injections of one of three acceptable vaccines, of which the human diploid cell and purified chick embryo forms are available in the U.S. [53]. Because the vaccine contains no preservative, an opened ampoule must be used within 8 h, and the remaining vaccine discarded; thus, in most cases, rabies vaccination is prohibitively expensive [53]. However, new data suggest that a cheaper, simpler two-site intradermal vaccination schedule is as effective as the traditional intramuscular regimen [54]. Cost is a frequently cited reason for why travelers do not receive rabies PrEP [54, 55]; this intradermal method could both reduce costs of PrEP and, by encouraging vaccination prior to travel, reduce consumption of costly immunoglobulin and rabies vaccine in resource-poor endemic countries. PEP is not effective once the virus has invaded the nervous system and, thus, should be administered urgently. However, because the rabies virus has a variable incubation period of weeks to years, an exposed individual should be treated with rabies immunoglobulin (RIG) regardless of the interval between exposure and reporting [56]. Although rare, side effects from first-generation neural tissue vaccines (NTVs) for rabies PEP have included encephalitis, GBS-like syndromes, and other neurological symptoms due to induction of immune response against the body’s own myelin basic protein and gangliosides [56, 57]. First-generation NTVs of unknown provenance are commonly used in rabies-endemic developing countries [58, 59]. Several studies have revealed poorly immunogenic NTVs or NTVs containing live virus at multiple sites in resourcelimited nations [60, 61]. Therefore, if a patient has received an NTV or a vaccine of unreliable source, he or she should be considered unvaccinated and receive PEP accordingly. Similarly, equine RIG is cheaper to prepare than human RIG and, thus, more widely available in developing countries [56, 61].

Bacterial Infections Bacterial Meningitis While epidemic Neisseria meningitis is rare in the United States, outbreaks typically caused by group A strains of N. meningitides are common in the 13 countries of sub-Saharan

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Africa’s “meningitis belt” (Fig. 2) [62]. Even in the absence of an epidemic, the dry season usually brings a “hyperendemic” period of increased N. meningitides and S. pneumococcus meningitis [63]. During the rainy season, the incidence of bacterial meningitis is approximately equal to that of many countries in Europe and North America, although the comparative rates of meningitic and pneumococcal meningitis during these periods are unknown [63]. Formerly, travelers returning from Islam’s hajj pilgrimage, in which large numbers of people gather in close quarters in the Saudi Arabian city of Mecca, were at increased risk for contracting meningitis or becoming N. meningitides carriers; there have been no hajj-related outbreaks since the introduction of the tetravalent meningococcus vaccine as a requirement for a hajj visa in 2002. In 2010, an N. meningitides serogroup A vaccine, MenAfriVac, was deployed in the meningitis belt, first in Burkina Faso among individuals between 1 and 29 years of age [64]. This has dramatically decreased the carrier rate and the incidence of meningitis among this population; for instance, in three surveyed districts in Burkina Faso, overall carriage prevalence decreased from 10.31 % to 3.29 % after the vaccine was deployed [64]. Additionally, while the expected number of N. meningitides carriers was 8.74 in the surveyed population, no carriers were found among unvaccinated study participants [64]. However, in Africa, the high-prevalence carrier period extends beyond young adulthood, unlike in the United States [65].

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The MenAfriVac does not offer coverage against the type C, B, X, Y, and W135 strains of N. meningitides [66]. Similarly, the tetravalent MPSV4 provided in the United States does not protect against serotype B and may lead to long-term hypoimmunity against type C [66]. Thus, while all nonimmune patients planning to travel to sub-Saharan Africa should be vaccinated according to CDC guidelines [67], bacterial meningitis should remain in the differential diagnosis in a vaccinated traveler with suggestive symptoms. The risk of acquiring bacterial meningitis abroad has been estimated at 0.4 per 100,000 travelers per month, although the risk is much higher among those visiting sub-Saharan Africa during the dry season or staying with local community members [68]. Treatment with ceftriaxone or other third-generation cephalosporin should be initiated. Regarding ceftriaxone resistance, one study showed that among N. meningitidis isolates recovered from countries within the meningitis belt from 2000 to 2006, only 2 % showed reduced susceptibility to penicillins, and all were susceptible to cephalosporins [69]. However, other studies did isolate higher numbers of ceftriaxone-resistant strains of S. pneumonia. Additionally, decreased susceptibility to chloramphenicol has been noted among African strains of both S. pneumoniae and H. influenzae [70, 71]. Returning travelers who continue to demonstrate symptoms after treatment abroad, particularly after receiving chloramphenicol, should be presumptively treated for resistant disease with the combination of a third-

Fig. 2 The meningitis belt in Africa: Areas with frequent epidemics of meningococcal meningitis (http://wwwnc.cdc.gov/travel/yellowbook/2012/ chapter-3-infectious-diseases-related-to-travel/meningococcal-disease)

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generation cephalosporin and vancomycin [72]. Alternatively, rifampin or a fluoroquinolone may be used [72].

Parasitic Infections Neurocysticercosis Neurocysticercosis (NCC) is caused by infection with the pork tapeworm, Taenia solium. The disease is endemic to South Asia, South America, and sub-Saharan Africa and is spread via fecal–oral contamination by a human or porcine host. The helminthic larvae lodge in the brain parenchyma, ventricles, or intradural space, where they form one or multiple cysts. A number of studies have shown that in travelers, as well as citizens of endemic areas, the infection usually manifests years later, most often with new-onset seizure [73–75]. Degeneration of the scolex and cyst can cause leptomeningeal or parenchymal inflammation, resulting in seizures, or increased intracranial pressure if debris obstructs CSF outflow, as well as cerebral hemorrhage [75]. Considering the high prevalence of NCC in developing countries, risk of contracting T. solium is relatively low and appears to be correlated to length of time spent abroad [74]. A number of reviews have found that single cysticercal granuloma is the most common presentation of NCC in citizens of nonendemic countries [74–76]. Meta-analysis has suggested that corticosteroids may not be particularly efficacious as adjunctive treatment to albendazole in solitary cysticercus granuloma (SCG) [77]; while limited by the small size of the RCTs included in the analysis, it may have implications for improved treatment regimens of SCG in returning travelers with NCC.

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inoculation period, followed by an initial stage of intermittent fever, pruritus, hepatosplenomegaly, and posterior cervical lymphadenopathy, known as Winterbottom’s sign (Fig. 3) [79]. This is followed by an asymptomatic stage lasting 1– 3 years, after which a chronic neurological syndrome develops. Signs and symptoms of this chronic stage are diverse and include severe headache, disturbance of circadian rhythm, psychiatric symptoms, and focal neurologic deficits. The acute onset of a relapsing-remitting fever in the first stage of HAT may lead to misdiagnosis and subsequent mistreatment for malaria, Epstein–Barr virus [80], or even Lyme disease [78] in patients with an unknown travel history. Adding to the diagnostic challenge, a number of studies have found that daytime somnolence and other sleep disorders are rare in infected travelers [81]; the absence of this familiar symptom may unjustly exclude HAT from the differential diagnosis. However, travelers are much more likely to have GI disturbances, jaundice, and a visible trypanosomal rash [81]. Travelers also more often develop chancre, which may facilitate the diagnosis if the patient comes to clinical attention early in the disease course [79]. Once HAT is suspected, diagnosis may be made by card agglutination test for trypanosomiasis (CATT) in the case of T. b. gambiense infection and by peripheral blood or CSF smear in infection with T. b. rhodesiense , which does not have the surface glycoproteins necessary for diagnosis via CATT [80]. Treatment for HAT is dependent on both the causative species and stage of the disease: Early- and late-stage T. b. rhodensiense infection is treated with intravenous suramin and IV melarsoprol, respectively, while early- and late-stage gambiense is treated with intramuscular pentamidine and IV

Trypanosomiasis Members of the genus Trypanosoma are responsible for human African trypanosomiasis (HAT) and Chagas disease, both of which can have serious neurological consequences. The protozoa Trypanosoma brucei gambiense causes West African sleeping sickness (WASS), and Trypanosome brucei rhodesiense causes East African sleeping sickness (EASS), both two-stage illnesses that are invariably fatal if untreated. EASS accounts for the majority of sleeping sickness in travelers [78] and is most often contracted in Tanzania, Malawi, and Zambia, frequently after travel in national parks and rural areas [78]. The first stage begins 1–2 weeks after inoculation with chancre at the site of the bite; diffuse, macular, evanescent skin rash; fatigue; intermittent fever; and myalgias. If untreated, invasion of the CNS by the parasite inevitably causes progressive meningoencephalitis that is fatal 6–9 months later. Symptoms of this second stage include circadian rhythm disturbances and headache, but rarely focal neurologic deficits. In contrast, WASS has a 2- to 3-week

Fig. 3 Enlarged cervical lymph nodes (Winterbottom's sign) is a characteristic sign for infection with T. b. gambiense (http://bestpractice. bmj.com/bestpractice/monograph/9999/resources/image/bp/3.html)

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eflornithine, respectively [79]. Of note, since suramin can be difficult to obtain in nonendemic countries, rhodensiense treatment may be initiated with pentamidine and then switched to suramin [79]. All treatments for HAT have significant toxicity; melarsoprol, in particular, causes an encephalopathic syndrome with a 50 % fatality rate in 5–10 % of patients [79, 82]. Chagas disease, or American trypanosomiasis, is caused by Trypanosoma cruzi and endemic to much of Central and South America. Organisms from the feces of Triatoma infestans, or the reduviid bug, enter the bloodstream via the insect’s bite or skin breaks due to scratching [83]. Initial symptoms of the illness are generally nonspecific flulike symptoms; occasionally, acute Chagas disease manifests as fulminant meningoencephalitis, typically in neonates or the immunocompromised [83]. The infection then remains silent for a number of years but may ultimately cause cardiomyopathy, arrhythmias, megaesophagus, and megacolon via a neurotropic autoimmune response directed against the autonomic ganglia supplying these tissues [83, 84]. Cardioembolic stroke accounts for virtually all the primary neurological morbidity of chronic Chagas disease [85], although rarely, immunocompromised patients develop a delayed or recurrent meningoencephalitis [83]. Patients with both acute and reactivated Chagas disease should undergo pharmacological treatment with either nifurtimox or benznidazole [83]. A number of recent outbreaks have resulted from consumption of fresh guava, sugarcane, or acai juice in which protozoa have been crushed or been deposited when containers were left uncovered [83, 84, 86]. Travelers should be cautioned to avoid all food, juices, and other drinks that have not been pasteurized or cooked to over 45 °C and meat that has not been cooked to over 60 °C [83]. Malaria Approximately 30 million international travelers visit malariaendemic countries annually. From 1991 to 2001, 13,900 cases of imported malaria were reported in the United States [87–91]. The major burden of malarial disease lies in Africa (81 %), followed by Southeast Asia (13 %) and the Eastern Mediterranean (5 %) [92, 93]. Malaria is caused by a protozoan parasite of the genus Plasmodium infecting red blood cells, transmitted by the female anophelous mosquito. The four Plasmodium species that infect humans are P. falciparum, P. vivax, P. ovale, and P. malariae. P. falciparum accounts for one half of infection in travelers, 85 percent of whom are infected during the rainy season in sub-Saharan Africa. Neurologic sequelae from uncomplicated malaria are uncommon and have been infrequently recognized in travelers returning from malaria-endemic regions. Cerebral malaria (CM) is a rare, serious complication presenting as a comatose state, which carries a 15 %–20 % case fatality rate, most

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commonly seen in children infected with P. falciparum in sub-Saharan Africa [94]. The prevalence and risk of CM in returning travelers is not known and has been described in few previously reported cases [95, 96]. Distinct from CM is a transient clinical syndrome known as postmalaria neurological syndrome. Patients typically present with neuropsychiatric symptoms, including psychosis, seizures, and cerebellar signs and symptoms [97–99]. More rarely described is a Guillian–Barré-syndrome-like presentation, as well as mononeuritic syndromes [100–102]. When visiting endemic regions, travelers should prevent mosquito bites by using adequate body-covering clothing, bed nets, and repellents. Up to 50 % DEET (chemical name, N,N-diethyl-metatoluamide) is recommended as an effective repellent for all individuals over the age of 2 months, including pregnant women. Recommendations for antimalarial prophylaxis should be initiated if traveling to locations where the annual incidence of malaria is above 10 cases per 1,000 individuals [103]. Treatment of CM consists of rapid administration of intravenous antimalarial medications. Of note, the antimalarial drug mefloquine can itself cause significant neuropsychiatric side effects, including dizziness, headache, vivid dreams, depression, and, more rarely, seizures, psychosis, and suicidality. Schistosomiasis Schistosomiasis, a widespread helminthic infection caused by a blood-dwelling trematode, infects 200 million people worldwide, with approximately 20 million developing severe symptoms, including neurologic manifestations [104–106]. Travelers are at risk when exposed to freshwater in regions of Southern and sub-Saharan Africa, the Mahgreb region of North Africa, and the Nile River valley in Egypt and Sudan, as well as regions of China, the Middle East, the Caribbean, and South America [107] (see Map). An infected individual transmits the infection by excreting schistosome eggs in the stool (S. mansoni, S. japonicum) or urine (S . haematobium ). Eggs that are not excreted remain trapped in the intestinal or bladder wall or are carried by the bloodstream to the liver and other sites, including the CNS, where a granulomatous reaction occurs in the acute infectious stage, which can occur up to 100 days after initial infection [108–112]. Clinically, patients with neurological manifestations may rarely have a history of an urticarial maculopapular rash after initial exposure. Symptomatic neurological involvement is more common in the postinfective stage than in chronic schistosomiasis. Most reported cases of neuroschistosomiasis are caused by infection with S. mansoni, S. haematobium , or S. japonicum [113–117]. S. mansoni and S. haematobium usually affect the spinal cord but are increasingly recognized as causes of encephalopathy. S. japonicum most commonly causes an encephalitic picture [108, 114, 116–121] but also causes pseudotumoral encephalitic schistosomiasis. Spinal

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cord schistosomiasis, usually due to S. mansoni, is an underrecognized cause of myelopathy among those living in and having visited endemic regions. Spinal cord schistosomiasis typically presents acutely or subacutely, initially with back pain commonly followed by cauda equina symptoms. MRI shows evidence of T2 hyperintensity with heterogeneous enhancement on T1 postcontrast sequences in the spinal cord, although this is not pathognomic for spinal schistosomiasis [122]. In spinal schistosomiasis, stool and urine studies are often negative, although rectal biopsy can be useful if testing is available. CSF studies show eosinophilia in approximately 50 % of patients [123, 124]. The eosinophil count in blood is elevated in approximately 50 % of cases. The urine should be examined for microscopic hematuria, which is common in individuals infected with S. haematobium. In travelers, antibody detection in serum samples is useful for diagnosis. Praziquantel is the treatment of choice for all schistosome species. Adverse effects are generally mild. Acute encephalopathy due to schistosomiasis should be treated with steroids initially followed by praziquantel [116]. Eosinophilic Meningitis Eosinophilic meningitis (EM) is a rare clinical syndrome characterized by meningeal inflammation and an eosinophilic pleocytosis in the CSF. Among travelers, EM is most commonly associated with nematodal infections, including Angiostrongylus cantonensis, Gnathostoma spinigerum, and Baylisascaris procyanis [125]. Human infection by Angiostrongylus cantonensis, the most frequent of the three, occurs when third-stage larvae are ingested in intermediate hosts (slugs and snails) or transport hosts (freshwater crustaceans) [126–130]. After ingestion, larvae penetrate the vasculature of the intestinal tract and travel hematogenously to the CNS. Following an average incubation period of 1–3 weeks, symptomatic patients often develop headache, meningeal symptoms, and sensory abnormalities. Uncommonly, infection results in severe neuropathic and motor symptoms, coma, and death [130–132]. CSF WBC is typically in the range of 100–5, 000 leukocytes/microliter, with varying degrees of eosinophilia [133, 134]. Angiostrongylus cantonensis is endemic to Southeast Asia, the Pacific Rim, Hawaii, and the Caribbean [135–138]. Spread of infection to regions such as Africa, India, Australia, and North America has increased in recent years by carriage through cargo ship rats, the dead end hosts of A. cantonensis, to these regions [135, 136, 139]. Precautions against infection include not eating raw or uncooked fish and not consuming unwashed vegetables. A course of albendazole therapy in addition to adjunctive steroid treatment may reduce the duration of severe headache [140–143]. Infection with Gnathostoma spinigerum in humans is usually acquired by the consumption of raw or undercooked fish or poultry. In Thailand and Japan, eating raw fish dishes

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such as sashimi is responsible for most cases. G. spinigerum larvae are not neurotropic but, instead, migrate indiscriminately through subcutaneous, visceral, and neural tissues. If they pass through the CNS, an EM may develop. Occasionally, permanent neurologic deficits or death occurs. In addition to a prolonged incubation period and the migratory nature of the disease, another pathognomonic feature of gnathostomiasis is a radiculomyelitis felt due to larvae migrating to the spinal cord via spinal nerves [144, 145]. Baylisascaris procyonis is a roundworm that infects raccoons found predominantly throughout the U.S., particularly in the Midwest, Northeast, and the West Coast. Few human cases of B. procyonis have been described in the literature. Of those described, consumption of soil, most often by children, in which infected raccoon feces are present may subsequently result in EM. Following a few weeks incubation period, neurotropic larvae migrate to the CNS, where they mature to adulthood [146]. Treatment includes albendazole and supportive management [147–152]. Other parasites may also be associated with EM, including schistosomiasis involving the cerebrum and spinal cord (Schistosoma japonicum infection in particular), toxocariasis (Toxocara canis or Toxocara catis), trichinellosis (Trichinella spiralis ), neurocysticercosis (Taenia solium ), fascioliasis (Fasciola hepatica ), and paragonimiasis (Paragonimus westermani). These parasitic infections are discussed in other sections. The best methods for preventing and controlling local outbreaks of helminthic causes of EM include dissemination of regional endemic disease risks, education on proper food washing and cooking, and reducing risk factors for fecal–oral transmission. Physicians should be cognizant of the possible causes of EM not only in those traveling from endemic regions, but also in those individuals who have been in countries in which infectious pathogens exist via transport.

Special Considerations in Immunocompromised Travelers Early and thorough pretravel preparation is particularly important for immunocompromised travelers, including HIVpositive patients with CD4 counts under 500, pharmacologically immunosuppressed patients such as those with solid organ transplants or chronic corticosteroid therapy, and patients with malignancy, poorly controlled diabetes mellitus, or other chronic illnesses. In addition to increased susceptibility to common infections, physicians and patients should be aware of the risks for unique infections with neurological consequences. Several diseases of particular concern are discussed below. Tuberculosis (TB) of the CNS occurs in approximately 1 % of infections overall, but patients who are immunocompromised are at increased risk; HIV-positive patients, in particular, carry a fivefold increased risk of developing CNS TB, including meningitis, intracranial abscess, and

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tuberculoma [153]. Treatment of TB in HIV-positive or transplant patients is complicated by adverse drug interactions between antimycobacterial antibiotics and antiretrovirals or immunosuppressant medications [153]. Rifampin significantly lowers the concentrations of most protease inhibitors used to treat HIV [154]. IRIS-related TB meningitis has been described as a potential complication of treatment in both HIV and transplant patients [155]. Multiple reports have also implicated HIV as a risk factor for acquiring MDR TB, whose treatment presents additional challenges [156]. Most increased TB risk in patients on anti-TNF-alpha drugs such as adalimumab is attributed to reactivation of latent TB infection, and there exist case reports of neurological consequences of this disease [157]. Serious new infection has been sporadically reported in patients on these medications; however, in general, patients should be advised of long-term, rather than acute, risk of active TB contracted while abroad [157]. Toxoplasma gondii is a parasitic infection of particular concern in immunocompromised patients. This protozoan is typically ingested in infected undercooked meat, other foods, or contaminated water [158]. It can cause severe and often fatal meningoencephalitis in immunocompromised hosts, including those on immunosuppressive medication regimens [158]. Seroprevalence is generally high in Europe, but there is a high burden of disease across South America (particularly Venezuela and Brazil [159]), Africa (particularly Tanzania and the Sudan [159]), the Middle East, and southern Asia, and particularly vigorous outbreaks have been recently reported in Brazil [160]. Immunocompromised travelers are also uniquely susceptible to fungal diseases, with known neurological complications. This includes Cryptococcus neoformans or Cryptococcus gattii infection, which is particularly common in Botswana [161]. Immunocompromised patients, particularly those on prolonged steroid therapy, have constituted a significant proportion of patients in recent outbreaks of C. gattii, which is more often lethal in immunocompromised patients as well [161]. Pretravel Recommendations in Immunocompromised Patients While live vaccinations are contraindicated in immunocompromised patients, there are a number of vaccines strongly recommended for the immunosuppressed individual. Patients should refer to the CDC travel medicine Web site for recommendations (http://wwwnc.cdc.gov/travel/yellowbook/ 2012/chapter-8-advising-travelers-with-specific-needs/ immunocompromised-travelers) and discuss vaccination at least 3–6 months prior to travel with an infectious disease physician with expertise in travel medicine. Asplenic patients, in particular, should be vaccinated against encapsulated organisms, including H. influenzae . Physicians may also provide prophylactic prescriptions of common antibiotics, to be used, if necessary, in areas where medications may not be reliably obtained. Finally, patients should be educated on safe

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travel with crucial medications, including keeping medications on hand at all times and refraining from packing them in checked baggage. Despite the above measures, there are points at which a patient should be strongly advised against traveling unless absolutely necessary. These include periods immediately postchemotherapy or postradiation, the first 3– 6 months after organ transplantation, and periods during or immediately following other active infection [162]. HIVpositive patients with unstable CD4 counts or CD4 counts under 500 ug/mL are at increased risk of disease and should be advised to postpone travel [163]. HIV-positive travelers, in particular, should also recognize that there are a number of countries with entry and/or residency restrictions related to HIV status, including countries of the Eastern Mediterranean and Australia [164], and plan travel accordingly.

Conclusion As travel to worldwide destinations becomes more accessible, neurologists must be aware of typical and atypical presentations of infectious diseases that may be acquired abroad. Patients should be advised to seek care from a travel medicine physician at least 6 months prior to traveling. The CDC (cdc.gov/travel) and U.S. Department of State (state.gov/travel) Web sites have important updates on current communicable and noncommunicable diseases worldwide, and both clinicians and patients should routinely check these Web sites prior to travel for up-to-date information. If a patient returns home with neurologic symptoms, history should be obtained from the patient, as well as fellow travelers, on exposures, sick contacts, exotic travel, and so on, and a thorough investigation should be obtained while treatment is rapidly initiated for conditions endemic to the region traveled. Compliance with Ethics Guidelines Conflict of Interest Hannah Kirsch, Kiran T Thakur, and Gretchen Birbeck declare that they have no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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