Neurologic Infections in Travelers

Malveeka Sharma, MD, MPH; Joseph R. Zunt, MD, MPH

Semin Neurol. 2019;39(3):399-414.

Zika Virus

Epidemiology

Zika virus belongs to the Flavivirus genus and is transmitted through the bite of an infected Aedes mosquito.^[49] Zika virus was first identified in 1947 in monkeys living in the Zika Forest of Uganda. Since 2007, outbreaks have occurred in Southeast Asia and the Western Pacific. In 2015, a large outbreak in Brazil marked the first occurrence in the Western Hemisphere; the introduction of the virus hypothesized to have occurred during the 2014 soccer World Cup or the 2014 World Spring Canoe championship.^[50] Transmission has now been identified via intrauterine, perinatal, and sexual routes, as well as through laboratory errors and contaminated transfusions.^[51]

Life Cycle, Ecology, and Species

Zika virus is a single-stranded RNA virus in the genus Flavivirus. The main vector is the Aedes mosquito.

Clinical Manifestations

Most symptomatic Zika virus infections present with a nonspecific mild febrile illness such as fever, arthralgia, myalgia, headache, and maculopapular rash, but 80% of infections are asymptomatic.^[50,51] Zika has been associated with severe congenital disease, specifically microcephaly. The neurological manifestations of Zika include virus-associated myelitis, encephalitis, meningoencephalitis, GBS, and acute disseminated encephalomyelitis.^[49] The most common manifestation is GBS. It has been postulated that prior infection with dengue or chikungunya may promote or be necessary to lead to the development of Zika immune-mediated GBS.^[52]

Diagnosis

Zika virus infection should be suspected in patients who live in or have recently traveled through endemic regions within 2 weeks of the onset of symptoms. Because of high rates of co-infection, evaluation for other flaviviruses should also be assessed at the time of diagnosis. CSF assays are available to detect viral RNA or antibodies.^[49] Due to the transient nature of viremia, real-time reverse transcription PCR (rRT-PCR) of the Zika virus can be detected in serum <7 days after onset of symptoms, but viremia persists in urine up to 14 days after onset of symptoms.^[51] Detection of serum IgM antibodies or a significant rise in IgG in samples collected 2 weeks apart can support the diagnosis as well. Another confirmatory test includes the plaque reduction neutralization test, which can discriminate anti-Zika virus antibodies from other cross-reacting antibodies.^[53] For evaluation of neurological manifestations, electromyography and nerve conduction studies should demonstrate a typical pattern to confirm GBS.

Treatment

As there is no specific treatment for Zika virus infection, supportive management is the mainstay of treatment.^[51] For patients with GBS manifestations, close monitoring of respiratory and cardiac systems in intensive care settings and the use of plasmapheresis or IV immunoglobulins should be used.^[54] Pregnant patients diagnosed with Zika virus infection should be educated and monitored for adverse outcomes.^[51] There is no vaccine or postexposure prophylaxis available. Vector control and personal protective measures are the best ways to prevent infection.^[51]

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Table 1. Neurologic infectious diseases in international travelers categorized by geographic regions
Africa
North Africa	Central, East, and West Africa	South Africa
Malaria	African sleeping sickness	Crimean–Congo hemorrhagic fever
West Nile fever	Typhus	Tick-bite fever
Rift Valley fever	Plague	Chikungunya virus
Dengue	Viral hemorrhagic fever (Ebola, Marburg)	African sleeping sickness
Leishmaniasis	Yellow fever	Leishmaniasis
Schistosomiasis	Meningococcal meningitis	Malaria
Poliomyelitis	Chikungunya virus	Schistosomiasis
	Leishmaniasis
	Malaria
	Poliomyelitis
Americas
North America	Central America	Tropical South America	Temperate South America
Lyme disease	Malaria	Neurocysticercosis	Chagas disease
Rocky Mountain spotted fever	Dengue	Malaria	Malaria
Tularemia	Schistosomiasis	Yellow fever	Rabies
Arthropod-borne encephalitis	Rabies	Viral encephalitis	Anthrax
West Nile virus	Chikungunya virus	Dengue	Epidemic meningococcal meningitis
Zika virus		Schistosomiasis	Chikungunya virus
Chikungunya virus		Brucellosis	Zika
Enterovirus 71		Rabies
Toxoplasmosis		Zika
		Chikungunya virus
Asia
East Asia	Southeast Asia	India, West Central Asia	Middle East
Malaria	Malaria	Malaria	West Nile virus
Plague	Dengue	Dengue	Meningococcal meningitis
Dengue	Nipah virus	Japanese encephalitis	Crimean–Congo hemorrhagic fever
Japanese encephalitis	Japanese encephalitis	Crimean–Congo hemorrhagic fever	Typhoid
Schistosomiasis	Plague	Poliomyelitis	Schistosomiasis
Brucellosis	Typhoid	Tick-borne hemorrhagic fevers
Leptospirosis	Chikungunya virus	Chikungunya virus
Rabies	Rabies
Meningococcal encephalitis
Europe
Tick-borne typhus
Tick-borne encephalitis
Lyme disease
West Nile virus
Chikungunya virus
Oceania
Mosquito-borne viral encephalitis
Rabies
Malaria
Dengue
Chikungunya virus
Nipah virus

Source: Adapted with permission from Han MH, Zunt JR. Neurologic aspects of infections in international travelers. Neurologist 2005;11(1): 30–44.

Table 2. Select parasitic infection CNS manifestations, common neuroimaging findings, and prevention
	Neurologic presentation	Common neuroimaging findings	Treatment
Schistosomiasis	Cauda equina or conus medullaris syndrome, transverse myelitis, encephalopathy ± focal neurological deficits	Solitary or multiple hyperdense lesions in brain or spinal cord	Schistosomiasis lesions that are edematous, especially when associated with neurologic deficits, or in the spinal cord, should be treated with steroids prior to starting anthelminthics, to avoid producing additional impairment with treatment. Praziquantel 40 mg/kg/d for 3 d (S. mansoni, S. haematobium) to 60 mg/kg/d for 6 d (S. japonicum). OR Oxamniquine is an option for S. mansoni infection.
African trypanosomiasis (sleeping sickness)	Neuropsychiatric, sleep disorder, meningoencephalitis, myelopathy, movement disorder	Diffuse hyperintensity in the basal ganglia bilaterally on T1-weighted MR images in deep gray matter, internal capsule	Melarsoprol 2–3.6 mg/kg/d IV × 3 d. After 7 d, 3.6 mg/kg/d × 3 d. Give a third series of 3.6 mg/kg/d after 7 d. OR Eflornithine 400 mg/kg/d in four doses × 14 d.
American trypanosomiasis (Chagas)	Stroke, meningoencephalitis, encephalopathy, neuropathy	Large solitary or multiple ring-enhancing lesions with surrounding edema	Benznidazole 5 mg/kg/d in BID dosing for 60 d, or nifurtimox 10 mg/kg/d in TID or QID dosing for 120 d. IV tPA okay for acute stroke.
Cerebral malaria	Coma, cerebral edema, and status epilepticus	Cerebral swelling, cortical infarcts, and hyperintensities in white matter, all of which are nonspecific	Artesunate: two 2.4 mg/kg doses given intravenously 12 h apart on day 1, then 2.4 mg/kg daily for 6 additional days. Options include: artemether, quinine, quinidine gluconate.

Abbreviations: BID, two times a day; CNS, central nervous system. IV, intravenous;MR, magnetic resonance; QID, four times a day; TID, three times a day; tPA, tissue plasminogen activator.

Table 3. Select bacterial infection neurologic presentation, diagnosis, treatment, and prevention
	Neurologic presentation	Diagnostics	Treatment	Prevention
Meningococcal meningitis	Acute: meningitis Chronic: learning disabilities, hearing impairment, behavioral issues, and chronic headaches	CSF culture, PCR, or latex agglutination assay.	Ceftriaxone IV 2 g every 12 h OR Penicillin G IV 4 million units every 4 h OR Chloramphenicol IV 50–100 mg/kg/d divided doses every 6 h Duration: 5–7 d	Chemoprophylaxis: close contacts with rifampin or ceftriaxone. Vaccination: multiple available
Scrub typhus	Meningitis, encephalitis, cranial nerve palsy, cerebellitis, stroke due to vasculitis, central venous thrombosis, parkinsonism, transverse myelitis, AIDP, neuropathy, and psychiatric manifestation	Indirect immunofluorescence assay (gold standard). Other options include ELISA, Weil–Felix testing	Tetracycline, doxycycline, azithromycin, or rifampicin	Chemoprophylaxis: doxycycline weekly (based on one study) Vaccination: none available.
Leptospirosis	Most common: aseptic meningitis Less common: facial palsy, Guillain–Barre syndrome, myeloradiculopathy, myelopathy, encephalitis, meningoencephalitis, intracranial hemorrhage (commonly subarachnoid or extradural), movement disorder, mononeuritis, polyneuritis, and polymyositis	Microscopic agglutination test (gold standard). Other options include ELISA, next-generation sequencing.	Penicillin, doxycycline, or ceftriaxone	Chemoprophylaxis: doxycycline weekly (based on two studies) Vaccination: none available.
Brucellosis	Encephalitis, meningoencephalitis, abscess formation, radiculitis, myelitis, peripheral and cranial neuropathies, subarachnoid hemorrhage, and neuropsychiatric issues	Culture from serum, bone marrow, CSF, or liver. Other options: serum agglutination and ELISA.	Combination of doxycycline, rifampicin, or ceftriaxone for 12 wk	Chemoprophylaxis: none Vaccination: available in China and Russia

Abbreviations: AIDP, acute inflammatory demyelinating polyneuropathy; CSF, cerebrospinal fluid; IV, intravenous; ELISA, enzyme-linked immunosorbent assay; PCR, polymerase chain reaction.

Table 4. Select viral infection CNS manifestations, treatment, and prevention
	Genus	Endemic regions	Neurologic presentation	Case fatality	Treatment	Prevention
Zika virus	Flavivirus	Africa, Southeast Asia, Western Pacific, Central and South America	Ascending paralysis (GBS). Less common: myelitis, encephalitis, meningoencephalitis	Unknown for neurological disease	Supportive. GBS can use IVIg or plasmapheresis	No vaccine available. Vector control
West Nile virus	Flavivirus	Africa, Europe, the Middle East, North America, and West Asia	Meningitis, encephalitis, and acute flaccid paralysis	7–9% (neuroinvasive disease)	Supportive. No benefit but trialed polyclonal immune globulin, monoclonal immune globulin, interferon, ribavirin, and corticosteroids	No approved vaccine available. Multiple in trials. Vector control
Japanese encephalitis	Flavivirus	Southeast Asia and Western Pacific	Parkinsonian features with masked facies, tremor, cogwheel rigidity, and choreoathetoid movements. Less common: meningoencephalitis, acute flaccid paralysis, cranial nerve palsies, and seizures.	30%	Supportive	Ixiaro Vero cell culture vaccine (Valneva) for U.S. travelers. SA-14–14–2 JE vaccine (Chengdu Institute of Biological Products), vector control
Rabies	Lyssavirus	Over 150 countries, mainly Africa and Asia	Encephalitis (most common) or flaccid paralysis	~100%	No curative treatment has been identified. Extensive wound washing, human rabies immune globulin within 0–3 d of exposure with vaccine. Tested ribavirin, amantadine, interferon-alfa, and favipiravir	Vaccine available (inactivated)
Poliomyelitis	Enterovirus	Nigeria, Pakistan, and Afghanistan	Acute flaccid paralysis (most common), meningitis	5–10% (with paralysis)	Supportive	Vaccine available (oral live attenuated and inactivated)

Abbreviations: CNS, central nervous system; GBS, Guillain–Barré syndrome; IVIg, intravenous immunoglobulin.

Table 5. Select VHF CNS manifestations, treatment, and prevention
	Genus	Neurologic Presentation	Mechanism of CNS disease	Treatment	Prevention
Ebola	Filovirus	Encephalopathy, acute meningitis, meningoencephalitis with cranial neuropathies, and radiculopathy	Metabolic derangements, immune-mediated, and neurocytopathic	Supportive. Human monoclonal antibodies and novel experimental drugs	rVSV-ZEBOV vaccine currently in late-stage clinical trials in Africa.
Lassa fever	Arenavirus	Aseptic meningitis, sensorineural deafness, encephalitis, encephalopathy, ataxia, subacute and chronic neuropsychiatric syndromes	Metabolic derangements, direct neurocytopathic, and immunologic.	Supportive. Ribavirin	LASSARAB (inactivated) developed but not approved for human use
Crimean–Congo hemorrhagic fever	Bunyavirus	Meningitis, confusion, irritability, mood swings, lassitude, and depression	Metabolic derangements related to renal and liver failure	Supportive. Ribavirin	No vaccines currently approved.
Rift Valley fever	Bunyavirus	Ocular disease, meningoencephalitis, or hemorrhagic fever	Direct spread to CNS either via the olfactory bulb or GI tract.	Supportive	Multiple inactivated and live vaccines available, however none are licensed for use
Argentine hemorrhagic fever	Arenavirus	Tremor of tongue and upper extremities, cerebellar signs, and confusion.	Immune-mediated	Supportive. Ribavirin, convalescent serum	Candid #1 vaccine (live attenuated)
Omsk hemorrhagic fever	Flavivirus	Headache, meningitis, hearing loss, neuropsychiatric syndromes	Neurocytopathic	Supportive	No vaccine available

Abbreviations: CNS, central nervous system; GI, gastrointestinal; VHF, viral hemorrhagic fever.

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Neurologic Infections in Travelers

Zika Virus

Epidemiology

Life Cycle, Ecology, and Species

Clinical Manifestations

Diagnosis

Treatment

Tables

Tables

Tables

Tables

Tables

References

Authors and Disclosures

Authors and Disclosures

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