Introduction
Since the advent of West Nile virus twenty years ago, there has been increased interest in numerous mosquito-borne encephalitis viruses, which some medical researchers collectively call the “encephalitides.” There are dozens of these arboviruses that have potential to infect people in the United States, but only about three of them are common in Mississippi. Each may have unique animal hosts in nature, mosquito vectors, and relative severity of illness in humans. For example, some encephalitis viruses are associated with mortality rates of less than 1%, while others may exceed 50%. Accordingly, it is important for physicians to be aware of the encephalitides and their associated clinical pictures and potential outcomes.
West Nile Virus (WNV). West Nile virus (WNV) was first detected in the Western Hemisphere in 1999 in New York City.1,2 Over the next 5 years, WNV spread across the continental U.S. as well as north into Canada, and southward into the Caribbean Islands. In Mississippi, there are usually about 10-50 WNV cases reported each year, but 2012 was an especially bad year, with 247 cases. Approximately 80% of all WNV infections are asymptomatic and 20% cause West Nile fever, and less than 1% cause West Nile neuroinvasive disease.3 WNV is a bird disease, and is transmitted by mosquitoes in the genus Culex. Although the virus has been isolated from at least 64 U.S. mosquito species, the main vectors are believed to be Culex pipiens, Cx. quinquefasciatus, Cx. salinarius, Cx. restuans, and Cx. Tarsalis.2,4,5
Eastern Equine Encephalitis (EEE). Of the all the North American mosquito-borne encephalitis viruses, the one causing EEE is the worst. EEE is a severe disease of horses and humans having a mortality rate of 30–60%. Although some cases may be asymptomatic, most are characterized by acute onset of headache, high fever, meningeal signs, stupor, disorientation, coma, spasticity, tremors, and convulsions.6,7 The disease is especially severe in children. EEE occurs in the central and northcentral United States, and especially along the Atlantic and Gulf Coasts (although cases occasionally occur several hundred miles inland8). In Mississippi, human cases are rare (1-3 cases per decade). EEE is seasonal; in the southernmost areas of the virus range, human cases may occur year-round, but are concentrated between May and August. EEE virus is sustained in freshwater swamps in a cycle involving birds and mosquitoes with the main enzootic vector being Culiseta melanura, which rarely bites humans or horses. Epidemics in horses and humans occur when prevalence of the virus in bird populations becomes high and other mosquito species become involved, such as Aedes sollicitans and Ae. taeniorhynchus on the coast, and Coquillettidia perturbans and perhaps Culex erraticus inland.
LaCrosse Encephalitis (LAC). LaCrosse encephalitis historically has affected children in the Midwestern states of Ohio, Indiana, Minnesota, and Wisconsin, and other states such as West Virginia. More recently, serological and epidemiological studies in North Carolina, Georgia, Tennessee, Mississippi, Virginia, and Florida have indicated that LAC is increasing in those states also, but not to the extent that it currently occurs in the midwestern United States. There were 4 cases of LAC reported from Mississippi during the 10-yr period, 2011-2020.9 The mortality rate of LAC is <1%, but seizure disorder may follow LAC infection. In nature, amplification of the virus takes place in an Aedes triseriatus-small mammal cycle.
Below are two cases the author helped investigate during his 40+ year career as a medical entomologist. Readers are challenged to decide which encephalitis virus was involved in each case. While diagnostic decisions may be hampered by lack of additional or specific laboratory findings, other clues-such as age of the patient, relative severity of illness, clinical presentation, and mosquito species collected, are discussed in the case histories. After the cases, a brief summary is provided of diagnosis, treatment, and presentation of these mosquito-borne encephalitis viruses.
Case 1
An eleven-year-old Native American male presented to the local emergency department in rural Mississippi during the summer season with fever and diarrhea (temperature of 39.4°C [103°F]). Gastroenteritis had been reported in his community at the time. He was given symptomatic treatment, and his condition improved until the night before admission, when he complained of headache, stomachache, and decreased appetite. He went to bed early, which was unusual for him. The next morning, he went with his family to a scheduled ophthalmologic examination and slept during most of the 1-hour drive. He was drowsy and nauseated upon arrival at the clinic, soon turned pale, and began generalized tonic clonic seizure activity. He was taken to the ED and given a loading dose of phenytoin, then transferred to the admitting hospital.
On admission, the patient was responsive but lethargic. Admission temperature was 39°C (102.2°F). Laboratory findings included a WBC count of 19,500/uL, with 59% neutrophils, 19% band forms, and 16% lymphocytes. The hematocrit was 34.4%, and the serum glucose level was 184 mg/dL. CSF examination revealed a WBC count of 980/μL, with 91% neutrophils; no organisms on Gram stain; a negative latex agglutination test; a protein level of 68 mg/dL; and a glucose level of 105 mg/dL. Additional blood, CSF, and stool cultures were obtained. The patient was given cefotaxime and phenytoin. He remained febrile, with temperatures reaching 40.6°C (105°F), but became more responsive and ambulatory by the second day after admission. At approximately 2 PM on hospital day 6, the patient experienced another seizure, with eye deviation to the right and head turning to the right. A CT scan showed enhancement of the cisterna but only mildly increased intracranial pressure. Respirations became irregular, and the patient was electively intubated and hyperventilated. Treatment with streptomycin, pyrazinamide, and isoniazid was started for possible tuberculosis, and acyclovir was given for possible CNS herpesvirus infection. His condition deteriorated rapidly over the next 24 hours, showing no evidence of brain stem function. A lumbar puncture was performed for viral studies, since no bacterial cultures were growing. He was taken off the ventilator the evening of hospital day 7. At autopsy, cerebral edema was evident but meninges were relatively clear.
Confirmation of infection with one of the mosquito-borne encephalitis viruses was made by CDC scientists at Fort Collins, Colorado; 2 separate serum samples indicated a 4-fold rise in hemagglutination inhibition antibody to the virus, and enzyme-linked immunosorbent assay showed the presence of specific IgM. Mosquito species collected around the home included Aedes albopictus, Anopheles crucians, and Coquillettidia perturbans.
Case 2
In June, a previously healthy infant was brought to an emergency department with a several-hour history of fever (maximum temperature 38.7°C [101.6°F]). He was experiencing a focal seizure characterized by uncontrollable blinking of the left eye, twitching of the left side of the mouth, and random tongue movement. In the ED, seizures continued intermittently despite administration of diazepam and lorazepam. The infant was admitted to the hospital, and treatment initiated with phenytoin.
Examination of cerebrospinal fluid (CSF) on admission showed 294 white blood cells (WBCs)/ul, with 47% polymorphonuclear leukocytes, 41% histiocytes, and 12% lymphocytes, and 3 red blood cells (RBCs)/uL. Protein and glucose levels were normal. A CT scan was read as normal. Therapy with acyclovir was initiated due to possibility of herpes encephalitis, and cefotaxime and vancomycin were started to cover possible bacterial infection. The seizures stopped; intravenous phenytoin was discontinued, and treatment with oral phenobarbital was started.
Focal seizures progressed to generalized tonic clonic seizures on hospital day 4, although a therapeutic blood level of phenobarbital had been achieved. After another CT scan, which read as normal, the child was transferred to a different hospital. On admission, the infant was noted to have continuous seizure like movements of the chin and face. A lumbar puncture this time revealed 307 WBCs/µL, with 33% polymorphonuclear leukocytes, 29% lymphocytes, and 38% histiocytes; 812 RBCs/µL, a protein level of 104 mg/dL, and a glucose level of 74 mg/dL. Treatment with acyclovir, cefotaxime, and vancomycin was continued. The patient was intubated because of excessive secretions and to avoid respiratory compromise. He was again treated with lorazepam, and phenytoin was restarted. Seizure activity ended. The patient continued to be intermittently febrile and was extubated on the sixth continuous hospital day.
PCR for herpesvirus from admission samples was negative. In addition, admission blood, urine, and CSF culture results were negative, and on the ninth hospital day, cefotaxime and vancomycin were discontinued. The patient’s maximum temperature on that day was 37.8°C (100.1°F), and he was becoming more alert and playful. He subsequently became and remained afebrile, without seizure activity, so he was transferred back to the original hospital on hospital day 12 for completion of 21 days of intravenous acyclovir. On day 21, he was discharged home on a regimen of oral phenytoin. He had some residual left-sided weakness requiring a few weeks of physical therapy. A CSF sample was sent to a reference laboratory for testing for antibodies to various encephalitis agents, including herpesviruses and arboviruses. Results showed an indirect fluorescent antibody titer of 1:8 to a mosquito-borne encephalitis virus. Serum was sent to the CDC for confirmation, which showed presence of IgM antibody to that same virus. Mosquito collections at the patient’s home revealed Culex restuans, Culex salinarius, Aedes albopictus, Aedes triseriatus, Anopheles crucians, and Anopheles quadrimaculatus.
Which mosquito-borne encephalitis viruses were involved in these two cases?
(answers at end of article, after references)
Diagnosis, management, and mosquito control
Arboviral infections can mimic many diseases and therefore differentiation must be made from post-vaccinal or post-infectious encephalitis; tick-borne encephalitis (not common in the United States); rabies; nonparalytic polio; mumps; meningoencephalitis; aseptic meningitis caused by enteroviruses; herpes encephalitis; various bacterial, mycoplasmal, protozoan, leptospiral, and mycotic meningitides or encephalitides; and other infections. Any cases of encephalitis in late summer should especially be suspect as mosquito-borne. Specific identification is usually made (sometimes with help from the CDC in Fort Collins) by PCR, or finding specific IgM antibody in serum or CSF samples taken during the acute phase of the infection, or by detecting antibody rises between early and late serum samples. Serologic identification of a particular virus can be complicated due to cross-reactivity with heterologous viruses of the same group. If available, PCR analysis is much more accurate.
Treatment of mosquito-borne encephalitis is supportive only. Management of seizures (if present) begins with support of an adequate airway and hemodynamic support. Prolonged convulsions require aggressive treatment. Since there is no specific treatment of arboviral infection, control of outbreaks relies solely on personal protective measures against mosquitoes and insecticidal spraying. Virus transmission can be interrupted if enough adult mosquitoes are killed. Elimination of mosquito breeding sites such as standing water can also reduce number of encephalitis cases in an area. An environmental survey of the area by a health department inspector or entomologist in places where cases are occurring may lead to further, more specific, prevention recommendations.
Use of personal protection techniques against mosquitoes and insect repellents in and around locations where encephalitis cases have occurred may prevent additional infections (Figure 1). For example, one study demonstrated that persons practicing two or more personal protective measures, including repellents, reduced their risk of West Nile virus infection by half.10 DEET (N, N-diethyl-3-methylbenzamide) is one of the most effective and widely used insect repellents available,11 providing protection from a variety of mosquitoes, chiggers, ticks, fleas, and biting flies. There have been a few reports of systemic reactions from repeated cutaneous exposure to DEET, but most of these resulted from misuse or over-application. A relatively new repellent called Picaridin is an effective alternative to DEET products that provides long-lasting protection against mosquito bites. For those looking for “green” or botanical repellents, the CDC lists on their website oil of lemon eucalyptus as an alternative to DEET.