Eastern Equine Encephalitis Presenting with a Focal Brain Lesion Richard P. Morse, MD*, Michael L. Bennish, MDt, and Basil T. Darras, MD*
Eastern equine encephalitis (EEE) virus causes a severe meningoencephaiitis with high morbidity and mortality. Despite numerous clinical reports of EEE, there are only 11 patients in whom cranial computed tomographic (CT) findings are described. In 6 patients, CT was normal and in 5 patients diffuse edema was present; none had a focal brain lesion. Based on these reports, it has been suggested that focal findings on CT support the diagnosis of herpes simplex encephalitis rather than EEE. The first patient with serologically-confirmed EEE and a focal lesion demonstrated by cranial CT and magnetic resonance imaging is described; these f'mdings underscore the importance of including EEE in the differential diagnosis of encephalitides that can cause focal brain lesions on neuroimaging. Morse RP, Bennish ML, Darras BT. Eastern equine encephalitis presenting with a focal brain lesion. Pediatr Neurol 1992;8:473-5.
Introduction Eastern equine encephalitis (EEE) virus causes severe meningoencephalitis with a reported mortality rate of 30% in symptomatic patients of all ages and a reported mortality rate of up to 75% in affected children [1-15]. Those who survive often have significant morbidity. EEE most often occurs in widely-spaced epidemics along the eastern seaboard of the United States and in isolated pockets in Michigan and upper New York state. Following recognition of the disease in horses in 1933, the first human cases were reported in Massachusetts in 1938 [2,3]. Since then, there have been 4 additional epidemics
From the Department of Pediatrics, Divisions of *Pediatric Neurology and tPediatric Infectious Diseases; Floating Hospital for Infants and Children; New England Medical Center Hospitals and Tufts University School of Medicine; Boston, Massachusetts.
in Massachusetts (1955 to 1956, 1972 to 1974, 1982 to 1984) and most recently in 1990 in which three human cases were reported. Numerous clinical descriptions of the presentation and features of EEE infection have been published [2-11] and more recently the neuroradiologic features have been reported [9,15]. In 11 previously reported patients in whom cranial computed tomography (CT) was performed, none had a focal lesion [6,9]. In this report, we present a patient with EEE found to have a focal lesion on CT and magnetic resonance imaging (MRI). This patient was the index case in the 1990 Massachusetts epidemic.
Case Report This previously healthy 71/2-year-old boy from Plymouth County, Massachusetts, developed low-grade fever, nausea, and mild headache. Over the next 4 days, lethargy, anorexia, and headache persisted; he developed a fever of 40.6°C, had 2 brief, generalized clonic seizures, and was admitted to a local hospital. On initial examination, he had marked nuchal rigidity and Kemig and Brudziuski signs were present. He was lethargic and disoriented with a nonfocal elemental neurologic examination. Cerebrospinal fluid (CSF) contained 494 leukocytes with 70% polymorphonuclear cells and 30% lymphocytes, 34 erythrocytes, glucose 3.5 mmol/L, and protein 4.9 gm/L. Peripheral leukocyte measurement was 14,400 and blood glucose concentration 5.8 mmol/L (104 mg/dl). Ceftriaxone and phenobarbital were administered. Over the ensuing 48 hours the lethargy worsened and urinary incontinence developed. Contrast-enhanced CT was interpreted to demonstrate a right frontal rim-enhancing lesion and mild, diffuse edema (Fig 1). He was transferred to the New England Medical Center for further care. Bacterial cultures of the CSF and blood taken before the administration of antibiotics remained sterile. On admission to the New England Medical Center his examination was unchanged. Acyclovir was added to his medications. Over the next 2 days, his neurologic condition further deteriorated. He developed increased tone in the left leg, with sustained clonus at the knee and ankle and a Babinski sign on the left. No further seizures occurred. Serum antibody titer to EEE virus, measured using an immunofluorescent antibody assay, and performed at the Massachusetts State Laboratories 4 days after the onset of severe symptoms, was < 1:10, which was considered to be a negative result. Cranial MRI with gadolinium was obtained and revealed a nonenhancing fight frontal lesion and no evidence of the diffuse brain swelling observed on CT (Fig 2). Electroencephalography (EEG) demonstrated diffuse slowing and periodic lateralizing epileptiform discharges (PLEDs) over the corresponding right frontal area. A second serum anti-EEE titer sent on hospital day 8 was 1:180, which was considered to be positive for EEE infection. Over the next l0 days he had substantial resolution of mental clouding. His left leg remained paretic but he was able to walk independently at the time of transfer to a rehabilitation center. Prior to discharge, a repeated cranial MRI disclosed marked improvement of the frontal lesion. EEG, although improved, continued to document right frontal PLEDs and mild background slowing. Neuropsychologic testing demonstrated deficits in sequencing skills (both auditory and visual), memory, attention, and visuospatial reasoning tasks, which represented a significant decline in overall cognitive function when compared to a premorbid evaluation performed one month earlier for evaluation of an attention deficit disorder.
Communications should be addressed to: Dr. Darras; Department of Pediatrics; #309; New England Medical Center Hospitals; 750 Washington Street; Boston, MA 02111. Received March 5, 1992; accepted May l, 1992.
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Figure 1. Contrast-enhanced CT revealing a right frontal rim-enhancing hypodensity on day 7 of illness.
He was transferred to a rehabilitation hospital where he remained for 2 months, requiring intensive cognitive rehabilitation for poorly controlled emotional outbursts and violent tendencies. He did not improve enough to return home and was placed in a psychiatric residential hospital where slow improvement has occurred. General neurologic examination now is normal. Discussion
Human cases of EEE continue to occur in epidemic fashion in specific geographic foci in Massachusetts and other states, and in sporadic fashion in Florida and parts
of southern Georgia. The median number of patients per year in the United States is 5. In 1990, there were 3 patients in Massachusetts, including our patient /I fatal, 2 survivors), one in South Carolina, and a presumptive patient in North Carolina [ 121. Clinical descriptions of patients during the acute phase of EEE infection and also in survivors have included focal abnormalities (e.g., hemiplegia, quadriplegia, aphasia, emotional instability) which suggest selective, focal areas of brain damage [3-11]. Pathologic examination of the brain in acute fatal cases has disclosed disseminated and focal encephalomyelitis, characterized by diffuse softening, vascular engorgement, perivascular cuffing, and parenchymatous polymorphonuclear and lymphocytic cellular infiltrates. Focal areas of neuronal cell death in the hippocampal formation, basal ganglia, pons, and frontal and occipital lobes have been described [ 1,7,10,11 ]. In survivors of the acute phase severe cystic changes with large, patchy areas of necrosis were reported [ 1 I. Few case descriptions of EEE have included neuroimaging studies. We found 11 patients in whom CT resuits were reported. Six of 11 CT scans were normal and 5 revealed diffuse edema; none described a focal brain lesion [6,9]. This surprising lack of focality contrasts sharply with both clinical and pathologic data and with the findings in our patient. The lesion in our patient had resolved nearly completely by the time of the second cranial MRI, performed 6 days later. We suggest that focal areas of transient, intense inflammation may escape detection depending on the timing of the scan with the stage of infection and whether a contrast agent is used. Recent reviews of experience with EEE emphasize the absence of focal findings as characteristic of the CT appearance [9,15]. It has been suggested that focal findings on CT or EEG may help the clinician distinguish Herpes simplex virus encephalitis (HSE) from EEE [9,13,15]. In our patient, focal neuroimaging and EEG features led to a presumptive diagnosis of HSE. As reviewed by Whitley et al., many diseases mimic HSE and clinicians must entertain a wide differential diagnosis in evaluating patients with meningoencephalitis [14]; in the proper clinical setting it is important to consider EEE. Wider public health concerns underscore the importance of diagnosing EEE. In the 1990 epidemic, the appearance of a human patient helped to support the decision to implement an aerial spraying program to control the mosquito vector (Dr. Alfred DeMaria, Massachusetts Department of Public Health; personal communication). Surveillance programs, which monitor the prevalence of the virus among the mosquito population and the occurrence of equine cases, can help to alert clinicians to the likelihood of human cases. Detection of human cases remains dependent on the inclusion of EEE in the differential diagnosis of meningoencephalitis. References
Figure 2. T2-weighted cranial MR1, demonstrating a high-signal intensity right frontal lesion on day 9 of illness.
474 PEDIATRICNEUROLOGY Vol. 8 No. 6
[1] Baker AB. Viral encephalitis. In: Baker AB, ed. Clinical neurology. Hagerstown:Harper and Row, 1976:9-11.
[2] Fothergill LD, Dingle JH, Farber S, Connerly ML. Human encephalitis caused by the virus of the eastern variety of equine encephalomyelitis. N Engl J Med 1938;219:411. [3] Getting VA. Equine encephalomyelitis in Massachusetts: An analysis of the 1938 outbreak. N Engl J Med 1941;224:999-1006. [4] Farber S, Hill A, Connedy ML, Dingle JH. Encephalitis in infants and children caused by a virus of the eastern variety of equine encephalitis. JAMA 1940;114:1725-31. [5] Feemster RF. Equine encephalitis in Massachusetts. N Engl J Med 1957;257:701-4. [6] Davenport DS, Batts DH, Carter JW. Eastern equine encephalitis in Michigan. Arch Neurol 1982;39:322-3. [7] Ayres JC, Feemster RF. The sequelae of eastern equine encephalomyelitis. N Engl J Med 1949;240:960-2. [8] Levitt LE Lovejoy FH, Daniels JB. Eastern equine encephalitis in Massachusetts-First human case in 14 years. N Engl J Med 1971; 284:540-1. [9] Przelomski MM, O'Rourke E, Grady GE Berardi VE Markley HG. Eastern equine encephalitis in Massachusetts: A report of 16 cases, 1970-1984. Neurology 1988;38:736-9.
[10] Winter WD. Eastern equine encephalomyelitis in Massachusetts in 1955: Report of two cases in infants. N Engl J Med 1956;255: 262-70. [11] Bastian FO, Wende RD, Singer DB, Zeller RS. Eastern equine encephalomyelitis: Histopathologic and ultrastructural changes with isolation of the virus in a human case. Am J Clin Pathol 1975;64:10-3. [12] Bartnett RE, Sprenger DA, Pappas J, et al. Arboviral surveillance-United States, 1990. In: Goodman RA, ed. Morbidity and mortality weekly report. Atlanta: Centers for Disease Control, 1990;39:593-7. [13] Birch WE, Rubin DVM, Hlady WG, et al. Eastern equine encephalitis-Florida, Eastern United States, 1991. In: Goodman RA, ed. Morbidity and mortality weekly report. Atlanta: Centers for Disease Control, 1991;40:533-5. [14] Whitley RJ, Cobbs CG, Alford CA Jr, et al. Diseases that mimic herpes simplex encephalitis: Diagnosis, presentation, and outcome. JAMA 1989;262:234-9. [15] Tsal TF. Arboviral infections in the United States. Infect Dis Clin North Am 1991 ;5:73-102.
Morse et al: Eastern Equine Encephalitis 475
Eastern equine encephalitis (EEE) virus causes a severe meningoencephaiitis with high morbidity and mortality. Despite numerous clinical reports of EEE, there are only 11 patients in whom cranial computed tomographic (CT) findings are described. In 6 patients, CT was normal and in 5 patients diffuse edema was present; none had a focal brain lesion. Based on these reports, it has been suggested that focal findings on CT support the diagnosis of herpes simplex encephalitis rather than EEE. The first patient with serologically-confirmed EEE and a focal lesion demonstrated by cranial CT and magnetic resonance imaging is described; these f'mdings underscore the importance of including EEE in the differential diagnosis of encephalitides that can cause focal brain lesions on neuroimaging. Morse RP, Bennish ML, Darras BT. Eastern equine encephalitis presenting with a focal brain lesion. Pediatr Neurol 1992;8:473-5.
Introduction Eastern equine encephalitis (EEE) virus causes severe meningoencephalitis with a reported mortality rate of 30% in symptomatic patients of all ages and a reported mortality rate of up to 75% in affected children [1-15]. Those who survive often have significant morbidity. EEE most often occurs in widely-spaced epidemics along the eastern seaboard of the United States and in isolated pockets in Michigan and upper New York state. Following recognition of the disease in horses in 1933, the first human cases were reported in Massachusetts in 1938 [2,3]. Since then, there have been 4 additional epidemics
From the Department of Pediatrics, Divisions of *Pediatric Neurology and tPediatric Infectious Diseases; Floating Hospital for Infants and Children; New England Medical Center Hospitals and Tufts University School of Medicine; Boston, Massachusetts.
in Massachusetts (1955 to 1956, 1972 to 1974, 1982 to 1984) and most recently in 1990 in which three human cases were reported. Numerous clinical descriptions of the presentation and features of EEE infection have been published [2-11] and more recently the neuroradiologic features have been reported [9,15]. In 11 previously reported patients in whom cranial computed tomography (CT) was performed, none had a focal lesion [6,9]. In this report, we present a patient with EEE found to have a focal lesion on CT and magnetic resonance imaging (MRI). This patient was the index case in the 1990 Massachusetts epidemic.
Case Report This previously healthy 71/2-year-old boy from Plymouth County, Massachusetts, developed low-grade fever, nausea, and mild headache. Over the next 4 days, lethargy, anorexia, and headache persisted; he developed a fever of 40.6°C, had 2 brief, generalized clonic seizures, and was admitted to a local hospital. On initial examination, he had marked nuchal rigidity and Kemig and Brudziuski signs were present. He was lethargic and disoriented with a nonfocal elemental neurologic examination. Cerebrospinal fluid (CSF) contained 494 leukocytes with 70% polymorphonuclear cells and 30% lymphocytes, 34 erythrocytes, glucose 3.5 mmol/L, and protein 4.9 gm/L. Peripheral leukocyte measurement was 14,400 and blood glucose concentration 5.8 mmol/L (104 mg/dl). Ceftriaxone and phenobarbital were administered. Over the ensuing 48 hours the lethargy worsened and urinary incontinence developed. Contrast-enhanced CT was interpreted to demonstrate a right frontal rim-enhancing lesion and mild, diffuse edema (Fig 1). He was transferred to the New England Medical Center for further care. Bacterial cultures of the CSF and blood taken before the administration of antibiotics remained sterile. On admission to the New England Medical Center his examination was unchanged. Acyclovir was added to his medications. Over the next 2 days, his neurologic condition further deteriorated. He developed increased tone in the left leg, with sustained clonus at the knee and ankle and a Babinski sign on the left. No further seizures occurred. Serum antibody titer to EEE virus, measured using an immunofluorescent antibody assay, and performed at the Massachusetts State Laboratories 4 days after the onset of severe symptoms, was < 1:10, which was considered to be a negative result. Cranial MRI with gadolinium was obtained and revealed a nonenhancing fight frontal lesion and no evidence of the diffuse brain swelling observed on CT (Fig 2). Electroencephalography (EEG) demonstrated diffuse slowing and periodic lateralizing epileptiform discharges (PLEDs) over the corresponding right frontal area. A second serum anti-EEE titer sent on hospital day 8 was 1:180, which was considered to be positive for EEE infection. Over the next l0 days he had substantial resolution of mental clouding. His left leg remained paretic but he was able to walk independently at the time of transfer to a rehabilitation center. Prior to discharge, a repeated cranial MRI disclosed marked improvement of the frontal lesion. EEG, although improved, continued to document right frontal PLEDs and mild background slowing. Neuropsychologic testing demonstrated deficits in sequencing skills (both auditory and visual), memory, attention, and visuospatial reasoning tasks, which represented a significant decline in overall cognitive function when compared to a premorbid evaluation performed one month earlier for evaluation of an attention deficit disorder.
Communications should be addressed to: Dr. Darras; Department of Pediatrics; #309; New England Medical Center Hospitals; 750 Washington Street; Boston, MA 02111. Received March 5, 1992; accepted May l, 1992.
Morse et al: Eastern Equine Encephalitis
473
Figure 1. Contrast-enhanced CT revealing a right frontal rim-enhancing hypodensity on day 7 of illness.
He was transferred to a rehabilitation hospital where he remained for 2 months, requiring intensive cognitive rehabilitation for poorly controlled emotional outbursts and violent tendencies. He did not improve enough to return home and was placed in a psychiatric residential hospital where slow improvement has occurred. General neurologic examination now is normal. Discussion
Human cases of EEE continue to occur in epidemic fashion in specific geographic foci in Massachusetts and other states, and in sporadic fashion in Florida and parts
of southern Georgia. The median number of patients per year in the United States is 5. In 1990, there were 3 patients in Massachusetts, including our patient /I fatal, 2 survivors), one in South Carolina, and a presumptive patient in North Carolina [ 121. Clinical descriptions of patients during the acute phase of EEE infection and also in survivors have included focal abnormalities (e.g., hemiplegia, quadriplegia, aphasia, emotional instability) which suggest selective, focal areas of brain damage [3-11]. Pathologic examination of the brain in acute fatal cases has disclosed disseminated and focal encephalomyelitis, characterized by diffuse softening, vascular engorgement, perivascular cuffing, and parenchymatous polymorphonuclear and lymphocytic cellular infiltrates. Focal areas of neuronal cell death in the hippocampal formation, basal ganglia, pons, and frontal and occipital lobes have been described [ 1,7,10,11 ]. In survivors of the acute phase severe cystic changes with large, patchy areas of necrosis were reported [ 1 I. Few case descriptions of EEE have included neuroimaging studies. We found 11 patients in whom CT resuits were reported. Six of 11 CT scans were normal and 5 revealed diffuse edema; none described a focal brain lesion [6,9]. This surprising lack of focality contrasts sharply with both clinical and pathologic data and with the findings in our patient. The lesion in our patient had resolved nearly completely by the time of the second cranial MRI, performed 6 days later. We suggest that focal areas of transient, intense inflammation may escape detection depending on the timing of the scan with the stage of infection and whether a contrast agent is used. Recent reviews of experience with EEE emphasize the absence of focal findings as characteristic of the CT appearance [9,15]. It has been suggested that focal findings on CT or EEG may help the clinician distinguish Herpes simplex virus encephalitis (HSE) from EEE [9,13,15]. In our patient, focal neuroimaging and EEG features led to a presumptive diagnosis of HSE. As reviewed by Whitley et al., many diseases mimic HSE and clinicians must entertain a wide differential diagnosis in evaluating patients with meningoencephalitis [14]; in the proper clinical setting it is important to consider EEE. Wider public health concerns underscore the importance of diagnosing EEE. In the 1990 epidemic, the appearance of a human patient helped to support the decision to implement an aerial spraying program to control the mosquito vector (Dr. Alfred DeMaria, Massachusetts Department of Public Health; personal communication). Surveillance programs, which monitor the prevalence of the virus among the mosquito population and the occurrence of equine cases, can help to alert clinicians to the likelihood of human cases. Detection of human cases remains dependent on the inclusion of EEE in the differential diagnosis of meningoencephalitis. References
Figure 2. T2-weighted cranial MR1, demonstrating a high-signal intensity right frontal lesion on day 9 of illness.
474 PEDIATRICNEUROLOGY Vol. 8 No. 6
[1] Baker AB. Viral encephalitis. In: Baker AB, ed. Clinical neurology. Hagerstown:Harper and Row, 1976:9-11.
[2] Fothergill LD, Dingle JH, Farber S, Connerly ML. Human encephalitis caused by the virus of the eastern variety of equine encephalomyelitis. N Engl J Med 1938;219:411. [3] Getting VA. Equine encephalomyelitis in Massachusetts: An analysis of the 1938 outbreak. N Engl J Med 1941;224:999-1006. [4] Farber S, Hill A, Connedy ML, Dingle JH. Encephalitis in infants and children caused by a virus of the eastern variety of equine encephalitis. JAMA 1940;114:1725-31. [5] Feemster RF. Equine encephalitis in Massachusetts. N Engl J Med 1957;257:701-4. [6] Davenport DS, Batts DH, Carter JW. Eastern equine encephalitis in Michigan. Arch Neurol 1982;39:322-3. [7] Ayres JC, Feemster RF. The sequelae of eastern equine encephalomyelitis. N Engl J Med 1949;240:960-2. [8] Levitt LE Lovejoy FH, Daniels JB. Eastern equine encephalitis in Massachusetts-First human case in 14 years. N Engl J Med 1971; 284:540-1. [9] Przelomski MM, O'Rourke E, Grady GE Berardi VE Markley HG. Eastern equine encephalitis in Massachusetts: A report of 16 cases, 1970-1984. Neurology 1988;38:736-9.
[10] Winter WD. Eastern equine encephalomyelitis in Massachusetts in 1955: Report of two cases in infants. N Engl J Med 1956;255: 262-70. [11] Bastian FO, Wende RD, Singer DB, Zeller RS. Eastern equine encephalomyelitis: Histopathologic and ultrastructural changes with isolation of the virus in a human case. Am J Clin Pathol 1975;64:10-3. [12] Bartnett RE, Sprenger DA, Pappas J, et al. Arboviral surveillance-United States, 1990. In: Goodman RA, ed. Morbidity and mortality weekly report. Atlanta: Centers for Disease Control, 1990;39:593-7. [13] Birch WE, Rubin DVM, Hlady WG, et al. Eastern equine encephalitis-Florida, Eastern United States, 1991. In: Goodman RA, ed. Morbidity and mortality weekly report. Atlanta: Centers for Disease Control, 1991;40:533-5. [14] Whitley RJ, Cobbs CG, Alford CA Jr, et al. Diseases that mimic herpes simplex encephalitis: Diagnosis, presentation, and outcome. JAMA 1989;262:234-9. [15] Tsal TF. Arboviral infections in the United States. Infect Dis Clin North Am 1991 ;5:73-102.
Morse et al: Eastern Equine Encephalitis 475
