This work presents synthetically recent data on viral encephalitides in children and teenagers, insisting on the particular aspects determined by various viral etiological agents and by the special profile concerning the field of children at different ages or of teenagers.
Infections of the central nervous system (CNS) continue to represent a major public health problem through its medical emergency character, psychomotor sequelae and high mortality rate. Encephalitides, in the most concise definition, are acute inflammations of the brain, of infectious etiology. Having a great etiological and pathological diversity, in practice most encephalitides are diagnosed based on the neurological clinical symptomatology, laboratory and imaging data which emphasize, more rarely the etiologic agent, more often, the inflammatory syndrome. Encephalitides often raise problems of positive diagnosis and are difficult to differentiate from the wide range of acute or chronic on onset encephalitides, which define cerebral pain set off by non-inflammatory causes (metabolic imbalances, organ dysfunctions, hypoxia, intoxications). These manifestations are differentiated from the viral encephalitides by the absence of the infectious syndrome, gradual onset, absence of modifications in the cerebrospinal fluid (CSF), in general the absence of neuroimaging changes, in some cases – positive toxicological tests or modifications of certain biochemical parameters (hypoglycemia, hyperammoniemia, hydroelectrolytic imbalances).
Encephalitides in children and teenagers may be caused by various infectious agents: viruses, bacteria, fungi, parasites, which develop injuries of the brain parenchyma through complex mechanisms, depending also of the virulence of the pathogenic agent, its tropism and the immune answer of the host. (Glaser et al, 2006; Willougby and Sara S. Long, 2008).
The most important group of encephalitides is the one of the viral encephalitides. There are described two major mechanisms through which viruses trigger encephalitis:
In acute viral encephalitis, viruses invade directly the brain tissue, hematogenously, either by extension of a viral meningitis, secondary to a viremia achieving a diffuse encephalitis, or by retrograde distribution of viruses by way of peripheral nerves (rabies virus, herpes simplex virus) achieving a focal encephalitis. In these situations viruses may be cultivated from the brain and may be identified at the histopathological examination.
In post-infectious/post-vaccinated encephalitides, the viral infection evolves, at distance from the central nervous system, triggers an immune response with a self-antibodies synthesis that determines in the brain disseminated injuries of demyelination, situation in which viruses cannot be isolated from the brain parenchyma, but there is in the anamnesis a record of vaccination or an episode of acute infectious disease, of 2-4 weeks ago. Post-infectious encephalitides are acute monophasic diseases, which clinically show a multitude of neurological signs which have as lesional substrate multiple inflammatory, disseminated, demyelinisation focuses. Several pathogenic agents are associated with post-infectious encephalitis: coronaviruses, coxsackie viruses, cytomegalovirus, Epstein-Barr virus, herpes simplex, hepatitis A virus, human immunodeficiency virus (HIV), influenza viruses, measles virus, rubella virus, varicella-zoster virus. Other possible etiologies of a post-infectious encephalitis may be: Borrelia burgdorferi, Chlamydia, Leptospira, Mycoplasma pneumoniae, Rickettsia and Streptococcus beta hemolytic. ( Glaser CA et al, 2006, Willougby and Sara S. Long, 2008, Tunkel AR et al.2008)
Viral encephalitides represent emergencies that impose prompt intervention. The onset is sudden, with high fever, cephalalgias, vomiting, nausea, alteration of general status. In evolution there are neuro-psychic signs associated: cephalalgia is deepening, agitation or sleepiness, cloudiness/obnubilation. In the state of prodrome are outlined the symptoms affecting the encephalon: tonic-clonic seizures located or generalized, encephalitic scream, state of psychomotor agitation, disorientation, myocloni, tremor, ataxia, cranial nerves palsy, pyramidal with various distribution: hemiplegia or hemiparesis, paraplegia, monoplegia, more seldom tetraplegia, extrapyramidal signs: hypertonia, waxy contracture, various dyskinesias, cerebellar signs, breathing disorders, coma.
Neurological, pathognomonical clinical manifestations are correlated with the affected central nervous segment. Rombencephalitis or brainstem encephalitis manifests itself with myocloni, ataxia, cranial nerves palsy, breathing disorders, coma. The encephalomyelitic form is characterized by the association of the myelitic syndrome with flaccid paralyses, sphincter disorders, diminution/abolition of osteotendinous reflexes. The associated radicular component manifests itself with muscular weakness, dysesthesias, diminished reflexes.
In newborns and suckling infants, encephalitis manifests itself atypically: cu fever, variably, seizures, capricious appetite, irritability, lethargy, circulatory and respiratory disorders. In a study that monitored 63 newborns with encephalitis with herpes simplex virus, 49% have presented only lethargy, 57% have developed seizures, 49% had fever, 63% specific cutaneous injuries, vesicles.( Glaser et al, 2006; Willougby and Long, 2008). Encephalitis in older children and teenagers manifests itself with fever, psychic disorders, emotional lability, ataxia, tremor, seizures, lethargy, coma and focal neurologic signs: hemipareses, affectation of cranial nerves, ataxia. In a retrospective study on a batch of 50 children (with ages between 6 weeks to 18 years old) diagnosed with encephalitis, the following clinical manifestations have been distinguished: lethargy, irritability, personality disorders, persisting over 24 hours, fever (80% of the cases), seizures (78% of the cases), neurologic signs of focus (56%), conscience alteration (47%).(Kolski H et al. 1988)
Encephalitides are diagnosed in most of the cases clinically by emphasizing the neurological dysfunction. Definite diagnosis imposes cerebrospinal fluid (CSF) analysis, imaging investigations, electroencephalographic track (EEG). Study of CSF is a useful instrument in establishing the infectious etiology of the encephalitides by identification of specific antibodies or viral genome through the (polymerase chain reaction) PCR-based genomic amplification test. Detection of IgM antiviral specific antibodies constitutes a definite argument of cerebral affectation being known that IgM antibodies do not trespass the hematoencephalic barrier. A positive PCR test confirms the etiology of encephalitis. A negative PCR test cannot definitely exclude the etiologic implication of a viral pathogen agent. For encephalitis with herpes simplex type 1, type 2 virus the PCR test of CSF is the chosen diagnosis test, is with high specificity and sensitivity. In order to confirm the enteroviruses involvement in the etiology of encephalitis, it has been demonstrated that PCR of CSF cannot identify the type of encephalitis ((Rotbart HA et al.1997)
Patients suspected of encephalitis need also imaging exploration. The images obtained may be normal or may reveal a diffuse cerebral edema or inflammatory injuries at the cortex level, in the grey/white matter junction area, thalamus, basal ganglia. Several prospective studies have demonstrated the fact that in children neuroimaging injuries are developing gradually, initially are distinguished in a percentage of 30-37%, and in evolution at 70% of cases. Magnetic resonance imaging (MRI) of the brain is the chosen one. Cranial computed tomography with or without contrast may constitute an alternative, in view of performing lumbar puncture, to exclude eventual secondary complications of associated intracranial hypertension syndrome (risk: engaging syndrome), especially in situations in which resonance is not accessible.
MRI injuries are defined by T2 weighted images and FLAIR (fluid-attenuated inversion recovery). The injuries shown on MRI vary as location. Those associated with post-infectious encephalitis are deep subcortical white matter injuries, asymmetrical, diffused. The periventricular zone is often unaffected. Multiple injuries may have variable dimensions from 5 mm to 5 cm. Large dimensions injuries may associate mass effect. ( Hynson JL et al. 2002)
At the encephalitis in children, grey matter injuries (thalamus, basal ganglia), also symmetrical, accompany white matter injuries. In contrast with supratentorial injuries found which are asymmetrical. Frequently there are involved the brainstem and spinal marrow, as at their level are detected extended injuries on more segments, confluent ones, with variable post contrast intensification. Injuries detected by imaging examinations improve in convalescence, or may persist, various months or years. (Maschke M et al, 2004, Zimmerman R D, 1999 )
Empiric therapy recommends initiating with acyclovir, administered intravenously to children and teenagers with acute cu encephalitis. The major indication of the prompt acyclovir therapy is encephalitis with herpes simplex. Survivors of the herpetic encephalitis present important neurological sequelae even if they have been treated with acyclovir. However mortality drops dramatically in cases treated promptly and aggressively with acyclovir (30% versus 70%), and equally the severity of cognitive sequelae.(James SH et al. 2009) Complications of acute viral encephalitides include status epilepticus, cerebral edema, inadequate antidiuretic hormone secretion, cardio-respiratory insufficiency, disseminated intravascular coagulation syndrome. (James SH et al. 2009)
Etiology of viral encephalitides: the most frequently etiologically involved viruses in the development of encephalitis: herpes simplex 1, 2 viruses and other viruses of the Herpesviridae family, enteroviruses, arboviruses, respiratory viruses etc.
Clinical aspects – particularities on age groups:
Encephalitis with herpes simplex viruses (HSV) evolves severely having the first rate of mortality, although it benefits of etiological treatment, the acyclovir. Cerebral infection with HSV realizes two distinct clinical entities:
- Encephalitis in adults and encephalitis in children aged over 3 months, produced by HSV-1, focal encephalitis with injuries in the temporal or frontal lobe.
- Encephalitis in newborn produced by HSV-2, acquired during birth, from mother carrier of genital herpes virus and which generates diffuse cerebral injuries in the context of a sepsis. The disease onset is atypical, at 6-12 days after birth, with a capricious appetite, lethargy, irritability, tremor, seizures. Neurological symptomatology is associated with hepatic affectation, thrombocytopenia, characteristic cutaneous, herpetic injuries. (Schleede L et al. 2013, Kimberlin DW et al 2001).2,8)
- Herpetic encephalitis in child with HSV-1 starts with fever, vomiting, behavioral disorders, focal neurological signs, seizures, cephalalgias, memory and vision disorders, ataxia, dysphasia. There is no causality or temporal relation between peripheral injuries (labial herpes) produced by HSX and cerebral affectation. CSF reveals a viral profile, it is clear or xantochrome, with a moderate lymphomonocytal pleocytosis (10-500 cells/μL), with a moderate number of red blood cells (500 cells /μL), with high proteinorrachia and normal glycorrhachia. It has to be mentioned that it is possible a normal CSF, without alterations, in a percentage of 5-10% children. (Mook- Kanamori B et al,2009)
Standard positive diagnostic criterion is PCR which outlines the DNA-HSV genome in CSF. The PCR test from CSF replaces the brain biopsy. It has a high specificity (98-100%) and a high sensitivity (94-98%). (Lakeman FD et al. 1995)
MRI images in T2 weighted, reveal hemorrhagic injuries of the inferomedial temporal lobe, and sometimes also in cingulate gyrus. It has to be mentioned that the MRI aspect possibly be normal in the first days of disease. The suspicion of herpetic encephalitis imposes prompt initiation of the acyclovir therapy. The prognostic of untreated herpetic encephalitis is infaust. Complications include comitial disease, memory and cognitive disorders. ((Kimberlin DW et al 2001,Schleede L et al 2013 ).
Encephalitides with enteroviruses. In pediatric pathology, enteroviral infections evolve with a various specter of clinical pictures, from feverish illnesses with specific exanthem and enanthem: herpangina, hand-foot-and-mouth disease, infections of skeletal muscles, pleurodynia (Bornholm disease) or myopericarditis, to neuro-infections – some severe which evolve with neuropsychic sequelae: meningitides, encefalitides, paralytic diseases poliomyelitis-like. Enteroviruses are small RNA viruses, belonging to the Picornaviridae family and they are grouped in two classes: poliomyelitic viruses and nonpoliomyelitic enteroviruses: 23 types of coxsackie A viruses, 6 types of coxsackie B viruses, 28 types of echoviruses, 5 non-classified enteroviruses. Recently, a related group of viruses has been redistributed to a new class of enteroviruses, parechoviruses. Coxsackie B viruses and echoviruses serotypes 11 and 30 are responsible for 80-90% of the aseptic meningitides diagnosed at children ( Gajan N Sapkal et al.2009,Kumar A. DS ). Enteroviral encephalitides are characterized by brutal onset, with fever, cephalalgias, personality disorders, conscience alteration, seizures, hemichorea, ataxia. Encephalitides with coxsackie viruses evolve more frequently in newborns and small suckling infants and manifest themselves especially with cranial nerves paralyses, isolated oculomotor nerves paralyses, generalized seizures, psychomotor agitation, coma. Encephalitides with echo viruses manifest themselves by choreiform movements, facial paralysis, cerebellar ataxia, passing pareses of limbs. (Bennett NJ et al. 2014)). In the last years, enterovirus 71 (EV71) has become notorious, because of the association to the clinical picture already known of the hand-foot-and-mouth disease, (syndrome characterized by febrile illness with papulovesicular rash on the palms, plant and multiple oral ulcers) of severe rombencephalitis with high fatality in children. Identified initially in the United States, in 1969, EV71 has been the cause of certain important epidemics in Europe, Australia, Asia. The infection with EV71 produces variable clinical manifestations, from herpangina, hand-foot-and-mouth disease, self-limited evolution, but it may progress developing meningitis or brainstem encephalitis, with a high mortality rate in children under 3 years old. ( Mong How Ooi et al. 2010, Kumar A DS et al,2012). The clinical picture complicates itself with acute pulmonary edema, by the increase of pulmonary vascular permeability as a result of the brainstem injuries and the systemic inflammatory response caused by the excess of cytokines. Children suffering from meningoencephalitis with EV71 present a deficit of cellular immune response, with the activation of a severe inflammatory response, excess of pro-inflammatory cytokines which determine the increase of pulmonary vascular permeability similar to the acute respiratory distress syndrome. The fatality rate is 14% of the cases. Specific symptomatology, early, is characterized by severe signs of infection, myocloni, sleeping disorders. High fever, over 380C, persisting over 78 hours, associated with lethargy constitutes a factor predicting neurological complications. The humoral immune response is the one controlling the infections with enteroviruses and prevents the ingress of viruses in CNS. Children with deficit of B lymphocytes, such as those with X-linked agammaglobulinemia, have a high risk of developing CNS infections with enteroviruses. Transmission of enteroviruses and parechoviruses is realized directly or indirectly by fecal-oral route. Transmission is possible by respiratory secretions for certain serotypes (coxsackie A21), especially under precarious hygiene conditions and crowdies. Enterovirus 70 is present in tears and may be transmitted through hands and fomites. It is difficult to estimate the incubation period, it varies with the type of virus and the clinical syndrome which it accomplishes. On average fever sets in after an incubation period of approximately 3-5 days. Comparatively with poliomyelitis, the paralytic forms which follow have a biphasic pattern, onsets with unspecified fever, 3-5 days post-exposure, it follows a period of apparent health, after which the neurological symptomatology sets in (9-12 days post-exposure). Viral replication and dissemination of enteroviruses follow the studied pattern in the infection with polioviruses, in primates. The initial situs of viral replication is the pharynx and ileum. The virus is stationed in the respiratory path 1-3 weeks, in feces the virus may persist 3-8 weeks, the maximum period of contagiousness is registered in the first 2 weeks since infection. Viral replication generates a minor, short term viremia which favors viral hematogenous dissemination, at the lymphatic system level of the whole body. The moment coincides with the major viremia and with onset of central nervous system symptomatology. The immune response in infections with enteroviruses and parechoviruses, is type specific, reinfecton witsame serotype is possible, but evolves asymptomatically. The humoral immune response is dominant both in acute infection and in prevention of reinfections .Secretory immunoglobulins A have a protective role against the infection (their titer increases to 2 weeks since disease onset). A particular role have the macrophages which accomplish the viral clearance, by contrast to cytotoxic T lymphocites which emphasize the inflammatory response at the myocard level (coxsackie B3 – myocarditis). Newborns develop severe systemic infections with enteroviruses, with multiorganic affectation, with guarded prognostic. Enteroviruses are transmitted from mother, in the perinatal period. (Kimberlin DW et al, 2001, Zimermann RD 1999, Bennett NJ at al, 2014)
Encephalitides produced by arboviruses represent the group of primary authentic viral encephalitides. Arboviruses are adapted to specific animal hosts, are viruses „arthropod-borne” transmitted by biting / sting of mite, mosquitoes or other vectors. Other ways of transmission, more seldom, include blood transfusion, organ transplant, perinatal transmission, consumption of unpasteurized milk and dairy products, breast milk, professional exposure in laboratories. Arboviruses are grouped on families Togaviridae, Flaviviridae, Bunyaviridae, Reoviridae, and they are spread on all continents. There have been identified over 130 arboviruses specific to human pathology. Arboviral encephalitis may be considered zoonoses, the person gets infected accidentally, especially in the hot season, in the summer. Depending on the presence of the virus reservoir and the vector agents, certain arboviroses are found only in certain geographical regions. On the Romanian territory there have been isolated: Central Europe Encephalitis virus, spring-summer Encephalitis virus, West-Nile virus (WNV), fit to induce specific encephalitides. (Tsai TF et al.,1988)
Pathogenesis of arboviral encephalitides, although similar, independently of etiology, is far from being well known. After the transmission of virus, by means of an infected vector, gets triggered the viremia which facilitates the invasion of the central nervous system, by cribriform plate achieving the infection of the olfactory neuroepithelium, or brain capillary infection. In consequence, nervous matter injuries consist in neuronal focal necrosis, lymphocytic perivacular infiltrate, inflammatory injuries of the glyal component.
Patients initially present, an unspecific prodrome with symptoms that include: fever, abdominal pains, dysphagia, vertigo. Progressively are associated cephalalgias, photophobia, vomiting, meningeal signs, lethargy, sleepiness, coma. Other neurological symptoms may be present: cranial nerves pareses, tremor, disappearance of abdominal cutaneous reflexes, hemipareses, monopareses, deglutition disorders, frontal lobe syndrome, seizures. The acute disease imposes the management of a comatose sick person, with intracranial hypertension, with inadequate antidiuretic hormone secretion, with respiratory insufficiency phenomena, seizures. There is no specific etiological therapy for these encephalitides. The diagnosis of arboviral encephalitides imposes the complex evaluation of the feverish patient, with neurological affectation, with fast identification of a possible encephalitis with herpes simplex virus, which can be treated etiologically, with exclusion of a possible bacterial meningitis, of a brain abscess, or other pathologies. The examination of the cerebrospinal fluid (CSF) reveals moderate pleocytosis, initially dominated by polymorphonuclears, and in evolution, by lymphomonocytes. Glycorrhachia is normal, proteinorrachia is moderately increased. The etiologic diagnosis is achieved by identification of the viral antigen or ARN viral genome, in serum or CSF. IgM specific antibodies may be identified in serum and CSF, by immunoenzymatic tests ELISA.
The pattern of imaging emphasizable injuries is variable. Both CT and MRI may be normal, or may suggest diffuse brain edema. Sometimes are detected injuries of the thalamus or the grey matter basal ganglia.
VWN virus belongs to Flaviviridae family, transmitted by means of mosquitos from Culex species. Recently, other possible ways of transmission have been identified: blood transfusions, organ transplant, transplacentally, breast milk. As such, since 2003, in USA, blood donors are tested by the genomic amplification technique also to identify a possible WNV infection.( Zou S et al 2010) Most WNV infections are asymptomatic, but after an incubation period of 2-14 days, 20% of the infected persons develop fever, associated with cu cephalalgias, myalgias, arthralgias, rash, gastrointestinal symptoms, rarely myocarditis, pancreatitis, hepatitis, ocular disorders: chorioretinitis, irridocyclitis. The neuroinvasion appears at a percentage of approximately 1% among patients, encephalitis being more frequent at those with immuno-compromised ground, in diabetics, in those with preexistent CNS disorders, elders. The clinical picture is characterized by fever suddenly set in, cephalalgias, vomiting, nausea, tremors, meningeal syndrome. In evolution are associated agitation, sleepiness, seizures, speech disorders, disorientation, coma. The severity is variable, deceases may reach to 10-20%. Sequelae are important: mental retard, behavioral disorders, rarely parkinsonian syndrome. ((Petersen LR et al. 2013, www.cdc.gov/ncezid/dvb/).
La Crosse Encephalitis is frequent in the months July-September, in children aged between five and nine years old, evolves as meningoencephalitis, average clinical form. 50% of the cases manifest seizures, electroencephalogram route reveals the focal activity (. (Mc Junin JE et al,2001)
Acute viral encephalitides in children and teenagers evolve with a wide range neurological manifestations correlated with the pathogen agent, the generated brain injuries, the ground of the host. Positive diagnosis is complex, the management of patient with encephalitis has an emergency character, imposes interdisciplinary collaboration: infectionist, neurologist, imagist, intensive care specialist.
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