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This paper seeks to discuss the differential diagnosis of childhood encephalitis and to review the course of investigation in a child presenting with encephalopathy, encephalitis and meningoencephalitis. The paper also reviews the current understanding of acute demyelinating encephalomyelitis (ADEM) and presents the crucial therapeutic alternatives in the management of childhood encephalitis, including ADEM and infectious diseases.
Le présent article porte sur le diagnostic différentiel de l’encéphalite infantile et sur l’approche de l’investigation d’un enfant atteint d’encéphalopathie, d’encéphalite ou de méningoencéphalite. Il examine également les connaissances actuelles de l’encéphalomyélite démyélinisante aiguë (EDA) et présente les possibilités thérapeutiques cruciales dans la prise en charge de l’encéphalite infantile, incluant l’EDA et les maladies infectieuses.
The clinical finding of an altered state of consciousness, ie, encephalopathy, with some or all of headache, neurological signs and fever, presents the physician with a variety of challenges. A number of infectious and noninfectious conditions can present with encephalopathy with or without cerebrospinal fluid (CSF) pleocytosis (Table 1). The purpose of this paper is to outline an approach to discovering the infectious causes of encephalitis and meningoencephalitis including those for which particular therapy may be urgently required, such as herpes simplex virus and acute demyelinating encephalomyelitis (ADEM). New microbiological molecular technology is evolving so that identification of an infectious agent is now possible through methods such as polymerase chain reaction (PCR) and highly sensitive antibody- or antigen-detection systems (1). ADEM can be diagnosed by highly sensitive (but less specific) magnetic resonance imaging (MRI), and responds well to steroid treatment. Etiological information may also be helpful from a prognostic standpoint for the individual patient and from a public health point of view for the community, particularly in the cases of enterovirus and arbovirus infections.
The following definitions of encephalopathy, acute encephalitis and meningoencephalitis are sumarized in Table 2.
Encephalopathy is defined as an altered or fluctuating state of consciousness including profound lethargy.
Acute encephalitis infection of brain parenchyma is manifest by an altered state of consciousness with headache, disorientation and neurological signs evolving within a two-week period (2). At some point in the illness, inflammation will be manifest as CSF pleocytosis, although this may not be present on admission to hospital. These findings of inflammation mark the difference between ‘opathy’ and ‘itis’. Clinically, encephalitis has been defined as encephalopathy plus two or more of fever, seizure, focal neurological findings, compatible electroencephalogram (EEG), abnormal diagnostic imaging or CSF pleocytosis (Encephalitis Registry, The Hospital for Sick Children).
ADEM or postinfectious encephalitis generally follows acute non-neurological infectious illness by one to three weeks. Symptoms begin with fever, headache, nuchal rigidity, nausea and vomiting, and progress to include alterations in mental status and focal neurological signs. The disease is characterized by global depression of the sensorium, ranging from drowsiness to coma. While the neurological findings vary, they may include ataxia, decreased deep tendon reflexes, urinary retention and bilateral optic neuritis (3). While CSF findings are variable, MRI findings in the white matter are highly suggestive in the correct clinical setting (ie, absence of a course compatible with multiple sclerosis) and can lead the clinician to highly effective steroid therapy (3).
Acute hemorrhagic leukoencephalitis (AHLE) is heralded by the briefest of prodromes, before patients spike a fever, and experience malaise and seizures. This fatal disease is associated with peripheral blood neutrophilic pleocytosis, and CSF abnormalities with predominant neutrophils, an increased protein level and a normal glucose level. There may also be hundreds of red cells. While most cases are diagnosed at autopsy, computed tomography (CT) abnormalities are a consistent finding (4).
Meningitis and meningoencephalitis are two separate diseases. The aforementioned features of encephalitis, ADEM and AHLE distinguish patients with encephalitis from those with meningitis in whom abrupt onset of fever, headache, photophobia, nuchal rigidity and other meningeal signs predominate. In meningoencephalitis, there are features of both encephalitis and meningitis.
A new condition of encephalomyeloradiculopathy has been reported by investigators in Halifax (5). This newly described entity is heralded by fever and headache, followed by neurogenic bladder, transverse myelitis and encephalopathy, in association with mononuclear pleocytosis of the CSF and nerve conduction studies showing polyradiculopathy.
In general, meningoencephalitis and encephalitis represent uncommon responses to common infections. Most infected patients have a mild syndrome of meningoencephalitis rather than severe encephalitis (6). Many cases are of viral origin. As well as acute encephalitis, ADEM and AHLE, viral encephalitis also includes slow viral and chronic degenerative diseases of presumed viral origin (6). This review focuses on acute and ADEM syndromes that represent, respectively, direct invasion of the brain or activation of autoreactive T cells by the primary infection, leading to autoimmune disease.
The involvement of the central nervous system (CNS) usually follows hematogenous dissemination of the pathogen. Direct parenchymal involvement occurs via the choroid plexus or endothelial cells. Herpes simplex and rabies infections follow axonal transmission. Specific viruses prefer particular brain cells, for example, polio virus prefers motor cells, rabies prefers limbic cells and mumps prefers ependymal cells (2).
Acute viral encephalitis is predominantly a disease of the grey matter while ADEM is a disease of the white matter characterized by demyelination (7). Pathologically, in acute encephalitis, acute capillary and endothelial inflammation of cortical vessels (‘eptomeningitis’) is a prominent finding with perivascular lymphocytic infiltrate (‘cuffing’). With disease progression, either astrocytosis and gliosis or immune-mediated demyelination occurs (7,8).
In ADEM, activated T cell clones recognize small fragments of two myelin proteins that induce inflammatory processes in the CNS, resulting in the destruction of normal brain white matter by the immune system (4). Autoreactive T cells recognizing myelin-specific proteins circulate in normal persons. A viral infection presumably activates these myelin reactive T cells, which migrate into the CNS and recruit neutrophils, triggering massive multifocal tissue destruction. Macrophages and lymphocytes predominate. In contrast, in acute hemorrhagic leukoencephalitis, there is a profound neutrophilic response (4).
Isolated angitis of the CNS may also occur. It is most commonly related to varicella zoster virus (VZV) infection but also to Bartonella henselae (cat scratch) infection, parvovirus, mycoplasma, Epstein-Barr virus, group A streptococcus, human immunodeficiency virus infection and others (9).
A list of many of the possible etiological agents, their clinical clues and recommended tests are provided in Tables 2 to to4.4. Diagnosis depends on timely collection of blood during the initial and convalescent phases (two to six weeks) of illness, testing of CSF and ideally MRI, to investigate possible ADEM.
In Canada, children with encephalitis who have no clinically obvious cause of infection (eg, exanthem of varicella or measles) and in whom an etiology is determined through laboratory testing are most likely to have an infection associated with an enterovirus, herpes simplex virus (HSV), influenza virus, human herpesvirus 6, Epstein-Barr virus or an arbovirus. Mycoplasma pneumoniae and Bartonella henselae also appear to be emerging as important causes of encephalitis. Infections that may mimic viral encephalitis include brain abscess, bacterial meningitis or sepsis, parameningeal infections, subacute bacterial endocarditis, tuberculosis, fungal infection, parasitic infection (Naegleria species, cysticercosis, toxoplasmosis), Rocky Mountain spotted fever, syphilis and leptospirosis (2).
Information to be obtained in in a history includes duration of illness before admission, temporally associated illness (eg, VZV, diarrhea, skin lesions), recent immunizations, animal exposures including bites or scratches, insect exposure including ticks and mosquitoes, travel, camping, the nature of the symptoms, the poorest level of consciousness (normal, disoriented, stuporous [rousable], unconscious [unrousable] and the occurrence of convulsions [one, focal, generalized]). Information obtained on history may lead the physician to the diagnosis before the microbiological testing is complete (Table 3).
Nonspecific prodromal findings may include malaise, anorexia, vomiting, myalgia and headache with or without symptoms of viral respiratory or enteric disease. In ADEM, the symptoms follow a vague viral syndrome by days or weeks, and findings are characterized by symptoms of demyelination, either focal or diffuse. Direct brain involvement may be heralded by a prodrome of lethargy, drowsiness or stupor and disorientation, hallucinations, behaviour and speech disturbances, and irritability lasting 24 h or longer.
In severe acute encephalitis including AHLE, patients experience an abrupt onset of convulsions, altered consciousness and focal neurological deficit over two to seven days (1). While seizures and focal neurological signs are variable features, there are ultimately characteristic CSF findings, EEG abnormalities, abnormalities in neuroimaging studies and, at some point in the illness, fever (2,10).
On physical examination, general physical findings should be noted including heart rate, respiratory rate, blood pressure, presence or absence of meningismus, and signs of involvement of other systems, particularly skin rashes and lymph nodes, as well as signs of trauma. Fundoscopical examination including indirect ophthalmoloscopy may elucidate the shaken baby syndrome or vasculitis. Neurological findings depend on which part of the brain is primarily involved. Findings may predominate in any part of the brain or non-CNS sites may predominate (2).
Specific neurological findings include mental status, Glasgow Coma Score, state (alert, disoriented/awake, stuporous, coma/decorticate or coma/decerebrate), the presence of photophobia, aphasia, abnormalities of cranial nerves (ophthalmoplegia, facial paralysis, ptosis), deep tendon reflexes, motor (hemiparesis) and sensory and cerebellar (ataxia) defects. Findings should be described as to whether they are intact or abnormal, their symmetry and focality.
Alterations in sensorium may range from mild somnolence and lethargy to intense irritability and deep coma (1). In infants, findings are commonly as vague as somnolence, irritability, high-pitched cry, diffuse hyper-reflexia, or a full or bulging fontanel and symptoms of poor feeding and vomiting (1). Some manifestations are the result of the increase in intracranial pressure. Findings of increased intracranial pressure (1) rather than direct brain infection include papilledema, abnormal respiratory pattern, flexor or extensor posturing, ophthalmoplegia or pupillary abnormalities, and bradycardia.
The etiology can rarely be determined on clinical examination alone unless it is associated with an exanthematous illness such as varicella or measles. The National Institute of Allergy and Infectious Diseases (NAIAD) Collaborative Antiviral Study Group found no statistical differences in the presenting signs and symptoms of patients with biopsy-proven herpes simplex encephalitis that distinguished them from those without that infection (5).
From the therapeutic point of view, the detection of the focal findings of possible HSV infection, the MRI changes in ADEM, the presence of continuous seizures and increased intracranial pressure are most important. All patients require prompt clinical evaluation, usually including neuroimaging studies, examination of the CSF and an EEG (1) (Table 5).
Neuroimaging studies such as MRI or cranial CT scan with and without contrast should be undertaken in children with clinical encephalitis. If the child has evidence of increased intracranial pressure with a closed fontanel or focal signs, this is usually undertaken before a lumbar puncture in order to rule out other lesions, such as abscess, subarachnoid hemorrhage, tumours and stroke, and to localize lesions (2). The need for diagnostic imaging will likely require prompt transfer of the child to a centre where such study is possible unless the cause is very obvious, eg, varicella or the child is only very transiently encephalopathic and completely normal within a short period of time, eg, 24 h. MRI may provide improved resolution and indeed suggest the etiology of ADEM (3) or a newly recognized multifocal or diffuse HSV encephalitis variant in preschoolers, requiring acyclovir therapy (4,11). CT scan may be preferable for sinuses and parameningeal foci. Brain scan may show early signs of HSV encephalitis that are not identifiable on CT scan.
The usual CSF findings are elevated protein, normal glucose levels and a pleocytosis (7 cells/μL or more) with a predominance of mononuclear cells. An exception is AHLE in which polymorphonuclear cells predominate. Also, especially early in the course of illness and hospitalization, CSF may be normal or show hypoglycorrachia and a predominance of polymorphonuclear cells. Approximately 3% to 5% of patients with severe viral infections of the CNS have no CSF pleocytosis on initial CSF examination. While pleocytosis should not be attributed to status epilepticus until all other causes have been ruled out, a white blood cell count of more than 6×106/L or one or more polymorphonuclear leukocytes have been found in 22% of these patients (12). While red blood cells may be suggestive of HSV infection or AHLE, they may be present or absent in these conditions (13).
While results of a second lumbar puncture 5 to 8 h after the first may demonstrate a shift in cells from polymorponuclear to monocyte response, it is generally not considered clinically useful (14).
Electroencephalography may further support the diagnosis by showing general findings compatible with encephalopathy. Of particular value in herpes simplex encephalitis is its characteristic periodic high voltage spike wave activity in the temporal regions and slow wave complexes (intervals of 2 to 3 s).
Obtaining an etiological diagnosis has been notoriously difficult in the past. A broad range of etiological agents are summarized in Table 3 while the diagnostic tests and potential for therapy are summarized in Table 4. With prompt, complete recovery within one to two days, testing may not be necessary.
In general, CSF, blood, throat, stool and urine specimens should be obtained for viral studies. These specimens can be held in the hospital laboratory for immediate evaluation and possible subsequent analysis in a reference laboratory, depending upon the child’s course. It is vitally important to collect and save adequate amounts of body fluids, specifically CSF and serum, should the need for confirmation of a diagnosis become imperative.
A minimum of 2 mL and preferably 3 mL of CSF is required for virological studies. CSF is useful for the isolation of enterovirus and mumps. Although the cell lines used for viral isolation will also permit isolation of HSV, it is not usually isolated. Rapid diagnostic methods are being developed, most notably PCR for the herpes viruses and enteroviruses (14). The number of agents that can be detected by molecular methods is increasing rapidly, and physicians are encouraged to check regularly with their laboratory to determine what is available. These methods are usually available only at reference laboratories. Interpretation of both positive and negative results should be undertaken very cautiously because the sensitivity and specificity of these tests outside of research protocols remains to be determined.
In many patients, paired serology will ultimately be helpful to establish the diagnosis, either because of a protracted and complicated course or the presence of adverse sequelae. The importance of timely collection of acute serum cannot be overstated. A minimum of 5 mL of blood should be taken in the acute phase, followed by a second serum two to six weeks later. Testing of paired sera can confirm the etiology of the infection through demonstration of seroconversion or a fourfold rise in antibody titre. As well, IgM antibody testing can be done for certain agents, such as EBV, measles and arbovirus.
Determination of antiviral antibody synthesis in the CSF is usually not undertaken because it has not been considered useful in the diagnosis of HSV infections (14,15). Occasionally it might be useful to test for intrathecal synthesis of viral specific antibodies against other organisms, eg, measles in subcutaneous sclerosing panencephalitis and Japanese encephalitis. It should be emphasized that additional amounts of CSF and serum must be obtained to allow for this testing when these diagnoses are suspected.
Of 145 patients admitted with encephalitis-like illness to The Hospital for Sick Children, Toronto in 1994 and 1995, 50 patients hospitalized 72 h or more underwent standardized microbiological investigations. A confirmed or very probable etiological agent was identified in 20 patients (40%); organisms included M pneumoniae (n=9), M pneumonia and enterovirus (n=2), HSV (n=4), EBV (n=1), human herpesvirus 6 (n=1), human herpesvirus 6 and influenza A (n=1), influenza A (n=1) and Powassan virus (n=1). In 13 cases (26%), a possible pathogen was identified based on lesser microbiological evidence, including nine M pneumoniae cases (17).
This should be reserved for patients who do not respond to acyclovir and supportive care and for whom there is an abnormality of unknown etiology on neuroimaging studies and a deteriorating clinical condition.
The infections for which there may be specific therapy are outlined in Table 4. The minimum investigations to be considered in the child who is severely or persistently encephalopathic are listed in Table 5. The efficacy of specific antiviral therapy has only been demonstrated for HSV, and questions about acylovir dosage, duration of therapy, and detection and management of relapses remain. While HSV is not the most common cause of encephalitis, empiric acyclovir therapy is justified until data from several sources (EEG, diagnostic imaging, clinical course) are available. The use of acyclovir in varicella depends on the timing of illness, with benefit likely only when the infection occurs before the rash or early in its course rather than as a postinfectious illness. The role of therapy in encephalitis caused by M pneumoniae and cat scratch disease is unproved. ADEM commonly responds to steroid therapy, as may vasculitis. In the child who fails to improve after several days of illness, the use of empiric steroids should be discussed with neurology colleagues. The importance of recognizing and treating continuous seizures and increased intracranial pressure cannot be overemphasized.
The spectrum of illness is highly variable and ranges from a short benign illness to a devastating one with severe sequelae and death. Physicians should understand that a child can make an apparently complete recovery following weeks of depressed consciousness in hospital. Persons taking part in bedside conversations should be aware that the child may make a full recovery with memory of such events. Conversely, children with apparently benign illness may show steady and profound deterioration in the subsequent weeks and months following hospital discharge. Both short term and long term follow-up of patients with encephalitis is important. The known risk of recurrence in patients with HSV encephalitis should be recognized.