Viral Encephalitis and Bacterial Meningitis
In the past 20 years the complexity of caring for patients with acute encephalitis and meningitis in the critical care setting has increased. This is the result of the emergence of new pathogens, advances in diagnostic technology, the development of new forms of antiviral and antibacterial chemotherapy, and the increasing sophistication of supportive care and monitoring techniques used in the neurological intensive care unit (neuro-ICU) setting. Defined in their simplest terms, encephalitis is inflammation of the brain, and meningitis is inflammation of the leptomeninges. In establishing the diagnosis, noninfectious inflammatory disorders need to be excluded. The archetypal presentation of infectious encephalitis or meningitis is the clinical triad of fever, headache, and altered mental status. Patients with encephalitis are more prone to develop seizures, mental status changes, and focal neurological deficits, which signify direct brain infection; whereas those with meningitis have more prominent signs of meningeal irritation. Both encephalitis and meningitis may present as isolated infections, or as a component of a systemic infection in which nervous system involvement is but one feature. This chapter focuses on the diagnosis and ICU management of severe acute viral encephalitis and bacterial meningitis.
VIRAL ENCEPHALITIS: GENERAL CONSIDERATIONS
Pathogenesis
Viruses may gain access to the central nervous system either by hematogenous of neuronal routes (1,2), the former being more common. Systemic viral infections arise from inoculation via a mosquito bite (arthropod-borne infection), animal bite, contaminated needle stick, or blood transfusion, or through direct infection of the mucous membranes lining the respiratory, gastroenteric, or genitourinary tracts (Table 21.1). After the initial infection of local tissues, continued viral replication results in transient viremia, diffuse seeding of the reticuloendothelial system, and secondary infection of other organs including the nervous system. Alternatively, a number of special viruses access the nervous system by intraneuronal routes, probably via retrograde transport through the peripheral or olfactory nerves, as occurs with herpes simplex, varicella-zoster, and rabies viruses.
Whether the virus reaches the central nervous system (CNS) via neural or hematogenous routes, widespread infection of the brain occurs only if the virus can attach to and penetrate susceptible cells (neurotropism), and continue to spread and replicate (2,3). Specific cell populations—including the leptomeningeal epithelial tissues, neurons, vascular endothelium, and glia—may have varying degrees of susceptibility to infection, which explains in part why the primary locus of viral infection of the nervous system is so variable. Clinical syndromes related to direct viral infection include encephalitis, meningitis, myelitis, and polyradiculitis, or combinations of these entities.
In viral encephalitis, inflammation occurs primarily in the gray matter and there is a predominance
of perivascular lymphocytic infiltrates. Disruption of the blood-brain barrier (BBB) is a component of all these viral invasions and results from the local expression of chemokines and nitric oxide synthetase, which incite vasogenic cerebral edema (4,5). As the infection progresses, reactive astrocytosis and gliosis become more prominent. Certain unique histopathologic features in encephalitis, such as Cowdry type A intranuclear inclusions with herpesvirus and Negri bodies with rabies virus infection, facilitate the pathologic diagnosis.
of perivascular lymphocytic infiltrates. Disruption of the blood-brain barrier (BBB) is a component of all these viral invasions and results from the local expression of chemokines and nitric oxide synthetase, which incite vasogenic cerebral edema (4,5). As the infection progresses, reactive astrocytosis and gliosis become more prominent. Certain unique histopathologic features in encephalitis, such as Cowdry type A intranuclear inclusions with herpesvirus and Negri bodies with rabies virus infection, facilitate the pathologic diagnosis.
TABLE 21.1. Causes of acute viral encephalitis in humans | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Epidemiology
The incidence of clinically diagnosed acute encephalitis is between 3.5 and 7.4 per 100,000 patient-years; in children, the incidence is far higher, exceeding 16 cases per 100,000 patient-years (6). Approximately 20,000 new cases are diagnosed in the United States each year, making this entity slightly less common than aneurysmal subarachnoid hemorrhage. The illness appears in epidemic or sporadic forms. Most epidemics occur in the summer or early fall,
and result from arboviruses or enteroviruses.
and result from arboviruses or enteroviruses.
Establishing the specific causative agent often is difficult, and the likely pathogen depends on geography, the time epoch studied, and the method of diagnosis. In the United States, the most common causes of acute viral encephalitis are herpesviruses, arboviruses, and enteroviruses. In 1977, of all cases of infectious encephalitis reported to the U.S. Centers for Disease Control, 73% were of undetermined etiology, 11% were associated with arboviruses, 6% with exanthem viruses, 3% with mumps, and 7% with other viruses (7). Other studies attempting to identify the most common causes of viral encephalitis have yielded highly variable results. In a classic study conducted from 1953 to 1963 at the Walter Reade Army Institute of Research, which relied on serologic confirmation of the diagnosis, mumps virus was the leading cause of viral encephalitis (Table 21.2) (8). With the advent of modern vaccination, mumps encephalitis is now rare. In two more recent European studies relying on polymerase chain reaction (PCR) technology to detect viral DNA in the cerebrospinal fluid (CSF), enteroviruses (9) and varicella-zoster (10) were the most common causes of CNS infection, whereas arboviral infections were uncommon (Table 21.2). In the United States, mundane encephalitic enteroviruses such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV) probably account for a large group of cases and among the enteroviruses, LaCrosse is currently the commonest but others, particularly West Nile, have evinced great interest because it is novel and may cause a poliomyelitis. In our experience, CSF PCR testing has greatly increased the frequency with which a specific cause of viral encephalitis is identified; however, a large number of cases still remain undiagnosed.
TABLE 21.2. Relative frequency of viral causes of central nervous system infection among patients referred for diagnostic testing | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Clinical Manifestations
The hallmark of viral encephalitis, well known to neurologists, is the clinical triad of fever, headache, and alteration of consciousness. Other neurological manifestations may include disorientation, delirium and other behavioral and language disturbances, memory impairment, hallucinations, hemiparesis, and (perhaps most characteristically) seizures. These illnesses usually reach their
full extent within 10 days (11), but severe cases may progresses rapidly to coma with motor posturing. Deterioration is most often owing to extension of the virus through the cerebrum, but cerebral edema with mass effect and elevated intracranial pressure (ICP) are as often responsible. Approximately 40% of severe cases are complicated by seizures. Convulsive or nonconvulsive status epilepticus tends to be highly refractory to treatment when it occurs.
full extent within 10 days (11), but severe cases may progresses rapidly to coma with motor posturing. Deterioration is most often owing to extension of the virus through the cerebrum, but cerebral edema with mass effect and elevated intracranial pressure (ICP) are as often responsible. Approximately 40% of severe cases are complicated by seizures. Convulsive or nonconvulsive status epilepticus tends to be highly refractory to treatment when it occurs.
Diagnosis
History and Examination
Noninfectious processes simulate viral encephalitis; among these, acute disseminated encephalomyelitis, CNS vasculitis, Behçet’s disease, or mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) should be considered (Table 21.3). Noninfectious processes frequently masquerade as viral encephalitis: In one prospective study (perhaps not representative of the modern era), 22% of brain biopsies for suspected herpes simplex encephalitis (HSE) yielded a noninfectious diagnosis (12). Many of these conditions are recognized by paying particular attention to extracranial manifestations of the disease, such as a rash, renal or cardiac involvement, or hematologic abnormalities. A large number of nonviral causes of infectious encephalitis must be considered also, particularly because the majority of these infections are treatable (Table 21.4).
TABLE 21.3. Noninfectious processes that can mimic viral encephalitis | |||||||||||||
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TABLE 21.4. Nonviral causes of infectious encephalitis | |||||||||||||||||||
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As mentioned, efforts to achieve a specific etiologic diagnosis rely on careful attention to the epidemiologic setting, clinical manifestations of the process, and the appropriate use of the laboratory tests. Important historical elements include recent travel and recreational activities, contact with animals, and occupational exposures (Table 21.5) (13). It has been noted by others that the features of the neurological syndrome itself generally are not helpful for differentiating between specific viral etiologies. For instance, when signs and symptoms of viral encephalitis were compared between patients with and without biopsy-proven HSE, no distinguishing characteristics could be identified (Table 21.6) (12). We are not in full agreement because language and memory difficulties early in the illness are suggestive of herpes infection and certain viruses cause basal ganglionic features. An important exception also is West Nile virus encephalitis, which is often associated with neuromuscular abnormalities, specifically the aforementioned poliomyelitis (14).
TABLE 21.5. Historical data and physical findings that suggest the cause of viral encephalitis | |||||||||||||||||||||||||||||||||||||||||||
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TABLE 21.6. Presenting symptoms and signs in patients with biopsy-proven herpes simplex encephalitis (HSE) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Cerebrospinal Fluid Examination
CSF examination is essential for establishing the diagnosis and identifying the cause of viral encephalitis. CSF abnormalities generally include pleocytosis (usually lymphocytic) and elevation of protein; glucose levels usually are normal. A small proportion of patients (3% to 5%) with severe viral infections of the CNS, including HSE, may have completely normal CSF, particularly early in the illness (15). We have twice in the last year given the erroneous opinion that a patient with headache, confusion, and fever did not have a meningoencephalitis because the spinal fluid on the first day was normal. Elevated intrathecal IgG production is a nonspecific finding that occurs with many CNS inflammatory or infectious processes and cannot be depended on to aid in diagnosis. An increase in CSF lactate levels has been associated with a poor prognosis, mainly in meningitis (16). Although cultures of CSF are of limited value for isolating virus, the detection of viral DNA with PCR technology has revolutionized the way in which viral encephalitis is identified, and it has become almost a necessity in modern diagnosis (9,10). In the National Institute of Allergy and Infectious Diseases (NIAID) collaborative study, CSF PCR was 98% sensitive and 94% specific when compared to brain biopsy as the standard for certain agents (17). Multiplex PCR assays that simultaneously test a single CSF sample for the most common and important causes of viral encephalitis are particularly useful and efficient (18).
Neuroimaging and Electroencephalogram
Magnetic resonance brain imaging is more sensitive than CT for evaluating cerebral pathology in viral encephalitis (19,20). Diffusion-weighted imaging (DWI), reflecting cytotoxic edema, is useful for identifying focal pathology when vague abnormalities are seen on T2-weighted and FLAIR sequences (Fig. 21.1) (21). Electroencephalography is of value for demonstrating periodic lateralized epileptiform discharges (PLEDs), a physiologic marker of structural temporal lobe damage, or electrographic seizure activity in comatose patients (22). Periodic lateralized epileptiform discharges are seen most commonly with HSE, which has a predilection for involvement of the temporal lobes, but are not sensitive or specific for this entity (15).
Ancillary Testing
Successful serologic or PCR confirmation of the cause of viral encephalitis usually occurs several weeks into the illness, and thus is not helpful for guiding therapy, which should be empiric. Nonetheless, it is of some value to establish a specific diagnosis if possible in order to identify epidemic forms of viral encephalitis, and for determining the prognosis. Serologic diagnosis depends on demonstrating the production of organism-specific IgM antibodies in the CSF or plasma, or seroconversion or seroboosting (a fourfold rise) of IgG titers between the acute and convalescent (3 to 4 weeks) phase of the illness. Even with PCR technology, it remains important to perform acute and convalescent serologic testing in patients with viral encephalitis, because CSF PCR is not 100% sensitive or specific. To facilitate diagnosis, viral cultures of throat (influenza, enterovirus), rectal (enterovirus), urine (adenovirus, CMV), saliva (rabies), and skin exudate (herpes) specimens also should be obtained (11).
Brain Biopsy
Tissue biopsy remains the gold standard for establishing the diagnosis of viral encephalitis but is unnecessary in most circumstances. Nonetheless, in experienced hands, the procedure has a low rate of complications (23). The morbidity consists primarily of bleeding or hematoma at the biopsy site and occurs in less than 3% of patients. The specificity of a positive brain biopsy approaches 100% (24). The sensitivity of brain biopsy for viral encephalitis is approximately 95%; a false-negative biopsy can result when an uninvolved area of brain is analyzed, or from errors in pathologic
specimen processing or interpretation. Immunohistochemical stains have recently made rapid diagnosis possible from brain biopsies, and confocal microscopy can facilitate these analyses by identifying specific regions of abnormal staining that then can be processed for more detailed ultrastructural and electron microscopy studies (25). Magnetic resonance imaging should be used for guidance in selecting an involved area for biopsy: Open leptomeningeal and tissue biopsies from cortical regions with contrast enhancement yield the best diagnostic results. Although specific histopathologic findings such as intranuclear inclusions may be present in only one third of brain biopsies from patients with HSE, a negative culture carries more diagnostic weight if it is obtained from an abnormal area of brain.
Brain biopsy is generally indicated only when a patient is responding poorly to treatment and the precise diagnosis remains in question after noninvasive testing. The exception is that biopsy should be performed with a lower threshold in immunocompromised patients, in whom opportunistic infections frequently mimic HSE.
specimen processing or interpretation. Immunohistochemical stains have recently made rapid diagnosis possible from brain biopsies, and confocal microscopy can facilitate these analyses by identifying specific regions of abnormal staining that then can be processed for more detailed ultrastructural and electron microscopy studies (25). Magnetic resonance imaging should be used for guidance in selecting an involved area for biopsy: Open leptomeningeal and tissue biopsies from cortical regions with contrast enhancement yield the best diagnostic results. Although specific histopathologic findings such as intranuclear inclusions may be present in only one third of brain biopsies from patients with HSE, a negative culture carries more diagnostic weight if it is obtained from an abnormal area of brain.
Brain biopsy is generally indicated only when a patient is responding poorly to treatment and the precise diagnosis remains in question after noninvasive testing. The exception is that biopsy should be performed with a lower threshold in immunocompromised patients, in whom opportunistic infections frequently mimic HSE.
 FIG. 21.1. Chronic magnetic resonance imaging abnormalities (left, T2; right, T1 with gadolinium) in a 56-year-old man with viral encephalitis who developed behavioral abnormalities consistent with the Klüver-Bucy syndrome (hyperphagia, hypersexuality, amnesia, visual agnosia). The causative viral agent was not identified by cerebral spinal fluid polymerase chain reaction studies or brain biopsy. The images reveal hemorrhagic necrosis with dystrophic calcification of the left medial temporal lobe, and laminar necrosis (increased T1 signal) of the left medial frontal and parietal lobes. |
Treatment
General Treatment Measures
As is the case for all serious neurological conditions managed in the ICU, treatment begins with meticulous attention to general supportive measures that can minimize complications. Comatose patients who are unable to protect their airway should be intubated. Unintubated patients who are agitated or delirious should be treated with general orienting measures at the bedside and haloperidol 1 to 10 mg every 2 to 6 hours or a similar agent. Intubated patients can be sedated with propofol or midazolam infusions, with frequent “wake-ups” to allow serial assessment of neurological status. In both cases, an opioid such as morphine or fentanyl or nonsteroidal analgesia such as ketorolac should be given if pain is felt to be a contributing factor. Only isotonic intravenous fluids such as 0.9% saline solution should be administered, to avoid the exacerbation of cerebral edema that can result from hypotonic fluids. Early and aggressive enteral feeding should be provided to combat the protein catabolism that is characteristic of most serious neurological illnesses.
With regard to seizures, phenytoin (15 to 20 mg/kg followed by 5 mg/kg per day) is recommended by some authorities to prevent seizures, and frequent drug levels should be obtained to ensure that serum concentrations are in the therapeutic range. However, we have not used anticonvulsants prophylactically and instead waited for an indication that seizures will be a problem. Surveillance EEG monitoring is advisable in patients whose level of consciousness is fluctuating or in those who are persistently comatose, to rule out nonconvulsive status epilepticus (Chapter 8). Aggressive intervention with acetaminophen and cooling blankets to control fever should be pursued, although these measures are often ineffective (26).
Intracranial Pressure Management
Clinical deterioration in patients with viral encephalitis may be associated with cerebral edema and increased ICP. In the NIAID collaborative antiviral study of herpes encephalitis, two thirds of patients had progression after the diagnosis was confirmed by brain biopsy, and one third of the patients lapsed into coma (27). As in other diseases, the indication for placement of an ICP monitor includes: (a) coma; (b) a CT or MR scan demonstrating significant intracranial mass effect (e.g., global edema with effacement of the basal cisterns); and (c) a prognosis that merits aggressive ICU intervention (28). In our small series of comatose encephalitis patients, intracranial monitoring revealed the progressive development of increased ICP during the first 2 weeks, and control of ICP was associated with better outcomes (29). The proportion of patients with encephalitis who may be expected to develop raised ICP is not known but is certainly highest among those with HSE.
The role of corticosteroids in treating brain edema associated with viral encephalitis is controversial. One small trial failed to demonstrate a benefit from dexamethasone in Japanese encephalitis (30). However, case reports have described dramatic clinical improvement after the initiation of steroid therapy for varied forms of encephalitis (31, 32 and 33). In our opinion, a brief course of dexamethasone (4 to 10 mg every 6 hours) is a reasonable treatment option for stuporous or comatose encephalitis patients with severe brain edema on neuroimaging. Mild to moderate hypothermia may be a promising treatment for these patients as well (34, 35 and 36). In febrile infants with influenza encephalitis and low CPP (less than 70 mm Hg), brain temperature can exceed core body temperature by greater than 2°C, a
phenomenon termed “brain thermo-pooling” (34). Therapeutic hypothermia has been associated with clinical and radiographic improvement and reduced ICP in case reports (35,36); however, well-designed studies of temperature modulation on the course of viral encephalitis have yet to be performed. As a last resort, decompressive hemicraniectomy may be life-saving for young patients with severe necrotizing viral encephalitis resulting in focal mass effect and transtentorial herniation; good recoveries after this procedure have been described (37,38).
phenomenon termed “brain thermo-pooling” (34). Therapeutic hypothermia has been associated with clinical and radiographic improvement and reduced ICP in case reports (35,36); however, well-designed studies of temperature modulation on the course of viral encephalitis have yet to be performed. As a last resort, decompressive hemicraniectomy may be life-saving for young patients with severe necrotizing viral encephalitis resulting in focal mass effect and transtentorial herniation; good recoveries after this procedure have been described (37,38).
Antiviral Therapy
Specific therapy is available for only a few of the viruses that cause acute encephalitis (Table 21.7). If there is any possibility of herpes simplex infection, intravenous acyclovir should be started immediately. Clinical trials indicate that acyclovir, when started early, reduces mortality from approximately 70% to 25%, and that almost 40% of those who survive make a good recovery with minimal long-term disability (27,39). Serious varicella-zoster infections, including encephalitis and polyradiculitis, can be treated with acyclovir in combination with other agents (Table 21.7). In patients with CMV encephalitis, ganciclovir is the preferred agent, with or without concurrent foscarnet. Though these agents have demonstrated efficacy against CMV retinitis in HIV infected patients, the clinical response of CMV encephalitis patients treated with a single agent is usually poor, which has prompted the recommendation for combination therapy (40). Pleconaril is a novel agent with activity against picornavirus enteroviral infections (e.g., polio, Coxsackie, enterovirus 71), which is currently in clinical trials and is available for compassionate use (41). Quantitative CSF PCR testing, which measures the burden of viral DNA (number of DNA copies per µL CSF), is becoming increasingly used to assess the response to treatment. Almost all patients with HSE have a negative CSF PCR after 14 days of treatment with acyclovir; persistence is associated with resistant strains and poor prognosis, and probably is an indication for prolonged therapy with additional agents (42).
Outcome
Outcome after encephalitis depends primarily on the virulence of the infecting agent. Rabies (mortality greater than 90%) and Eastern equine encephalitis (mortality greater than 30%) are generally regarded as the most lethal forms of viral encephalitis in the United States. Other determinants of poor outcome include increasing age, absent or late (greater than 4 days) initiation of antiviral therapy, coma, status epilepticus, and elevated ICP (11). Approximately half of those who survive
an episode of viral encephalitis are disabled by cognitive or motor impairment, which can be profound (43). Focal damage of the hippocampi, medial temporal lobes, and frontal and cingulate cortex from HSE and other infections can result in dramatic amnestic and behavioral abnormalities, including the Klüver-Bucy syndrome (hyperphagia, hypersexuality, amnesia, and visual agnosia, Fig. 21.1) (44,45). Although functional independence can improve with intensive rehabilitation, the rate of recovery varies and is generally less than that for traumatic brain injury (46). Late epilepsy develops in up to 20% of encephalitis patients (47). The majority of this latter group has survived severe infections complicated by coma and seizures, experience complex-partial seizures related to multiple seizure foci, and are highly refractory to anticonvulsant therapy (48).
an episode of viral encephalitis are disabled by cognitive or motor impairment, which can be profound (43). Focal damage of the hippocampi, medial temporal lobes, and frontal and cingulate cortex from HSE and other infections can result in dramatic amnestic and behavioral abnormalities, including the Klüver-Bucy syndrome (hyperphagia, hypersexuality, amnesia, and visual agnosia, Fig. 21.1) (44,45). Although functional independence can improve with intensive rehabilitation, the rate of recovery varies and is generally less than that for traumatic brain injury (46). Late epilepsy develops in up to 20% of encephalitis patients (47). The majority of this latter group has survived severe infections complicated by coma and seizures, experience complex-partial seizures related to multiple seizure foci, and are highly refractory to anticonvulsant therapy (48).
TABLE 21.7. Antiviral agents for serious acute central nervous system viral infections | ||||||||||||||||||||||||||||||||
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SPECIFIC CAUSES OF ACUTE VIRAL ENCEPHALITIS
Herpes Simplex Encephalitis
Clinical Presentation
Herpes simplex virus comprises approximately 10% of cases of viral encephalitis in the United States, and is the most frequently cause of fatal sporadic encephalitis (49). Occurring throughout the year, about one half of cases develop in patients older than 50 (1). The majority of HSE is caused by HSV-1. It has been proposed that approximately half of HSE cases are related to primary infection, and half are the result of viral reactivation (1,50). Experimental evidence suggests that latent HSV-1 infection may result from reactivation of the virus in the trigeminal ganglia, with transport of the virus from the nasal mucosal to the olfactory tract to the brain (1). The medical history with respect to prior labial or genital herpes simplex infection is not helpful in establishing the diagnosis. A history of herpes simplex labialis or genitalis is elicited in approximately 25% of patients with HSE, and in the same percentage of patients with other forms of encephalitis.
The stereotypical presentation of a patient with HSE includes 24 to 48 hours of gradually increasing headache, fever, and confusion, which may be preceded by olfactory hallucinations (15). In addition, patients may experience memory loss, personality changes, aphasia, and focal or generalized seizures, and may or may not have focal motor findings (Table 21.6). Although this clinical constellation should raise the suspicion of HSE, few patients present in such a straightforward fashion, and no single finding or combination of findings rules in or out the diagnosis. The more recent use CSF PCR instead of brain biopsy to establish the diagnosis of HSE has expanded awareness of milder or atypical forms of presentation, such as brainstem encephalitis (51), which comprise approximately 20% of all cases (52). This subset of patients has a higher than expected number of individuals infected with HSV-2 rather than HSV-1, suggesting that HSV-2 is more likely to cause milder or atypical disease.
Diagnosis
Most but not all HSE patients have abnormal CSF. The initial lumbar puncture usually exhibits a moderate pleocytosis (50 to 500 lymphocytes/mm3), which is usually primarily lymphocytic. Even though HSE is often thought of as a hemorrhagic, only 20% of patients have more than 500 red blood cells/mm3. The CSF glucose may be normal or decreased, but is only rarely extremely low. The CSF protein is usually mildly elevated, but it is normal at clinical presentation in approximately 20% of patients. Herpes simplex virus is only rarely cultured from the spinal fluid of adults with HSE.
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