Central nervous system (CNS) infections, including meningitis, encephalitis, and brain abscess, are rare but time-sensitive emergency department (ED) diagnoses. Patients with CNS infection can present to the ED with nonspecific signs and symptoms, including headache, fever, altered mental status, and behavioral changes. Neuroimaging and CSF fluid analysis can appear benign early in the course of disease. Delaying therapy negatively impacts outcomes, particularly with bacterial meningitis and herpes simplex virus encephalitis. Therefore, diagnosis of CNS infection requires vigilance and a high index of suspicion based on the history and physical examination, which must be confirmed with appropriate imaging and laboratory evaluation.
Key points
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The classic triad of fever, neck stiffness, and altered mental status is present in only a minority of patients with meningitis.
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Kernig’s and Brudzinski’s signs are poorly sensitive but relatively specific physical examination maneuvers for identifying meningitis.
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Imaging tests and lumbar puncture should not delay initiation of empiric antibiotic therapy in patients suspected to have bacterial meningitis.
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Although certain cerebrospinal fluid (CSF) profiles are highly suggestive of viral or bacterial meningitis infection, emergency physicians should not be not falsely reassured by a benign CSF fluid profile supporting a viral cause.
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Encephalitis should be considered in any patient presenting with new-onset seizure or focal neurologic deficit accompanied by fever, headache, altered mental status, or behavioral changes.
Introduction
A key clinical responsibility of the emergency physician is to consider the “worst case scenario” for a given chief complaint. When it comes to infections of the central nervous system (CNS), the greatest challenge is identifying patients that have a rare life-threatening diagnosis amid the multitude of patients presenting with nonspecific symptoms. Alone or in combination, fever, headache, altered mental status, and behavior changes encompass a broad differential diagnosis. A diagnosis not considered is a diagnosis never made. In this vein, this review discusses the clinical signs and symptoms that should lead emergency physicians to consider CNS infection, paying particular attention to the sensitivity and specificity of different clinical findings at the bedside. Subsequently, the diagnostic workup and management of patients for whom there is high clinical suspicion for CNS infection is discussed.
Introduction
A key clinical responsibility of the emergency physician is to consider the “worst case scenario” for a given chief complaint. When it comes to infections of the central nervous system (CNS), the greatest challenge is identifying patients that have a rare life-threatening diagnosis amid the multitude of patients presenting with nonspecific symptoms. Alone or in combination, fever, headache, altered mental status, and behavior changes encompass a broad differential diagnosis. A diagnosis not considered is a diagnosis never made. In this vein, this review discusses the clinical signs and symptoms that should lead emergency physicians to consider CNS infection, paying particular attention to the sensitivity and specificity of different clinical findings at the bedside. Subsequently, the diagnostic workup and management of patients for whom there is high clinical suspicion for CNS infection is discussed.
Meningitis
The term “meningitis” applies broadly to inflammation of the meninges. While meningitis can arise from a wide variety of pathologies, infectious and non-infectious, for the purpose of this review we specifically refer to acute infections of the meninges of bacterial, viral, or fungal origin. Bacterial meningitis occurs when organisms gain access to the subarachnoid space either through bacteremia (usually from an upper airway source), contiguous spread from dental or sinus infections, traumatic or congenital communications with the exterior, or a neurosurgical procedure. The severe inflammation associated with bacterial meningitis results in edema of the brain and meninges, and eventually increased intracranial pressure once the compensatory mechanisms for cerebrospinal fluid (CSF) displacement have been overwhelmed. Bacterial meningitis is associated with significant morbidity with mortality rates ranging from 13 to 27%.
In contrast to bacterial infection, meningitis caused by viral infection is usually less severe. The most common causes are enteroviruses (eg, Coxsackie A and B, echovirus). Herpes simplex virus (HSV, types 1 and 2), cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella zoster virus (VZV), mumps virus, and human immunodeficiency virus (HIV) may also cause viral meningitis. Fungal meningitis is usually secondary to systemic mycoses (eg, Cryptococcus neoformans , Coccidioides immitis, Histoplasma capsulatum ) originating elsewhere in the body, usually from a pulmonary focus of infection in an immunocompromised patient. Rare fungal infections have also been associated with contaminated glucocorticoid injections to treat chronic pain.
Meningitis is a poster child for the success of childhood vaccination in reducing the incidence of many life-threatening infectious diseases. Before the introduction of an effective vaccine in 1988, Haemophilus influenzae type B (Hib) was the leading cause of bacterial meningitis in the United States. After the recommendation that all infants receive the Hib vaccination starting at age 2 months, the incidence of Hib meningitis among children less than 5 years of age declined by greater than 99%. Similarly, the advent of the pneumococcal seven-valent conjugate vaccine and the meningococcal conjugate vaccine significantly decreased the incidence and mortality of pneumococcal and meningococcal meningitis in the United States. Meningitis due to nosocomial pathogens, including Gram-negative bacteria and Staphylococcus , have now surpassed Neisseria meningitidis and H influenzae in incidence. With changing pathogen demographics, the average age of a patient with meningitis has increased from 15 months of age in 1986 to 35 years in the present day.
Meningitis is a relatively rare diagnosis in US emergency departments (ED). Between 1993 and 2008, approximately 66,000 US ED patients were diagnosed with meningitis annually, with an incidence of 62 per 100,000 visits. With regards to the cause of meningitis, ED diagnoses include unspecified (60%), viral (31%), bacterial (8%), and fungal (1%) causes. Bacterial meningitis is much more prevalent in developing countries, where the average incidence approaches 50 cases per 100,000 and 1 in 250 children are affected within the first year of life.
Clinical Presentation
The number of patients presenting to the ED with symptoms suggestive of meningitis far exceeds the number of patients who actually have the disease. The classic symptom triad of fever, neck stiffness, and altered mental status is present in only a minority of patients. Other associated symptoms may include nausea and vomiting, cranial nerve abnormalities, rash, and seizure. Infants can also present with nonspecific symptoms such as lethargy and irritability. With regards to the accuracy of the clinical history and physical examination in diagnosing meningitis in adults, low sensitivity plagues common complaints and findings, including headache (27%–81%), nausea and vomiting (29%–32%), and neck pain (28%). Sensitivity varies for individual components of the “classic triad” of fever (42%–97%), neck stiffness (15%–92%), and altered mental status (32%–89%). In some cases, 99% to 100% of patients found to have meningitis had at least one component of the classic triad. Therefore, if the patient presenting with acute headache does not have neck stiffness or fever and is mentating normally, it is extremely unlikely that they have meningitis. A prospective study of children ages 2 months to 16 years from Israel also demonstrated the nondiscriminatory value of symptoms in diagnosing meningitis.
Classic physical examination maneuvers for the evaluation of meningitis have been taught to generations of physicians. Kernig’s sign, first described in 1882, consists of flexing the patient’s neck and then extending the patient’s knees. It is considered positive when the maneuver elicits pain at an angle of less than 135°. First reported in 1909, Brudzinski’s sign, where the neck is passively flexed with the patient in supine position, is considered positive if it results in flexion of the hips and knees. The sensitivities of Kernig’s and Brudzinski’s signs reported in Brudzinski’s original paper were 42% and 97%, respectively. However, most of Kernig’s and Brudzinski’s patients were children with meningitis due to Mycobacterium tuberculosis and Streptococcus pneumoniae , both of which are associated with severe meningeal inflammation. Several recent studies have examined the usefulness of these classic signs in contemporary patient populations. These studies collectively demonstrate that these signs have low sensitivity in predicting CSF pleocytosis ( Table 1 ). The absence of these clinical signs, therefore, cannot adequately rule out of the presence of meningitis or obviate the need for a lumbar puncture (LP). However, Kernig’s and Brudzinski’s signs are quite specific (92%–98%) for predicting CSF pleocytosis, and therefore, their presence should increase clinical suspicion for meningitis.
| Sensitivity (95% CI) | Specificity (95% CI) | LR+ | LR− | Reference | |
|---|---|---|---|---|---|
| Nuchal rigidity | 30 | 68 | 0.94 | 1.02 | Thomas et al, 2002 |
| 39.4 (29.7, 49.7) | 70.3 (59.8, 79.5) | 1.33 (0.89, 1.98) | 0.86 (0.7, 1.06) | Waghdhare et al, 2010 | |
| 13 (8, 17) | 80 (74, 85) | 0.6 | 1.1 | Nakao et al, 2014 | |
| Kernig’s sign | 5 | 95 | 0.97 | 1.0 | Thomas et al, 2002 |
| 14.1 (7.95, 22.6) | 92.3 (84.8, 96.9) | 1.84 (0.77, 4.35) | 1.0 | Waghdhare et al, 2010 | |
| 2 (0, 4) | 97 (95, 99) | 0.8 | 0.93 (0.84, 1.03) | Nakao et al, 2014 | |
| Brudzinski’s sign | 5 | 95 | 0.97 | 1.0 | Thomas et al, 2002 |
| 11.1 (5.68, 19) | 93.4 (86.2, 97.5) | 1.69 (0.65, 4.35) | 1.0 | Waghdhare et al, 2010 | |
| 2 (0, 4) | 98 (96, 100) | 1.0 | 0.95 (0.87, 1.04) | Nakao et al, 2014 | |
| Head jolt | 6.06 (2.26, 12.7) | 98.9 (94, 100) | 5.52 (0.67, 44.9) | 0.95 (0.89, 1.0) | Waghdhare et al, 2010 |
| 21 (15, 27) | 82 (76, 87) | 1.2 | 1.0 | Nakao et al, 2014 |
An additional maneuver to elicit meningeal irritation is the “head-jolt” test. The patient is asked to move their head back and forth in the horizontal plane at a rate of 2 to 3 turns per second. It is considered positive if the patient’s headache worsens. It was initially tested in a cohort of patients with both fever and headache and had a reported sensitivity of 97% for CSF pleocytosis. Two subsequent studies in US ED patients and intensive care unit patients in India demonstrated much lower sensitivity (6%–21%), suggesting that the absence of a positive head jolt does not effectively rule out meningitis.
Given the poor performance of clinical signs and the physical examination in ruling out meningitis, overall clinical gestalt remains an important part of making the diagnosis. In a prospective cohort, Nakao and colleagues found that physician suspicion had a sensitivity of only 44% in predicting pleocytosis. However, in 3 patients where the CSF culture grew an infective organism ( N meningitidis, C. neoformans, and Enterovirus ), clinicians suspected bacterial meningitis before performing the LP, suggesting that physician judgment may be the best current diagnostic tool.
Diagnostic Workup
In the absence of clear contraindications, patients suspected of having meningitis should undergo LP. If the clinical suspicion for bacterial meningitis is high, empiric antibiotics should be started immediately when the LP cannot be performed right away. Although the sensitivity of the CSF culture decreases with antibiotic administration, cultures can remain positive for up to 4 hours afterward.
In patients at risk for an intracranial mass or midline shift, it is recommended that computed tomography (CT) of the head be obtained before LP given the potential for brain herniation. Current guidelines from the Infectious Disease Society of America recommend obtaining a head CT before LP in patients who are immunocompromised, have a history of CNS disease, have had a new-onset seizure within 1 week of presentation, or have examination findings consistent with papilledema, abnormal level of consciousness, or focal neurologic deficit. In patients in whom head CT is thought to be necessary, the correct sequence of actions are first, immediate administration of antibiotics, then CT, followed by LP as soon as possible.
In Sweden, it was found that adoption of guidelines recommending head CT before LP in patients with altered mental status led to increased CT use even in patients who did not meet criteria. Far worse, adherence to guidelines for early empiric antibiotics in suspected bacterial meningitis was poor. This undesirable practice pattern has been replicated in other environments as well. In 2009, moderate-to-severe impairment of mental status and new onset seizures were removed from the list of indications for head CT before LP in the Swedish guidelines, leading to significantly earlier treatment of bacterial meningitis and a decrease in overall mortality.
Once the LP has been completed, ideally with an opening-pressure performed, CSF fluid analysis can help predict a bacterial, viral, or fungal cause for meningitis ( Table 2 ). In addition to cell count, glucose, and protein, CSF should be sent for culture. Molecular studies such as polymerase chain reaction (PCR) assays for HSV should be considered in immunocompetent individuals. Special CSF testing for fungal (eg, cryptococcal antigen, fungal culture) and mycobacterial infection (eg, acid fast bacteria stain and mycobacterial culture) can be sent in cases where there is higher clinical suspicion for an atypical infection, particularly in immunocompromised patients.
| Parameter | Normal | Bacterial | Viral a | Fungal a |
|---|---|---|---|---|
| CSF opening pressure | <170 mm | Elevated | Normal | Normal or elevated |
| Cell count | <5 cells/mm 3 | >1000/mm 3 | <1000 mm 3 | <500/mm 3 |
| Cell predominance | — | Neutrophils | Lymphocytes | Lymphocytes |
| CSF glucose | >0.66 × serum | Low | Normal | Low |
| CSF protein | <45 mg/dL | Elevated | Normal | Elevated |
a CSF consistent with these profiles are not sufficient to rule out bacterial meningitis.
Although certain CSF profiles are highly suggestive of viral or bacterial infection, emergency physicians should not be falsely reassured by CSF profiles suggestive that a patient has viral rather than bacterial meningitis. In a prospective study of 696 patients with culture-proven bacterial meningitis, only 88% of patients had one or more CSF findings predictive of bacterial meningitis. A fifth had a negative CSF Gram stain. Two studies have assessed the discriminatory value of CSF laboratory tests in distinguishing viral versus bacterial meningitis in the setting of a negative Gram stain. Both studies found low discriminatory value for classic CSF parameters, including significantly elevated neutrophil count, high protein, or low glucose in distinguishing bacterial from viral meningitis. For example, 50% of patients with bacterial meningitis had a neutrophil count less than 440/mm 3 and greater than 10% of the patients with viral meningitis had a neutrophil count of greater than 500/mm 3 .
Several studies have assessed the discriminatory value of CSF lactate in distinguishing viral from bacterial meningitis. CSF lactate, produced by bacterial anaerobic metabolism or ischemic brain tissue, is not affected by blood lactate concentration. A meta-analysis assessing the diagnostic accuracy of CSF lactate for differentiating bacterial from viral meningitis found that in both pediatric and adult patients with Gram stain–positive or culture-proven bacterial meningitis, a CSF lactate level of greater than 3.9 mmol/L had a sensitivity of 96% (95% confidence interval [CI] 93%–98%) and specificity of 97% (95% CI 96%–99%) for differentiating bacterial meningitis. The sensitivity of the test dropped dramatically to 29% (95% CI 23%–75%) in the subset of patients pretreated with antibiotics.
Apart from CSF analysis, procalcitonin is a serum marker that has shown promise in distinguishing bacterial from viral meningitis. In general, serum procalcitonin is an inflammatory marker that increases disproportionately in patients with underlying bacterial infection. It has been used in a wide variety of clinical settings to assess likelihood of underlying bacterial infection. In the setting of suspected meningitis but a negative CSF Gram stain, a serum procalcitonin level of greater than 0.98 ng/mL was found to have a sensitivity of 87%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 99% for identifying bacterial meningitis.
Generally, in patients with CSF pleocytosis or with moderate-to-high clinical suspicion for bacterial meningitis, empiric antibiotics should be continued pending finalization of CSF cultures and other diagnostic tests when indicated. In the pediatric population, the bacterial meningitis score is a validated clinical prediction tool that identifies children with CSF pleocytosis at very low risk for bacterial meningitis. Patients are considered “very low risk” for bacterial meningitis if they lack all of the following criteria: positive CSF Gram stain, CSF absolute neutrophil count (ANC) of at least 1000 cell/μL, CSF protein of at least 80 mg/dL, peripheral blood ANC of at least 10,000 cells/μL, and a history of seizure before or at time of presentation. As the bacterial meningitis score was developed to assist clinicians in deciding which patients warrant admission for parental antibiotics in the presence of CSF pleocytosis, patients warranting admission regardless were excluded from the derivation and validation cohorts. Thus, the score does not apply to patients less than 29 days of age or those with critical illness, a ventricular shunt device, recent neurosurgery, immunosuppression, or other bacterial infection necessitating inpatient antibiotic therapy. Patients who were pretreated with antibiotics were also excluded. In a meta-analysis of 8 independent validation studies, the bacterial meningitis score was 99.3% (95% CI 98.7% to 99.7%) sensitive for bacterial meningitis, with a negative predictive value of 99.7% (95% CI 99.3% to 99.9%). Of 4896 patients with CSF pleocytosis, the bacterial meningitis score misclassified 9 as having aseptic rather than bacterial meningitis. As 7 of these children were either less than 2 months of age or had petechiae or purpura on examination, the authors recommended that the score only be applied to non-ill-appearing children older than 2 months of age who do not have petechiae or purpura on examination and have not been pretreated with antibiotics.
Treatment
Bacterial meningitis
Common pathogens responsible for bacterial meningitis vary with age, degree of immunocompromise, and clinical history ( Table 3 ). For example, in neonates, the most common causative organisms in the first week of life, Streptococcus galactiae , Escherichia coli , and Listeria monocytogenes , are replaced by S pneumoniae and N meningitidis by the sixth week. Antibacterial therapy should be geared toward the most likely pathogen (see Table 2 ). With the exception of the very young, patients who have recently undergone a neurosurgical procedure, or those who have suffered penetrating head trauma, S pneumoniae remains the most common bacterial pathogen. Meningitis due to S pneumoniae is treated intravenously with a combination of a high-dose third-generation cephalosporin (eg, ceftriaxone) and vancomycin in light of worldwide emergence of resistant S pneumoniae.
| Patient Subgroup | Most Common Bacterial Pathogen | Initial Intravenous Therapy |
|---|---|---|
| Neonates, <1 wk | S agalactiae , E coli , L monocytogenes | Ampicillin (50 mg/kg every 8 h) AND Cefotaxime (50 mg/kg every 8 h) |
| Neonates, >1 wk and <6 wk | L monocytogenes , S agalactiae , Gram-negative bacilli | Ampicillin (50 mg/kg every 6 h) AND Cefotaxime (50 mg/kg every 6 h) |
| Infants and children | S pneumoniae , N meningiditis | Cefriaxone (80–100 mg daily) OR Cefotaxime (75 mg/kg every 6 h) AND Vancomycin (15–20 mg/kg every 8 h) |
| Adults | S pneumoniae , N meningiditis | Ceftriaxone (2 g every 12 h) OR Cefotaxime (3 g every 6 h) AND Vancomycin (15–20 mg/kg every 8 h) |
| Elderly | S pneumoniae , N meningiditis , L monocytogenes | Ceftriaxone (2 g every 12 h) OR Cefotaxime (3 g every 6 h) AND Vancomycin (15–20 mg/kg every 8 h) AND Ampicillin (2 g every 4 h) |
| Immunocompromised | S pneumoniae , N meningiditis , H influenzae , aerobic Gram-negative bacilli | Vancomycin (15–20 mg/kg every 8 h) AND Ceftazidime (2 g every 8 h) OR Cefepime (2 g every 8 h) OR Meropenem (2 g every 8 h) AND Ampicillin (2 g every 4 h) |
| Nosocomial | S aureus , S epidermidis , aerobic Gram-negative bacilli | Vancomycin (15–20 mg/kg every 8 h) AND Ceftazidime (2 g every 8 h) OR Cefepime (2 g every 8 h) OR Meropenem (2 g every 8 h) |
In addition to prompt antibiotic therapy, corticosteroids should be considered as adjunctive therapy in some cases of suspected bacterial meningitis. The use of corticosteroids for the treatment of meningitis was prompted by the finding in animal models that meningitis outcomes were worse with increasing severity of the inflammatory process in the subarachnoid space. There have been conflicting results as to their benefit in bacterial meningitis ever since the first clinical trials examining their use were published in the 1960s. A 2013 Cochrane Review analyzed 25 randomized control trials spanning patients of all ages and types of bacterial meningitis to determine the benefit of corticosteroids in reducing overall mortality, deafness, and other neurologic sequelae. Overall, there was a nonsignificant reduction in mortality (17.7% vs 19.9%; risk ratio [RR] 0.90, 95% CI 0.80–1.01) with corticosteroid use. However, in subgroup analysis, corticosteroids reduced mortality in patients with bacterial meningitis due to S pneumoniae (RR 0.84, 95% CI 0.72–0.98) but not H influenzae or N meningitidis . There was a significant reduction in hearing loss (RR 0.74, 95% CI 0.63–0.87) and subsequent neurologic sequelae (RR 0.83, 95% CI 0.69–1). There was no benefit found for patients treated with corticosteroids in low-income countries. With regards to the timing of corticosteroid administration, it is traditionally thought that they should be administered before or at the time of antibiotic infusion. However, the results of the Cochrane Review suggest that there is no significant difference in mortality reduction if corticosteroids are administered before, with, or after antibiotics are given. There was a slightly more favorable effect on reducing hearing loss and short-term neurologic sequelae if corticosteroids were administered before or with antibiotics.
Viral meningitis
There is no specific antiviral therapy for most viral causes of meningitis, and treatment is largely supportive with spontaneous recovery anticipated in most cases. HSV-1 and HSV-2 cause different CNS diseases in adults. Although HSV-1 is associated with devastating encephalitis, HSV-2 causes a benign viral meningitis with meningeal signs and CSF pleocytosis, usually in the concurrent setting of primary genital infection. If HSV-2 meningitis is suspected or confirmed in an adult , treatment with acyclovir can be initiated but is of unclear benefit. In stark contrast, HSV-2 infection in an infant can lead to life-threatening encephalitis.
Fungal meningitis
Fungal meningitis is almost always a disease of the immunocompromised. If the clinical suspicion for fungal meningitis is high, empiric antifungal therapy with amphotericin B is appropriate pending isolation of a specific fungus to tailor antifungal therapy.
Encephalitis
Encephalitis is inflammation of the brain parenchyma. It is technically a pathologic diagnosis, but the term is commonly used to describe a clinical syndrome of brain inflammation. The differential diagnosis for encephalitis is broad, with infectious (viral, bacterial, or parasitic), postinfectious, and noninfectious (metabolic, toxic, autoimmune, paraneoplastic) causes possible. Viral infections are associated with 2 distinct forms of encephalitis. The first is a direct infection of the brain parenchyma due to viremia (eg, West Nile virus) or viral reactivation in neuronal tissue (eg, HSV, VZV). The second is a postinfectious encephalomyelitis (also known as acute disseminated encephalomyelitis), likely an autoimmune phenomenon more often seen in children and young adults following a disseminated viral illness or vaccination. This review focuses on viral encephalitis due to direct infection because it is responsible for the majority of acute encephalitis encountered in emergency care.
In the Western world, encephalitis is an uncommon disorder. The reported incidence of encephalitis from all causes ranges from 0.7 to 12.6 per 100,000 adults and 10.5 to 13.8 per 100,000 children. Worldwide, the causes of encephalitis remain unidentified in up to 85% of cases, due in part to limited diagnostic capabilities as well as emerging pathogens. Even in a British study in which 203 patient samples underwent exhaustive testing for infectious and noninfectious causes of encephalitis, 37% of causes were unknown. HSV encephalitis (HSV-1) remains the most common cause of sporadic viral encephalitis in industrialized nations, accounting for 10% to 15% of cases with an annual incidence of 1 in 250,000 to 500,000, and a bimodal age distribution primarily affecting the very young and the elderly. VZV comes in at a close second and is actually more common than HSV in immunocompromised individuals, accounting for 19% to 29% of encephalitis cases.
Clinical Presentation
The first step in approaching a patient with suspected CNS infection is to determine if bacterial meningitis is present, necessitating emergent empiric antibiotic therapy. However, when there is also evidence of brain parenchymal involvement in the form of focal neurologic findings or seizures, one must consider encephalitis as well. The clinical presentation of encephalitis correlates with the underlying function of the brain parenchyma involved ( Table 4 ). For example, because HSV encephalitis is classically associated with the temporal lobes, it can present with personality changes, psychosis, olfactory or gustatory hallucinations, or acute episodes of terror that may initially be misdiagnosed as a psychiatric disorder. Inferior frontal and temporal lobe involvement may also present with upper-quadrant visual field deficits, difficulty storing or recalling new information, hemiparesis with greater involvement of the face and arm, or aphasia when the dominant hemisphere is involved. Certain viruses, such as West Nile virus and Eastern equine encephalitis virus, have a predilection for basal ganglia and thalamus and are associated with tremors or other movement disorders. Several bacterial and viral causes, including Bartonella henselae , M tuberculosis , Enterovirus-71, flaviviruses (eg, West Nile virus, Japanese encephalitis virus), and alphaviruses (eg, Eastern equine encephalitis virus), can cause brainstem encephalitis manifesting as autonomic dysfunction, lower cranial nerve involvement, and respiratory drive disturbance. Despite these classic associations, no presenting sign, symptom, or CSF finding alone or in combination with another can accurately distinguish one cause of encephalitis from another.
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