on 08-Jun-2022 (Wed)

Mumps — Aseptic meningitis is the most frequent extrasalivary complication of mumps virus infection. Prior to the introduction of the mumps vaccine in 1967, this paramyxovirus was a relatively common cause of viral meningitis, accounting for between 10 and 20 percent of all cases [4,20].

The most frequent manifestations are headache, low-grade fever, and mild nuchal rigidity. The onset of meningitis is variable and can occur before, during, or after an episode of mumps parotitis, although salivary gland enlargement is only present in about 50 percent of patients with mumps CNS disease. (See "Mumps".)

The CSF profile typically reveals fewer than 500 WBC/microL with a lymphocytic predominance, but more than 1000 WBC/microL and an early neutrophil predominance can occasionally be seen. The CSF total protein is generally normal or mildly elevated and the CSF glucose levels may be mildly depressed.

Miscellaneous viruses — A number of other viruses can infrequently be associated with viral meningitis. In certain areas of the United States, arthropod-borne viruses can cause aseptic meningitis. West Nile virus, St. Louis encephalitis virus, and California encephalitis group of viruses all can cause aseptic meningitis but more frequently are associated with encephalitis. (See "Epidemiology and pathogenesis of West Nile virus infection" and "St. Louis encephalitis" and "Viral encephalitis in adults".)

Aseptic meningitis can also be associated with varicella zoster virus infection [21], Epstein-Barr virus, cytomegalovirus, human herpes virus-6, and adenoviruses.

Spirochetes — The two major spirochetes that need to be considered in the differential diagnosis of aseptic meningitis are Treponema pallidum, the causative agent of syphilis, and Borrelia burgdorferi, the spirochete that causes Lyme disease. Leptospirosis can also cause an aseptic meningitis syndrome.

Syphilis — Treponema pallidum, the causative agent of syphilis, disseminates to the central nervous system during early infection. Syphilitic meningitis can present in the setting of secondary syphilis with headache, malaise, and disseminated rash. (See "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV", section on 'Neurologic/ocular findings'.)

Cerebrospinal fluid (CSF) findings include a lymphocytic pleocytosis with an elevated protein concentration; occasionally a depressed glucose concentration may also be seen. Specific serum treponemal tests are almost always positive. The CSF venereal disease research laboratory test (VDRL) has a generally accepted sensitivity of 30 to 70 percent, but is highly specific in the absence of visible blood contamination.

Lyme disease — Lyme meningitis typically occurs in the late summer and early fall, the same time as the peak incidence of enteroviral meningitis. During the acute primary infection, some patients develop headache, neck stiffness, and photophobia. Fever is usually mild; Kernig and Brudzinski signs are usually absent on physical examination, and neurologic features can include cranial nerve palsies, especially involving the facial nerve which may be bilateral.

The diagnosis of aseptic meningitis due to Lyme disease is facilitated when other characteristic findings are present, such as erythema migrans. When Lyme meningitis occurs alone, the diagnosis can be missed unless the clinician considers other risk factors, such as potential exposure to ticks or travel history. (See "Epidemiology of Lyme disease" and "Diagnosis of Lyme disease".)

Fungal infections — The two major fungal infections that should be considered in the differential diagnosis of aseptic meningitis include cryptococcus and coccidioidomycosis.

Cryptococcal infection — Cryptococcus neoformans produces infection following inhalation through the respiratory tract. The organism disseminates hematogenously and has a propensity to localize to the CNS, particularly in patients with severe deficiencies in cell-mediated immunity. (See "Clinical manifestations and diagnosis of Cryptococcus neoformans meningoencephalitis in HIV-seronegative patients" and "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in patients with HIV".)

Symptoms typically begin in an indolent fashion, usually over a period of one to two weeks. The three most common symptoms are fever, malaise, and headache. Stiff neck, photophobia, and vomiting are seen in one-fourth to one-third of patients.

The CSF WBC count is typically low (<50/microL) with a mononuclear predominance and the protein and glucose concentrations are usually only slightly abnormal.

Coccidioidal infection — Coccidioides immitis is endemic in desert regions of the southwestern United States and Central and South America. This infection has protean manifestations, and primary infection is frequently unrecognized. Meningitis is the most lethal complication of coccidioidomycosis and is therefore crucial to recognize.

Symptoms of meningitis, including persistent and severe headache, usually develop within several months of the initial infection. Abnormal neurologic findings on physical examination are frequently absent early in the course of coccidioidal meningitis.

The CSF WBC counts ranges from one to several hundred cells. A significant numbers of eosinophils may be present, but this finding is not specific for coccidioidal meningitis. The CSF glucose concentration may be depressed and is occasionally profoundly low in association with an elevation of the CSF protein concentration. (See "Coccidioidal meningitis".)

Tuberculous meningitis — Patients with tuberculous meningitis frequently have protracted headache, vomiting, confusion, and varying degrees of cranial nerve signs. Mental status changes can occur, leading to coma, seizures, and at times hemiparesis. Signs of disseminated TB are of diagnostic importance, but are often absent.

CSF analysis typically shows elevated protein and lowered glucose concentrations with a mononuclear pleocytosis. (See "Central nervous system tuberculosis: An overview".)

Bacterial infections — There are a variety of ways in which bacterial infections can lead to a clinical picture of aseptic meningitis with a CSF pleocytosis:

● Parameningeal sources, such as an epidural abscess or subdural empyema, sinus, or ear infection, can occasionally lead to meningitis. A thorough history and physical examination can lead to appropriate imaging and the correct diagnosis. (See "Spinal epidural abscess" and "Intracranial epidural abscess" and "Acute sinusitis and rhinosinusitis in adults: Clinical manifestations and diagnosis" and "Acute otitis media in children: Epidemiology, microbiology, and complications", section on 'Complications and sequelae'.)

● Bacterial endocarditis can lead to brain abscesses and seeding of the cerebrospinal fluid via hematogenous seeding. (See "Complications and outcome of infective endocarditis", section on 'Neurologic complications'.)

● A lymphocytic CSF profile and sterile cultures may be seen in partially treated bacterial meningitis. (See "Clinical features and diagnosis of acute bacterial meningitis in adults".)

Angiostrongylus infection — Angiostrongylus cantonensis, the rat lungworm, is a parasite that is endemic in Southeast Asia and Pacific that can also cause an aseptic meningitis. Symptoms include severe headache, stiff neck, paresthesias, and uncommonly facial nerve palsy [22,23].

The diagnosis of cerebral angiostrongyliasis is generally based upon the clinical presentation, CSF eosinophilia, and an epidemiologic history of known or possible exposure to infective A. cantonensis larvae. The CSF protein concentration is usually elevated, but the glucose concentration is normal or only minimally reduced. Peripheral blood and CSF eosinophilia frequently occur. (See "Eosinophilic meningitis".)

Hematologic malignancies, have a particular propensity to seed the CNS, especially large cell lymphomas and acute leukemias. Solid tumors frequently causing carcinomatous meningitis include breast cancer, lung cancer, melanoma, gastrointestinal malignancies, and cancers of unknown primary origin

Meningeal signs caused by tumor invasion of the leptomeninges and secondary inflammation are common. Headache, nausea, and vomiting may be presenting symptoms of increased intracranial pressure.

The diagnosis of neoplastic meningitis is the cytologic identification of malignant cells within the cerebrospinal fluid (CSF). The CSF profile may include an elevated protein concentration and a lymphocytic pleocytosis; a very high protein concentration suggests a CSF block. There may be a low glucose concentration, sometimes close to zero. CSF eosinophilia can be seen in Hodgkin lymphoma.

Drug-induced meningitis is an unusual adverse reaction that is usually a diagnosis of exclusion [24-26]. A number of drugs can induce symptoms and signs of aseptic meningitis including nonsteroidal anti-inflammatory drugs (NSAIDs) [24-28], certain antibiotics (eg, trimethoprim-sulfamethoxazole) [29], intravenous immune globulin [24,25,30], rofecoxib, cetuximab [31], antiepileptic drugs [32,33], infliximab [34], and OKT3 antibodies.

Two mechanisms have been proposed for drug-induced meningitis: a delayed hypersensitivity type reaction and direct meningeal irritation [26].

The cerebrospinal fluid (CSF) profile typically has a neutrophilic pleocytosis. Symptoms often resolve a few days after drug discontinuation [24,30,31].

There are also multiple reports of drug-induced meningitis in patients with autoimmune disease [27,29,35]. Many of these reports implicate use of NSAIDs. It is unclear whether these patients are inherently at increased risk or whether the incidence is greater as a result of the prevalent usage of nonsteroidal anti-inflammatory drugs [36]. (See "Manifestations of systemic lupus erythematosus affecting the peripheral nervous system".)

APPROACH TO THE PATIENT — The clinical presentation of aseptic meningitis is generally nonspecific, with fever, headache, nausea and vomiting, occasionally accompanied by photophobia and a stiff neck. Physical examination typically reveals signs of nuchal rigidity.

As noted above, the approach to patients with aseptic meningitis is complicated by the diverse range of etiologic agents and relatively limited available diagnostic tools

Historical clues — Clinicians should bear in mind the following points:

● Obtain a comprehensive travel and exposure history, including exposure to rodents (LCMV), ticks (Lyme), and tuberculosis, sexual activity (HSV-2, HIV, syphilis), and contact with other individuals with similar symptoms or viral exanthems (enteroviruses).

● Consider potential nonviral etiologies. Patients should be specifically questioned about preceding use of drugs associated with meningitis (eg, NSAIDs, intravenous immune globulin, trimethoprim-sulfamethoxazole).

Clues on physical examination — Physical examination may reveal findings suggestive of a specific agent:

● A diffuse maculopapular exanthem in a mildly ill patient may be consistent with enteroviral infection, primary HIV, or syphilis.

● Parotitis suggests mumps meningitis in an unvaccinated patient.

● Severe vesicular and ulcerative genital lesions suggests a primary episode of HSV-2 infection.

● Oropharyngeal thrush and cervical lymphadenopathy is consistent with primary HIV infection.

● Asymmetric flaccid paralysis strongly suggests the possibility of West Nile virus meningitis [26]. (See "Clinical manifestations and diagnosis of West Nile virus infection".)

Management — Based upon the history, physical examination, and cerebrospinal fluid (CSF) findings, patients can be classified as having probable bacterial meningitis, probable viral meningitis, or indeterminant (table 2).

For patients with suspected bacterial meningitis (eg, WBC count >1000/microL, glucose concentration <40 mg/dL [2.2 mmol/L], protein concentration >100 mg/dL), antibiotics should be initiated promptly.

Patients with probable viral meningitis include those with CSF findings of cell count <500/microL, >50 percent CSF lymphocytes, protein concentration less than 80 to 100 mg/dL, normal glucose concentration, and negative Gram stain. Patients who are elderly, immunocompromised, or have received antibiotics prior to presentation should be given antibiotics even if viral meningitis is the suspected diagnosis. Otherwise, the clinician can consider observing the patient without antibiotic therapy.

When it is not clear whether the patient has a viral or bacterial process, the treating physician can choose empiric antibiotics after obtaining blood and CSF cultures or observation with repeat lumbar puncture (LP) in 6 to 24 hours. The majority of clinicians opt for empiric antibiotics until culture results are available in 24 to 48 hours. If the patient is symptomatically improved and culture results are negative, then antibiotics can generally be stopped without a repeat LP if the suspicion for bacterial meningitis is unlikely. However, repeat LP may be indicated in patients with persistent symptoms who do not have a clear diagnosis

Many patients fall into the indeterminate category because of the lack of specificity of presenting symptoms and signs and because each CSF finding taken in isolation often displays significant overlap among patients with viral and bacterial meningitis.

Thus, in view of the serious consequences if treatment of bacterial meningitis is delayed, the threshold to initiate empiric antibiotic therapy pending the results of cultures should be relatively low.

For patients with suspected viral meningitis or indeterminate CSF results, the CSF should be sent for virus detection assay (eg, polymerase chain reaction [PCR] for HSV and enteroviruses), as well as for bacterial culture and routine CSF studies. In patients with cutaneous clues as to the etiology (eg, genital herpes or herpes zoster), PCR testing is preferred. Other tests to consider in selected patients include: serum treponemal and nontreponemal tests and CSF Venereal Disease Research Laboratory (VDRL) and fluorescent treponemal antibody absorption (FTA-ABS) tests, HIV antigen/antibody or RNA tests, Lyme serology, and acute/convalescent serologic testing for specific viruses (LCMV, mumps, measles).

The differential diagnosis should be broadened for the patient with lymphocytic predominance in the CSF and negative bacterial cultures if symptoms worsen or persist. Evaluation should include a repeat CSF analysis with removal of large volume of fluid (3 to 5 mL, if possible) for fungal and mycobacterial cultures, and imaging of the CNS and sinuses with magnetic resonance imaging (MRI) or computed tomography (CT). Potential noninfectious etiologies should also be considered (table 1)

Management — A careful history should include travel and exposure history, including exposure to rodents (LCMV), ticks (Lyme disease), mosquitoes (West Nile virus, St. Louis encephalitis virus) and patients with tuberculosis, sexual activity (HSV-2, HIV, syphilis), travel (C. immitis, A. cantonensis) and contact with other individuals with similar symptoms or viral exanthems (enteroviruses). The patient should also be questioned about medications and other comorbidities.

Patients who are elderly, immunocompromised, or have received antibiotics prior to presentation may be considered for empiric therapy for 48 hours, even if viral meningitis is the suspected diagnosis. Otherwise, the clinician can consider observing the patient without antibiotic therapy.

If aseptic meningitis due to HSV is suspected (eg, concomitant genital lesions), empiric therapy with acyclovir (10 mg/kg intravenously every eight hours) can be considered for hospitalized patients.

Unclear etiology — When it is not clear whether the patient has a viral or bacterial process, we recommend empiric antibiotics after obtaining blood and CSF cultures or observation with repeat lumbar puncture in 6 to 24 hours. If the patient is symptomatically improved and culture results are negative, then antibiotics can generally be stopped without a repeat LP. However, repeat LPs may be indicated in patients with persistent symptoms who do not have a clear diagnosis.

The presence or absence of normal brain function is the important distinguishing feature between encephalitis and meningitis. Patients with meningitis may be uncomfortable, lethargic, or distracted by headache, but their cerebral function remains normal. In encephalitis, however, abnormalities in brain function are a differentiating feature, including altered mental status, motor or sensory deficits, altered behavior and personality changes, and speech or movement disorders

Seizures and postictal states can be seen with meningitis alone and should not be construed as definitive evidence of encephalitis. Other neurologic manifestations of encephalitis may include hemiparesis, flaccid paralysis, and paresthesias

The importance of distinguishing between encephalitis and aseptic meningitis relates to the fact that the likely cause of each syndrome is different. Some viral agents are more likely to cause aseptic meningitis, and others are more likely to cause encephalitis. (See "Aseptic meningitis in adults".)

Viral encephalitis can be either primary or postinfectious (ie, it occurs after the infection has resolved) [5].

● Primary infection is characterized by viral invasion of the central nervous system (CNS). Neuronal involvement can be identified on histologic examination, which may show inclusion bodies on light microscopy or viral particles on electron microscopy. The virus can often be cultured from brain tissue.

● In postinfectious encephalitis (also called acute disseminated encephalomyelitis, or ADEM), a virus cannot be detected or recovered, and the neurons are spared [5]. However, perivascular inflammation and demyelination are prominent in this entity. The inability to recover a virus and the type of histologic abnormalities observed suggest that postinfectious encephalitis is an immune-mediated disease [6]. (See "Acute disseminated encephalomyelitis (ADEM) in adults".)

Despite the differences in pathogenesis and histologic findings, the clinical significance of viral versus postinfectious encephalitis is often limited. It is also important to note that a number of viral infections, such as measles, varicella, or rubella, can produce either syndrome. (See 'Viral pathogens' below.)

A wide variety of different viruses can infect the central nervous system (CNS). Most viruses are capable of causing either meningitis or encephalitis, although, in general, a given virus is more likely to cause one syndrome rather than the other.

A common cause of sporadic encephalitis is herpes simplex virus (HSV) type 1 [7]. It is important to diagnose this virus because it is treatable, and the success of treatment is related to how early therapy is initiated.

Other viral pathogens may be suggested by geographic location (eg, Eastern equine encephalitis in North America and Japanese encephalitis in Asia) and epidemiologic clues, such as exposure history (eg, bat exposure or dog bite and rabies), regional outbreaks (eg, enterovirus type 71 in Denver, Colorado) [8], and clinical clues, such as profound weakness and rash with West Nile. Uncommon causes include varicella zoster virus, Epstein-Barr virus, HIV, human herpes virus-6, parvovirus, and Zika virus [9-13]. (See "St. Louis encephalitis" and "Arthropod-borne encephalitides" and "Clinical manifestations and diagnosis of rabies".)

Arboviruses (eg, eastern equine, western equine, St. Louis, Venezuelan equine encephalitis, and West Nile virus) cause disease when mosquitoes are active, whereas HSV can occur at any time

In contrast, walking in woods or marshy areas with high tick populations might suggest tick-borne encephalitides seen in Eastern Europe, Colorado tick fever (western United States), and Powassan virus encephalitis. Powassan virus is transmitted by Ixodes ticks and should be considered in regions where these ticks are found (eg, eastern Canada and the north central and northeastern United States). Other tick-borne but nonviral etiologies include Lyme disease and Rocky Mountain spotted fever.

West Nile virus has been by far the most common cause of proven viral encephalitis in the United States [14,15]. West Nile virus first appeared in the United States in 1999, even though it had already been established in Africa, Asia, and Europe, and then spread rapidly across the country.

Nipah virus encephalitis, which appeared in Malaysia and Singapore and is now present in Bangladesh, may be associated with exposure to pigs or bats [18-20]

Human infection with Hendra virus, which is seen in Australia, results from direct contact with infected horses.

Avian influenza infection was associated with encephalitis in two patients from Vietnam; the source of exposure was unclear but both children swam in a canal that was frequented by ducks [ 21].

Lymphocytic choriomeningitis virus (LCMV) is a human-acquired zoonosis caused by a rodent-borne arenavirus, which can be transmitted through exposure to secretions of mice, rats, and hamsters.

Encephalitis resulting from a bornavirus was reported in three German breeders of variegated squirrels; the virus was also detected in a squirrel from the breeding population of one of the patients [ 22].

Prior history of an animal exposure or bite may also suggest the possibility of rabies encephalitis; however the absence of such a history does not eliminate the diagnostic possibility of rabies.

Patients with encephalitis have an altered mental status ranging from subtle deficits to complete unresponsiveness. Symptoms and signs of meningeal irritation (photophobia and nuchal rigidity) are usually absent with a pure encephalitis, but often accompany a meningoencephalitis

Seizures are common with encephalitis, and focal neurologic abnormalities can occur, including hemiparesis, cranial nerve palsies, and exaggerated deep tendon and/or pathologic reflexes. Patients may appear confused, agitated, or obtunded

The clinical presentation of aseptic meningitis is generally nonspecific, with fever, headache, nausea, and vomiting, occasionally accompanied by photophobia and a stiff neck. Physical examination characteristically reveals signs of nuchal rigidity, but its absence does not rule out the diagnosis.

Parotitis strongly suggests the diagnosis of mumps encephalitis in an unvaccinated patient with mental status changes. (See "Mumps".)

Flaccid paralysis, a polio-like presentation, that evolves into an encephalitis strongly suggests the possibility of West Nile virus infection [23]. In fact, it has been misdiagnosed as Guillain-Barré syndrome. A maculopapular rash is also seen in approximately half of patients with this infection and is not expected in other viral encephalitides.

Tremors of the eyelids, tongue, lips, and extremities may suggest the possibility of St. Louis encephalitis or West Nile encephalitis in the appropriate geographic location or travel history

Findings of hydrophobia, aerophobia, pharyngeal spasms, and hyperactivity suggest encephalitic rabies. Atypical presentations of rabies include seizures, cranial nerve palsies, and myoclonus

Grouped vesicles in a dermatomal pattern may suggest varicella zoster virus (VZV), which can occasionally cause encephalitis; however, the absence of rash does not eliminate VZV from consideration [24]. (See "Epidemiology, clinical manifestations, and diagnosis of herpes zoster".)

Temporal lobe involvement is strongly suggestive of herpes simplex virus (HSV) encephalitis, although other herpes viruses (eg, VZV, Epstein-Barr virus, human herpesvirus 6) can also produce this clinical picture [25,26].

Involvement of the thalamus or basal ganglia may be observed in the setting of encephalitis due to respiratory viral infection, Creutzfeldt-Jakob disease, arbovirus, and tuberculosis [27-29].

In a study of 17 patients with confirmed West Nile infection, MRI imaging demonstrated a variety of abnormalities in the basal ganglia, thalami, mesial temporal structures, brainstem, and cerebellum in eight patients [30]. Three patients with muscle weakness also had abnormalities noted in the spinal cord and cauda equina.

The presence of hydrocephalus may suggest nonviral etiologies such as bacteria, fungal, or parasitic agents [26].

MRI during postinfectious encephalitis may demonstrate multifocal lesions mainly involving supratentorial white matter [6]. (See 'Viral versus postinfectious encephalitis' above.)

Electroencephalography is often abnormal in acute encephalitis. Focality in the temporal lobe region is suggestive of HSV encephalitis, as noted above [31].

The findings with aseptic meningitis and encephalitis are generally indistinguishable (although, rarely, there may be few, if any, CSF abnormalities with a pure encephalitis).

The following findings are characteristic of viral CNS infections (table 2):

● Increased white blood cell (WBC) count, but usually less than 250/mm³. The differential shows a predominance of lymphocytes, although early infection may reveal a predominance of neutrophils. In the latter setting, a repeat CSF cell count eight hours later will generally show a shift from neutrophils to lymphocytes [32].

● Elevated protein concentration, but usually less than 150 mg/dL.

● Usually normal glucose concentration (>50 percent of blood value), but moderately reduced values are occasionally seen with HSV, mumps, or some enteroviruses.

● Red cells are usually absent (in a nontraumatic tap); their presence in the appropriate clinical setting suggests HSV-1 infection or other necrotizing encephalitides [33].

Analysis of the cerebrospinal fluid (CSF) is required as an initial diagnostic step in patients with suspected viral encephalitis.

● The opening CSF pressure should be noted and CSF should be analyzed for cell count, glucose, and protein.

● In addition to this basic testing, the initial work-up for the etiology of a viral infection should generally include: CSF polymerase chain reaction (PCR) testing for herpes simplex virus (HSV)-1, HSV-2, VZV, and enteroviruses.

● Additional testing (eg, serology for arboviruses, HIV testing) should be considered based on geographic considerations, the clinical presentation, and the exposure history. (See 'Historical clues' above.)

● Diagnostic evaluation for nonviral infectious (eg, bacteria, fungi, and mycobacteria) and noninfectious etiologies should also be considered. (See 'Differential diagnosis' below.)

The most important viral etiology to rule out in a patient with encephalitis is HSV, since this clinical entity is usually fatal if untreated. HSV should be considered, particularly if there is temporal lobe focality suggested by symptoms, signs, or imaging studies.

Diagnosis is most readily made by detecting HSV DNA by PCR on CSF [ 35]. While awaiting confirmation, empiric therapy with acyclovir should be initiated. (See 'Empiric therapy' below.)

Enteroviruses are more commonly associated with viral meningitis, but infrequently they may cause encephalitis as well. PCR testing on the CSF sample is the diagnostic test of choice. The pathogen can also be cultured from the stool and throat; however, a positive stool or throat culture is not necessarily diagnostic of disease, especially in summer months.

Rabies should also be considered in any patient with an undiagnosed encephalitis even with a negative exposure history. Diagnosis of rabies requires several specimens including saliva, skin biopsy, and CSF since the sensitivity of any single test is limited.

Viral culture has been routinely ordered by most clinicians after obtaining CSF samples. However, one review demonstrated that viruses were recovered from only 6 percent of 22,394 viral cultures of CSF samples [36].

Culture may still be important when rare causes of encephalitis are being considered (eg, influenza, parainfluenza, measles, mumps) for which PCR testing is unavailable.

Identification of HSV-1 in the CSF is a rapid, sensitive, and specific diagnostic test for HSV-1 encephalitis [38]. Likewise, identification of HSV-2 in CSF is a rapid diagnostic test for HSV-2 meningitis.

PCR testing for other viruses will depend on the clinical situation, epidemiology, and availability. For West Nile virus, PCR testing is not as sensitive as IgM serology (the preferred test). (See "PCR testing for the diagnosis of herpes simplex virus in patients with encephalitis or meningitis".)

Serology — Serologic testing is most important for patients who are not improving and who do not have a diagnosis based upon PCR. Most viral etiologies require paired sera for diagnosis; thus it is prudent to save serum in the setting of acute illness that can later be used if necessary. Convalescent serology should be obtained no sooner than three weeks after the onset of the clinical illness. As an example, the presence of IgM antibodies in a single serum provides presumptive evidence of St. Louis encephalitis; however, a significant rise or fall between appropriately timed acute convalescent or early-late convalescent sera is diagnostic.

West Nile has emerged as the most common cause of viral encephalitis in the United States. A single specimen looking for IgM antibodies in the serum or CSF is sufficient for diagnosis. A single serum specimen can also be used to diagnose mumps. Serology may also be helpful in obtaining evidence for primary Epstein-Barr virus infection, a rare cause of meningoencephalitis.

In a report of 432 high-risk patients who underwent brain biopsy of presumptive herpes simplex encephalitis, 45 percent had the diagnosis confirmed, 9 percent had another virus detected, and 9 percent had another treatable cause [33]. This underscores the point that the clinical diagnosis of HSV encephalitis is often incorrect and needs to be confirmed by PCR testing.

Among 334 patients with a case definition of encephalitis in the California Encephalitis Project, a confirmed or probable viral cause was present in 9 percent [39]; a possible cause was identified in 12 percent, a noninfectious etiology in 10 percent, and a bacterial cause in 3 percent. Despite extensive testing, 62 percent of cases were unexplained.

In a series from the New York State Department of Health of 106 patients with presumed viral CNS infection seen in 1997 and 1998, PCR testing revealed a viral cause in 38 (36 percent) [40]. The rate of detection in earlier time periods before PCR testing was much lower (about 10 percent), employing cell culture and serologic testing.

In a later, larger series of almost 3500 patients from the same laboratory, PCR identified a viral etiology in CSF or brain tissue in only 14 percent (498 patients); selection bias may have accounted for much of the difference [41]. The most common viral causes were enterovirus (72 percent), herpes simplex (15 percent), VZV (6 percent), and West Nile virus (4 percent).

It is critical that the clinician considers a broad range of causes when evaluating patients who present with encephalitis. Only some of the causes are infectious, and not all infections are viral.

A number of noninfectious etiologies can mimic central nervous system (CNS) infections. These include primary intracranial or metastatic tumors, adverse effects of medications, and autoimmune or paraneoplastic diseases, such as those associated with vasculitis or the anti-NMDA receptor (table 3). (See "Paraneoplastic and autoimmune encephalitis".)

Nonviral infectious etiologies to consider in the patient with suspected CNS infection include brain abscess, syphilis, tuberculous meningitis, and fungal meningitis (eg, coccidioides), which can affect the sensorium. Amoebic encephalitis, often associated with freshwater swimming, should also be an occasional consideration. (See "Pathogenesis, clinical manifestations, and diagnosis of brain abscess" and "Central nervous system tuberculosis: An overview" and "Coccidioidal meningitis" and "Neurosyphilis".)

Regular Bayesian networks are purely statistical models, so we can only talk about the flow of association in Bayesian networks.