on 30-May-2022 (Mon)

The term aseptic meningitis refers to patients who have clinical and laboratory evidence for meningeal inflammation with negative routine bacterial cultures. The most common causes are the enteroviruses [1]. Additional etiologies include other infections (mycobacteria, fungi, spirochetes), parameningeal infections, medications, and malignancies (table 1) [2]

Aseptic meningitis often has a similar presentation to that of bacterial meningitis (ie, fever, headache, altered mental status, stiff neck, photophobia), which can be a life-threatening illness. However, in contrast to bacterial meningitis, many patients with aseptic meningitis (particularly those who have disease caused by viruses or medications) have a self-limited course that will resolve without specific therapy

The assessment of patients with probable aseptic meningitis is complicated by the large number of potential etiologic agents and the relatively limited diagnostic tools for identifying specific pathogens. (See "Clinical features and diagnosis of acute bacterial meningitis in adults" and "Herpes simplex virus type 1 encephalitis".)

Patients with meningitis may be lethargic or distracted by headache, but their cerebral function remains normal. In contrast, patients with encephalitis commonly present with abnormalities in brain function such as 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 include hemiparesis, flaccid paralysis, and paresthesias

However, the distinction between the two entities is frequently blurred since some patients may have both a parenchymal and meningeal process with clinical features of both. The patient is usually labeled as having meningitis or encephalitis based upon which features predominate in the illness although meningoencephalitis is also a common term that recognizes the overlap.

A number of viruses produce aseptic meningitis including enteroviruses, herpes simplex virus (HSV), human immunodeficiency virus (HIV), West Nile virus (WNV), varicella-zoster virus (VZV), mumps, and lymphocytic choriomeningitis virus (LCM)

Enteroviruses — Aseptic meningitis occurring during the summer or fall is most likely to be caused by enteroviruses (eg, Coxsackievirus, echovirus, other non-poliovirus enteroviruses), the most common causes of viral meningitis [3]. However, seasonal variation of certain CNS viral infections is relative and not absolute. Enteroviruses continue to cause 6 to 10 percent of cases of viral meningitis in the winter and spring despite their predilection for inciting illness in the late summer and fall [4]

The presenting signs and symptoms of enteroviral meningitis are not distinctive. The onset of symptoms is characteristically abrupt and typically includes headache, fever, nausea or vomiting, malaise, photophobia, and meningismus. Rash, diarrhea, and upper respiratory symptoms may also be present

Cerebrospinal fluid (CSF) findings are typical of other viral meningitides and include a white blood cell (WBC) count that is generally less than 250 cells/microL, a modest elevation in CSF protein concentration (generally less than 150 mg/dL), and a normal glucose concentration (table 2).

Up to two-thirds of patients with enteroviral meningitis have a polymorphonuclear predominance in the CSF when examined early in the course of the illness. Repeat lumbar puncture after 12 to 24 hours, if performed, generally shows an evolution to a lymphocytic predominance

Polymerase chain reaction (PCR) testing for enteroviruses can be considered if a definitive diagnosis is desired, or in the setting of an outbreak situation, but is not necessary in all patients.

CSF nucleic acid amplification tests (NAATs) for enteroviruses yield sensitivities that range from 86 to 100 percent and specificities that range from 92 to 100 percent [ 5]. Among patients with CNS manifestations and a negative CSF NAAT, upper respiratory tract and gastrointestinal tract specimens for enterovirus may be useful to establish a diagnosis of enterovirus infection [6]. However, detection of enterovirus from the throat or stool of an individual with aseptic meningitis may represent an infection that occurred weeks previously and is unrelated to the present syndrome [5].

HIV infection — Primary infection with HIV frequently presents as a mononucleosis-like syndrome manifested by fever, malaise, lymphadenopathy, rash, and pharyngitis. A subset of these patients will develop meningitis or meningoencephalitis, manifested by headache, confusion, seizures or cranial nerve palsies.

In most patients with HIV-1 meningitis, the clinical findings resolve without treatment, and patients may be erroneously assumed to have a benign cause of viral meningitis. Thus, clinicians should have a high index of suspicion for primary HIV infection in patients at increased risk for acquisition of this virus. The identification of the patient with acute HIV infection is also important from a public health viewpoint since the risk of transmission is facilitated by high levels of viremia

The CSF profile characteristically has a lymphocytic pleocytosis, an elevated protein concentration, and normal glucose concentration (table 2). Documentation of primary HIV infection is accomplished by demonstration of seroconversion or detection of HIV-1 viremia in the absence of HIV antibody.

Herpes simplex meningitis — Primary HSV has been increasingly recognized as a cause of viral meningitis in adults. In contrast to HSV encephalitis, which is almost exclusively due to HSV-1, viral meningitis in immunocompetent adults is generally caused by HSV-2 [3].

Between 13 and 36 percent of patients presenting with primary genital herpes have clinical findings consistent with meningeal involvement, including headache, photophobia and meningismus. On the other hand, genital lesions are present in approximately 85 percent of patients with primary HSV-2 meningitis and generally precede the onset of CNS symptoms by approximately seven days. The CSF profile includes a pleocytosis with a predominance of lymphocytes, and a normal CSF glucose concentration (table 2). HSV meningitis can also occur without evidence of genital lesions, although this is less common [3,7]. Thus, the absence of genital lesions should not deter the clinician from testing for HSV-2 infection in a patient with aseptic meningitis.

There is no standard approach to the treatment of HSV meningitis [8]. For hospitalized patients, intravenous acyclovir at 10 mg/kg administered every eight hours is reasonable. The dose should be adjusted for individuals with reduced kidney function, and recommendations are provided in the Lexicomp drug information topic within UpToDate. Patients can be switched to an oral agent on discharge for a total of 10 to 14 days of treatment.

However, the role of antiviral therapy for HSV meningitis remains unclear, especially in immunocompetent hosts. As an example, a retrospective observational study that evaluated forty-two patient episodes of HSV meningitis found that immunocompromised patients had fewer neurologic sequelae when treated with a short course of antiviral therapy [9]. By contrast, this benefit was not seen in the 27 patient episodes that occurred in immunocompetent patients. More studies are needed to help guide management decisions.

Recurrent (Mollaret's) meningitis — Mollaret's meningitis is a form of recurrent benign lymphocytic meningitis (RBLM), an uncommon illness characterized by greater than three episodes of fever and meningismus lasting two to five days, followed by spontaneous resolution [10]. There is a large patient-to-patient variation in the time course to recurrence that can vary from weeks to years. One-half of patients can also exhibit transient neurological manifestations, including seizures, hallucinations, diplopia, cranial nerve palsies, or altered consciousness

The most common etiologic agent in Mollaret's meningitis is HSV-2, although some patients do not have evidence of genital lesions at the time of presentation [11]. Studies suggest that recurrent meningitis occurs in approximately 20 percent of patients who present with primary HSV-2 infection with meningitis [12,13]. The diagnosis can be made by PCR testing for HSV DNA in the CSF.

Noninfectious etiologies for Mollaret's meningitis have also been proposed. As an example, patients with an intracranial epidermoid cyst or other cystic abnormalities in the brain can develop meningeal irritation due to intermittent leakage of irritating squamous material into the CSF [15,16]. This may be detected acutely by polarizing microscopy of CSF. Imaging studies should be performed subsequently when the patient is asymptomatic, since the epidermoid cyst is often collapsed immediately after leaking its contents

Lymphocytic choriomeningitis virus — Lymphocytic choriomeningitis virus (LCMV) is a human zoonosis caused by a rodent-borne arenavirus. LCMV is excreted in the urine and feces of rodents, including mice, rats, and hamsters, and is transmitted to humans by exposure to secretions or excretions (by direct contact or aerosol) of infected animals or contaminated environmental surfaces [17-19]. Infection is more common during winter months.

Affected patients generally present with an influenza-like systemic illness accompanied by headache and meningismus. A minority of patients develop orchitis, parotitis, myopericarditis, or arthritis

CSF findings are typical of other causes of viral meningitis except that low glucose concentrations are observed in 20 to 30 percent of patients with LCMV meningitis and CSF WBC counts of greater than 1000/microL are not unusual [20]. The diagnosis is established by documentation of seroconversion to the virus in paired serum samples; in addition, cell culture of CSF usually detects the presence of LCMV [5]. There is no specific antiviral therapy for LCMV

It is common to classify economic activity into two sectors: the public sector and the private sector.

It is com- monly assumed that all businesses in the private sector have profit maximisation as their prime objective

Objectives can change over time. A business trading in a period of reduced econ- omic activity (especially a recession) may focus on survival rather than profit maxi- misation

Assets Assets are the resources which are used by the business as part of the activities of the business (e.g. property, equipment and cash).

Liabilities represent the debts of the business – i.e. what is owed by the business to others. These may be short-term debts which are to be repaid soon or long-term debts which may be outstanding and owing for many years (e.g. a mortgage)

Capital refers to the resources supplied to the business by the owner(s) of the (or equity) business. This capital could be in the form of money or as other assets.

This relates to the idea that accounting transactions can be considered from two different perspectives

Assets == Capital ++ Liabilities

Rules and regulations are not as important for the purpose of internal accounts as they are for those for external publication and external use.

Accounting standards are a set of continually evolving documents which provide guidance on various aspects of financial accounting

When there is an association between A and Y, even if A has a null causal effect, a zero causal effect on Y, then we say that there is bias under the null.

We have seen that confounding is a systematic bias when we are conducting causal inference research.

Systematic bias is an association between the treatment A and the outcome Y that does not arise from the causal effect of A on Y.

A typical adult patient with acute bacterial meningitis usually seeks medical attention within a few hours to several days after the onset of illness

The most common etiologic agents of acute meningitis are unknown. When a cause is identified, viruses (most often enteroviruses; children > adults), West Nile virus (WNV), and herpes simplex virus (HSV) type 2 (adults), but also human immunodeficiency virus (HIV), varicella-zoster virus (VZV), less likely mumps virus, and bacteria (e.g., Streptococcus pneumoniae, Neisseria meningitidis, and Listeria monocytogenes). 2 Less commonly, parasites (e.g., Naegleria fowleri and Angiostrongylus can- tonensis) may cause acute meningitis

In contrast, patients with subacute (>5 days but <30 days="" of="" symptoms)="" or="" chronic="" meningitis="" (="">30 days of symptoms) typically present over weeks to months, or even years (see Chapter 88). 1,2 These patients are more likely to be immunosuppressed, have abnormal neurologic findings, and to have hypoglycorrhachia with less pronounced CSF pleocytosis. 2

The most common etiology is idiopathic, but tuberculous meningitis and fungal meningitis (e.g., caused by Cryptococcus neoformans, His- toplasma spp., and Coccidioides spp.) are important considerations. 1,2

The clinical presentation of cryptococcal meningitis is different in patients with and without acquired immunodeficiency syndrome (AIDS). In non-AIDS patients cryptococcal meningitis is typically a subacute process, in which patients have days to weeks of symptoms characterized by headache, fever, meningismus, and personality changes. In AIDS patients the presentation is subtler with minimal, if any, symptoms; these patients may present with only headache and lethargy, with meningeal findings seen in only a few cases.

An international consortium recently defined encephalitis with a combination of major and minor criteria. The major criteria are altered mental status (defined as a decreased, altered level of consciousness, lethargy, or personality change) lasting ≥24 hours without an alternative diagnosis and is a requirement for the diagnosis. The six minor criteria are (1) documented fever ≥38°C (100.4°F) within 72 hours before or after presentation, (2) seizures not attributable to a preexisting seizure disorder, (3) new-onset focal neurologic findings, (4) CSF white blood cells (WBCs) ≥5/mm 3 , (5) new- or acute-onset neuroimaging abnormali- ties consistent with encephalitis, and (6) abnormalities on electroen - cephalography consistent with encephalitis and not secondary to other etiologies. The presence of two minor criteria indicate possible encephalitis, and greater than or equal to three indicate probable or confirmed encephalitis, if the etiologic agent is confirmed by brain biopsy, serologies, polymerase chain reaction (PCR), or antibodies in patients with autoimmune encephalitis.

A clinical overlap between encephalitis and encephalopathy may exist, the latter referring to a clinical state of altered mental status that can manifest as confusion, disorientation, or other cognitive impairment, with or without evidence of brain tissue inflammation; encephalopathy can be triggered by a number of metabolic or toxic conditions but occasionally occurs in response to certain infectious agents, such as Bartonella henselae and influenza virus. 6

Of all the pathogens reported to cause encephalitis, most are viruses that may be associated with specific clinical and neuroimaging findings that suggest their diagnosis. 4,5 Unilateral temporal lobe encephalitis is classically caused by HSV, leading to clinical manifestations characterized by personality changes, altered mentation, a decreasing level of conscious- ness, seizures, and focal neurologic findings (e.g., dysphasia, weakness, and paresthesias). Bilateral temporal lobe involvement or lesions outside the temporal lobe, insula, or cingulate are less likely caused by HSV. 7

Other herpesviruses that cause encephalitis during any season include VZV, cytomegalovirus (CMV), and human herpesvirus 6 and are usually seen more frequently in immunosuppressed individuals. Arboviruses (e.g., West Nile, eastern equine, St. Louis, La Crosse, and Japanese encephalitis viruses) and respiratory viruses can present with a thalamic and basal ganglia encephalitis presenting with tremors, including Parkinsonism features. 8

Patients with WNV infection typically present between June and October, whereas respiratory viruses are usually present in children during the winter season.

Rabies virus is still a frequent cause of encephalitis in Asia (India especially) and in Africa.

Nonviral causes of encephalitis include Mycobacterium tuberculosis, L. monocytogenes, Rickettsia, Ehrlichia spp., Bartonella spp., Mycoplasma pneumoniae, and Toxoplasma gondii (more often seen in transplant patients with Toxoplasma encephalitis). 4

Several free-living amebae (i.e., N. fowleri, Acanthamoeba spp., and Balamuthia mandrillaris) may cause a fatal encephalitis, usually during the summer months. 4

In many cases of encephalitis (32%–75%) the etiology remains unknown, however, despite extensive diagnostic testing. 4,5,10

Anti–N-methyl-d-aspartate receptor (NMDAR) encephalitis 11,12 is the most common cause of antibody-associated encephalitis and is typically seen in young females with an associated ovarian teratoma. Anti- NMDAR encephalitis has now also been associated with both HSV and VZV infections. 13

Although patients may be brought to medical attention after development of a seizure or alteration in consciousness, fever is usually seen in less than 50% of patients.

In patients with fungal brain abscess caused by Aspergillus spp. or the Mucorales, the clinical presentation may be that of a stroke syndrome because of the propensity of these organisms to invade blood vessels.

The most common complication after lumbar puncture is headache, which is generally observed in 10% to 25% of patients; the headache is characteristically absent when the patient is recumbent and appears rapidly when the patient stands

A recommendation from the American Academy of Neurology supports the use of atraumatic (Sprotte or Pajunk) needles, rather than the standard (Quincke) needle, to reduce the risk of postlumbar puncture headache. 15 Reinsertion of the stylet before needle removal has also been shown to decrease the risk of headache. 15

Infection is a very rare complication after lumbar puncture (1/50,000 procedures), even in patients with concomitant bacteremia. 1,15

Lumbar puncture should not be performed in patients with established local infection in the lumbar space (e.g., spinal epidural abscess, spinal subdural empyema, or superficial or deep paraspinal infection); in these cases, CSF analysis should be obtained under fluoroscopic guidance via high cervical or cisternal puncture. 15

Bleeding may occur from inadvertent puncture of the venous plexuses located dorsally and ventrally to the spinal dura or secondary to injury to vessels that accompany the cauda equina. This local bleeding rarely does harm to the patient, although patients with coagulation disturbances or who are receiving anticoagulants may develop continued bleeding with the development of spinal subdural or epidural hematomas, which may compress the cauda equina and produce permanent neurologic injury. This complication is extremely rare, even in patients with coagulopathies, with only 35 cases described in the literature over the last 42 years. 18

Local bleeding is a more common complication after lumbar puncture 1,15 ; up to 20% of patients have a so-called traumatic tap. 1,15

The Infectious Diseases of America (IDSA) guidelines recommend that patients with suspected meningitis with the following characteristics should get a cranial imaging study before the lumbar puncture: immunocompromised state (HIV infection or AIDS, receiving immunosuppressive therapy, or after transplantation), history of CNS disease (mass lesion, stroke, or focal infection), new- onset seizure, abnormal level of consciousness, papilledema, or focal neurologic deficit (including dilated, nonreactive pupil; abnormalities of ocular motility; abnormal visual fields; gaze palsy; or arm or leg drift). 19

However, adherence to the IDSA guidelines is low (40%), with no clinical benefit in those patients undergoing cranial imaging without an indication. 20

Other guidelines (from the United Kingdom [UK], Europe, and Sweden) are more restrictive, with some guidelines (UK and Sweden) not recommending cranial imaging in immunosup- pressed individuals but recommending cranial imaging only with focal neurologic deficits or finding a Glasgow Coma Scale score <3

It has been suggested, however, that a normal CT scan does not always mean performance of a lumbar puncture is safe. Certain clinical signs of impending herniation, such as a deteriorating level of consciousness (particularly a Glasgow Coma Scale score ≤11), brainstem signs (including pupillary changes, posturing, or irregular respirations), or a very recent seizure, may be predictive of patients in whom lumbar puncture should be delayed. 24

CSF opening pressure is measured with an air-water manometer; in adults placed in the lateral decubitus position, the normal CSF opening pressure ranges from 50 to 195 mm H 2 O; values <150 mm="" H="" 2="" O="" are="" clearly="" normal,="" and="" those="">200 mm H 2 O are abnormal.

The CSF is normally clear and colorless but may appear cloudy or turbid in patients with increased concentrations of WBCs (>200/mm 3 ), red blood cells (RBCs, >400/mm 3 ), bacteria (>10 5 colony- forming units/mL), or protein.

Xanthochromia, a yellow or yellow-orange supernatant of centrifuged CSF, is usually a result of RBC lysis and the presence of oxyhemoglobin, methemoglobin, and bilirubin; it characteristically appears 2 to 4 hours after RBCs have entered the subarachnoid space, although it has occasion- ally been seen for 12 hours. 1,15

The normal CSF WBC count in children and adults is 0 to 5/mm 3 . CSF WBC counts in term neonates may be 32/mm 3 (mean, 8–9/mm 3 ), although by 1 month of age normal CSF has less than 10 WBCs/mm 3 .

Elevated CSF concentrations of WBCs are seen in patients with men- ingitis, encephalitis, and parameningeal foci of infection (e.g., space- occupying lesions). 1,15

Generalized seizures may also induce a transient CSF pleocytosis that is primarily neutrophilic, although the total WBC count should not exceed 80/mm 3 . Pleocytosis should not be ascribed to seizure activity alone, however, unless the fluid is clear and colorless, the opening pressure and CSF glucose are normal, the CSF Gram stain is negative, and the patient has no clinical evidence of CNS infection. 1

Although CSF pleocytosis is suggestive of inflammation of the brain and/or meninges, the absence of CSF pleocytosis does not exclude the diagnosis of encephalitis. 25,26

Two sources of bias:

- common cause (confounding)

- conditioning on common effect (selection bias)

In patients with CSF pleocytosis, differential counts should be performed; a neutrophilic, mononuclear, or eosinophilic predominance may be suggestive of certain etiologies in the right clinical setting (see Table 86.2 and Chapters 88 and 89).

CSF hypoglycorrhachia is seen in many CNS infections. The patho- genesis of CSF hypoglycorrhachia is multifactorial and may include an increased rate of macrovesicular glucose transport across arachnoid villi, increased glycolysis by leukocytes and bacteria, increased metabolic rate of the brain and spinal cord, or inhibition of glucose entry into the subarachnoid space caused by alterations in the membrane carrier system responsible for glucose transfer from blood to CSF. 15,27

Today we will focus on confounding in a setting with no selection bias, with no measurement error, and with such a large population that we do not need to worry about chance variability

The CSF glucose should always be compared with a simultaneous serum glucose that is drawn before lumbar puncture; the normal lumbar CSF-to–serum glucose ratio is approximately 0.6, and ratios <5

Let's start by considering two extreme examples. In the first causal graph here you see that A and Y have no common causes. And therefore, any association between them will be causation. This is the setting that we expect to find in a randomized experiment.

An absolute CSF glucose < 45 mg/dL can be used to define hypoglycorrhachia, as hypoglycemia and hyperglycemia are rarely seen in patients with meningitis. 27

Unfortunately, only 13% of patients with community-acquired meningitis have a simultaneous serum and CSF glucose performed. 27

The CSF protein concentration is also elevated in numerous CNS infections, presumably because of disruption of the blood-brain barrier, manifested morphologically by separation of intercellular tight junctions and increased numbers of pinocytotic vesicles in microvascular endo- thelial cells. 1

Lumbar CSF protein concentrations >50 mg/dL and ventricular CSF concentrations >15 mg/dL are considered abnormal. A CSF protein >100 mg/dL is a risk factor for an urgent treatable cause of meningitis in adults, and a CSF protein <29

In patients with a traumatic lumbar puncture the true CSF protein concentration is determined by subtracting 1 mg/dL of protein for every 1000 RBCs/mm 3 , although these determinations must be made in the same CSF tube. 15

The CSF Gram stain is positive in 60% to 90% of patients with acute bacterial meningitis, although this sensitivity varies depending on the concentra- tion of microorganisms in the CSF and the specific causative bacteria

In patients with tuberculous meningitis, less than 15% to 25% of specimens are smear-positive by acid-fast stain and 20% of patients with tuberculous meningitis have persistently negative CSF cultures

In patients with spirochetal meningitis (i.e., caused by Treponema pallidum or Borrelia burgdorferi) and Tox o- plasma encephalitis, there are no effective specialized stains that identify these organisms in CSF; in these cases serum or CSF antibody studies are most often used to aid in the diagnosis (see Chapters 88 and 89)

CSF India ink examination is positive in 50% to 75% of patients with cryptococcal meningitis, and the yield increases to 88% in patients with AIDS

The presence of virus-specific immunoglobulin M (IgM) in CSF is usually indicative of CNS disease because IgM antibodies do not readily diffuse across the blood-brain barrier; detection of IgM antibodies from patients with presumed flavivirus encephalitis is considered diagnostic of neuroinvasive disease. 4

Today we will focus on confounding in a setting with no selection bias, with no measurement error, and with such a large population that we do not need to worry about chance variability Let's start by considering two extreme examples. In the first causal graph here you see that A and Y have no common causes. And therefore, any association between them will be causation. This is the setting that we expect to find in a randomized experiment. In the second graph here, you see that A and Y have a common cause, L. But there is no causal effect of A on Y. In this setting, all the association between A and Y is due to confounding.

In patients with herpes simplex encephalitis CSF PCR is 96% to 98% sensitive and 95% to 99% specific in adult patients 30 ; CSF PCR results are positive early in the disease course and remain positive during the first week of therapy, although false-negative results may occur if hemoglobin or other inhibitors are present in CSF.

An initially negative CSF PCR result for HSV may become positive if the test is repeated 1 to 3 days after the initiation of treatment 4,31 ; in undiagnosed cases in which patients have clinical or neuroimaging features suggestive of HSV encephalitis, consideration should be given to repeating the PCR for HSV 3 to 7 days later on a second CSF specimen. 4

Diagnosis of CMV encephalitis by PCR has a high sensitivity and specificity for the diagnosis of CNS involvement 32 ; the absence of CMV DNA by PCR has a high negative predictive value.

Nucleic acid amplification with reverse-transcriptase PCR has also been found to be highly sensitive (86%–100%) and specific (92%–100%) for the diagnosis of enteroviral infections of the CNS, 15 and it has high specificity for the diagnosis of other viral causes of CNS infections, such as VZV and JC virus. 15,29

Use of PCR to detect the fragments of mycobacterial DNA in CSF has also been used for rapid diagnosis of tuberculous meningitis. 35 The sensitivity for the different Mycobacterium tuberculosis (MTB) PCR technologies ranges from 55.8% to 87.6%, with recent nested MTB PCR showing sensitivity and specificity up to 89% and 100%, respectively. 36

What is the backdoor path criterion?

This is a graphical rule that tells us whether we can identify the causal effect of interest if we know the causal DAG. And the rule is the following: we can identify the causal effect of A and Y if we have sufficient data to block all backdoor paths between A and Y. We sometimes refer to these variables that we use to eliminate the backdoor path as confounders.

The clinical utility of PCR in patients with bacterial meningitis has been investigated with the use of a broad range of bacterial primers (i.e., broad-based PCR). 15,33 In one study 33 the broad range was highly sensitive and was able to detect pathogens up to 1 week after antibiotic therapy. A rapid (<

At present, however, with the currently available MTB PCRs a negative CSF PCR result cannot be used to exclude the diagnosis of tuberculous meningitis.

In addition to conventional MRI sequences, recent advances have added further sensitivity and specificity to the diagnosis of brain infection. 38 These include diffusion-weighted imaging (DWI), diffusion tensor imaging, susceptibility-weighted imaging (SWI), perfusion-weighted imaging (PWI), and 1 H magnetic resonance spectroscopy.

DWI is superior to conventional MRI for the detection of early signal abnormalities in viral encephalitis caused by HSV, enterovirus 71, and WNV. 38,39,40

Neuroimaging studies are less important in the diagnosis of patients with bacterial meningitis but may be useful in patients who are not responding as expected, that is, have persistent or prolonged fever, clinical evidence of increased ICP, focal neurologic findings, new or recurrent seizures, enlarging head circumference (in neonates), persistent neurologic dysfunction, or persistently abnormal CSF parameters or cultures. 1

The key to distinguishing abscess from other cystic intracranial processes (e.g., necrotic tumors) is DWI 40 ; pus in the abscess has restricted diffusion and appears DWI hyperintense.

In AIDS patients with positive immu- noglobulin G (IgG) antibody titers to T. g ond ii, the detection of multiple ring-enhancing lesions by CT with contrast enhancement or MRI is enough evidence to initiate a trial of anti-Toxoplasma chemotherapy 38 (see Chapter 90); CT or MRI is repeated in 10 to 14 days to document a clinical response.

Drug penetration into CSF depends on the status of the blood-brain barrier, which is disrupted in the presence of meningeal inflammation. Some agents (e.g., corticosteroids) may reduce meningeal inflammation and reduce blood-brain barrier penetration of antimicrobial agents even though appropriate CSF vancomycin concentrations were documented in patients treated with adjunctive dexamethasone in one study. 42

Entry of antimicrobial agents into CSF is also enhanced by drugs that have a low molecular weight, low degree of ionization at physiologic pH, high lipid solubility, and low degree of protein binding. 1,41

Other (wrong definitions of confounder):

- change in estimate definition

- conventional definition

In addition, intraventricular or intrathecal therapy may be required for eradication of resistant pathogens in patients with health care–associated ventriculitis and meningitis. 43 These principles are reviewed in further detail in Chapters 87 and 92

In the therapy of focal intracranial infections, clinicians often rely on agents that are known to have efficacy in experimental animal models, which includes extrapolating data from animal models of meningitis, and based on anecdotal case series or case reports. This approach is reasonable because these infections are uncommon, and randomized trials of specific agents are not likely to be performed

Adjunctive dexamethasone, given concomitant with or just before the first antimicrobial dose, improves outcomes in infants and children with H. influenzae type b, and perhaps pneumococcal meningitis, and in adults with pneumococcal meningitis (see Chapter 87). 1,19,44

Adjunctive corticosteroids may not be beneficial, however, in patients with bacterial meningitis in the developing world, most likely because of their delayed presentation. 45

Corticosteroids may also be beneficial in patients with focal intracranial infections and cerebral edema associated with significant mass effect. 44

Although it should be noted that randomized studies of various strategies to lower ICP in patients with CNS infections have not been performed, some maneuvers may be beneficial. 45,46 Head elevation of 30 degrees is considered standard, and other factors that might increase ICP, such as pain, bladder distention, and agitation, should be avoided. Hyperventilation (to maintain the partial pressure of carbon dioxide in arterial blood at 27–30 mm Hg), which causes vasoconstriction and reduction in intracerebral volume, may also be used to reduce ICP, although it should be used only as a short-term intervention to quickly reduce ICP when it is dangerously elevated because it may induce cerebral ischemia (see Chapter 87).

Hyperosmolar agents decrease ICP by making the intravascular space hyperosmolar relative to the brain, permitting movement of water from the brain tissue to the intravascular compartment. However, a controlled trial from Malawi of adjunctive glycerol in adult patients with bacterial meningitis showed that it was harmful and increased mortality. 47 Similarly, a clinical trial of hypothermia (to reduce ICP) in bacterial meningitis showed a trend toward worse clinical outcomes. 48

There is some evidence to support the use of IV maintenance fluids in the first 48 hours in patients with bacterial meningitis 50 ; although there is insufficient evidence to guide this practice, adult patients with meningitis should be treated with the goal of attaining a normovolemic state. 1,50

Seizures may occur in patients with CNS infections and must be managed quickly and aggressively to avoid permanent anoxic ischemic changes. 1,45,46 Status epilepticus that is continuous for 90 minutes or more can lead to permanent neurologic injury. Short-acting anticon- vulsants with a rapid onset of action (e.g., lorazepam or diazepam) should be given, followed by a long-acting agent, such as phenytoin.

Meningitis, or infl ammation of the meninges, is typically identified by means of a cerebrospinal fluid (CSF) pleocytosis of more than five white blood cells (WBCs) in the CSF, even though approximately up to 8% of patients with central nervous system (CNS) infections can present with absence of CSF pleocytosis. 1

Acute meningitis (duration of symptoms of less than 5 days) accounts for 75% of all community-acquired meningitis cases and is most commonly caused by unknown pathogens, as well as viral and bacterial organisms. 2

In contrast, patients with subacute meningitis (duration of 5 days or more) are more likely to have comorbidi- ties, be immunosuppressed, have fungal etiologies, or present with abnormal neurologic examination findings or with hypoglycorrhachia (CSF glucose < 45 mg/dL). 2

Chronic meningitis (>4 weeks’ duration of symptoms and signs and CSF abnormalities) has a broad differential diagnosis that includes conditions such as fungal infection, mycobacterial infection, neurobrucellosis, neurosyphilis, sarcoidosis, autoimmune disorders, paraneoplastic disorders, and vasculitis. 3

Encephalitis is a community-acquired illness with altered mental status for more than 24 hours with at least two (possible encephalitis) or three (probable encephalitis) of the following criteria: fever, new-onset seizure, new-onset focal neurologic finding, CSF pleocytosis, and abnormal findings at magnetic resonance imaging (MRI) of the brain or electro- encephalogram (EEG) consistent with encephalitis. 4

Viruses are the most commonly identified cause of the aseptic meningitis syndrome, a term used for a community-acquired illness with CSF pleocytosis, a negative CSF or blood culture, normal neurologic examination findings, and a benign clinical outcome.5

The most common viral etiologic agents that cause the acute aseptic meningitis syndrome are enteroviruses (EVs), herpesviruses, and arboviruses such as WNV. 5

Enteroviruses EVs are currently the leading recognizable cause of aseptic meningitis syndrome, accounting for 48% to 95% of all cases in which a causative virus is identified. 5–7

in adults, in whom a CSF EV polymerase chain reaction (PCR) assay is performed in only 15%. 5–7

A total of 118 types of EVs and 16 types of human parechoviruses (HPeVs) (both small viruses of the Picornaviridae family) have been described as causes of viral meningitis in the United States. 7 In addition to aseptic meningitis, these viruses can sometimes also cause acute flaccid paralysis (AFP), encepha- litis, myocarditis, and sepsis, with worse clinical presentations most commonly seen in neonates or infants. 7

EVs have a worldwide distribution and, in temperate climates, have a summer/fall seasonality, although in tropical and subtropical areas they can occur perenially. 6

Transmission is mainly via the fecal-oral route, but it has also been documented via respiratory droplets. 6

From 2009 to 2013, based on data from the CDC laboratory-based surveillance system (the National Enterovirus Surveil- lance System), the majority of cases occurred from April to November and the two most common viruses identified were coxsackievirus A6, and HPeV type 3, accounting for a total of 24.6% of total serotypes detected. 7

In addition, EV 71 can also cause AFP, in addition to aseptic meningitis and a brainstem encephalitis, which may manifest with shock and pulmonary edema.

Infants and young children are the primary victims of enteroviral meningitis because they are the most susceptible host population within the community.

In a study of 156 enteroviral infections in children, risk factors for severe disease were absence of oral lesions, seizures, and lethargy, with the majority of the severe cases caused by EV 71 and coxsackievirus A16. 16

Herpesviruses Herpesviruses include HSV types 1 and 2, varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpesvirus (HHV) types 6, 7, and 8. Although neurologic complications are known to occur with some of these viruses, complications associated with HSV are of the greatest significance.

In patients beyond the neonatal period, it is critical to differentiate between HSV encephalitis (usually caused by HSV type 1), a potentially fatal infection, and HSV meningitis (most commonly caused by HSV type 2), a self-limited syndrome.