611

A Practical Approach to Meningitis and

Encephalitis
Megan B. Richie, MD1 S. Andrew Josephson, MD1

1 Department of Neurology, University of California, San Francisco, California Address for correspondence Megan B. Richie, MD, Department of
Neurology, UCSF, 505 Parnassus Avenue, Box 0114, San Francisco, CA
Semin Neurol 2015;35:611–620. 94143-0114 (e-mail: [email protected]).

Abstract Meningitis is an inflammatory syndrome involving the meninges that classically

manifests with headache and nuchal rigidity and is diagnosed by cerebrospinal fluid
examination. In contrast, encephalitis refers to inflammation of the brain parenchyma
itself and often results in focal neurologic deficits or seizures. In this article, the authors
review the differential diagnosis of meningitis and encephalitis, with an emphasis on
infectious etiologies. The recommended practical clinical approach focuses on early

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Keywords high-yield diagnostic testing and empiric antimicrobial administration, given the high
► meningitis morbidity associated with these diseases and the time-sensitive nature of treatment
► encephalitis initiation. If the initial workup does not yield a diagnosis, further etiology-specific testing
► infectious disease based upon risk factors and clinical characteristics should be pursued. Effective
► autoimmune treatment is available for many causes of meningitis and encephalitis, and when
encephalitis possible should address both the primary disease process as well as potential
► cerebrospinal fluid complications.

Meningitis and encephalitis are syndromes with indepen- treatable conditions. Infectious etiologies are initially empha-
dently broad differential diagnoses that have substantial sized given their high prevalence, but inflammatory, neoplas-
clinical and etiologic overlap. Both have the potential for tic, and toxic/metabolic causes should also be considered.
high morbidity and mortality, and many causes are treatable.
Although meningitis refers to inflammation of the meningeal
Acute Evaluation and Management
space, typically resulting in headache, nuchal rigidity, photo-
phobia, and cerebrospinal fluid (CSF) pleocytosis, encephali- Initial history and physical examination should be targeted
tis refers to inflammation of the brain parenchyma itself, toward identifying “red flags” that suggest acute bacterial
which manifests with focal or diffuse neurologic deficits. The meningitis or HSV meningoencephalitis. Empiric treatment
two can co-occur together as meningoencephalitis, resulting for these entities should be initiated while awaiting results of
in symptoms of both disorders.1,2 Managing a case of sus- early diagnostics. ►Fig. 1 provides a suggested algorithm to
pected meningitis or encephalitis can be a significant chal- guide early diagnostic and therapeutic management.2–4
lenge and requires a systematic approach focusing initially on
rapid triage and consideration of empiric therapies, followed Acute Bacterial Meningitis
by etiologic-specific testing based upon risk factors and Acute bacterial meningitis can result in significant morbid-
clinical characteristics. ity and mortality if treatment is delayed. Early initiation of
Early management should focus on evaluation and treat- empiric antibiotic and often corticosteroid treatment is
ment of acute bacterial meningitis and herpes simplex virus therefore critical in management, and providers must
(HSV) meningoencephalitis. If initial diagnostics do not maintain a high index of suspicion for this disorder. Specific
confirm either of these diagnoses, a more thorough evalua- features on history concerning for bacterial meningitis
tion process must be undertaken, prioritizing testing for include headache, acute time course (usually hours to

Issue Theme Hospitalist Neurology; Copyright © 2015 by Thieme Medical DOI http://dx.doi.org/
Guest Editors: S. Andrew Josephson, MD, Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0035-1564686.
and Vanja C. Douglas, MD New York, NY 10001, USA. ISSN 0271-8235.
Tel: +1(212) 584-4662.
612 A Practical Approach to Meningitis and Encephalitis Richie, Josephson

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Fig. 1 Management of acute bacterial meningitis and herpes encephalitis in adults. 2–4 BMP, basic metabolic panel; CSF, cerebrospinal fluid; CBC,
complete blood count; CT, computed tomography; HSV, herpes simplex virus; INR, international normalized ratio; LFTs, liver function tests; PTT,
partial thromboplastin time; PCR, polymerase chain reaction; PT, prothrombin time.

days), rapid progression, sick contacts, dormitory living, or Herpes Simplex Meningoencephalitis
recent systemic illnesses such as ear, sinus, or lung infec- Herpes simplex virus infection is the most common infectious
tion. In addition to fever and meningismus, concerning cause of encephalitis, and treatment with acyclovir can
examination findings include mental state alteration, pap- reduce mortality by more than 70%.1 Symptoms progress
illedema, cranial nerve palsies, or petechial rash character- over days to around one week, and may include behavioral
istic of Neisseria meningitidis.4 The most common disturbances, memory dysfunction, or an altered level of
pathogens include Streptococcus pneumoniae and N. men- consciousness; language disturbance and seizures are espe-
ingitidis. Streptococcus agalactiae (Group B streptococcus) cially common given tropism of HSV for the temporal lobes.
is a frequent pathogen among neonates, whereas Listeria Patients often report headache, but meningeal signs such as
monocytogenes may be seen in neonates, immunocompro- nuchal rigidity or photophobia may not be present. A preced-
mised patients, pregnant women, and the elderly. Once a ing flu-like illness including malaise, myalgias, cough, nausea,
common cause of meningitis, Haemophilus influenzae is vomiting, or diarrhea may be reported.5 Neurologic exami-
now rare in countries with routine vaccination. Empiric nation should focus on evaluating cortical function, including
antibiotic therapy targets the most likely pathogens, taking a detailed mental state evaluation. A thorough skin exam
into consideration age and other risk factors (►Fig. 2).3 (including the tympanic membranes) should be performed to

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 A Practical Approach to Meningitis and Encephalitis Richie, Josephson 613

Fig. 2 Empiric treatment for acute bacterial meningitis and herpes encephalitis.3 IV, intravenous.

evaluate for the vesicular rash classically seen in HSV infec- treatment.7 Although treatment failure has been observed

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tion, although the neurologic syndrome often occurs without in patients receiving vancomycin and adjunctive dexametha-
any systemic signs of the virus. Herpes simplex virus menin- sone for pneumococcal meningitis, serial lumbar punctures
goencephalitis can be diagnosed with high sensitivity and have not revealed a reduction in CSF vancomycin levels in
specificity using viral deoxyribonucleic acid (DNA) polymer- patients receiving dexamethasone. Nevertheless, caution is
ase chain reaction (PCR) sent from CSF.6 Intravenous acyclovir advised in patients with cephalosporin-resistant pneumococ-
is the appropriate empiric treatment for HSV, but should be cal meningitis treated with dexamethasone. If S. pneumoniae
used cautiously in patients with renal dysfunction.1 is ultimately excluded, corticosteroids may be discontinued,
although dexamethasone administration may still protect
Early Management against sequelae such as hearing loss and arthritis.7,8
Initial evaluation of suspected acute bacterial meningitis and If lumbar puncture is not performed prior to antibiotic
HSV meningoencephalitis should concentrate on patient treatment, CSF should still be sent as soon as possible for
stabilization and information gathering (►Fig. 1). Once analysis. A CSF culture may remain positive up to 4 hours even
hemodynamic stability is ensured, a focused history and after antibiotic administration, although treatment for great-
physical examination should be performed as basic laborato- er than 8 hours generally leads to culture sterility.9 The
ry data and blood cultures are collected and intravenous remainder of the CSF profile is helpful even if cultures are
access is obtained. Management decisions then hinge upon sterile. Typical findings in bacterial meningitis include a
the rapidity with which a lumbar puncture can be performed. polymorphonuclear predominant CSF pleocytosis, elevated
Unstable patients, patients who require cranial imaging prior protein, and low glucose (less than 40% of a simultaneously
to lumbar puncture, or patients with a coagulopathy that sampled serum glucose).2,10 Even in patients on antibiotic
precludes immediate lumbar puncture should be started on therapy, pleocytosis and glucose only begin to normalize after
empiric therapy without delay. Indications requiring a head 48 to 72 hours of treatment.11
computed tomography (CT) scan prior to lumbar puncture The typical CSF profile in HSV meningoencephalitis includes a
include new-onset seizures, altered level of consciousness, mononuclear-predominant pleocytosis, normal or elevated pro-
papilledema, focal neurologic deficits, immunocompromised tein, and normal glucose. Red blood cells may be variably
state, or a history of known intracranial lesion. In stable elevated, but this feature is not diagnostic. Herpes simplex virus
patients with normal coagulation profiles who do not require meningoencephalitis is best diagnosed with high sensitivity and
a prior head CT, clinicians should rapidly proceed with specificity using CSF HSV 1 and 2 DNA PCR. Early in the course of
lumbar puncture.3,4 disease (< 24 hours), HSV PCR may be falsely negative in over
Once lumbar puncture has been either completed or one-quarter of patients, and the CSF profile may be completely
deemed acutely inadvisable, empiric treatment should be normal.12 Therefore, if there is a high suspicion for HSV menin-
initiated in all patients with suspected acute bacterial men- goencephalitis, empiric treatment should be continued and a
ingitis or HSV meningoencephalitis. The clinical scenario second lumbar puncture for repeat studies is required after at
dictates whether coverage should include acute bacterial least 3 days’ delay. A HSV PCR remains a useful test even after
meningitis, HSV meningoencephalitis, or both.2,4 Treatment starting acyclovir, as DNA titers typically begin to fall after
of suspected acute bacterial meningitis should include dexa- 10 days of antiviral treatment.13
methasone given prior to antibiotics.3,4 Dexamethasone has
been shown to improve outcomes and reduce mortality in After Definitive Diagnosis
patients with Streptococcus pneumoniae (pneumococcal) Once a lumbar puncture is obtained, patients with CSF
meningitis when given before antibiotics, possibly due to consistent with acute bacterial meningitis should be contin-
a reduction in the inflammatory response following ued on antibiotics for 7 to 14 days, depending on the

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614 A Practical Approach to Meningitis and Encephalitis Richie, Josephson

organism. In cases in which no organism is found despite differential. A nasopharyngeal swab for respiratory viruses is
clinical and CSF features concerning for bacterial meningitis, indicated, especially during influenza season. A chest radio-
an empiric 14-day course of broad-spectrum antibiotics is graph is helpful when considering tuberculosis, fungal infec-
indicated. Blood cultures may also be positive in 50 to 80% of tion, and sarcoidosis.1,4
patients with bacterial meningitis if drawn prior to anti- Noninfectious causes are often high enough on the differ-
biotics, and it can be assumed that the causative organism has ential diagnosis at this point to warrant workup during the
been identified based on positive blood cultures with an first tier of testing. Inflammatory causes should be investi-
appropriate CSF profile.4 After 48 hours of treatment, patients gated through serum rheumatologic studies and possibly
who have not responded clinically should undergo repeat autoimmune or paraneoplastic autoantibodies in the serum
lumbar puncture to ensure that CSF pleocytosis is resolving.3 and CSF.6,15,16 If neoplastic etiologies such as carcinomatous
If HSV meningoencephalitis is confirmed, antibiotics for meningitis or lymphoma are being considered, CSF cytology
bacterial meningitis can be stopped and intravenous acyclovir and flow cytometry should be performed.17
continued for 21 days.1 Patients should be monitored clini- All patients with encephalitis and most patients with
cally for complications related to meningitis, such as hydro- meningitis require a brain MRI scan.1,4 Not only is MRI
cephalus or stroke, as discussed below. potentially helpful in determining disease etiology, but it
also investigates complications of meningitis such as infarc-
tion or hydrocephalus. When possible, brain MRI should
Diagnostic Approach to Meningitis and
include contrast-enhanced, diffusion-weighted, and iron-
Encephalitis: After the Acute Evaluation

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sensitive sequences. Head computed tomography (CT) with
In many cases, a diagnosis is not made during the initial and without contrast is an alternative if MRI is not possible,
evaluation, and the practitioner must broaden the differential although the sensitivity and specificity is significantly lower.
and direct further workup based upon risk factors, clinical In patients with strokes or those with suspicion for vascul-
characteristics, availability of testing, and potential for treat- opathy, vessel imaging with MR or CT angiography is indicat-
ment.10 Additional history should include geographic and ed.18 Spinal MRI with contrast should be performed if
environmental factors such as travel, occupation, vaccination myelopathy or radiculopathy is present.
status, dormitory living, animal or arthropod exposure (in- Electroencephalography is indicated in patients with
cluding ticks or mosquitos), diet and ingestions, sick contacts, encephalitis, coma, or a waxing and waning mental status
recreational substances, and other toxic exposures. A review to evaluate for subclinical seizure activity.1,4,6 Occasionally,
of systems is helpful, including weight loss, night sweats, an EEG may also help determine the etiology of illness. For
fever, rash, cough, nausea, vomiting, diarrhea, and rheuma- example, more than 80% of patients with HSV meningoen-
tologic symptoms such as joint pain, xerostomia, or xeroph- cephalitis have unilateral or bilateral periodic epileptiform
thalmia1 A neurologic exam provides information regarding discharges in the temporal lobes, and patients with subacute
localization, while brain magnetic resonance imaging (MRI) sclerosing panencephalitis may have high-amplitude period-
and electroencephalogram (EEG) are highly useful diagnostic ic bursts of activity that correlate with clinical myoclonic
tests. jerks.1 More commonly, EEG findings in meningitis and
encephalitis are nonspecific, and may include epileptiform
First-Tier Diagnostic Testing discharges, generalized or focal slowing, or intermittent
All patients with suspected meningitis or encephalitis under- rhythmic delta activity.
go a lumbar puncture with CSF sent for cell count and
differential, protein, glucose, Gram stain, and
Second-Tier Testing: Clues to Elusive
culture. ►Table 1 provides an overview of the typical CSF
Etiologies
profile seen in subcategories of infectious meningitis and
encephalitis.2 Opening pressure should be obtained when Environmental Factors
possible, and is best recorded with the patient in the lateral Both season and geographic prevalence influence the differ-
decubitus position with legs outstretched. If encephalitis is ential diagnosis of meningitis and encephalitis. During winter
suspected, CSF should be sent for HSV-1 and 2 and varicella months, influenza viruses should be considered in patients
zoster virus (VZV) PCR, although a negative VZV PCR does not with meningitis or encephalitis regardless of vaccination
exclude the diagnosis and may be supplemented with VZV status, although generally neurologic complications of influ-
serum and CSF immunoglobulin M (IgM) and IgG serologies.1 enza are rare.6 In late summer and early fall, the differential
Depending on the clinical scenario, acid-fast bacilli smear and diagnosis should include enteroviruses as well as tick- and
culture, Venereal Disease Research Laboratory (VDRL) and mosquito-borne infections, the prevalence of which varies
cryptococcal antigen testing may be indicated. ►Table 2 pro- based upon geography.1 Ehrlichia ruminantium is primarily
vides a list of diagnoses to consider based upon CSF character- seen in southern and eastern United States, Borrelia burgdor-
istics.10,14 Important serum studies in most patients include feri (Lyme) in the Northeast, whereas Rickettsia rickettsii
blood cultures, human immunodeficiency virus (HIV) serol- (Rocky Mountain spotted fever) and West Nile virus (WNV)
ogies, rapid plasma reagin (RPR), erythrocyte sedimentation infections are seen throughout the country. Eastern equine
rate (ESR), and C-reactive protein (CRP), with consideration encephalitis virus is most prevalent in the eastern United
for QuantiFERON-TB Gold testing when tuberculosis is on the States, and St. Louis encephalitis virus in the South.19,20

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 A Practical Approach to Meningitis and Encephalitis Richie, Josephson 615

Table 1 Typical cerebrospinal fluid profiles of infectious subcategories of meningitis and encephalitis2

Meningitis Encephalitis
Bacterial Viral Mycobacterial Fungal
Opening pressure Elevated Normal Normal or elevated Normal or elevated Normal or
elevated
White cells Increased Increased Increased Increased Increased
Differential Predominantly Predominantly Predominantly Mononuclear
Mononuclear
polymorphonuclear mononuclear mononuclear eosinophils
Glucose Often decreased Normal Often decreased Often decreased Normal
Protein Usually increased Normal or increased Usually increased Usually increased Normal or
increased

Table 2 Select diagnoses to consider based upon cerebrospinal fluid characteristics10,14

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CSF profile Suspect:
Differential Glucose
PMNs Low Bacterial meningitis, amoebic meningitis
PMNs Normal Bacterial meningitis (
partially treated), L. monocytogenes, C. albicans
Mononuclear Low Bacterial meningitis (
partially treated), mycobacterial, fungal, carcinomatous meningitis
Mononuclear Normal B. Burgdorferi, mycobacterial, fungal, T. pallidum, most viruses, SLE, carcinomatous
meningitis, chemical/iatrogenic
Variable Sarcoidosis, Leptospira species
Atypical lymphocytes EBV, CMV, JE, WNV, enteroviruses, VZV, Mollaret’s
Abnormal cells Carcinomatous meningitis, CNS lymphoma
Eosinophils T. solium, C. immitis, Angiostrongylus cantonensis, Gnathostoma species, NMO,
neurosurgical hardware, chemical/iatrogenic

Abbreviations: CMV, cytomegalovirus; CNS, central nervous system; CSF, cerebrospinal fluid; EBV, Epstein-Barr virus; JE, Japanese encephalitis; LCMV,
lymphocytic choriomeningitis virus; NMO, neuromyelitis optica; PMN, polymorphonuclear lymphocyte; SLE, systemic lupus erythematosus; VZV,
varicella zoster virus; WNV, West Nile virus.

Western equine encephalitis virus has been the cause of Valley, and Eastern equine encephalitis viruses cause enceph-
several epidemics, but there have been no documented cases alitis.1,3 Over age 50, L. monocytogenes and aerobic gram-
since 1994.1 Certain fungal infections also have geographic negative rods join S. pneumoniae and N. meningitidis as
variability and may cause disease at any time of year. common causes for bacterial meningitis. These patients are
Coccidioides immitis is common in the Southwest and Cal- also at higher risk for WNV, St. Louis, and Eastern equine
ifornia, Histoplasma capsulatum in the Ohio and Mississippi encephalitis, presumably due to waning immunity.1
River valleys, and Blastomyces dermatitidis in the Mississippi The list of pathogens related to exposures such as animal
River valley and mid-Atlantic states.21 contact, ingestion, or international travel is extensive.1,2,6
Coxiella burnetii, Bartonella henselae, and T. gondii are treat-
Patient-Specific Risk Factors able causes of encephalitis related to cat exposure. Coxiella
Before 1 month of age, the most common infections are burnetii may also be seen after contact with sheep or after
driven by perinatal transmission from mother to infant. ingesting unpasteurized milk. Bartonella henselae, Leptospira
Neonatal meningitis is most frequently due to Group B species, and Hantavirus infection are contracted through
streptococcus, Escherichia coli, Klebsiella pneumoniae, and contact with rodents, and Chlamydia psittaci from birds.
Listeria monocytogenes.3,4 Listeria monocytogenes may also Ingesting raw or partially cooked meat is related to T. gondii
cause encephalitis in this population, as can cytomegalovirus and Gnathostoma species infections, two parasitic causes of
(CMV), HSV-2, rubella, Toxoplasma gondii, and Treponema encephalitis.
pallidum (syphilis).1 Between 1 and 23 months of age, International travel is another risk factor for parasitic
pneumococcus, N. meningitidis, and H. influenzae commonly infection, even years prior to presentation. Taenia solium is
cause meningitis, whereas influenza, La Crosse, Murray found in Asia, and Central and South America, Trypanosoma

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616 A Practical Approach to Meningitis and Encephalitis Richie, Josephson

species in Africa, and Leptospira species in tropical areas. reveal retinitis in cases of CMV, WNV, B. henselae, or syphilis,
Malaria, caused by protozoan Plasmodium species, is common and conjunctival suffusion in leptospirosis, Colorado tick
worldwide in an equatorial band across areas with high fever, WNV, and St. Louis encephalitis.1,10 Pulmonary disease
rainfall and mosquito proliferation. Patients who have spent may be seen in all fungal infections, as well as pneumococcus,
time where tick-borne illness is endemic should be ques- influenza, Mycoplasma pneumoniae, C. burnetii, and myco-
tioned about time spent outdoors and contact with animals bacterial infections.1,15,16 In patients with diarrhea, clinicians
that carry ticks such as dogs or deer.1,2,6,14,22,23 should consider M. pneumoniae, L. monocytogenes, or viral
A broad range of infectious causes of meningitis and encephalitides such as St. Louis, Japanese, La Crosse, and
encephalitis should be considered in immunocompromised WNV.1,10
patients, including patients with HIV, hematologic malignan- Rash may be a particularly helpful sign. Hemorrhagic
cies, or those taking immunosuppressant therapy. In addition purpura are highly suggestive of meningococcemia, although
to the usual bacterial causes of meningitis, patients with they may occasionally be seen with pneumococcus.10 A
decreased cell-mediated immunity are at higher risk for L. vesicular pattern may be seen in herpesvirus infections
monocytogenes regardless of age.1 Cryptococcus neoformans is such as VZV and HSV, whereas a nonspecific macular or
an important cause of meningitis in these populations; it may maculopapular exanthem occurs with M. pneumoniae, EBV,
be diagnosed with high sensitivity and specificity using CSF or HHV-6, rubella, WNV, and Colorado tick fever.1,10 Rickettsia
serum cryptococcal antigen and classically causes increased rickettsii infection classically features a maculopapular rash
intracranial pressure requiring serial therapeutic lumbar that begins on the wrists and ankles and may spread to the

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punctures. Although fungal infection with Aspergillus species, palms and soles.1 Borrelia burgdorferi infection causes a
B. dermatitidis, and C. immitis may occur in normal popula- targetoid rash followed by erythema migrans, although
tions, neurologic involvement is more common in those with rash may be absent in 20% of patients.23,26 Enterovirus is
decreased immunity, as are other features of disseminated one cause of the vesicular hand, foot, and mouth disease;
disease including infection of skin, soft tissue, and bone, and enteroviral rashes may also be maculopapular, morbilliform,
severe pulmonary symptoms including cavitary or reticulo- hemorrhagic, or petechial.10 Disseminated fungal infections
nodular pneumonia.1,15,16,21 may also have skin manifestations, including pustules and
Many viral infections are also more common in immuno- abscesses.16 Skin manifestations of secondary syphilis are
compromised hosts, including WNV and Epstein-Barr virus diverse, but may appear maculopapular or pustular, often
(EBV). Some are almost exclusively seen in those with involving the palms or soles. Gummas are the classic skin
depressed immune function, including CMV, human herpes finding of tertiary syphilis, and these necrotic granulomatous
virus 6 (HHV-6), and John Cunningham (JC) virus.1,5,24 lesions may also be found in other organs including the liver,
Transplant or transfusion recipients are at particular risk brain, and spinal cord.15,16
for CMV, EBV, and HHV-6 as these may be passed from tissue
to host. Cytomegalovirus may cause ventriculitis and poly- Neurologic Tropism
radiculitis; HHV-6 presents as limbic encephalitis.1 Epstein- Analyzing the specific pattern of neurologic involvement
Barr virus is difficult to determine as a causative agent of can be helpful in determining the cause of encephalitis.
meningitis or encephalitis because the virus may be harbored Ataxia may be prominent in Trypanosoma species, Tropher-
in lymphocytes in the absence of active infection.5 A positive yma whipplei (Whipple’s) disease, or Creutzfeldt-Jakob
CSF EBV PCR may indicate central nervous system lymphoma disease (CJD), along with many viral infections including
rather than true infection, particularly in patients with HIV.25 VZV, EBV, WNV, St. Louis, Powassan, Murray Valley, and
John Cunningham virus causes progressive multifocal leu- mumps.1,2,10 Viral infections are the cause of flaccid paral-
koencephalopathy (PML), classically presenting with areas of ysis, typically WNV and enterovirus.1,10,27 Myoclonus is a
confluent, nonenhancing subcortical white matter T2 hyper- distinctive feature of HSV, enterovirus, Japanese encepha-
intensity on MRI. Populations at risk for PML include those litis, rabies, Whipple’s disease, CJD, and autoimmune en-
with HIV-acquired immunodeficiency syndrome (AIDS) or cephalitis.1,27 Extrapyramidal symptoms are most common
patients taking immunosuppressants such as natalizumab, in encephalitis due to WNV, St. Louis, Japanese encephali-
rituximab, methotrexate, cyclophosphamide, or azathio- tis, or lymphocytic choriomeningitis virus, as well as
prine.5 Varicella zoster virus may cause meningitis or en- T. gondii or Trypanosoma species infection. Oculomastica-
cephalitis in any host, but the characteristic rash may not be tory myorhythmia, while extremely rare, is pathognomon-
present in those with immunodeficiency, and disseminated ic for Whipple’s disease.1
disease is more common.24
Subacute, Chronic, or Recurrent Time Course
Systemic Signs and Symptoms Many fungal infections have subacute or chronic presenta-
Systemic symptoms can guide the differential diagnosis of tions. Fungal cultures or direct microscopic visualization are
meningitis and encephalitis. Many viruses cause lymphade- insensitive, posing a diagnostic challenge. Serum and CSF
nopathy including HIV, EBV, CMV, HHV-6, WNV, Coltivirus antigen are highly sensitive and specific for C. neoformans,
(Colorado tick fever), measles, and rubella. Lymphadenopathy while serum and CSF serology for C. immitis is more reliable
may also be seen in syphilis, B. henselae, T. gondii, and than for other fungal mycoses and are performed using
mycobacterial infections. Ophthalmologic evaluation may complement fixation, immunodiffusion, or enzyme

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 A Practical Approach to Meningitis and Encephalitis Richie, Josephson 617

immunoassay.1 Further fungal testing includes urine antigen Noninfectious Meningitis and Encephalitis
for B. dermatitidis and H. capsulatum, CSF serology for H.
capsulatum, and serum or CSF β-d glucan and galactomannan Although the predominant concern in patients with meningitis
for Aspergillus.15,16 When possible, clinicians should seek a or encephalitis may be infectious, many inflammatory, neoplas-
systemic source of culture; often this will involve pulmonary, tic, or toxic causes are treatable. Particularly suspicious for
nasal, or cutaneous samples. inflammatory disease are subacute or relapsing symptoms,
Mycobacterial infection is another consideration in pa- younger patients, or those with a personal or family history of
tients with a subacute or chronic time course. Typical tuber- autoimmune disease. Subacute cognitive or psychiatric symp-
culous meningitis is basilar-predominant, with cranial nerve toms, movement disorders, ataxia, brainstem dysfunction, or
involvement and striking enhancement on MRI. There may be autonomic instability should prompt evaluation for autoimmune
associated vasculopathy and cerebral infarction. The charac- or paraneoplastic encephalitis if the initial infectious workup is
teristic CSF profile includes a mononuclear predominant unrevealing. Neoplastic disorders should be considered in older
pleocytosis, hypoglycorrhachia, and elevated protein. Cere- patients or those with a history of malignancy. Exposure to
brospinal fluid microscopy and culture for acid-fast bacilli is agents such as intravenous immunoglobulin, nonsteroidal anti-
specific, but slow and highly insensitive.15,16,18,28 Practi- inflammatory drugs (NSAIDs), sulfa-containing drugs, or intra-
tioners should therefore supplement the workup with pul- thecal chemotherapy should raise suspicion for a toxic cause of
monary imaging, cutaneous tuberculin sensitivity testing, the meningitis as a diagnosis of exclusion.
serum QuantiFERON-TB Gold test, and induced sputum test- Investigating noninfectious etiologies requires additional

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ing for acid-fast bacilli, with the caveat that these tests may first-tier CSF and serum studies including paraneoplastic and
also have false-negative results and empiric treatment for autoimmune antibody panels, and serum studies including
tuberculosis may be warranted when there is high clinical ESR, CRP, antinuclear antibody (ANA), angiotensin converting
suspicion. enzyme (ACE), anti-double-stranded DNA, and anti-Sjögren’s-
Secondary syphilis may also cause subacute meningitis, syndrome-related-antigen A or B (SSA, SSB).16 Neoplastic
and tertiary syphilis causes chronic psychiatric or cognitive meningitis and encephalitis are best evaluated using three
symptoms.15,16 Subacute cognitive decline is also associated separate large-volume, fresh CSF specimens sent for cytology,
with HIV, CJD, CMV, measles, Whipple’s disease, neoplastic and flow cytometry if lymphoma is under consideration.16,17,32
meningitis, and autoimmune encephalitis.1,2,5,16 Cysticerco- Suspected autoimmune vasculitis should prompt vessel
sis may cause chronic meningitis with CSF eosinophilia and imaging.1,15 Computed tomography and full-body positron
characteristic cysts on MRI scan.22 Herpes simplex virus-2 emitted tomography (PET) are helpful in the evaluation of
may have a distinctive relapsing course in which patients sarcoidosis, granulomatosis with polyangiitis, neoplastic, and
experience recurrent lymphocytic meningitis (also known as paraneoplastic etiologies.1,16 In many cases, making a secure
Mollaret’s meningitis) that may be shortened with antivirals diagnosis will involve biopsying an affected organ identified
or suppressed with prophylactic therapy.2,9 Recurrent bacte- with systemic imaging.
rial meningitis should raise suspicion for a parameningeal
focus of infection or CSF leak.10
Therapeutic Approach
Special Laboratory Testing Despite exhaustive testing, a definitive cause of meningitis or
Clinicians may take advantage of cellular targets unique to encephalitis is not found in over half of cases.33 In patients who
specific categories of infection to gauge their likelihood. are deteriorating or failing to improve after initial treatment
These tests do not require live organisms and therefore are with antimicrobials and acyclovir, clinicians should consider
unaffected by prior antibiotic therapy. Latex agglutination additional empiric therapy for atypical bacterial, fungal, and
is a rapid and specific test that uses antibodies to detect inflammatory disorders. ►Table 3 lists atypical bacterial causes
capsular polysaccharides present in bacterial infection; it of meningitis and encephalitis and their associated fea-
has the disadvantages of high cost, low availability, and tures.14,22,23,27,34,35 Many of these infections are difficult to
variable sensitivity.4 Polymerase chain reaction-based diagnose, and given the relatively low risk of treatment, a 21-
techniques utilize conserved genetic sequences to amplify day course of doxycycline is often begun to cover many of these
and detect DNA or ribonucleic acid (RNA) from particular organisms. The threshold to start empiric mycobacterial or
pathogens. The 16S component of ribosomal RNA is highly fungal therapy should be higher given the increased potential
conserved among bacterial organisms and may be investi- risks of these medications. However, in areas where fungal
gated using this method.29 Fungal infections may also be infection is endemic, fluconazole is a well-tolerated drug that
found by targeting 18S and 28S rRNA, and mycobacteria is reasonable to administer when suspicion is high. Treatment
using 16s rRNA, heat shock protein- (Hsp-) 65, and with corticosteroids for suspected inflammatory disease may
rpoB. 28,30,31 Although these PCR tests are highly specific, occur, keeping in mind that rare infections may worsen with
sensitivity depends on the concentration of the organism, corticosteroid exposure, and many others may temporarily
and may be further lowered when blood is present.29 improve only to later deteriorate. Corticosteroids also reduce
Research is currently underway to use deep sequencing the yield of biopsy in lymphoma and inflammatory diseases, and
of DNA found in blood and CSF to look for specific therefore empiric corticosteroid treatment should be postponed
organisms.14 until tissue samples are obtained.

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 618

Table 3 Features of atypical bacterial causes of bacterial meningitis and encephalitis14,22,23,27,34,35

Meningitis Meningoencephalitis Risk factors Clinical features Treatment

L. monocytogenes þþ þþ Age < 1 month or > 50 years, pregnancy, Brainstem signs, Ampicillin
alcoholism, immunocompromised cranial neuropathies, ataxia or

Seminars in Neurology
trimethoprim-sulfamethoxazole
B. burgdorferi þþ þ Tick exposure, geography Cranial neuropathies, radiculitis, Ceftriaxone or penicillin G

Vol. 35
(Eastern USA, Central Europe, Asia), targetoid rash, erythema migrans,
season (May–November) arthritis, arrhythmia
R. rickettsii þ Tick exposure, season (April–September) Seizures, coma, maculopapular Doxycycline

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petechial rash on wrists/ankles

hands/feet, periorbital and
extremity edema
B. henselae þ Cats (scratch/bite), rodents, dogs Seizures, neuroretinitis, regional Doxycycline
lymphadenopathy, anemia,
pneumonia, endocarditis
C. burnetii þ þþ Tick exposure, cats, sheep, goats Brainstem signs, ataxia, Doxycycline þ
cerebral edema, seizures, fluoroquinolone þ
rifampin
A Practical Approach to Meningitis and Encephalitis

flu-like syndrome, hepatitis,

pneumonia
Brucella species þþ þ Unpasteurized milk, geography Cranial neuropathy, radiculopathy, Doxycycline þ rifampin
(Central & South America, encephalopathy, seizures, stroke,
Mediterranean region, Asia, Africa) flu-like syndrome, arthritis
Leptospira species þ þþ Fresh water exposure, geography Myalgias, headache, conjunctivitis, Penicillin G or
(Latin America, the Caribbean, nephritis, cholecystitis, uveitis doxycycline
Taiwan, Hawaii)
Richie, Josephson

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 A Practical Approach to Meningitis and Encephalitis Richie, Josephson 619

Complications 2 Beaman MH, Wesselingh SL. 4: Acute community-acquired men-

ingitis and encephalitis. Med J Aust 2002;176(8):389–396
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7 Brouwer MC, McIntyre P, Prasad K, van de Beek D. Corticosteroids
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possibly requiring external ventricular drainage or ventricu- CD004405
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ture to ensure that CSF pleocytosis is resolving, particularly 343–364
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17 Chamberlain MC. Neoplastic meningitis. Handb Clin Neurol 2012;
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