Meningitis and Encephalitis: Overview and Management

Dr. Uzma Aneeza Foondun

Background
Infections of the central nervous system (CNS) can be divided into 2 broad categories: those primarily involving the meninges (meningitis) and those primarily confined to the parenchyma (encephalitis). Meningitis is a clinical syndrome characterized by inflammation of the meninges Dura Arachnoid Subarachnoid space

Risk factors for meningitis include: Age of 60 years or greater Age of 5 years or less Diabetes mellitus, renal or adrenal insufficiency, hypoparathyroidism, orcystic fibrosis Immunosuppression, which increases the risk of opportunistic infections and acute bacterial meningitis Human immunodeficiency virus (HIV) infection, which predisposes to bacterial meningitis caused by encapsulated organisms, primarily S pneumoniae, and opportunistic pathogens

 Crowding (eg, military recruits and college dorm residents), which increases the risk of outbreaks of meningococcal meningitis Splenectomy and sickle cell disease, which increase the risk of meningitis secondary to encapsulated organisms Alcoholism and cirrhosis Recent exposure to others with meningitis, with or without prophylaxis Contiguous infection (eg, sinusitis) Dural defect (eg, traumatic, surgical, congenital) Thalassemia major Intravenous (IV) drug abuse Bacterial endocarditis Ventriculoperitoneal shunt Malignancy (increased risk of Listeria species infection) Some cranial congenital deformities

Fungal meningitis-predisposing factors.

1. Glucosteroid therapy 2. Malignancy (particularly of the lymphoreticular system) 3. Collagen - vascular disease. 4. Sarcoidosis - a disorder involving many organs where there is formation of epithelioid cell tubercles. 5. Diabetes mellitus 6. Pregnancy 7. Alcoholism 8. Genetic impairment of host defense mechanisms - 50%. T-cell diseases (Di George Syndrome, Nezelof's syndrome) 9. AIDS

 Clinically, meningitis manifests with meningeal symptoms (eg, headache, nuchal rigidity, photophobia), as well as pleocytosis (an increased number of white blood cells) in the cerebrospinal fluid (CSF). Depending on the duration of symptoms, meningitis may be classified as acute or chronic. Meningitis can also be also classified more specifically according to its etiology. Numerous infectious and noninfectious causes of meningitis have been identified. Meningitis can also be divided into the following 3 general categories: Pyogenic (bacterial) Granulomatous Lymphocytic Examples of common noninfectious causes include medications (eg, nonsteroidal anti-inflammatory drugs [NSAIDs], antibiotics) and carcinomatosis.

Pyogenic meningitis.

ETIOLOGICAL AGENT
Normal" Adults (6-21 yrs) Neisseria meningitidis Streptococcus pneumoniae Children (3 months - 6 years) Haemophilus influenzae Neisseria meningitidis : Streptococcus pneumoniae Staphylococcus aureus Mycobacterium tuberculosis Infants ( - 3 months) Streptococcus, Group B Listeria monocytogenes Escherichia coli
"

Neonates Escherichia coli Streptococcus, Group B Staphylococcus aureus Listeria monocytogenes Streptococcus, Group A Diabetics, alcoholics, elderly, debilitated, diseased (untreated) Listeria monocytogenes Streptococcus pneumoniae Treponema pallidum

VIRAL MENINGITIS

ETIOLOGICAL AGENTS:

Mumps virus Polio virus Coxsackie B virus Echovirus Arboviruses Human Herpesvirus 1 (Herpes simplex 1 virus) Lymphocytic choriomeningitis viruses-Arenavirus Encephalomyocarditis viruses Louping ill virus Pseudolymphocytic meningitis virus Hepatitis viruses Adenovirus Rhinovirus

CHRONIC MENINGITIS

ETIOLOGICAL AGENTS:
Cryptococcus neoformans (Serotypes A,B,C,D) Treponema pallidum ) All slow Mycobacterium tuberculosis ) growers in Naegleria fowleri ) the CNS Human immunodeficiency virus ) Coccidioides immitis )

Pathophysiology
Bacteria reach the meninges through: bloodstream direct contact between the meninges either through the nasal cavity or the skin.

Bacterial Meningitis
Mechanism of invasion is not completely understood. Host defense mechanism within the CSF are often ineffective. Bacterial proliferation stimulates a convergence of leukocytes into the CSF. Meningeal and subarachnoid space inflammation release of cytokines into the CSF ( TNF, interleukin 1,6 )

Infectious agent enters Blood circulation Fever, chills Tachycardia Induce a meningeal inflammatory reaction Meningeal vessels become Hyperemic-Permiable Neutrophils migrate into SAS

Choroid plexus/Altered BBB Produce exudates and thickens the CSF Interferes CSF flow Hydrocephalus Macewens sign Inflammation brain parenchyma Meningeal irritation
+ Kernigs /+ Brudzinskis Sign

IICP
Headache, vomiting, papilledema

Seizures

Clinical feature.
Fever and headache in majority. Headache severe and generalized. Most have fever but small percentage have hypothermia. CNS symptoms: photophobia, and cloudy sensorium. Changes in mentation and level of consciousness, seizures, and focal neurological signs tend to appear later in the course of the disease.

Nuchal rigidity.
The patients might not complain of neck stiffness but easy to find it by passive or active flexion of the neck will usually result in inability to touch the chin to the chest. Brudzinski sign refers to spontaneous flexion of the hips during attempted passive flexion of the neck. The kernig signs refers to the inability to allow full extension of the knee when the hip is flexed 90 degree.

Neck Stiffness (nuchal rigidity)

* Pathogenesis: Meningeal irritation.

Other findings.
Skin manifestation in form of petechiae and palpable purpura.( N. meningitides ). If sequelae of infection in other part of the body, there may the feature of that infection. ( sinusitis and otitis).

WORK-UP

The cornerstone in the diagnosis of meningitis is examination of the CSF The opening pressure should be measured and the fluid sent for cell count (and differential count), chemistry (ie, CSF glucose and protein), and microbiology (ie, Gram stain and cultures). A computed tomography (CT) scan of the brain may be performed prior to lumbar puncture in some patient groups with a higher risk of herniation. These groups include those made up of patients with the following risk factors: Newly onset seizures An immunocompromised state Signs suspicious for space-occupying lesions (such as papilledema and focal neurologic signs) Moderate to severe impairment in consciousness

 Special studies, such as serology and nucleic acid amplification, may also be performed, depending on clinical suspicion of an offending organism.

 CBC Count with Differential Complete blood cell (CBC) count with differential demonstrates polymorphonuclear leukocytosis with left shift in bacterial meningitis. Serum electrolytes, to determine dehydration or syndrome of inappropriate secretion of antidiuretic hormone [SIADH]) Serum glucose (which is used in comparison with the CSF glucose) BUN and/or creatinine and liver profile, to assess organ functioning and adjust antibiotic dosing Coagulation profile and platelets are indicated in patients with chronic alcohol use or liver disease or if disseminated intravascular coagulation (DIC) is suspected. (Patients may require platelets or fresh frozen plasma [FFP] prior to lumbar puncture.)

 Serum Test for Syphilis Special Studies Cultures prior to instituting antibiotics may be helpful if diagnosis is uncertain. These cultures include the following: Blood - 50% positive in meningitis caused by H influenzae, S pneumoniae, or N meningitidis Nasopharynx Respiratory secretions Urine Skin lesions Latex agglutination or counter immunoelectrophoresis (CIE) of blood, urine, and CSF for specific bacterial antigens is recommended occasionally if diagnosis is challenging or in patients with partially treated meningitis.

Lumbar Puncture
Elevated opening pressure correlates with increased risk of morbidity and mortality in bacterial and fungal meningitis. In bacterial meningitis, elevated opening pressure (reference range is 80-200 mm water) suggests increased ICP from cerebral edema. In viral meningitis, the opening pressure is usually within the reference range. The CSF opening pressure may be elevated at times in cryptococcal meningitis, suggesting increased ICP. The opening CSF pressure is usually elevated in tuberculous meningitis. The CSF cell count varies depending on the offending pathogen. It is usually in the few hundreds (100-1000 cells/L) with a predominance of lymphocytes in patients with viral meningitis.

 CSF characteristics of acute bacterial meningitis Examination of the CSF in patients with acute bacterial meningitis reveals the characteristic neutrophilic pleocytosis (usually hundreds to a few thousand, with >80% PMN cells). In some cases of L monocytogenes meningitis (25-30%), a lymphocytic predominance may occur. Low CSF WBC count (< 20 cells/L) in the presence of a high bacterial load suggests a poor prognosis. CSF characteristics of viral meningitis In viral meningitis, the opening pressure is 90-200 mm H2 0, and the WBC count is 10-300 lymphocytes/L. Although the glucose concentration is typically normal, in LCM, HSV, mumps, and polio, it can be below normal. The protein concentration tends to be slightly elevated, but it can be within the reference range. CSF characteristics of fungal meningitis The diagnosis of cryptococcal meningitis relies on the identification of the pathogen in the CSF. The CSF is characterized by a lymphocytic pleocytosis (10-200 lymphocytes), a reduced glucose level, and an elevated protein level.

 CSF characteristics of tuberculous meningitis The CSF of patients with tuberculous meningitis is characterized by a predominantly lymphocytic pleocytosis, usually in the hundreds. CSF glucose study In bacterial meningitis, the CSF glucose (reference range is 40-70 mg/dL) is less than 40 mg/dL in 60% of patients In viral meningitis, these levels are also usually elevated, although they can be within the reference range. In syphilitic meningitis, abnormal CSF protein levels (elevated) and CSF glucose levels (decreased) may be observed in 10-70% of cases. CSF Gram stain and acid-fast bacilli stain CSF Gram stain permits rapid identification of the bacterial cause in 6090% of patients with bacterial meningitis. The presence of bacteria is 100% specific, but the sensitivity for detection is variable. The likelihood of detection is higher in the presence of a higher bacterial concentration and diminishes with prior antibiotic use. The demonstration of the acid-fast bacilli (eg, with auramine-rhodamine stain, Ziehl-Neelsen stain, Kinyoun stain) in the CSF is difficult and usually requires a large volume of CSF.

CSF culture and antigen testing CSF bacterial cultures yield the bacterial cause in 70-85% of cases. Blood cultures Nucleic acid amplification Serology The demonstration of a 4-fold rise in antibodies between acute and convalescent sera traditionally has been used to document meningeal infection in many viral pathogens. Chest Radiography 50% of patients with pneumococcal meningitis also have evidence of pneumonia on initial chest radiograph.

TREATMENT

Initial Care in Meningitis

Evaluate and treat the patient for shock or hypotension, and infuse crystalloid until he or she is euvolemic. Consider seizure precautions, treat seizures according to the usual protocol, and consider airway protection in patients with altered mental status. For alert patients in stable condition who have normal vital signs, administer oxygen, establish IV access, and transport them rapidly to the ED.

Antibiotic Therapy
Predisposing Feature Antibiotic(s)

Age 0-4 weeks

Age 1-3 months Age 3 months to 50 years Older than 50 years

Ampicillin plus cefotaxime or an aminoglycoside

Ampicillin plus cefotaxime plus vancomycin* Ceftriaxone or cefotaxime plus vancomycin* Ampicillin plus ceftriaxone or cefotaxime plus vancomycin*

Impaired cellular immunity Neurosurgery, head trauma, or CSF shunt

Ampicillin plus ceftazidime plus vancomycin* Vancomycin plus ceftazidime

*Vancomycin is added empirically to the initial regimen if the presence of penicillin-resistant S pneumoniae is suspected or if a high incidence of resistance is reported in the community.

Gram Stain Morphology Gram-positive cocci

Gram-negative cocci Gram-positive bacilli Gram-negative bacilli

Antibiotic(s) Vancomycin plus ceftriaxone or cefotaxime

Penicillin G* Ampicillin plus an aminoglycoside Broad-spectrum cephalosporin plus an aminoglycoside

*Use ceftriaxone if penicillin-resistant N meningitidis occurs in the community.

Steroid Therapy

May improve outcome in Acute Bacterial meningitis such as in infections with H influenzae, tuberculous, and pneumococcal meningitis.

Viral Meningitis
self-limited. Often, they require only supportive care and do not require specific therapy. If indicated, Herpes simplex meningitis--Acyclovir 10 mg/kg IV q8h CMV meningitis--Ganciclovir (induction dose of 5 mg/kg IV q12h, maintenance dose of 5 mg/kg q24h) and foscarnet (induction dose of 60 mg/kg IV q8h, maintenance dose of 90120 mg/kg IV q24h) HIV meningitis Instituting highly active antiretroviral therapy (HAART) may be necessary for patients with HIV meningitis that occurs during an acute seroconversion syndrome.

Fungal Meningitis (AIDS-Related Cryptococcal Meningitis)

amphotericin B (0.7-1 mg/kg/d IV) for at least 2 weeks, with or without flucytosine (100 mg/kg PO) in 4 divided doses.

Tuberculous Meningitis
Isoniazid (INH) and pyrazinamide (PZA) attain good CSF levels (approximate blood levels). Rifampin (RIF) penetrates the blood-brain barrier less efficiently but still attains adequate CSF levels. The use of a combination of the first-line drugs (ie, INH, RIF, PZA, ethambutol, streptomycin) is advocated. The dosage is similar to what is used for pulmonary tuberculosis (ie, INH 300 mg qd, RIF 600 mg qd, PZA 15-30 mg/kg qd, ethambutol 15-25 mg/kg qd, streptomycin 7.5 mg/kg q12h).
The use of corticosteroids is indicated for individuals with stage 2 or stage 3 disease (ie, patients with evidence of neurologic deficits or changes in their mental function). The recommended dose is 60-80 mg/d, which may be tapered gradually during a span of 6 weeks

Complication.
Cerebrovascular involvement. Cerebral odema. Hydrocephalus. Septic shock. Disseminated intravascular coagulation. Acute respiratory distress syndrome.

Complication of Bacterial meningitis

coma
death
Loss of airway reflexes

Pericardial effusion

seizures
immediate Cerebral edema

Dehydration

Respiratory arrest

Vasomotor collapse

DIC

Complication of Bacterial meningitis

Seizure disorder Death Focal paralysis

Bilateral adrenal hemorrhage

Subdural effusion

Delayed
Blindness Hydrocephalus

Ataxia
SNHL

Intellectual deficits

Encephalitis

Encephalitis
Inflammation of the brain parenchyma, presents as diffuse and/or focal neuropsychological dysfunction Most commonly a viral infection with parenchymal damage varying from mild to profound.

Etiology-encephalitis
Arboviruses and herpes simplex virus, are the most common causes of endemic and sporadic cases of encephalitis, respectively. Varicella, herpes zoster and Epstein-Barr virus - cause of encephalitis in immunocompromised hosts. Severe and Fatal Encephalitis-Arthropodborne viruses and HSV.

Diagnostic Strategies

Lumbar Puncture
Contraindication Presence of infection on the skin or soft tissues at the puncture site. Diagnostic Strategies Likelihood of brain herniation.

Diagnosis
The diagnostic evaluation in patients with encephalitis should include a complete blood cell count, tests of renal and hepatic function, coagulation studies, and chest radiography, although results of these studies are generally nonspecific. Neuroimaging studies and CSF analyses are critical to document CNS pathology. Although there may be no definitive treatment for many causes of encephalitis, establishing the diagnosis may still affect management (e.g., discontinuation of therapy that is not necessary).

What General Diagnostic Studies Outside the CNS Should Be Performed in Patients with Suspected
Cultures. Cultures of specimens of body fluids other than CSF may be useful in establishing the etiologic diagnosis in selected patients with encephalitis. All patients with encephalitis should undergo blood culturing to identify potential bacterial and fungal etiologies, although positive culture results may be indicative of encephalopathy secondary to systemic infection rather than encephalitis. Specific clinical findings should also direct other sites for culture (e.g., stool, nasopharynx, and sputum). In patients with varicella or herpes zoster, the etiology may be determined by scrapings from the base of active vesicles and testing by direct fluorescent antibody to identify viral antigen. Biopsy. Biopsy of specific tissues with culture, antigen detection, nucleic acid amplification testing (e.g., PCR), and histopathologic examination of specimens may aid in the etiologic diagnosis. Biopsy of skin lesions should be performed; this may identify R. rickettsii, the etiologic agent of Rocky Mountain spotted fever. In patients with rabies, full-thickness skin biopsy from the nape of the neck with staining of sensory neurons using immunofluorescent antibodies is done.

 Serologic testing. Some causes of encephalitis may be diagnosed by detection of IgM antibodies in serum (e.g., primary varicella virus and many arboviruses). In recent years, IgM and IgG capture ELISAs have become the most useful and widely used tests for the diagnosis of arboviral encephalitis, although there may be crossreactivity, particularly among the flaviviruses (e.g., Japanese encephalitis, St. Louis encephalitis, and West Nile viruses). Nucleic acid amplification tests. PCR of biologic specimens for amplification of microbial nucleic acid from outside the CNS has been used to establish the etiology of some cases of encephalitis and should be performed in the proper clinical setting

What Neurodiagnostic Tests Should Be Performed in Patients with Suspected Encephalitis? Neuroimaging. CT and MRI are most frequently used to evaluate patients with encephalitis, with MRI being more sensitive and specific . Some characteristic neuroimaging patterns have been observed in patients with encephalitis caused by specific agents. In patients with herpes simplex encephalitis, there may be significant edema and hemorrhage in the temporal lobes, as well as hypodense areas on T1-weighted images and nonhomogeneous contrast enhancement; bilateral temporal lobe involvement is nearly pathognomonic for herpes simplex encephalitis, but this is a late development. In patients with encephalitis caused by flaviviruses and Eastern equine encephalitis virus, MRI may display a characteristic pattern of mixed intensity or hypodense lesions on T1-weighted images in the thalamus, basal ganglia, and midbrain; these lesions are hyperintense on T2. Follow-up MRI may also be useful for evaluation of evolving necrosis or demyelination.

 EEG. EEG is a sensitive indicator of cerebral dysfunction and may demonstrate. In >80% of patients with herpes simplex encephalitis, there is a temporal focus demonstrating periodic lateralizing epileptiform discharges. These are typically seen on days 2-14 after symptom onset. CSF analysis. Evaluation of CSF samples is essential (unless contraindicated) for all patients with encephalitis. In instances in which CSF specimens are not available, the likely etiology of the encephalitis should be based on epidemiology, clinical features, and results of other diagnostic studies (tables 2, 3 and 5). In patients with viral encephalitis, CSF analysis typically reveals a mild mononuclear pleocytosis, although a polymorphonuclear cell predominance may initially be seen if the sample is obtained early in the course of illness; persistent neutrophilic pleocytosis has been observed in patients with West Nile virus encephalitis.

 CSF protein concentration is generally mildly or moderately elevated. Patients may have significant numbers of RBCs in the CSF, as a result of the development of hemorrhagic encephalitis. The presence of CSF eosinophils may suggest certain etiologic agents (i.e., highest with the helminths, but this may be seen with T. pallidum, M. pneumoniae, R. rickettsii, C. immitis, and T. gondii), and accurate laboratory identification of these cells is important. Eosinophils can be mistaken for neutrophils if CSF cell counts are done in an automated cell counter; eosinophils can also be easily distorted or destroyed during CSF processing, and the cytologic features of eosinophils are not easily discernible without Wright or Giemsa staining. A decreased CSF glucose concentration is unusual in viral encephalitis and suggests disease caused by bacteria (e.g., L. monocytogenes andM. tuberculosis), fungi, or protozoae (e.g., Naegleria species). Up to 10% of patients with viral encephalitis can have completely normal CSF findings. Despite clues provided by conventional CSF analysis, additional CSF studies (see below) (table 5) are needed to establish the specific cause of encephalitis.

What Tests of CSF and Brain Tissue Specimens Can Help in Establishing the Etiology of Encephalitis?
Antibody. Detection of CSF antibody is a helpful diagnostic tool in some patients with encephalitis. The presence of virus-specific IgM in CSF is usually indicative of CNS disease, because IgM antibodies do not readily diffuse across the blood-brain barrier. For example, the detection of IgM antibodies by an ELISA assay in CSF specimens obtained from patients with presumed flavivirus encephalitis is considered to be diagnostic of neuroinvasive disease. CSF varicella zoster virus IgM antibodies may also be present in patients with a negative CSF varicella zoster virus PCR result.

 PCR can detect : varicella zoster virus DNA, although a negative test result does not exclude the diagnosis of varicella encephalitis. Cytomegalovirus. Epstein-Barr. Although a positive CSF PCR result is very helpful for documentation of infection caused by a specific pathogen, a negative PCR result cannot be used as definitive evidence against the diagnosis. Culture. CSF cultures remain important in the diagnosis of nonviral causes of encephalitis, especially encephalitis caused by bacteria (e.g., L. monocytogenes) and fungi, although a number of the bacterial causes (e.g., Mycoplasma, Bartonella, Ehrlichia, and Rickettsiae species and T. pallidum) cannot be isolated in culture.

 Brain biopsy. Brain biopsy to establish the etiology of encephalitis is rarely used today and is not routinely recommended.

Treatment
Although a wide range of viruses have been reported to cause encephalitis, specific antiviral therapy for viral encephalitis is generally limited to disease caused by the herpesviruses, especially herpes simplex virus. acyclovir (10 mg/kg intravenously every 8 h in children and adults with normal renal function; 20 mg/kg intravenously every 8 h in neonates) should be initiated in all patients with suspected encephalitis as soon as possible, pending results of diagnostic studies.

Other empirical antimicrobial agents should be initiated on the basis of specific epidemiologic or clinical factors including appropriate therapy for presumed bacterial meningitis if clinically indicated . In patients with clinical clues suggestive of rickettsial infection during the appropriate season, doxycycline should be added to empirical treatment regimens.

Once the Etiology of Encephalitis Is Determined, What Specific Treatment Regimen Should Be Administered?
Herpes simplex virus. Acyclovir is the treatment of choice for patients with herpes simplex encephalitis. The dosage of acyclovir in patients with normal renal function is 10 mg/kg intravenously every 8 h for 1421 days.

 Varicella zoster virus. Although no clinical trial has established the efficacy of antiviral therapy for varicella zoster virus-associated encephalitis, on the basis of case reports and small series, acyclovir (1015 mg/kg intravenously every 8 h for 1014 days) is the drug of choice [95]. Ganciclovir has shown efficacy in some patients with varicella zoster virus meningoencephalitis [96] and can be considered as an alternative agent for treatment.

A combination of ganciclovir (5 mg/kg intravenously every 12 h) and foscarnet (60 mg/kg intravenously every 8 h or 90 mg/kg intravenously every 12 h) for 3 weeks, followed by maintenance therapy, is recommended and has led to success in HIV-infected patients,

 Epstein-Barr virus. Acyclovir provides little or no benefit and is not recommended. Corticosteroids are helpful.

References
The Oxford Journals Medscape

Special Thanks To:

Dr. Shaheera

THANK YOU