Viral Meningitis



Viral Meningitis

• Aseptic meningitis a term used to define any meningitis (infectious or noninfectious) characterized by lymphocytic pleocytosis of no apparent cause after initial evaluation and routine stains and cultures of CSF. (viruses are the major cause)

ETIOLOGY

|Nonpolio enteroviruses (Echoviruses 6, 9, 11, 25, 30) (Coxsackie viruses A9, B1,2,3,4) |HIV |

|Arboviruses (St. Louis encephalitis, La Crosse, Colorado tick fever, West Nile virus) |Adenovirus |

|Herpesviruses |Influenza virus |

|Lymphocytic choriomeningitis virus |Measles virus |

|Parainfluenza virus type 3 | |

EPIDEMIOLOGY

Enteroviruses

• The leading cause of aseptic meningitis syndrome (85% to 95%).

• Worldwide distribution.

• Infants and young children are primarily affected

• Also a common cause of aseptic meningitis in adults.

Arboviruses

• Arthropod-transmitted.

• Children are primarily affected

• Those older than 60 years present with encephalitis

Mumps Virus

• In an unimmunized population or vaccine associated.

• 10% to 30% of mumps patients.

• Males 2-5 times > females -- peak incidence 5 to 9 years.

Lymphocytic Choriomeningitis Virus

• Now rarely reported.

• Transmitted by contact with rodents, ingestion of food contaminated with animal urine and exposure of open wounds to dirt.

Herpesviruses

• 0.5% to 3% of all cases of aseptic meningitis.

• Self-limited syndrome.

• Most commonly associated with primary genital infection with HSV type 2.

• Acute aseptic meningitis ( HZ in patients with or without typical skin lesions.

• DNA of HSV-2 has been detected in the CSF ( Mollaret’s recurrent meningitis.

• HSV 6 has also been associated with meningitis in conjunction with roseola infantum.

• CMV and EBV in association with mononucleosis syndrome in immunocompromised host.

Human Immunodeficiency Virus

• Can cross the meninges early and persist in the CNS after initial infection.

• Meningitis may occur as part of the primary infection or may occur in an already infected patient.

Pathogenesis

1. Initiation of Infection

a. Colonization of mucosal surfaces by various viruses.

b. Barriers to prevent viral entry are on call.

▪ Thin film of mucus and mucociliary elevator in the respiratory tract.

▪ Alveolar macrophages ( phagocytic for viral particles.

▪ Gastric acidity, gastrointestinal enzymes and bile

▪ Some nonenveloped, acid-resistant viruses (e.g., enteroviruses, adenoviruses, parvoviruses) are adapted for replication in the GIT.

▪ If certain viruses escape these defenses ( replicate (CNS invasion.

2. Viremia and Central Nervous System Invasion

a. Hematogenous dissemination of the virus.

b. CNS infection.

c. Neurotropic viruses first multiply at extraneural sites (portal of entry) ( viremia( cross the blood-brain barrier (BBB) to invade the CNS.

d. CNS invasion by viruses may occur via several mechanisms.

▪ Directly across cerebral capillary endothelial cells.

▪ Others may be carried in infected leukocytes after BBB disruption.

▪ Through choroid plexus epithelium (mumps).

▪ Spread along olfactory nerves (HSV).

▪ Peripheral nerve spread.

3. Virus Spread within the Central Nervous System

a. Viral attachment to and penetration of susceptible cells, spread within the nervous system, and induction of cellular changes.

▪ Viral entry into the subarachnoid space via the choroid plexus ( dispersion of virus within CSF ( sequential spread to glia and neurons.

▪ Spread through extracellular gaps between cells and CNS processes (axons).

▪ Carried by mobile leukocytes in the inflammatory response.

b. Inflammatory response

▪ Sensitized lymphocytes respond to a virus-specific protein ( transported to the luminal surface of the endothelium( release of inflammatory cytokines (IL-6, IFN-γ, TNF-α, IL-1β).

c. Alterations in the BBB ( traversal into CSF of serum proteins, including immunoglobulins.

Clinical picture

Enteroviruses

• Depend on host age and immune status.

• Neonatal period

• Fever accompanied by vomiting, anorexia, rash, and upper respiratory symptoms.

• Neurologic involvement ( nuchal rigidity and a bulging anterior fontanelle.

• Less meningeal signs.

• Mental status may be altered, but focal neurologic signs are uncommon.

• With disease progression, a sepsis-like syndrome characterized by multiorgan involvement (e.g., hepatic necrosis, myocarditis, and necrotizing enterocolitis), disseminated intravascular coagulation, and cardiovascular collapse may develop.

• Older children and adults

• Onset is usually sudden, with fever which may be biphasic, initially appearing with nonspecific constitutional symptoms, disappearing, and then reappearing with the onset of meningeal signs.

• Nuchal rigidity.

• Headache (often severe and frontal in location) & photophobia

• Vomiting, anorexia, rash, diarrhea, cough, upper respiratory findings (especially pharyngitis), and myalgias.

• Other enteroviral epidemic diseases may be presenting in the community, include the presence of exanthems, myopericarditis, pleurodynia, herpangina, and hand-foot-and-mouth disease.

• The duration of illness is usually less than 1 week

• In agammaglobulinemic, a chronic enteroviral meningitis or meningoencephalitis may develop and last several years, often with a fatal outcome (CEMA).

Mumps Virus

• CNS symptoms follow the onset of parotitis by about 5 days.

• Triad of fever, vomiting, and headache

• Salivary gland enlargement is present in only about 50% of patients.

• Signs of meningitis (Meningismus) but no evidence of cortical dysfunction.

• Lethargy and Seizures.

• The total duration of illness is 7 to 10 days.

Lymphocytic Choriomeningitis Virus LCMV

• Nonspecific viral symptoms.

• After a brief period of improvement, severe headache, photophobia, lightheadedness, lumbar myalgias, and pharyngitis.

Herpesviruses

• HSV type 2 ( stiff neck, headache, and fever.

• Urinary retention, dysesthesias, paresthesias, neuralgia, motor weakness, paraparesis and impaired hearing.

• EB virus ( pharyngitis, lymphadenopathy, and splenomegaly + meningeal signs.

• VZV ( diffuse vesiculopustular rash.

Human Immunodeficiency Virus

• Typical aseptic meningitis syndrome associated with mononucleosis-like syndrome.

• Atypical aseptic meningitis chronic, tends to recur, cranial neuropathies (V, VII, and VIII).

• Most common features are headache, fever, and meningeal signs.

Diagnosis

• A variety of conditions that may mimic viral meningitis or encephalitis need to be excluded in the diagnostic evaluation.

Differential Diagnosis of Viral Meningitis

|Bacterial meningitis |Fungal meningitis |Behçet’s disease |Drug-induced meningitis |

|Parameningeal infections |Lyme disease |Vasculitis |Muromonab-CD3 (OKT-3) |

|Sinusitis |Leptospirosis |SLE |Carbamazepine (Tegretol) |

|Paravertebral abscess |Syphilis | |COX-2 inhibitors |

|Parasitic meningoencephalitis |Sarcoidosis | |Metronidazole (Flagyl) |

|Tuberculosis meningitis |Lymphomatous and carcinomatous meningitis |NSAIDs |

MRI

• Usually normal in viral meningitis.

• HSV-1 encephalitis( lesion with ↑signal on T2 in the medial and inferior temporal lobe.

• CMV encephalitis (enhancement of meninges.

• White matter lesions are found with VZV, JCV, and NV.

CSF

Opening pressure

• Normal or mildly elevated.

CELLS

• Lymphocytic pleocytosis 100 to 1000 cells/mm3

• An early PNL response may be found in the first 24 hours.

• CMV is associated with a persistent PNL pleocytosis in immunosuppressed.

Protein

• Elevated may be normal.

Glucose

• Normal.

• Depressed with CMV, mumps, and the herpesviruses.

Tissue culture

• Enteroviral meningitis ( isolation of the virus from the CSF in tissue culture.

• LCMV cultured from blood and CSF early in infection and later from urine.

Animal inoculation

• Coxsackie virus A serotypes ( suckling mouse inoculations.

PCR

• The most sensitive and specific technique for viral diagnosis.

• WNV, HSV-2.

Serology

• Virus-specific IgM responses in blood or CSF.

• Fourfold elevations of specific IgG in convalescent serum.

• Complement fixation and hemagglutination inhibition on serum specimens ( mumps.

• WNV

o Specific IgM in CSF by the end of the first week.

o IgM antibodies may persist in serum for 6 months.

o IgG antibodies appear after a week in serum but may cross-react with SLE or JEV ( confirmed with plaque neutralization assay.

• Other arbovirus infections ( virus-specific IgM antibody in CSF, a fourfold rise in titer of specific viral antibodies in serum, or isolation of the pathogen.

• Enteroviruses

o Isolated from stool or throat cultures

o PCR testing is available for enteroviruses.

Postinfectious encephalitis

• Viral encephalitis may present with combinations of fever, headache, seizures, confusion or obtundation, and focal neurologic deficits.

• CSF ( lymphocytic pleocytosis + normal glucose + ↑protein, and myelin basic protein, sometimes with oligoclonal bands.

• EEG ( periodic lateralized epileptiform discharges in patients with HSV-1 or LACV.

 

Septic meningitis

|Opening pressure |200–500 mm H2O |

|White blood cell count |1000–5000/mm3 (range, 10,000) |

|Percentage of neutrophils |≥ 80% |

|Protein |100–500 mg/dL |

|Glucose |≤40 mg/dL |

|CSF-to-serum glucose ratio |≤0.4 |

|Gram stain |Positive in 60%-90% |

|Culture |Positive in 70%-85% |

|LDH |35 mg/dL useful in differentiating bacterial from nonbacterial |

|Latex agglutination techniques |Antigens of H. influenzae type B, S. pneumoniae, N. meningitidis, E. coli K1, and the group B |

| |streptococci. |

|PCR |Under study |

|C-Reactive Protein and |Detected either in serum or CSF |

|Procalcitonin |> 0.2 ng/mL S & S 100% in the diagnosis of bacterial meningitis |

| |Useful in discriminating between bacterial and viral meningitis |

|L. monocytogenes 30% of cases |Predominance of lymphocytes |

Other causes of Aseptic meningitis

CSF studies

|Spirochetal Meningitis |

|Treponema pallidum |Highest incidence in 2ry syphilis |

| |Mononuclear pleocytosis ( > 10 cells/mm3 |

| |Elevated CSF protein concentrations (78% of patients), and |

| |Mild decreases in CSF glucose (less than 50 mg/dL in 55% of |

| |Oligoclonal bands |

| |Antitreponemal antibodies |

| |Venereal Disease Research Laboratory [VDRL] |

| |Fluorescent treponemal antibody tests |

| |PCR detect T. pallidum DNA in CSF |

|Borrelia burgdorferi (Lyme |Pleocytosis (usually < 500 cells/mm3, but up to 3500 cells/mm3 |

|meningitis) |90% lymphocytes in 75% of cases |

| |Plasma cells may also be present. |

| |Protein concentrations ↑ (up to 620 mg/dL) |

| |CSF glucose normal (low in patients with illness of long duration) |

| |Oligoclonal bands reactive to B. burgdorferi antigens. |

| |Demonstration of specific serum antibody to B. burgdorferi |

| |PCR |

|Protozoal and Helminthic Meningitis |

|Amebas |Neutrophilic pleocytosis |

|(primary amebic |Low glucose concentration |

|meningoencephalitis) |An elevated protein concentration |

| |↑Red blood cells |

| |Examination of fresh, warm specimens of CSF can reveal the ameboid movements of motile trophozoites |

| |Trophozoites can be demonstrated by light or electron microscopy of brain tissue |

|Subacute or chronic |Less florid CSF inflammatory response (predominant mononuclear leukocytosis |

| |CSF protein concentration is elevated |

| |Glucose content is often normal or slightly reduced |

| |Biopsy or necropsy specimen revealing the characteristic cysts |

| |Serum immunofluorescence, amebic immobilization titers, and complement-fixing antibodies |

|Angiostrongylus cantonensis |Moderate to high peripheral eosinophilia |

| |CSF eosinophilia |

| |Moderate CSF leukocytosis |

| |Larvae are occasionally found on microscopy of CSF |

Treatment

• In the immunocompetent individual, most episodes of viral meningitis are self-limited.

• Antibiotics ( until bacterial meningitis is excluded

o Ceftriaxone (Rocephin), 2 g every 12 hours.

o Cefotaxime (Claforan), 2 g every 6 hours.

o Vancomycin, 500 to 750 mg every 6 hours.

o Ampicillin Listeria monocytogenes is of concern.

• Analgesics and antipyretics.

• Monitoring fluid and electrolyte balance.

• Antiviral therapy

o HSV-2 meningitis ( immunocompetent patients

▪ Acyclovir (Zovirax), 200 mg five times daily. or

▪ Valacyclovir (Valtrex), 1000 mg twice daily.

o HSV-1 encephalitis or VZV encephalitis

▪ Acyclovir (Zovirax) 10 mg/kg IV / 8 hours for 14 to 21 days.

o CMV or HHV-6 meningoencephalitis ( in immunosuppressed

▪ Ganciclovir (Cytovene), 5 mg/kg / 12 hours.

▪ Foscarnet (Foscavir), 90 mg/kg / 12 hours.

▪ Once- weekly cidofovir (Vistide), 5 mg/kg given over 1 hour IV + 2 g probenecid 3 hours before, and 1 g of probenecid 2 and 8 hours following the infusion ( for CMV.

▪ Following successful induction, doses are lowered for maintenance therapy.

▪ Careful monitoring of hepatic and renal function is required for all of these agents.

o Enteroviruses ( Pleconaril

o WNV ( Ribavirin (being investigated).

• Postinfectious encephalomyelitis ( IV methylprednisolone (Solu-Medrol) in 1000 mg daily for 5 days, followed by an oral tapering dose

• Supportive measures

o Anticonvulsants to control seizures.

o Control of increased intracranial pressure

▪ Mannitol, 0.25 to 0.5 g/kg every 3 to 4 hours.

o Management of fluid and electrolyte balance.

o Assisted ventilation.

o Prophylaxis for deep vein thrombophlebitis.

o Nutritional support.

o Early initiation of physical therapy to prevent contracture formation.

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