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Bacterial Meningitis beyond the Newborn Period Abd El-Salam Dawood MD Interventional Pediatric Cardiologist FIBMS-Ped FIBMS-PedCard Meningitis is an inflammation of the meninges. Because death can occur in more than 5% of cases and morbidity may occur in 30% of survivors, it is still a feared childhood infection. Epidemiology: Common causes of bacterial meningitis in children older than 1 month of age are Neisseria meningitidis, Streptococcus pneumoniae and, until recently, Hemophilus influenzae type b (Hib). While in those < 1 mo, group B streptococcus (GBS) followed by Listeria monocytogenes are the most common. Most cases occur in children between 1 month and 5 years of age, with the highest risk being in infants aged 6 to 12 months. The incidence of meningococcal meningitis in the developed countries in those aged 1 to 23 months is 4.5 per 100,000. It is a Gram-negative diplococcus. Meningococcal disease is more common in males. The disease generally is acquired from carriers who can harbor the organism for months. The incidence of disease peaks in winter. The incubation period is from 1 to 10 days. Host factors, such as terminal complement deficiency, complement-depleting diseases, or properdin deficiency, increase susceptibility to disease. S. pneumoniae is a gram-positive diplococcus with tens serotypes. Sepsis and meningitis occur most frequently with specific serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F). Hib is a gram-negative coccobacillus. Historically, it was the leading cause of bacterial meningitis in many developed countries. In countries where Hib vaccination is not yet widespread, the disease continues to be a common occurrence, with a peak incidence occurring in late autumn or early winter. Host factors are important because meningitis occurs with increased frequency in children with diabetes mellitus, Cushing syndrome, and coma secondary to drug overdose. Genetic factors also may play a role. Other bacteria, such as group B streptococcus, Listeria monocytogenes, Salmonella, and Fusobacterium necrophorum, can cause meningitis in "normal" children. Skin flora should be suspected in children with a dermoid sinus, meningomyelocele, or hydrocephalus and a cerebrospinal fluid (CSF) shunt. Cystic fibrosis or burn patients may develop Staphylococcus aureus or Pseudomonas aeruginosa meningitis after colonization. In a humidified atmosphere, P. aeruginosa or Serratia marcescens infection may occur. Children with sickle cell disease, and congenital asplenia are especially susceptible to Salmonella infection, in addition to H. influenzae and S. pneumoniae. Children who have reticuloendothelial malignancies, are undergoing chemotherapy, or have indwelling catheters may develop meningitis from organisms of low virulence, such as Streptococcus mitis. In immunocompromised children, Bacteroides fragilis is a frequent anaerobic cause of meningitis. Congenital or acquired anatomic defects, such as a cribiform plate fracture, should be investigated in cases of recurrent meningitis. Meningitis with two bacterial types in a CSF culture may occur in 1% of cases. Meningitis with a bacteria and a virus or fungus occurs rarely. The clinical course usually is that of bacterial meningitis. Pathogenesis: Initially, upper respiratory tract infection occurs. Bacteremia follows, with opsonization and phagocytosis inhibited by bacterial capsules. Meningeal seeding occurs. Invasion from a contiguous infection (e.g., mastoiditis) also can occur. Page 1 of 10 Organisms initially are found in the lateral and dorsal longitudinal (sagittal) sinuses. Central nervous system (CNS) blood flows may be reduced by 25% to 50%. Dural inflammation slows the flow from the subarachnoid space to the sinuses, thereby permitting spread of infection. A meningeal exudate occurs over the brain. The spinal cord may be encased in pus. Purulent material may develop in the ventricles and the ventricular wall and around the veins and venous sinuses. Hypoglycorrhachia and acidosis result in part from increased glucose use and decreased glucose transport across the inflamed choroid plexus. Increased glucose use results in the excess production of lactate production and the depletion of the highenergy compounds adenosine triphosphate and phosphocreatine. Increased CSF protein is caused partly by the flow of albumin-rich fluid into the subdural space secondary to inflammation and increased vascular permeability. Cerebral cortex damage produces the neurologic sequelae of meningitis. Clinical manifestations and complications: Nerve inflammation leads to meningeal symptoms and signs. Early pressure on peripheral nerves may lead to motor or sensory deficits. Meningitis can develop slowly over the course of several days, or it can be fulminant, with onset occurring within hours. The clinical presentation depends on the age of presentation: Cerebral edema results from vasogenic, interstitial, and cytotoxic processes. Vasogenic edema results from increased permeability of the blood brain barrier. Interstitial edema occurs with decreased CSF resorption as proteins, leukocytes, and debris interfere with the function of the arachnoid villi. Cytotoxic edema results from host and bacterial toxic factors, which increase intracellular water and sodium and loss of intracellular potassium. Increased ICP often exceeds 300 mm H2O. Hypoxemia and ischemia from decreased perfusion may result. Papilledema is a rare occurrence because of the brief duration of increased pressure. Hydrocephalus rarely occurs beyond the neonatal period. Communicating hydrocephalus may result from adhesive arachnoid thickening about the basal cisterns. Obstructive hydrocephalus may result from fibrosis and reactive gliosis obliterating the aqueduct of Sylvius or the foramina of Magendie and Luschka. In some cases, meningitis is associated with the syndrome of inappropriate antidiuretic hormone release (SIADH), causing water retention and a relative sodium loss by the kidney. SIADH increases the risk of developing electrolyte abnormalities, increased ICP, and seizures. Dehydration also can occur from increased insensible losses and decreased intake. In infants: fever or hypothermia, lethargy, respiratory distress, jaundice, vomiting, diarrhea, poor feeding, restlessness, irritability, decreased muscle tone, full fontanelle, seizures. In children: fever, chills, photophobia, anorexia, confusion, altered consciousness, coma, cranial nerve palsies, upper respiratory symptoms, petechial or purpuric rash, myalgia, arthralgia, nuchal rigidity, headache, nausea, vomiting, malaise, restlessness, lethargy, ataxia, hyperesthesia, back pain, seizures, kernig sign, brudzinski sign. Fever and meningeal inflammation symptoms occur in 85% of patients. Nuchal rigidity may appear late, especially in a young child. Seizures occur in 30% of cases at some time before or during the course of illness. Infants may have a bulging fontanelle, but such appears late and in only approximately 30% of infants (13% of children without meningitis). Papilledema is a rare development; if present, a search for other processes (e.g., brain abscess, venous sinus occlusion, subdural empyema) should be performed. Transient or permanent cranial nerve damage may cause deafness, vestibular disturbance, ataxia, and extraocular or facial nerve paralysis. Optic-nerve arachnoiditis may lead to optic atrophy and blindness. Page 2 of 10 Focal neurologic deficits may exist on admission in 15% of children and in 30% of children with pneumococcal meningitis. When focal signs are present without seizures, cortical necrosis, occlusive vasculitis, or thrombosis of cortical veins probably has occurred. Infants may have only restlessness, irritability, poor feeding, or unstable temperature. Adolescents may present with behavioral abnormalities that may be confused with drug abuse or psychiatric disorders. Kernig sign (while supine with the leg flexed at the hip to 90 degrees and the knee flexed, pain occurs on leg extension beyond 135 degrees) and Brudzinski sign (while supine, leg flexion occurs when the neck is flexed) may be absent in 50% of cases, especially if antibiotics have been given. Subdural effusions may occur in 50% of cases. Although usually asymptomatic, they may cause increasing head circumference, abnormal transillumination, vomiting, seizures, full fontanelle, focal neurologic signs, or persistent fever. They usually resolve spontaneously. Meningomyelitis or spinal cord infarction may lead to spastic paraparesis, with or without sensory loss. Early arthritis may be caused by invasions of the organism itself, whereas late arthritis more likely is immunologically induced. Arthralgia and myalgia also may occur. Pericardial effusions usually resolve with the administration of antibiotic therapy. However, pericardial effusion with persistent fever may require drainage. Facial cellulitis, pneumonia, epiglottitis, and endophthalmitis also can be presenting signs of meningitis. In one-half or more cases of meningococcal disease, the patient may have purpura or petechiae (a nonblanching rash) during the course. Shock with profound hypotension may occur in 5% of meningococcal and Hib meningitis cases. Disseminated intra-vascular coagulation (DIC) may occur. Death can occur within hours, administration of adequate therapy. despite the Diagnosis: No single symptom or sign is pathognomonic for meningitis because any, none, or all of the clinical manifestations described may be present. Definitive diagnosis is established through a positive identification of the organism in the CSF. Lumbar Puncture: A lumbar puncture (LP) must be performed if meningitis is suspected. Increased numbers of neutrophils and increased protein and decreased glucose concentrations suggest the presence of bacterial infection (see table 1). Contraindications to performing an LP are cardiopulmonary compromise, signs of possible increased ICP (e.g., papilledema, altered respiratory efforts, focal neurologic signs), and skin infection over the LP site. "Herniation rarely may occur with increased ICP". Papilledema is a late sign of increased ICP, so a careful neurologic examination should be done. In children with suspected increased ICP or altered mental status, antibiotics should be given immediately after taking blood cultures and an emergency computed tomographic (CT) scan should be done before the LP is performed. A reliance on blood cultures and clinical signs is inadequate because both may be misleading, particularly if prehospital antibiotics have been given. If an LP cannot be performed, meningitic doses of antibiotics should be administered until the procedure can be performed. When an LP is performed, CSF pressure should be measured. CSF color should be recorded. Microscopy should include a total leukocyte count and differential. Most (95%) healthy children older than 3 months of age have no CSF neutrophils, which are the initial leukocytes in the CSF. A later change to monocytes and lymphocytes occurs during recovery. If Page 3 of 10 the LP is traumatic, a safe approach is to wait for culture results. A Gram stain should be performed. Most results will be positive. Prehospital administration of antibiotics may reduce Gram-stain yields to 40% to 60%. Normal CSF may be found (10%), therefore, cultures should be performed regardless of fluid appearance or cell count. Blood cultures may be positive in as many as 90% of cases if antibiotics have not been given. Routine prehospital antibiotics generally do not have a significant effect on CSF cell counts, but they may reduce culture yields to less than 50% from a normal yield of up to 85%. A Gram stain from purpuric or petechial skin lesions may reveal the organism. A urine culture should be obtained in a child younger than 1 year of age before giving antibiotics, if possible. Throat or nasopharyngeal cultures are not helpful (colonization by one organism can occur with infection by another). TABLE 1: CSF FINDINGS IN DIFFERENT CONDITIONS. WBC (/mm3) Protein (mg/dl) Glucose (mg/dl) < 5; 75% lymphocytes 100-10,000 or more; Polymorphonuclear cells (PMNs) predominate 5-10,000; PMNs usual 20 – 45 >50 (75% of blood level) Decreased, usually <40 (<50% serum glucose) Normal or decreased Normal or slightly elevated (80150) Rarely >1,000 cells. PMNs early but mononuclear cells predominate through most of the course Usually 50200 Generally normal; (decreased in mumps 1520% of cases) Usually elevated 10-500; PMNs early, but lymphocytes predominate through most of the course 100-3,000; may be higher in presence of block <50 in most cases; decreases with time if treatment is not provided Condition Pressure (mm H2O) Normal child 50-80 Acute bacterial meningitis Usually elevated (100300) Partially treated bacterial meningitis Normal or elevated Viral meningitis or meningoencephalitis Tuberculous meningitis Rapid Diagnostic Tests: Because countercurrent immunoelectrophoresis and latex particle agglutination tests provide results rapidly, these tests are used most commonly, but both have limitations. Enzyme-linked immunosorbent assays Usually 100-500 Usually 100-500 Comments Organisms usually seen on Gram stain and recovered by culture Organisms may be seen on Gram stain Pretreatment may render CSF sterile. Antigen may be detected by agglutination test Herpes Simplex (HSV) encephalitis is suggested by focal seizures or by focal findings on CT or MRI scans or EEG. Enteroviruses and HSV infrequently recovered from CSF. HSV and enteroviruses may be detected by PCR of CSF Acid-fast organisms almost never seen on smear. Organisms may be recovered in culture of large volumes of CSF. Mycobacterium tuberculosis may be detected by PCR of CSF (ELISA), polymerase chain reaction assay (PCR), and others are helpful in some cases. Countercurrent immunoelectrophoresis in 1 hour identifies Hib, S. pneumoniae, N. meningitidis, group B streptococcus, and other bacteria. A negative countercurrent immunoelectrophoresis result does not Page 4 of 10 exclude bacteremia or meningitis caused by these organisms. A PCR analysis of CSF has been used to detect microbial DNA in patients with bacterial meningitis. Primers are available for detection of S. pneumoniae, N. meningitidis, and Hib simultaneously. No falsepositive results were noted. Rapid detection tests are not necessary for all patients. They may be helpful in situations such as a traumatic LP or in a patient who has been pretreated with antibiotics. Differential Diagnosis: Many other processes produce signs and symptoms that mimic meningitis. High on the list should be infection with mycobacteria, fungi, viruses, or protozoa. Other noninfectious processes include a CNS abscess, bacterial endocarditis with embolism, subdural empyema, and brain tumor. Treatment: Because of increasing penicillin resistance in S. pneumoniae, most centers use cefotaxime (225 to 300 mg/kg/day in three to four divided doses) or ceftriaxone (100 mg/kg/day in two divided doses) for children older than 3 months of age. In children aged 1 to 3 months, ampicillin (400 mg/kg/day in four divided doses) should be added because of the possible presence of L. monocytogenes or enterococcal infection. Because of the high frequency of S. pneumoniae resistant to penicillin and to thirdgeneration cephalosporins, vancomycin (60 mg/kg/day in four divided doses) should be given with cefotaxime or ceftriaxone until an organism is identified and its sensitivities determined. If an organism other than S. pneumoniae is suspected, such as when a Gram stain shows gram-negative organisms in a meningococcal outbreak, alternative therapy can be considered. N. meningitidis penicillin resistance also is widely variable. Vancomycin combined with ceftriaxone or cefotaxime appears to be synergistic. It should not be used as monotherapy. When cephalosporin resistance is demonstrated or patients are allergic to cephalosporins, vancomycin can be combined with rifampin. Meropenem (a carbapenem) either alone (120 mg/kg/day every 8 hours) or in combination with other drugs, may be effective for treating patients who cannot tolerate vancomycin. The duration of antibiotic therapy depends on the causative agent and the clinical response. Minimal duration for Hib and S. pneumoniae is 10 days. A minimum of 7 days is required for meningococcal meningitis. The patient should be afebrile for 5 days before halting therapy. Although outpatient therapy is less costly than is hospitalization and it returns patients to their normal environment sooner, it currently is not recommended. Gram-negative meningitis should be treated for a minimum of 3 weeks. If clinical improvement is slow, if dexamethasone is used, or if a resistant strain is identified on the initial culture, a repeat LP is indicated after 24 to 48 hours of therapy. Cell counts, protein, and glucose levels may be abnormal, but a repeat LP must have a negative Gram stain and sterile culture results. If S. pneumoniae is present in the repeat culture, rifampin (20 mg/kg/day in two divided doses) should be added. Another LP should be performed 24 to 48 hours after starting rifampin. Adjunctive Therapy: Because the effect of bacterial meningitis is affected greatly by the host response, corticosteroids have been suggested as adjunctive therapy. In experimental meningitis, corticosteroids reduce meningeal inflammation, thereby reducing ICP and significantly increasing cerebral perfusion. Sensorineural hearing loss is an important sequela of bacterial meningitis. In children with Hib meningitis, numerous studies have shown that dexamethasone (0.15 mg/kg per dose every 6 hours for 2 days) given rapidly just before or with administration of antibiotics significantly reduces hearing loss. Studies of Page 5 of 10 corticosteroids in pneumococcal meningitis are more limited. Some have shown a benefit, but others have not. A meta-analysis found that dexamethasone given before the first dose of antibiotics in pneumococcal meningitis resulted in improved outcome for severe hearing loss. In meningococcal meningitis, the use of corticosteroids has not been studied adequately. The benefit of administering corticosteroids for other neurologic sequelae also is controversial. The use of corticosteroids is not benign. They may delay CSF sterilization, especially in pneumococcal meningitis. Corticosteroids should not be used for more than 2 days because studies have shown no improvement with a longer course. The risk of gastrointestinal bleeding occurring is not significantly increased in a 2-day course. Dexamethasone also can suppress clinical signs, leading to a false sense of clinical improvement. It should not be used in children with partially treated bacterial meningitis, nonbacterial meningitis, or CNS abnormalities. Supportive Care: The first 3 days of treatment for bacterial meningitis are the most critical. Vital signs should be taken every 30 minutes until the patient is stable, then hourly for 48 hours, with rectal temperatures measured every 4 hours. The patient's body weight, urine specific gravity, serum electrolytes (sodium, potassium, chloride, and bicarbonate), and osmolality of serum and urine should be measured on admission and every 12 hours for the first 36 hours. A complete blood count with differential and platelets should be performed on admission and repeated as indicated. Coagulation factors should be checked if petechiae, purpura, or abnormal bleeding is present. A complete neurologic evaluation should be performed on admission, followed by brief neurologic checks every 4 hours for the first several days. Complete neurologic evaluation should be performed daily. In children younger than 18 months, daily head circumference measurements and transillumination should be done. These procedures may permit the detection of subdural effusion or hydrocephalus. To prevent vomiting and aspiration, and to allow better assessment of fluid intake, the patient should receive nothing by mouth initially. A careful intake and output record is required. All patients should be assessed carefully for hydration status and development of syndrome of inappropriate ADH secretion (SIADH). The best indicators of SIADH are absence of signs of dehydration, increased body weight, decreased serum osmolality, and continued sodium excretion despite hyponatremia. If SIADH is demonstrated, fluids should be given at 1,000 mL/m2/day. Fluids can be liberalized to maintenance requirements (1,600 mL/m2/day) as the serum sodium level normalizes, usually within 1 day. Restriction of fluids should not occur in all patients. If dehydration is present, maintenance fluids plus sodium and water deficit replacement over the course of 24 to 48 hours can be given. In patients with septic shock, fluid must be provided to maintain circulation and blood pressure. Central venous pressure monitoring helps to avoid fluid overload. Plasma or albuminized saline and dopamine and dobutamine may improve blood pressure while minimizing fluid intake. When signs of increased ICP such as a bulging anterior fontanelle or progressive lethargy occur, elevation of the head to 30 degrees may help. Increased ICP with deterioration of mental status or signs of cerebral herniation may be treated with intravenous mannitol (0.5 g/kg over 30 minutes, repeated as necessary) and, if necessary, placement of an ICP monitoring device. ICP should be kept at less than 20 mm Hg. Hyperventilation may compromise cerebral blood flow and increase the risk of infarction. In the absence of focal neurologic signs, a CT scan is not needed to identify effusions because they are part of the normal pathophysiology of the disease. Other indications for obtaining a CT scan include focal neurologic signs, prolonged obtundation, focal seizures, rapidly increasing head circumference, persistently increased CSF protein, persistent CSF Page 6 of 10 granulocytosis, or chronically recurring meningitis. Radioisotope imaging may be helpful in some patients to show collections of purulent material. Seizures must be controlled with emergency management and anticonvulsants as needed. If the seizures no longer are apparent by the third or fourth hospital day, anticonvulsants can be discontinued. An electroencephalogram may be indicated when (a) focal seizures are noted, (b) seizures persist beyond the third hospital day, or (c) prolonged alteration of consciousness occurs. The treatment of subdural effusions usually is not necessary unless the effusions are suspected as being the cause of focal seizures or increased ICP, or the source of prolonged fever. Subdural empyema should be drained and treated with antibiotics. Intravenous heparin (1 mg/kg every 4 hours) may be beneficial in disseminated intravascular coagulation, although no controlled studies have documented the benefit of this course of action. Fever lasts for 5 days in most children. If fever lasts longer than 8 days, a thorough search for brain abscess, subdural or pleural empyema, septic arthritis, thrombophlebitis, or pericarditis should be done. Nosocomial infections and drugs may prolong the duration of fever. Persistent fever also may arise from poor therapeutic response associated with the presence of organisms resistant to the antibiotics chosen for therapy. Although serum CRP is not sensitive enough to distinguish bacterial from aseptic meningitis on admission, an admission CRP determination can be drawn and compared with subsequent CRP levels. A secondary increase in CRP or a slow decline may indicate complications not yet clinically evident. Performing a predischarge LP normally is not necessary. Prognosis: Poor prognosis occurs with young age, delays before appropriate antibiotics are started, and the presence of disorders that compromise the host response to infection. Patients whose CSF cultures grow more than 107 organisms frequently have more seizures, subdural effusions, bacteremia, speech disturbance, hearing loss, and prolonged fevers. Elevated CNS IL1ß and TNF have been associated with a higher risk of developing neurologic sequelae, as has very low CSF white blood cell count. Complications such as focal neurologic findings at admission, focal deficits, seizures during the infection, SIADH, purpura, shock, hypothermia, or a low white or red blood cell count at admission all have been associated with poor prognosis. Death rates vary widely. Rates up to 55% have been reported in developing countries. Meningitis sequelae include hearing loss, mental retardation, seizures, spasticity and paresis, hydrocephalus, blindness, behavior disorders, and neuropsychological or auditory dysfunctions that adversely affect academic performance. Prevention: Prophylaxis can prevent the spread of N. meningitidis and H. influenzae. Pneumococcal prophylaxis is not recommended because contacts are not at significantly increased risk of developing infection. Anyone who develops fever after exposure to patients with any form of bacterial meningitis should get prompt medical attention. N. meningitidis prophylaxis with rifampin (10 mg/kg, with a 600 mg maximum, every 12 hours) for 2 days should be given within 24 hours of case recognition. Household, day-care, and close contacts of the patient during the previous 7 days should receive rifampin. Medical personnel exposed to the patient's secretions in the first 24 hours after the start of antibiotics should receive prophylaxis. Ciprofloxacin (500 mg orally) in one dose can be used for contacts older than 18 years of age. Ceftriaxone (125 mg intramuscularly in those younger than 12 years of age and 250 mg for those older than 12 years) is an effective alternative to rifampin and can be used. The index patient should Page 7 of 10 receive prophylaxis on discharge unless treated with ceftriaxone or cefotaxime. Hib prophylaxis with rifampin (20 mg/kg, with a 600 mg maximum, once daily) for 4 days eliminates most nasopharyngeal carriage of Hib. Rifampin should be given to day-care or nursery school contacts if two or more cases occur within 60 days. Children who have received Hib vaccine should receive prophylaxis. Vaccines: Hib conjugate vaccine (0.5 mL per dose) has two dosing schedules. The child may receive the vaccine at 2, 4, and 6 months and requires a 12 to 15-month booster. Hib conjugate vaccine is recommended routinely for children to prevent invasive Hib disease. S. pneumoniae vaccine (Pneumovax 23, 0.5 mL per dose) is recommended for use after 2 years of age for high-risk children, such as those with sickle cell disease, functional or anatomic asplenia, nephrotic syndrome, or immunocompromised, or when the effect of infection could be severe, as in children with certain congenital heart diseases. This vaccine is recommended for all children younger than 24 months of age and generally is given at 2, 4, 6, and 12 months of age (four doses). N. meningitidis vaccine is recommended for individuals at high risk for the acquisition of disease. The American Academy of Pediatrics has recommended that conjugate mcv4 vaccine should be given to adolescents, to adolescents at high school entry and to college freshman living in dormitories. Immunization with meningococcal polysaccharide quadrivalent vaccine (mpsv4) recommended for children 2 years of age and older in high-risk groups, including those with asplenia, and those with terminal deficiencies of the complement system or with properdin deficiency. It also is recommended for individuals travelling to hyperendemic areas or in an epidemic due to a meningococcal type contained in the vaccine. Meningitis in the newborn: Any newborn with bacterial sepsis is also at risk for meningitis. The incidence is low in infants with earlyonset (first 7 days) sepsis but much higher in infants with late-onset (>7 days) infection. The workup for any newborn with signs of infection should include a spinal tap. Diagnosis is suggested by a CSF protein greater than 150 mg/dL, glucose less than 30 mg/dL, more than 25 leukocytes/mL, and a positive Gram stain. The diagnosis is confirmed by culture. The most common organisms are GBS and gram-negative enteric bacteria. Although sepsis can be treated with antibiotics for 10–14 days, meningitis should be treated for 21 days. The mortality rate of neonatal meningitis is approximately 25%, with significant neurologic morbidity present in one third of the survivors. Use of dexamethasone has not been studied in neonates. Viral Meningoencephalitis: Viral meningoencephalitis is an acute inflammatory process involving the meninges and, to a variable degree, brain tissue. These infections are relatively common and may be caused by a number of different agents. In most instances, the infections are selflimited. Etiology: Enteroviruses are the most common cause of viral meningoencephalitis. The severity of infection caused by enteroviruses ranges from mild, self-limited illness to severe encephalitis resulting in death or significant sequelae. Page 8 of 10 Arboviruses are arthropod-borne agents, responsible for some cases of meningoencephalitis during summer months. Mosquitoes and ticks are the most common vectors after biting infected birds or small animals. The cerebral cortex, especially the temporal lobe, is often severely affected by HSV; the arboviruses tend to affect the entire brain; rabies has a predilection for the basal structures. Several members of the herpes family of viruses can cause meningoencephalitis. Herpes simplex virus type 1 (HSV-1) is an important cause of severe, sporadic encephalitis in children and adults. Brain involvement usually is focal; progression to coma and death occurs in 70% of cases without antiviral therapy. Severe encephalitis with diffuse brain involvement is caused by herpes simplex virus type 2 (HSV-2) in neonates who usually contract the virus from their mothers at delivery. Varicella-zoster virus (VZV) may cause CNS infection in close temporal relationship with chickenpox. Cytomegalovirus (CMV) infection of the CNS may be part of congenital infection or disseminated disease in immunocompromised hosts. Epstein-Barr virus (EBV) has been associated with myriad CNS syndromes. Human herpes virus 6 (HHV6) can cause encephalitis, especially among immunocompromised hosts. Clinical Manifestations: Mumps is a common pathogen in regions where mumps vaccine is not widely used. Mumps meningoencephalitis is mild, but deafness may be a sequela. Meningoencephalitis is caused occasionally by respiratory viruses (adenovirus, influenza virus, parainfluenza virus), rubeola, rubella, or rabies; it may follow live virus vaccinations against polio, measles, mumps, or rubella. Epidemiology and pathogenesis: Infection with enteroviruses is spread directly from person to person, with a usual incubation period of 4-6 days. Most cases in temperate climates occur in the summer and fall. Neurologic damage is caused by direct invasion and destruction of neural tissues by actively multiplying viruses or by a host reaction to viral antigens. A marked degree of demyelination with preservation of neurons and their axons is considered to represent predominantly “postinfectious” or “allergic” encephalitis. The progression and severity of disease are determined by the relative degree of meningeal and parenchymal involvement, which is determined by the specific etiology. Some children may appear to be mildly affected initially, only to lapse into coma and die suddenly. In others, the illness may be ushered in by high fever, violent convulsions interspersed with bizarre movements, and hallucinations alternating with brief periods of clarity, followed by complete recovery. The onset of illness is generally acute. The presenting manifestations in older children are headache and hyperesthesia, and in infants, irritability and lethargy. Headache is most often frontal or generalized; adolescents frequently complain of retrobulbar pain. Fever, nausea and vomiting, photophobia, and pain in the neck, back, and legs are common. As body temperature increases, there may be mental dullness, progressing to stupor in combination with bizarre movements and convulsions. Focal neurologic signs may be stationary, progressive, or fluctuating. Exanthems often precede or accompany the CNS signs, especially with echoviruses, coxsackieviruses, VZV, measles and rubella. Examination often reveals nuchal rigidity without significant localizing neurologic changes. Specific forms or complicating manifestations of CNS viral infection include Guillain-Barre syndrome, transverse myelitis, hemiplegia, and cerebellar ataxia. Diagnosis: The diagnosis of viral encephalitis is usually made on the basis of the clinical presentation of nonspecific prodrome followed by progressive CNS symptoms. The diagnosis is supported by examination of the CSF (see table 1). The CSF should be cultured for viruses, Page 9 of 10 bacteria, fungi, and mycobacteria; in some instances, special examinations are indicated for protozoa, mycoplasma, and other pathogens. Other tests of potential value in the evaluation of patients with suspected viral meningoencephalitis include an electroencephalogram (EEG) and neuroimaging studies. The EEG typically shows diffuse slow-wave activity, usually without focal changes. Neuroimaging studies (CT or MRI) may show swelling of the brain parenchyma. Focal seizures or focal findings on EEG, CT, or MRI, especially involving the temporal lobes, suggest HSV encephalitis. Detection of viral antigen by polymerase chain reaction may be useful in the diagnosis of CNS infection caused by HSV and enteroviruses. A serum specimen should be obtained early in the course of illness and, if viral cultures are not diagnostic, again 2-3 wk later for serologic studies. Treatment: With the exception of the use of acyclovir for HSV encephalitis, treatment of viral meningoencephalitis is supportive. Treatment of mild disease may require only symptomatic relief. Headache and hyperesthesia are treated with rest, non–aspirin-containing analgesics, and a reduction in room light, noise, and visitors. Acetaminophen is recommended for fever. Codeine, morphine, and medications to reduce nausea may be useful. Intravenous fluids are occasionally necessary because of poor oral intake. More severe disease may require hospitalization and intensive care. It is important to monitor patients with severe encephalitis closely for convulsions, cerebral edema, inadequate respiratory exchange, disturbed fluid and electrolyte balance, aspiration and asphyxia, and cardiac or respiratory arrest of central origin. In patients with evidence of increased ICP, placement of a pressure transducer in the epidural space may be indicated. The risks of cardiac and respiratory failure or arrest are high with severe disease. All fluids, electrolytes, and medications are initially given parenterally. In prolonged states of coma, parenteral alimentation is indicated. SIADH is common in acute CNS disorders; monitoring of serum sodium concentrations is required for early detection. Normal blood levels of glucose, magnesium, and calcium must be maintained to minimize the likelihood of convulsions. If cerebral edema or seizures become evident, vigorous treatment should be instituted. Prognosis: Motor incoordination, convulsive disorders, total or partial deafness, and behavioral disturbances may follow viral CNS infections. Visual disturbances due to chorioretinopathy and perceptual amblyopia may also occur. Neurodevelopmental and audiologic evaluations should be part of the routine follow-up of children who have recovered from viral meningoencephalitis. Most children completely recover from viral infections of the CNS. If the clinical illness is severe and substantial parenchymal involvement is evident, the prognosis is poor, with potential deficits being intellectual, motor, psychiatric, epileptic, visual, or auditory in nature. Severe sequelae should also be anticipated in those with infection caused by HSV. Approximately 10% of children younger than 2 yr with enteroviral CNS infections suffer an acute complication such as seizures, increased ICP, or coma. Almost all have favorable long-term neurologic outcomes. Prevention: Widespread use of effective viral vaccines for polio, measles, mumps, rubella, and varicella has almost eliminated CNS complications from these diseases. Control of encephalitis due to arboviruses has been less successful because specific vaccines for the arboviral diseases are not available. Page 10 of 10